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In order to study any enzyme-catalyzed reaction, a researcher must have available some sort of test, or assay, in order to observe and measure the reaction's progress and measure its rate. In many cases, an assay simply involves running the reaction for a specified length of time, then isolating and quantifying the product using a separation technique such as high performance liquid chromatography (HPLC) or gas chromatography (GC). This type of assay can be extremely time-consuming, however, so it is to the researcher's great advantage if a more convenient assay can be found.
Redox reactions in which a nicotinamide coenzyme participates as a hydride donor or acceptor are generally quite convenient to assay. In fact, the progress of these reactions can usually be observed in real time, meaning that the researcher doesn't need to stop the reaction in order to see how far it has progressed. $NADPH$ and $NADH$ have distinctive $n-\pi$* UV absorbance bands centered at 340 nm, with a molar absorptivity of 6290 M-1 cm-1 (section 4.4). The oxidized coenzymes $NADP^+$ and $NAD^+$ do not absorb at this wavelength.
Therefore, the course of a hydrogenation reaction, in which $NAD(P)H$ is converted to $NAD(P)^+$, can be observed in real time if it is run in a quartz cuvette in a UV spectrometer. By observing the decrease in absorbance at 340 nm, the researcher can calculate how much $NAD(P)H$ has been oxidized to $NAD(P)^+$ at any given time point, and this number is the molar equivalent of the amount of organic substrate that has been reduced:
Likewise, a $NAD^+$-dependent dehydrogenase reaction can be followed in real time by monitoring the increase in absorbance at 340 nm as $NAD^+$ is converted to $NADH$.
Exercise 15.6.1
You are observing the progress of the (R)-glycerol phosphate dehydrogenase reaction shown in the figure below.
You run the reaction in a quartz cuvette (path length 1 cm) in a total solution volume of 1 mL. start with 200 mM substrate and 100 mM $NADP^+$ in solution, zero the UV spectrophotometer, then add the enzyme to start the reaction. After 5 minutes, the A340 reading has climbed from 0.000 to 0.096. At this time point:
1. How many moles of substrate have been oxidized?
2. What is the solution concentration of $NADP^+$?
3. The enzyme has a mass of 25 kilodaltons (25,000 g/mol).You added 5 mL of a 2 ng/mL solution of pure enzyme to start the reaction. How many reactions does each enzyme molecule catalyze, on average, per second? (This number is referred to by biochemists as the 'turnover number').
15.07: Redox Reactions of Thiols and Disulfides
A disulfide bond is a sulfur-sulfur bond, usually formed from two free thiol groups.
The interconversion between dithiol and disulfide groups is a redox reaction: the free dithiol form is in the reduced state, and the disulfide form is in the oxidized state. Notice that in the oxidized (disulfide) state, each sulfur atom has lost a bond to hydrogen and gained a bond to sulfur.
As you should recall from your Biology courses, disulfide bonds between cysteine residues are an integral component of the three-dimensional structure of many extracellular proteins and signaling peptides.
A thiol-containing coenzyme called glutathione is integrally involved in many thiol-disulfide redox processes (recall that glutathione was a main player in this chapter's introductory story about concussion research). In its reduced (thiol) form, glutathione is abbreviated 'GSH'. In its oxidized form, glutathione exists as a dimer of two molecules linked by a disulfide group, and is abbreviated 'GSSG'.
Disulfide bonds and free thiol groups in both proteins and smaller organic molecules like glutathione can 'trade places' through a disulfide exchange reaction. This process is essentially a combination of two direct displacement ($S_N2$-like) events, with sulfur atoms acting as nucleophile, electrophile and leaving group.
Disulfide exchange reaction
Mechanism:
In eukaryotes, the cysteine side chains of intracellular (inside the cell) proteins are almost always in the free thiol (reduced) state due to the high concentration of reduced glutathione (GSH) in the intracellular environment. A disulfide bond in an intracellular protein will be rapidly reduced in a disulfide exchange reaction with excess glutathione.
The interconversion of free thiols and disulfides is also mediated by flavin in some enzymes.
Flavin-mediated reduction of a protein disulfide bond
Flavin-mediated oxidation of a protein disulfide bond
As was stated earlier, a high intracellular concentration of reduced glutathione (GSH) serves to maintain proteins in the free thiol (reduced) state. An enzyme called glutathione reductase catalyzes the reduction of GSSG in a flavin-mediated process, with $NADH$ acting as the ultimate hydride donor.
Gluthione reductase reaction:
This figure shows oxidized glutathione converted to reduced glutathione by NADPH.
The mechanism for this and other similar reactions is not yet completely understood, but evidence points to an initial thiol-disulfide exchange reaction with a pair of cysteines from the enzyme, (phase 1 below) followed by flavin-dependent reduction of the cysteine-cysteine disulfide (phase 2). Finally, (phase 3) $FAD$ is reduced back to $FADH_2$ by $NADH$. Frey and Hegeman, Enzymatic Reaction Mechanisms, p. 699
Phase 1: thiol-disulfide exchange (see earlier figure for mechanism):
Phase 2: Reduction of protein disulfide by $FADH_2$ (see earlier figure for mechanism)
Phase 3: regeneration of $FADH_2$ by $NADH$ (see section 15.4B for mechanism)
In the biochemistry lab, proteins are often maintained in their reduced (free thiol) state by incubation in buffer containing an excess concentration of $\beta$-mercaptoethanol (BME) or dithiothreitol (DTT). These reducing agents function in a manner similar to that of GSH, except that DTT, because it has two thiol groups, can form an intramolecular disulfide in its oxidized form.
Exercise 15.7.1
Draw structures of the oxidized (disulfide) forms of BME and DTT. | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/15%3A_Oxidation_and_Reduction_Reactions/15.06%3A_Monitoring_Hydrogenation_and_Dehydrogenation_Reactions_by_UV_Spectroscopy.txt |
Up to now, the redox reaction examples we have seen have all been either hydrogenation/dehydrogenation transformations or interconversions between free thiols and disulfides. However, there are many important redox reactions in biological chemistry which do not fall under either of these descriptions. Oxygenase enzymes catalyze the insertion of one or two oxygen atoms from molecular oxygen (\(O_2\)) into an organic substrate molecule. Enzymes which insert a single oxygen atom are called monooxygenases. Below are two examples of biochemical transformations catalyzed by monooxygenase enzymes: one is a hydroxylation, the other is an epoxidation (an epoxide functional group is composed of a three-membered carbon-carbon-oxygen ring - epoxides are somewhat rare in biological organic chemistry but are very common and useful intermediates in laboratory organic synthesis).
Dioxygenase enzymes insert both oxygen atoms from \(O_2\) into the substrate, and usually involve cleavage of an aromatic ring. Below is an example of a dioxygenase reaction, catalyzed by catechol dioxygenase:
In the reduction direction, reductases remove oxygen atoms, or sometimes other electronegative heteratoms such as nitrogen or halides. For example, DNA deoxyribonucleosides are converted from their corresponding RNA ribonucleosides by the action of reductase enzymes:
Many oxygenase and reductase reactions involve the participation of enzyme-bound transition metals - such as iron or copper - and the mechanistic details of these reactions are outside the scope of our discussion. A variety of biochemical monooxygenase reactions, however, involve flavin as a redox cofactor, and we do have sufficient background knowledge at this point to understand these mechanisms. In flavin-dependent monooxygenase reactions, the key intermediate species is flavin hydroperoxide.
The term 'peroxide' refers to a functional group characterized by an oxygen-oxygen single bond. The simplest peroxide is hydrogen peroxide (\(HOOH\)) about which we will have more to say below. In flavin hydroperoxide, the peroxide group is linked to one of the carbons of the reactive triple-ring system of the coenzyme. A possible mechanism for the formation of flavin peroxide from \(FADH_2\) and molecular oxygen is shown below.
Silverman, R.B. The Organic Chemistry of Enzyme-Catalyzed Reactions, p. 121-122, Scheme 3.33. 2000, Academic Press, San Diego.
Mechanism for the formation of flavin hydroperoxide:
(Note: Implicit in this mechanism is that the molecular oxygen first undergoes spin inversion from the triplet state to the higher energy 'singlet' state. You may recall from your general chemistry course that molecular oxygen exists in two states: 'singlet' oxygen has a double bond and no unpaired electrons, while 'triplet' oxygen has a single \(O-O\) bond and two unpaired electrons - a kind of 'double radical'. Molecular orbital theory - and experimental evidence - show that the triplet state is lower in energy.
The mechanism shown above is one proposed mechanism, another proposal involves triplet oxygen reacting with flavin in a series of radical-intermediate, single-electron steps.)
Flavin hydroperoxide can be thought of as an activated form of molecular oxygen. Peroxides in general are potent oxidizing agents, because the oxygen-oxygen single bond is quite weak: only 138 kJ/mole, compared to 339 kJ/mol for a carbon-carbon bond, and 351 kJ/mol for a carbon-oxygen bond. When the 'outer' oxygen of flavin hydroperoxide (red in our figure above) comes into close proximity to the p-bonded electrons of an alkene or aromatic group, the \(O-O\) bond will break, leaving an empty orbital on the outer oxygen to be filled by the p electrons - thus, a new carbon-oxygen bond is formed. This is what is happening in step 1 of a reaction in the tryptophan degradation pathway catalyzed by kynurenine 3-monooxygenase. Step 2 completes what is, mechanistically speaking, an electrophilic aromatic substitution reaction (section 14.4) with an peroxide oxygen electrophile.
Mechanism for the flavin hydroperoxide-dependent hydroxylation of kynurenine:
Elimination of water from the hydroxyflavin intermediate then leads to formation of \(FAD\) (step 3), which is subsequently reduced back to \(FADH_2\) by \(NADH\) (step 4).
The \(N\)-hydroxylation reaction below, which is part of the of the biosynthetic pathway of an iron-binding molecule in the pathogenic bacterium Pseudomonas aeruginosa, is mechanistically similar to the \(C\)-hydroxylation reaction we just saw, except that the nucleophile is an amine nitrogen. Note that \(FADH_2\) is shown in brackets below the reaction arrow, indicating that reduced flavin participates in the reaction but is not used up - rather it is regenerated in the active site at the end of the reaction cycle.
Exercise 15.8.1
Draw arrows for the \(N-O\) bond-forming step in the ornithine hydroxylation reaction above.
Epoxides, characterized by a three-membered ring composed of two carbons and one oxygen, are a very common and useful functional group employed in synthetic organic chemistry. Although rare, there are some interesting epoxide-forming reactions in biochemical pathways, catalyzed by flavin-dependent monooxygenase enzymes.
In a key step in the biosynthesis of cholesterol and other steroid compounds, an alkene is converted to an epoxide in a precursor molecule called squalene. Flavin hydroperoxide also serves as the direct oxidizing agent in this step:
Mechanism for the flavin-hydroperoxide-dependent epoxidation of squalene:
Oxidosqualene goes on to cyclize to lanosterol in a complex and fascinating electrophilic reaction which we discussed in section 14.5.
Epoxidation reactions have a parallel in the synthetic organic laboratory, and in fact are very important tools in organic synthesis. In laboratory epoxidations, peroxyacids are the counterpart to flavin hydroperoxide in biochemical epoxidations. meta-chloroperoxybenxoic acid (MCPBA) is a commonly used peroxyacid.
The Baeyer-Villiger oxidation, in which a ketone is converted to an ester through treatment with a peroxide reagent, is an extremely useful laboratory organic synthesis reaction discovered in the late 19th century. Recently, many biochemical examples of Baeyer-Villiger oxidations have been discovered: the reaction below, for example, is catalyzed by a monooxygenase in a thermophilic bacterium:
(Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 13157)
A Baeyer-Villiger oxidation:
Mechanism:
The Baeyer-Villiger mechanism is differs significantly from the hydroxylation reactions we saw earlier, although flavin hydroperoxide (abbreviated in the above figure) still plays a key role. Here, the peroxide oxygen is a nucleophile, rather than an electrophile, attacking the ketone carbonyl in step 1. Step 2 is a rearrangement, similar in many ways to the hydride and alkyl shifts we learned about in section 14.5. The electrons in the red bond in the figure shift over one atom: from the carbonyl carbon to the outer peroxide oxygen. The end result is that an oxygen atom, from \(O_2\) via flavin hydroperoxide, has been inserted between the carbonyl carbon and a neighboring methylene (\(CH_2\)) carbon, forming an ester.
Note that in the reaction mechanism above, the ketone substrate is asymmetric: on one side of the carbonyl there is a benzyl group (\(CH_2\)-phenyl), and on the other side a methyl group. Note also that it is the benzyl group, not the methyl, that shifts in step 2 of the mechanism. For reasons that are not yet well understood, in Baeyer-Villiger reactions the alkyl group with higher carbocation stability has a higher migratory aptitude: in other words, it has a lower energy barrier for the shifting step.
Exercise 15.8.2
Draw the product of a hypothetical Baeyer-Villiger reaction involving the same substrate as the above figure, in which the methyl rather than the benzyl group shifts.
Exercise 15.8.3
Draw the likely major product of a hypothetical Baeyer Villiger reaction starting with 2-methylcyclopentanone as the substrate. Take into account the idea of migratory aptitude.
Below is another example of a Baeyer-Villiger reaction in which a cyclic ketone is oxidized to a lactone (cyclic ester). Notice that oxygen insertion expands the ring from 6 to 7 atoms. This is the third-to-last step in the biosynthesis of the anti-cancer agent mithromycin in some bacterial species (ACS Chem. Biol. 2013, 8, 2466).
Yet another variety of flavin-dependent monooxygenase, which bears some mechanistic similarity to the Baeyer-Villiger oxidation, is the decarboxylative reaction below from biosynthesis of the plant hormone auxin: (J. Biol. Chem. 2013, 288, 1448)
Exercise 15.8.4
Propose a mechanism for the above reaction, starting with flavin hydroperoxide.
15.09: Hydrogen Peroxide is a Harmful - Reactive Oxygen Species
We get our energy from the oxidation of organic molecules such as fat and carbohydrates, as electrons from these reduced compounds are transferred to molecular oxygen, thereby reducing it to water. Reducing \(O_2\), however, turns out to be a hazardous activity: harmful side products called reactive oxygen species (ROS) are inevitably formed in the process. Recall from the story introducing this chapter that ROS appear to play an important role in the damage that occurs to the brain immediately after a concussion.
Hydogen peroxide, \(HOOH\), is an ROS. Recall peroxides are potent oxidizing agents due to the weakness of the \(O-O\) single bond. It is this same weak bond that causes hydrogen peroxide to be dangerous when produced in our bodies, as it can react spontaneously with oxygen or nitrogen nucleophiles and p bonds.
Peroxide formed as a by-product of our metabolism is particularly harmful when it oxidizes DNA bases. In just one of many known examples of oxidative damage, the DNA base cytosine is oxidized to thymine glycol in the presence of hydrogen peroxide. Although mechanistic details for reactions such as these are not yet well understood, one possibility is electrophilic addition:
Our bodies have evolved ways to dispose of the harmful reactive oxygen species that are continuously being formed (the only way to stop the production of ROS is to stop breathing oxygen!). Glutathione peroxidase is a remarkable enzyme in that its active site contains selanocysteine, a modified cysteine residue in which the side chain sulfur is replaced by selenium (selenium is very toxic, but we do need a very small amount of it in our diet). Look at a periodic table: selenium is below oxygen and sulfur in the same column. If you think back to the vertical periodic trends in nucleophilicity (section 8.2), you'll recall that just as a thiol is a better nucleophile than an alcohol, a selanol (RSeH) is even more nucleophilic than a thiol. Moreover, the vertical periodic trend in acidity (section 7.3) tells us that a selenol should be more acidic than a thiol - in fact, the pKa of a selenocysteine is about 5.5, meaning that it is mostly in its deprotonated state at physiological pH, making it even more nucleophilic.
Glutathione peroxidase very efficiently catalyzes the reduction of hydrogen peroxide to water and the oxidation of glutathione (GSH) to GSSG, beginning with nucleophilic attack by the enzymatic selanocysteine on a peroxide oxygen. The intermediates in this process are shown below: each step can be thought of as a concerted nucleophilic displacement similar to those that take place in a disulfide exchange reaction.
86 | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/15%3A_Oxidation_and_Reduction_Reactions/15.08%3A_Flavin-Dependent_Monooxygenase_Reactions_-_Hydroxylation_Epoxidation_and_the_Baeyer-V.txt |
P15.1: Show a mechanism for each of the redox reactions below. Do not abbreviate the reactive parts of the redox coenzyme.
g) regeneration of reduced flavin by $NADH$):
h) In reaction (a), near which face of the substrate is the cofactor bound in the active site?
i) In reaction (d), near which face of the product is the cofactor bound in the active site?
P15.2: In the reactions below ((EC 2.7.2.4; EC 1.2.1.11) , the side chain of aspartate is altered, but the main peptide chain is not affected. Show the most probable structure of species A and B.
P15.3: Propose complete mechanisms for the following reactions.
1. (EC 1.3.1.26, from lysine biosynthesis)
1. (EC 1.1.1.205, from guanosine ribonucleotide biosynthesis) The mechanism involves a covalent cysteine-linked enzyme-substrate intermediate.
P15.4: The first step in the lysine degradation pathway is a reductive condensation with a-ketoglutarate to form an intermediate called saccharopine. (EC 1.5.1.8)
1. Propose a mechanism for this transformation.
1. Saccharopine (see part (a) above) is then broken up to yield glutamate and a second product that contains an aldehyde group. Predict the structure of this second product, and propose a likely mechanism for the reaction which involves and imine intermediate. (EC 1.5.1.10)
P15.5: Predict the structures of species A and B in the pathway below.
P15.6: Bilirubin, the molecule responsible for the yellowish color of bruises, is formed from the $NADPH$-dependent hydrogenation of a double bond in biliverdin (EC 1.3.1.24), which is a product of heme degradation (heme is an iron-containing coenzyme in the oxygen-carrying blood protein hemoglobin). Draw a likely mechanism for this reaction.
P15.7: Draw a likely mechanism for each of the reactions below.
1. From the oxidation of polyunsaturated fatty acids:
P15.8: Predict the structures of pathway intermediates A, B, and C:
P15.9: An enzyme called DsbA (EC1.8.4.2) is responsible for the formation of disulfide bonds in bacterial proteins. The process - which can be thought of as a 'disulfide exchange', involves the cleavage of a disulfide bond between two active site cysteines in DsbA. It is accomplished through two successive $S_N2$ displacements.
DsbA is then returned to it's starting (disulfide) state through a second disulfide exchange reaction with another protein called DsbB:
Scientists were interested in studying the intermediate species formed in step 3, but found that it is very short-lived and difficult to isolate. In order to address this problem, they ran the reaction with a synthetic analog of DsbB that contained an unnatural bromoalanine amino acid in place of one of the active site cysteines.
1. Draw a complete mechanism for the disulfide exchange reaction between DsbA and DsbB.
2. Show how the bromoalanine-containing DsbB analog allowed for the isolation of an intermediate that resembles the true, short-lived intermediate. (J. Am. Chem. Soc. 2004, 126, 15060; J. Nat. Prod. 2001, 64, 597).
P15.10:
1. In chapter 16 we will learn how ascorbate (vitamin C) acts as a 'radical scavenger' antioxidant to protect our cells from damage by free radical species. When ascorbate scavenges a radical, it ends up being converted to dehydroascorbate . One possible metabolic fate of dehydroascorbate is to be recycled back to ascorbate through an enzyme-free reaction with glutathione. Biocemistry 1999, 38, 268.
Suggest a likely mechanism for the enzyme-free reaction.
1. In the introduction to chapter 16, we will learn that most animals - but not humans - are able to synthesize their own ascorbate. Humans cannot synthesize vitamin C because we lack the enzyme for the final step in the biosynthetic pathway, gulonolactone oxidase:
This enzyme uses $FAD$ as an oxidizing agent, and $FADH_2$ is oxidized back to $FAD$ at the end of the catalytic cycle by molecular oxygen, with hydrogen peroxide as a side product. Draw out a likely mechanism showing how gulonolactone is converted to ascorbate, and how $FAD$ is regenerated.
1. Artemisinin is a naturally occurring compound with demonstrated antimalarial properties. It is thought to act by depleting the malaria-causing microbe's store of reduced flavin, thus disrupting the redox balance. The relevant reaction is shown below:
Draw mechanistic arrows for the step as shown above. (Molecules 2010, 15, 1705)
1. Draw the mechanistic step in the reaction below in which the C-O bond indicated by the arrow in the figure below is formed.
P15.11: Methanogens are a class of microorganisms in the domain archaea which inhabit a diversity of anaerobic (oxygen-lacking) environments, from the intestines of humans, to swamp mud, to the base of deep sea hot water vents. They obtain energy by reducing carbon dioxide to methane:
$CO_2 + 4H_2 \rightarrow CH_4 + 2H_2O + \text{energy}$
Methanogenesis', like the oxidation of glucose in animals, is not accomplished in a single reaction - it requires a long series of enzymatic steps, and involves the participation of several unique coenzymes (if you are interested in learning more, see FEMS Microbiol. Rev. 1999, 23, 13 for a detailed review of the enzymatic reactions of methanogenesis).
The oxidation of methane to carbon dioxide when you burn natural gas for heating your house is obviously an exergonic process. How then is it possible that reducing carbon dioxide to methane could also be exergonic? Explain.
Multistep pathway prediction problems
In chapters 12 and 13, we were introduced to the challenge of mapping out potential multi-step transformations using the retrosynthesis approach, where we start with the more complex molecule and take it apart step be step. These problems have necessarily involved hypothetical, generalized transformations, because many of the reaction types involved in actual biochemical transformations were as-yet unfamiliar to us.
We have now reached a point in our study of organic reactivity where we can look at an actual metabolic pathway and probably recognize most of the reactions taking place - so were are ready to try our hand at mapping out real metabolic pathways.
Before we dive in, you may want to go back to the retrosynthesis interchapter and review the key elements of the retrosynthetic approach. You may (or may not) also need a little more practice with some simpler, shorter, hypothetical problems, similar to what we worked on in the last three chapters but incorporating some of the redox reactions that we have just finished learning about. These are provided in problems 15.12 and 15.13 below.
As before, your job is to draw out a 'pathway diagram' for each transformation, using the 'arrow in - arrow out' convention to indicate the role of other necessary participants in each reaction, such as ATP, $NADH$, water, or another organic molecule. An example for a simple two-step pathway is provided in problem 15.12 below. A three-step pathway would of course show two intermediate compounds.
Remember, it is most important that your proposed pathway be chemically reasonable - in other words, each hypothetical reaction that you propose should be very similar to a reaction pattern that we have seen in chapters 8-15. You should be able to put a name on each step: for example, 'step 1 is a Claisen condensation; step 2 is a ketone reduction', and so forth.
Also remember that there is usually no one correct way to approach problems like this - they are puzzles to solve, and success will be dependent in large part on having a solid grasp on the chemical 'tools' available to us: in other words, the biochemical reaction types that we have been studying, starting with nucleophilic substitutions in chapter 8.
P15.12: Hypothetical 2-step transformations:
Each of the generalized transformations below would be expected to require two enzymatic steps. Draw a reasonable pathway diagram for each transformation.
Example:
Diagram:
The first step is a nicotinamide-dependent ketone reduction/hydrogenation, and step 2 is ATP-dependent phosphorylation (ie. a kinase reaction). Note that the reducing agent in the first step could also be $NADPH$)
P15.13: Hypothetical 3-step transformations:
Each of the generalized transformations below would be expected to require three enzymatic steps. Draw a reasonable pathway diagram for each transformation.
P15.14: Now, let's try our hand at predicting the steps of some actual metabolic pathways. For each, draw a complete pathway diagram. As needed, use any of the coenzymes we have studied, water, and ammonia.
Note: you will probably find these quite challenging! Do not expect to be able to figure them out in a few minutes - rather, think of them as puzzles to work on over a period of time, sharing ideas and strategies with classmates. Remember, if one side of the transformation is larger or more complex, start there and work towards the simpler molecules. It is also a good idea, when applicable, to start the process by a) counting carbons on each side of the transformation, and b) identifying the key bond being formed (or broken) in the transformation.
P15.15: Propose a pathway diagram for each of the metabolic pathways below. Note that some pathways contain steps that will be unfamiliar to you, and are therefore provided already.
1. one cycle of fatty acid biosynthesis:
1. one cycle of fatty acid degradation:
1. Diabetics and people who adopt an extreme low-carbohydrate diet sometimes have breath that smells like acetone, due to 'ketone body' formation that occurs when acetyl-$CoA$ from fatty acid oxidation (see part (b) above) is not able to enter into the citric acid cycle. Draw a pathway diagram showing how three molecules of excess acetyl $CoA$ combine to form acetone (all three acetyl-$CoA$ molecules first link together, but one is left over at the end of the process).
1. Pentose phosphate pathway (oxidative branch):
1. Citric acid (Krebs) cycle:
1. proline biosynthesis:
1. First half of lysine biosynthesis:
1. From the biosynthesis of membrane lipid in archaea: J. Bacteriol. 2003, 185, 1181
15.0S: 15.S: Oxidation and Reduction Reactions (Summary)
Before moving on to the next chapter, you should be able to:
• Recognize when an organic molecule is being oxidized or reduced, and distinguish between redox and non-redox organic reactions.
• Draw complete mechanisms for the following reaction types, including the structure of the reactive part of the redox coenzyme (it is strongly recommended that you commit to memory the structures of the reactive parts of the nicotinamide and flavin coenzymes).
• oxidation of an alcohol to an aldehyde or ketone
• oxidation of an amine to an imine
• oxidation of an aldehyde to a carboxylic acid derivative (usually a thioester or carboxylate)
• oxidation of an alkane to an alkene at the a,b position relative to a carbonyl or imine
• reduction of an aldehyde or ketone to an alcohol
• reduction of an imine to an amine
• reduction of a carboxylic acid derivative to an aldehyde
• reduction of an $\alpha, \beta$ - conjugated alkene to an alkane
• oxidation of two thiol groups to a disulfide in a disulfide-exchange type reaction
• reduction of a disulfide group by flavin
• flavin hydroperoxide-dependent hydroxylation, epoxidation, and Baeyer-Villiger reactions
• reduction of $FAD$ (or $FMN$) to $FADH_2$ (or $FMNH_2$) by $NAD(P)H$.
• spontaneous oxidation of an alkene group in a biomolecule by hydrogen peroxide
• reduction of hydrogen peroxide by glutathione peroxidase
• In addition, you should be able to draw complete mechanisms for hydrogenation-dehydrogenation and disulfide exchange reactions that we have not yet seen specific examples of, based on your understanding of the chemistry involved in these reaction types and organic reaction patterns in general. Several exercises and end-of-chapter problems provide opportunities practice with inferring and drawing mechanisms of less familiar redox reactions.
• Given a multistep pathway diagram, you should be able to recognize the transformations taking place and fill in missing intermediate compounds or reagents ( problem 15.5 is an example of this type).
• You should be working on gaining proficiency at solving multi-step pathway elucidation problems, such as those at the end of this chapter's problem section. | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/15%3A_Oxidation_and_Reduction_Reactions/15.0E%3A_15.E%3A_Oxidation_and_Reduction_Reactions__%28Exercises%29.txt |
• 16.1: Prelude to Radical Reactions
The subject of this chapter is single-electron chemistry, and the free radical intermediates that are involved in single electron reaction steps.
• 16.2: Overview of Single-Electron Reactions and Free Radicals
Beginning with acid-base reactions in chapter x and continuing though the chapters on nucleophilic substitution, carbonyl addition, acyl substitution, a-carbon chemistry, and electrophilic reactions , we have been studying reaction mechanisms in which both electrons in a covalent bond or lone pair move in the same direction. In this chapter, we learn about reactions in which the key steps involve the movement of single electrons.
• 16.3: Radical Chain Reactions
Because of their high reactivity, free radicals have the potential to be extremely powerful chemical tools - but as we will see in this chapter, they can also be extremely harmful in a biological/environmental context. Key to understanding many types of radical reactions is the idea of a radical chain reaction
• 16.4: Useful Polymers formed by Radical Chain Reactions
Many familiar household materials polymers made from radical chain reaction processes. Polyethylene (PET), the plastic material used to make soft drink bottles and many other kinds of packaging, is produced by the radical polymerization of ethylene (ethylene is a common name for what we call 'ethene' in IUPAC nomenclature). The process begins when a radical initiator such as benzoyl peroxide undergoes homolytic cleavage at high temperature.
• 16.5: Destruction of the Ozone Layer by a Radical Chain Reaction
The high reactivity of free radicals and the multiplicative nature of radical chain reactions can be useful in the synthesis of materials such as polyethylene plastic - but these same factors can also result in dangerous consequences in a biological or ecological context.
• 16.6: Oxidative Damage to cells, Vitamin C, and Scurvy
While the hydroxide radical can be a beneficial 'detergent' in the atmosphere, it is harmful when present in a living cell. Hydroxide radical is one of the reactive oxygen species (ROS) that we learned about earlier.
• 16.7: Flavin as a One-Electron Carrier
In chapter 15 we saw how a nicotinamide and flavin coenzymes can act as acceptors or donors of two electrons in hydride-transfer redox steps. Recall that it was mentioned that flavin, (but not nicotinamide) can also participate in single-electron transfer steps through a stabilized radical intermediate called a semiquinone.
• 16.E: Radical Reactions (Exercises)
16: Radical Reactions
Introduction
Imagine that you are an 18th century British sailor about set out with Commodore George Anson to raid Spanish shipping fleets in the Pacific. You know full well that you are signing up for a long and arduous ordeal, with months of constant seasickness, bad food, cramped, unsanitary conditions, and brutal warfare. You are mentally ready for these hardships, but what you are not prepared for is to watch your own body rot away – to literally fall apart.
Below is a description of the suffering endured by many sailors of the time:
Some lost their very substance and their legs became swollen and puffed up while the sinews contracted and turned coal-black and, in some cases, all blotched with drops of purplish blood. Then the disease would creep up to the hips, thighs and shoulders, arms and neck. And all the sick had their mouths so tainted and their gums so decayed that the flesh peeled off down to the roots of their teeth, which almost all fell out. . .
There were devastating neurological as well as physiological effects. Scurvy had the ability to inhibit a person's normal restraints on emotion: they became intensely homesick and nostalgic, wept at the slightest disappointment, and screamed in agony upon smelling the scent of flower blossoms drifting across the water from a nearby shore.
The disease afflicting the sailors was scurvy, which we now know is caused by a deficiency of vitamin C in the diet. European sea voyagers in the 18th century and earlier subsisted mainly on a diet of salted meat, hard biscuits, pea soup, oatmeal, and beer. After the first couple of weeks at sea, fresh fruits and vegetables - and the nutrients they contained – were all consumed or spoiled. The salted meat and hardtack diet provided salt and calories, but little else of nutritional value.
Although it is rare now, scurvy has plagued sailors for centuries, with records of its occurrence on ships going back as far as the 15th century voyages of Magellan and Vasco de Gama, both of whom lost up to three quarters of their crew to the disease on long ocean crossings. Various cultures made the connection between scurvy and diet, and learned effective preventative measures: sailors with the 16th century French explorer Jacques Cartier, for example, were cured of their scurvy upon arriving in Canada and taking the advice of native people to eat the leaves and bark of pine trees. These were lessons, unfortunately, that often had to be relearned time and again, as the knowledge gained by one culture was not effectively recorded and passed along to others.
Vitamin C, or ascorbic acid as it is known to chemists, plays an essential helping role in a variety of essential biochemical reactions. Most living things are able to synthesize ascorbic acid – the exceptions include humans and other higher primates, several species of bats, and some rodents such as guinea pigs and capybaras. Humans lack the last enzyme in the ascorbic acid biosynthetic pathway, L-gulonolactone oxidase. (EC 1.1.3.8) (You were invited to propose the mechanism for this redox reaction in problem 15.10).
Because we cannot make our own ascorbic acid, we need to get it in our diet. It is abundant in many plant-based foods, citrus fruits in particular. The traditional diet of the Inuit people of the arctic region contains virtually no plant products, but vitamin C is obtained from foods such as kelp, caribou livers, and whale skin. For a time in the 18th century, the observation that citrus fruits quickly cured scurvy led to the practice of including in a ship's stores a paste prepared from boiled lemon juice. Unfortunately, ascorbic acid did not survive the boiling process, rendering the paste ineffective against scurvy. Captain James Cook, the legendary explorer and the first European to make it to the east coast of Australia and the Hawaiian islands, brought along sourkraut (fermented cabbage), a somewhat more effective vitamin C supplement. According to his own account, Cook's sailors at first refused to eat the pungent preparation, so the captain engaged in a little psychological trickery: he declared that it would only be served to officers. The enlisted sailors quickly took offense, and demanded their own sourkraut ration. Later, the British navy famously adopted the practice of adding lemon or lime juice to their ships' rum rations, leading to the birth of the slang term 'Limey' used by European and American sailors to refer to their British counterparts.
The biochemical role of ascorbic acid is to facilitate the transfer of single electrons in a variety of redox reactions - note here the emphasis on single electrons, as opposed to the redox reactions we studied in chapter 15 in which electrons were transferred in pairs. The subject of this chapter is single-electron chemistry, and the free radical intermediates that are involved in single electron reaction steps.
Later in this chapter we will learn the chemical details of why ascorbic acid deficiency causes scurvy, how the act of breathing makes you get old, how polystyrene packing foam is made, and other interesting applications of single-electron chemistry. But first we need to cover some basics ideas about single electron chemical steps, and the free radical intermediates that result from them. | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/16%3A_Radical_Reactions/16.01%3A_Prelude_to_Radical_Reactions.txt |
Beginning with acid-base reactions in chapter x and continuing though the chapters on nucleophilic substitution, carbonyl addition, acyl substitution, a-carbon chemistry, and electrophilic reactions , we have been studying reaction mechanisms in which both electrons in a covalent bond or lone pair move in the same direction. In this chapter, we learn about reactions in which the key steps involve the movement of single electrons. Single electron movement is depicted by single-barbed 'fish-hook' arrows (as opposed to the familiar double-barbed arrows that we have been using throughout the book to show two-electron movement).
Single-electron mechanisms involve the formation and subsequent reaction of free radical species, highly unstable intermediates that contain an unpaired electron. Free radicals are often formed from homolytic cleavage, an event in which the two electrons in a breaking covalent bond move in opposite directions. The bond in molecular chlorine, for example, is subject to homolytic cleavage when chlorine is subjected to heat or light. The result is two chlorine radicals. Note that each radical has a formal charge of zero.
In contrast, essentially all of the reactions we have studied up to now involve bond-breaking events in which both electrons move in the same direction: this is called heterolytic cleavage.
Two other homolytic cleavage reactions that we will see in this chapter can be described as 'radical hydrogen atom abstraction' and 'radical alkene addition':
Single-electron reaction mechanisms involve the formation of radical species, and in organic reactions these are often carbon radicals. A carbon radical is \(sp^2\) hybridized, with three s bonds arranged in trigonal planar geometry and the single unpaired electron occupying an unhybridized p orbital. Contrast this picture with a carbocation reactive intermediate, which is also \(sp^2\) hybridized with trigonal planar geometry but with an empty p orbital.
When we studied electrophilic reactions in chapter 14, a major concern when evaluating possible mechanisms was the stability of any carbocation intermediate(s). Likewise, the stability of proposed radical intermediates is of great importance when evaluating the likelihood of possible single-electron mechanisms. Fortunately, the trend in the stability of carbon radicals parallels that of carbocations (section 8.5): tertiary radicals, for example, are more stable than secondary radicals, followed by primary and methyl radicals. This should make intuitive sense, because radicals, like carbocations, are electron deficient, and thus are stabilized by the electron-donating effects of nearby alkyl groups.
Benzylic and allylic radicals are more stable than alkyl radicals due to resonance effects - an unpaired electron (just like a positive or negative charge) can be delocalized over a system of conjugated π bonds. An allylic radical, for example, can be pictured as a system of three parallel p orbitals sharing three electrons.
The drawing below shows how a benzylic radical is delocalized to three additional carbons around the aromatic ring:
Exercise 16.2.1
Just as phenolate ions are less reactive (less basic) than alkoxide ions, phenolic radicals are less reactive than alkoxide radicals. Draw one resonance contributor of a phenolic radical showing how the radical electron is delocalized to a ring carbon. Include electron-movement arrows.
While radical species are almost always very reactive and short-lived, in some extreme cases they can be unreactive. One example of an inert organic radical structure is shown below.
The already extensive benzylic resonance stabilization is further enhanced by the fact that the large electron clouds on the chlorine atoms shield the radical center from external reagents. The radical is, in some sense, inside a protective 'cage'.
Exercise 16.2.2
Draw a resonance contributor of the structure above in which the unpaired electron is formally located on a chlorine atom (include electron movement arrows)
16.03: Radical Chain Reactions
Because of their high reactivity, free radicals have the potential to be extremely powerful chemical tools - but as we will see in this chapter, they can also be extremely harmful in a biological/environmental context. Key to understanding many types of radical reactions is the idea of a radical chain reaction.
Radical chain reactions have three distinct phases: initiation, propagation, and termination. We'll use a well-known example, the halogenation of an alkane such as ethane, to illustrate. The overall reaction is:
$CH_3CH_3 + Cl_2 \underset{h\nu\: or\: \Delta }{\rightarrow} CH_3CH_2Cl + HCl\cdots h\nu \text{ means light }\Delta \text{ means heat}$
The initiation phase in a radical chain reaction involves the homolytic cleavage of a weak single bond in a non-radical compound, resulting in two radical species as products.
Often, heat or light provides the energy necessary to overcome an energy barrier for this type of event. The initiation step in alkane halogenation is homolysis of molecular chlorine ($Cl_2$) into two chlorine radicals. Keep in mind that that virtually all radical species, chlorine radicals included, are highly reactive.
$Cl\curvearrowleft \curvearrowright Cl \rightarrow 2Cl$
The propagation phase is the 'chain' part of chain reactions.
Once a reactive free radical (chlorine radical in our example) is generated in the initiation phase, it will react with relatively stable, non-radical compounds to form a new radical species. In ethane halogenation, a chlorine radical generated in the initiation step first reacts with ethane in a hydrogen abstraction step, generating $HCl$ and an ethyl radical (part a above). Then, the ethyl radical reacts with another (non-radical) $Cl_2$ molecule, forming the chloroethane product and regenerating a chlorine radical (part b above). This process repeats itself again and again, as chlorine radicals formed in part (b) react with additional ethane molecules as in part (a).
The termination phase is a radical combination step, where two radical species happen to collide and react with each other to form a non-radical product and 'break the chain'. In our ethane chlorination example, one possible termination event is the reaction of a chlorine radical with an ethyl radical to form chloroethane.
Exercise 16.3.1
Draw two alternative chain termination steps in the ethane chlorination chain reaction. Which one leads to an undesired product?
Because radical species are so reactive and short-lived, their concentration in the reaction mixture at any given time is very low compared to the non-radical components such as ethane and $Cl_2$. Thus, many cycles of the chain typically occur before a termination event takes place. In other words, a single initiation event leads to the formation of many product molecules.
Compounds which readily undergo homolytic cleavage to generate radicals are called radical initiators. As we have just seen, molecular chlorine and bromine will readily undergo homolytic cleavage to form radicals when subjected to heat or light. Other commonly used as radical initiators are peroxides and $N$-bromosuccinimide (NBS). | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/16%3A_Radical_Reactions/16.02%3A_Overview_of_Single-Electron_Reactions_and_Free_Radicals.txt |
Many familiar household materials polymers made from radical chain reaction processes. Polyethylene (PET), the plastic material used to make soft drink bottles and many other kinds of packaging, is produced by the radical polymerization of ethylene (ethylene is a common name for what we call 'ethene' in IUPAC nomenclature). The process begins when a radical initiator such as benzoyl peroxide undergoes homolytic cleavage at high temperature:
In the propagation phase, the benzoyl radical (\(X\)· in the figure below) adds to the double bond of ethylene, generating a new organic radical.
Successive ethylene molecules add to the growing polymer, until termination occurs when two radicals happen to collide.
The length of the polymer is governed by how long the propagation phase continues before termination, and can usually be controlled by adjusting reaction conditions.
Other small substituted alkene monomers polymerize in a similar fashion to form familiar polymer materials. Two examples are given below.
Exercise 16.4.1
Show a mechanism for the formation of a 2-unit long section of polystyrene, starting with the monomer and benzoyl peroxide initiator. Keep in mind the relative stability of different radical intermediates.
A common way to separate proteins in the biochemistry lab is through a technique called polyacrylamide gel electrophoresis (PAGE). The polyacrylamide gel is formed through radical polymerization of acrylamide monomer, with the ammonium salt of persulfate used as the radical initiator.
In the end of chapter problems, you will be invited to propose a mechanism showing how a molecule called 'bis-acrylamide' serves as a 'crosslinker' between linear polyacrylamide chains to allow for formation of a net-like structure for the PAGE gel.
16.05: Destruction of the Ozone Layer by a Radical Chain Reaction
The high reactivity of free radicals and the multiplicative nature of radical chain reactions can be useful in the synthesis of materials such as polyethylene plastic - but these same factors can also result in dangerous consequences in a biological or ecological context. You are probably aware of the danger posed to the earth's protective stratospheric ozone layer by the use of chlorofluorocarbons (\(CFCs\)) as refrigerants and propellants in aerosol spray cans. Freon-11, or \(CFCl_3\), is a typical \(CFC\) that was widely used until late in the 20th century. It can take months or years for a \(CFC\) molecule to drift up into the stratosphere from the surface of the earth, and of course the concentration of \(CFCs\) at this altitude is very low. Ozone, on the other hand, is continually being formed in the stratosphere. Why all the concern, then, about destruction of the ozone layer - how could such a small amount of \(CFCs\) possibly do significant damage? The problem lies in the fact that the process by which ozone is destroyed is a chain reaction, so that a single \(CFC\) molecule can initiate the destruction of many ozone molecules before a chain termination event occurs.
Although there are several different processes by which the ozone destruction process might occur, the most important is believed to be the chain reaction shown below.
First, a \(CFC\) molecule undergoes homolytic cleavage upon exposure to UV radiation, resulting in the formation of two radicals (step 1). The chlorine radical rapidly reacts with ozone (step 2) to form molecular oxygen and a chlorine monoxide radical. Step 3 appears to be a chain termination step, as two chlorine monoxide radicals combine. The \(Cl_2O_2\) condensation product, however, is highly reactive and undergoes two successive homolytic cleavage events (steps 4 and 5) to form \(O_2\) and two chlorine radicals, which propagates the chain.
To address the problem of ozone destruction, materials chemists have developed new hydrofluorocarbon refrigerant compounds. The newer compounds contain carbon-hydrogen bonds, which are weaker than the carbon-halogen bonds in \(CFCs\), and thus are susceptible to homolytic cleavage caused by small amounts of hydroxide radical present in the lower atmosphere:
This degradation occurs before the refrigerant molecules have a chance to drift higher up to the stratosphere where the ozone plays its important protective role. The degradation products are quite unstable and quickly degrade further into relatively harmless by-products. The hydroxide radical is sometimes referred to as an atmospheric 'detergent' due to its ability to degrade escaped refrigerants and other volatile organic pollutants.
Hydrofluorocarbons do, however, act as greenhouse gases, and are thought to contribute to climate change. | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/16%3A_Radical_Reactions/16.04%3A_Useful_Polymers_formed_by_Radical_Chain_Reactions.txt |
While the hydroxide radical can be a beneficial 'detergent' in the atmosphere, it is harmful when present in a living cell. Hydroxide radical is one of the reactive oxygen species (ROS) that we learned about in chapter 15. Recall that ROS are continuously produced as minor but harmful side-products in the reduction of \(O_2\) to \(H_2O\) in respiration.
You may recall from your general chemistry course that molecular oxygen exists in two states: 'singlet' oxygen has a double bond and no unpaired electrons, while 'triplet' oxygen has a single O-O bond and two unpaired electrons. Molecular orbital theory - and experimental evidence - show that the triplet state is lower in energy.
Figure 16.6.1
ROS are highly reactive oxidizing agents, capable of inflicting damage to DNA, proteins, and the lipids of cell membranes - they are thought to play a major role in the aging process. Hydroxide radical, for example, can initiate a radical chain reaction with the hydrocarbon chain of an unsaturated membrane lipid molecule, resulting in the formation of lipid hydroperoxide.
Figure 16.6.2
The allylic lipid radical formed as the result of homolytic hydrogen abstraction by hydroxide radical (step 1 above) reacts with one of the unpaired electrons in triplet oxygen (step 2) forming a peroxy radical. This radical species in turn homolytically abstracts a hydrogen from another lipid molecule (step 3), thus propagating the chain.
Many edible plants contain various antioxidant compounds, also known as 'free radical scavengers', which serve to protect cells from the oxidative effects of hydroxide radical and other harmful radical intermediates. Simply put, a free radical scavenger is a molecule that reacts with a potentially damaging free radical species, forming a more stable radical species which can be metabolized by the body before any damage is done to cell constituents.
Figure 16.6.3
In the introduction to this chapter, we learned about scurvy, the disease long dreaded by sailors, and how it is caused by a deficiency of ascorbic acid (vitamin C) in the diet. We will soon get to the connection between ascorbic acid and scurvy, but first, let's look at how ascorbic acid functions as a free radical scavenger in your body.
The \(pK_a\) of ascorbic acid is about 4.1, so in a physiological environment it exists mainly as ascorbate anion, the conjugate base. When ascorbate encounters a hydroxide radical (or any other potentially damaging radical species), it donates a single electron, thus reducing the hydroxide radical to hydroxide ion and becoming itself an ascorbyl radical.
Figure 16.6.4
The ascorbyl radical is stabilized by resonance. The end result of this first step is that a very reactive, potentially harmful hydroxide radical has been 'quenched' to hydroxide ion and replaced by a much less reactive (and thus less harmful) ascorbyl radical.
The ascorbyl radical can then donate a second electron to quench a second hydroxide radical, resulting in the formation of dehydroascorbate, the oxidized form of ascorbate.
Figure 16.6.5
One ascorbate molecule is thus potentially able to scavenge two harmful radical species.
Dehydroascorbate is subsequently either broken down and excreted, or else enzymatically recycled (reduced) back to ascorbic acid. You were invited to propose a mechanism for the latter (redox) step in problem 15.10. J. Am. Coll. Nutr., 2003, 22, 18
We learned in the introduction to this chapter about the gruesome effects of long-term ascorbic acid deficiency. What, then, is the chemical connection between ascorbic acid and scurvy?
The symptoms association with scurvy are caused by the body's failure to properly synthesize collagen, the primary structural protein in our connective tissues. Essential to the stability of collagen is its ability to form a unique triple-helical structure, in which three protein strands coil around each other like a woven rope. Collagen strands are not able to pack together properly into their triple helix structure unless certain of their proline amino acid residues are hydroxylated: the electronegative OH group on hydroxyproline causes the five-membered ring in the amino acid to favor a particular 'envelope' conformation (section 3.2) as well as the 'trans' peptide conformation, both of which are necessary for stable triple-helix formation.
Figure 16.6.6
Figure 16.6.7
Figure 16.6.8
Proline hydroxylase, the enzyme responsible for this key modification reaction, depends in turn upon the presence of ascorbate. The hydroxylating reaction is complex, and involves electron-transfer steps with enzyme-bound iron - mechanistic details that are well outside of our scope here, but which you may learn about in a bioinorganic chemistry course. It is enough for us to know that iron starts out in the \(Fe^{+2}\) state, and during the course of the reaction it loses an electron to assume the \(Fe^{+3}\) state. In order for the enzyme to catalyze another reaction, the iron must be reduced back to its active \(Fe^{+2}\) state - it must accept a single electron. The donor of this single electron is ascorbate.
(For more information, see Crit. Rev. Biochem. Mol. Biol. 2010, 405, 106.)
So, to sum up: If we fail to get enough ascorbic acid in our diet (in other words, if we don't eat our fruits and vegetables!) the iron in our proline hydroxylase enzymes won't be returned to the active \(Fe^{+2}\) state, so the catalytic cycle is broken and we can't turn prolines into hydroxyprolines. Without the hydroxy group, the proline residues of our collagen proteins won't assume the proper conformation, and as a consequence the collagen triple helix structures will be unstable. At physiological temperature, our collagen will literally melt apart - and with it, our gums, our capillaries, and anything else held together by connective tissue. This is scurvy.
You have probably heard that many fruits and vegetables contain natural 'polyphenol' antioxidant compounds that are thought to be beneficial to our health. Apigenin, for example, is found in parsley and celery, while the skins of grapes used to produce red wine are particularly rich in resveratrol, as well as many other polyphenols. Curcumin is the compound responsible for the distinctive yellow color of turmeric, a ubiquitous spice in Indian cuisine.
Figure 16.6.9
While much remains to be learned about exactly how these polyphenols exert their antioxidant effects, it is likely that they, like ascorbic acid, act as radical scavengers. For example, resveratrol could donate a single electron (and a proton) to hydroxide radical to reduce it to water. The phenolic radical that results is stabilized by resonance, and is much less likely than hydroxide radical to cause damage to important biomolecules in the cell.
Figure 16.6.10 | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/16%3A_Radical_Reactions/16.06%3A_Oxidative_Damage_to_cells_Vitamin_C_and_Scurvy.txt |
In chapter 15 we saw how a nicotinamide and flavin coenzymes can act as acceptors or donors of two electrons in hydride-transfer redox steps. Recall that it was mentioned that flavin, (but not nicotinamide) can also participate in single-electron transfer steps through a stabilized radical intermediate called a semiquinone.. Frey p. 162 fig 3-30; Silverman p. 122 sch. 3.34; J Phys Chem A. 2013, 117, 11136 fig 2)
Note in this reaction that overall, flavin loses or gains two electrons and two protons, just like in the flavin-dependent redox reactions we saw in chapter 15. The difference here is that the electrons are transferred one at a time, rather than paired in the form of a hydride ion.
Two important examples single-electron acceptor species in human metabolism are ubiquinone (coenzyme \(Q\)) and the oxidized form of cytochrome. Ubiquinone is a coenzyme that can transfer single electrons via a semiquinone state analogous to that of flavin, and cytochrome is a protein containing a 'heme' iron center which shuttles between the \(Fe^{+3}\) (oxidized) and \(Fe^{+2}\) (reduced) state.
Further discussion of the mechanisms of single-electron flavin reactions is beyond our scope here, but when you study the 'respiratory chain' in a biochemistry course you will gain a deeper appreciation for the importance of flavin in single-electron transfer processes.
16.0E: 16.E: Radical Reactions (Exercises)
P16.1: Plexiglass is a polymer of methyl methacrylate. Show a mechanism for the first two propagation steps of polymerization (use $X\cdot$ to denote the radical initiator), and show a structure for the plexiglass polymer. Assume an alkene addition process similar to that shown in the text for polyethylene.
P16.2: In section 16.3 we saw how acrylamide polymerizes to form the polyacrylamide used in PAGE protein gels. Polyacrylamide by itself is not sufficient by itself to form the gel - the long polyacrylamide chains simply slip against each other, like boiled spaghetti. To make a PAGE gel, with pores for the proteins to slip through, we need a crosslinker - something to tie the chains together, forming a three-dimensional web-like structure. Usually, a small amount of bis-acrylamide is added to the acrylamide in the polymerization mixture for this purpose.
Propose a radical mechanism showing how bis- acrylamide might form crosslinks between two polyacrylamide chains.
P16.3: Resveratrol is a natural antioxidant found in red wine (see section 16.5 for the structure).
1. Draw one resonance structure to illustrate how the resveratrol radical is delocalized by resonance.
2. Indicate all of the carbons on your structure to which the radical can be delocalized.
3. Draw an alternate resveratrol radical (one in which a hydrogen atom from one of the other two phenolic groups has been abstracted). To how many carbons can this radical be delocalized?
4. The curcumin structure is shown in the same figure as that of resveratrol, in section16.5. Draw two resonance contributors of a curcumin radical, one in which the unpaired electron is on a phenolic oxygen, and one in which the unpaired electron is on a ketone oxygen.
P16.4: Draw the radical intermediate species that you would expect to form when each of the compounds below reacts with a radical initiator.
P16.5: Azobis(isobutyronitrile) is a widely used radical initiator which rapidly undergoes homolytic decomposition when heated.
Predict the products of this decomposition reaction, and show a likely mechanism. What is the thermodynamic driving force for homolytic cleavage?
P16.6:
1. When 2-methylbutane is subjected to chlorine gas and heat, a number of isomeric chloroalkanes with the formula $C_5H_{11}Cl$ can form. Draw structures for these isomers, and for each draw the alkyl radical intermediate that led to its formation.
2. In part a), which is the most stable radical intermediate?
3. In the reaction in part a), the relative abundance of different isomers in the product is not exclusively a reflection of the relative stability of radical intermediates. Explain.
P16.7: We learned in chapter 14 that $HBr$ will react with alkenes in electrophilic addition reactions with 'Markovnikov' regioselectivity. However, when the starting alkene contains even a small amount of contaminating peroxide (which happens when it is allowed to come into contact with air), a significant amount of 'anti-Markovnikov' product is often observed.
1. Propose a mechanism for formation of the anti-Markovnikov addition product when 1-butene reacts with $HBr$ containing a small amount of benzoyl peroxide
2. Predict the product and propose a mechanism for the addition of ethanethiol to 1-butene in the presence of peroxide.
P16.8: In section 11.5 we learned that aspirin works by blocking the action of an enzyme that catalyzes a key step in the biosynthesis of prostaglandins, a class of biochemical signaling molecules. The enzyme in question, prostaglandin $H$ synthase (EC 1.14.99.1) catalyzes the reaction via several single-electron steps. First, an iron-bound oxygen radical in the enzyme abstracts a hydrogen atom from arachidonate. The arachidonate radical intermediate then reacts with molecular oxygen to form a five-membered oxygen-containing ring, followed by closure of a cyclopentane ring to yield yet another radical intermediate. (Biochemistry 2002, 41, 15451.)
Propose a mechanism for the steps of the reaction that are shown in this figure.
P16.9: Some redox enzymes use copper to assist in electron transfer steps. One important example is dopamine b-monooxygenase (EC 1.14.1.1), which catalyzes the following reaction:
The following intermediates have been proposed: (see Biochemistry 1994, 33, 226) Silverman p. 222
Draw mechanistic arrows for steps 1-4. | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/16%3A_Radical_Reactions/16.07%3A_Flavin_as_a_One-Electron_Carrier.txt |
• 17.1: Prelude to the Organic Chemistry of Vitamins
In this final chapter, we focus on the organic chemistry of folate, along with three other coenzymes: pyridoxal phosphate, thiamine diphosphate, and lipoamide. Humans can synthesize lipoamide, but we depend on dietary sources for the other three: pyridoxal phosphate is a form of vitamin B6, and thiamine diphosphate is a form of vitamin B1.
• 17.2: Pyridoxal Phosphate (Vitamin B6)
The coenzyme pyridoxal phosphate (commonly abbreviated PLP) is the active form of vitamin B6 , or pyridoxine. PLP is required for over 100 different reactions in human metabolism, primarily in the various amino acid biosynthetic and degradation pathways. The essential function of PLP is to act as an 'electron sink', stabilizing a negative formal charge that develops on key reaction intermediates.
• 17.3: Thiamine Diphosphate (Vitamin B1)
Thiamine diphosphate (ThDP, sometimes also abbreviated TPP or ThPP) is a coenzyme which, like PLP, acts as an electron sink to stabilize key carbanion intermediates. The most important part of the ThDP molecule from a catalytic standpoint is its thiazole ring.
• 17.4: Thiamine Diphosphate, Lipoamide and the Pyruvate Dehydrogenase Reaction
The enzyme pyruvate dehydrogenase is one of the most central of all the enzymes of central metabolism: by converting pyruvate to acetyl-CoA, it links glycolysis (where glucose is broken down into pyruvate) to the citric acid cycle, into which carbons enter in the form of acetyl-CoA.
• 17.5: Folate
Folate, or vitamin B9 , is essential for a variety of important reactions in nucleotide and amino acid metabolism. The reactive part of folate is the pterin ring system, shown in red below. The conventional atom numbering system for folate is also indicated.
• 17.E: The Organic Chemistry of Vitamins (Exercises)
• 17.S: The Oganic Chemistry of Vitamins (Summary)
17: The Organic Chemistry of Vitamins
The old black and white photograph is haunting. A young boy, perhaps 10 or 11 years old, huddles against a wall outside a soup kitchen, his mouth in an odd twisted shape that could be expressing either pain or defiance, his eyes staring straight into those of the viewer. Tucked into his pants, almost like a pistol in a holster, is a metal spoon.
The photograph was taken in the Netherlands in 1945, at the height of what the Dutch people still refer to simply as "The Hunger Winter". With the western part of the country still occupied by the Nazis, the Dutch resistance government, based in London, had called for a railway strike with the aim of stopping German troop movements before a planned airborne invasion by Allied forces. In retaliation, the Germans cut off all food shipments to cities in the western Netherlands. The Allied invasion failed to liberate the country, and the winter of 1944-1945 turned out to be bitterly cold. With food supplies dwindling, rations were cut first to 1000 calories per day, then to 500. People resorted to eating grass and tulip bulbs just to stay alive. Over 20,000 people died of starvation before food shipments were restored in the spring.
As tragic as the Hunger Winter was for the Dutch people, some good did come from it. For medical scientists, the event became a unique 'social experiment': unlike most episodes of famine throughout human history, the Hunger Winter had a clearly defined beginning, end, and geographic boundary, and it occurred in a technologically advanced society that continued to keep thorough records before, during, and after the ordeal. Scientists knew exactly who suffered from famine and for precisely how long, and in the years that followed they were able to look at the long-term effects of famine, particularly on developing embryos. Researchers found that babies who had been conceived during the famine were born with a significantly higher incidence of neurological birth defects such as spina bifida, a condition in which a portion of the neural tube protrudes from between vertebrae which did not properly fuse together during fetal development. Later in life, members of this same cohort of 'famine babies' were more likely to be obese, and to suffer from schizophrenia.
These initial findings spurred interest in further research into the consequences of prenatal deprivation. In particular, carefully controlled studies later led to the recognition of the importance of the vitamin folate in ensuring proper neurological development in early-term fetuses.
Folate - the conjugate base of folic acid - is an organic coenzyme: a helper molecule that binds in the active site of certain enzymes and plays a critical role in the biochemical reaction being catalyzed. Recall that we have seen coenzymes at work before: \(SAM\), \(ATP\), \(NAD(P)^+\) and \(NAD(P)H\), flavin and glutathione are all important coenzymes with which we are already familiar.
Because prenatal folate deficiency was found to be directly related to the incidence of spina bifida and other neural tube defects, health officials in the United States and many other countries changed their official guidelines to include a specific recommendation that women begin taking folate supplements as soon as they knew that they are pregnant, or better yet as soon as they begin trying to become pregnant. A number of studies conducted during the 1980s and early 1990s consistently showed that folate supplementation correlated with a 50-70% reduction in neural tube defects.
The molecular role of folate in prenatal neurological development is not understood in detail, but most researchers agree that it probably has a lot to do with DNA biosynthesis. Like \(S\)-adenosyl methionine (\(SAM\)), folate functions in 1-carbon transfer reactions, including several critical steps in the nucleic acid biosynthesis pathways. The rapidly dividing cells of the developing brain of an early term fetus appear to be especially sensitive to folate deficiency in the mother's diet: insufficient folate leads to impaired DNA biosynthesis, which in turn leads to defects in brain development.
Folate also serves as a 1-carbon donor in the pathway by which \(SAM\) is regenerated after it donates a methyl group. You may recall from the introduction to chapter 8 that methylation of cytosine bases in DNA by \(SAM\) results in permanent changes to a individual's genome - this was the reason why the two 'identical' twin sisters in that introductory story turned out to be, as they grew older, not so identical after all. It is likely that the folate deprivation that afflicted expectant mothers during the Dutch Hunger Winter also caused epigenetic changes (in other words, changes in the extent of DNA methylation) in their developing fetuses, which decades later manifested in the form of an increased incidence of conditions such as obesity and schizophrenia. All the more reason, we now know, to make sure that women get plenty of folate in their diet early in the first trimester of pregnancy.
In this final chapter, we focus on the organic chemistry of folate, along with three other coenzymes: pyridoxal phosphate, thiamine diphosphate, and lipoamide. Humans can synthesize lipoamide, but we depend on dietary sources for the other three: pyridoxal phosphate is a form of vitamin B6, and thiamine diphosphate is a form of vitamin B1. In a mechanistic sense, there is really nothing new in this chapter. All of the reaction mechanism types that we will see are already familiar to us, ranging from nucleophilic substitutions (chapter 8) to disulfide exchanges (chapter 15). We will soon see, however, how each coenzyme plays its own specific and crucial role in assisting enzymes with the catalysis of key reactions of metabolism. We will begin with pyridoxal phosphate and its various roles in amino acid metabolism.
Additional reading:
http://www.naturalhistorymag.com/fea...na-epigenetics | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/17%3A_The_Organic_Chemistry_of_Vitamins/17.01%3A_Prelude_to_the_Organic_Chemistry_of_Vitamins.txt |
The coenzyme pyridoxal phosphate (commonly abbreviated PLP) is the active form of vitamin $B_6$, or pyridoxine.
PLP is required for over 100 different reactions in human metabolism, primarily in the various amino acid biosynthetic and degradation pathways. The essential function of PLP is to act as an 'electron sink', stabilizing a negative formal charge that develops on key reaction intermediates. Some of reactions will be familiar to you from chapter 12 and 13 we will see examples, for instance, of -dependent $\alpha$-carbon racemization, as well as aldol- and Claisen-type reactions. Other reactions will be less familiar: for example, the participation of allows for decarboxylation of amino acids, a chemical step which would be highly unlikely without the coenzyme, and PLP is also required for a very important class of biochemical transformation called 'transamination', in which the amino group of an amino acid is transferred to an acceptor molecule. Before we dive into the reactions themselves, though, we need to begin by looking at a key preliminary step that is common to all of the PLP reactions we will see in this section.
PLP in the active site: the imine linkage
The common catalytic cycle of a PLP-dependent enzyme begins and ends with the coenzyme covalently linked to the enzyme's active site through an imine linkage between the aldehyde carbon of PLP and the amine group of a lysine residue (see section 10.5 to review the mechanism for imine formation). For a PLP-dependent enzyme to become active, a PLP molecule must first enter the active site of an enzyme and form an imine link to the lysine. This state is often referred to as an external aldimine.
The first step of virtually all PLP-dependent reactions is transimination (section 10.5), as the amino group on the amino acid substrate displaces the amino group of the enzymatic lysine. This state - where the coenzyme is covalently linked to the substrate or product of the reaction - is often referred to as an internal aldimine.
With the preliminary transimination accomplished, the real PLP chemistry is ready to start. The versatility of PLP in terms of its ability to assist with a wide variety of reaction types is illustrated by the figure below, showing how, depending upon the reaction/enzyme in question, PLP can assist in the cleavage of any one of the four bonds to the $\alpha$-carbon of the amino acid substrate.
Let's look first at the reaction catalyzed by PLP-dependent alanine racemase. (EC 5.1.1.1).
PLP-dependent amino acid racemization
In section 12.2 we saw an example of a PLP-independent amino acid racemization reaction, in which the negatively-charged intermediate was simply the enolate form of a carboxylaten:
Many other amino acid racemase reactions, however, require the participation of PLP.
Like all other PLP-dependent reactions that we will see in this section, PLP-dependent amino acid racemization begins with a preliminary step in which the substrate becomes attached to the coenzyme through a transimination. Once it is linked to PLP in the active site, the a-proton of an amino acid substrate is abstracted by an active site base (step 1 below). The negative charge on the carbanion intermediate can, of course, be delocalized to the carboxylate group. The PLP coenzyme, however, provides an expanded network of conjugated $\pi$-bonds over which the electron density can be delocalized all the way down to the PLP nitrogen. This is what we mean when we say that the job of PLP is to act as an ‘electron sink’: the coenzyme is very efficient at absorbing, or delocalizing, the excess electron density on the deprotonated $\alpha$-carbon of the reaction intermediate. PLP is helping the enzyme to increase the acidity of the $\alpha$-hydrogen by stabilizing the conjugate base. A PLP-stabilized carbanion intermediate is commonly referred to as a quinonoid intermediate. Note that in the overall reaction equation below, PLP appears below the reaction arrow in brackets, indicating that it participates in the mechanism but is regenerated as part of the reaction cycle.
PLP-dependent amino acid racemization:
Mechanism:
Preliminary step - transimination
First step - deprotonation:
Second step - reprotonation from the opposite side:
Final step - transimination:
Just as in the PLP-independent racemase reactions, reprotonation occurs on the opposite side of the substrate (step 2), leading to the $D$-amino acid product.
All that remains is the final imine exchange which frees the $D$-amino acid product and re-attaches the coenzyme to the enzymatic lysine side-chain, ready to begin another catalytic cycle.
To simplify matters, from here on we will not include the preliminary and final transimination steps in our PLP reaction figures - we will only show mechanistic steps that occur while the substrate is attached to the coenzyme (the internal aldimine forms).
PLP-dependent decarboxylation
In the amino acid racemase reaction above, PLP assisted in breaking the $\alpha$-carbon to $\alpha$-proton bond of the amino acid. Other PLP-dependent enzymes can catalyze the breaking of the bond between the $\alpha$-carbon and the carboxylate carbon by stabilizing the resulting carbanion intermediate: these are simply decarboxylation reactions.
PLP-depended amino acid decarboxylation:
Mechanism:
Notice something very important here: while in racemization reactions the assistance of PLP can be seen as 'optional' (in the sense that some racemase enzyme use PLP and others do not), the coenzyme is essential for amino acid decarboxylation steps. Without PLP, there is no way to stabilize the carbanion intermediate, and decarboxylation is not a chemically reasonable step.
One example of a PLP-facilitated decarboxylation reaction is the final step in the lysine biosynthesis pathway: (EC 4.1.1.20).
Exercise 17.2.1
Draw mechanistic arrows for the carbon-carbon bond-breaking step of the PLP-dependent decarboxylation reaction above.
PLP-dependent retroaldol and retro-Claisen cleavage
(It would be a good idea before reading this section to review aldol/retro-aldol and Claisen/retro-Claisen reaction mechanisms in sections 12.3 and 13.3, respectively)
So far we have seen PLP playing a role in breaking the bond between the $\alpha$-carbon and its $\alpha$-proton (in the racemization reaction), and the bond between the $\alpha$-carbon and carboxylate carbon (in the decarboxylation reaction).
Other PLP-dependant enzymes catalyze cleavage of the bond between the $\alpha$-carbon and the first carbon on the amino acid side chain, otherwise known as the $\beta$-carbon. In the serine degradation pathway, serine is first converted to glycine by a retro-aldol cleavage reaction. (). Although a reasonable mechanism could be proposed without the participation of PLP, this reaction in fact requires the coenzyme to assist in stabilization of the negative charge on the carbanion intermediate.
A PLP-dependent retro-aldol cleavage reaction
(serine hydroxymethyl transferase, EC 2.1.2.1)
Mechanism:
Note that, in this reaction just as in the racemase reaction described previously, the key intermediate is a PLP-stabilized carbanion, or quinonoid.
What happens to the (toxic!) formaldehyde produced in this reaction? We will see later in this chapter how the serine hydroxymethyltransferase enzyme goes on to use another coenzyme called tetrahydrofolate to prevent the formaldehyde from leaving the active site and causing damage to the cell.
PLP also assists in retro-Claisen cleavage reactions (section 13.3), such as this step in the degradation of threonine. (EC 2.3.1.29)
A PLP-dependent retro-Claisen reaction:
Mechanism:
Notice how, like the retro-aldol reaction, the bond between the $\alpha$-carbon and the $\beta$-carbon of the amino acid substrate is broken (in step 1b).
PLP-dependent transamination
One of the most important reaction types in amino acid metabolism is transamination, in which an amino group on a donor molecule (often an amino acid) is transferred to a ketone or aldehyde acceptor molecule.
A transamination reaction:
Transamination phase 1 (transfer of amino group from amino acid substrate to coenzyme)
Mechanism:
Once again, step 1 is abstraction of the $\alpha$-proton from the PLP-substrate adduct. However, in a transaminase reaction this initial deprotonation step is immediately followed by reprotonation at what was originally the aldehyde carbon of PLP (step 2 above), which results in a new carbon-nitrogen double bond (in other words, an imine) between the $\alpha$-carbon and the nitrogen atom of the original amino acid. The repositioned imine group is then hydrolyzed (step 3 above), breaking the carbon-nitrogen bond, transferring the amino group to the coenzyme, and releasing an $\alpha$-keto acid.
The coenzyme, which now carries an amine group and is called pyridoxamine phospate ($PMP$), next transfers the amine group to $\alpha$-ketoglutarate (to form glutamate) through a reversal of the whole process depicted above.
Transamination reaction, phase 2
(transfer of amino group from coenzyme to acceptor molecule)
Mechanism:
see exercise below
In a transamination reaction, the PLP coenzyme not only provides an electron sink, it also serves as a temporary 'parking place' for an amino group as it is transferred from donor to acceptor.
Exercise 17.2.2
Show a complete, step-by-step mechanism for 'phase 2' of the transamination reaction above.
Here is an example of a transamination reaction in the arginine biosynthesis pathway: EC 2.6.1.11
Exercise 17.2.3
1. Draw arrows for the first mechanistic step of 'phase 2' of the above transaminase reaction.
2. Which carbon on the substrate side of the reaction will eventually become the $\alpha$-carbon of arginine?
Exercise 17.2.4
Propose a pathway, with three enzymatic steps, for the biosynthesis of serine from 3-phosphoglycerate. Include a generalized ('-ase') enzyme name for each step. Glutamate plays a role in the process as an amino group donor.
PLP-dependent $beta$-elimination and $\beta$-substitution
(Before starting this section, it would be a good idea to review $E1cb$ $\beta$-elimination and conjugate addition reaction mechanisms in section 13.4)
By now it should be pretty apparent that PLP is a pretty versatile coenzyme! Two more reaction types in the PLP toolbox are $\beta$-elimination and $\beta$-substitution on amino acid substrates.
In a PLP-dependent $\beta$-elimination reaction, the coenzyme simply helps to stabilize the carbanion intermediate of the $E1cb$ mechanism:
PLP-dependent $\beta$-elimination reaction
Mechanism:
Serine dehydratase (EC 4.2.1.13) catalyzes a PLP-dependent $\beta$-elimination in the first step of the serine degradation pathway:
A $\beta$-substitution reaction is simply $E1cb$ elimination followed directly by the reverse reaction (conjugate addition) with a different nucleophile (Y in the figure below):
A $\beta$-substitution reaction:
In many bacteria, the synthesis of cysteine from serine includes a PLP-dependent $\beta$-substitution step (EC 2.5.1.47).
Exercise 17.2.5
Draw a mechanism for the conjugate addition phase of the reaction above (end with the cysteine-PLP adduct).
PLP-dependent $\gamma$-elimination and $\gamma$-substitution reactions
The electron sink capability of PLP allows some enzymes to catalyze eliminations at the $\gamma$-carbon of some amino acid side chains, rather than at the $\beta$-carbon. secret to understanding the mechanism of a $\gamma$-elimination is that PLP essentially acts as an electron sink twice - it absorbs the excess electron density from not one but two proton abstractions.
$\gamma$-elimination
Mechanism:
In a familiar first step, the $\alpha$-proton of the amino acid is abstracted by an enzymatic base, and the electron density is absorbed by PLP. Next comes the new part - before anything happens to the electron density from the first proton abstraction, a second proton, this time from the $\beta$-carbon on the side chain, is abstracted, forming an enamine intermediate (step 2). The phenolic proton on the pyridoxal ring of PLP donates a proton to the nitrogen. step 3, the leaving is expelled and a new $\pi$-bond forms between the $\beta$ and $\gamma$ carbons (step 3). This $\pi$-bond is short-lived, however, as the electron density from the first proton abstraction, which has been 'stored' in PLP all this time, flows back up to protonate the $\alpha$-carbon (step 4), leaving the $\gamma$-elimination product linked to PLP via the usual imine connection.
An example is the cystathionine $\gamma$-lyase reaction in the methionine degradation pathway (EC 4.4.1.1):
fig 2
A related reaction is PLP-dependent $\gamma$-substitution, which again is simply $\gamma$-elimination of a leaving group (X in the figure below) followed directly by the reverse process (a $\gamma$-addition) with a different nucleophile ('Nu' in the figure below).
PLP-dependent $\gamma$-substitution:
Mechanism:
Below is a PLP-dependent $\gamma$-substitution reaction in the methionine degradation pathway (EC 4.2.1.22):
Racemase to aldolase: altering the course of a PLP reaction
We have seen how PLP-dependent enzymes catalyze a variety of reaction types - racemization, retroaldol/retro-Claisen cleavage, transaminination, elimination, and substitution - which, despite their apparent diversity, are all characterized by formation of a critical carbanion intermediate which is stabilized by the 'electron sink' property of the PLP coenzyme. Given this common mechanistic feature, it would be reasonable to propose that the active site architecture of these enzymes might also be quite close. This idea was nicely illustrated by an experiment in which researchers found that changing a single active site amino acid of PLP-dependent alanine racemase was sufficient to turn it into a retro-aldolase (J. Am. Chem. Soc. 2003, 125, 10158).
In the 'wild-type' (natural) alanine racemase reaction, an active site histidine (red in figure below) deprotonates a neighboring tyrosine residue (blue), which in turn acts as the catalytic base abstracting the $\alpha$-proton of the substrate. When researchers changed the tyrosine to an alanine (using a technique called 'site-directed mutagenesis'), and substituted $\beta$-hydroxytyrosine for the alanine substrate, the new 'mutant' enzyme catalyzed a retro-aldol reaction.
Notice what has happened here: the basic histidine, with no tyrosine to deprotonate because of the mutation, is instead positioned to abstract a proton from the $\beta$-hydroxyl group of the new substrate, setting up a retroaldol cleavage. That was all it took to change a racemase into a retroaldolase, because the necessary PLP electron sink system was all left in place. The researchers predicted correctly that the phenyl ring of $\beta$-hydroxy tyrosine would fit nicely in the space left empty due to the tyrosine to alanine change in the mutant enzyme's structure
These results underline the close mechanistic relationship between two PLP-dependent reactions which, at first glance, appear to be quite different - and suggest that PLP-dependent racemases and aldolases may have evolved from a common 'ancestor' enzyme.
Stereoelectronic considerations of PLP-dependent reactions
Recall that all PLP-dependent reactions involve the cleavage of one of the bonds coming from the $\alpha$-carbon of an amino acid substrate, with the coenzyme serving as an 'electron sink' to stabilize the intermediate that results. PLP-dependent enzymes accelerate this bond-breaking step by binding the substrate-PLP adduct in a conformation such that the bond being broken is close to perpendicular to the plane formed by the conjugated $\pi$ system of PLP: this way, as the $\alpha$-carbon transitions from $sp^3$ to $sp^2$ hybridization, the unhybridized $\pi$ orbital is already oriented to overlap with the rest of the conjugated system. For example, in alanine racemase the first step is cleavage of the $C\alpha -H$ bond, so it must be that bond which is positioned near-perpendicular to the PLP plane:
Likewise, in an amino acid decarboxylase, the $C\alpha$-carboxylate bond is held near-perpendicular to the PLP plane, and in hydroxymethyltransferase, the $C\alpha -C\beta$ bond is in the perpendicular orientation:
These are all good examples of how enzymatic catalysis is achieved, in part, by the ability of the active site to bind the substrate molecule in a specific conformation which contributes to the lowering of the activation energy of a key reaction step. | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/17%3A_The_Organic_Chemistry_of_Vitamins/17.02%3A_Pyridoxal_Phosphate_%28Vitamin_B6%29.txt |
Thiamine diphosphate (\(ThDP\), sometimes also abbreviated \(TPP\) or \(ThPP\)) is a coenzyme which, like PLP, acts as an electron sink to stabilize key carbanion intermediates. The most important part of the \(ThDP\) molecule from a catalytic standpoint is its thiazole ring.
The proton on the carbon between nitrogen and sulfur on the thiazole ring is weakly acidic, with a \(pK_a\) of about 18.
The reason for its acidity lies partly in the ability of the neighboring sulfur atom to accept, in its open \(d\)-orbitals, some of the excess electron density of the conjugate base. Another reason is that the positive charge on the nitrogen helps to stabilize the negative charge on the conjugate base. The deprotonated thiazole is called an ylide, which is a general term for a species with adjacent positively and negatively charged atoms.
The negatively charged carbon on the ylide form of \(ThDP\) is nucleophilic, and as we shall soon see, the first step of most \(TPP\)-dependent reactions is nucleophilic attack of the ylide carbon on a carbonyl group of the reaction substrate.
\(ThDP\) plays a key role in a variety of reaction types, but the common theme in all \(ThDP\)-dependent reactions is cleavage of a bond adjacent to the carbonyl carbon of a ketone or aldehyde.
Thiamine diphosphate assists in breaking bonds next to a ketone or aldehyde:
Consider this hypothetical decarboxylation step:
Hopefully, you can quickly recognize that this is not a chemically reasonable step, because the intermediate species which results from decarboxylation has a negative charge localized on the ketone carbon - a very unstable, unlikely intermediate indeed.
(Recall from section 13.1 that decarboxylation steps usually result in intermediates in which the negative formal charge is delocalized to an oxygen or nitrogen - in other words, enolates or enamines.)
Now consider, however, a reaction going on in your cells right now, catalyzed by the enzyme pyruvate decarboxylase (EC 4.1.1.1):
Somehow, the enzyme manages to accomplish this 'impossible' decarboxylation. How does this happen? Here is where the thiamine diphosphate coenzyme comes in.
A \(ThDP\)-dependent decarboxylation reaction (pyruvate decarboxylase):
Mechanism:
Upon binding to the enzyme's active site, \(ThDP\) quickly loses a proton. The nucleophilic ylide carbon then adds to the carbonyl carbon of pyruvate.
Look carefully at the intermediate that results from step 1 in the mechanism above. The thiazole ring of \(ThDP\), once it has added to the carbonyl of pyruvate, provides an 'electron sink' to absorb the electrons from decarboxylation (step 2). Note which bond is breaking in step 2 - as was mentioned earlier, the common function of \(ThDP\) is to make possible the cleavage of a bond to a carbonyl carbon.
In step 3, the electrons from decarboxylation flow back to abstract a proton from an acidic group in the active site. All that remains is for the product to break free of thiamine in step 4.
Thiamine can also assist in decarboxylation-addition reactions:
\(ThDP\)-dependent decarboxylation-addition:
Mechanism:
Here, the electron-rich intermediate formed from the decarboxylation step (step 2) simply goes on to act as a nucleophile rather than as a base, adding to the carbonyl group of an aldehyde or ketone (step 3). As before, the product breaks free of \(ThDP\) in step 4.
An example is the first step in the biosynthetic pathway for isoprenoid compounds in bacteria:
Transketolase, a \(ThDP\)-dependent enzyme in the pentose phosphate pathway of sugar metabolism, catalyzes a carbon-carbon bond break step, followed by a carbon-carbon bond forming step. The substrates and products are at similar energy levels, so the reaction is completely reversible.
Transketolase reaction:
Mechanism:
Below is an actual example of a transketolase-catalyzed transformation from the pentose phosphate pathway (shown in Fischer projections, as is common for sugar structures).
Exercise 17.3.1
As was mentioned above, the transketolase reaction is highly reversible. Do you think the same can be said for the decarboxylation and decarboxylation-addition reactions we saw in this section? Why or why not?
Exercise 17.3.2
(Challenging!) Propose a mechanism for the reaction below.
Hint
This is a \(ThDP\)-facilitated decarboxylation/ Michael addition, followed by \(E1cb\) elimination of pyruvate. A Michael addition is the name for a conjugate addition with a carbon nucleophile. (J. Mol. Biol. 2010, 401, 253).
Exercise 17.3.3
Propose a mechanism for the reaction below.
Hint
The mechanism can be described as a \(ThDP\)-facilitated dehydration step, followed by a tautomerization step, followed by a hydrolytic expulsion of \(ThDP\) (a different kind of \(ThDP\) expulsion from what we have seen so far!)
17.04: Thiamine Diphosphate Lipoamide and the Pyruvate Dehydrogenase Reaction
The enzyme pyruvate dehydrogenase is one of the most central of all the enzymes of central metabolism: by converting pyruvate to acetyl-\(CoA\), it links glycolysis (where glucose is broken down into pyruvate) to the citric acid cycle, into which carbons enter in the form of acetyl-\(CoA\). Five ceonzymes are involved: coenzyme A, nicotinamide, thiamine diphosphate, \(FAD\), and finally lipoamide, one which is new to us at this point.
Reaction catalyzed by pyruvate dehydrogenase:
You will learn more about the structure and metabolic role of this complex and remarkable enzyme in a biochemistry course. Here, we will focus on the multi-step organic reaction it catalyzes, which we are at long last equipped to understand.
Looking at the reaction, you should recognize that, first of all, the pyruvate substrate is being oxidized - it starts out as a ketone, and ends up as a thioester, losing carbon dioxide in the process. Ultimately, the oxidizing agent in this reaction is \(NAD^+\), but the reduction of \(NAD^+\) is linked to the oxidative decarboxylation of pyruvate by \(FAD\) and a disulfide-containing coenzyme called lipoamide, which is lipoic acid attached by an amide linkage to a lysine residue on the enzyme.
The second thing to notice is that, because the reaction involves breaking the bond between the ketone carbon and an adjacent carbon, thiamine diphosphate (\(ThDP\)) coenzyme is required. In fact, the first phase of the reaction (steps 1 and 2 below) is identical to that of pyruvate decarboxylase, an enzyme we discussed a few pages ago.
The pyruvate decarboxylase reaction mechanism
Phase 1: Decarboxylation of pyruvate
The \(ThDP\)-stabilized carbanion then acts as a nucleophile, cleaving the disulfide bridge of lipoamide (step 3 below). It is in this step that oxidation of the substrate is actually occurring. After the resulting thioester product is released from \(ThDP\) (step 4 below), it undergoes transesterification form acetyl-\(CoA\), the product of the reaction.
Phase 2 of the pyruvate decarboxylase reaction mechanism: lipoamide-mediate oxidation to acetyl-\(CoA\)
We are not done yet! In order for the catalytic cycle to be complete, the reduced dihydrolipoamide must be regenerated back to its oxidized state through disulfide exchange with a disulfide bond on the enzyme. The pair of enzymatic cysteines is then oxidized back to disulfide form by an \(FAD\)-dependent reaction.
Phase 3 of the pyruvate decarboxylase reaction mechanism: regeneration of lipoamide
Finally, \(FAD\) is regenerated with concurrent reduction of \(NAD^+\):
Phase 4: Regeneration of \(FADH_2\): | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/17%3A_The_Organic_Chemistry_of_Vitamins/17.03%3A_Thiamine_Diphosphate_%28Vitamin_B1%29.txt |
Folate, or vitamin \(B_9\), is essential for a variety of important reactions in nucleotide and amino acid metabolism. The reactive part of folate is the pterin ring system, shown in red below. The conventional atom numbering system for folate is also indicated.
Active forms of folate
Folate is active as a coenzyme in its reduced forms, dihydrofolate and tetrahydrofolate, which are formed by \(NADPH-\)dependent imine hydrogenation steps (section 15.3).
The metabolic role of folate is to serve as a donor or acceptor in single-carbon transfer reactions. How is folate different from \(S\)-adenosylmethionine (\(SAM\), section 8.8) which also serves as a single-carbon donor? Recall that \(SAM\) donates a single carbon in the form of a methyl group: essentially, the single carbon of \(SAM\) is in the methanol (\(CH_3OH\)) oxidation state, because it has only one bond to a heteroatom (specifically, to sulfur). (Refer to section 15.1 for a review of oxidation states).
Folate coenzymes, on the other hand, can carry a single carbon in the formaldehyde and formate oxidation states, in addition to the methanol oxidation state. By 'formaldehyde' and 'formate' oxidation state, we mean that the carbon has two and three bonds to heteroatoms, respectively.
Some key reactions in nucleic acid and amino acid metabolic pathways involve transfer of a single carbon in the formaldehyde or formate states. However, this could present problems. Formaldehyde by itself is very toxic: in particular, it tends to spontaneously form unwanted crosslinks between amine groups (eg. lysine side chains) in proteins.
fig 53
Free formaldehyde is too reactive, and would cause damage to a cell. The \(CH_2-THF\) coenzyme is stable in solution, but in the active site of certain enzymes it is reactive enough to serve as a formaldehyde donor, as we will see shortly.
Free formate, on the other hand, is a carboxylate, and we know from chapter 11 that carboxylates are not reactive in acyl substitution steps. Formate could be activated by phosphorylation, of course, but the resulting formyl phosphate would be too reactive in many enzyme active sites. A 'happy medium' has been found in which carbons in the formate oxidation state are carried by folate in the form of \(f-THF\): once again, the carbon donor is stable in solution, but sufficiently reactive in certain enzyme active sites to accomplish controlled transfer of a formate group.
Formation of formyl-\(THF\) and methylene-\(THF\)
Formyltetrahydrofolate (\(f-THF\)) is formed from \(THF\) and a formate molecule which has been activated by phosphorylation (formyl phosphate, as stated in the paragraph above, is a high reactive intermediate, but is held inside the enzyme's active site for immediate reaction with the incoming amine group of \(THF\)).
There are two main metabolic routes to \(CH_2-THF\). One route is just the last step of the serine hydroxymethyltransferase reaction we have already seen in section 17.1: the formaldehyde formed in the PLP-dependent phase of the reaction stays in the active site, and the oxygen is displaced by successive attacks from the amine nucleophiles at the 5 and 10 positions of \(THF\). (Notice the similarity to the formaldehyde-protein crosslinking reaction shown earlier in this section.)
In the second route, \(f-THF\) is dehydrated, then the resulting methenyl-\(THF\) intermediate is reduced by \(NADPH\).
Methylene-\(THF\) (\(CH_2-THF\)) is reduced to methyl-\(THF\) (\(CH_3-THF\)) in a flavin-dependent reaction. Biochemistry 2001, 40, 6216
Recall from the introduction to this chapter that babies who were in the womb during the Dutch Hunger Winter faced a higher risk, when they reached adulthood, of conditions such as obesity and schizophrenia, most likely caused by disruptions in the \(S\)-adenosylmethionine-dependent methylation of their DNA, which was in turn caused by their mothers not getting enough folate. \(CH_3-THF\) is the source of the methyl group in methionine, which ultimately becomes the methyl group in \(SAM\). The methylation of homocysteine to methionine (below) involves a cobalt-containing coenzyme called cobalamin, but the mechanism for this reaction is beyond the scope of our discussion. The second reaction below (formation of \(SAM\)) is simply an \(SN_2\) displacement of the inorganic triphosphate leaving group on ATP by the nucleophilic sulfur in methionine.
Single-carbon transfer with formyl-\(THF\)
There are two important \(f-THF\)-dependent formylation steps in the biosynthetic pathways for purine nucleophiles. Both are simply transamidation reactions: in other words, conversion by the nucleophilic acyl substitution mechanism (chapter 11) of one amide to another.
Glycinamide ribonucleotide transformylase reaction:
Aminoimidazole carboxamide transformylase reaction:
Exercise 17.5.1
Which of the two transformylase reactions above would you expect to be more kinetically favorable? Explain your reasoning.
Exercise 17.5.2
Predict the structure of 'product X' in the reaction below, from the histidine degradation pathway.
Single-carbon transfer with methylene-\(THF\)
\(CH_2-THF\) serves as a single-carbon donor in a somewhat complicated reaction in the biosynthesis of the DNA monomer doexythymidine monophosphate (\(dTMP\)).
The reactions begins with the five-membered ring of \(CH_2-THF\) breaking apart to create an imine intermediate (step 1 below). The imine becomes an electrophile in a conjugate addition step (section 13.4, steps 2-3 below). Note that after step 1, the second ring in the pterin system of the coenzyme is abbreviated for clarity.
Next, tetrahydrofolate is eliminated in an \(E1cb\) elimination mechanism (steps 4 and 5). Notice that this is where the single carbon is transferred from methyl-\(THF\) to dUMP.
The final step in the mechanism is where it gets really interesting: a hydride ion is transferred from the tetrahydrofolate coenzyme to the methylene (\(CH_2\)) group on the deoxynucleotide substrate. Essentially, this is a conjugated \(SN_2\) step with hydride as the nucleophile and the active site cysteine as the leaving group. | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/17%3A_The_Organic_Chemistry_of_Vitamins/17.05%3A_Folate.txt |
P17.1: Here is a chance to test your ability to recognize reactions catalyzed by enzymes using three coenzymes - thiamine diphosphate, pyridoxal phosphate, and folate - that we have studied in this chapter. For each generalized reaction, look carefully at the transformation that is taking place, and decide which of the three coenzymes is likely to be required. Then, draw the single mechanistic step by which the bond identified by an arrow is broken or formed. In the cases where a double bond is indicated, show the mechanistic step in which the s bond is formed. In each case, your drawing should include the structure of the reactive part of the coenzyme, and should clearly show the role it plays in catalyzing the mechanistic step you are drawing.
P17.2: The final step in the biosynthesis of the amino acid tryptophan is a PLP-dependent condensation between serine and indole, shown below (EC 4.2.1.20). The reaction mechanism involves steps that are familiar from this chapter, but also incorporates a reaction type we studied in chapter 14. Propose a mechanism.
P17.3: Draw a reasonable mechanism for the following reaction, identifying the species denoted by questions marks. (Biochemistry 2012, 51, 3059)
P17.4: Propose a mechanism for the reaction below, which is part of the anaerobic catabolism of alcohols in some species of bacteria. (ChemBioChem 2014, 15, 389)
P17.5: Identify cosubstrate A and propose a mechanism for the reaction shown below, which was reported to occur in the thermophilic bacterium Thermosporothrix hazakensis. (ChemBioChem 2014 15, 527).
P17.6: Propose a mechanism for each of the reactions below, being sure to show the role played by the coenzyme (you need to determine which coenzyme is needed in each case).
P17.7: Acetohydroxybutyrate is formed in a coenzyme-dependent reaction between pyruvate and a 4-carbon compound. What is a likely second substrate, coenzyme, and by-product (indicated below with a question mark)?
http://www.sciencedirect.com/science...67593105001043
P17.8: The 'benzoin condensation' reaction was discovered in the 19th century, and led eventually to a better understanding of $ThDP$-dependent reactions in the cell. In a traditional benzoin condensation reaction, cyanide ion (instead of ThDP) plays the role of electron acceptor. Enzyme-catalyzed benzoin condensation reactions are also known to occur in some bacteria: Pseudomonas fluorescens, for example, contains an enzyme that catalyzes the synthesis of (R)-benzoin.
1. Draw a mechanism for the enzyme-catalyzed ($ThDP$-dependent) benzoin condensation reaction.
2. Draw a mechanism for the cyanide-catalyzed benzoin condensation reaction (non-enzymatic, basic conditions).
3. The following $ThDP$-reaction was recently reported to be part of the biosynthetic pathway for clavulanic acid, a compound that inhibits the action of b-lactamases (b-lactamases are bacterial enzymes that hydrolyze penicillin-based antibiotic drugs, rendering them ineffective). As is typical for $ThDP$-dependent reactions, the first step is addition of the ylide form of the coenzyme to the substrate carbonyl. The next steps are (in order): dehydration, tautomerization, elimination of phosphate, conjugate addition of arginine, and finally hydrolytic cleavage of the coenzyme-product bond. Draw out a complete mechanism that corresponds to this description.
P17.9: Practice with PLP-dependent reactions:
1. Propose a mechanism for this reaction, which is part of the tryptophan degradation pathway (EC 3.7.1.3).
1. Propose a mechanism for the final step of the threonine biosynthesis pathway (EC 4.2.3.1).
1. Propose a mechanism for the reaction catalyzed by aspartate $\beta$-decarboxylase (EC 4.1.1.12), which converts aspartate to alanine in a PLP-dependent reaction.
2. Sphingolipids are a type of membrane lipid found in the membranes of all eukaryotic cells, and are most abundant in the cells of central the central nervous system. Synthesis of sphingolipids involves the PLP-dependent reaction below, catalyzed by serine palmitoyl transferase (EC 2.3.1.50). Propose a mechanism.
P17.10: As we saw in this chapter, PLP-dependent enzymes usually catalyze reactions involving amino acid substrates. Here is an exception, a PLP-dependent $\beta$-elimination reaction in the folate biosynthetic pathway (EC 4.1.3.38). Propose a mechanism for this reaction.
P17.11: The final step in the degradation pathway for the amino acid glycine (also known as the 'glycine cleavage system') is shown below. Propose a likely mechanism, given that evidence suggests that $CH_2NH_2^+$ is an intermediate.
P17.12: As we saw in chapter 15, the usual biochemical role of $NAD^+$ is to act as a hydride acceptor in dehydrogenation reactions. An exception is the reaction catalyzed by the histidine degradation pathway enzyme urocanase (EC 4.2.1.49).
In this reaction, $NAD^+$ acts as a catalytic, electron-sink coenzyme - it temporarily accepts electrons from a pi bond in the substrate, resulting in a covalent substrate-$NAD$ adduct. This allows a key isomerization step to occur on the substrate through a protonation-deprotonation mechanism, followed by addition of water, cleavage of the substrate-$NAD$ adduct to regenerate $NAD^+$, and finally tautomerization to the product. Propose a mechanism that fits this description, and involves the intermediate below.
Pathway prediction problems
P17.13: Propose a multistep pathway for each of the following transformations. All involve at least one step requiring PLP, $ThDP$, or folate.
1. Below is portion of the biosynthesis of a modified membrane lipid in Salmonella and other pathogenic bacteria. The modified membrane confers antibiotic resistance to the bacterium. Biochemistry 2014, 53, 796
1. Below is the biosynthetic pathway for phenethanol in yeast. Phenethanol, which has a rose scent, is commonly used as a fragrance - this pathway has been proposed as a potential 'green' enzymatic synthesis to replace the traditional industrial synthesis, which uses toxic reagents.
1. Below is an incomplete pathway diagram for the biosynthesis of the amino acid lysine, starting from aspartate. Fill in the missing steps and reactants/coenzymes to complete the diagram. The solid dot and dashed circle are provided to help you to trace two of the carbons from substrate to product.
1. Below is the second half of the tryptophan degradation pathway. Fill in the missing steps and reactants/coenzymes to complete the diagram.
1. Below is an incomplete pathway diagram for the biosynthesis of inosine monophosphate, a precursor to the nucleotides adenosine monophosphate ($AMP$) and guanosine monophosphate ($GMP$). Fill in missing steps and reactants/coenzymes to complete the diagram. Note that one enzymatic step is provided (this is a carboxylation reaction of a type that we have not studied).
1. We begin our study of organic chemistry with a story about a hot pepper eating contest in Wisconsin (see the introduction the Chapter 1), and a compound called capsaicin which causes the 'hot' in hot peppers. As our last problem, let's try to predict some of the key steps in the biosynthesis of capsaicin.
Phase 1:
Phase 2:
17.0S: 17.S: The Oganic Chemistry of Vitamins (Summary)
After completing this chapter, you should be able to:
• Understand how pyridoxal phosphate (PLP) acts as an 'electron sink' in a variety of reactions in amino acid metabolism.
• Recognize and draw mechanisms for PLP-dependent transformations of the following types:
• racemization
• decarboxylation
• transamination
• retroaldol cleavage
• retro-Claisen cleavage
• $\beta$-elimination
• $\beta$-substitution
• $\gamma$-elimination
• $\gamma$-substitution
• Recognize transformations - amino acid decarboxylation and transamination, for example - in which chemical steps occur that simply don't 'make sense' unless the electron sink role of PLP is taken into account.
• Understand how the orientation of the substrate in relation to the plane formed by the conjugated $\pi$ system of PLP is a major factor in catalysis of PLP-dependent reactions.
• Understand how thiamine diphosphate ($ThDP$) acts as an 'electron sink' in a variety of reactions in which a bond to a carbonyl carbon is broken, and how these steps do not 'make sense' unless the electron sink role of $ThDP$ is taken into account.
• Recognize transformations for which $ThDP$ is likely required, and be able to draw reasonable mechanisms for them.
• Understand how $ThDP$ acts in tandem with lipoamide, flavin, and nicotinamide in the reaction catalyzed by pyruvate dehydrogenase.
• Recognize folate in its various forms - $DHF$, $THF$, $f-THF$, $CH_2-THF$, and $CH_3-THF$ - functions in a variety of one-carbon transfer steps. Be able to recognize the oxidation state of the carbon being transferred in a folate-depenent step. | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/17%3A_The_Organic_Chemistry_of_Vitamins/17.0E%3A_17.E%3A_The_Oganic_Chemistry_of_Vitamins_%28Exercises%29.txt |
While Organic Chemistry With a Biological Emphasis is organized, like most sophomore-level organic chemistry texts, around a structural and mechanistic framework, students of biochemistry may often want to clarify the mechanism of an enzymatic reaction which they encounter when studying the central metabolic pathways. An excellent resource for this purpose is John McMurry's The Organic Chemistry of Biological Pathways (Roberts and Company, 2005), but also helpful will be this index of enzymatic reactions organized by pathway, with links to sections/problems in this text where the reaction mechanism is addressed. Sections/problems listed with an asterisk (*) do not discuss the exact reaction indicated, but do discuss a closely related reaction.
EC numbers are provided whenever possible, with links to the corresponding page in the BRENDA database of enzymes. Clicking on the 'reaction flask' icon on a BRENDA page brings up the reaction diagram.
NOTE: content below redirects to an older edition of the text, which differs from the current version in some content and organization.
Pathways
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Appendix I: Index of enzymatic reactions by pathway
Sections/problems listed with an asterisk (*) do not discuss the exact reaction indicated, but do discuss a closely related reaction.
Arginine (from glutamate via ornithine, urea cycle)
to arginine via urea cycle:
• Ornithine transcarbamylase (EC 2.1.3.3) Section 12.2A,B*
• Argininosuccinate synthetase (EC 6.3.4.5) Section 12.6, Section 14.1D
• Arginosuccinate lyase (EC 4.3.2.1) Section 14.1D
• Arginase (EC 3.5.3.1) P12.16
or, in bacteria:
Isoleucine, leucine, and valine (from pyruvate):
to isoleucine:
• Branched-chain-amino-acid aminotransferase (EC 2.6.1.42) Section 14.4E*
to valine:
• Valine—pyruvate aminotransferase (EC 2.6.1.66) Section 14.4E*
to leucine:
• 2-isopropylmalate synthase (EC 2.3.3.13) Section 13.3*
• Isopropylmalate isomerase (EC 4.2.1.33) P14.7
• 3-isopropylmalate dehydrogenase (EC 1.1.1.85) Section 16.4*
• Leucine aminotransferase (EC 2.6.1.6) Section 14.4E*
Aromatic amino acids
Erythrose-4-phosphate to chorismate:
• DAHP synthase (EC 2.5.1.54) Section 15.2C
• Dehydroquinate synthase (EC 4.2.3.4) C13.1, 14.1A
• Dehydroquinate dehydratase (EC 4.2.1.10) Section 14.1D
• Shikimate dehydrogenase (EC 1.1.1.25) Section 16.4*
• Shikimate kinase (EC 2.7.1.71) P10.2 Section 10.2*
• 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase (EC 2.5.1.19) Section 14.3B, Section 15.4
• Chorismate synthase (EC 4.2.3.5) Section 14.3B, Section 17.3C
chorismate to tryptophan:
• Anthranilate synthase (EC 4.1.3.27) P14.8a
• Anthranilate phosphoribosyltransferase (EC 2.4.2.18) Section 11.5*
• Phosphoribosyl anthranilate isomerase (EC 5.3.1.24) P11.12, P13.12
• Indole-3-glycerol phosphate synthase (EC 4.1.1.48) Section 15.5B
• Tryptophan synthase (EC 4.2.1.20) Section 13.3C, E13.7, Section 15.5B
chorismate to phenylalanine/tyrosine:
• Chorismate mutase (EC 5.4.99.5) Section 15.10
• Prephenate decarboxylase (EC 4.2.1.51) Section 14.3B
• Aromatic-amino-acid aminotransferase (EC 2.6.1.57) Section 14.4E*
• Tyrosine aminotransferase (EC 2.6.1.5) Section 14.4E*
Histidine
• ATP phosphoribosyltransferase (EC 2.4.2.17) Section 11.5*
• Phosphoribosyl-ATP diphosphatase (EC 3..6.1.31) Section 10.3*
• Phosphoribosyl-AMP cyclohydrolase (EC 3.5.4.19) P12.12
• 1-(5-phosphoribosyl)-5-[(5-phosphoribosylamino)methylideneamino]imidazole-4-carboxamide isomerase (EC 5.3.1.16) P14.8b
• Imidazole glycerol-phosphate synthase (no EC number assigned) Section 11.6*, C11.1
• Imidazoleglycerol-phosphate dehydratase (4.2.1.19) Section 14.3B
• Histidinol-phosphate transaminase (EC 2.6.1.9) Section 14.4E*
• Histidinol-phosphatase (EC 3.1.3.15) Section 10.3*
• Histidinol dehydrogenase (EC 1.1.1.23) Section 16.4D*
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/Appendix_I%3A_Index_of_enzymatic_reactions_by_pathway/Amino_acid_biosynthesis.txt |
Sections/problems listed with an asterisk (*) do not discuss the exact reaction indicated, but do discuss a closely related reaction.
• Transaminase (EC 2.6.1.1, EC 2.6.1.2) Section 14.4E
• Carbamoyl phosphate synthetase (EC 6.3.4.16) P12. 4
Urea cycle:
• Ornithine transcarbamylase (EC 2.1.3.3) Section 12.2A,B*
• Argininosuccinate synthetase (EC 6.3.4.5) Section 12.6, Section 14.1D
• Arginosuccinate lyase (EC 4.3.2.1) Section 14.1D
• Arginase (EC 3.5.3.1) P12.16
Glycine (glycine cleavage system)
• Glycine dehydrogenase (decarboxylating) (EC 1.4.4.2) P16.4b
• Aminomethyltransferase (EC 2.1.2.10) C11.5
Alanine (to pyruvate and glutamate):
• Alanine transaminase (EC 2.6.1.2) Section 14.4E
Serine
• (to pyruvate): Serine dehydratase (EC 4.3.1.17) Section 13.1B, Section 14.4F
• (to glycine): Serine hydroxymethyltransferase (EC 2.1.2.1) Section 11.6D, Section 14.4D
Cysteine (to pyruvate)
• Cysteine dioxygenase (EC 1.13.11.20) not covered
• Aspartate aminotransferase (2.6.1.1) Section 14.4E
Threonine
pathway 1 (to glycine and acetyl CoA):
• Threonine dehydrogenase (EC 1.1.1.103) Section 16.4D*
• Glycine C-acetyltransferase (EC 2.3.1.29) Section 14.4D
pathway 2 (to glycine and acetaldehyde):
• Threonine aldolase (EC 4.1.2.5) Section 14.4D*, P14.10a
pathway 3 (to succinyl-CoA via propionyl CoA):
• Threonine dehydratase (EC 4.3.1.19) P14.2
• 2-oxobutanoate dehydrogenase (EC 1.2.4.4) Section 16.12B*
• Propionyl-CoA carboxylase (EC 6.4.1.3) Section 13.5D*, P13.2*
• Methylmalonyl-CoA mutase (EC 5.4.99.2) not covered
Tryptophan (to glutaryl-CoA)
• Tryptophan 2,3-dioxygenase (EC 1.13.11.11) not covered
• Arylformamidase (EC 3.5.1.19) Chapter 12*
• Kynurenine 3-monooxygenase (EC 1.14.13.9) Section 16.10
• Kynurenimase (EC 3.7.1.3) P14.10b
• 3-hydroxyanthranilate 3,4-dioxygenase (EC 1.13.11.6) not covered
• Aminocarboxymuconate-semialdehyde decarboxylase (EC 4.1.1.45) Section 13.5C*, P13.5a
• 2-aminomuconate semialdehyde dehydrogenase (EC 1.2.1.32) Section 16.4D*, P16.2a
• 2-aminomuconate deaminase (EC 3.5.99.5) Section 11.6*, P11.1
• 2-oxoglutarate dehydrogenase (EC 1.2.4.2) Section 16.12B*
Asparagine (to aspartate)
• Asparaginase (EC 3.5.1.1) Chapter 12*
Aspartate
• (to oxaloacetate): Aspartate transaminase (EC 2.6.1.1) Section 14.4E
• (to fumarate): Aspartate-ammonia lyase (EC 4.3.1.1) P14.3
Glutamine (to glutamate)
• Glutaminase (EC 3.5.1.2) Chapter 12
Glutamate (to alpha-ketoglutarate):
• Glutamate dehydrogenase (EC 1.4.1.2) Section 16.4D
Arginine (to glutamate):
• Arginase (EC 3.5.3.1) P12.16b
• Ornithine transaminase (EC 2.6.1.13) Section 14.4E*
• Glutamate semialdehyde dehydrogenase (EC 1.2.1.41) Section 16.4D
Histidine (to glutamate):
• Histidine ammonia-lyase (EC 4.3.1.3) C14.5
• Urocanate hydratase (EC 4.2.1.49) C16.1
• Imidazolonepropionase (EC 3.5.2.7) Chapter 12*
• Formimidoylglutamase (EC 3.5.3.8) P11.13b
Valine, isoleucine, leucine:
• Branched chain amino acid transaminase (EC 2.6.1.42) Section 14.4E*
• Branched chain ketoacid dehydrogenase complex (EC 1.2.4.4) Section 16.12B*
• Acyl CoA dehydrogenase (eg. EC 1.3.99.13) Section 16.5C, Section 17.3C
valine (to succinyl CoA):
• Enoyl-CoA hydratase (EC 4.2.1.17) P16.9
• 3-hydroxyisobutyryl-CoA hydrolase (EC 3.1.2.4) P16.9
• 3-hydroxyisobutyrate dehydrogenase (EC 1.1.1.31) P16.9
• Methylmalonate-semialdehyde dehydrogenase (1.2.1.27) P16.9
• Propionyl-CoA carboxylase (EC 6.4.1.3) Section 13.5D*, P13.2*
• Methylmalonyl-CoA mutase (EC 5.4.99.2) not covered
isoleucine (to succinyl CoA and acetyl CoA):
• Enoyl-CoA hydratase (EC 4.2.1.17) P16.9
• Methyl-hydroxybutyryl CoA dehydrogenase (EC 1.1.1.178) Section 16.4*
• 3-ketoacyl-CoA thiolase (EC 2.3.1.16) Section 13.4B*
• Propionyl-CoA carboxylase (EC 6.4.1.3) Section 13.5D*, P13.2*
• Methylmalonyl-CoA mutase (EC 5.4.99.2) not covered
leucine (to acetyl CoA)
• Methylcrotonoyl-CoA carboxylase (EC 6.4.1.4) Section 13.5*
• Methylglutaconyl-CoA hydratase (EC 4.2.1.18) Section 14.1*
• Hydroxymethylglutaryl-CoA lyase (EC 4.1.3.4) Section 13.3C*
Methionine (to cysteine and succinyl-CoA):
• Methionine adenosyltransferase (EC 2.5.1.6) E9.1
• Methyltransferase (eg. 2.1.1.37) Section 9.1A
• Adenosylhomocysteinase (EC 3.3.1.1) Section 14.1A
• Cystathionine beta-synthase (EC 4.2.1.22) Section 14.4G*
• Cystathionine gamma-lyase (EC 4.4.1.1) Section 14.4G
• 2-oxobutanoate dehydrogenase (EC 1.2.4.4) Section 16.12B*
• Propionyl-CoA carboxylase (EC 6.4.1.3) Section 13.5D*, P13.2*
• Methylmalonyl-CoA mutase (EC 5.4.99.2) not covered
Lysine (to glutaryl-CoA)
• Saccharopine dehydrogenase (EC 1.5.1.8) P11.6, P16.7a
• Saccharopine reductase (EC 1.5.1.10) P11.7, P16.7b
• Aminoadipate-semialdehyde dehydrogenase (EC 1.2.1.31) Section 16.4D*
• 2-aminoadipate transaminase (EC2.6.1.39) Section 14.4E*
• 2-oxoglutarate dehydrogenase (EC 1.2.4.2) Section 16.12B*
Phenylalanine (to tyrosine):
• Phenylalanine hydroxylase (EC 1.14.16.1) not covered
Tyrosine (to fumarate and acetoacetate):
• Tyrosine transaminase (EC 2.6.1.5) Section 14.4E*
• 4-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27) not covered
• Homogentisate 1,2-dioxygenase (EC 1.13.11.5) not covered
• Maleylacetoacetate isomerase (EC 5.2.1.2) Section 14.2A*
• Fumarylacetoacetase (EC 3.7.1.2) Section 13.4B*
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/Appendix_I%3A_Index_of_enzymatic_reactions_by_pathway/Amino_acid_catabolism.txt |
Sections/problems listed with an asterisk (*) do not discuss the exact reaction indicated, but do discuss a closely related reaction.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Fatty acid metabolism
Sections/problems listed with an asterisk (*) do not discuss the exact reaction indicated, but do discuss a closely related reaction.
Fatty acid biosynthesis
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Glycolysis Gluconeogenesis Fermentation
Sections/problems listed with an asterisk (*) do not discuss the exact reaction indicated, but do discuss a closely related reaction.
Fermentation
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Isoprenoid biosynthesis
Sections/problems listed with an asterisk (*) do not discuss the exact reaction indicated, but do discuss a closely related reaction.
Synthesis of isopentenyl diphosphate building blocks
Mevalonate pathway
Deoxyxylulose phosphate pathway (bacteria, plant plastids)
Chain elongation and prenyl transfer
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Nucleoside biosynthesis
Sections/problems listed with an asterisk (*) do not discuss the exact reaction indicated, but do discuss a closely related reaction.
Uridine
• Carbamoyl phosphate synthase (EC 6.3.5.5) Section 12.2*
• Aspartate carbamoyltransferase (EC 2.1.3.2) Section 12.2*
• Dihydroorotase (EC 2.5.2.3) C12.4
• Dihydroorotate dehydrogenase (EC 1.3.3.1) P16.5
• Orotate phosphoribosyltransferase (EC 2.4.2.10) Section 10.2C
• Orotidine monophosphate decarboxylase (EC 4.1.1.23) C14.1
Thymine
• Thymidylate synthase (EC 2.1.1.45) C14.2
Deoxynucleotides
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Nucleotide catabolism
Sections/problems listed with an asterisk (*) do not discuss the exact reaction indicated, but do discuss a closely related reaction.
Cytidine (to uridine)
• Cytidine deaminase (EC 3.5.4.5) P11.4
Adenosine (to uric acid via xanthine)
• Adenosine deaminase (EC 3.5.4.4) P11.5
• Purine nucleoside phosphorylase (EC 2.4.2.1) Section 9.2*
• Xanthine oxidase (EC 1.17.1.4; EC 1.17.3.2) not discussed
Guanosine (to uric acid via xanthine)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Pentose Phosphate Pathway Calvin Cycle
Sections/problems listed with an asterisk (*) do not discuss the exact reaction indicated, but do discuss a closely related reaction.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Appendix II: Review of laboratory synthesis reactions
While the focus of this textbook is on organic reactions occuring in living cells, if you are a chemistry major, or are planning to take a standardized exam such as the MCAT, you will need to be familiar with a number of laboratory synthesis reactions. Here, we review the lab synthesis reactions covered in this text, which include most of the reactions typically covered in traditional organic texts. Click on the chapter/section number for direct links to the section where these reactions are introduced.
NOTE: content below redirects to an older edition of the text, which differs from the current version in some content and organization.
Section 8.5B:
alcohols converted into good leaving groups
Section 9.1B:
Williamson ether synthesis
alkyl halide must be methyl or primary to avoid competing elimination
Section 11.4B:
cyclic acetal ‘protects’ ketone/aldehyde group – stable to bases/nucleophiles
deprotect with aqueous acid
Section 12.2D:
activates carboxylic acids
acetic anhydride is a good acetyl group donor (activated acetic acid)
adds acetyl group to acohols, amines
Section 13.6A
goes through enamine intermediate
haloform reaction – also works with Br2, I2
Section 13.6B
Wittig reaction
Section 13.6C
Section 13.6D
Grignard reagent – carbon nucleophile
No acidic protons can be present (it’s a strong base)
Can also use R-Cl
Grignards add to esters, acid chlorides twice
organolithium – similar to Grignard
Gilman reagent
Gilman reagent will react with alkyl, vinyl halides as well as carbonyls
Gilman reagent will add once to acid chlorides to make a ketone
Section 14.2B
nucleophilic aromatic substitution
Section 14.3A
Hoffman elimination - least substituted alkene produced
Cope elimination
Section 15.2B
Section 15.2D
anti-Markovnikov addition of water to alkene. Notice syn addition!
method to protect alcohol – remove with H3O+
another alcohol protecting group: remove with F- ion
Section 15.6A:
watch out for the possibility of carbocation rearrangements!
watch out for the possibility of carbocation rearrangements!
ortho-para directing vs. meta-directing groups
Section 15.7A:
Markovnikov addition of water without possibility of carbocation shifting
Section 15.7C:
pinacol rearrangement
Hoffman rearrangement
Section 15.10:
Diels-Alder: cis/trans stereoselectivity
bicyclic Diels-Alder product - no stereoselectivity
Cope rearrangement
Claisen rearrangement
Section 16.11B:
Section 16.13A:
reduces aldehydes/ketones, but not carboxylic acid derivatives
reduces aldehydes, ketones, carboxylic acid derivatives
can reduce ester/amide to aldehyde (LiAlH4 can't do this)
Section 16.13B:
alkynes, aldehyde, ketones, nitro groups also reduced by H2/Pt (but not acid derivatives!)
alkyne to cis-alkene
alkyne to trans-alkene
Section 16.13C:
Section 16.13D:
primary alcohol to acid
secondary alcohol to ketone
oxidation at the benzylic position
Swern oxidation
abbreviated PCC
cis diols cleaved, not trans
KMnO4 also oxidizes primary alcohols and aldehydes to acids
Section 17.2B:
radical halogenation is regiospecific – depends on stablity of radical intermediate
NBS can be source of Br in radical halogenation reactions
regiospecificity: benzylic / allylic
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/Appendix_I%3A_Index_of_enzymatic_reactions_by_pathway/Citric_Acid_Cycle.txt |
These pages are under construction. A complete 2016 edition of Organic Chemistry With a Biological Emphasis is available here as a free PDF download.
Imagine that you are a biological chemist doing research on bacterial metabolism. You and your colleagues isolate an interesting biomolecule from a bacterial culture, then use mass spectrometry, NMR, and other analytical techniques to determine its structure. Using your 'toolbox' of known organic reaction types - nucleophilic substitution, phosphorylation, aldol additions, and so forth - can you figure out a chemically reasonable pathway by which your compound might be enzymatically synthesized from simple metabolic precursors? In other words, can you fill in the missing biochemical steps (or at least some of them) to come up with a potential new metabolic pathway, which can then be used a hypothesis for future experimental work to try to find and study the actual enzymes involved?
An actual example approximating this scenario is shown below. A complete biosynthetic pathway for isopentenyl diphosphate (IPP), the building block molecule for all isoprenoid compounds, has been known since the 1960's. This pathway, which begins with acetyl-CoA, was shown to be active in yeast, plants, and many other species including humans. However, researchers in the late 1980s uncovered evidence indicating that the known pathway is not present in bacteria, although they clearly use IPP as a building block molecule just as other forms of life do.
Over the next several years, the researchers conducted a number of experiments in which bacteria were grown on a medium containing glucose 'labeled' with the 13C isotope. With the results from these experiments, combined with their knowledge of common biological organic reaction types, the researchers were able to correctly predict that the bacterial pathway starts with two precursor molecules (pyruvate and glyceraldehyde phosphate instead of acetyl CoA) and they also correctly predicted the first two enzymatic steps of the newly discovered bacterial pathway. This accomplishment eventually led to elucidation of every step in the pathway, and isolation of the enzymes catalyzing them. (Biochem J. 1993, 295, 517; J. Am. Chem. Soc. 1996, 118, 2564; Lipids 2008, 43, 1095)
Why weren't they able to predict the whole pathway? It turns out that several of the later steps were somewhat unusual, unfamiliar reaction types - but discovery of these reactions hinged upon the correct prediction of the more familiar first two steps.
Multi-step transformation problems of this type offer an unparalleled opportunity to use our knowledge of biological organic chemistry combined with creative reasoning to solve challenging, relevant scientific puzzles. At this point in your organic chemistry career, you have not yet accumulated quite enough tools in your reaction toolbox to tackle most real-life biochemical pathway problems such as the one addressed above - but by the time we finish with oxidation and reduction chemistry in chapter 15, you will be able to recognize most of the reaction types that you will encounter in real metabolism, and will be challenged to predict some real pathways in the end-of-chapter problems.
You do, however, have right now enough of a bioorganic repertoire to begin to learn how multi-step pathway problems can be approached, using for practice some generalized, hypothetical examples in which the reaction types involved are limited to those with which you are already familiar.
Imagine that you want to figure out how an old-fashioned mechanical clock is put together. One way to do this is to start with a working clock, and take it apart piece-by-piece. Alternatively, one could start with all of the disassembled pieces, plus a lot of other small parts from different clocks, and try to figure out how to put together the specific clock you are interested in. Which approach is easier? The answer is intuitively obvious - it's usually easier to take things apart than to put them back together.
The same holds true for molecules. If we want to figure out the biosynthetic pathway by which a large, complex biomolecule might be made in a cell, it makes sense to start with the finished product and then mentally work backwards, taking it apart step-by-step using known, familiar reactions, until we get to simpler precursor molecules. Starting with a large collection of potential precursor molecules and trying to put the right ones together to make the target product would be a formidable task.
Retrosynthetic analysis - the concept of mentally dismantling a molecule step by step all the way back to smaller, simpler precursors using known reactions - is a powerful and widely-used intellectual tool first developed by synthetic organic chemists. The approach has also been adapted for use by biological chemists in efforts to predict pathways by which known biomolecules could be synthesized (or degraded) in living things.
In retrosynthesis, we think about a series of reactions in reverse. A backwards (retro) chemical step is symbolized by a 'thick' arrow, commonly referred to as a retrosynthetic arrow, and visually conveys the phrase 'can be formed from'.
Consider a simple, hypothetical example: starting with the target molecule below, can we come up with a chemically reasonable pathway starting from the precursors indicated?
A first step is to identify the relevant disconnection: a key bond (usually a carbon-carbon bond) that must be formed to make the target product from smaller precursors. We search our mental 'toolbox' of common biochemical reaction types, and remember that the only way we know of (so far!) to make a new carbon-carbon bond is through an aldol addition reaction, which takes place at an alpha-carbon. Therefore, we can make a likely disconnection next to the alpha-carbon in the target molecule.
Next, we need to recognize that the aldol addition reaction results in a beta-hydroxy ketone. But our target molecule is beta-methoxy ketone! Working backwards, we realize that the beta-methoxy group could be formed from beta-hydroxy group by a SAM methylation reaction. This is our first retrosynthetic (backwards) step.
The second retro step (aldol) accounts for the disconnection we recognized earlier, and leads to the two precursor molecules.
Now, consider the more involved (but still hypothetical) biochemical transformation below:
Often the best thing to do first in this type of problem is to count the carbons in the precursor compounds and product - this allows us to recognize when extra carbons on either side must at some point be accounted for in our solution. In this case, one carbon (labeled 'f'') has been gained in the form of a methyl ether in the product. This is easy to account for: we know that the coenzyme S-adenosyl methionine (SAM) often serves as the methyl group donor in enzymatic O- or N-methylation reactions. So, we can propose our first backwards (retro) step: the product as shown could be derived from SAM-dependent methylation of an alcohol group on a proposed intermediate I.
Retrosynthetic step 1:
How do we know that the methylation step occurs last? We don't - remember, we are proposing a potential pathway, so the best we can do is propose steps that make chemical sense, and which hopefully can be confirmed or invalidated later through actual experimentation. For now, we'll stick with our initial choice to make the methylation step the last one.
Now that we have accounted for the extra carbon, a key thing to recognize regarding the transformation in question is that two linear molecules are combining to form a cyclic product. Thus, two connections need to be made between reactants A and B, one to join the two, the other to close the circle. Our primary job in the retro direction, then, is to establish in the product the two points of disconnection: in other words, to find the two bonds in the product that need to be taken apart in our retrosynthetic analysis. Look closely at the product: what functional groups do you see? Hopefully, you can identify two alcohol groups, a methyl ether, and (critically) a cyclic hemiketal. We've already accounted for the methyl ether. Identifying the cyclic hemiketal is important because it allows us to make our next 'disconnection': we know how a hemiketal forms from a ketone and an alcohol, so we can mentally work backwards and predict the open-chain intermediate II that could cyclize to form our product.
Now, starting with the R1 group and working along the carbon chain, we can account for carbons a-e on the two precursors.
Thus, the next disconnection is between carbons b and c. Here's where our mastery of biological organic reactivity really comes into play: the OH at carbon c of intermediate II is in the beta position relative to carbonyl carbon a. Aldol addition reactions result in beta-hydroxy ketones or aldehydes. Therefore, we can work backward one more step and predict that our intermediate II was formed from an aldol addition reaction between intermediate III (as the nucleophile) and precursor molecule A (as the electrophile).
We are most of the way home - we have successfully accounted for given precursor A. Intermediate III, however, is not precursor B. What is different? Both III and B have a carbonyl and two alcohol groups, but the positioning is different: III is an aldehyde, while B is a ketone. Think back to earlier in this chapter: intermediate III could form from isomerization of the carbonyl group in compound B. We have now accounted for our second precursor - we are done!
In the forward direction, a complete pathway diagram can be written as follows:
A full 'retrosynthesis' diagram for this problem looks like this:
Practice problems for retrosynthesis/pathway prediction
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
INTERCHAPTER: Retrosynthetic analysis and metabolic pathway prediction
In the multi-step pathway prediction problems that you will be asked to solve below and in the remainder of this book, you will be instructed to present your solution in the form of a proposed 'forward' pathway diagram, showing the participation of all coenzymes and other species such as water. At first, we'll start with relatively simple, hypothetical (not real) biochemical transformations. As you learn more reaction types, the range and complexity of problems that you will be able to solve will expand correspondingly, and you will eventually be able to tackle real-life pathways.
For each transformation below, draw a pathway diagram illustrating a potential biosynthetic pathway. Indicate other molecules participating in the reaction but not shown below (eg. coenzymes, water, etc.). Each step should be recognizable as a reaction type that we have covered through the end of chapter 13. (Note - you are being asked to draw your pathways in the 'forward' direction, but you should attack each problem using a retrosynthetic analysis strategy).
1:
2:
3:
4:
5:
6:
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris) | textbooks/chem/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_v2.0_(Soderberg)/INTERCHAPTER%3A_Retrosynthetic_analysis_and_metabolic_pathway_prediction/Pathway_prediction_practice_problems.txt |
Structure & Bonding
• Electron Configurations of Atoms
• Chemical Bonding & Valence
• Charge Distribution in Molecules
• Practice Problems
• The Shape of Molecules
• Isomers
• Analysis of Molecular Formulas
• Resonance
• Atomic and Molecular Orbitals
• Practice Problems
02: Intermolecular Forces
Intermolecular Forces
• Boiling & Melting Points
• Hydrogen Bonding
• Crystalline Solids
• Water Solubility
• Practice Problems
03: Chemical Reactivity
Chemical Reactivity
• Reaction Classification
• By Structural Change
• By Reaction Type
• Acid-Base Reactions
• Oxidations & Reductions
• By Functional Group
• Reaction Variables
• Reactants & Reagents
• Product Selectivity
• Other Variables
• Reaction Rate
• Intermediates
• Reaction Energetics
• Bond Energy
• Electronic Effects
• Steric Effects
• Solvent Effects
• Reaction Mechanisms
• Curved Arrow Notation
• Reactive Intermediates
• Reaction Illustrations
• Nucleophilicity & Basicity
• Acid-Base Catalysis
• Practice Problems
07: Stereoisomers Part II
Stereoisomers Part II
• Chirality & Symmetry
• Symmetry Elements
• Enantiomorphism
• Optical Activity
• Configurational Nomenclature
• Compounds with Several Stereogenic Centers
• Stereogenic Nitrogen
• Fischer Projection Formulas
• Achiral Diastereomers
• Other Configurational Notations
• Resolution
• Conformational Enantiomorphism
• Practice Problems
08: Alkanes
• Combustion
• Halogenation of Alkanes
09: Alkenes
• Addition Reactions
• Addition of Strong Bronsted Acids
• Addition of Lewis Acids (Electrophilic Reagents)
• Rearrangement of Carbocations
• Stereoselectivity in Addition Reactions to Double Bonds
• Addition Reactions Initiated by Electrophilic Halogen
• Addition Reactions involving other Cyclic Onium Intermediates
• Brønsted Acid Additions
• Hydrogenation of Alkenes
• Oxidations
• Epoxidation
• Hydroxylation
• Oxidative Cleavage of Double Bonds
• Free Radical Reactions of Alkanes
• Addition of Radicals to Alkenes
• Allylic Substitution
• Dienes
• Addition Reactions
• Diels-Alder Cycloaddition
10: Alkynes
• Addition Reactions
• Addition Reactions by Elecrophilic Reagents
• Catalytic Hydrogenation
• Hydration & Tautomerism
• Hydroboration
• Nucleophilic Addition & Reduction
• Acidity of Terminal Alkynes
13: Ethers
Nomenclature
Preparation of Ethers
Reactions of Ethers
Acid Cleavage
Peroxide Formation
Epoxide Reactions
Practice Problems
14: Thiols and Sulfides
1. Nucleophilicity of Sulfur Compounds
Sulfur analogs of alcohols are called thiols or mercaptans, and ether analogs are called sulfides. The chemical behavior of thiols and sulfides contrasts with that of alcohols and ethers in some important ways. Since hydrogen sulfide (H2S) is a much stronger acid than water (by more than ten million fold), we expect, and find, thiols to be stronger acids than equivalent alcohols and phenols. Thiolate conjugate bases are easily formed, and have proven to be excellent nucleophiles in SN2 reactions of alkyl halides and tosylates.
R–S(–) Na(+) + (CH3)2CH–Br (CH3)2CH–S–R + Na(+) Br(–)
Although the basicity of ethers is roughly a hundred times greater than that of equivalent sulfides, the nucleophilicity of sulfur is much greater than that of oxygen, leading to a number of interesting and useful electrophilic substitutions of sulfur that are not normally observed for oxygen. Sulfides, for example, react with alkyl halides to give ternary sulfonium salts (equation # 1) in the same manner that 3º-amines are alkylated to quaternary ammonium salts. Although equivalent oxonium salts of ethers are known, they are only prepared under extreme conditions, and are exceptionally reactive. Remarkably, sulfoxides (equation # 2), sulfinate salts (# 3) and sulfite anion (# 4) also alkylate on sulfur, despite the partial negative formal charge on oxygen and partial positive charge on sulfur.
2. Oxidation States of Sulfur Compounds
Oxygen assumes only two oxidation states in its organic compounds (–1 in peroxides and –2 in other compounds). Sulfur, on the other hand, is found in oxidation states ranging from –2 to +6, as shown in the following table (some simple inorganic compounds are displayed in orange).
Try drawing Lewis-structures for the sulfur atoms in these compounds. If you restrict your formulas to valence shell electron octets, most of the higher oxidation states will have formal charge separation, as in equation 2 above. The formulas written here neutralize this charge separation by double bonding that expands the valence octet of sulfur. Indeed, the S=O double bonds do not consist of the customary σ & π-orbitals found in carbon double bonds. As a third row element, sulfur has five empty 3d-orbitals that may be used for p-d bonding in a fashion similar to p-p (π) bonding. In this way sulfur may expand an argon-like valence shell octet by two (e.g. sulfoxides) or four (e.g. sulfones) electrons. Sulfoxides have a fixed pyramidal shape (the sulfur non-bonding electron pair occupies one corner of a tetrahedron with sulfur at the center). Consequently, sulfoxides having two different alkyl or aryl substituents are chiral. Enantiomeric sulfoxides are stable and may be isolated.
Thiols also differ dramatically from alcohols in their oxidation chemistry. Oxidation of 1º and 2º-alcohols to aldehydes and ketones changes the oxidation state of carbon but not oxygen. Oxidation of thiols and other sulfur compounds changes the oxidation state of sulfur rather than carbon. We see some representative sulfur oxidations in the following examples. In the first case, mild oxidation converts thiols to disufides. An equivalent oxidation of alcohols to peroxides is not normally observed. The reasons for this different behavior are not hard to identify. The S–S single bond is nearly twice as strong as the O–O bond in peroxides, and the O–H bond is more than 25 kcal/mole stronger than an S–H bond. Thus, thermodynamics favors disulfide formation over peroxide.
Mild oxidation of disufides with chlorine gives alkylsulfenyl chlorides, but more vigorous oxidation forms sulfonic acids (2nd example). Finally, oxidation of sulfides with hydrogen peroxide (or peracids) leads first to sulfoxides and then to sulfones.
The nomenclature of sulfur compounds is generally straightforward. The prefix thio denotes replacement of a functional oxygen by sulfur. Thus, -SH is a thiol and C=S a thione. The prefix thia denotes replacement of a carbon atom in a chain or ring by sulfur, although a single ether-like sulfur is usually named as a sulfide. For example, C2H5SC3H7 is ethyl propyl sulfide and C2H5SCH2SC3H7 may be named 3,5-dithiaoctane. Sulfonates are sulfonate acid esters and sultones are the equivalent of lactones. Other names are noted in the table above.
15: Benzene and Derivatives
Electrophilic Substitution
A Substitution Mechanism
Reactions of Substituted Benzenes
Reaction Characteristics
Reactions of Disubstituted Rings
Reactions of Substituent Groups
Nucleophilic Substitution, Elimination & Addition Reactions
Practice Problems
16: Amines
Nomenclature & Structure
Properties of Amines
Boiling Point & Solubility
Basicity of Nitrogen Compounds
Acidity of Nitrogen Compounds
Important Reagent Bases
Reactions of Amines
Electrophilic Substitution at Nitrogen
Preparation of 1º-Amines
Preparation of 2º & 3º-Amines
Practice Problems
Reactions with Nitrous Acid
Reactions of Aryl Diazonium Intermediates
Elimination Reactions of Amines
Oxidation States of Nitrogen
Practice Problems
17: Phosphines
Phosphorus Analogs of Amines
18: Aldehydes and Ketones
Nomenclature of Aldehydes & Ketones
Occurrence of Aldehydes & Ketones
Natural Products
Synthetic Preparation
Properties of Aldehydes & Ketones
Reversible Addition Reactions
Hydration & Hemiacetal Formation
Acetal Formation
Imine Formation
Enamine Formation
Cyanohydrin Formation
Irreversible Addition Reactions
Complex Metal Hydrides
Organometallic Reagents
Carbonyl Group Modification
Wolff-Kishner Reduction
Clemmensen Reduction
Hydrogenolysis of Thioacetals
Oxidations
Reactions at the α-Carbon
Mechanism of Electrophilic α-Substitution
The Aldol Reaction
Ambident Enolate Anions
Alkylation of Enolate Anions
Practice Problems
19: Carboxylic Acids
Nomenclature of Carboxylic Acids
Natural Products
Related Derivatives
Physical Properties
Acidity
Preparation of Carboxylic Acids
Reactions of Carboxylic Acids
Salt Formation
Substitution of Hydroxyl Hydrogen
Substitution of the Hydroxyl Group
Reduction & Oxidation
Practice Problems
20: Carboxylic Derivatives
Physical Properties
Nomenclature
Reactions of Carboxylic Acid Derivatives
Acyl Group Substitution
Mechanism
Reduction
Catalytic Reduction
Metal Hydride Reduction
Diborane Reduction
Reaction with Organometallic Reagents
Practice Problems
Reactions at the α Carbon
Acidity of α C–H
The Claisen Condensation
Synthesis Applications
Practice Problems
21: Spectroscopy
Mass Spectrometry
Ultraviolet-Visible Spectroscopy
Infrared Spectroscopy
Nuclear Magnetic Resonance Spectroscopy | textbooks/chem/Organic_Chemistry/Book%3A_Virtual_Textbook_of_OChem_(Reusch)_UNDER_CONSTRUCTION/01%3A_Structure_and_Bonding.txt |
Carbohydrates
Lipids
Proteins and Amino Acids
Nucleic Acids
22: Biochemicals
The lipids are a large and diverse group of naturally occurring organic compounds that are related by their solubility in nonpolar organic solvents (e.g. ether, chloroform, acetone & benzene) and general insolubility in water. There is great structural variety among the lipids, as will be demonstrated in the following sections. You may click on a topic listed below, or proceed page by page.
Fatty Acids
The common feature of these lipids is that they are all esters of moderate to long chain fatty acids. Acid or base-catalyzed hydrolysis yields the component fatty acid, some examples of which are given in the following table, together with the alcohol component of the lipid. These long-chain carboxylic acids are generally referred to by their common names, which in most cases reflect their sources. Natural fatty acids may be saturated or unsaturated, and as the following data indicate, the saturated acids have higher melting points than unsaturated acids of corresponding size. The double bonds in the unsaturated compounds listed on the right are all cis (or Z).
Saturated
Formula
Common Name
Melting Point
CH3(CH2)10CO2H lauric acid 45 ºC
CH3(CH2)12CO2H myristic acid 55 ºC
CH3(CH2)14CO2H palmitic acid 63 ºC
CH3(CH2)16CO2H stearic acid 69 ºC
CH3(CH2)18CO2H arachidic acid 76 ºC
Unsaturated
Formula
Common Name
Melting Point
CH3(CH2)5CH=CH(CH2)7CO2H palmitoleic acid 0 ºC
CH3(CH2)7CH=CH(CH2)7CO2H oleic acid 13 ºC
CH3(CH2)4CH=CHCH2CH=CH(CH2)7CO2H linoleic acid -5 ºC
CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7CO2H linolenic acid -11 ºC
CH3(CH2)4(CH=CHCH2)4(CH2)2CO2H arachidonic acid -49 ºC
The higher melting points of the saturated fatty acids reflect the uniform rod-like shape of their molecules. The cis-double bond(s) in the unsaturated fatty acids introduce a kink in their shape, which makes it more difficult to pack their molecules together in a stable repeating array or crystalline lattice. The trans-double bond isomer of oleic acid, known as elaidic acid, has a linear shape and a melting point of 45 ºC (32 ºC higher than its cis isomer). The shapes of stearic and oleic acids are displayed in the models below. You may examine models of these compounds by clicking on the desired model picture.
stearic acid
oleic acid
Two polyunsaturated fatty acids, linoleic and linolenic, are designated "essential" because their absence in the human diet has been associated with health problems, such as scaley skin, stunted growth and increased dehydration. These acids are also precursors to the prostaglandins, a family of physiologically potent lipids present in minute amounts in most body tissues.
Because of their enhanced acidity, carboxylic acids react with bases to form ionic salts, as shown in the following equations. In the case of alkali metal hydroxides and simple amines (or ammonia) the resulting salts have pronounced ionic character and are usually soluble in water. Heavy metals such as silver, mercury and lead form salts having more covalent character (3rd example), and the water solubility is reduced, especially for acids composed of four or more carbon atoms.
RCO2H + NaHCO3 RCO2(–) Na(+) + CO2 + H2O
RCO2H + (CH3)3N: RCO2(–) (CH3)3NH(+)
RCO2H + AgOH RCO2δ(–) Agδ(+) + H2O
Unusual Fatty Acids: Nature has constructed a remarkable variety of fatty acid derivatives. To see some of these compounds Click Here.
Soaps and Detergents
Carboxylic acids and salts having alkyl chains longer than eight carbons exhibit unusual behavior in water due to the presence of both hydrophilic (CO2) and hydrophobic (alkyl) regions in the same molecule. Such molecules are termed amphiphilic (Gk. amphi = both) or amphipathic.
Fatty acids made up of ten or more carbon atoms are nearly insoluble in water, and because of their lower density, float on the surface when mixed with water. Unlike paraffin or other alkanes, which tend to puddle on the waters surface, these fatty acids spread evenly over an extended water surface, eventually forming a monomolecular layer in which the polar carboxyl groups are hydrogen bonded at the water interface, and the hydrocarbon chains are aligned together away from the water. This behavior is illustrated in the diagram on the right. Substances that accumulate at water surfaces and change the surface properties are called surfactants.
Alkali metal salts of fatty acids are more soluble in water than the acids themselves, and the amphiphilic character of these substances also make them strong surfactants. The most common examples of such compounds are soaps and detergents, four of which are shown below. Note that each of these molecules has a nonpolar hydrocarbon chain, the "tail", and a polar (often ionic) "head group". The use of such compounds as cleaning agents is facilitated by their surfactant character, which lowers the surface tension of water, allowing it to penetrate and wet a variety of materials.
Very small amounts of these surfactants dissolve in water to give a random dispersion of solute molecules. However, when the concentration is increased an interesting change occurs. The surfactant molecules reversibly assemble into polymolecular aggregates called micelles. By gathering the hydrophobic chains together in the center of the micelle, disruption of the hydrogen bonded structure of liquid water is minimized, and the polar head groups extend into the surrounding water where they participate in hydrogen bonding. These micelles are often spherical in shape, but may also assume cylindrical and branched forms, as illustrated on the right. Here the polar head group is designated by a blue circle, and the nonpolar tail is a zig-zag black line.
An animated display of micelle formation is presented below. Notice the brownish material in the center of the three-dimensional drawing on the left. This illustrates a second important factor contributing to the use of these amphiphiles as cleaning agents. Micelles are able to encapsulate nonpolar substances such as grease within their hydrophobic center, and thus solubilize it so it is removed with the wash water. Since the micelles of anionic amphiphiles have a negatively charged surface, they repel one another and the nonpolar dirt is effectively emulsified. To summarize, the presence of a soap or a detergent in water facilitates the wetting of all parts of the object to be cleaned, and removes water-insoluble dirt by incorporation in micelles. If the animation has stopped, it may be restarted by clicking on it.
The oldest amphiphilic cleaning agent known to humans is soap. Soap is manufactured by the base-catalyzed hydrolysis (saponification) of animal fat (see below). Before sodium hydroxide was commercially available, a boiling solution of potassium carbonate leached from wood ashes was used. Soft potassium soaps were then converted to the harder sodium soaps by washing with salt solution. The importance of soap to human civilization is documented by history, but some problems associated with its use have been recognized. One of these is caused by the weak acidity (pKaca. 4.9) of the fatty acids. Solutions of alkali metal soaps are slightly alkaline (pH 8 to 9) due to hydrolysis. If the pH of a soap solution is lowered by acidic contaminants, insoluble fatty acids precipitate and form a scum. A second problem is caused by the presence of calcium and magnesium salts in the water supply (hard water). These divalent cations cause aggregation of the micelles, which then deposit as a dirty scum.
These problems have been alleviated by the development of synthetic amphiphiles called detergents (or syndets). By using a much stronger acid for the polar head group, water solutions of the amphiphile are less sensitive to pH changes. Also the sulfonate functions used for virtually all anionic detergents confer greater solubility on micelles incorporating the alkaline earth cations found in hard water. Variations on the amphiphile theme have led to the development of other classes, such as the cationic and nonionic detergents shown above. Cationic detergents often exhibit germicidal properties, and their ability to change surface pH has made them useful as fabric softeners and hair conditioners. These versatile chemical "tools" have dramatically transformed the household and personal care cleaning product markets over the past fifty years.
Fats and Oils
The triesters of fatty acids with glycerol (1,2,3-trihydroxypropane) compose the class of lipids known as fats and oils. These triglycerides (or triacylglycerols) are found in both plants and animals, and compose one of the major food groups of our diet. Triglycerides that are solid or semisolid at room temperature are classified as fats, and occur predominantly in animals. Those triglycerides that are liquid are called oils and originate chiefly in plants, although triglycerides from fish are also largely oils. Some examples of the composition of triglycerides from various sources are given in the following table.
Saturated Acids (%)
Unsaturated Acids (%)
Source
C10
& less
C12
lauric
C14
myristic
C16
palmitic
C18
stearic
C18
oleic
C18
linoleic
C18
unsaturated
Animal Fats
butter 15 2 11 30 9 27 4 1
lard - - 1 27 15 48 6 2
human fat - 1 3 25 8 46 10 3
herring oil - - 7 12 1 2 20 52
Plant Oils
coconut - 50 18 8 2 6 1 -
corn - - 1 10 3 50 34 -
olive - - - 7 2 85 5 -
palm - - 2 41 5 43 7 -
peanut - - - 8 3 56 26 7
safflower - - - 3 3 19 76 -
As might be expected from the properties of the fatty acids, fats have a predominance of saturated fatty acids, and oils are composed largely of unsaturated acids. Thus, the melting points of triglycerides reflect their composition, as shown by the following examples. Natural mixed triglycerides have somewhat lower melting points, the melting point of lard being near 30 º C, whereas olive oil melts near -6 º C. Since fats are valued over oils by some Northern European and North American populations, vegetable oils are extensively converted to solid triglycerides (e.g. Crisco) by partial hydrogenation of their unsaturated components. Some of the remaining double bonds are isomerized (to trans) in this operation. These saturated and trans-fatty acid glycerides in the diet have been linked to long-term health issues such as atherosclerosis.
Triglycerides having three identical acyl chains, such as tristearin and triolein (above), are called "simple", while those composed of different acyl chains are called "mixed". If the acyl chains at the end hydroxyl groups (1 & 3) of glycerol are different, the center carbon becomes a chiral center and enantiomeric configurations must be recognized.
The hydrogenation of vegetable oils to produce semisolid products has had unintended consequences. Although the hydrogenation imparts desirable features such as spreadability, texture, "mouth feel," and increased shelf life to naturally liquid vegetable oils, it introduces some serious health problems. These occur when the cis-double bonds in the fatty acid chains are not completely saturated in the hydrogenation process. The catalysts used to effect the addition of hydrogen isomerize the remaining double bonds to their trans configuration. These unnatural trans-fats appear to to be associated with increased heart disease, cancer, diabetes and obesity, as well as immune response and reproductive problems.
Waxes
Waxes are esters of fatty acids with long chain monohydric alcohols (one hydroxyl group). Natural waxes are often mixtures of such esters, and may also contain hydrocarbons. The formulas for three well known waxes are given below, with the carboxylic acid moiety colored red and the alcohol colored blue.
spermaceti
beeswax
carnuba wax
CH3(CH2)14CO2-(CH2)15CH3
CH3(CH2)24CO2-(CH2)29CH3
CH3(CH2)30CO2-(CH2)33CH3
Waxes are widely distributed in nature. The leaves and fruits of many plants have waxy coatings, which may protect them from dehydration and small predators. The feathers of birds and the fur of some animals have similar coatings which serve as a water repellent. Carnuba wax is valued for its toughness and water resistance.
Phospholipids
Phospholipids are the main constituents of cell membranes. They resemble the triglycerides in being ester or amide derivatives of glycerol or sphingosine with fatty acids and phosphoric acid. The phosphate moiety of the resulting phosphatidic acid is further esterified with ethanolamine, choline or serine in the phospholipid itself. The following diagram shows the structures of some of these components. Clicking on the diagram will change it to display structures for two representative phospholipids. Note that the fatty acid components (R & R') may be saturated or unsaturated.
To see a model of a phospholipid Click Here.
As ionic amphiphiles, phospholipids aggregate or self-assemble when mixed with water, but in a different manner than the soaps and detergents. Because of the two pendant alkyl chains present in phospholipids and the unusual mixed charges in their head groups, micelle formation is unfavorable relative to a bilayer structure. If a phospholipid is smeared over a small hole in a thin piece of plastic immersed in water, a stable planar bilayer of phospholipid molecules is created at the hole. As shown in the following diagram, the polar head groups on the faces of the bilayer contact water, and the hydrophobic alkyl chains form a nonpolar interior. The phospholipid molecules can move about in their half the bilayer, but there is a significant energy barrier preventing migration to the other side of the bilayer. To see an enlarged segment of a phospholipid bilayer Click Here.
This bilayer membrane structure is also found in aggregate structures called liposomes. Liposomes are microscopic vesicles consisting of an aqueous core enclosed in one or more phospholipid layers. They are formed when phospholipids are vigorously mixed with water. Unlike micelles, liposomes have both aqueous interiors and exteriors.
A cell may be considered a very complex liposome. The bilayer membrane that separates the interior of a cell from the surrounding fluids is largely composed of phospholipids, but it incorporates many other components, such as cholesterol, that contribute to its structural integrity. Protein channels that permit the transport of various kinds of chemical species in and out of the cell are also important components of cell membranes. A very nice dynamic display of the gramicidin channel has been created by a collaboration of Canadian, French, Spanish and US scientists, and may be examined by Clicking Here.
The interior of a cell contains a variety of structures (organelles) that conduct chemical operations vital to the cells existence. Molecules bonded to the surfaces of cells serve to identify specific cells and facilitate interaction with external chemical entities. The sphingomyelins are also membrane lipids. They are the major component of the myelin sheath surrounding nerve fibers. Multiple Sclerosis is a devastating disease in which the myelin sheath is lost, causing eventual paralysis.
Prostaglandins Thromboxanes & Leukotrienes
The members of this group of structurally related natural hormones have an extraordinary range of biological effects. They can lower gastric secretions, stimulate uterine contractions, lower blood pressure, influence blood clotting and induce asthma-like allergic responses. Because their genesis in body tissues is tied to the metabolism of the essential fatty acid arachadonic acid (5,8,11,14-eicosatetraenoic acid) they are classified as eicosanoids. Many properties of the common drug aspirin result from its effect on the cascade of reactions associated with these hormones.
The metabolic pathways by which arachidonic acid is converted to the various eicosanoids are complex and will not be discussed here. A rough outline of some of the transformations that take place is provided below. It is helpful to view arachadonic acid in the coiled conformation shown in the shaded box.
Leukotriene A is a precursor to other leukotriene derivatives by epoxide opening reactions. The prostaglandins are given systematic names that reflect their structure. The initially formed peroxide PGH2 is a common intermediate to other prostaglandins, as well as thromboxanes such as TXA2. To see a model of prostaglandin PGE2 Click Here.
Terpenes
Compounds classified as terpenes constitute what is arguably the largest and most diverse class of natural products. A majority of these compounds are found only in plants, but some of the larger and more complex terpenes ( e.g. squalene & lanosterol ) occur in animals. Terpenes incorporating most of the common functional groups are known, so this does not provide a useful means of classification. Instead, the number and structural organization of carbons is a definitive characteristic. Terpenes may be considered to be made up of isoprene ( more accurately isopentane ) units, an empirical feature known as the isoprene rule. Because of this, terpenes usually have 5n carbon atoms ( n is an integer ), and are subdivided as follows:
Classification
Isoprene Units
Carbon Atoms
monoterpenes
1. 2
C10
sesquiterpenes
3 C15
diterpenes
4 C20
sesterterpenes
5 C25
triterpenes
6 C30
Isoprene itself, a C5H8 gaseous hydrocarbon, is emitted by the leaves of various plants as a natural byproduct of plant metabolism. Next to methane it is the most common volatile organic compound found in the atmosphere. Examples of C10 and higher terpenes, representing the four most common classes are shown in the following diagram. The initial display is of monoterpenes; larger terpenes will be shown by clicking the "Toggle Structures" button under the diagram. Most terpenes may be structurally dissected into isopentane segments. To see how this is done click directly on the structures in the diagram.
The isopentane units in most of these terpenes are easy to discern, and are defined by the shaded areas. In the case of the monoterpene camphor, the units overlap to such a degree it is easier to distinguish them by coloring the carbon chains. This is also done for alpha-pinene. In the case of the triterpene lanosterol we see an interesting deviation from the isoprene rule. This thirty carbon compound is clearly a terpene, and four of the six isopentane units can be identified. However, the ten carbons in center of the molecule cannot be dissected in this manner. Evidence exists that the two methyl groups circled in magenta and light blue have moved from their original isoprenoid locations (marked by small circles of the same color) to their present location. This rearrangement is described in the biosynthesis section. Similar alkyl group rearrangements account for other terpenes that do not strictly follow the isoprene rule.
To see a model of the monoterpene camphor Click Here.
Polymeric isoprenoid hydrocarbons have also been identified. Rubber is undoubtedly the best known and most widely used compound of this kind. It occurs as a colloidal suspension called latex in a number of plants, ranging from the dandelion to the rubber tree (Hevea brasiliensis). Rubber is a polyene, and exhibits all the expected reactions of the C=C function. Bromine, hydrogen chloride and hydrogen all add with a stoichiometry of one molar equivalent per isoprene unit. Ozonolysis of rubber generates a mixture of levulinic acid ( CH3COCH2CH2CO2H ) and the corresponding aldehyde. Pyrolysis of rubber produces the diene isoprene along with other products.
The double bonds in rubber all have a Z-configuration, which causes this macromolecule to adopt a kinked or coiled conformation. This is reflected in the physical properties of rubber. Despite its high molecular weight (about one million), crude latex rubber is a soft, sticky, elastic substance. Chemical modification of this material is normal for commercial applications. Gutta-percha (structure above) is a naturally occurring E-isomer of rubber. Here the hydrocarbon chains adopt a uniform zig-zag or rod like conformation, which produces a more rigid and tough substance. Uses of gutta-percha include electrical insulation and the covering of golf balls.
To see a model of the rubber chain Click Here.
Steroids
The important class of lipids called steroids are actually metabolic derivatives of terpenes, but they are customarily treated as a separate group. Steroids may be recognized by their tetracyclic skeleton, consisting of three fused six-membered and one five-membered ring, as shown in the diagram to the right. The four rings are designated A, B, C & D as noted, and the peculiar numbering of the ring carbon atoms (shown in red) is the result of an earlier misassignment of the structure. The substituents designated by R are often alkyl groups, but may also have functionality. The R group at the A:B ring fusion is most commonly methyl or hydrogen, that at the C:D fusion is usually methyl. The substituent at C-17 varies considerably, and is usually larger than methyl if it is not a functional group. The most common locations of functional groups are C-3, C-4, C-7, C-11, C-12 & C-17. Ring A is sometimes aromatic. Since a number of tetracyclic triterpenes also have this tetracyclic structure, it cannot be considered a unique identifier.
Steroids are widely distributed in animals, where they are associated with a number of physiological processes. Examples of some important steroids are shown in the following diagram. Different kinds of steroids will be displayed by clicking the "Toggle Structures" button under the diagram. Norethindrone is a synthetic steroid, all the other examples occur naturally. A common strategy in pharmaceutical chemistry is to take a natural compound, having certain desired biological properties together with undesired side effects, and to modify its structure to enhance the desired characteristics and diminish the undesired. This is sometimes accomplished by trial and error.
The generic steroid structure drawn above has seven chiral stereocenters (carbons 5, 8, 9, 10, 13, 14 & 17), which means that it may have as many as 128 stereoisomers. With the exception of C-5, natural steroids generally have a single common configuration. This is shown in the last of the toggled displays, along with the preferred conformations of the rings.
Chemical studies of the steroids were very important to our present understanding of the configurations and conformations of six-membered rings. Substituent groups at different sites on the tetracyclic skeleton will have axial or equatorial orientations that are fixed because of the rigid structure of the trans-fused rings. This fixed orientation influences chemical reactivity, largely due to the greater steric hindrance of axial groups versus their equatorial isomers. Thus an equatorial hydroxyl group is esterified more rapidly than its axial isomer.
To see a model of the steroid cholesterol Click Here.
It is instructive to examine a simple bicyclic system as a model for the fused rings of the steroid molecule. Decalin, short for decahydronaphthalene, exists as cis and trans isomers at the ring fusion carbon atoms. Planar representations of these isomers are drawn at the top of the following diagram, with corresponding conformational formulas displayed underneath. The numbering shown for the ring carbons follows IUPAC rules, and is different from the unusual numbering used for steroids. For purposes of discussion, the left ring is labeled A (colored blue) and the right ring B (colored red). In the conformational drawings the ring fusion and the angular hydrogens are black.
The trans-isomer is the easiest to describe because the fusion of the A & B rings creates a rigid, roughly planar, structure made up of two chair conformations. Each chair is fused to the other by equatorial bonds, leaving the angular hydrogens (Ha) axial to both rings. Note that the bonds directed above the plane of the two rings alternate from axial to equatorial and back if we proceed around the rings from C-1 to C-10 in numerical order. The bonds directed below the rings also alternate in a complementary fashion.
Conformational descriptions of cis- decalin are complicated by the fact that two energetically equivalent fusions of chair cyclohexanes are possible, and are in rapid equilibrium as the rings flip from one chair conformation to the other. In each of these all chair conformations the rings are fused by one axial and one equatorial bond, and the overall structure is bent at the ring fusion. In the conformer on the left, the red ring (B) is attached to the blue ring (A) by an axial bond to C-1 and an equatorial bond to C-6 (these terms refer to ring A substituents). In the conformer on the right, the carbon bond to C-1 is equatorial and the bond to C-6 is axial. Each of the angular hydrogens (Hae or Hea) is oriented axial to one of the rings and equatorial to the other. This relationship reverses when double ring flipping converts one cis-conformer into the other.
Cis-decalin is less stable than trans-decalin by about 2.7 kcal/mol (from heats of combustion and heats of isomerization data). This is due to steric crowding (hindrance) of the axial hydrogens in the concave region of both cis-conformers, as may be seen in the model display activated by the following button. This difference is roughly three times the energy of a gauche butane conformer relative to its anti conformer. Indeed three gauche butane interactions may be identified in each of the cis-decalin conformations, as will be displayed by clicking on the above conformational diagram. These gauche interactions are also shown in the model.
To see models of cis & trans-decalin Click Here.
Steroids in which rings A and B are fused cis, such as the example on the right, do not have the same conformational mobility exhibited by cis-decalin. The fusion of ring C to ring B in a trans configuration prevents ring B from undergoing a conformational flip to another chair form. If this were to occur, ring C would have to be attached to ring B by two adjacent axial bonds directed 180º apart. This is too great a distance to be bridged by the four carbon atoms making up ring C. Consequently, the steroid molecule is locked in the all chair conformation shown here. Of course, all these steroids and decalins may have one or more six-membered rings in a boat conformation. However the high energy of boat conformers relative to chairs would make such structures minor components in the overall ensemble of conformations available to these molecules.
Lipid Soluble Vitamins
The essential dietary substances called vitamins are commonly classified as "water soluble" or "fat soluble". Water soluble vitamins, such as vitamin C, are rapidly eliminated from the body and their dietary levels need to be relatively high. The recommended daily allotment (RDA) of vitamin C is 100 mg, and amounts as large as 2 to 3 g are taken by many people without adverse effects. The lipid soluble vitamins, shown in the diagram below, are not as easily eliminated and may accumulate to toxic levels if consumed in large quantity. The RDA for these vitamins are:
Vitamin A 800 μg ( upper limit ca. 3000 μg)
Vitamin D 5 to 10 μg ( upper limit ca. 2000 μg)
Vitamin E 15 mg ( upper limit ca. 1 g)
Vitamin K 110 μg ( upper limit not specified)
From this data it is clear that vitamins A and D, while essential to good health in proper amounts, can be very toxic. Vitamin D, for example, is used as a rat poison, and in equal weight is more than 100 times as poisonous as sodium cyanide.
From the structures shown here, it should be clear that these compounds have more than a solubility connection with lipids. Vitamins A is a terpene, and vitamins E and K have long terpene chains attached to an aromatic moiety. The structure of vitamin D can be described as a steroid in which ring B is cut open and the remaining three rings remain unchanged. The precursors of vitamins A and D have been identified as the tetraterpene beta-carotene and the steroid ergosterol, respectively. Structures for these will be displayed by clicking on the vitamin diagram above.
Biosynthesis
The complex organic compounds found in living organisms on this planet originate from photosynthesis, an endothermic reductive condensation of carbon dioxide requiring light energy and the pigment chlorophyll.
x CO2 + x H2O + energy CxH2xOx + x O2
The products of photosynthesis are a class of compounds called carbohydrates, the most common and important of which is glucose (C6H12O6). Subsequent reactions effect an oxidative cleavage of glucose to pyruvic acid (CH3COCO2H), and this in turn is transformed to the two-carbon building block, acetate. The multitude of lipid structures described here are constructed from acetate by enzymatic reactions that in many respects correspond to reactions used by chemists for laboratory syntheses of similar compounds. However, an important restriction is that the reagents and conditions must be compatible with the aqueous medium, neutral pH and moderate temperatures found in living cells. Consequently, the condensation, alkylation, oxidation and reduction reactions that accomplish the biosynthesis of lipids will not make use of the very strong bases, alkyl halides, chromate oxidants or metal hydride reducing agents that are employed in laboratory work.
1. Condensations
Claisen condensation of ethyl acetate (or other acetate esters) forms an acetoacetate ester, as illustrated by the top equation in the following diagram. Reduction, dehydration and further reduction of this product would yield an ester of butyric acid, the overall effect being the elongation of the acetate starting material by two carbons. In principle, repetition of this sequence would lead to longer chain acids, made up of an even number of carbon atoms. Since most of the common natural fatty acids have even numbers of carbon atoms, this is an attractive hypothesis for their biosynthesis.
Nature's solution to carrying out a Claisen-like condensation in a living cell is shown in the bottom equation of the diagram. Thioesters are more reactive as acceptor reactants than are ordinary esters, and preliminary conversion of acetate to malonate increases the donor reactivity of this species. The thiol portion of the thioester is usually a protein of some kind, with efficient acetyl transport occurring by way of acetyl coenzyme A. Depending on the enzymes involved, the condensation product may be reduced and then further elongated so as to produce fatty acids (as shown), or elongated by further condensations to polyketone intermediates that are precursors to a variety of natural phenolic compounds. Click on the diagram to see examples of polyketone condensations.
The reduction steps (designated by [H] in the equations) and the intervening dehydrations needed for fatty acid synthesis require unique coenzymes and phosphorylating reagents. The pyridine ring of nicotinamide adenine dinucleotide (NAD) and its 2'-phosphate derivative (NADP) function as hydride acceptors, and the corresponding reduced species (NADH & NADPH) as a hydride donors. Partial structures for these important redox reagents are shown on the right. Full structures may be seen by clicking on the partial formulas.
As noted earlier, the hydroxyl group is a poor anionic leaving group (hydroxide anion is a strong base). Phosphorylation converts a hydroxyl group into a phosphate (PO4) or pyrophosphate (P2O7) ester, making it a much better leaving group (the pKas at pH near 7 are 7.2 and 6.6 respectively). The chief biological phosphorylation reagents are phosphate derivatives of adenosine (a ribose compound). The strongest of these is the triphosphate ATP, with the diphosphate and monophosphate being less powerful. Formulas for these compounds may be seen by Clicking Here
The overall process of fatty acid synthesis is summarized for palmitic acid, CH3(CH2)14CO2H, in the following equation:
8 CH3CO-CoA + 14 NADPH + 14 H(+) + 7 ATP + H2O CH3(CH2)14CO2H + 8 CoA + 14 NADP(+) + 7 ADP + 7 H2PO4(–)
2. Alkylations
The branched chain and cyclic structures of the terpenes and steroids are constructed by sequential alkylation reactions of unsaturated isopentyl pyrophosphate units. As depicted in the following diagram, these 5-carbon reactants are made from three acetate units by way of an aldol-like addition of a malonate intermediate to acetoacetate. Selective hydrolysis and reduction gives a key intermediate called mevalonic acid. Phosphorylation and elimination of mevalonic acid then generate isopentenyl pyrophosphate, which is in equilibrium with its double bond isomer, dimethylallyl pyrophosphate. The allylic pyrophosphate group in the latter compound is reactive in enzymatically catalyzed alkylation reactions, such as the one drawn in the green box. This provides support for the empirical isoprene rule.
The simplest fashion in which isopentane units combine is termed "head-to-tail". This is the combination displayed in the green box, and these terms are further defined in the upper equation that will appear above on clicking the "Toggle Examples" button. Non head-to-tail coupling of isopentane units is also observed, as in the chrysanthemic acid construction shown in the second equation. A second click on the diagram displays the series of cation-like cyclizations and rearrangements, known as the Stork-Eschenmoser hypothesis, that have been identified in the biosynthesis of the triterpene lanosterol. Lanosterol is a precursor in the biosynthesis of steroids. This takes place by metabolic removal of three methyl groups and degradation of the side chain.
3. An Alternative Isoprenoid Synthesis
For many years, the mevalonic acid route to isopentenyl pyrophosphate was considered an exclusive biosynthetic pathway. Recently, an alternative reaction sequence, starting from pyruvic acid and glyceraldehyde-3-phosphate, has been identified (bottom equations in the following diagram). By labeling selective carbon atoms (colored red) these distinct paths are easily distinguished. The new, DXP (1-deoxyxylulose-5-phosphate) path is widespread in microorganisms and chloroplast terpenes. The rearrangement to 2-methylerythritol-4-phosphate is an extraordinary transformation. | textbooks/chem/Organic_Chemistry/Book%3A_Virtual_Textbook_of_OChem_(Reusch)_UNDER_CONSTRUCTION/22%3A_Biochemicals/22.1%3A_Lipids.txt |
https://www2.chemistry.msu.edu/facul...ionic.htm#rad1
24: Heterocycles
Heterocycles
25: Macromolecules
Macromolecules
26: Organometallic Chemistry
Organometallic Chemistry
27: Pericyclic Reactions
Pericyclic Reactions
28: Photochemistry
Photochemistry
29: Anionic Rearrangements
Anionic Rearrangements
30.1: Wagner-Meerwein Rearrangements
In the first half of the nineteenth century it was generally believed that reactions of organic compounds proceeded with minimal structural change. This tenet simplified the elucidation of the numerous substitution, addition and elimination reactions that characterized the behavior of common functional groups. However, subsequent discoveries showed that nature was not always so obliging, leaving chemists and chemistry students to grapple with the possibility of deep seated structural change occurring during certain reactions. A large number of these structural rearrangements are triggered by intermediates incorporating positively charged or electron deficient atoms, which in the case of carbon are carbocations. Two such examples, already noted, are the addition of HCl to 3,3-dimethyl-1-butene and forced hydrolysis of neopentyl bromide. This chapter will describe and discuss other cases of this intriguing group of transformations.
30: Cationic Rearrangements
The chemical behavior of neopentyl bromide, 2,2-dimethyl-1-bromopropane, is an instructive place to begin this discussion. The very low SN2 reactivity of this 1º-bromide was noted earlier, and explained by steric hindrance to the required 180º alignment of reacting orbitals. Under conditions that favor SN1 reactivity, such as solution in wet formic acid, neopentyl bromide reacts at roughly the same rate as ethyl bromide. Both of these compounds are 1º-alkyl halides, and for an SN1 reaction the rate determining step requires ionization to a 1º-carbocation. As noted in the carbocation stability order shown below, such carbocations are relatively unstable and are formed slowly. The product from ethyl bromide is ethanol, the simple and direct substitution product, but neopentyl bromide yields 2-methyl-2-butanol instead of the expected neopentyl alcohol. A change in the way the five carbon atoms in this product are bonded to each other has clearly taken place.
Carbocation
Stability
CH3(+) < CH3CH2(+) < (CH3)2CH(+) CH2=CH-CH2(+) < C6H5CH2(+) (CH3)3C(+)
Once formed, the ethyl cation can only be transformed by a substitution or elimination process. In the case of the neopentyl cation, however, the initially formed 1º-carbocation may be converted to a more stable 3º-carbocation by the 1,2-shift of an adjacent methyl group with its bonding electrons. A mechanism demonstrating such a rearrangement is shown below, and it explains the overall structural changes very nicely.
Increasing the stability of carbocation intermediates is not the only factor that leads to molecular rearrangement. If angle strain , torsional strain or steric crowding in the reactant structure may is relieved by an alkyl or aryl shift to a carbocation site, such a rearrangement is commonly observed. The following examples illustrate rearrangements induced by the strain in a small ring. Although a 3º-carbocation is initially formed, the angle and torsional strain of the four-membered ring is reduced by a methylene group shift resulting in ring expansion to a 2º-carbocation. Clicking on the equation diagram will display a mechanism for these transformations.
Following the ring expansion step other reactions may take place, depending on the conditions. In aqueous acid the rearranged 2º-carbocation may bond to a water nucleophile, producing a 2º-alcohol, lose a proton to water, giving 3,3-dimethylcyclopentene (not shown), or undergo a second rearrangement to a 3º-carbocation, which then forms 1,2-dimethylcyclopentene. Indeed, it is not uncommon to encounter sequences of rearrangements in more complex compounds, and these may produce products with structures remarkably different from that of the starting compound. The following equation shows one such reaction. A curved arrow representation of the five sequential ring expansion steps will be added to the equation by clicking on the diagram.
In the terminology of pericyclic reactions, 1,2-alkyl shifts of this kind are classified as [1,2]-sigmatropic shifts. Since this is a two-electron process (the 2 electrons in the relocated sigma bond), the rearrangement is predicted to be suprafacial. Considerable evidence supporting this conclusion has been obtained, as the following example shows. Protonation of the double bond gives a 3º-carbocation. An adjacent hydrogen atom (colored blue) shifts as a hydride moiety to create a new 3º-carbocation, which in turn induces the shift of a methyl group (colored green) with formation of yet another 3º-carbocation. This electrophilic center then bonds to the nucleophilic oxygen of the carboxylic acid function, releasing a catalytic proton to continue the process. Because of the fused polycyclic structure of this compound, the relative orientation of the migrating groups is easily determined, and is seen to be suprafacial. Rearrangements consisting of consecutive 1,2-shifts often take place in a concerted, and therefore stereospecific fashion; however, it must not be assumed that the group shifts are simultaneous. Each shift involves a separate transition state in which the positive charge is delocalized over the migration terminus, origin and migrating group.
Many of the most interesting rearrangements of this kind were discovered during structural studies of naturally occurring compounds. Among these the terpenes presented numerous remarkable reactions, and the names of two chemists who were instrumental in unraveling their complex transformations, H. Meerwein and G. Wagner, are permanently associated with these rearrangements. The addition of gaseous HCl to α-pinene proved particularly puzzling to these early chemists. Under ordinary conditions, this liquid component of turpentine gave a crystalline C10H17Cl compound, originally called "artificial camphor", now known as bornyl chloride. An unstable isomer, pinene hydrochloride, can be isolated under mild conditions, but it rapidly isomerizes to bornyl chloride. Treatment of bornyl chloride with base gave a crystalline isomer of pinene called camphene, together with small amounts of another unsaturated hydrocarbon (bornylene). Addition of HCl to camphene, in a similar fashion, initially produces an unstable chloride (camphene hydrochloride) which quickly isomerizes to isobornyl chloride, a stereoisomer of bornyl chloride. We now know that bornyl chloride and isobornyl chloride are endo / exo-2-chloro isomers of the 1,7,7-trimethylbicyclo[2.2.1]bicycloheptane system. Structural formulas for these compounds are drawn below, along with camphene, the rearranged elimination product.
Mechanisms for these rearrangements will be pictured by clicking on the above diagram. In the new display we see that both pinene and camphene form 3º-carbocations when the double bond is protonated. Rearrangement to a 2º-carbocation is favored by relief of small-ring strain in the case of pinene, and relief of steric congestion in the case of camphene. However, this is an oversimplification which ignores the fact that these reactions take place in nonpolar solvents, and are unlikely to involve discrete, unassociated carbocations. Some of the stereoelectronic effects that influence these reactions will be shown by clicking on the above diagram a second time. Structures for the initially formed unstable hydrochlorides of pinene and camphene are drawn on the left. Optimal orbital overlap of breaking and forming bonds requires rear-side approach of the shifting alkyl group to the site of the leaving chloride anion, in a manner similar to a SN2 reaction. The chloride anion is located on one side of the carbocation formed by the alkyl shift, and immediately bonds to that face of the tricoordinate carbon. In this view of these rearrangements, the chloride anion never escapes the attractive influence of its cationic partner, and the product stereoselectivity is understandable. Lewis acid catalysts (e.g. FeCl3) catalyze these rearrangements, and the product favored at equilibrium is bornyl chloride.
The rearrangement that occurs under base catalyzed elimination conditions reflects the eclipsed configuration of the two-carbon bridge bearing the chlorine atom. Because of this configuration, the anti-coplanar structure favored by the E2 transition state cannot be achieved. Syn elimination gives a small amount of bornylene, but rearrangement to a camphene precursor predominates. Repeated clicking on the above diagram will cycle the displays.
Yet another example of the remarkable acid-catalyzed rearrangements found to occur with terpenes was observed in a study of the sesquiterpene caryophyllene (from oil of cloves). Here it is evident that reactive sites may interact and form bonds from one side of a medium-sized ring to another side. The mechanisms for many such rearrangements have been, and still are studied with great interest. | textbooks/chem/Organic_Chemistry/Book%3A_Virtual_Textbook_of_OChem_(Reusch)_UNDER_CONSTRUCTION/23%3A_Free_Radicals.txt |
The pinacol rearrangement was the first molecular rearrangement identified as such by early chemists. The defining example of a pinacol rearrangement is shown in the following diagram. Pinacol itself is produced by magnesium reduction of acetone, probably by way of a ketyl intermediate. Since the diol is symmetrical, protonation and loss of water takes place with equal probability at either hydroxyl group. The resulting 3º-carbocation is relatively stable, and has been shown to return to pinacol by reaction in the presence of isotopically labeled water. A 1,2-methyl shift generates an even more stable carbocation in which the charge is delocalized by heteroatom resonance. Indeed, this new cation is simply the conjugate acid of the ketone pinacolone, which is the product of repeated rearrangements catalyzed by proton transfer. Each step in this rearrangement is potentially reversible, as demonstrated by the acid catalyzed dehydration of pinacolone (and pinacol) to 2,3-dimethyl-1,3-butadiene under vigorous conditions.
Many factors must be considered when analyzing the course of a pinacol rearrangement. These include:
Which hydroxyl group is lost as water? or Which intermediate carbocation is more stable?
What is the inherent shifting tendency (migratory aptitude) of different substituent groups?
What is the influence of steric hindrance and other strain factors on the rearrangement?
Are epoxides formed as intermediates in the pinacol rearrangement?
Does product stability govern the outcome of competing rearrangements?
Do the reaction conditions (i.e. type of acid, concentration, solvent and temperature) influence the course of rearrangement?
Virtually all of these factors have been shown to be important in one or more cases, and a full analysis of their complex interaction is beyond the scope of this text. Nevertheless, a few examples will be presented to demonstrate the general nature of this transformation, and to illustrate the action of some of the above factors. In the first reaction shown below, we see an example of kinetic versus thermodynamic product control. Under mild acid treatment, the diol rearranges rapidly to an aldehyde by way of a 1,2-hydrogen shift to the initially formed diphenyl 3º-carbocation. More vigorous acid treatment of the diol or the aldehyde generates the more stable phenyl ketone (conjugation of the phenyl and carbonyl groups). Mechanisms for this and the other reactions will be presented by clicking on the diagram. A pink colored arrow designates rearrangement; light blue arrows indicate epoxide ring closing or opening reactions. Repeated clicking toggles the reaction and mechanism displays.
The second example describes a similar reacting system, which provides additional information from stereochemical and isotopic labeling features. Loss of water from the 3º-carbinol site, followed by a reversible 1,2-hydride shift, generates the conjugate acid of the ketone product. At short reaction times, racemization of recovered diol starting material occurs at the same rate as rearrangement. A corresponding phenyl shift to the initially formed 3º-carbocation generates the aldehyde conjugate acid, and the aldehyde itself has been shown to isomerize to the same rearranged ketone under the conditions of this pinacol rearrangement. An isotopic carbon label (colored green) in either the diol or aldehyde is scrambled (colored brown) in the course of these reactions, suggesting an epoxide intermediate.
In reaction # 3 either the cis or trans diol may be used as a reactant. These isomers are rapidly interconverted under the rearrangement conditions, indicating that the initial water loss is reversible; a result confirmed by isotopic oxygen exchange. The clear preference for a methylene group shift versus a methyl group shift may reflect inherent migratory aptitudes, or possibly group configurations in the 3º-carbocation intermediate. In the conformation shown here both methyl and methylene groups may shift, or an epoxide ring may be formed reversibly. An alternative chair-like conformation having an equatorial methyl group should be more stable, but would not be suitable for a methyl shift. The predominant ring contraction is therefore understandable. Reaction # 4 is an unusual case in which a strained ring contracts to an even smaller ring. Phenyl groups generally have a high migratory aptitude, so the failure to obtain 2,2-diphenylcyclobutanone as a product might seem surprising. However, the carbocation resulting from a phenyl shift would be just as strained as its precursor; whereas the shift of a ring methylene group generates an unstrained cation stabilized by phenyl and oxygen substituents. Conjugative stabilization of the phenyl ketone and absence of sp2 hybridized carbon atoms in the small ring may also contribute to the stability of the observed product.
Finally, reaction # 5 clearly shows the influence of reaction conditions on product composition, but explaining the manner in which different conditions perturb the outcome is challenging. Treatment with cold sulfuric acid should produce the more stable diphenyl 3º-carbocation, and a methyl group shift would then lead to the observed product. The action of a Lewis acid in acetic anhydride, on the other hand, may selectively acetylate the less hindered dimethyl carbinol. In this event the acetate becomes the favored leaving group (presumably coordinated with acid), followed by a 1,2-phenyl shift. It is reported that the symmetrically substituted isomeric diol (drawn in the shaded box) rearranges exclusively by a methyl shift, but the configuration of the starting material was not stated (two diastereomers are possible).
Because of the influence of other factors (above), it has not been possible to determine an unambiguous migratory order for substituents in the pinacol rearrangement. However, some general trends are discernible. Benzopinacol, (C6H5)2C(OH)C(OH)(C6H5)2, undergoes rapid rearrangement to (C6H5)3CCOC6H5 under much milder conditions than required for pinacol. Indeed, it is often the case that phenyl or other aromatic substituents adjacent to a forming carbocation will facilitate that ionization in the course of their migration to the cationic site. In non-aromatic compounds of the type (CH3)2C(OH)C(OH)RCH3, migration of R increases in the manner R = CH3 < R = C2H5 << R = (CH3)3C. Since the shifting alkyl group must carry part of the overall positive charge, alkyl substitution should have a stabilizing influence on the rearrangement transition state. Finally, fluorine substitution, as in C6H5(CF3)C(OH)C(OH)(CF3)C6H5 renders the diol unreactive under acid catalyzed rearrangement conditions. Here, the powerful inductive withdrawal of electrons by fluorine inhibits positive charge formation. | textbooks/chem/Organic_Chemistry/Book%3A_Virtual_Textbook_of_OChem_(Reusch)_UNDER_CONSTRUCTION/30%3A_Cationic_Rearrangements/30.2%3A_Pinacol_Rearrangement.txt |
Ambiguity in determining the initial site of carbocation formation presented a problem in the analysis of many pinacol rearrangements. This uncertainty can be removed by nitrous acid deamination of the corresponding 1º-aminoalcohols, as shown in the following equation. Since this reaction is normally carried out under very mild conditions, the possibility that subsequent transformations may obscure the initial rearrangement is reduced considerably.
The Tiffeneau-Demjanov rearrangement is often used to transform a cyclic ketone into a homologue that is one ring size larger. Such an application, which proceeds by way of a cyanohydrin intermediate, is shown in the first example below. Cyclic ketones have two alpha-carbon atoms, each of which might shift to the nascent 1º-carbocation. If R = H in the case shown here, these two groups are identical and on shifting give the same product. If R = CH3, the 2º-alkyl group shifts preferentially, the chief product being 3-methylcyclohexanone; the 2-methyl isomer is a minor product. The second reaction is informative because it demonstrates that the chiral 2º-butyl group moves with retention of configuration.
The third example illustrates the importance of substrate configuration on the course of rearrangement. The initial stage of an aryl group shift to an adjacent carbocation site may be viewed as an intramolecular electrophilic substitution of the Friedel-Crafts type. Aryl ring approach from the side opposite to the departing nitrogen of the diazonium ion generates a phenonium ion intermediate (shown in brackets above), the structure of which is similar to a benzenonium ion. In these two examples, diastereomeric reactants lead preferentially to diastereomeric intermediates, even though the anisyl group has a much greater migratory aptitude than phenyl. Electron pair donation by the hydroxyl substituent then acts to open the three-membered ring of these intermediates, yielding the ketone products.
30.4: Anchimeric Assistance
When the solvolysis rates of alkyl halides and sulfonate esters are measured, some curious influences of neighboring substituents are observed. For example, ethyl chloride, neopentyl chloride (2,2-dimethylpropyl chloride) and 2,2,2-triphenylethyl chloride are all 1º-alkyl chlorides, which hydrolyze in wet formic acid to mixtures of alcohols and olefins (SN1 & E1 mechanisms). The reaction rates for ethyl chloride and neopentyl chloride are nearly identical, but the triphenyl compound reacts 60,000 times faster. Equations for the latter two solvolyses are shown in the following diagram. It is apparent that in both cases an initially formed 1º-carbocation has rearranged prior to product formation, as depicted by clicking on the diagram. However, the increased rate of the phenyl substituted compound is perplexing, especially in view of the greater electronegativity of phenyl groups relative to methyl (note that diphenylacetic acid is over nine times more acidic than isobutyric acid). To explain the unexpected reactivity of 2,2,2-triphenylethyl chloride it is proposed that the pi-electrons of a suitably oriented phenyl group assist the 1º-chloride ionization by bond formation from the side opposite the C-Cl bond, as shown by clicking on the diagram a second time. This intramolecular interaction corresponds to the last example in the previous section, and is similar to an intramolecular SN2 reaction. The resulting phenonium ion would immediately open to a 3º-carbocation, in which the assisting phenyl group has shifted to an adjacent position. In this manner a neighboring aromatic ring accelerates the rate-determining (endothermic) ionization step, an influence called anchimeric assistance (Greek: anchi = neighbor).
The following energy profiles for these reactions illustrate the sequence of events. Both reactions begin by an initial rate-determining ionization step, the transition state of which is colored pink. The activation energy for this step is larger for neopentyl chloride because it leads to a discrete 1º-carbocation. On the other hand, the ionization of triphenylethyl chloride proceeds with assistance from a neighboring phenyl group, and the resulting phenonium ion immediately opens to a very stable diphenyl 3º-carbocation. The second step in the neopentyl chloride solvolysis is a rapid rearrangement of the 1º-carbocation to an isomeric 3º-carbocation. The transition state for this rearrangement is colored green. In both cases, the 3º-carbocation intermediate finally disproportionates to a mixture of substitution and elimination products. The essential difference is that the ionization transition state for neopentyl chloride suffers all the disadvantages associated with the generation of a 1º-carbocation; whereas, the transition state for ionization of triphenylethyl chloride is lowered in energy by its phenonium-like character.
Anchimeric assistance not only manifests itself in enhancement of ionization, but also influences the stereochemical outcome of reactions. The acetolysis of diastereomeric 3-phenyl-2-butanol derivatives provides an example. This alcohol has two chiral centers, and therefore has four stereoisomers in the form of two pairs of enantiomers. The diastereomeric configurations are called erythro and threo, according to their correlation with the tetroses erythrose and threose. As a rule, erythro isomers may assume an eclipsed conformation in which identical or similar substituents on the two stereogenic sites eclipse each other. Threo isomers cannot assume such a conformation. In the following diagram, a tosylate derivative of one enantiomer of each diastereomer is drawn as a Fischer projection. These isomers were solvolyzed in hot acetic acid solution, buffered with sodium acetate, and the configurations of the resulting acetate esters were determined. As expected from a SN1 process, some E1 elimination product was also obtained. Remarkably, each diastereomer is converted to its equivalent diastereomeric acetate (retention of configuration). Furthermore,the erythro compound retains its enantiomeric purity; whereas the threo tosylate gives racemic acetate and is itself racemized during reaction. If an open carbocation intermediate were formed in these reactions, mixtures of erythro and threo acetates would be expected from both tosylates, but only trace amounts of the opposite diastereomer were found among the products.
By clicking on the diagram the controlling influence of phenyl group anchimeric assistance will be demonstrated. First, the molecule assumes a conformation in which the phenyl substituent is oriented anti to the tosylate group. Next, a pair of pi-electrons from the benzene ring bonds to C2 as the tosylate anion departs, generating a phenonium intermediate (in brackets). The intermediate from the erythro tosylate is chiral, but that from the threo tosylate is achiral (note the plane of symmetry bisecting the three-membered ring). In each case C2 & C3 are constitutionally equivalent, and nucleophilic attack by acetate anion takes place equally well at either position (green and light blue arrows). As a result of equal rates of product formation by acetate bonding to C2 & C3, the achiral threo intermediate yields a 50:50 (racemic) mixture of threo enantiomers: (2R,3S) from the blue arrows and (2S, 3R) from the green arrows. In contrast, acetate bonding to C2 & C3 of the erythro intermediate produces the same enantiomer of the erythro product (2S,3S). Since the initial ionization to phenonium intermediates is reversible, we are not surprised to find that unreacted erythro tosylate is unchanged; whereas, unreacted threo tosylate is racemized. | textbooks/chem/Organic_Chemistry/Book%3A_Virtual_Textbook_of_OChem_(Reusch)_UNDER_CONSTRUCTION/30%3A_Cationic_Rearrangements/30.3%3A_Tiffeneau-Demjanov_Rearrangement.txt |
5. Anchimeric Assistance by Other Neighboring Groups
The ability of the pi-electrons in a suitably oriented, neighboring benzene ring to facilitate C-X ionization, where X is a halogen or a sulfonate ester, was described in the previous section. Other aromatic rings, such as naphthalene, furan and thiophene, may function in a similar manner, as may the pi-electrons of double and triple bonds. The following diagram shows three examples of neighboring double bond interaction, the first being one of the most striking cases of anchimeric assistance on record. The use of dashed lines to show charge delocalization is a common practice. The text box below the diagram provides additional commentary concerning these examples.
Neighboring
Group
Double Bonds
Triple Bonds
Sulfur Atoms
Oxygen Atoms
Nitrogen Atoms
Examples of other neighboring group perturbations, including non-bonding electron pair assistance by neighboring sulfur, oxygen and nitrogen atoms will be displayed above by clicking the appropriate button under the diagram. The text box commentary will change to suit the examples. In most of the cases involving heteroatom assistance, an "onium" intermediate is formed, in which the heteroatom is charged. Adjacent halogen atoms may also stabilize carbocations, as noted earlier with respect to trans-anti additions to cyclic alkenes. Functional rearrangement by way of halonium intermediates has also been reported. For example, a chloroform solution of the diaxial 2-bromo-3-chlorosteroid, shown on the left below, spontaneously rearranges to the more stable diequatorial 2-chloro-3-bromo isomer drawn on the right. The rearrangement is reversible and proceeds by way of the cyclic bromonium ion written in brackets.
30.6: The Nonclassical Carbocation Hypothesis
The role of carbocation intermediates in many organic reactions is well established. Some, such as tert-butyl, are localized. Some,such as allyl and benzyl, are stabilized by conjugation to pi-electron systems. Some, as described above, are stabilized by bridging to neighboring nucleophiles. In all cases of anchimeric assistance described above, a charge delocalized or redistributed species is an intermediate on the reaction path. Such intermediates can be isolated in some cases, but they usually have only transitory existence. The rate acceleration of ionization is attributed to structural and energetic similarities of the transition states to the intermediates they produce (the Hammond postulate).
Anchimeric assistance is usually associated with one or more of the following observable characteristics.
Rate acceleration compared with similar reactions lacking assistance.
Stereoelectronic control that results in rate and product differences between stereoisomers.
Retention of configuration in substitution products.
Racemization of products (and often reactants) when a symmetrical bridged intermediate is involved.
Solvolysis of the exo and endo-2-norbornyl sulfonate esters disclosed differences that suggested anchimeric assistance for the exo-isomer. As shown in the following diagram, the rate of acetolysis of the exo-isomer is substantially faster than that of the endo-isomer, which reacts at a rate similar to the cyclohexyl derivative. The former substitution proceeds with complete retention of configuration and racemization; whereas the endo-isomer is substituted with inversion of configuration and retains a small degree of optical activity. The source of this assistance was proposed to be the electron pair of the C1 : C6 sigma bond, which is ideally oriented anti to the sulfonate leaving group. A sigma-delocalized ion (drawn in brackets), was proposed as an intermediate, displayed by clicking on the diagram. Since this bridged ion is symmetrical, formation of racemic acetate is expected. The term "nonclassical" was applied to this charge delocalized cation, inasmuch as it appeared to be unique.
By comparison, the endo-isomer ionizes to a classical 2º-carbocation, which is rapidly converted to the more stable nonclassical ion. Some acetate anion may bond to the 2º-carbocation before it changes, accounting for the residual optical activity in this reaction.
Not everyone was convinced by this interpretation of the evidence. The chief protagonists favoring the nonclassical view were S. Winstein and J. D. Roberts. The primary opposition came from H. C. Brown, who espoused a more conventional rationalization. Brown pointed out that the norbornyl compounds are better compared with cyclopentyl than with cyclohexyl analogs (eclipsing strain), and in such a comparison the endo isomer is abnormally slow, the exo isomer being only 14 times faster than cyclopentyl. The racemic product was explained by assuming the interconversion of enantiomeric classical carbocations was very rapid on the reaction time scale. Brown also noted that attachment of a stabilizing aryl substituent at C2 did not reduce the rate enhancement of exo-ionization or the preference for exo-product formation. Since these latter solvolyses proceed by way of a benzylic cation, sigma-bond assistance was assumed to be minimal. Consequently, rate enhancement and retention of configuration become less significant as nonclassical indicators. This latter experiment, in which the aryl substituent was p-anisyl (An), is depicted on the left side of the diagram below.
Despite Brown's damaging arguments, other experiments provided additional support for the nonclassical view. As shown on the right side of the diagram, electron withdrawing substituents on C6 (2R) retarded exo-reactivity more severely than endo-reactivity. A similar effect was noted for such substituents at C1 (1R). This influence is best explained by the nonclassical hypothesis, in which partial positive charge must be carried by C1, C2 & C6.
Interpretations of the considerable body of evidence amassed at this point may be summarized in the diagram on the right. In the first display, the nonclassical bridged cation is shown as a transition state for the interconversion of the classical carbocations. A relationship of this kind corresponds to the rearrangement of neopentyl chloride. A second possibility, presented by clicking on the diagram, has the nonclassical ion as a higher energy intermediate, linking the classical ions. Finally, by clicking on the diagram a second time, the possibility that the nonclassical ion represents the more stable intermediate is drawn.
By the mid 1960's chemical and nmr techniques had improved to a stage that allowed direct observation of carbocations in low nucleophilic, acidic solutions, often referred to as "super acids". Much of this work was conducted by George Olah (Nobel Prize, 1994), using mixed solvents composed of SbF5, SO2, SO2F2 & SO2FCl. At low temperatures, 1H and 13C nmr spectra of (CH3)3C(+) and (CH3)2CH(+) were obtained and interpreted. As anticipated, the charged tricoordinate carbon atom exhibited a 13C signal over 300ppm downfield from TMS. When similar nmr measurements were applied to the 2-norbornyl cation, a number of fast proton shifts were disclosed. These could be "frozen out" by working at low temperature, the 3,2-shift at -70º C and a faster 6,2-shift at -130º C. The resulting spectrum, which remained unchanged at temperatures as low as -160º C, had no low field signals near that expected for a classical 2º-carbocation, and was supportive of the nonclassical structure. Recently, a solid state 13C nmr spectra at 5º K proved consistent with the nonclassical ion. From these and other spectroscopic studies, the sigma-bridged nonclassical cation has been firmly identified as the more stable carbocation species having the 2-norbornyl structure. Further confirmation was provided in 2013 by researchers in Germany, employing careful X-ray crystallographic measurements of an annealed [C7H11]+[Al2Br7] salt at 40º K.
Are there other relatively stable nonclassical carbocations? Several that seem to fit this classification have been identified, but few have been as exhaustively studied as the 2-norbornyl. One of the best criteria for evaluating candidate ions is to establish whether one or more of the participating carbon atoms is hypervalent (has more than four coordinating groups). In the following diagram, the simplest hypervalent carbocation, methanonium, is drawn on the left in the gray shaded box. This ion is commonly seen in the mass spectrum of methane (gas phase), but decomposes in solution as a consequence of its extreme acidity. To its right are two larger non-classical ions, 2-norbornyl and 7-norbornenyl. A pentacoordinate carbon atom is identified in each case. Resonance contributors to these ions are shown to the right of the dashed bond representation, and in all the drawings the delocalized electron pair is colored blue. Finally, a broad overview of this classification, offered by Olah in his Nobel lecture, will be displayed by clicking on the diagram.
To see a model of the 2-norbornyl cation
. | textbooks/chem/Organic_Chemistry/Book%3A_Virtual_Textbook_of_OChem_(Reusch)_UNDER_CONSTRUCTION/30%3A_Cationic_Rearrangements/30.5%3A_Anchimeric_Assistance_by_Other_Neighboring_Groups.txt |
Protonation of the divalent oxygen atom of alcohols and ethers by strong acids produces a tricoordinate oxonium cation. Because the oxygen of an oxonium ion has a valence shell octet, it does not constitute an electron deficient site and cannot serve as a rearrangement terminus. To induce rearrangement in the same manner as a tricoordinate carbocation, oxygen must be converted to a unicoordinate oxacation, as noted in the following diagram. A 1,2-alkyl or aryl shift then transforms a relatively unstable oxacation into a more stable carbocation.
The simplest precursor of an oxa cation is a peroxide or equivalent derivative (e.g. R-O-OH or R-O-X). Removal of hydroxide anion from a hydroperoxide is energetically unfavorable, unless it is initially converted to a better leaving group in a manner similar to that used to facilitate substitution reactions of alcohols. By protonating the hydroxyl group, the leaving group becomes water, thus generating an oxacation. A useful industrial procedure for preparing phenol (and acetone) is based on this strategy.
Baeyer-Villiger Rearrangement
The acid-catalyzed reaction of ketones with hydroperoxide derivatives is known as the Baeyer-Villiger reaction. A general equation illustrating this oxidation reaction is shown below, and it may be noted that the rearrangement step is similar to that of a pinacol rearrangement. Esters or lactones are the chief products from ketone reactants. In this equation a discrete oxacation is drawn as an intermediate, but it is more likely that the rearrangement is concerted, as will be shown by clicking on the equation. Once the peracid has added to the carbonyl group, the rearrangement may be facilitated by an intramolecular hydrogen bond, in the manner depicted in brackets on the right.
The migratory aptitude of various substituent groups (e.g. 1R & 2R) is generally: 3º-alkyl > 2º-alkyl ~ benzyl ~ phenyl > 1º-alkyl > methyl. Stereoelectronic factors favor an anti-periplanar orientation of the migrating group to the leaving moiety, and will control the rearrangement in some cases. An example will be displayed below on clicking the display a second time. Peracid exchange with peracetic acid leads to an intramolecular Baeyer-Villiger reaction by way of the bicyclic acylperoxide drawn in brackets. Here stereoelectronics favor migration of the less substituted α-carbon. The lactone product was identified by esterification and ester exchange with methanol to give methyl 2-carbomethoxy-7-hydroxyheptanoate.
Aldehydes are usually oxidized to carboxylic acids under the conditions used for the Baeyer-Villiger reaction.
Although hydrogen peroxide itself may be used in the Bayer-Villiger reaction, it may add at both ends to reactive carbonyl groups, producing cyclic dimeric, trimeric and higher addition compounds. Consequently, derivatives such as peracids (Z = RCO & ArCO above) are the preferred reagents for this reaction. Among the most common peracids used in this respect are: peracetic acid, perbenzoic acid & meta-chloroperbenzoic acid (MCPBA). Four examples of this oxidative rearrangement are given in the following diagram. In most of these examples the migrating group retains its configuration in the course of the rearrangement, as expected for a concerted process. In example #3 it is interesting that migration of the bridgehead 3º-alkyl group is preferred over a possible phenyl shift. | textbooks/chem/Organic_Chemistry/Book%3A_Virtual_Textbook_of_OChem_(Reusch)_UNDER_CONSTRUCTION/30%3A_Cationic_Rearrangements/30.7%3A_Rearrangements_of_Cationic_Oxygen.txt |
Since many simple nitrogen compounds are bases, they form "onium" cations when protonated. Two such cations are shown on the left (in the blue box) below. Because ammonium and iminium cations have a nitrogen valence shell electron octet, such a nitrogen atom cannot serve as a site for nucleophile bonding or a migration terminus. For a nitrogen cation to initiate rearrangement it must have an unfilled valence shell, and two such azacations are shown in the center of the diagram (pink box). An electron deficient nitrogen atom does not have to be a cation, as the nitrene example on the right (green box) demonstrates.
The Beckmann Rearrangement
If the hydroxyl group of a ketoxime is removed by the action of strong acid or phosphorous pentachloride, followed by hydrolysis, an amide is formed. Complete removal of the derivatized hydroxyl group and its bonding electron pair would generate a divalent sp-hybridized azacation of the type depicted in the previous diagram. Were this to occur, both carbon substituents (1R & 2R) would be candidates for the subsequent 1,2-shift. In practice, however, it is always the group anti to the departing OH that migrates to nitrogen. This stereospecificity indicates that the 1,2-shift is concerted with N-O cleavage, as shown below. The resulting N-alkylated nitrilium intermediate will react with nucleophiles (e.g. water) at the electrophilic carbon atom adjacent to the "onium" nitrogen. Note that the structure drawn for this intermediate is the more favored of two resonance contributors, inasmuch as all heavy atoms have filled valence shell octets. Bonding of a nucleophile to the nitrogen atom would require expanding its valence shell to include ten electrons, or formation of an unstable dipolar species. The initial product from hydration at carbon is an iminol, which immediately tautomerizes to the more stable amide. Reactions with PCl5 probably give an iminochloride, and this in turn is hydrolyzed to the same amide.
The first example in the following group of reactions is a typical Beckmann rearrangement. The oxime from cyclohexanone has identical carbonyl substituents. and therefore exists as a single isomer. The product of the rearrangement is a lactam (a cyclic amide), which can be hydrolyzed to an omega-amino acid. This lactam serves as an important industrial precursor to nylon 6. The second example involves an oxime derivative with different carbonyl substituents, which exists as a pair of stereoisomers (syn & anti). The anti isomer rearranges by a 1,2-phenyl shift, whereas the syn isomer undergoes a 1,2-isopropyl shift. The former reaction is much faster than the latter, presumably because it proceeds by way of a relatively stable phenonium ion intermediate (structure in shaded box). Note that the picrate leaving group (2,4,6-trinitrophenolate) is a stable anion. Example #3 is another case that demonstrates the stereospecificity of the Beckmann rearrangement. The 1,2-shift of the ortho-phenol substituent is faster than that of the unsubstituted phenyl group, and the hydroxyl is ideally located to bond to the electrophilic carbon of the intermediate. Consequently, the product from the anti isomer is a benzoxazole heterocycle.
The fourth example above shows an unusual divergence in behavior that sometimes occurs when the migrating substituent fragments from the intermediate, leaving a nitrile as a stable product. This has been called an abnormal Beckmann reaction.
The rigid configuration of the phenonium cation shown above imposes a structural constraint that is nicely demonstrated by the rates of rearrangement of some fused ring bicyclic compounds. Clicking on the diagram will show the results of such a study. Oxime derivatives of phenyl ketones incorporated in six, seven and eight-membered fused rings were studied. Because of the carbon chain joining the oxime function to the ortho-carbon of the benzene ring, the phenonium ion that normally facilitates phenyl migration may be unable to assume its preferred structure (three-membered ring orthogonal to the phenyl ring). The three-carbon bridging chain for n = 6 is such a case, and rearrangement of the anti isomer is very slow. As the length of the bridging chain increases, its constraint is less severe, and the rate of rearrangement increases. The eight-membered oxime picrate hydrolyzes rapidly, producing a nine-membered lactam in high yield.
R2C=N-NH2 + HNO2 RCONHR + N2
Beckmann type rearrangements may also be carried out by treating hydrazones with nitrous acid, as shown on the right. As a rule, this is a less desirable procedure because pure hydrazones are more difficult to acquire, and the yield of pure product is inferior.
A direct rearrangement of ketones, thereby avoiding the necessity of preparing an derivative, is possible by a procedure known as the Schmidt rearrangement. Acid-catalyzed addition of hydrazoic acid to the carbonyl group of a ketone creates an unstable azidocarbinol that, on dehydration, produces the same triazonium cation presumably formed as an intermediate in the nitrous acid deamination of a hydrazone. Rearrangement of this species by rapid nitrogen loss then initiates a Beckmann-like rearrangement. By clicking the upper diagram a second time, two examples of the Schmidt rearrangement will be presented.
The Stieglitz Rearrangement
Examples of rearrangements to sp2 hybridized azacations are relatively rare compared with their carbon analogs. The starting materials for generating such azacations are usually chloramines or hydroxyl amines. Four examples of these transformations, sometimes called "Stieglitz rearrangements", are shown below. The first example is similar to a Wagner-Meerwein rearrangement, and the second to a pinacol rearrangement. Competitive shifts of para-substituted phenyl groups in reactions similar to example #3, demonstrate that a methoxy substituent facilitates rearrangement, whereas a nitro substituent retards it. In the last example, a conjugated azacation activates the benzene ring to nucleophilic substitution, in contrast to the usual role played by amine substituents.
Rearrangement of Acyl Nitrenes to Isocyanates
Several useful and general procedures for degrading carboxylic acid derivatives to amines all involve the rearrangement of an acyl nitrene to an isocyanate. Although the nitrogen atom of a nitrene has no formal charge, it is electron deficient and serves as a locus for 1,2-rearrangements. As illustrated in the following diagram, acyl nitrenes may be generated from different amide-like starting compounds. Once formed, acyl nitrenes quickly rearrange to relatively stable isocyanate isomers, which may be isolated or reacted with hydroxylic solvents. The most common application of this rearrangement is for the synthesis of amines. Thus, addition of water to the ketene-like isocyanates produces an unstable carbamic acid that decomposes to an amine and carbon dioxide. General procedures for obtaining the nitrene precursors are listed below the diagram.
• Hofmann Route: Primary amides are converted to N-halogenated derivatives by the action of HOX or X2 in alkaline solution. Excess base generates a conjugate base of the product.
• Lossen Route: A hydroxamic acid derivative (RCONHOH) is made by reacting an ester with hydroxyl amine. The hydroxamic acid is O-acylated and then converted to its conjugate base.
• Curtius Route: An acyl azide (RCON3) is prepared in one of two ways. (i) Reaction of an acyl chloride with sodium azide, or (ii) Reaction of an ester with excess hydrazine, followed by reaction of the acylhydrazide product (RCONHNH2) with cold nitrous acid. Acyl azides decompose to isocyanates on heating.
• Schmidt Route: A variant of the Curtius procedure in which a carboxylic acid is heated with hydrazoic acid (HN3) and an acid catalyst.
Some examples of these different rearrangements are shown in the following diagram. In each case a green capitol letter (C, H, L or S) designates the type of reaction. The first three reactions illustrate the Hofmann rearrangement, which is a particularly useful method for preparing amines. The last example shows a Curtius reaction applied to a diester by way of an intermediate bis-acylhydrazide. An alternative Curtius approach to the amine product of example # 2 is also shown. The Curtius procedure is particularly useful if the isocyanate is the desired product, since the decomposition of the acyl azide intermediate can be conducted in the absence of hydroxylic solvents that would react with the isocyanate.
Five more examples will be displayed above by clicking on the diagram. Example # 5 shows a Schmidt reaction in which an optically active carboxylic acid is the substrate. The S-configuration of the migrating phenethyl group is retained in the amine product, confirming the intramolecular character of these rearrangements. Retention of configuration is also observed in Curtius, Lossen and Hofmann rearrangements of this kind. Reactions # 6 & # 7 are interesting cases in which water is absent during the formation and reaction of the isocyanate. The alcohol solvent in # 6 adds to the isocyanate to produce a carbamate ester, known as a urethane. Unlike the unstable carbamic acids, urethanes do not decompose and may be isolated as pure compounds. If water had been the solvent, the resulting 1º-enamine would have rearranged to an imine and hydrolyzed to an aldehyde. In the Lossen rearrangement (# 7) butyl amine adds to the isocyanate to give a substituted urea (urea is NH2CONH2).
The Hofmann rearrangement in reaction # 8 provides a novel example of the tautomerism of an acetylenic 1º-amine to a nitrile. Finally, the last example illustrates a selective Hofmann rearrangement of a bromo-imide. The reactivity of the carbonyl group para to the electron withdrawing nitro substituent is increased relative to the other imide carbonyl. Consequently, base-catalyzed hydrolysis takes place there preferentially, leaving the acyl nitrene moiety meta to the nitro function. | textbooks/chem/Organic_Chemistry/Book%3A_Virtual_Textbook_of_OChem_(Reusch)_UNDER_CONSTRUCTION/30%3A_Cationic_Rearrangements/30.8%3A_Rearrangements_of_Cationic_or_Electron_Deficient_Nitrogen.txt |
1. The Arndt-Eistert Reaction
The rearrangement of acyl nitrenes to isocyanates that is the crux of the Hofmann, Curtius and Lossen rearrangements, is paralleled by the rearrangement of acyl carbenes to ketenes, a transformation called the Wolff rearrangement. This rearrangement is a critical step in the Arndt-Eistert procedure for elongating a carboxylic acid by a single methylene unit, as described in the diagram below. The starting acid, written on the left, is converted first to an acyl chloride derivative, and then to a diazomethyl ketone. Diazomethane has a nucleophilic methylene group, as indicated by the resonance formulas drawn in the shaded box. Acylation of the methylene carbon produces an equilibrium mixture of a diazonium species and the diazomethyl ketone plus hydrogen chloride (written in brackets). If the HCl is not neutralized by a base, this mixture reacts further to give a chloromethyl ketone with loss of nitrogen. However, if the HCl is neutralized as it is formed, the relatively stable diazo ketone is obtained and may be used in subsequent reactions.
Since diazomethane itself may function as a base, the course of a given reaction is established by the manner in which the reactants are combined. When an ether solution of diazomethane is slowly added to a warm solution of the acid chloride, nitrogen evolution is observed and the chloromethyl ketone is the chief product. One equivalent of diazomethane is required for this reaction. If the addition is reversed, so that a cold solution of the acid chloride is added slowly to an excess of diazomethane in cold ether solution, nitrogen evolution is again observed; but two equivalents of diazomethane are consumed. The products are the diazo ketone and methyl chloride (a gas) from the reaction of diazomethane with HCl..
To carry out the Arndt-Eistert reaction the diazo ketone is decomposed in the presence of a silver catalyst (usually AgO2 or AgNO3 ) together with heat or light energy. The resulting Wolff rearrangement generates a ketene, which quickly reacts with any hydroxylic or amine reactants that may be present in solution. The general equations on the left below illustrate that the end product from the Arndt-Eistert reaction may be a carboxylic acid, an ester or an amide.
RCH=C=O +
H2O RCH2CO2H
R'OH RCH2CO2R'
NH3 RCH2CONH2
R'NH2 RCH2CONHR'
Three specific examples of this procedure are presented to the right of the general equations. The first two examples are typical Arndt-Eistert reactions. Tolerance for other functional groups, such as nitro, is demonstrated by the first case; and the second example shows that the configuration of the migrating group is retained in the rearrangement. Other ketene reactions, such as a [2 + 2] cycloaddition, may take place in the absence of hydroxylic solvents or amines. Reaction #3 is an example of such an alternative reaction. The new bonds in the cycloadduct are colored pink.
2. Diazo Ketone Reactions
The Arndt-Eistert reaction is a special case of a more general class of diazo ketone reactions. If we assume that diazo ketones normally decompose to acyl carbenes, then numerous subsequent reactions can be imagined, and many have been realized. The following diagram outlines some of these transformations, originating from the diazo ketone formula in the center of the diagram. Molecular nitrogen is lost in each case, and the Wolff rearrangement path is on the left. Most of the other reactions reflect the ability of carbenes to insert into sigma bonds or add to double bonds. Metal catalysts are sometimes used to facilitate certain reactions, and may associate with carbenes to generate carbenoid intermediates.
By clicking on the diagram some examples of these diazoketone reactions will be shown.
31: Introduction to Synthesis
https://www2.chemistry.msu.edu/facul...jml/synth1.htm
32: Exercises
The practice problems provided as part of this text are chiefly interactive, and should provide a useful assessment of the reader's understanding at various stages in the development of the subject. Some of these problems make use of a Molecular Editor drawing application created by Peter.Ertl. To practice using this editor Click Here.
Since problem solving is essential to achieving an effective mastery of the subject, it is recommended that many more problems be worked. Most organic chemistry textbooks contain a broad assortment of suitable problems, and paperback collections of practice problems are also available. In addition, a large collection of multiple choice problems may be viewed Here.
The following button will activate a collection of problems concerning the reactivity of common functional groups.
The following web-sites provide nice collections of problems and answers:
Towson University-reaction quizzes and summaries
Ohio State University-electronic flashcards
University of Wisconsin-concept questions
UCLA-helpful advice
Notre Dame-spectroscopy problems
For a useful collection of study materials, including links to other sites, visit the Organic chemistry tool-kit. Prepared by Bob Hanson, St. Olaf College | textbooks/chem/Organic_Chemistry/Book%3A_Virtual_Textbook_of_OChem_(Reusch)_UNDER_CONSTRUCTION/30%3A_Cationic_Rearrangements/30.9%3A_Rearrangements_of_Acyl_Carbenes.txt |
This module presents the recent developments in chiral Lewis acid and Brønsted acid catalysis, especially the systems having the combination of Lewis acids and Brønsted acids. This combined catalytic system has been useful in asymmetric synthesis over the past 20 years.
• 1.1: Brønsted Acid-Assisted Lewis Acid (BLA)
Chiral Brønsted acid-assisted Lewis acids (BLAs) are efficient and versatile chiral Lewis acids for a wide range of catalytic asymmetric cycloaddition reactions.
• 1.2: Lewis Acid-Assisted Lewis Acid (LLA)
In Lewis acid assisted chiral Lewis acids (LLAs), achiral Lewis acid is added to activate chiral Lewis acid via complex formation. The reactivity of LLA is much greater compared to that of achiral Lewis acid, and thus, the latter's presence does not affect the selectivity of the reaction.
• 1.3: LBA Catalysts
The combination of Lewis acids and chiral Brønsted acids affords LBA catalysts. In this system, the coordination of the Lewis acids to the heteroatom of the chiral Brønsted acid results in increase the acidity of the latter.
• 1.4: Problems + Reference
• 1.5: Chiral Phosphoric Acids (PAs)
The combination of Lewis acids and chiral Brønsted acids affords LBA catalysts. In this system, the coordination of the Lewis acids to the heteroatom of the chiral Brønsted acid results in increase the acidity of the latter.
01: Reactions using Chiral Lewis Acids and Brnsted Acid
This module presents the recent developments in chiral Lewis acid and Brønsted acid catalysis, especially the systems having the combination of Lewis acids and Brønsted acids. This combined catalytic system has been useful in asymmetric synthesis over the past 20 years.
Chiral Brønsted acid-assisted Lewis acids (BLAs) are efficient and versatile chiral Lewis acids for a wide range of catalytic asymmetric cycloaddition reactions. Some of the representative examples follow:
1.1.1: Diels Alder Reaction
Brønsted acid-assisted chiral oxazaborolidine-based Lewis acids have been found to be versatile chiral Lewis acids for asymmetric Diels-Alder reactions. These chiral BLAs can be readily prepared by protonation of the chiral proline-derived oxaborolidines using protic acids such as trifluoromethanesulfonic acid (TfOH) and bis ( trifluoromethane) sulfonamide (Tf2 NH) (Scheme \(1\)).
BLAs 1a-b activate various electrophiles, including α,β -unsaturated ketones, esters, carboxylic acids, lactone, enals and quinones towards Diels-Alder reaction with various dienes (Scheme \(2\)). The stereochemical outcome can be predicted using the transition state assemblies shown in Scheme \(3\). The face selectivity of α -substituted α,β -unsaturated enals is found to be opposite to α,β -unsaturated ketones, esters, and acrylic acids.
Examples using 1b :
The chiral BLAs having counteranion triflimide (Tf2N ) provides remarkable catalytic stability compared to that bearing trilfate (CF3SO3). In addition, BLAs with triflimide are found to be versatile catalysts for wide range of Diels-Alder reactions. For examples, the reactions of the challenging unsymmetrical benzoquinones with 2-triisopropyloxy-1,3-butadiene has been shown with excellent enantio- and regioselectivities (Scheme \(4\)).
The observed results suggest that the BLA coordination to the oxygen of unsymmetrical quinones takes place as shown in Scheme \(5\). The coordination predominately takes place with the more basic oxygen of the quinones.
The catalytic system is also effective for intramolecular reactions to afford trans -fuzed bicyclic structures with excellent enantioselectivity (Scheme \(6\)).
Michel Addition
Michel addition of silyl ketene acetals to cyclic and acyclic α,β -unsaturated ketones has been studied. In these reactions, the addition of catalytic amount of Ph3PO increases the enantioselectivity because it could trap Me3Si species that could form during the reaction. For example, BLA 1b has been used for the Michel addition of cyclo hexenone with silyl ketene acetal to afford key intermediate for the enantioselective synthesis of caryophyllene (Scheme \(7\)). The absolute stereochemical course of the reaction can be rationalized by the above proposed transition states.
Examples:
Scheme \(7\)
[3+2] Cycloaddition
Several benzoquinones proceed reactions with 2,3-dihydrofuran in the presence of BLA 1b to afford a variety of chiral phenolic tricycles with high enantioselectivities. The application of this reaction has been demonstrated in the total synthesis of aflatoxin B2. The reaction pathway has been elucidated by performing the reaction in the presence of excess of 2,3-dihydrofuran (Scheme \(8\)).
1.1.4: β-Lactone Synthesis
Chiral BLA 1c , derived from precatalyst zwitterions and tributyltintriflate, has been investigated for the reaction of aldehydes with ketene to afford β -lactones (Scheme \(9\)).
Examples:
Proposed Mechanism
Reaction of the precatalyst 1c with tri- n -butyltintriflate may give an ion pair that could react with ketene to give sufficiently strong Lewis acid intermediate to make chelation with aldehydes. It is important to note that the formation β -lactone from α -branched aldehydes has been demonstrated for the first time.
Modified BLA Catalysts
The following modified BLA catalysts 1d-e has been subsequently developed. These catalysts have also been demonstrated as powerful catalysts for Diels-Alder reactions. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/01%3A_Reactions_using_Chiral_Lewis_Acids_and_Brnsted_Acid/1.01%3A_Brnsted_Acid-Assisted_Lewis_Acid_%28BLA%29.txt |
In Lewis acid assisted chiral Lewis acids (LLAs), achiral Lewis acid is added to activate chiral Lewis acid via complex formation. The reactivity of LLA is much greater compared to that of achiral Lewis acid, and thus, the latter's presence does not affect the selectivity of the reaction.
Diels-Alder Reaction
The LLA 2a , derived from chiral valine-based oxazaborolidine and SnCl4 as an activator, has been utilized as an efficient catalyst the for Diels-Alder reaction of wide range of substrates (Scheme \(1\)). In this system, the LLA 2a is more reactive compared to SnCl4 and the ee is not affected because of the addition of excess SnCl4.
Additional examples:
The LLA 2b , derived from the complexation of AlBr3 with chiral oxazaborolidine, has been shown as useful catalyst for Diels-Alder reaction (Scheme \(2\)). The observed results suggest that LLA 2b is considerably is more efficient catalyst than the corresponding BLA 1a or 1b since 10-20 mol% of BLA is usually needed for the optimum results.
Additional examples:
[2+2]-Cycloaddition
The utility of LLA 2b has been further extended to [2+2]-cycloaddition reactions of trifluoroethyl acrylate with enol ethers (Scheme 1.1.1). The protonated BLA 1a was found to inferior to LLA 2b in catalyzing the [2+2]-cycloaddition due to side reactions involving the enol ether component. The stereochemical outcome could be predicted using the transition states proposed earlier in Scheme 1.1.3, Lecture 1.
Examples:
Allylation
Maruoka group has developed chiral bis -Ti oxide complex 2c as LLA (Lewis Acid-Assisted chiral Lewis Acid) for the enantioselective allylation of aldehydes with allylbutyltin (Scheme \(5\)).
Examples:
For the high reactivity of the catalyst 2c , two different transition states are proposed (Scheme \(6\)). In the first, intramolecular coordination of one isopropoxy oxygen to the other titanium has been proposed which could lead to enhancement in Lewis acidity of the original Ti center for the carbonyl activation. In the second system, the simultaneous coordination of the two Ti centers to the carbonyl group has been proposed which may also lead to the high reactivity.
The catalyst 2c has also been found to effective for 1,3-dipolar cycloaddition reaction between diazoacetates and α -substituted acroleins to give 2-pyrazolines with a quaternary carbon centre (Scheme \(7\)).
Examples:
1.03: LBA Catalysts
The combination of Lewis acids and chiral Brønsted acids affords LBA catalysts. In this system, the coordination of the Lewis acids to the heteroatom of the chiral Brønsted acid results in increase the acidity of the latter. For examples, the LBA, derived from optically active monoalkylated-1,2-diaryl ethane- 1,2-diol and SnCl4, has been found to be an effective catalyst for the enantioselective protonation of silyl enol ethers and ketene disilyl acetals (Scheme \(1\)).
Examples:
Based on the related X-ray crystal structure, the following transition states , controlled by a linear O-H— π bonding interaction, are proposed for the stereochemical course of the reactions (Scheme \(2\)).
The chiral catechol-derived LBA 1 has been employed as an artificial cyclaze for the cyclization of various 2-(polyprenyl)phenol derivatives with good yield and enantioselectivity. For example, a short total synthesis of (-)-chromazonarol can be accomplished with 88% enantioselectivity (Scheme \(3\)).
In addition, LBAs have been used as powerful catalysts for allylation reactions. For examples, LBA 2has been used as an effective catalyst for allylation of aldehydes with high diasterofacial selectivity (Scheme \(4\)).
1.04: Problems Reference
Problems:
What products would expect from the following reactions using BLA 1b as a catalyst?
Provide suitable catalysts/reagents for the following conversions.
A. What major products would you expect from the following reactions?
B. Write synthetic routes for the following compounds using chiral phosphoric acid catalysts.
How would you employ chiral phosphoric acids in the synthesis of the following?
Reference/Text Book
1. I. Ojima, Catalytic Asymmetric Synthesis , 3 rd ed., Wiley, New Jersey, 2010.
2. M. B. Smith, Organic Synthesis , 2 nd edition, McGraw Hill, New Delhi, 2004.
I. Ojima, Catalytic Asymmetric Synthesis, John Wiley & Sons, New Jersey, 2010. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/01%3A_Reactions_using_Chiral_Lewis_Acids_and_Brnsted_Acid/1.02%3A_Lewis_Acid-Assisted_Lewis_Acid_%28LLA%29.txt |
Chiral phosphoric acids (PAs) derived from optically active BINOL carrying 3,3'-substituents have been utilized as effective chiral catalysts to various organic transformations. Phosphoric acids act as bifunctional catalysts bearing both Brønsted acidic site and a Lewis basic site and the 3,3'-substituents play a crucial role in attaining high stereoinduction by controlling the structural and electronic properties.
Asymmetric Counterion Directed Catalysis (ACDC)
ACDC is a new concept of enantioselective synthesis. In 2006, List group first reported ACDC concept for the 1,4-hydrogenation of α,β -unsaturated aldehydes using the combination of morpholine and PA 1 at moderate temperature (Scheme \(1\)). In this reaction, PA 1 reacts with morpholine to give the morpholine salt of chiral anion PA 1 that catalyzes the reaction. The reaction takes place via the formation of iminium salt, wherein phosphate anion is believed to effectively shield one of the enantioface of the iminium salt.
This method has been subsequently utilized for the reduction of α,β -unsaturated ketones (Scheme \(2\)). In which both cation and anion are chiral that catalyze with high enantioselectivity.
Examples:
The PA 2 has been further utilized for the asymmetric epoxidation of α,β -unsaturated aldehydes in the presence of t-BuOOH (Scheme \(3\)). The proposed catalytic cycle is shown in Scheme 12. The initial addition product is achiral and the subsequent cyclization to iminium ion leads to the stereogenic center.
This methodology has been further extended for the epoxidation of α,β -unsaturated ketones (Scheme \(5\)). In this system, the diamine salt may serve as a bifunctional catalyst to possibly activate the enone substrate via iminium ion formation and hydrogen peroxide via general base catalysis as shown in Scheme \(6\).
Examples:
A dual catalytic procedure has been developed for the enantioselective activation of imines by a Brønsted acid combined with BINOL phosphate complex that results in a new metal catalyzed reaction in which the chiral counterion induces the enantioselectivity (Scheme 15).
Nucleophilic Additions of Aldimines
Chiral phosphoric acids (PAs) have been investigated as effective catalysts for Mannich type reactions. For examples, the reaction of imines with ketene silyl acetals has been studied using PA 1 in which introduction of 4-nitrophenyl substituents at 3,3'-positions has a beneficial effect on obtaining the high enantioselectivity (Scheme \(8\)). Based on DFT calculations a nine-membered zwitterionic transition state has been proposed to explain the stereoinduction.
The reaction of acetylacetone with N -boc-protected imines has been subsequently reported employing 2 mol% PA 2 with excellent yield and enantioselectivites (Scheme \(9\)). The procedure is compatible with a series of substrates to afford target products in high enantioselectivities.
Examples:
Phosphoric acid PA 3 derived from H8-BINOL derivative has been further studied for the direct Mannich reactions between in situ generated N -aryl imines and ketones (Scheme \(10\)). The authors have proposed TS-1 for the acid-promoted enolization of the ketone and its addition to the protonated aldimine.
Examples:
Hydrophosphorylation of aldimines with dialkyl phosphate has been studied using PA 4 to afford optically active α -amino phosphonates in good to high yields and enantioselectivities (Scheme \(11\)). The proposed transition state is shown in TS-2, where PA 4 acts as a bifunctional catalyst: the OH in phosphoric acid activates the aldimine as Brønsted acid and the phosphoryl oxygen activates the nucleophile as a Lewis base, thereby orienting both nucleophile and electrophile.
Examples:
Aza-Friedel-Crafts Reactions
The first organocatalytic aza-Friedel-Crafts reaction of aldimines has been accomplished using PA 5 (Scheme \(12\)). It is important to note that N-boc-protected aryl imines having electron-donating or –withdrawing groups at either the ortho -, meta -, or para - positions are compatible with the reaction condition.
Examples:
The reaction of indoles with enecarbamates has been successfully accomplished in the presence
Examples:
of PA 6 (Scheme \(13\)). Use of either pure regioisomers (E) or (Z)-enecarbamate gives the same product with similar enantioselectivities. Thus, the reaction is believed to takes place via a common intermediate A that could be generated by the protonation of the enecarbamates.
The reactions of indole with a wide range of imines, derived from aromatic aldehydes, have been demonstrated using PA 7 with excellent enantioselectivities (Scheme \(14\)).
Examples:
The Pictet-Spengler reaction of N-tritylsulfenyl tryptamines with various alphatic and aromatic aldehydes has been accomplished using PA 7 (Scheme \(15\)). The sulfenyl substituent stabilizes the intermediate iminium ion and favours the Pictet-Spengler cyclization compared to the undesired enamine formation.
Examples:
The quite interesting alkylation of α -diazoesters with N -acyl imines has been shown using PA 8 with high enantioselectivities (Scheme \(16\)). Diazoacetate is generally used in aziridine formation in the presence of Lewis acidic and Brønsted acidic conditions. Under these conditions, the competing aziridine formation has been eliminated by decreasing nucleophilicity of resulting amine intermediates and thus, the Friedel-Crafts adduct could be formed via C-H bond cleavage by the phosphoryl oxygen of phosphoric acid.
Examples:
1.4.4: Diels-Alder Reaction
Chiral phosphoric acids (PAs) are excellent catalysts for the Diels-Alder reaction. For examples, the aza- Diels Alder reaction of Danishefsky's diene with aldimines is effective using PA 1 with good enantioselectivities (Scheme \(17\)). The addition of acetic acid leads to increase significantly the yield and enantioselectivities.
Although the aza- Diels Alder reaction of Brassard's diene using a Brønsted acid is rare due to the labilitiy of the diene in the presence of a strong Brønsted acid, PA 2 has been found to be an effective catalyst for the aza- Diels Alder reaction of Brassard's diene (Scheme \(18\)). The yield of the product could be improved using the pyridinium salt of the phosphoric acid as catalyst.
The PA 2 has also been found to effective for the inverse electron-demand aza -Diels Alder reaction of electron-rich alkenes with 2-aza dienes with excellent enantioselectivities (Scheme \(19\)). The presence of OH group is crucial for the cis selectivity in the products.
Examples:
The aza- Diels Alder reaction of aldimines with cyclohexenone has been accomplished using either PA 4 or PA 5 /AcOH (Scheme \(20\)). A cooperative catalytic is proposed for the reaction using PA 5 /AcOH, where both the activation of an electrophile and a nucleophile takes place cooperatively (Scheme \(21\)).
Transfer Hydrogenation
Chiral phosphoric acids (PAs) are effective catalysts for the biomimetic hydrogenation using Hantzsch ester as a hydride source. For examples, the reduction of ketimines using Hantzsch ester can be accomplished using PA 6 with good yield and enantioselectivities (Scheme \(22\)). PA 1 bearing bulky 2,4,6-(i-Pr)3 C6 H3 at the 3,3'-positions of BINOL is found to superior to PA 6 for this purpose.
Examples:
A three-component reductive amination reactions starting from ketones, amines and Hantzsch ester can be accomplished using PA 7 with excellent yield and enantioselectivities (Scheme \(23\)). This method is also compatible for the reactions of methyl phenyl ketones as well as methyl alkyl ketones.
Examples:
Following these initial studies, the reduction of wide of range of heterocycles has been explored. For examples, the reduction of a series of substituted quinonlines, benzoxazines, benzothiazines and benzoxazinones can be accomplished using PA 8 with excellent enantioselectivities (Scheme \(24\)).
Asymmetric reductive amination of α -branched aldehydes and p -anisidine with Hantzch ester can be performed employing PA 1 with high enantioselectivities (Scheme \(25\)). The observed results suggest that the reaction proceeds via a dynamic kinetic resolution (Scheme \(26\)).
Examples:
Proposed Mechanism
Chiral phosphoric acid PA 9 derived from ( S )-VAPOL is found to superior to PAs derived from BINOL for the reduction of α -imino esters using Hantzsh ester to afford α -amino esters with higher enantioselectivities (Scheme \(27\)).
Examples:
Mannich-type Reaction
The utility of PA 9 has been further extended as excellent catalyst for the addition of nitrogen nucleophiles such as sulfonamides and imides to imines to give protected aminals (Scheme \(28\)). The procedure has wide substrate scope to give the target products in 73-99% ee and 80-99% yield.
Examples:
Asymmetric Desymmetrization of meso-Aziridines
The application of PA 9 has been further extended to ring opening of meso -pyridines. This is the first example of organocatalyic desymmetrization of meso -aziridines. The substrates having electron-withdrawing protecting groups on the nitrogen proceed reaction with enhanced yields and enantioselectivity of the products (Scheme \(29\)).
Examples:
Proposed Mechanism
The phosphoric acid first reacts with TMSN 3 to give silylated phosphoric acid as the active catalyst (Scheme \(30\)). The latter activates the aziridine by coordination of its carbonyl group, and subsequent attack of azide affords the precursor of the product and regeneration of the phosphoric acid. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/01%3A_Reactions_using_Chiral_Lewis_Acids_and_Brnsted_Acid/1.05%3A_Chiral_Phosphoric_Acids_%28PAs%29.txt |
• 2.1: Enantioselective Ene and Cycloaddition Reactions
Alder-ene and Diels-Alder reactions are six electron pericyclic processes between a “diene” or an alkene bearing an allylic hydrogen and an electron-deficient multiple bond to form two bonds σ with migration of the π bond. The lecture covers the examples of recent developments in enantioselective intermolecular Alder-ene glyoxylates with alkenes.
• 2.2: Enantioselective Alkene Metathesis
Among the alkene metathesis catalysts, Mo and Ru-based complexes have emerged as powerful exhibiting complementary reactivity and functional group tolerance. The asymmetric alkene metathesis provides access to enantiomerically enriched molecules that can not be generally prepared through the commonly practiced strategy.
• 2.3: Carbometallation and Carbocyclization Reactions
Organometallic compounds add to carbon-carbon multiple bonds to give a new organometallic species, which could be further modified to yield new carbon-carbon bonds. These processes are called as “carbometallation reactions”. It primarily refers to the relationship between the reactants and products. This section covers some examples of the asymmetric carbometallation reactions using Rh, Cu and Pd-based systems.
• 2.4: Metal-Catalyzed Asymmetric Conjugate Addition Reactions
• 2.5: Allylic Substitution with Carbon Nucleophiles
The metal-catalyzed allylic substitution is one most of the important processes in organic synthesis.
• 2.6: Problems and Reference
02: Asymmetric Carbon-Carbon Bond Forming Reactions
Alder-ene and Diels-Alder reactions are six electron pericyclic processes between a “diene” or an alkene bearing an allylic hydrogen and an electron-deficient multiple bond to form two bonds σ with migration of the π bond. The lecture covers the examples of recent developments in enantioselective intermolecular Alder-ene glyoxylates with alkenes.
Carbonyl-Ene Reaction
Chiral Lewis acid catalyzed enantioselective ene reaction is one of the efficient methods for atom economical carbon-carbon bond formation. For example, Ti-BINOL prepared in situ catalyzes efficiently the carbonyl-ene reaction of glyoxylate with α -methylstyrene in the presence of molecular sieves with high enantioselectivity (Scheme \(1\)).
Besides the early transition metal based Lewis acid catalysts, square planar dicationic late transition metal complexes bearing C 2-symmetric diphosphine ligands have also been considerably studied as chiral Lewis acids for carbonyl-ene reactions. For example, the isolated MeO-BIPHEP-Pd complex 1a bearing electron withdrawing benzonitrile as the labile, stabilizing ligands has been used for the ene reaction of ethyl glyoxylate with up to 81% ee (Scheme \(2\)). The isolated 1a exhibits more catalytic activity compared to that 1b which is in situ generated although both offer similar enantioselectivity.
MeO-BIPHEPs-Pt complexes 3 with OTf - as counter anion also exhibit similar catalytic activity and selectivity in the asymmetric glyoxylate ene reaction (Scheme 3). The addition of phenol facilitates the reaction by trapping the OTf anion and traces of water.
The glyoxylate ene reaction is also effective using tropox dicationic DPPF-Ni complex 4 with enantioselectivity up to 90% ee (Scheme \(4\)).
The glyoxylate-ene reaction can also be carried out using chiral C 2-symmetric bisoxazolinyl copper(II) complexes 5 and 6 as Lewis acid catalysts (Scheme \(5\)). The aqua complex is air and water stable and exhibits only slight decrease in the reaction rate compared to the anhydrous complex 6 . The sense of asymmetric induction depends on the oxazoline ring substituents, which can be rationalized by the tetrahedral and square-planer intermediates to account for the absolute configuration of the products.
In addition, chiral C2-symmetric trivalent pybox-Sc complex 7 is studied for the carbonyl-ene reactions with N -phenyl glyoxamides (Scheme \(6\)). The ene products are obtained with excellent diastereo- and enantioselectivity. Presumably, the products are formed via proton transfer from the β - cis substituent through an exo -transition state.
Co and Cr-based chiral complexes have also been explored for the carbonyl-ene reaction with glyoxylates. For example, chiral β-ketoiminato complex 8 catalyzes efficiently the reaction of 1,1-disubstiuted alkene and glyoxyl derivative in high enantioselectivity (Scheme \(7\)). Similar to the earlier described Pd, Pt and Ni-based catalysts, hexafluoroantimonate as a counter anion is found to be the most effective.
Chiral Cr(III)-salen complex 9 bearing adamantyl group in the salen ligand has been used for the reaction of ethyl glyoxylate with 1,2-disubstituted alkenes (Scheme \(8\)). The catalyst can be prepared in multigram scale and the ene products are obtained with up to 92% ee. The presence of adamantyl substituent essential for the enhancement in the enantioselectivity.
Besides the metal based catalysts, chiral organocatalysts have also been considerably explored during the recent years for the carbonyl-ene reactions. For example, the chiral phosphoric acid 10 as a chiral Bronsted acid catalyzes readily the enantioselective aza-ene reaction of enamides to imines with excellent enantioselectivity even on a gram scale (Scheme \(9\)).
Besides the intermolecular reactions, intramolecular version of this reaction has also been well explored using chiral metal as well as chiral phosphoric acids as catalysts. For example, the palladium-phosphine complex catalyzed cyclization of 1,7-enyenes bearing benzene ring takes place efficiently to afford six membered quinoline derivatives with quaternary stereogenic centers as single enantiomer (Scheme \(10\)).
Diels-Alder Type Reactions
Asymmetric intra- and intermolecular Diels-Alder reactions have made remarkable progress using chiral metal complexes as catalysts. Subsequently, several studies are focused on the use of chiral organocatalysis for this reaction. Since the organocatalysis based reactions are covered in module I, this lecture covers recent examples of the metal catalyzed reactions.
Intramolecular [4+2]-Cycloaddition
Intramolecular Diels-Alder reactions of unactivated dieneynes provide powerful tool to construct 5,6- or 6,6-fuzed rings. These fuzed rings can be inducted in the synthesis of many natural products. Therefore, a number of methods using transition metal catalysis have been developed over the past two decades. The chiral Rh complex bearing chiral diene and chiral phosphine has been shown to give better enantioselectivity compared to that bear achiral diene and chiral phosphine complex (Scheme \(11\)).
Intermolecular Diels-Alder Reactions
Intermolecular hetero Diels-Alder reactions have also been extensively explored using both chiral metal complexes as well as chiral organocompounds as catalysts. Since the use of chiral organocatalysis has been covered in module I, this section focuses on few examples using chiral metal complexes as the catalysts. The reaction of benzaldehyde with Danishefsky's diene proceeds in the presence of BINOL/diimine/Zn complex with excellent enantioselectivity and yield (Scheme \(12\)).
Chiral box-Cu(II) complexes are found to be excellent catalysts for a variety of hetero Diels-Alder reactions (Scheme \(13\)).
The readily accessible oxazaborolidine-aluminum bromide catalyst catalyzes the reaction of furan with diethyl fumarate with excellent enantioselectivity (Scheme \(14\)).
Scheme \(14\) | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/02%3A_Asymmetric_Carbon-Carbon_Bond_Forming_Reactions/2.01%3A_Enantioselective_Ene_and_Cycloaddition_Reactions.txt |
Among the alkene metathesis catalysts, Mo and Ru-based complexes have emerged as powerful exhibiting complementary reactivity and functional group tolerance. The asymmetric alkene metathesis provides access to enantiomerically enriched molecules that can not be generally prepared through the commonly practiced strategy. Unlike most of the other enantioselective processes, alkene metathesis, which entails the formation and cleavage of carbon-carbon double bonds, does not involve the direct construction of sp 3 -hybridized stereogenic center. Instead, the stereochemistry is created indirectly, often by desymmetrization of an achiral substrate (Scheme \(1\)), wherein the chiral catalyst has to discriminate between enaniotopic groups or sites of the molecule.
Scheme \(1\): Desymmetrization in catalytic enantioselective alkene metathesis .
Ring-Closing Metathesis (RCM) Reactions
2.2.1.1 Ru-Catalyzed Reactions
RCM is most commonly used in organic synthesis to construct cyclic systems, which are sometimes difficult to prepare by most of the other methods. During the past decade, several Ru and Mo-based chiral catalysts have been developed for the enantioselective RCM process and made remarkable progress. Scheme \(2\) summarizes examples for enantioselective RCM employing monodentate chiral NHC-Ru and chiral Mo-diolate complexes. The Ru-based catalysts are selective compared to Mo-based one, which catalyzes a wide range of substrates.
The mechanism of the Ru-catalyzed RCM is outlined in Scheme \(3\). Initiation of the reaction may take place via the dissociation of either the phosphine ligand or chelated etherate moiety. Subsequently, the less substituted alkene may make coordination to the Ru center, which could proceed [2+2]-cycloaddition, followed by cycloreversion and ruthenacyclobutane formation that could lead to the target product. The formation and cleavage of the cyclobutanes are crucial for the enantioselectivity of the products.
2.2.1.2 The Synthesis of Cyclic Enol Ethers using Mo-Catalyzed RCM
Mo-based RCM is found to be successful for the synthesis of furan and pyran products with up to 98% ee (Scheme \(4\)). Although high catalyst loading is required, the products can be constructed with tertiary and quaternary stereogenic centers. In contrast, the Ru-based catalysts are not successful for this transformation.
Ring-Opening/Ring-Closing Metathesis (RORCM) and Ring-Opening/Cross Metathesis (ROCM)
Following the ring opening, the resulting carbene intermediate can be traped intramolecularly by a pendant alkene (RORCM, Path A) or intermolecularly using a cross-partner (ROCM, Path B) (Scheme \(5\)). These reaction pathways can be controlled by selection of the appropriate catalyst and cross partner, which can lead to a wide range of enantiomerically enriched products from common starting material. In the absence of intramolecular trap (ROCM process), a number of complex mixture of products can be generated.
Scheme \(6\) presents examples for the Mo and Ru-catalyzed enantioselective ROCM processes. Norbornenes react with styrene via ROCM with high enantioselectivities. In both cases, E -alkenes are generated. In the absence of styrene, in the case of Mo-based system, RORCM product is formed with 92% ee. The substrate used for the Ru-catalyzed ROCM process, proceed polymerization in the presence of Mo-catalyst instead of ROCM process.
Scheme \(7\) shows the comparison of the Ru-catalyzed ROCM of norbornenes. The catalysts 7 and 8 bearing monodendate NHC ligands exhibit greater reactivity (i.e., lower catalyst loading) compared to the complex bearing bidendate NHC ligand 6 . But the systems using 7 and 8 produce poor E / Zselectivity, whereas the reaction using 6 gives exclusively E -isomer.
The synthesis of isoindole has been recently shown using chiral Ru-catalyzed RORCM with moderate enantioselectivity (Scheme \(8\)). In this reaction the use of ethylene is to facilitate the release of the catalyst. The direct alkene metathesis product is unstable and thus it was isolated after hydrogenation.
2,6-Disubstituted piperidines are important structural unit present in medicinally significant compounds. Using the Mo-based enantioselective ROCM reactions, the synthesis of the N -protected 2,6-substituted piperidines can be accomplished from of meso -azabicycles with moderate to high enantioselectivities (Scheme \(9\)).
Cross-Metathesis (CM)
Catalytic enantioselective CM is least developed in enantioselective alkene metathesis reactions. Unlike the ring-closing and ring-opening metatheses that are thermodynamically driven, there is minimal driving force for the CM. In addition, selectivity between two different cross partners leads to complex. Scheme \(10\) presents some examples of CM using chiral Ru complexes with moderate enantioselectivity. These substrates don't proceed RCM due to ring strain of the products. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/02%3A_Asymmetric_Carbon-Carbon_Bond_Forming_Reactions/2.02%3A_Enantioselective_Alkene_Metathesis.txt |
Organometallic compounds add to carbon-carbon multiple bonds to give a new organometallic species, which could be further modified to yield new carbon-carbon bonds. These processes are called as “carbometallation reactions”. It primarily refers to the relationship between the reactants and products (Scheme \(1\)). This section covers some examples of the asymmetric carbometallation reactions using Rh, Cu and Pd-based systems.
Rhodium-Catalyzed Reactions
Hydrogen-mediated carbon-carbon bond formation has emerged as powerful industrial process in chemical industries. For example, the hydroformylation and Fischer-Tropsch reactions are well known for the hydrogen-mediated carbon-carbon bond formation reactions. These processes require heterolytic activation of molecular hydrogen to give monohydride species, where the C-H reductive elimination pathway is disabled. Addition of a metal hydride to carbon-carbon multiples bonds (i.e., alkene and alkyne) give organometallic species that could be rapidly captured by an electrophile (i.e., aldehydes and imine) prior to its reaction with molecular hydrogen via oxidative addition or σ-bond metathesis of carbon-metal bond. Scheme \(2\) illustrates metal-dihydride route (leading to hydrogenation) and metal-monohydride route (leading to C-C bond formation) with an alkyne.
Formation of the monohydride organometallic species depends on the choice of the catalytic system. For example, the heterolytic activation of molecular hydrogen is observed with cationic rhodium complexes in the presence of base. The reaction takes place via the oxidation addition of the molecular hydrogen with metal species followed by a base induced reductive elimination of HX (Scheme \(3\)).
For example, Scheme \(4\) presents enantioselective reductive cyclization of 1,6-enynes using Rh(COD)2 OTf and ( R )-BINAP in the presence of molecular hydrogen. This carbocyclization reaction is compatible with various functional groups, however, the yield and enantioselectivity of the product depends on the structure of 1,6-enynes and the ligands.
A possible mechanism has been proposed for this reaction based on deuterium labeling control experiments (Scheme \(5\)). The catalytic cycle starts with cycloaddition of RhLn and 1,6-enyne forming rhodacyclopentene. Homolytic hydrogen activation via oxidative addition of molecular hydrogen or σ-bond metathesis may lead to the formation of vinyl-rhodium vinyl species that could afford cyclization product by reductive elimination to complete the catalytic cycle.
1,4-Conjugate addition of organometallic reagents to α,β -unsaturated carbonyl compounds afford effective method for carbon-carbon bond formation. Much effort has been on the development of asymmetric version of the reaction using a series of catalytic systems. The first reductive aldol cyclization of keto-enone with phenylboronic acid has been shown utilizing Rh[(COD)Cl]2 and (R)-BINAP with yield and enantioselectivity (Scheme \(6\)).
The mechanism of the reaction is presented in Scheme 7. The observed stereochemistry has been rationalized by assuming Z -enolate formation.
Copper-Catalyzed Reactions
CuH is found to be highly efficient catalyst for the asymmetric reductive aldol cyclization of keto-enones to give the target product as a singly diastereoisomer with high enantiopuritiy (Scheme \(8\)). These reactions use ferrocenylphosphines, (S, R)-PPE-P(t -Bu)2, as effective chiral ligands in the presence of silane as a hydride source (Scheme \(8\)). These reactions can also be carried out under heterogeneous as well as aqueous conditions with surfactant.
Palladium-Catalyzed Reactions
The palladium-catalyzed cross-coupling reactions of aryl or alkenyl halides with alkenes in the presence of base are among the powerful reactions in organic synthesis to construct carbon-carbon bonds. The asymmetric version of the reaction is also well explored. Scheme \(9\)-\(12\) illustrates some examples for the intramolecular and intermolecular Heck reactions. In 1970, the Heck reaction was discovered and, in 1989, the first example of asymmetric intramolecular Heck reactions appeared using Pd(OAc)2 with (R)-BINAP with moderate enantioselectivity (Scheme \(9\)).
The intramolecular Heck reaction finds wide applications in organic synthesis. Among those applications the synthesis of optically active oxindoles having a quaternary asymmetric center has been considerably explored. Because the oxindole moiety serves as useful synthetic intermediate in the synthesis of numerous natural products. For example, (E)- α,β -unsaturated-2-iodoanilide undergoes cyclization in the presence of Pd2 (dba)3-CHCl3 and (R)-BINAP to give oxindoles with (S) or (R) configuration under cationic and neutral conditions, respectively. It is noteworthy that a dramatic switching in the direction of asymmetric induction has been observed between the two conditions even though the same chiral ligand (R)-BIANP is employed. In these reactions, Ag3PO4and PMP act as HI scavenger.
The use of TADDOL-based monophosphoramide has been demonstrated instead of BINAP in the reaction of intramolecular cyclization of cyclohexadienone derivatives (Scheme \(11\)). This reaction can be performed in the absence of silver salt.
Intermolecular Heck reaction is also well studied. For example, dihydrofuran reacts with phenyl triflate to give 2-phenyl-2,3-dihydrofuran along with small amount 2-phenyl-2,5-dihydrofuran in the presence of Pd-BINAP with excellent enantioselectivity (Scheme \(12\)). A mechanism has been proposed to explain the high enantioselectivity of the major product and inversion configuration of the minor product (Scheme \(13\)). It involves a kinetic resolution process that enhances the enantioselectivity of the major product.
Scheme \(14\) exemplifies the reactions of 2,3-dihydrofuran and 2,2-dimethyl-2,3-dihydrofuran with phenyl triflate, 2-carbethoxy cyclohexenyl triflate and cyclohexenyl trilfate using palladium complexes with oxazoline based aminophosphine and (D-glucosamine)phosphiteoxazoline as the ligands. The reactions are effective affording the products with excellent enantioselectivity. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/02%3A_Asymmetric_Carbon-Carbon_Bond_Forming_Reactions/2.03%3A_Carbometallation_and_Carbocyclization_Reactions.txt |
Asymmetric conjugate addition is one of the powerful tools for the construction carbon-carbon and carbon-heteroatom bonds in organic synthesis. This reaction finds extensive applications for the construction enantioenriched carbon skeletons for the total synthesis of numerous biologically active compounds. Sometimes possible to construct multiple stereocentres in single synthetic operation. This lecture covers some examples for the recent developments in the conjugate addition of Grignard, organozinc, organolithium, organocopper and organoborane reagents with activated alkenes in the presence of chiral ligand or chiral catalysts.
Reactions of Grignard Reagents
The conjugated addition of Grignard reagents with electrophilically activated alkenes is well explored. Some of the chiral ligands developed for the conjugate addition reactions of Grignard reagents with α,β -unsaturated carbonyl compounds are shown in Scheme \(1\).
One of the recent examples is the addition of alkyl magnesium bromide to α,β -unsaturated thioesters using Josiphos ligand L-1 (Scheme \(2\)). The reactions of a series of examples can be accomplished with up to 96% enantioselectivity.
Compared to the 1,4-conjugate addition reaction, the reactions with extended Michael acceptors needs additional control of the regioselectivity. For example, using the ( R,S )-reversed Josiphos ligand L-2 , 1,6-asymmetric conjugate addition to α,β,γ,δ -unsaturated esters has been developed (Scheme \(3\)).
Besides the ferrocenyl ligands L1-2 , taniaphos L-3 with CuBr∙SMe2 is also highly effective for the conjugate addition of allylic electrophiles with Grignard reagents (Scheme \(4\)). In this reaction, aliphatic allylic bromides have been found to be excellent substrates.
Reactions of Organozinc Reagents
The asymmetric conjugate addition of dialkylzinc to prochiral α,β -unsaturated compounds is one of the powerful methods for carbon-carbon bond formation in organic synthesis. Much attention has been made on the development of new ligands for this reaction. Phosphoramidite ligand from BINOL L-4 has been found to be effective for the conjugate addition to cyclic substrates with up to 98% ee (Scheme \(5\)).
Subsequently, copper(I)-catalyzed enantioselective addition of dialkylzinc to 3-nitroacrolein derivatives has been demonstrated using phosphoramidite ligands L-5 and L-6 with up to 98% ee (Scheme \(6\)).
Scheme \(7\) summarizes some of the peptide based ligands for the dialkylzinc addition to α,β -unsaturated compounds. For example, the copper-catalyzed conjugate addition of dialkylzinc reagents to acyclic aliphatic α,β -unsaturated ketones proceed in the presence of L-9 with up to 94% ee, while the reaction using L-10 gives up to 98% ee (Scheme \(8\)).
Later, the chiral ligands L-10 to L-12 have been studied for the reactions of dialkylzinic reagents to heterocyclic enones such as furanones, pyranones and their derivatives (Scheme \(9\)-\(10\)).
Reactions of Organolithium Reagents
Organolithium reagents are highly reactive species and their conjugate addition reactions with α,β-unsaturated carbonyl compounds are of great interests. One of the recent examples is the reaction of configurationally stable organolithium to α,β -unsaturated cyclic carbonyl compounds using (-)-sparteine that can be performed with high enantioselectivity (Scheme \(11\)).
Reactions of Organoboranes
The asymmetric conjugate addition of organoboranes using chiral rhodium phosphine complex is a successful process. For example, arylboronic and alkenylboronic acids undergo reaction with cyclic and acyclic α,β -unsaturated ketones in the presence of chiral rhodium complex bearing (S)-BINAP with high enantioselectivity (Scheme \(12\)). The reaction proceeds via phenylrhodium, oxa- π -allylrhodium and hydroxorhodium intermediates (Scheme \(13\)).
Besides chiral biphosphines, chiral dienes and chiral phosphoramidite ligands are also effective for the rhodium catalyzed conjugate addition of organoboranes. For example, the rhodium catalyzed conjugate addition of boronic acids and potassium trifluoroborates to enones occurs with high enantioselectivity (Scheme \(14\)). | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/02%3A_Asymmetric_Carbon-Carbon_Bond_Forming_Reactions/2.04%3A__Metal-Catalyzed_Asymmetric_Conjugate_Addition_Reactions.txt |
The metal-catalyzed allylic substitution is one most of the important processes in organic synthesis. Scheme 1 represents the catalytic cycle of a transition metal based allylic substitution reaction. The reaction begins with the coordination of the low valent metal complex to the double bond of an allylic system. Subsequent oxidative addition by removal of the leaving group X gives a π -allyl complex as intermediate. The intermediate could be a neutral or cationic species, depending on the nature of the ligands and the counter ion X. The nucleophile typically adds to the terminal carbon with inversion of configuration rather than via the metal cation with retention (Scheme \(1\)).
Palladium-Catalyzed Reactions
The palladium catalyzed allylic substitution reaction is a very powerful process. This section covers some recent examples on the palladium catalyzed enantioselective allylic substitution with carbon nucleophiles. The use of azlactones as a soft stabilized pronucleophile is particularly important because they give rise to amino acids as products. Scheme \(2\) presents Trost's synthesis of spingofungins via alkylation of a geminal diacetate with an azlactone. The product is formed with good diastereo- and enantioselectivity.
Atom economical method to obtain (π -allyl)Pd intermediates from allenes by addition of hydrido-Pd complexes has been demonstrated (Scheme \(3\)). This method affords the same products as that of the standard alkylation of allylic substrates. The pronucleophile are sufficiently acidic to produce HPdL2 species (Scheme \(4\)).
The palladium catalyzed reaction of vinyl epoxide with nucleophiles provides branched products (Scheme \(5\)). This is due to interaction of the nucleophile with an alkoxy or OH moiety produced by reaction with the Pd(0) species. For example, the reaction of isoprene monoepoxide with β-keto esters preferentially gives the branched alkylation products in the form of the hemiacetals (Scheme \(6\)). The nature of the β-ketoester and optimization of the reaction conditions are crucial for the success of this process.
Bimetallic system having Rh(acac)(CO)2, Pd(Cp)(π -C3H5) and the ligand Anis Trap has been used for the allylic alkylation with α -cyanopropionic acid derivative as pronucleophile (Scheme \(7\)). The control of the stereochemistry is believed to take place via the nucleophile with a chiral Rh complex coordinating to the cyano group.
Recently, allylic alkylation has been realized by enolate generated in situ by decarboxylation (Scheme \(8\)). Both allylic β -keto carboxylates and allyic enol carbonates undergo facile decarboxylation after oxidative addition of a Pd(0) species (Scheme \(9\)).
Nickel-Catalyzed Reactions
In comparison to the palladium catalyzed reactions, the nickel based chemistry is less explored. In addition, the nickel based chemistry less popular with the reactions of soft nucleophiles and few examples only so far investigated. For example, the reaction of allylic acetates has been studied with soft nucleophiles such as dimethyl malonate using a wide range of phosphine ligands (Scheme \(10\)). Linear allylic substrates give a mixture of regioisomers, whereas in cyclohexenyl acetate, the regioselectivity does not play any role affording the alkylated product with moderate enantioselectivity in the presence of chiral phosphine L1.
However, the nickel based systems are very popular with the reactions of hard nucleophiles such as boronic acids, borates and Grignard reagents. For example, the reaction of 1,3-disubstituted allyl ethers with Grignard reagents can be accomplished using nickel phosphine complex with good enantioselectivity (Scheme \(11\)). The reaction of methyl ether gave better results compared to phenyl ethers. In this reaction, if the reaction is quenched before complete consumption of the staring material, a significant kinetic resolution is observed.
Molybdenum-Catalyzed Reactions
Although the palladium catalyzed systems dominate in π-allyl chemistry, analogues Mo-catalyzed reactions have also emerged as powerful reactions in organic synthesis. The Mo-based reactions are the one first showed different regioselectivity compared to the palladium catalyzed systems. Scheme \(12\) illustrates the mechanism for the asymmetric Mo-catalyzed allylic alkylation.
Copper-Catalyzed Reactions
In case of the nonsymmetrical allylic substrates, the palladium catalyzed allylic alkylation reactions show poor regioselectivity. In this context, the copper based chemistry is an interesting alternative and lots of efforts have been made on this topic during last years. The copper based systems tolerate a wide range of hard and nonstabilized nucleophiles. Scheme \(13\) presents the regioselectivity in copper-catalyzed allylation reactions. In unsymmetrical substrates, nucleophile may attack directly at the leaving group (SN2) or at the allylic position (SN2’) under migration of the double bond depending on the reaction parameters as well as the substrate and nucleophile.
The observed results suggest that the regioselectivity and stereoselectivity are established at different stages (Scheme \(14\)). For example, the reaction of chiral carbamates with achiral copper reagent gives SN2’ product with excellent enantioselectivity (Scheme \(15\)).
2.06: Problems and Reference
Problems:
Complete the following reactions.
How will you synthesis the following compounds using alkene metathesis?
Give some examples of chiral Zr-catalyzed carbometallation reactions.
Complete the following reactions.
Describe conjugate addition reactions using organocatalysis.
Complete the following reactions.
Predict the major product for the following reactions.
Describe the chiral Fe, Ru, Ir and Rh-catalyzed asymmetric allylic alkylation reactions.
Reference /Text Book
• I. Ojima, Catalytic Asymmetric Synthesis , 3 rd ed., Wiley, New Jersey, 2010.
• M. B. Smith, Organic Synthesis , 2 nd edition, McGraw Hill, New Delhi, 2004. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/02%3A_Asymmetric_Carbon-Carbon_Bond_Forming_Reactions/2.05%3A_Allylic_Substitution_with_Carbon_Nucleophiles.txt |
• 3.1: Reactions with Metal Carbenoid
Functionalization of C-H bonds constitutes an attractive approach for the direct synthesis of complex organic molecules such as pharmaceuticals, natural products, and other industrially relevant targets. Two major directions evolved for the C-H functionalization process are (i) direct C-H activation involving oxidative addition to the C-H bond onto an active metal center, and (ii) insertion of transition metal-coordinated carbenes or nitrenes into the C-H bond to give functionalized products.
• 3.2: Reactions With Metal Nitrenoid and Direct C-H Oxidation
The nitrene insertion into C-H bonds provides powerful tool for the direct introduction of C-N bond from C-H bonds. The mechanism of metal nitrenoid formation is believed to take place via an in situ-formed iodonium ylide that produces the reactive metal nitrenoid intermediate in the presence of suitable metal.
• 3.3: Problems and Reference
03: Synthesis via C-H Activation
Functionalization of C-H bonds constitutes an attractive approach for the direct synthesis of complex organic molecules such as pharmaceuticals, natural products, and other industrially relevant targets. Thus, much effort has been devoted to achieve practical, catalytic and selective methods for the C-H functionalization. Scheme \(1\) presents the two major directions evolved for the C-H functionalization process: (i) direct C-H activation involving oxidative addition to the C-H bond onto an active metal center, and (ii) insertion of transition metal-coordinated carbenes or nitrenes into the C-H bond to give functionalized products.
Metal carbenes generally produced from diazo compound by metal-catalyzed nitrogen extrusion. Alternative carbene precursors include iodonium, sulfonium, sulfoxonium, thiophenium and phosphonium ylides, but their synthetic application is less explored. The general mechanism for the generation of carbene via dirhodium complexes is shown in Scheme \(2\). In the presence of suitable metal complex, the diazo compound can coordinate reversibly and undergo rate limiting extrusion of nitrogen to give reactive metal carbenoid intermediate. The latter will react with a suitable trapping agent present in the reaction mixture.
For example, chiral dirhodium complexes catalyze the intramolecular C-H insertion of α -diazo -β -ketoester to give the intermediate for the total synthesis of the marine secosteroid (-)-astrogorgiadiol (Scheme \(3\)). Up to 58% de is observed with moderate yield of 38% employing Rh2( S -biTISP)2 as the catalyst. The reaction using Rh2 (S-PTPA)2 afforded excellent yield but with lower diastereoselectivity.
ortho -Metallated arylphosphine dirhodium(II) complexes are found to be effective catalysts for intramolecular C-H insertions of certain diazoketones (Scheme \(4\)). One of the examples is the use of dirhodium complex 1 for the reaction of chloro-substituted system to afford cyclophentanone in 74% ee and 87% yield. This system works well with the aryl portion having electron withdrawing group.
Scheme \(5\) illustrates an example for the stereocontrolled formation of quaternary stereocenter using chiral Rh2 (S-PTTL)4 catalyzed carbenoid C-H insertion process.
The above catalytic system is also effective for the desymmetrization of aryl-substituted diazo ketoesters (Scheme \(6\)). This reaction proceeds via electrophilic aromatic substitution and turnover numbers of up to 98000 have been achieved.
Furthermore, the construction of cis -cyclopentanones from diazoester can be achieved via exclusive insertion (Scheme \(7\)). In addition, the construction of disubstituted cis -indane can be accomplished with 85% yield and 92% ee (Scheme \(8\)). These examples illustrate that the choice of the reaction conditions and catalysts for carbenoid transformation are crucial for selectivity.
Both the first (Rh2(MEOX)4 and Rh2 (MEPY)4) and second (Rh2(4S-MACIM)4) generation carboxamidate catalysts show very good enantiocontrol for the desymmetrization reaction of cyclohexyl diazoacetate (Scheme \(9\)). In terms diastereoselectivity, the latter gives the best results of 99:1 which is attributed to the N -substituent that control the carbenoid orientation.
In case of cyclohexyl diazoacetate having the tertiary system, a mixture of the expected insertion into methylene group and insertion into the methyl group has been observed in the presence of Rh2(4S-MACIM)4 (Scheme \(10\)). Cyclopentane system also provides similar results with somewhat lower yield and enantioselectivity.
The construction of γ -lactone has been demonstrated via intramolecular C-H insertion of diazoacetates that find wide applications in the synthesis of natural products and pharmaceutical agents. For example, the synthesis of (+)-isodeoxypodophyllotoxin, (-)-enterolactone, (S)-(+)-imperanene and (R)-(-)-baclofen have been accomplished with the lactone formation as a key step in the presence of Rh2 (4S/R-MPPIM)4 (Scheme \(11\)).
The carbenoid insertion reactions have also been used for amplification of asymmetric induction. For example, sequential intramolecular C-H insertions have been carried out on meso -cyclohexyl diazoacetate (Scheme \(12\)). The formation of a 1:1 mixture of a and b is observed using Rh2(4 S,S -BSPIM)4 with over 90% yield and 99% enantioselectivity.
Synthetic application of the dirhodium catalyzed carbenoid C-H insertion chemistry has been demonstrated as key step for the site controlled γ -lactam formation to the syntheses of (R)-(-)-baclofen, GABAB receptor agonist and (R)-(-)-rolipram (Scheme \(13\)). Rh2 (S-BPTTL) is found to be the optimal catalyst for the synthesis of the intermediate for (R)-(-)-rolipram with 74% yield and 88% ee, while Rh2 (S-BPTTL) is effective for the synthesis of the intermediate to (R)-(-)-baclofen with 83% yield and 82% ee.
So far we have seen intramolecular carbenoid C-H insertion reactions. Intermolecular carbenoid C-H insertion reactions have been recently explored. Scheme 6 illustrates the reaction N-Boc piperidine with methylphenyldiazoacetate in the presence of Rh2(S-biDOSP)2 at ambient temperature. Two diastereomers in a 71:29 ratio is formed in overall 73% yield and up to 86% ee. The racemic threo -methylphenidate is currently marketed drug for treatment of attention hyperactivity disorder. Seven and eight member nitrogen heterocycles afford higher selectivity. The use of dirhodium carboxamidate Rh2(5R-MEPY)4 for this chemistry shows improved diastereoselectivity but with low yield and enantioselectivity. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/03%3A_Synthesis_via_C-H_Activation/3.01%3A__Reactions_with_Metal_Carbenoid.txt |
3.2.1 Reactions with Metal Nitrenoid
The amine functional group is an important component of many biologically active compounds. The nitrene insertion into C-H bonds provides powerful tool for the direct introduction of C-N bond from C-H bonds. The mechanism of metal nitrenoid formation is believed to take place via an in situ-formed iodonium ylide that produces the reactive metal nitrenoid intermediate in the presence of suitable metal (Scheme \(1\)). The major intrinsic factors controls the selectivity are (i) the catalyst and (ii) the electron withdrawing group.
3.2.1.1 Intramolecular Reactions
3-Amino glycol derivatives serve as intermediates for the synthesis of 2-oxygenated sugars, 2-deoxysugars and antibiotics. Dirhodium-catalyzed nitrene transfer has been utilized as a key step in the synthesis of carbamate-protected 3-aminoglycols. For example, Scheme \(2\) illustrates the selective transformation of carbamate into oxazolidinone via nitrene insertion with 86% yield. The resulting oxazolidinone can be converted into L-vancosamine. This method has been employed for the synthesis of protected glycols of L-daunosamine, D-saccharosamine and L-ristosamine.
Chiral Ru(II) porphyrin complex catalyzes the C-H amination of prochiral sulfonamides with good enantioselectivity (Scheme \(3\)). This procedure can be used for the synthesis of both five and six membered cyclic sulfamidates.
Chiral dirhodium has been shown effective catalyst for the cyclization of sulfonamides (Scheme \(4\)). This procedure is an example for the highly enantioselective amination process catalyzing the reactions of heteroaromatic substituents with up to 99% ee.
3.2.1.2 Intermolecular Reaction
Intermolecular amination of benzylic C-H bonds can be accomplished using the chiral tosylsulfonylimidamide as a nitrene precursor in the presence of chiral dirhodium carboxylate Rh2(S-NTTL)4 with excellent diastereoselectivity (Scheme \(5\)).
3.2.2 C-H Activation via Direct C-H Oxidation
Chiral Ru-porphyrin complex has been shown to catalyze benzylic C-H hydroxylation with moderate enantioselectivity (Scheme \(6\)).
C-H functionalization via insertion of a reactive metal complex is one of the emerging areas for the development of practical C-H activation. The synthesis of alkynyl tetrahydroisoquinoline has been shown by double C-H activation in the presence of copper-pyBox at moderate temperature (Scheme \(7\)). The reaction of series of alkynes and aryl substituents is demonstrated. However, the presence of ortho methoxy substituent is essential for the success of the reaction.
Intramolecular alkylation of ketimines has been shown using chiral rhodium complex bearing chiral phosphoramidite L1* (Scheme \(8\)). The observed results suggest that the reaction involves substrate directed oxidative addition of rhodium into the arene C-H bond. This approach provides a new cyclization strategy for the construction of five and six membered cyclic system.
The scope of the above procedure has been expanded for the reactions of 1,2-disbstituted and 1,1,2-trisubstituted alkenes to give chiral indane, dihydrobenzofuran and dihydropyrroloindole with high enantioselectivity (Scheme \(9\)). The formation of syn -products is observed regardless the configuration of the starting alkenes. Thus, a mixture of E and Z alkenes may be used as starting material.
3.03: Problems and Reference
Complete the following reactions.
What product would you expect from the following reactions?
Describe rhodium catalyzed combined C-H activation and cope rearrangement reactions.
Predict the major product for the following reactions.
Reference/Text Book
• I. Ojima, Catalytic Asymmetric Synthesis , 3 rd ed., Wiley, New Jersey, 2010.
• M. B. Smith, Organic Synthesis , 2 nd edition, McGraw Hill, New Delhi, 2004. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/03%3A_Synthesis_via_C-H_Activation/3.02%3A_Reactions_With_Metal_Nitrenoid_and_Direct_C-H_Oxidation.txt |
Asymmetric carbon-heteroatom bond formation is among the fundamentally important reactions. This module covers the carbon-heteroatom bond-forming reactions using transition-metal-complex as well as the chiral Lewis acid catalyzed protocols.
04: Carbon-Heteroatom Bond-Forming Reactions
Much effort has been devoted on controlling the regioselectivity and enantioselectivity in allylic substitution of substrates 1 or 2 (Scheme \(1\)). The palladium-catalyzed allylic substitution is versatile, however, the (E)-linear product 3 is often formed. Thus, the control of regioselectivity has been recently the main focus to provide product 4.
4.1.1 Allylic Amination and Etherification of Allylic Alcohol Derivatives
Chiral iridium complex having phosphoramidate 4a or 5a has been shown to catalyze the allylic amination of carbonate to give branched product with excellent enantioselectivity (Scheme \(2\)). An activated form of the iridium complex by in situ C-H activation at CH3 group of a hindered ligand 4a has been identified.
The direct reaction of allylic alcohols has been studied to give allylic amines in the presence of chiral iridium complex derived from [Ir(COD)Cl]2 and ligand 6 (Scheme \(3\)). In this reaction, sulfamic acid serves not only as a nitrogen source but also as an in situ activator of the hydroxyl group of the allylic alcohol.
Allylic amination is important for the construction of nitrogen-based heterocyclic compounds (Scheme \(4\)). The enantioselective intramolecular allylic amination has been accomplished using chiral iridium complex derived from [Ir(CDD)Cl2]2 and ligand 7. Good enantioselectivity has been obtained upon activation using 1,5,7-triazabicylo[4.4.0]undec-5-ene (TBD) as base. The catalytic system has also been used for the sequential aminations of bis -allylic carbonate via an inter- followed by an intramolecular reactions.
Enantioselective allylic amination is also a powerful tool for the construction of natural products. For example, asymmetric desymmetrization of meso -diol with p -tosylisocyanate using chiral palladium complex gives easy access to chiral nitrogen-substituted heterocycles which are precursor for the synthesis of (-)-swainsonine (Scheme \(5\)).
The chiral palladium catalyzed enantioselective allylic amination has also been utilized for the total synthesis of (-)-tubifoline, (-)-dehydrotubifoline and (-)-strychnine (Scheme \(6\)).
The one-pot enantioselective synthesis of azacycle has been shown using a ruthenium-catalyzed ene-yne addition followed by a palladium-catalyzed asymmetric allylic amination (Scheme \(7\)).
The regio- and enantioselective allylic etherification has been studied using chiral ruthenium complex. For example, planar-chiral cyclopentadienyl ruthenium complex 9 catalyzes efficiently the reaction of cinnamoyl chloride with 3-methylphenol with high enantioselectivity and yield (Scheme \(8\)).
Enantioselective allylic substitutions of carbonates with a diboron using copper(I)-based catalysts has been demonstrated. For example, Cu(I)-phosphine complex generated in situ from Cu(O-t-Bu) with ligand 10 has been shown to catalyze the reaction of allylboronate with carbonate in excellent regioselectivity and enantioselectivity (Scheme \(9\)). Addition-elimination mechanism having the generation of Cu-alkene π -complex and borylalkylcopper intermediate has been suggested.
4.1.2 Reaction of π -Allyl Intermediates
Nucleophilic attack of an amine to a π -allyl intermediate can afford an allylic amine derivative. For example, palladium complex derived from [Pd(C3H5)Cl]2 and ligand 11 catalyzes the reaction of racemic vinyloxirane with phthalimide in nearly quantitative yield (Scheme \(10\)). Involvement of the hydrogen bond of the nucleophile to the oxygen leaving group is proposed to deliver the nucleophile to the adjacent carbon to provide the target molecule. The process has been utilized for the synthesis of (+)-broussonetine G.
Palladium based systems has also been utilized for the cycloaddition reaction of epoxides and aziridines with heterocumulenes (Scheme \(11\)).
Enantioselective copper(I)-catalyzed substitution reactions of propargylic acetates with amines has been explored. For examples, copper complexes derived from copper(I) salts and ligands 12 and 13 catalyze the reaction of propargylic amination with 85% ee (Scheme \(12\)). | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/04%3A_Carbon-Heteroatom_Bond-Forming_Reactions/4.01%3A_Allylic_Substitution_Reactions.txt |
Aza-Claisen rearrangement, known as the Overman rearrangement, has been extensively studied that allows us to synthesize chiral allylic amines from achiral allylic imidates with excellent enantioselectivity. For example, prochiral N -arylbenzimidates can be converted into chiral N- a rylbenzamides in the presence of ferrocenyloxazoline palladacycle , FOP-TFA, (Scheme \(1\)).
This catalytic system has also been shown to promote the cyclization of allylic N -arylsulfonyl carbamates to give five-membered nitrogen containing heterocycles (Scheme 2). An involvement of aminopalladation of the alkene followed by insertion of the alkene into the Pd-N has been proposed.
This procedure has also been extended for the allylic etherification reaction. For example, the reaction of ( Z )-allylic trichloroacetimidates with carboxylic acids in the presence of COP-OAc 2 gives chiral allylic esters in high enantiopurity (Scheme \(3\)). Under these reaction conditions, E -stereoisomer show inferior results. In these reactions, the COP-OAc activates the carbon-carbon double bond for attack by external oxygen nucleophile and the trichloroacetimidate group serves as a leaving group along with templating the catalyst to the double bond.
4.03: Hydroamination of Alkenes
Scandium 3,3'-tris(phenylsilyl)binaphtholate can be used as a highly active catalyst for the synthesis of pyrrolidine via intramolecular hydroamination (Scheme \(1\)).
Chiral neutral zirconium amidate has been used for hydroamination of primary aminoalkenes with 93% ee (Scheme \(1\)).
4.04: Hydroalkoxylation of Allenes
Hydroalkoxylation of allenes has been accomplished using 1:2 mixture of the dppm(AuCl)2 and chiral silver phosphonate to give furan with 97% ee (Scheme \(1\)).
4.05: Oxidation Reactions
Wacker-type tandem cyclization reaction of alkenyl alcohol is reported using chiral palladium(II)-spirobis(isoxazoline) with excellent enantioselectivity (Scheme \(1\)). In this reaction, benzoquinone reoxidizes the reduced palladium(0) to palladium(II) species to complete the catalytic cycle.
Palladium complex derived from Pd(TFA)2 and (S,S)-BOXAX has been found to be effective for the synthesis of chiral chroman framework in the presence of benzoquinone (Scheme \(2\)).
The mercury(II) complex derived from Hg(TFA)2 and bisoxazoline has been used for the mercuriocyclization with high enantioselectivity (Scheme \(3\)).
Chiral cobalt(II)-salen has been used for the enantioselective intramolecular iodoetherification to procure 2-substituted tetrahydrofurans with up to 90% ee (Scheme \(4\)).
4.06: Aziridination of Alkenes
The aziridination of alkenes has been successfully accomplished using chiral Mn-salen with 94% ee. The presence of catalytic amount of 4-phenylpyridine- N -oxide leads to enhancement in the enantioselectivity (Scheme \(1\)).
Chiral Ru(salen)(CO) can be utilized for the aziridination using 2-(trimethylsilyl)ethanesulfonyl (SES) group as a nitrene precursor, because the SES group is an easily removable N -protecting group under milder conditions (Scheme \(2\)). These reaction conditions are compatible for the reactions of conjugated alkenes with high enantioselectivity.
Although the aziridination of alkenes has been explored well, the reaction of enols remains elusive. The aziridination of enols generally lead to α -amino ketones via the ring opening process of the aziridine intermediates. The chiral dirhodium complex, Rh2(S -TFPTTL)4, catalyses efficiently the amination of enol ethers employing NsN=IPh as a nitrogen source (Scheme \(3\)). The use of the N-2-nitrophenylsulfonyl (Ns) group is synthetically valuable, because the alkylation and deprotection of N -monosubstituted Ns-amide takes under milder conditions. The application of this protocol has been shown in the formal synthesis of (-)-metazocine.
The use of chiral amine has been demonstrated for the reaction of electron deficient alkenes. For example, the use of aminimide as an effective NH-transfer reagent for the aziridination of electron deficient alkenes is reported (Scheme \(4\)). In this reaction, in situ generation of a hydrazinium salt from tertiary amine and O-mesitylenesulfonylhydroxylamine (MSH), deprotonation of the hydrazinium salt to form an aminimide, and subsequent aziridination is involved.
4.07: Amination of Carbonyl Compounds
The electrophilic amination reaction is useful technology for the introduction of an amine functionality next to carbonyl carbon. Asymmetric version of this process has been considerably explored. Recently, the use of the combination of copper and palladium based catalytic system has been demonstrated for the asymmetric one-pot tandem addition-cyclization reaction of 2-(2',3'-dienyl)- β-keto esters, aryl halides, and dibenzylazodicarboxylate to afford pyrazolidine (Scheme \(1\)). An involvement of π -allylpalladium intermediate via the carbopalladation of allene has been proposed.
The use of bifunctional chiral amide iridium complex for the direct amination of α -substituted α -cyanoacetate with azodicarboyxlate has been demonstrated with excellent enantioselectivity (Scheme \(2\)). In this reaction, the chiral amide complexmay be involved in the deprotonation of cyanoacetate that would lead to the formation of N -bound nitrile complex; thus, cyanoacetate and azodicarboxylate are activated sequentially by the bifunctional catalyst that could facilitate the transformation.
Using chiral diamine-copper(II) the amination of enecarbamates can be accomplished with excellent enantioselectivities (Scheme \(3\)). Under these conditions, the changing the enecarbamate geometry from Z to E resulted in a dramatic improvement of the reactivity.
4.08: Boration of Alkenes
Organoboranes are useful reagents for organic synthesis. Recently, catalytic methods have been developed for enantioselective boration of unsaturated substrates. For example, the diboration of alkenes with bis(catecholato)diboron using rhodium(I) salt and (S)-quinap can be accomplished (Scheme \(1\)). Oxidation of the diborane derivatives can lead to chiral 1,2-diols. Furthermore, tandem diboration, Suzuki cross-coupling and oxidation reaction can lead to carbohydroxylation with similar enantioselectivity.
The asymmetric silaboration of symmetrically substituted meso -methylcyclopropanes can be accomplished via carbon-carbon bond cleavage employing chiral palladium-catalyzed boration withMe2PhSiB(pin) as the silylboron reagent (Scheme \(2\)). The catalytic system is also effective for the silaboration of mono-substituted allene to give allylsilane with good enantioselectivity (Scheme \(3\)).
The diboration of terminal allenes is also demonstrated using palladium complex derived from Pd(dba)2 and a chiral phosphoramidite to give 1,2-bis(boronate)ester with high enantioselectivity (Scheme \(4\)). The rate determining step involves the oxidative addition of the diboron to Pd, which is followed by the transfer of both boron groups to the unsaturated substrate via a π -allyl complex.
4.09: Hydrophosphonylation of Imines
The hydrophosphonylation of aldehydes and imines affords an effective route for the formation of C-P bonds. Recently, the reaction of cyclic phosphate with cyclic imines has been shown employing bimetallic chiral (S)-YbPB with excellent enantioselectivity (Scheme \(1\)).
4.10: Problems and Reference
Problems:
What major products would you expect from the following reactions?
Describe Rh-catalyzed allylic substitution.
Complete the following reactions.
Provide some examples for the chiral Y and Au-catalyzed hydroamination reactions.
Predict the major product for the following reactions.
Describe asymmetric oxygenation of carbonyl compounds.
Reference /Text Book
• I. Ojima, Catalytic Asymmetric Synthesis , 3 rd ed., Wiley, New Jersey, 2010.
• M. B. Smith, Organic Synthesis , 2 nd ed., McGraw Hill, New Delhi, 2004. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/04%3A_Carbon-Heteroatom_Bond-Forming_Reactions/4.02%3A_Aza-Claisen_Rearrangement_and_Related_Reactions.txt |
• 5.1: Oxidation of Alcohols
Oxidation of alcohols to carbonyl compounds is a pivotal process in organic chemistry. In particular, the oxidations that use readily available molecular oxygen, especially ambient air, as the stoichiometric oxidant are the most preferable.
• 5.2: Epoxidation of Allylic Alcohols
Epoxidation of allylic alcohols is a well developed practical process in asymmetric catalysis.
• 5.3: Epoxidation of Unfunctionalized Alkenes
Asymmetric epoxidation of unfunctionalized alkenes affords an appealing strategy for the synthesis optically active organic compounds. This section covers some of the recent developments on this protocol.
• 5.4: Enantioselective Sulfoxidation
Enantiopure sulfoxides serve as chiral auxiliary as well as intermediates for the synthesis of optically active compounds. Optically active sulfoxide structural unit is also present in many compounds that exhibit interesting biological properties. Development of methods for the asymmetric sulfoxidation has thus been active topic in asymmetric catalysis. This lecture covers the common methods that are used for the synthesis of optically active sulfoxides.
• 5.5: Baeyer-Villiger Oxidation (BVO)
Insertion of oxygen atom in between the ketone carbonyl and an adjacent carbon yielding the expanded ester is called as Baeyer-Villiger oxidation (BVO). Under the influence of a chiral reagent, this oxidation can be carried out asymmetrically. In case of a racemic ketone, a chiral catalyst has the potential of performing a kinetic resolution. The catalytic asymmetric BVO remains as one of the most powerful methods to convert a ketone into an ester.
• 5.6: Dihydroxylation, Aminohydroxylation and Aziridination Reactions
Insertion of oxygen atom in between the ketone carbonyl and an adjacent carbon yielding the expanded ester is called as Baeyer-Villiger oxidation (BVO). Under the influence of a chiral reagent, this oxidation can be carried out asymmetrically. In case of a racemic ketone, a chiral catalyst has the potential of performing a kinetic resolution. The catalytic asymmetric BVO remains as one of the most powerful methods to convert a ketone into an ester.
• 5.7: Problems and Reference
05: Oxidation Reactions
Oxidation of alcohols to carbonyl compounds is a pivotal process in organic chemistry. In particular, the oxidations that use readily available molecular oxygen, especially ambient air, as the stoichiometric oxidant are the most preferable. During the recent years, asymmetric version of the process has been developed using molecular catalysis, which can be divided into kinetic resolution of secondary alcohols and desymmetrization of meso - or prochiral diols (Scheme \(1\)).
5.1.1 Palladium Catalyst
The palladium catalyzed aerobic oxidation of alcohols to carbonyl compounds has received much attention in recent years and the catalytic cycle for this process is presented in Scheme \(2\). The cycle consists two separate processes: the oxidation of alcohols and the regeneration of the catalyst. In the oxidation of alcohols palladium alkoxide is generated after the coordination of the alcohol, and then β -hydride elimination occurs to afford the carbonyl compounds. The resultant palladium hydride reacts with molecular oxygen to generate palladium hydroperoxo complex and the subsequent ligand exchange reproduce the catalyst.
A series of experiments by three research groups have carried out using palladium complex bearing naturally occurring diamine, (-)-sparteine, to catalyzes the oxidation of aliphatic, benzylic and allylic alcohols with moderate to good krel values (Scheme \(3\)).
However, the isolated palladium-sparteine complex shows no catalytic activity and the reaction is effective employing additional (-)-sparteine (Scheme \(4\)). This result suggest that the additional (-)-sparteine serves as base to abstract a proton to a palladium bound alcohol in the alkoxide formation process.
Subsequently, the combination of palladium complexes bearing chiral and achiral N-heterocyclic carbene lignads with (-)-sparteine has been used for the kinetic resolution of secondary alcohols with high selectivity (Scheme \(5\)).
The reaction is found to be accelerated in the presence of Cs2CO3 under ambient air (Scheme \(6\)). The procedure is found to be useful for the synthesis of several pharmaceutically important substances including Prozac®, Singlair®, and Merck's h-NK1 receptor antagonist.
5.1.2 Ruthenium Catalyst
Chiral Ru-salen complex 3 having nitrosyl ligand has been found to be effective catalyst for the oxidative kinetic resolution of secondary alcohols under ambient air as oxidant under visible light (Scheme \(7\)). The irradiation of the visible light promotes dissociation of the nitrosyl ligand and generates a catalytically active ruthenium species. Kinetic resolution of aryl, alkynyl and alkyl alcohols has been observed with krel up to 30.
Scheme \(7\)
The chiral ruthenium based complex 4 is also effective for the oxidative desymmetrization of 1,4- meso -diols (Scheme \(8\)).
Scheme \(9\) shows the proposed mechanism for the Ru-catalyzed aerobic oxidation of alcohols which is similar to the galactose oxidase system.
5.1.3 Vanadium Catalyst
Vanadium complexes having chiral tridentate Schiff base ligand 5 derived from optically active amino alcohol and benzaldehyde derivative catalyze efficiently the kinetic resolution of α -hydroxy carbonyl compounds (Scheme \(10\)). The reactions of α -hydroxy esters can be accomplished with krelranging from 6 to 50. Subsequently, the chiral tridentate Schiff base ligand 6 derived from optically active α -amino acids and aldehydes have also been found to be effective for the vanadium catalyzed aerobic kinetic solution of hydroxy compounds (Scheme \(11\)). For example, the reaction of α -hydroxyphosphonic acids can be accomplished with excellent selectivity (krel 99). The observed experimental results suggest that these oxidation reactions don't involve radical process.
5.1.4 Iridium Catalyst
Few studies are focused on the use of chiral iridium complexes for the oxidative kinetic resolution of racemic secondary alcohols. Chiral iridium complex 6 has been shown to catalyze the oxidation benzylic alcohols with high krel under air. Using these reaction conditions, the oxidation of 1-indanol is reported with enantioselectivity of up to 99% and 50 yield.
Iridium chloride complex 7 has been used for the oxidation of racemic secondary alcohols with krelas high as 48.8 (Scheme \(13\)). The Rh analogue 8 exhibits high catalytic activity in the presence of base, while the related Ru complex 9 gives diminished result. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/05%3A_Oxidation_Reactions/5.01%3A_Oxidation_of_Alcohols.txt |
Epoxidation of allylic alcohols is a well developed practical process in asymmetric catalysis.
Titanium-Catalyzed Epoxidation
The Sharpless asymmetric epoxidation of allylic alcohol provides a powerful tool for the synthesis of optically active epoxy alcohol. For example, hexe-2-en-1-ol undergoes epoxidation to give chiral epoxy alcohols with 94% ee and 85% yield in presence of 5-10 mol% of Ti(OiPr)4 , L-(+)-DET and t -BuOOH (Scheme \(1\)). Using D-(-)-DET as chiral source the opposite enantiomer can be obtained with similar yield and enantioselectivity.
Examples:
In case the substrates having more double bonds, the allylic double bond can be oxidized. For example, the allylic double bond of geraniol can be selectively oxidized with 95% ee (Scheme \(2\)).
Mechanism
The reaction of titanium alkoxide with tartrate ligands leads to the formation of the dimers 1 and 4 that in the presence of t -BuOOH are converted into the intermediates 2 and 5, respectively, by displacement of the isopropoxide and tartrate carbonyl groups (Scheme \(3\)-\(4\)). Reaction of 2 and 5 with allylic alcohol give the intermediates 3 and 6, respectively. The stereochemistry of the epoxide is determined by the diastereomer of the chiral tartrate diester.
The product stereochemistry can be predicted using the model shown in Scheme \(5\).
Application
The reaction has been applied for the synthesis of a number of natural products, antibiotics and pharmaceuticals. For examples, the synthesis of the sex pheromone of gypsy moth (Lymantria dispar) (+)-disparlure 12 has been accomplished (Scheme \(6\)). The epoxidation of allyl alcohol 7 by Sharpless procedure affords optically active epoxy alchohol 8 with 95% ee that in presence of pyridinium dichlorochromate (PDC) gives chiral aldehyde 9 . The latter with Wittig salt 10 affords trans -alkene 11 that could be reduced using Pd/C to give the target (+)-disparlure 12 .
The Scheme \(7\) shows the use of the Sharpless asymmetric epoxidation for the synthesis of gastric inhibitor (S) -propanolol. The epoxidation of 3-(trimethylsilyl) prop-2-en-1-ol 13 affords epoxy alcohol 14 with 90% ee that could be converted into 16 by mesylation 15 followed by coupling with 1-naphthol. Opening of the epoxide 16 with isopropylamine leads to the formation of the target (S) -propanolol 17 .
Vanadium-Catalyzed Epoxidation
Few Studies are focused on chiral vanadium catalyzed the epoxidation of allylic alcohols. The epoxidation of homoallylic alcohol has been found to be successful (Scheme \(8\)).
Examples:
Niobium-Catalyzed Epoxidation
Chiral niobium-complexes catalyze the epoxidation of allylic alcohols in the presence of hydrogen peroxide (H2O2) or urea hydrogen peroxide (UHP). From environmental and economic standpoint, this process is more attractive because it is atom economical and generates water as by-product. For example, [(μ-oxo){Nb(salan)}2] 20 catalyzes the epoxidation of allylic alcohols in the presence of UHP at ambient conditions (Scheme \(9\)-\(10\)).
In this protocol, the μ-oxo dimer dissociates into a monomeric species that catalyzes the reaction (Scheme \(11\)). Moreover, monomeric Nb(salan) complexes prepared in situ from Nb(OiPr)5 and salan ligands followed by water treatment are found to catalyze the epoxidation better using aq. H2O2with enantioselectivity ranging from 83 to 95% ee. This is the first example of the enantioselective epoxidation of allylic alcohols using aq. H2O2 as terminal oxidant. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/05%3A_Oxidation_Reactions/5.02%3A_Epoxidation_of_Allylic_Alcohols.txt |
Asymmetric epoxidation of unfunctionalized alkenes affords an appealing strategy for the synthesis optically active organic compounds. This section covers some of the recent developments on this protocol.
5.3.1 Manganese-Catalyzed Reactions
In 1990, Jacoben and Katsuki groups independently reported the chiral Mn-catalzyed asymmetric epoxidation of unfunctionalized alkenes. The catalysts can readily be synthesized by the reaction of Mn(OAc)2 with Schiff base derived from chiral 1,2-diamines and 2-hydroxybenzaldehyde derivatives (Scheme \(1\)). Reaction with Mn(OAc)2 in the presence of air gives the Mn(III) complex that may be isolated as the chloro derivative after the addition of lithium chloride.
For example, chiral Mn-salen 22 catalyzes the epoxidation of trisubstituted unfunctionalized alkenes with 88-95% ee (Scheme \(2\)).
Examples:
Styrene derivatives can be successfully epoxidized using 23a-b with good enantioselectivity (Scheme \(3\)). The reaction is effective using the combination of N -morpholine oxide and m -chloroperbenzoic acid.
Mechanism
The epoxidation may proceed via a concerted (A) or radical-mediated (B) stepwise manner that depends on the electronic and oxidation state of the oxo species (Scheme \(4\)).
To account the degree and sense of the enantioselectivity, side-on perpendicular approach of the alkene to the high valent metal-oxo intermediate has been invoked (Scheme \(5\)).
Scheme \(6\): Construction of Anti-hypertensive Agents.
Applications
The epoxidation of 6-cyano - 2,2-dimethylchormene 24 with 22 affords 25 that can be converted into anti-hypertensive agents cromakalim and EMD-52692 by reaction with appropriate nitrogen nucleophiles (Scheme \(6\)).
The catalyst 22 has been further utilized for the epoxidation of cis -cinnamic ester in 97% ee and 56% yield that can be converted into taxol side chain by opening of the epoxide with ammonia followed by hydrolysis and protection using (t-BuCO)2O (Scheme \(7\)).
5.3.2 Ruthenium-Catalyzed Aerobic Epoxidation
Chiral Ru(NO)-salen complexes has been found to catalyze the aerobic epoxidation of alkenes in presence of water under visible light irradiation at room temperature (Scheme \(8\)). This method is attractive from environmental and economic standpoint. The observed preliminary experimental results suggest that an aqua ligand coordinated with the ruthenium ion acts as a proton transfer agent for the oxygen activation process.
5.3.3 Titanium-Catalyzed Epoxidation with Hydrogen Peroxides
The use of Ti(salan) for the epoxidation of alkenes has been demonstrated in the presence of aqueous H2O2. The reaction is stereospecific and decomposition of H2O2 has not been observed. The most striking feature of this system is aliphatic alkenes that are one of the most challenging substrates for asymmetric epoxidation can be successfully oxidized with high enantioselectivity (Scheme \(9\)). Furthermore, the in situ generated titanium complex derived from 3 (SALANEL) and Ti(OiPr)4 in CH2 Cl2 catalyzes the epoxidation of alkenes in the presence of phosphate buffer with excellent enantioselectivity (Scheme \(10\)).
This epoxidation protocol has been successfully applied to a multigram scale synthesis of indene oxide. While the proline-based C1 -symmetric Ti-(salan) from 4 and Ti(OiPr)4 has been found to be excellent catalyst for the epoxidation of styrene derivatives (Scheme \(11\)).
5.3.4 Lanthanoid-Catalyzed Epoxidation
Nucleophilic epoxidation methods represent a viable alternative to electrophilic methods, many of which do not epoxidize electron-poor double bonds. The lanthanide based catalysts derived from chiral ligands 5-7 have been found to be effective in the epoxidation of α,β-unsaturated ketones (Scheme \(12\)). It is mainly nucleophilic epoxidation of electron-deficient double bonds through the action of nucleophilic oxidants.
Proposed Mechanism
A 1:1:1 mixture of La(OiPr)3 , BINOL and Ph3As=O may afford the active complex a in the reaction medium (Scheme \(13\)). Activation of the enone b by coordination to lanthanum metal followed by 1,4-addition of lanthanum peroxide may lead to the formation of enolate c that could provide the epoxide and intermediate d . The latter with TBHP can provide the active complex a to regenerate the catalytic cycle.
Replacement of La(OiPr)3 by Sm(Oi-Pr)3 , (R)-BINOL 5 by (R)-H8-BINOL 6, Ph3As=O by Ph3P=O and TBHP by CHMP greatly enhances the yield and enantiomeric purity under similar condition for alkenes bearing amides (Scheme \(14\)).
The catalyst derived from 7 and Y(OiPr)3 catalyzes the epoxidation of α,β -unsaturated esters with excellent enantioselectivity (Scheme \(15\)). The system is compatible with alkenes bearing heteroaromatic rings.
5.3.5 Organocatalysis
Remarkable progress has been made on the asymmetric epoxidation of alkenes using organo catalysis. Chiral ketones are among the some of the most developed epoxidation catalysts. Active dioxirane is generated from ketone and oxone (potassium peroxomonosulfate) or hydrogen peroxide under milder reaction conditions. Among the many useful chiral ketones reported, fructose derived ketone developed by Shi group is the most reliable catalyst with respect to high enantioselectivity and broad substrate scope (Scheme \(16\)).
For example, in presence of 8 (typically 20-30 mol%), a variety of trisubstituted alkenes proceed reaction with excellent enantioselectivity (Scheme \(17\)).
Examples:
In case of cis and terminal alkenes, the glucose-derived ketone 9 with N -Boc oxazolidinone provides high enantioselectivity. A carbocyclic analogue 10 and N -aryl substituted variants 11 have also been introduced for the epoxidation of styrene derivatives and cis -disubstituted alkenes. Furthermore, the chiral ketone 12 with electron-withdrawing acetate has been found to catalyze the epoxidation of α,β -unsaturated ester with high enantioselectivies.
Proposed Mechanism
Scheme \(18\) shows the proposed catalytic cycle and the most favored transition state for the chiral ketone based epoxidations in the presence of oxone as terminal oxidant.
The chiral ketone-catalyzed epoxidation has been subsequently found to be effective using the combination of hydrogen peroxide and acetonitrile as an alternative oxidant. For example, chiral ketone 8 has been used for the epoxidation of a variety of alkenes with comparable yields and enantioselectivity (Scheme \(19\)).
Proposed Mechanism
In this protocol, acetonitrile reacts with hydrogen peroxide to generate peroxyimidic acid and then reacts with the ketone to give the active dioxirane. Under these conditions, a stoichiometric amount of the amide is generated as a product.
Besides the chiral ketones, chiral amine based catalysts 13 and 14 have been explored for the epoxidation of unfunctionalized alkenes. For example, chiral pyrrolidine 15 has been used for the α,β -unsaturated aldehydes with excellent enantioselectivity in the presence of 35% H2O2 (Scheme \(20\)). α,β -Unsaturated aldehydes containing an aromatic substituent at the β -position are good substrates affording the epoxides with high diastereo- and enantioselectivities.
Proposed Mechanism
The proposed mechanism states that the reaction takes place through the Weitz-Scheffer mechanism (Scheme \(22\)). The addition of hydrogen peroxide to the β -carbon atom of the electrophilic iminium ion is reversible and the attack on the electrophilic oxygen atom by the nucleophilic enamine determines the product stereochemistry.
While chiral N -spiro ammonium salt 14 bearing an axially chiral binaphthyl unit functions as phase transfer catalyst for the epoxidation of enones with high enantioselectivity (Scheme \(22\)). The hydroxyl groups are appropriately bonded to recognize and activate the enone substrate by hydrogen bonding. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/05%3A_Oxidation_Reactions/5.03%3A_Epoxidation_of_Unfunctionalized_Alkenes.txt |
Enantiopure sulfoxides serve as chiral auxiliary as well as intermediates for the synthesis of optically active compounds. Optically active sulfoxide structural unit is also present in many compounds that exhibit interesting biological properties (Scheme \(1\)). Development of methods for the asymmetric sulfoxidation has thus been active topic in asymmetric catalysis. This lecture covers the common methods that are used for the synthesis of optically active sulfoxides.
5.4.1 Enzyme-Catalyzed Reactions
Enzyme catalyzed asymmetric oxidation of sulfides provides effective methods for the synthesis of optically active sulfoxides. For example, cyclohexanone monooxygenase (CHMO), a bacterial flavoenzyme, catalyzes the oxidation of prochiral thioethers with excellent enantioselectivity (Scheme \(2\)).
5.4.2 Chiral Reagents Based Reactions
Chiral reagents have been used for the oxidation of prochiral sulfides. For example, chiral hydroperoxides, N -sulfonyl oxaziridines and chiral oxaziridines can oxidize prochiral sulfides to optically active sulfoxides with moderate to good enantioselectivity (Scheme \(3\)).
In addition, chiral sulfinates are precursors of chiral sulfoxides (Scheme \(4\)). This approach is of preparative interest to provide the sulfoxides with high enantioselectivity. The important issue is need to prepare the menthyl- p -tolylsulfinates from L-(-)-menthol and then to separate them.
Furthermore, N -tosyl-norephedrine can be reacted with thionyl chloride to afford heterocyclic compound A, which could be reacted via the sequential addition of R1MgX and R2MgX, in a one-pot procedure to give sulfoxides in >99% ee (Scheme \(5\)). The configuration depends on the order of introduction of the two Grignard reagents.
5.4.3 Metal-Catalyzed Reactions
5.4.3.1 Reactions with Diethyl Tartrates
In the middle of 1980, Kagan and Modena groups independently modified the conditions that were employed by Sharpless group for the asymmetric epoxidation of allylic alcohols, and used for the oxidation of sulfides. The modified conditions involve the combination of Ti(OiPr)4, ( R,R)- diethyl tartrate (DET) and t -BuOOH (TBHP) in water (Scheme \(6\)). The replacement of TBHP with cumyl hydroperoxide (CHP) led to improvement in the enantioselectivity of the sulfoxide.
5.4.3.2 Reactions with Tridentate Ligands
In the middle of 1990, vanadium complexes having the tridentate Schiff base ligands L1-2 derived from optically active amino alcohols and aryl aldehydes have been studied for the oxidation of sulfides in the presence of aq. H2O2 as terminal oxidant (Scheme \(7\)). The catalysts are prepared in situ and the effect of series Schiff base ligands is studied.
In case of di- tert -butyldisulfide, monoxidation occurs selectively with up to > 90% ee (Scheme \(8\)).
Subsequently, the reaction has also been found to be effective with Fe(acac)3 in the presence of additive such as p-methoxybenzoic acid (Scheme \(9\)). For example, the oxidation of p -chlorophenyl methyl sulfide can be accomplished with 92% ee and 60% yield. In some cases, kinetic resolution is observed.
5.4.3.3 Reactions with Salen Based Ligands
Chiral Ti-salen has been found to be effective catalyst for the oxidation of sulfides in the presence of urea hydrogen peroxide (UHP) or aqueous H2O2 . First, Ti-salen is converted into cis - μ -dioxo Ti-dimer that reacts with H2O2 to give peroxo species. The latter can oxidize the sulfide to sulfoxide (Scheme \(10\)). The oxidation of several alkyl aryl sulfides can be accomplished with 92–99% ee.
Subsequently, Fe(salan) has been found to catalyze the oxidation of sulfides in the presence of a queous H2O2 in water (Scheme \(11\)). This procedure has the advantages of high catalytic turnover number (TON) of 8000 as well as the use of water as reaction medium.
Furthermore, Al(salalen), which is compatible in water, catalyzes the oxidation of sulfides with aqueous H2O2 at room temperature in phosphate buffer condition (Scheme \(12\)). The reactions of a variety of sulfides have been demonstrated with high enantioselectivity.
Meanwhile, chiral Ru(NO)-salen has been found to catalyze the sulfoxidation under aerobic conditions in the presence of water under visible light irradiation at room temperature (Scheme \(13\)). Unlike biological oxygen atom transfer reactions that need a proton and electron transfer system, this aerobic oxygen atom transfer reaction requires neither such a system nor a sacrificial reductant.
Although the mechanism of this oxidation has not been completely clarified, some experimental results support the notion that an aqua ligand coordinated with the ruthenium ion serves as a proton transfer agent for the oxygen activation process, and it is recycled and used as the proton transfer mediator during the process. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/05%3A_Oxidation_Reactions/5.04%3A_Enantioselective_Sulfoxidation.txt |
Insertion of oxygen atom in between the ketone carbonyl and an adjacent carbon yielding the expanded ester is called as Baeyer-Villiger oxidation (BVO). Under the influence of a chiral reagent, this oxidation can be carried out asymmetrically. In case of a racemic ketone, a chiral catalyst has the potential of performing a kinetic resolution. A century after its discovery, the catalytic asymmetric BVO remains as one of the most powerful methods to convert a ketone into an ester proceeding by insertion of an oxygen atom into a bond.
Metal-Catalyzed Reactions
Copper(II) complexes with oxazoline-based ligands are studied for the oxidation of substituted cyclic ketones to give lactones with high enantioselectivity (Scheme \(1\)). These reactions employ isobutanal as co-reductant under aerobic conditions. During the reaction isobutanal is oxidized to the corresponding carboxylic acid.
Platinum complexes bearing chiral phosphines catalyze oxidation of substituted cyclic ketones in the presence of hydrogen peroxide (Scheme \(2\)). Coordination of Pt and peroxide to the carbonyl leads to the formation of a metallocycle that could be decomposed into the target lactone. Chiral ligands associated with Pt allow for diastereomeric transition states, which discriminate between the two possible migrating carbon atoms resulting in enantioselectivity.
The reaction conditions used for the enantioselective epoxidation of allylic alcohols (Sharpless epoxidation) is also effective for the oxidation of substituted cyclobutanones to give lactones with moderate to good enantioselectivity (Scheme \(3\)).
The oxidation of symmetrical cyclobutanones is effective using chiral palladium complex bearing phosphinooxazoline ( PHOX) in the presence of urea hydrogen peroxide. For example, prochiral 3-substituted cyclobutanones undergoes oxidation to give γ -lactones, which can be recrystallized to obtain the target products with 93% ee and 91% yield. This procedure has been utilized for the synthesis of GABA-B receptor agonist (R) -( _ )-baclofen (Scheme \(5\)). The racemic form of baclofen is commercially available to treat spasticity and alcoholism; however, the ( R ) - isomer has been shown to be predominantly responsible for the molecule's bioactivity. The molecule has been the target of many asymmetric syntheses. Several of these strategies start from enantioenriched lactone using enzymatic BVO or from an enantioselective C-H insertion.
In addition to the metal-catalyzed BVOs, chiral auxiliary approach is also followed to synthesis lactone with good enantioselectivity (Scheme \(6\)). For example, reaction of optically active 1,3-diol with an achiral cyclobutanone can give chiral ketal. The latter can be reacted with m CPBA and SnCl4 to give an orthoester, which upon acidic work-up affords the lactone.
Enzyme Catalyzed Reactions
Baeyer-Villiger monooxygenases are enzymes that catalyze the insertion of an oxygen atom in a ketone, next to the carbonyl carbon atom. So far, only a limited number of BVMO have been identified from bacteria and fungi. These enzymes typically contain FAD or FMN as a cofactor and catalyze highly regio- and stereoselective oxygenations at the expense of NAD(P)H and molecular oxygen. Bio-catalyzed BVO proceeds with high levels of enantioselectivity. For example, cyclohexanone monooxygenase (CHMO), a bacterial flavoenzyme, carries out an oxygen insertion reaction on cyclohexanone to form a seven-membered cyclic product, ε-caprolactone (Scheme \(7\)). This reaction involves the four-electron reduction of O2 at the expense of a two-electron oxidation of NADPH and a two-electron oxidation of cyclohexanone to form ε-caprolactone. The CHMO has been employed successfully for the oxidative desymmetrization of cyclobutanone and cyclopentanone rings with high enantioselectivity. CHMO mutant 1K2 -F5 (Phe432 Ser) has been used with air as the oxidant in a whole-cell process. Mutant Phe432 Ser also tested for oxidative desymmetrization of a set of 4-substituted cyclohexanone derivatives (methyl, ethyl, methoxy, chloro, bromo, iodo) and in all cases enantioselective transformations are observed with up to 99% ee.
Similarly, PAMO mutant Gln93 Asn/ Pro94 Asp is tested for the asymmetric desymmetrization of 4-substituted cyclohexanone derivatives to give chiral lactones with high enantioselectivity (Scheme \(8\)). It is interesting to note that the absolute configuration of the lactone products is opposite to what is observed with the thermolabile cyclohexanone monooxygenase (CHMO) as the catalyst.
Reactions using Organocatalysis
Readily available glucose-derived oxazolidinone containing ketone can be employed for BVO of a variety of benzylidenecyclopropanes in the presence of oxone (Scheme \(9\)). Optically active α -aryl- γ-butyrolactones and α -aryl- γ - methyl- γ-butyrolactones can be obtained in reasonable yields and enantioselectivities. The reaction works via in situ epoxide rearrangement and BVO. Chiral cyclobutanones can also be obtained by suppressing BVO with more ketone catalyst and less oxone. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/05%3A_Oxidation_Reactions/5.05%3A_Baeyer-Villiger_Oxidation_%28BVO%29.txt |
5.6.1 Dihydroxylation Reaction
In 1980, the first attempt for enantioselective cis -dihydroxylation of alkenes with osmium tetroxide was appeared. Subsequent continuous efforts led to improve the reaction yield and enantioselectivity in the presence of osmium-cinchona alkaloid complexes (Scheme \(1\)). The reactions can be performed at ambient conditions in liquid-liquid biphase system having water and t-BuOH employing secondary oxidant such as K3Fe(CN)6 to afford the target 1,2- cis diols with high enantioselectivity. Please see Module I, Reagents and Organic Reactions, for the mechanism.
K3Fe(CN)6 is used as a oxidant to reoxidize the Os(VI) after each catalytic cycle. Since OsO4 is volatile and toxic, the osmium is usually added as K2OsO2 (OH)4, which forms OsO4 in the reaction mixture. K2CO3 and methanesulfonamide (MeSO2 NH2) are used as additive to enhance the rate of the reaction. Scheme 2 summarizes some of the successful cinchona alkaloid based ligands for the asymmetric dihydroxylation reactions. The approach of hydroxyl group is directed to either the top face or the bottom face of the alkene which depends on the nature of the ligands, DHQD or DHQ, are used.
In parallel to the above described catalytic processes, the use of optically active bidentate 1,2-diamine based ligand L has been demonstrated in place of alkaloid as a chiral source for the asymmetric dihydroxylation of alkenes using OsO4 (Scheme \(3\)). The reactions of a series of alkenes can be accomplished with good to excellent yield and enantioselectivity.
In addition, the bidentate ligand L 1 is found to effective for the OsO4 -mediated dihydroxylation of trans -disubstituted and monosubstituted alkenes (Scheme\(4\)). The reaction is believed to involve intermediate A and the products are obtained with high yield and enantioselectivity.
5.6.1.1 Synthesis of Biologically Important Molecules
The Os-catalyzed enantioselective dihydroxylation is used as a key step in the highly expeditious synthesis of the antibacterial agent (–)-chloramphenicol (Scheme \(5\)).
The synthesis of the β -receptor-blocking drug ( S ) - propranolol has been demonstrated employing osmium-catalyzed dihydroxylation as a key step (Scheme \(6\)). Reaction of α - naphthol with allylic bromide gives allyl naphthyl ether that could be dihydroxylated using AD-mix - β with 91% ee. The diol derivative could be converted into ( S ) - propranolol by classical methods.
The synthesis of chromophore of anthracycline antibiotic uses chiral osmium complex bearing chiral diamine L for asymmetric dihydroxylation with good enantioselectivity (Scheme \(7\)). The resultant 1,2-diol could be subsequently converted into the desired chromophore of anthracycline antibiotic in good yield.
5.6.2 Asymmetric Aminohydroxylation
The chiral β-amino alcohol structural unit is a key motif in many biologically important molecules. It is difficult to imagine a more efficient means of creating this functionality than by the direct addition of the two heteroatom substituents to an alkene, especially if this transformation could be achieved in regioselective and enantioselective fashion. In parallel to allylic epoxidation and dihydroxylation of alkenes; Sharpless group has developed asymmetric aminohydroxylation of alkenes using osmium based catalysis.
Synthesis of chiral α -sulfonamido hydroxy compounds can be obtained when the alkene substrates are subjected to the aminohydroxylation reaction using chloramine-T (TsNClNa) as the nitrogen source and H2O as the oxygen source. The reaction is found to be successful in the presence of osmium complex bearing (DHQ)2 PHAL or (DHQD)2 PHAL. The α -sulfonamido hydroxy compounds can be isolated with high yield and enantiomeric purity. Better results are obtained with chloramine-T (oxidant) salts bearing smaller organic substituents on the sulfur. This reagent could be prepared separately and added to the reaction mixture as the stable anhydrous salt or it can be generated in situ (Scheme \(8\)). The methyl (E )-cinnamate can be successfully converted into α-hydroxy- β-amino product with high enantioselectivity. The resultant product is used to construct the taxol side chain, and this process establishes the shortest and the most efficient route to the side chain of this pharmaceutically important agent.
The key issue is the regioselectivity of the reaction. Replacement of sulfonamide in chloramine-T with alkyl carbamates like BnO2CNH2 , EtO2CNH2, and t-BuO2CNH2 or amides greatly improves the reaction scope of the substrate and selectivity up to 99% ee and 80% yield. Also carbamate product could be easily converted into free amino alcohol. t -Butyl carbamate is superior to ethyl carbamate in terms of yield, enantioselectivity, and ease of removal of the N -protecting group.
Nitrogen source 2-trimethylsilylethyl N -chloro- N -sodiocarbamate (TeoCNClNa) could be synthesized by reacting NaOH and t -BuOCl with 2-(trimethylsilyl)ethyl carbamate, which can be prepared by successively adding carbonyl diimidazole and ammonia to 2-trimethylsilylethanol in benzene (Scheme \(9\)-\(10\)). The TeoC group can be cleaved by fluoride under very mild conditions, yielding the free amino alcohol with high enantiomeric purity.
The mechanism of the reaction is shown in Scheme \(11\). The Os(VI) azaglycolate is reoxidized by the N -chloroamide substrate and releases the target product after hydrolysis. The reoxidized metallacycle undergoes a second cycloaddition leading to an Os(VI) bis(azaglycolate). Conducting the reaction in an aqueous medium under more dilute conditions favors the hydrolysis.
5.6.3 Asymmetric Aziridination
Aziridines are versatile building blocks in organic synthesis. Considerable progress has been made in the area of asymmetric aziridination employing copper based systems. Mn(porphyrin) and Mn-salen complexes have been shown as effective catalysts for this reaction. The reactions proceed via active nitrenoid species and most of the methods use a hypervalent iodine reagent such as PhI=NTs as nitrenoid source. The deprotection of N-sulfonyl groups require harsh reaction conditions, development of new methods has thus been focused without protecting group or with a readily removable group. In this context, the use of azide compounds as nitrogen source has been recently demonstrated.
Ru-salen is found to be effective catalyst for the aziridination of alkenes with TsN3 at room temperature with excellent enantioselectivity (Scheme \(12\)). p -Nitro and o -nitrobenzenesulfonyl azide and 2-(trimethylsilyl)ethanesulfonyl azide (SESN3) are also effective for this reaction affording the aziridine with high enantioselectivity. Furthermore, less nucleophilic α, β -unsaturated esters proceed aziridination with high enantioselectivity.
An aminimide that is generated by deprotonation of the corresponding aminimine undergoes aziridination of chalcone via conjugate addition and ring closure by N-N bond cleavage. For example, O-mesitylenesulfonylhydroxylamine proceeds reaction in the presence of (+)-Troger base and CsOH∙.H2O with moderate enantioselectivity (Scheme \(13\)). Soon after the use of quiniclidine for the reaction of O -(diphenylphosphinyl)hydroxylamine with chalcone is shown with 56% ee (Scheme \(14\)).
5.07: Problems and Reference
Problems:
Complete the following transformations.
How will you prepare the following chiral ligands?
Complete the following reactions.
Predict the major products for the following reactions.
List three effective organo catalysts for the epoxidation of α,β -unsaturated ketones. Provide mechanism.
List three effective organo catalysts for the epoxidation of α,β -unsaturated aldehydes. Provide mechanism.
Complete the following reactions.
Describe chiral phosphoric acid catalyzed asymmetric Baeyer-Villiger oxidation.
Complete the following reactions.
What product(s) would you expect from the following reactions?
Reference/Text Book
1. I. Ojima, Catalytic Asymmetric Synthesis , 3 rd ed., Wiley, New Jersey, 2010.
2. M. B. Smith, Organic Synthesis , 2 nd edition, McGraw Hill, New Delhi, 2004.
• Ojima, Catalytic Asymmetric Synthesis, VCH Publishers, Inc., New York 1993. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/05%3A_Oxidation_Reactions/5.06%3A_Dihydroxylation%2C_Aminohydroxylation_and_Aziridination_Reactions.txt |
• 6.1: Reactions Carbon-Carbon Double Bonds
Enantioselective reduction of C=C double bonds have important applications in the synthesis of many natural products and pharmaceutically important compounds.
• 6.2: Reactions of Ketones
Enantioselective reduction of C=O double bond in organic synthesis has important application in synthesis of many natural products as well as pharmaceutical products.
• 6.3: Reactions of Imines (C=N)
An important field of investigation for new industrial catalysts is the development of improved catalysts for the reduction of imines to obtain the corresponding chiral amines. These chiral amines are used as key components in many active pharmaceutical intermediates.
• 6.4: Problems and Reference
06: Hydrogenation Reactions
Enantioselective reduction of C=C double bond has important application in the synthesis of many natural products and pharmaceutically important compounds. Scheme \(1\) summarizes some of the common successful phosphine based chiral ligands developed for the catalytic asymmetric hydrogenation of alkenes.
BINAP based ligands play an important role for asymmetric hydrogenation of alkenes. Both (S)- BINAP and (R)- BINAP could be synthesized by resolution methods using (1S,2S)- tartaric acid as well as (8R,9S)- N - benzylcinchonidinium chloride as the chiral sources . Synthesis of (S)- BINAPcould be performed from racemic 2,2'-dibromo BINAP (Scheme \(2\)). Resolution of the corresponding phosphine oxide with (1S,2S)- tartaric acid and subsequent reduction with HSiCl3 can afford (S)- BINAP in gram scale.
Alternatively, (S)- BINAP and (R)- BINAP can be synthesized by resolution of racemic BINOL using (8R,9S)- N - benzylcinchonidinium chloride (Scheme \(3\)) . Converting them into triflate derivative and subsequent cross-coupling with Ph2 PH using NiCl2 to afford (S)- BINAP and ( R ) - BINAP in gram scale. (S)- BINAP ; light brown solid, mp 205°C , 99 % ee, [α]21D= −29.4° ( THF , c =1). (R)- BINAP; white crystalline solid, mp 207°C , 99% ee, [α]21D = 26.2 - 30.9° ( THF , c 1).
6.1.1 Reduction of α,β -Unsaturated Carboxylic acids
Chiral Ru(II)-BINAP catalyzes the hydrogenation of α,β- unsaturated carboxylic acids. For example, the hydrogenation of naphthacrylic acid can be performed using a Ru-( S )-BINAP with 134 atm H2pressure (Scheme \(4\)). The reaction affords chiral ( S )-naproxen with 98% ee, which is a nonsteroidal anti-inflammatory drug.
Hydrogenation has been explored for the synthesis of intermediate of (S)- mibefradil. For this reaction chiral Ru-complex bearing ( R )-MeO-BIPHEP is found to be effective affording the target intermediate with 92% ee (Scheme \(5\)).
6.1.2 Reduction of Allylic alcohol
Allylic alcohols can be reduced with high selectivity using chiral Ru-( S )-BINAP as a catalyst. For example, the reduction of geraniol can be accomplished with 94% ee (Scheme \(6\)). The reduced product is used for the large scale synthesis of L-(+)-menthol. Under these conditions, nerol undergoes reduction to give ( S )-citronellol in 99% ee. Chiral iridium-based catalytic systems have also been subsequently explored for the asymmetric reduction of allylic alcohols. For example, the complex bearing chiral phosphanodihydrooxazole L1 catalyzes asymmetric reduction of an allyl alcohol, which is used as a key step in the synthesis of lillial (Scheme \(7\)). Scheme \(8\) illustrates the synthesis of chiral phosphanodihydrooxazole L1.
6.1.3 Reduction of Allylic Amines
In parallel to the reduction of allylic alcohol, Rh-( S )-BINAP system has been used for the reduction of allylic amine. For example, the synthesis of (R)- citronellal can be accomplished via reduction of allylic amine (Scheme \(9\)). The key step is the isomerization of geranyl diethylamine forming (R)-citronellal enamine . The Rh-complex performs the rearrangement of this allylic amine to the enamine creating a new chiral centre with >98% ee, which upon hydrolysis gives (R)-citronellal in 96–99% ee. The latter serves as substrate precursor for the synthesis of L-(+)-menthol via intramolecular ene reaction followed by hydrogenation (Scheme \(10\)).
6.1.4 Reduction of α, β-Unsaturated Aldehydes
Asymmetric reduction of α, β -unsaturated aldehydes with transition metal catalysts has not yet proven ready for wide spread industrial application. In comparison to CBS catalyst, the Baker's yeast is most useful, since the precursor (R)-proline used to synthesize CBS is expensive. The chiral reduction of enals to chiral alcohols using Baker's yeast has been known for over 30 years. Scheme \(11\) summarizes some of the examples for the Baker yeast catalyzed reduction of C=C of α, β -unsaturated aldehydes.
Subsequently, organocatalysis has been found be effective for the asymmetric reduction. A recent interesting development is the organocatalytic hydride transfer reductions of α, β -unsaturated aldehydes to chiral aldehyde. Hantzsch ester acts as a good NADH mimic in the hydride transfer to an iminium ion, formed when the α,β -unsaturated aldehyde reacts with the amine of the organocatalyst (Scheme \(12\)).
Similarly, chiral phosphoric acid L2 catalyses the reduction of C=C of α, β -unsaturated aldehyde with 90% ee and 98% yield in the presence of Hantzsch ester (Scheme \(13\)).
6.1.5 Reduction of α, β-Unsaturated α-Amino Acid
Asymmetric reduction of α, β -unsaturated α-amino acid has wide application in organic synthesis. Chiral biphosphines in combination with Rh acts as the best combination for the reduction α, β-unsaturated α -amino acids. Scheme \(14\) summarizes some of the successful chiral phosphines for the Rh-catalyzed reactions.
Rh-DIPAMP has been explored for the reduction of α, β-unsaturated α-amino acids. For example, L-DOPA, a chiral drug for treating Parkinson's disease, is synthesized using Rh-( R,R )-DIPAMP catalyzed reduction of α, β-unsaturated α -amino acid as a key step (Scheme \(15\)).
Rh -(R,R)- DuPHOS can be used for the reduction of α, β-unsaturated α-amino acid to give chiral amino acid (Scheme \(16\)). Using this procedure many of the unnatural α-amino acids can be obtained directly with enantioselectivity approaching 100% ee and S/C ratio 10000-50000. The rhodium-catalyzed hydrogenation of the E- and Z -isomers, with BINAP in THF, affords products with opposite absolute configurations. Remarkably, the (R,R)- DuPHOS system provides excellent enantioselectivity for both isomeric substrates with the same absolute configuration, irrespective of the E/Z -geometry. This result is particularly important for the construction of alkyl dehydroamino acid derivatives, which are difficult to prepare in enantiomerically pure form.
The hydrogenation of the ( E)- or ( Z)- isomer of β-(acetylamino)- β-methyl- α-dehydroamino acids with Rh(I)-Me-DuPHOS provides either diastereomers of the N, N -protected 2,3-diaminobutanoic acid derivatives with 98% ee (Scheme \(17\)-\(18\)).
(S)- SEGPHOS and its analogous provide superior results in Ru-catalyzed hydrogenation of four and five-membered cyclic lactones or carbonates bearing an exocyclic methylene group. For example, the reduction of the four membered lactone can be achieved with excellent enantioselectivity using S/C=12270 (Scheme \(19\)).
Scheme \(20\) describes the synthesis of SEGPHOS. The key step is the resolution of racemic phosphine oxide with (S,S)- DBTA (di-benzoyl-tartaric acid) to provide chiral phosphine oxide. Subsequent reduction with HSiCl3 affords the target SEGPHOS in good yield.
Moreover, chiral 1,10-diphosphetanylferrocene Et-FerroTANE serves as an effective ligand for the rhodium-catalyzed hydrogenation of β -aryl- and β -alkyl-substituted monoamido itaconate (Scheme \(21\)). For example, Et-DuPHOS–Rh is utilized for the asymmetric hydrogenation of the trisubstituted alkene to afford the reduced product, which is used for synthesis of intermediate of the drug candoxatril in 99% ee . Candoxatril is the orally active prodrug of candoxatril (UK-73967) human neutral endopeptidase (Neprilysin).
The above described alkyl/aryl-ferro-TANE family ligands could be synthesized from optically active diols (Scheme \(22\)). Cyclization with SO2Cl2 in presence of RuCl3 and NaIO4 affords chiral cyclized sulfonate, which reacts with ferro-phosphine in the presence of n-BuLi to give the target chiral alkyl/aryl-Ferro-TANE family in good yield.
Similarly, the reduction of α,α -disubstituted α, β-unsaturated ester can be carried out using chiral Ru-Et-Ferro TANE (Scheme \(23\)). The reaction is compatible with different electron donating and withdrawing groups attached to benzene ring.
6.1.6 Reduction of α -Alkyl Substituted Acids
Another important chiral acid is the α -alkyl substituted acid which is used in the synthesis of aliskiren (the active ingredient of Tekturna1) (Scheme \(24\)). The key step for the synthesis requires the hydrogenation of cinnamic acid derivative in the presence of Rh-phosphoramidite . The reduction also affords 97% ee using Rh-WALPHOS.
6.1.7 Reduction of α, β-Unsaturated Nitriles
The asymmetric reduction of unsaturated nitriles is a very useful process for the synthesis of many pharmaceutical intermediates. An important application of this strategy involves the further reduction of the nitrile group to yield chiral amines. For example, chiral Rh-phosphine catalyzes the asymmetric hydrogenation of an unsaturated nitrile (Scheme \(25\)). The reduced product is used for the synthesis of the Pregabalin.
A more challenging example of an unsaturated nitrile reduction that lacks the carboxylate functional group is the asymmetric reduction of the nitrile shown in Scheme \(26\). The reduced product is used for the synthesis of chiral 3,3-diarylpropylamine, which is an intermediate for the synthesis of the Arpromidines. The arpromidines analogues are the most potent histamine H2 receptor agonists known and are promising positive inotropic vasodilators for the treatment of severe congestive heart failure.
In parallel to Ru, Rh and Ir-based catalytic systems, chiral copper hydride catalysis have been demonstrated for enantioselective 1,4-reductions of 2-alkenyl heteroarenes. Both azoles and azines serve as efficient activating groups for this process (Scheme \(27\)). | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/06%3A_Hydrogenation_Reactions/6.01%3A_Reactions_Carbon-Carbon_Double_Bonds.txt |
Enantioselective reduction of C=O double bond in organic synthesis has important application in synthesis of many natural products as well as pharmaceutical products. The lecture covers the representative examples of metal catalyzed reactions. The reactions using CBS and enzymes are covered in the other modules of this course. The frequently used chiral ligands for the metal catalyzed enantioselective reduction reactions of ketones are listed in Scheme \(1\).
6.2.1 Reactions of α-Keto Amides
Asymmetric hydrogenation of α -keto esters has been studied with several rhodium catalysts. Neutral rhodium catalysts with chiral ligands such as Cr(CO)3-Cp,Cp-Indo-NOP demonstrate excellent enantioselectivity and reactivity in the hydrogenation of amides (Scheme \(2\)).
6.2.2 Reactions of β - Keto Esters
Asymmetric hydrogenation of β -keto esters has been extensively studied using chiral ruthenium catalysts. However, only handful of examples analogous to rhodium-catalyzed reaction are explored (Scheme 3). The Rh-( R,S )-Josiphos complex provides an effective catalyst for the asymmetric hydrogenation of ethyl 3-oxobutanoate affording the corresponding β -hydroxy ester in 97% ee. The above ligands Josiphos family such as chiral Walphos, Joshiphos, BPPFOH, TRAP and PIGIPHOS ligands could be easily synthesized from commercially available Ugi amine (Scheme \(4\)-\(6\)).
Iridium/spiro PAP has been used as effective catalyst for the asymmetric hydrogenation of β-aryl β-ketoesters (Scheme \(7\)). The reaction provides a readily accessible method for the synthesis of β-hydroxy esters in high enantioselectivity up to 99.8% ee and high TONs up to 1230000.
6.2.3 Reactions of Aromatic Ketones
Amino ketones and their hydrochloride salts can be effectively hydrogenated with chiral rhodium catalysts (Scheme \(8\)). The rhodium precatalysts, combined with chiral phosphorous ligands (S,S)- MCCPM provide excellent enantioselectivity and reactivity for the asymmetric hydrogenation of α, β, and γ -alkyl amino ketone hydrochloride salts with S/C=100000.
The enantioselective hydrogenation of 3,5-bistrifluoromethyl acetophenone (BTMA) can be carried out using a Ru/phosphine-oxazoline complex (Scheme \(9\)) . The reaction is compatible with 140-kg scale at 20 bar and 25°C with S/C ratios of 20,000. The synthesis of the ligand is shown in Scheme \(10\).
The enantioselective hydrogenation of amino ketones has been applied extensively to the synthesis of chiral drugs and pharmaceuticals (Scheme \(11\)). For example, direct enantioselective hydrogenation of 3-aryloxy-2-oxo-1-propylamine leads to 1-amino-3-aryloxy-2-propanol using 0.01 mol % of the neutral Rh-(S, S)-MCCPM complex. The chiral product 1-amino-3-aryloxy-2-propanol serves as β-adrenergic blocking agents. (S)-Propranolol is obtained in 90.8% ee from the corresponding α-amino ketone.
6.2.4 Reactions of Aliphatic Ketones
The asymmetric hydrogenation of simple aliphatic ketones remains still a challenging problem. This is due to the difficulty to design the appropriate chiral catalyst that will easily differentiate between the two-alkyl substituents of the ketone. Promising results have been obtained in asymmetric hydrogenation of aliphatic ketones using the ( R,S,R,S )-PennPhos- Rh complex in combination with 2,6-lutidine and KBr. For example, the reaction of tert -butyl methyl ketone takes place with 94% ee . Similarly, isopropyl-, n -butyl- and cyclohexyl methyl ketones can be reduced with 85% ee , 75% ee and 92% ee, respectively.
The chiral Ru-diphosphine/diamine derived from chiral BINAP, DPEN (diphenylethylene diamine) and indanol effect enantioselective hydrogenation of certain amino or amido ketones via a non-chelate mechanism without interaction between Ru and nitrogen or oxygen (Scheme \(14\)). The diamine catalyst can be synthesized from chiral 1,2- diphenylethylene diamine (Scheme \(15\)).
These catalysts have been employed for the asymmetric synthesis of various important pharmaceuticals, including (R)-denopamine, a β 1-receptor agonist, the anti -depressant (R)-fluoxetine, the anti -psychotic BMS 181100 and (S)-duloxetine (Scheme \(16\)).
Unsymmetric benzophenones could also be hydrogenated with high S/C ratio of up to 20000 without over-reduction (Scheme \(17\)). Enantioselective hydrogenation of certain ortho -substituted benzophenones leads to the unsymmetrically substituted benzhydrols, allowing convenient synthesis of the anti- cholinergic and anti -histaminic (S)-orphenadrine and antihistaminic (R)-neobenodine.
The asymmetric hydrogenation of simple ketone is generally achieved by the combined use of an (S)-BINAP and an (S)-1,2-diphenylethylenediamine. However, the reaction of 2,4,4-trimethyl-2-cyclohexenone can be effectively done with racemic RuCl2 [-tol-BINAP]- and chiral DPEN with up to >95% ee (Scheme \(18\)). | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/06%3A_Hydrogenation_Reactions/6.02%3A_Reactions_of_Ketones.txt |
An important field of investigation for new industrial catalysts is the development of improved catalysts for the reduction of imines to obtain the corresponding chiral amines. These chiral amines are used as key components in many active pharmaceutical intermediates.
Synthesis of (S)-metolachlor (widely used as an herbicide) has been achieved by enantioselective hydrogenation of imine in presence of a catalyst generated in situ from [Ir(COD)Cl]2 and (R, S)-PPF–P(3,5-Xyl)2 (xyliphos) (Scheme \(1\)). This catalyst shows a high catalytic activity with TOF=396 h-1 and enantioselectivity of 79% ee.
Subsequently, an air- and moisture-tolerant enantioselective reduction of N -phosphinyl imines has been performed with (CNbox)Re(O)Cl2 (OPPh3) (Scheme \(2\)). A wide range of aromatic imines, including cyclic, acyclic and heteroaromatic, α -iminoesters, and α,β -unsaturated imines undergo reaction with good to excellent enantioselectivity.
The use of modified CBS-type catalysts has been extended to the reduction of oximes into chiral amines (Scheme \(3\)). The BINOL-proline-borate complex reduces acetophenone oxime into chiral 1-phenylethylamine with 98% ee, but the ee drops when the borate complex is used catalytically.
A new method for the reduction of α -imino esters using Hantzsch ester is reported with chiral phosphoric acid (Scheme 4). A series of α -imino esters could be reduced to the corresponding α-amino esters in excellent yield with up to 94% ee.
An efficient metal/brønsted acid relay catalysis has been shown for the highly enantioselective hydrogenation of quinoxalines through convergent disproportionation of dihydroquinoxalines with up to 94% (Scheme \(5\)).
Employing hydrogen gas as the reductant makes this convergent disproportionation an ideal atom-economical process. A dramatic reversal of enantioselectivity is observed for the hydrogenation relative to the transfer hydrogenation of quinoxalines promoted by chiral phosphoric acids L2.
Asymmetric Transfer Hydrogenation Reactions (ATHRs)
Another field where asymmetric transfer hydrogenation (ATH) catalysts have made an industrial impact is in the area of chiral amine synthesis by stereo controlled reduction of imines. The reduction of cyclic imines to yield chiral amines is proved to be a highly versatile and successful strategy for the synthesis of chiral tetrahydroisoquinolines and related compounds (Scheme \(6\)).
The enantioselective preparation of Praziquantel (PZQ) a pharmaceutical for the treatment of schistosomiasis and soil-transmitted helminthiasis has been accomplished. The synthesis is completed from staring chiral reduction of imine which could be synthesized from readily available phenyl ethyl amine, phthalic anhydride and glycine (Scheme \(7\)).
In parallel to metal catalysis, organo catalyst like chiral thiourea and chiral imidazoilidines have been used for the asymmetric hydrogen transfer (ATS) reaction in presence of Hantzsch ester. For example, enantioselective Hantzsch ester mediated conjugate transfer hydrogenation of α,β -disubstituted nitro-alkenes has been shown using chiral thiourea (Scheme \(8\)). A broad range of substrates including β,β -unsaturated aldehydes and ketones, ketimines and aldimines, α -keto esters, and now nitro alkenes are successfully employed for hydrogenation.
The above catalyst is also used for enantioselective Hantzsch ester mediated conjugate reduction of β -nitroacrylates (Scheme \(9\)). After subsequent reduction with Pd-H2-MeOH, chiral β -amino acids can be synthesized with high yield and ee. This provides a key step in a new route to optically active β2-amino acids.
In parallel to the chiral thiourea catalyst, the use of iminium catalysis for the enantioselective reduction of β, β -substituted α, β -unsaturated aldehydes to generate β -stereogenic aldehydes has been shown (Scheme \(10\)). The capacity of the catalyst to accelerate ( E)-(Z) isomerization prior to selective ( E) -alkene reduction allows the implementation of geometrically impure enals in this operationally simple protocol.
The above catalytic system is used for transfer hydrogenation of cyclic enones (Scheme \(11\)). Cycloalkenones with 5-, 6-, and 7-membered ring systems undergo reaction with high stereoselectivity.
6.04: Problems and Reference
Problems
Predict the major product of the following reactions.
List the phosphine ligands for the asymmetric hydrogenation of carbon-carbon double bonds.
Complete the following reactions.
Complete the following reactions.
How will you carry out the following hydrogenation reactions?
Reference/Text Book
• I. Ojima, Catalytic Asymmetric Synthesis , 3 rd ed., Wiley, New Jersey, 2010.
• M. B. Smith, Organic Synthesis , 2 nd edition, McGraw Hill, New Delhi, 200 | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/06%3A_Hydrogenation_Reactions/6.03%3A_Reactions_of_Imines_%28C%3DN%29.txt |
• 7.1: Reactions in Water
Many of the organic solvents are volatile, flammable, sometimes explosive and have damaging effect to human health or on the environment. Thus, effort has been made to use nonconventional solvents which are not only attractive from economical aspects, they can provide advantages of recovery and recyclability of the catalysts. The section covers the use of water, fluorous solvents, supercritical fluids and ionic liquids as nonconventional solvents.
• 7.2: Reactions in Fluorous Solvents
Fluorous solvents having suitable boiling and melting points can be used as solvent. Importantly, the fluorous solvents are different from the corresponding hydrocarbons and form two layers with conventional organic solvents. Thus, some catalysts can be immobilized in fluorous solvents in biphase system and can be recovered and recycled.
• 7.3: Reactions in Supercritical Fluids (SCFs)
Supercritical carbon dioxide (scCO2) offers the advantages that simple depressurization leads to removal of the residual scCO2, and thus, no hazardous solvent is produced, providing effective route for the separation of the products. Thus the synthesis of organic compounds can be accomplished under solvent-free conditions that find wide applications in pharmaceutical, food and cosmetic industries.
• 7.4: Reactions in Ionic Liquids (IL)
Ionic liquids are composed of ions having melting points below 100°C. They are nonvolatile and facilitate the recovery and recyclability of the catalysts.
• 7.5: Microwave-Assisted Reactions
Ionic liquids are composed of ions having melting points below 100°C. They are nonvolatile and facilitate the recovery and recyclability of the catalysts.
• 7.6: Problems and Reference
07: Reactions in Nonconventional Conditions
Many of the organic solvents are volatile, flammable, sometimes explosive and have damaging effect to human health or on the environment. Thus, effort has been made to use nonconventional solvents which are not only attractive from economical aspects, they can provide advantages of recovery and recyclability of the catalysts. The section covers the use of water, fluorous solvents, supercritical fluids and ionic liquids as nonconventional solvents.
The use of water as a reaction medium for organic synthesis has attracted much interest in recent years. Because water is the most abundant liquid on the planet, cheap, readily available, non-toxic and non-flammable. This section covers some of the recent developments in asymmetric catalysis that have been performed in water as reaction medium.
Mannich Reaction
Mannich reaction affords useful route for the synthesis of β -amino ketones and esters that serve as building blocks for the construction of nitrogen containing compounds. The asymmetric version of the reaction has been shown from α -hydrazono ester and silicon enoate using chiral ZnF2 - L-1 complex in aqueous medium (Scheme \(1\)). The reaction proceeds without any organic solvents or additives and the presence of cetyltrimethyl ammonium bromide (CTAB) is necessary to accelerate the reaction.
Michel Reaction
Michel addition of β -ketoesters to nitroalkanes using AgOTf-PPh3 proceeds efficiently in water but not in organic solvents (Scheme \(2\)). Regarding the mechanism, the reaction in water becomes heterogeneous, and the metal enolate stays in organic phase, while TfOH is excluded into water phase because of the difference between their hydrophobicity (Scheme \(3\)). Thus, the metal enolate B does not have the contact with TfOH, and the reverse reaction from B to A is suppressed. In contrast, in normal organic solvent, the reaction mixture becomes homogeneous and the reverse reaction from B to A is fast.
This reaction has been applied for the asymmetric version employing L-2 as chiral source to afford the target products with up to 78% ee (Scheme \(4\)).
Desymmetrization of Epoxides
This reaction condition has been subsequently used for the asymmetric desymmetrization of epoxides with nitrogen nucleophiles using L-3 as chiral source (Scheme \(5\)). The reaction proceeds with high enantioselectivity and no diol formation has been observed.
The asymmetric desymmetrization of the epoxides is also successful with indoles, alcohols and thiols with high enantioselectivities (Schemes \(6\) and \(7\)).
Aldol Reaction
The reaction of silyl enol ethers with aldehydes has been demonstrated using scandium trisdodecylsulfate (Sc(DS)3 ) as a Lewis acid as well as surfactant in water (Scheme \(8\)). The reaction is sluggish when Sc(OTf)3 is used as a catalyst. In this process, the formation of stable emulsions takes place.
The reaction condition has also been further demonstrated for the hydroxymethylation using aq HCHO with excellent enantioselectivity (Scheme \(9\)).
Silica gel-supported scandium (Silica-Sc) with ionic liquid, [DBIm]SBF6, is a heterogeneous catalytic system works efficiently in Mukaiyama aldol reaction in water (Schemes \(10\) and \(11\)). The reaction proceeds efficiently in water medium compared to that in organic solvents, without solvent or in the absence of ionic liquid (IL).
Asymmetric version of the reaction has been subsequently developed employing L-1 as chiral source with moderate enantioselectivity (Scheme \(12\)).
Michael Reaction
Asymmetric Michael reaction of ketones with β -nitrostyrene has been studied using proline derivative L-2 in brine with good enantioselectivity (Scheme \(13\)).
Mannich Reaction
Asymmetirc Mannich reaction of aryl aldehydes, aryl amines and aliphatic ketones occurs in water in the presence of threonine derivative L-3 with excellent diastereoselectivity (Scheme \(14\)).
Addition Reactions of Alkynes
Propargylamines are important synthetic intermediates for the synthesis of nitrogen containing compounds in organic synthesis. The direct alkyne-imine addition can be accomplished employing chiral CuOTf- L-4 complex (Scheme \(15\)). The method is simple and affords a diverse range of propargylic amines with high enantioselectivity.
Pauson-Khand Reaction
Asymmetric Pauson-Khand reaction can be performed using chiral Rh complexes in water. The complex derived from [RhCl(cod)]2 and (S)-tol-BINAP has been found to be effective for the Pauson-Khand reaction employing HCHO as CO source with good enantioselectivity (Scheme \(16\)). Chiral rhodium complex derived from [RhCl(cod)]2 and S-P-Phos has also been used for the Pauson-Khand reaction with similar enantioselectivity (Scheme \(17\)). | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/07%3A_Reactions_in_Nonconventional_Conditions/7.01%3A_Reactions_in_Water.txt |
Fluorous solvents having suitable boiling and melting points can be used as solvent. Importantly, the fluorous solvents are different from the corresponding hydrocarbons and form two layers with conventional organic solvents. Thus, some catalysts can be immobilized in fluorous solvents in biphase system and can be recovered and recycled. In addition, in some combination, the fluorous and organic solvents on heating are miscible at elevated temperature leading to a homogeneous mixture, which, after the reaction, on cooling to room temperature lead to the formation of a biphase system. The products stay in organic phase and the catalysts move to fluorous phase that can be recovered and recycled.
7.2.1 Cyclopropanation
Fluorous complex tetrakis-dirhodium(II)-( S )-N-(n-perfluorooctylsulfonyl) pollinate L-6 exhibits good chemo- and diastereoselectivity in cyclopropanation of styrene (Scheme \(1\)). The advantage of the protocol is that the catalyst can be separated from the reaction mixture and recycled.
7.03: Reactions in Supercritical Fluids (SCFs)
SCF is a substance above its critical temperature (Tc) and pressure (Pc), but below the pressure condensation leads to a solid. At the critical point, high temperature and pressure, the substance can exit both as a vapor and a liquid in equilibrium. Thus, in a closed system, as both the temperature and pressure increase, the liquid becomes less dense due to thermal expansion, and the gas becomes dense as the pressure rises. Thus, the densities of both the phases converge until they become identical at the critical point. At this point, both the phases become indistinguishable and SCF is formed. In such SCF, a high reactivity and selectivity are sometime observed.
Supercritical carbon dioxide (scCO2) offers the advantages that simple depressurization leads to removal of the residual scCO2, and thus, no hazardous solvent is produced, providing effective route for the separation of the products. Thus the synthesis of organic compounds can be accomplished under solvent-free conditions that find wide applications in pharmaceutical, food and cosmetic industries.
7.3.1 Hydrogenation of Alkenes
Asymmetric hydrogenation of alkenes can be carried out in scCO2 using chiral Rh complex with good enantioselectivity (Scheme \(1\)). The catalyst is dissolved in scCO2 during the reaction making the process homogeneous.
7.3.2 Cyclopropanation
The continuous flow of scCO2 has been used for the asymmetric cyclopropanation using an immobilized chiral Ru complex (Scheme \(2\)). The reaction has been reported 7.7 fold more efficient compared to that within dichloromethane solvent. In addition, easy product separation and environmental friendliness makes the process more attractive.
7.04: Reactions in Ionic Liquids (IL)
Ionic liquids are composed of ions having melting points below 100°C. They are nonvolatile and facilitate the recovery and recyclability of the catalysts. Scheme \(1\) presents some the typical ILs.
7.4.1 Hydrogenation of Alkenes
Asymmetric hydrogenation of alkenes using molecular hydrogen as hydrogen source is one of the useful chemical transformation. For example, the chiral rhodium complex Rh L-1 catalyses the hydrogenation of α -acetoamide cinnamic acid and related enamides with high enantioselectivity in IL [C4C2 im][PF6 ]. The catalyst can be reused and IL can suppress the catalyst aging in some cases.
The modified rhodium complex bearing chiral diphosphine with imidazolium moieties has been used as effective catalyst for hydrogen reaction in IL (Scheme \(3\)). The catalyst can be recovered and recycled without loss of activity and selectivity.
The asymmetric hydrogenation of methyl acetamidiacrylate can be accomplished in biphasic cosolvent/IL combination in the presence of chiral rhodium complex bearing Josephose with imidazolium tag in tert -butyl methyl ether/[bmim]BF4 (Scheme \(4\)). The presence of imidazolium tag in the Josephose ligand enhances the affinity of the Rh complex for the IL and suppresses the catalyst leaching. The catalyst can be recycled without loss of activity.
The hydrogenation of tiglic acid has been successible using Ru-BINAP in [bimm]PF6 /H2O with good enantioselectivity (Scheme \(5\)). The enantioselectivity depends on the pressure of the reaction. At high pressure the presence of water increases the enantioselectivity, but low pressure show no effect.
7.4.2 Diels-Alder Reaction
Copper(II) bisoxazoline complex having imidazolium tag can catalyze the Diels-Alder reaction of N -crotonyloxazolidinones with cyclopentadienes in [C4C1 im][NTf2] (Scheme \(6\)). The catalyst can be recovered and recycled without loss of activity and enantioselectivity at least 10 times. The presence of imidazolium tag to bisoxazoline considerably enhances the recovery and reuse of the catalyst from the IL.
7.4.3 Epoxidation
The epoxidation of alkenes using chiral Mn(III) salen has been successful in a mixture of [C4C1 im][PF6]/CH2Cl2 (Scheme \(7\)). Since IL is solidified at 0°C, the reaction requires CH2Cl2 to form homogeneous solution. The catalyst and IL can be recycled with slight drop in the enantioselectivity.
The ring opening of epoxides with TMSN3 can be pursued using chiral Cr(III)salen complex in [C4C1im][OTf] and [C4C1 im][PF6] at ambient temperature (Scheme \(8\)). The catalyst can be recycled up to five times without loss of activity.
7.4.4 Epoxide Opening
Hydrolytic resolution of racemic epoxides is effective using chiral Co(II)salen complex in THF and [C4C1 im][PF6] with excellent enantioselectivity (Scheme \(9\)). In this reaction, Co(II) is oxidized to Co(III) catalyzes the reaction. The catalyst can be recycled 10 times without loss of activity and selectivity.
7.4.5 Dihydroxylation Reaction
The asymmetric dihydroxylation of trans -stilbene has been done using OsO4 (1.5 mol%) and L-3 (2 mol%) in the presence of N -methylmorpholine N -oxide (NMO) (2.6 mol%) and [C4 C1 im][PF6] (2 mL) in acetone-water (v/v, 10/1) at °C. The catalyst can be recovered in IL and recycled up to three times without significant loss of activity and with a small amount of OsO4 leaching from the IL to organic phase.
7.4.6 Fluorination
Fluorination of β -ketoester can be accomplished employing chiral Pd-BINAP in [C4 C1 im][BF4]. (Scheme \(10\)). The reaction proceeds smoothly with good enantioselectivity and the catalyst can be recycled up to 10 times without slight loss of activity.
7.05: Microwave-Assisted Reactions
The use of microwave irradiation can reduce the reaction time compared to the conventional heating. Thus, sometimes, the side reactions can be minimized with increase of the product yield. Thus, microwave assisted organic synthesis has been widely accepted in academia as well as pharmaceutical industries.
Asymmetric allylic alkyaltions can be effective using chiral molybdenum complex under microwave irradiation in THF (Scheme \(1\)). For example, carbonate reacts with dimethyl malonate with high enantioselectivity. Under these conditions, palladium based system gives different regioisomer.
Microwave irradiation has also been found to be effective for the arylation of aromatic aldehydes with high enantioselectivity (Scheme \(2\)). For example, the reaction of arylboronic acid with aryl aldehydes in the presence of diethylzinc and aziridine based ligand L5 gives arylated product with up to 98% ee. The reaction time can be decreased from 1 h to 15 min by changing conventional heating to microwave irradiation.
7.06: Problems and Reference
Problems:
Complete the following reactions.
Describe chiral Fe, Ti and Co-catalyzed asymmetric oxidations in water medium.
Write the major product for the following reactions.
Provide some examples for asymmetric Heck reaction in water.
Describe asymmetric organocatalysis in water.
Complete the following reactions.
Reference/Text Book
• I. Ojima, Catalytic Asymmetric Synthesis , 3 rd ed., Wiley, New Jersey, 2010.
• M. B. Smith, Organic Synthesis , 2 nd edition, McGraw Hill, New Delhi, 2004. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/07%3A_Reactions_in_Nonconventional_Conditions/7.02%3A_Reactions_in_Fluorous_Solvents.txt |
Asymmetric hydrosilylation and hydroboration of carbon-carbon double bonds followed by oxidative cleavage of the C-Si and C-B bonds give effective methods for the construction of optically active alcohols (Scheme \(1\)).
Asymmetric hydrosilylation of carbon-carbon unsaturated substrates provides effective methods for the synthesis of optically active organosilanes, which are versatile intermediates in organic synthesis. Chiral alkyl and aryl silanes can be converted into optically active alcohols with retention configuration by oxidative cleavage of a carbon-silicon bond into carbon-oxygen bond, while the diastereoselective reaction of chiral allyl- and allenyl silanes with C=O bond can give homoallylic and homopropargylic alcohols.
8.1.1 Reactions of Styrene and its Derivatives
Chiral Palladium-catalyzed asymmetric hydrosilylation of styrene with trichlorosilane has been extensively studied. The reaction proceeds with excellent regioselectivity to give 1-phenyl-1-silylethane via a stable π -benzyl palladium intermediate (Scheme \(2\)).
Scheme \(3\) illustrates the possible mechanism. Deuterium-labeling studies suggest that the β -hydrogen elimination is found to be much faster compared to the reductive elimination from the intermediate II . The involvement hydropalladation in the catalytic cycle has been revealed by the side product analysis from the reaction of o -allylstyrene.
The reaction has been utilized in the synthesis of 1-aryl-1,2-diols from arylacetylenes (Scheme \(4\)). Platinum-catalyzed hydrosilylation of arylacetylene gives (E )-1-aryl-2-(trichlorosilyl)ethanes that could be further reacted with trichlorosilane in the presence of chiral palladium complex to afford optically active 1-aryl-1,2-bis(trichlorosilyl)ethanes. The latter could be transformed into optically active 1,2-diol via oxidative cleavage of the carbon-silicon bond into carbon oxygen bond.
Other chiral catalysts have also been employed for the asymmetric hydrosilylation of alkenes. The chiral bis (oxazolinyl)phenylrhodium complex catalyzes the asymmetric hydrosilylation of styrenes with hydro(alkoxy)silanes in high enantioselectivity, although the regioselectivity is found to be somewhat moderate (Scheme \(5\)).
α -Substituted styrenes proceed reaction with phenylsilane to afford benzylic tert -alkylsilanes in the presence chiral organolanthanide as catalyst in moderate enantioselectivity (Scheme \(6\)).
8.1.2 Reactions of 1,3-Dienes
The reaction of 1,3-dienes with hydrosilanes having electron-withdrawing groups on silicon affords synthetically useful optically active silanes in the presence of chiral palladium complex (Scheme \(7\)). The reaction proceeds in a 1,4-fashion providing chiral allylsilanes that could be converted into homoallylic alcohols on the reaction with aldehydes.
The use of ferrocenylphosphine and mop-phen ligands has been demonstrated for the hydrosilylation of cyclo-1,3-hexadiene in the presence of palladium salts (Scheme \(8\)). The reaction with phenyldifluorosilane afforded the highest enantioselectivity compared to that with trichlorsilane or methyldichlorosilane. Based on the reaction of with deuterium-labeled silane the involvement of π-allylpalladium intermediate and 1,4-cis-addition has been proposed.
In case of linear 1,3-dienes, the regioselectivity has become an issue. In the reaction of 1-phenyl-1,3-butadiene using ferrocenyl ligand, (R)-(S)-ppfa, the formation of a mixture of regioisomeric allylsilanes is observed (Scheme \(9\)). However, in the reaction of alkyl substituted 1,3-dienes, 1,3-hexadiene and 1,3-decadiene, a single regioisomer is obtained with moderate enantioselectivity. Improvement in the enantioselectivity is observed employing the bis (ferrocenyl)monophophine ligands a-d having two planar chiral ferrocenyl moieties on phosphorus atom.
The reaction of 1-buten-3-ynes substituted with bulky groups at the alkyne terminus affords enantiomerically enriched allenylsilanes in the presence of palladium complex (Scheme \(10\)). For example, the reaction of 5,5-dimethyl-1-hexen-3-yne using (S)-(R)-bisppfOMe a proceeds in a 1,4-fashion to give allenyl(trichloro)silanes in high regio- and enantioselectivity. Further enhancement in the enantioselectivity is shown employing chiral phosphametallocene b having a sterically demanding η5 -C5 Me5 moiety.
8.1.3 Reactions of Alkyl Substituted Alkenes
Hydrosilylation of simple terminal alkenes give branched products with high regioselectivity. The palladium systems show exceptional catalytic system compared to Pt, Ni and Rh based systems. For example, the hydrosilylation of 1-octene with trichlorosilane using palladium-(S)—MeO-mop gives a 93:7 mixture of 1-octylsilane and 2-octylsilane with 95% ee (Scheme \(11\)).
The above catalytic system is also effective for the hydrosilylation of cyclic alkenes, such as norbornene and bicyclo[2.2.2]octane, 2,5-dihydrofuran and norbornadiene. For example, the reaction of norbornene gives exo adduct exclusively (Scheme \(12\)). The hydrosilylated product can be transformed into exo -2-norbornanol or endo -2-bromonorbornane via the corresponding pentafluorosilicate. In addition, chiral ferrocenylmonophosphines a-d are too found to be effective for this process with excellent enantioselectivity.
Chiral yttrium hydride complex (d0 metal complex) bearing non-Cp ligand catalyzes the hydrosilylation of norbornene with phenylsilane to produce exo -adduct with 90% ee (Scheme \(13\)). More recently, the first chirality transfer from silicon to carbon in a reagent-controlled reaction of norbornene is reported in the presence of achiral palladium complex. The hydrosilylation of norbornene with chiral silane A having 85% ee is found to form the hydrosilylated product B with 93% ee exhibiting asymmetric amplification (Scheme \(14\)).
8.1.4 Intramolecular Hydrosilylation
Synthesis of optically active polyols from allylic alcohols can be achieved using chiral Rh-catalyzed intramolecular hydrosilylation followed by oxidation of allyloxy hydrosilanes (Scheme \(15\)). For example, hydrosilyl ether of di(2-propenyl)methanol can be converted into optically active 1,3-diol using intramolecular hydrosilylation in the presence of chiral rhodium-(R,R)-diop followed by oxidation. Rh-BINAP is also found to be effective catalyst for the intramolecular hydrosilylation of hydrosilyl ethers of allyl alcohols.
8.1.5 Cyclization/Hydrosilylation
Asymmetric cyclization and hydrosilylation of a ,ω-diunsaturated compounds such as 1,6-dienes and 1,6-enynes affords powerful tool for the construction of optically active functionalized carbocycles. For example, the tandem reaction of diallylmalonate in the presence of cationic Pd complex bearing a chiral pyridine-oxazoline proceeds with high diastereoselectivity to yield the corresponding trans-substituted cyclopentane with 90% ee (Scheme \(16\)).
The reactions of 1,6-diynes using cationic Rh complexes bearing chiral bisphosphine gives the hydrosilylated alkylidenecyclopentanes with high enantioselectivity. For example, the 1,6-enyne proceeds reaction with triethylsilane in the presence of cationic Rh and ( R )-biphemp to give hydrosilylated alkylidene cyclopentane in 92% ee (Scheme \(17\)). Subsequently, chiral Rh complex containing spiro diphosphine ( R )-sdp is found to be effective for this process.
The synthesis of carbocycles can also be accomplished by the cyclization of ω-formyl-1,3-dienes in the presence of hydrosilanes and chiral nickel complex (Scheme \(18\)). For example, zerovalent nickel complex of (2 R ,5 R )-2,5-dimethyl-1-phenylphospholane catalyzes the cyclization of 1,3-dienes with a tethered formyl group in the presence of triethoxysilane to give five-membered carbocycle with 73% ee.
8.02: Hydroboration, Hydroalumination and Hydrostannation of Alkenes
8.2.1 Hydroboration of Alkenes
Chiral Rh catalyzed hydroboration of alkenes provides effective method for the synthesis of optically active organoboranes, which are versatile intermediates in organic synthesis. The carbon-boron bond can be converted into several functional group by subsequent carbon-carbon, carbon-oxygen, boron-carbon or carbon-nitrogen bond-forming reactions with retention of stereochemistry (Scheme \(1\)).
The first catalytic asymmetric hydroboration of norbornene and 2-tert-butylpropene with catecholborane appeared in the presence of Rh-(R, R)-diop complex (Scheme 2). The products, 2-hydroxynorbornane and 2,3,3-trimethylbutanol are obtained after the treatment with alkaline hydrogen peroxide solution.
The use of the combination of chiral borane and achiral catalyst has been demonstrated for the asymmetric hydroboration. For example, the hydroboration of 4-methoxystyrene proceeds with chiral borane derived from pseudoephedrine in the presence of achiral rhodium complex to the corresponding secondary alcohol with 76% ee after the oxidation (Scheme \(3\)).
The reaction of vinylarenes with catecholborane has been extensively studied using chiral Rh complex. For example, the cationic Rh-(R)-BIANP catalyzes the hydroboration of styrene with complete branch selectivity to afford 1-phenylethanol with 96% ee after oxidation. The regioselectivity is opposite to that observed with uncatalyzed reactions (Scheme \(4\)).
Asymmetric desymmetrization of meso -bicyclic hydrazines has been shown with catecholborane using chiral Rh and Ir-based complexes (Scheme \(5\)). A reversal of enantioselectivity is observed between the Rh and Ir catalysts.
The reaction of cyclopropene is studied with pinacolborane as a new hydroborating agent in the presence of a series of chiral Rh phosphine complexes (Scheme \(6\)). The reaction using pinacolborane showed enhanced selectivity compared to that with catecholborane due to steric control between the substrates and the hydroborating agent.
Rh complexes with chiral monodentate phosphate and phosphoramidite derived from taddol are studied for the hydroboration of vinylarenes with pinacolborane (Scheme \(7\)). The reactions of a series of vinylarenes having electron withdrawing- and donating substituted proceed with high enantioselectivity.
8.2.2 Hydroalumination and Hydrostannation of Alkenes
While the catalytic asymmetric hydrosilylation and hydroboration reactions are well known, the catalytic hydroalumination and hydrostannation of alkenes are rare. Chiral nickel complex is used for the asymmetric hydroalumination of oxabicyclic alkenes. For example, Ni-( R )-BINAP catalyzes the reaction of A with iso -Bu2 AlH to give B with 97% ee (Scheme \(8\)).
The first example for the asymmetric hydrostannation of cyclopropenes is appeared using Rh-complex bearing chiral diphenylphosphinobenzoic acid-derived L* (Scheme \(9\)). The product trans- cyclopropylstannane is obtained with 94% ee. The procedure is general and the reaction a series of substituted cyclopropenes is demonstrated.
8.03: Problems and Reference
Problems
Write the major products for the following reactions.
Complete the following reactions.
Predict the major product for the following reactions.
How will you prepare the following hydroborating agents?
Reference/Text Book
• I. Ojima, Catalytic Asymmetric Synthesis , 3 rd ed., Wiley, New Jersey, 2010.
• M. B. Smith, Organic Synthesis , 2 nd edition, McGraw Hill, New Delhi, 2004 | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/08%3A_Asymmetric_Hydrosilylation_and_Related_Reactions/8.01%3A_Hydrosilylation_of_Alkenes.txt |
Carbonylation of the unsaturated substrates using transition metal catalysis provides powerful tool to produce fine chemical intermediates. The asymmetric carbonylation is among the most challenging homogeneous process and their potential is yet to be made. The Rh-catalyzed hydroformylation of alkenes together with the Pd-catalyzed hydroxy and alkoxycarbonylation of alkenes are the most famous examples for the asymmetric carbonylation reactions. The important difference between these reactions is the Rh-catalyzed hydroformylation is of greater industrial interest than the palladium based carbonylation process.
The conversion of alkenes to aldehydes is the largest volume homogeneous transition metal-catalyzed reaction. This process has been extensively explored and a number of methods and catalysts have been developed to control the regioselectivity in internal and terminal aldehydes (Scheme \(1\)).
9.1.1 Reaction of Vinyl Arenes
The asymmetric hydroformylation of vinyl arenes is an attractive route to afford optically active aldehydes, which are substrate precursors for the synthesis of high-value pharmaceuticals, agrochemicals, biodegradeful polymers and liquid crystals (Scheme \(2\)). Since the beginning of 1970, chiral Rh-diphosphine complexes have been used as catalysts for this transformation with moderate enantioselectivity (below 60%). From beginning of 1990, the use of bisphophacyclic ligands, diphosphites and phosphine-phosphite, has emerged as alternative for this reaction. Scheme \(3\) summarizes some of the new diphosphite ligands developed with biaryl, spiro, pyranoside, mannitol and macrocyclic backbones for the asymmetric hydroformylation of vinyl arenes with low to moderate success (ee's from 16% to 76%).
Scheme \(4\) summarizes some of successful phosphine-phosphite ligands for the asymmetric hydroformylation of vinyl arene. The enantioselectivity depends on the configuration of both the binaphthyl moieties. The best enantioselectivity is observed when the configurations of the two binaphthyl moieties are opposite.
9.1.2 Reaction of Vinyl Acetate
The reaction of vinyl acetate is more challenging compared to that of vinylarenes. This process affords 2- and 3- acetoxy propanals with high selectivity (Scheme \(5\)). Ethyl acetate and acetic acid are produced as by-products.
Scheme \(6\) illustrates some of the successful ligands for the Rh-catalyzed hydroformylation of vinyl acetate. The enantioselectivity of the reactions are shown in the brackets.
9.1.3 Reaction of Allyl Cyanide
The asymmetric hydroformylation of allyl cyanide is of great interest because the iso-aldehyde derivative can be converted into 2-methyl-4-butanol, which is intermediate, for the asymmetric synthesis of tachikinin, a novel NK1 receptor agonist (Scheme \(7\)). The reaction has been studied using diphosphite, phosphine-phosphite, bis-phosphacyclic and phosphoroamidite ligands with up to 96% ee.
9.1.4 Reaction of Heterocyclic Alkenes
Few studies are focused on the hydroformylation of heterocyclic alkenes. For these substrates, the regioselectivity is of special interest because it is different from that of the acyclic alkenes. For example, the hydroformylation of 2,5-dihydrofuran can lead to the formation of both the tetrahydrofuran-3-carbaldehyde A (expected product) and tetrahydrofuran-2-carbaldehyde B (could be formed via an isomerization process). The regioselectivity is to be controlled by the modification of the ligands and reaction conditions.
Scheme \(9\) summarizes the reaction of 2,5-dihdyrofuran, 3-pyrroline derivative and 4,7-dihdyro-1,3-dioxepin derive using chiral Rh-complex bearing R,S-BINAPHOS. The optically active aldehydes are obtained as single products with enantioselectivities between 64-97%. In case of 2,5-dihydrofuran, up to 64% regioselectivity is observed for the formation of tetrahydrofuran-3-carbaldehyde A , while the reaction of 2,3-dihyrofuran led to the formation of a mixture of A and B (1:1) with an ee of 38% in A.
9.1.5 Reaction of Bicyclic Alkenes
The asymmetric hydroformylation of bicyclic alkenes has received little attention. This reaction is interesting because of the following features: (i) the reaction can lead to the formation of three chiral centers upon one C-C bond formation; (ii) there is no regioselectivity problem; (iii) functional groups located opposite to the carbon-carbon double bond could be versatile. Scheme \(10\) summarizes some of the examples for the asymmetric hydroformylation of bicyclic alkenes employing Rh-TangPhos. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/09%3A_Carbonylation_Reactions/9.01%3A_Hydroformylation_Reaction.txt |
Reaction of Vinylarenes
From academic and industrial standpoint, the Pd-catalyzed asymmetric hydroxy- and alkoxycarbonylation reactions are attractive processes. However, they are less successful compared to the Rh-catalyzed hydroformylation reactions. This is because of the difficulty in getting simultaneously both high regio- and enantioselectivities.
The alkoxycarbonylation of vinylarenes is an important process and the resulting products (2-arylpropanoic acids and derivatives) serve as substrate precursors for nonsteroidal anti-inflammatory drugs, particularly ibuprofen and naproxen (Scheme \(1\)).
The coexistence of two catalytic cycles has been suggested for the alkoxycarbonylation reaction (Scheme \(2\)). In the hydrido-palladium complex cycle A, the insertion of the alkene to the Pd-H bond can give alkyl palladium complex that could react with CO via coordination and migratory insertion to yield Pd-acyl complex. Alcoholysis of the Pd-acyl complex can regenerate the Pd-H species and yield the ester. In the alkoxycarbonyl cycle B, the alkene inserts into the palladium-carbon bond of alkoxycarbonyl-palladium complex and the resulting product on alcoholysis gives an alkoxy-palladium complex and the ester. The alkoxy-palladium complex then reacts with CO via coordination and migratory insertion to regenerate the alkoxycarbonyl-palladium complex. The formation of the Pd-H species may also take place from the complexes formed in the catalytic cycle B via β -elimination of an unsaturated ester after the alkene insertion. In case of vinylarene, the branched alkyl intermediate could be stabilized through the formation of π -benzylic species.
In case of asymmetric synthesis, the regioselectivity of these reactions is of critical importance due to the branched products only contain the chiral center. Figure \(1\) summarizes the some of the diphosphine ligands used for the palladium catalyzed hydroxy- and alkoxycarbonylation of vinylarenes. Although the enantioselectivity is found to be moderate to good (up to 98%), in most of the methods, the regioselectivity is found to be low.
Bidentate pyridine-phosphine ligands have also been studied for palladium catalyzed asymmetric ethoxycarbonylation of styrene (Figure \(2\)). The regioselectivity of branched products is to be good but the enantioselectivity is found to be low (l/b = linear/branched).
Figure \(3\) summarizes the selective monodentate ligands studied for the palladium catalyzed asymmetric methoxycarbonylation of vinaylarenes. The ligand 18 is found to be effective for the hydroxycarbonylation of 2-vinyl-6-methoxynaphthalene under 1 atm of a mixture of CO and O2 in the presence of PdCl2 -CuCl2 at room temperature affording the target product with 91% ee and 100% regioselectivity.
Figure \(1\): Diphosphine Ligands used in the Asymmetric Hydroxy- and Alkoxycarbonylation of Vinylarenes.
Figure \(2\): P-N Ligands used for Alkoxycarbonylation Reactions.
Figure \(3\): Monodentate Phosphine Ligands used for methoxcarbonylation of vinylarenes.
9.2.2 Reaction of Other Substrate
The methoxycarbonylation of 1,2-dichlorobenzene-Cr(CO)3 has been studied using palladium complex bearing chiral ferrocenyl ( R,S )-PPF-pyrrolidine system to introduce planar chirality in p -complexes (Scheme \(3\)). The reaction provides up to 95% ee in the presence 1 atm of CO at 60°C in the presence of triethylamine.
Bis-Alkoxycarbonylation of Vinylarenes
Optically active butanedioic acid derivatives are important class compounds that can be used as intermediates for the synthesis of pharmaceuticals and building blocks for the construction of inhibitors. Palladium-catalyzed bis-alkoxycarbonylation of alkenes provides effective methods for the construction of these compounds. In 1970, Heck reported the first example of the reaction and its asymmetric version appeared after nearly 20 years. Figure \(4\) summarizes some of the ligands employed for the bis-alkoxycarbonylation reactions. Chiral bidentate phosphine, P-N and S,N-ligands have been screened and high enantioselectivity (92%) is reported in the bis-methoxycarbonylation of styrene with moderate chemoselectivity (50%) employing 21 as the ligand. In case of propene, 60% ee is observed as the highest enantioselectivity with poor chemoselectivity and conversion (13% and 23%, respectively), while the reaction of 4-methyl-1-pentene afforded good chemoselectivity (79%) but with lower enantioselectivity (14% ee).
Figure \(4\): Ligands used in Asymmetric Bis-alkoxycarbonylation of Alkenes | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/09%3A_Carbonylation_Reactions/9.02%3A_Asymmetric_Alkoxycarbonylation_and_Related_Reactions.txt |
The catalytic copolymerization of alkenes with carbon monoxide to afford polyketones is of the industrial interest (Scheme \(1\)). Polyketones represent low-cost thermoplastics whose synthesis, properties and applications are thus the object of intense fundamental and applied research. The properties of polyketones can be modified by changing the nature or number of monomers, which makes them superior to polyalkenes, polyamides and polyacetals.
The reaction involves two competing catalytic cycles (Scheme \(2\)). One of the cycles initiates via a Pd-H species, in which, rapid insertion with ethylene with Pd-H leads to the formation of Pd-alkyl species A that reacts with CO to give Pd-acyl complex B . The latter irreversibly can insert with second ethylene molecule. Thus, the chain propagation occurs through alternating ethylene and CO insertions. Depending on the termination path, the catalytic cycle gives diketones or ketoesters. For example, methanolysis can lead to the formation of ketoester, while protonolysis can give diketones. While the second catalytic cycle initiates via a Pd-OMe species, in which, CO reacts with the Pd-OMe species to a form a Pd-carbomethoxy complex C . By this cycle ketoester is also produced along with copolymer diester that is produced via methanolysis of a Pd-acyl complex. Thus, the methonolysis is the main terminating step of the reaction and the ethylene insertion is the rate determining step of the reaction.
With respect to the CO/vinylarene copolymerization, the main features of the catalytic cycle are comparable to that of the CO/ethylene copolymerization. In particular, the chain propagation step is similar, although, the termination and initiation steps will depend on the nature of the alkenes.
9.3.1 Asymmetric Copolymerization of CO with Aliphatic Alkenes
Unlike the reaction with ethylene, the CO/propene copolymerization can afford stereoregular copolymers. The mode of insertion of the propene into the Pd-acyl or Pd-carbomethoxy bond in a 1,2 or 2,1-fashion governs the regiochemistry (Scheme \(3\)). The stereochemistry of the reaction can lead to the formation of isotactic, syndiotactic or atactic structure (Scheme \(4\)).
The best results are obtained utilizing catalyst containing bidentate phosphine ligands. The steric and electronic properties of the ligands control the activity of the catalyst and selectivity of the products. Scheme \(5\) summarizes some of the active ligands for the CO/propene copolymerization process that provide highly regio- and stereoselective co-polymers.
These catalysts are also effective for the copolymerization of CO with higher aliphatic 1-alkenes but slightly lower activity is observed compared to that with the reaction of propene. However, the regio- and stereoselectivities are found to be similar to that of propene reaction.
9.3.2 Asymmetric Copolymerization of CO with Vinylarenes
Unlike the CO/propene polymerization process that employs phosphine based ligands, the copolymerization of styrene with CO is generally found to be successful with dinitrogen ligands. Scheme 6 summarizes some of the successful dinitrogen based chiral ligands and chiral Pd-complexes for the CO/styrene copolymerization process.
9.3.3 Asymmetric CO/Alkenes Terpolymerization
The CO/alkene copolymer is packed in orderly that makes highly crystalline and very fragile. One of the ways to somewhat disturb the orderly crystal packing in the copolymer is the introduction two different kinds of alkenes so that they can have two types of units: CO/alkene1 and CO alkene2(Scheme \(7\)). Both chiral phosphines and chiral diamine ligands are found to be effective for these reactions.
9.04: Problems and Reference
Problems
How does the product formation differ from cyclic alkenes compared to that of acyclic alkenes?
Write a mechanism for the Rh-catalyzed hydroformylation of alkenes.
What is the major difference between the Rh-catalyzed hydroformylation and the Pd-catalyzed hydroxy- and alkoxycarbonylation reactions?
What is the role of benzoquinone in the palladium-catalyzed bis-alkoxycarbonylation of alkenes?
Complete the following reactions.
Propose synthetic routes for the preparation of the following chiral ligands.
How will you prepare the following syndiotactic copolymer.
Reference
I. Ojima, Catalytic Asymmetric Synthesis , 3 rd ed., Wiley, New Jersey, 2010. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/09%3A_Carbonylation_Reactions/9.03%3A_Co-_and_Terpolymerization_of_Alkenes_with_Carbon_Monoxide.txt |
Enantioselective organocatalysis has emerged as a powerful synthetic method complementary to the metal- and enzyme-catalyzed reactions. The low toxicity associated with organocatalysis and operational simplicity makes it an attractive method to synthesize complex structures. Among the organocatalysts, small molecules like chiral proline, chiral thiourea, chiral TADDOL and chiral alkaloids have special reactivity in the asymmetric synthesis.
Chiral proline is termed as the simplest bifunctional organocatalysts (Scheme \(1\)). This amino acid is called as “simplest enzyme” due to its ability to catalyze reactions with high stereoselectivity.
L-Proline is a small molecule, non-toxic, inexpensive, readily available in both enantiomeric forms having bifunctional acid-base sites (Scheme \(2\)). The reaction may proceed through either iminium catalysis, or enamine catalysis or bifunctional acid–base catalysis.
In the early 1970, the first L-proline-catalyzed aldol cyclization was appeared (Scheme \(3\)). After nearly 25 years, the expected transition state for the reaction has been illustrated (Scheme \(4\)).
Intermolecular Aldol Reaction
The enantioselective aldol reaction is one of the most powerful methods for the construction of chiral polyol. The first intermolecular direct enantioselective aldol reaction catalyzed by L-proline appeared employing acetone and 4-nitrobenzaldehyde as the substrates (Scheme \(5\)). This result sparked high interest from several groups in further investigating proline-catalyzed direct asymmetric aldol reactions. Subsequently, modified chiral proline derived catalysts L1-3 has been developed to enhance the selectivity of the reaction.
For the mechanism, reaction of pyrrolidine with the carbonyl donor can give enamine a that could proceed reaction with the re -face of the aldehydes to give the iminium ion b (Scheme \(6\)). The latter can undergo hydrolysis to afford chiral β-hydroxyketone. The proposed transition state illustrates that enamine attack occurs on the re -face of the aldehyde d and e. This facial selectivity of attack by the enamine is dictated by minimizing steric interactions between the aldehyde substituent and the enamine substituent. The attack of the enamine on the si -face of the aldehyde leads to the unfavorable transition state c .
Mannich Reaction
Parallel to the aldol reaction, enantioselective Mannich reaction of aldehyde, acetone and p -anisidine as the substrates has been explored with 50% yield and 94% ee (Scheme \(7\)).
The mechanism is analogous to that of the aldol reactions (Scheme \(8\)). The reaction of proline with aldehyde or ketone can give enamine that could undergo reaction with the imine to form new stereocenters as iminium product. The latter on hydrolysis can give the target Mannich product. The reaction of ( E )-aldimine with the enamine on its si -face can give the syn product. Because of the re -face is blocked by steric interactions between the aromatic ring of the p -methoxyphenyl group and the ring of proline.
The proline-catalyzed Mannich reactions of N -PMP-protected α-imino ethyl glyoxylate with a variety of ketones afford functionalized α-amino acids (Scheme 9). These reactions can generate two adjacent stereogenic centers simultaneously upon C-C bond formation with complete syn -stereocontrol and can be performed in a gram scale with operational simplicity.
The proline-catalyzed reaction of N -PMP-protected α-imino ethyl glyoxylate with aliphatic aldehydes provides a general method for synthesis of β-amino and α-amino acid derivatives (Scheme \(10\)). The diastereoselectivity depends on the bulkiness of the substituents of the aldehyde donor. In most of cases high syn stereoselectivity can be achieved.
The synthesis of chiral quaternary amino acid derivatives can be accomplished using proline based catalysis (Scheme \(11\)). The nitrogen is tethered to the α -aryl amine in order to increase the reactivity through ring strain and the products are obtained with high enantioselectivity.
( S )-Proline-catalyzed Mannich-type reaction of aldehydes with α-imino ethyl glyoxylate affords syn -products, while the reaction utilizing (3R, 5R)-5-methyl-3-pyrrolidinecarboxylic acid gives anti -selective product (Scheme \(12\)).
In addition , (R )-3-pyrrolidinecarboxylic acid catalyzes the Mannich-type reactions of ketones with α-imino ethyl glyoxylate to give anti -products, while (S)- proline based reactions give syn -products (Scheme \(13\)). Thus, the position of the carboxylic acid group on the pyrrolidine ring directs the stereoselection of the catalyzed reaction providing either syn - or anti -Mannich products.
Michael Reaction
In 2001, the first example for a direct asymmetric Michael reaction employing an enamine-activated donor appeared. The proline-catalyzed reaction of acetone and cyclopentanone with benzalmalonate and nitrostyrene affords the Michael product with low enantiomeric excess. However, the use of chiral diamine improves the ee significantly with both nitrostyrene and alkylidene malonates as acceptors and ketone donors (Scheme \(14\)).
Possible stereochemical result has been accounted by assuming acyclic transition states A and B . These Michael reactions constituted the first direct catalytic asymmetric reactions of any type s involving aldehyde donors and encouraged the development of aldehyde-based reactions with a range of electrophiles (Scheme \(15\)).
The iminium-enamine activation mode can be envisaged to explain the domino oxa-Michael–Michael reaction occurring between 3-methylbut-2-enal and ( E )-2-(2-nitrovinyl)-benzene-1,4-diol upon catalysis with chiral diphenyl prolinol silyl ether, which afford the corresponding enantiopure oxa-Michael–Michael cycloadduct in 76% yield and 99% ee (Scheme \(16\)). The latter can be further implicated in a Michael–aldol sequence through the reaction with crotonaldehyde to afford corresponding hexahydro-6H-benzo-chromene in 74% yield. These two domino reactions have constituted the key steps of the first asymmetric total synthesis of the natural biologically active product (+)-conicol. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/10%3A_Organocatalysis/10.01%3A_Chiral_Proline_Based_Reactions.txt |
Conjugate Addition Reactions
Cinchona alkaloids are a large class of compounds extracted from the bark of homonym trees cultivated in equatorial climatic zones, between Bolivian and Venezuelan Andes, and Indonesia. In the extract of the bark are present more than 30 alkaloids (5-15% w/w). Four of them represent 50% of all the alkaloids such as quinine ( QN ), quinidine ( QD ), cinchonidine ( CD ) and cinchonine ( CN ) (Scheme \(1\)).
QN is the most well known alkaloid and used as the anti-malarial drug of choice for over 400 years until chloroquine discovered, while QD is used as an anti-arrhythmic agent. In chemistry, all these compounds ( QN , QD , CD and CN) are used as cheap chiral source. These molecules activate the nucleophile by enamine and carbanion formation, and electrophile via hydrogen bond.
These compounds are diastereomers having five stereogenic centers and the chiral quinuclidinyl nitrogen is the most important as it is responsible of the direct transfer of chirality during catalysis. Quinine vs quinidine and cinchonidine vs cinchonine have opposite absolute configuration this means that very often these pairs of diastereomers act as enantiomers at C-9 position. Furthermore, the C-9 OH group acts as Brønsted acid. So acid and base coexist in these molecules, and thus, it is possible to activate both the nucleophile and the electrophile simultaneously to use as bifunctional organocatalysts (Scheme \(2\)).
The catalytic asymmetric 1,4-addition of thiols to cyclic enones with modified cinchona alkaloid has been demonstrated (Scheme \(3\)). The Michael products can be isolated with high yield and enantioselectivity for a range of substances.
Later, tandem Michael-aldol reactions have been developed for the preparation of medicinally important chiral thiochromanes (Scheme \(4\)). This new one-pot process proceeds with 1 mol % of the cinchona alkaloid derived thiourea catalyst L2 , which synergistically activates both the Michael donor and acceptor.
Similarly, the conjugate addition has been reported with catalyst L3 for a direct, stereocontrolled construction of adjacent carbon- or heteroatom-substituted quaternary and tertiary stereocenters from readily available starting β -ketoester (Scheme \(5\)).
Chiral oxacyclic structures such as tetrahydrofuran rings are commonly found in many bioactive compounds. Cinchona-alkaloid-thiourea L4 catalyzes the cycloetherification of ε-hydroxy-α,β-unsaturated ketones with excellent enantioselectivity, even with low catalyst loadings at room temperature. The probable activation intermediate might go through TS-1.
The catalyst L4 can also catalyze the domino aza-Michael–Michael reactions of anilines with nitroolefin enoates to afford chiral 4-aminobenzopyrans bearing two consecutive stereogenic centers and one quaternary stereocenter (Scheme \(7\)). The products can be isolated with high yield and enantioselectivity.
Chiral amine L5 has been used to activate α,β -unsaturated enones with nitro alkenes toward a well-defined enamine-iminium activation mode in presence of 2-fluorobenzoic acid as an additive. The reaction affords the Diels–Alder adduct bearing three or four stereogenic centers with high enantioselectivity (Scheme \(8\)). The extension of this process to other Michael acceptors such as N -benzyl maleimide leads to the formation of cyclohexanones with up to >99% ee
The synthesis of trifluoromethyl-substituted 2-isoxazolines can be accomplished by a domino Michael–cyclization–dehydration reaction of hydroxylamine (NH2OH) with a range of (E)- trifluoromethylated enone derivatives in the presence of N -3,5-bis(trifluoromethyl benzyl) quinidinium bromide L6 as a chiral phase transfer catalyst (Scheme \(9\)).
Aldol Reaction
The cross-aldol reaction between enolizable aldehydes and α -ketophosphonates can be achieved using 9-amino-9-deoxy- epi -quinine L7 (Scheme 10). The reaction works especially well with acetaldehyde, which is a tough substrate for organocatalyzed cross-aldol reaction.
10.2.3 Henry Reaction
Henry reaction is a classical carbon-carbon bond forming reaction in organic synthesis. Aryl aldehydes react with nitromethane in the presence of 6'-thioureasubstituted cinchona alkaloid L8with high enantioselectivity (Scheme \(11\)). Hydrogen-bond donor at the C6′ of L8 has been found to induce preferential formation of one enantiomer.
The 6'-OH cinchona alkaloid L-9 is an excellent catalyst for the reaction of α- ketoesters with nitromethane (Scheme \(12\)). The highly enantioenriched products from the Henry reaction could be elaborated to aziridines, β- lactams and α -alkylcysteines. This reaction is operationally simple and affords high enantioselectivity as well as good to excellent yield for a broad range of α-ketoesters .
Bifunctional cinchona alkaloid-thiourea L10 can catalyze efficiently the aza-Henry reaction of cyclic trifluoromethyl ketimines with nitromethanes (Scheme \(13\)). The title reaction can provide biologically interesting chiral trifluoromethyl dihydroquinazolinone frameworks with high yield and enantioselectivity.
Hydroxyalkylation Reaction
The readily available cinchonidine (CD) and cinchonine (CN) can be used for the catalysis of the hydroxyalkylation of heteroaromatics. For example, the hydroxyalkylation of indoles with ethyl-3,3,3-trifluropyruvate occurs to afford corresponding 3-substituted products in high yields and ee values (Scheme \(14\)) . | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/10%3A_Organocatalysis/10.02%3A_Alkaloid_Based_Reactions.txt |
Strecker Synthesis
In 1996 the first asymmetric organocatalytic Strecker synthesis appeared employing L1 as a catalyst (Scheme \(1\)). The reaction involves the addition of HCN to imines in the presence of diketopiperazine derivative with up to >99% ee.
Subsequently, chiral thiourea derivative L2 has been used for this reaction to afford the cyanohydrins with 98% ee (Scheme \(2\)).
Further improvement in this reaction has been made employing thiourea derivative L3 (Scheme \(3\)). The active site of the catalyst, the relevant stereoisomer of the imine substrate and the solution structure of the imine−catalyst complex are elucidated using kinetics, structural activity and NMR experiments. An unusual bridging interaction between the imine and the urea hydrogens of the catalyst is identified.
Mannich Reaction
In parallel to Strecker reaction, the Mannich reaction of a wide variety of N -Boc aryl imines is studied in the presence of thiourea derivative L3 with high enantioselectivity (Scheme \(4\)). The catalyst L3 is as highly effective for the asymmetric addition of silyl ketene acetal derivatives to aldimines. From a steric and electronic standpoint, the N -Boc imine substrates utilized in this reaction are fundamentally different from the N -alkyl derivatives employed in the Strecker reaction.
Bifunctional thiourea derivative L4 can catalyze the Michael reaction of malonates with various nitro olefins in high enantioselectivity (Scheme \(5\)). The catalyst activates nucleophile by general base catalysis and electrophile by H-bonding to the nitro group. This methodology has been applied for enantioselective additions of substituted keto ester and double Michael additions of α,β -unsaturated ketoesters.
Chiral primary amine - thiourea L5 is effective for the direct conjugate addition of ketones to nitroalkenes (Scheme \(6\)) . The observed anti diastereoselectivity suggests the participation of a (Z) -enamine intermediate which is complementary to the diastereoselectivity obtained in analogous reactions involving (E) -enamines generated from secondary amine catalysts.
Likewise, the addition of a range of nitroalkanes to aromatic N -Boc imines has been shown using the thiourea derivative L6 with mostly anti diastereoselectivity (Scheme \(7\)).
The thiourea catalyst L7 bearing 3,5-bis(trifluoromethyl) benzene and dimethylamino groups has been revealed to be efficient for the asymmetric Michael reaction of 1,3-dicarbonyl compounds to nitroolefins (Scheme \(8\)). This methodology has been applied for the total synthesis of (R)-(−)-baclofen. Reaction of 4-chloronitrostyrene and 1,3-dicarbonyl compound generates quaternary carbon center with 94% ee. Reduction of the nitro gruop to amine and subsequent cyclization, esterification and ring opening provides ( R )-(−)-baclofen in 38% yield.
The mechanism of above enantioselective Michael addition of acetyl acetone to a nitroolefin catalyzed by a thiourea-based chiral bifunctional organocatalyst has been investigated using density functional theory calculations and the results suggests that both substrates coordinate preferentially via bidentate hydrogen bonds (H-bond) (Scheme \(9\)). The deprotonation of the enol form of acetylacetone by the amine of the catalyst is found to occur easily, leading to an ion pair characterized by multiple H-bonds involving the thiourea unit as well. Two distinct reaction pathways have been explored toward the formation of the Michael product that differs in the mode of electrophile activation. Both reaction channels are shown to be consistent with the notion of non-covalent organocatalysis in that the transition states leading to the Michael adduct are stabilized by extensive H-bonded networks.
A thiourea-catalyzed asymmetric Michael addition of activated methylene compounds to α,β- unsaturated imides have been developed (Scheme \(10\)). N -Alkenoyl-2-methoxybenzamide is the best substrate among the corresponding benzamide derivatives bearing different substituents on the aromatic ring and react with several activated methylene compounds such as malononitrile, methyl α -cyanoacetate, and nitromethane with up to 93% ee. The reactivity can be attributed to the intramolecular H-bonding interaction between the N-H of the imide and the methoxy group of the benzamide moiety.
Thiourea catalyst L9 has been explored for the activation of quinoline with organoboronic acids to facilitate stereocontrol in the Petasis transformation even at low temperatures (Scheme \(11\)). The quinoline gets activated by formation of N-COBz with PhCOCl and a high degree of stereo control can be achieved using a combination of H2O and NaHCO3 as additives.
The domino thia-Michael–Michael reaction of thiols with nitro olefin enoates provides polyfunctionalized chroman derivatives in a highly stereoselective manner in the presence of thiourea L10 . Three consecutive stereogenic centers including one quaternary stereocenter can be generated with high enantioselectivity (Scheme \(12\)). The catalyst L10 activates nitroolefin enoates through H-bonding activation, and its tertiary amino moiety activates the nucleophilic thiols, forming an intermediate which undergo the intermolecular thia-Michael addition.
The synthesis of chiral N-Boc- β-Amino- α -methylene carboxylic esters can be performed by reaction of stabilized phosphorus ylides and Boc-protected aldimines in presence of readily available bisthiourea L11 (Scheme \(13\)). Subsequent reaction with formaldehyde provides a facile access to chiral N -Boc- β-amino- α -methylene carboxylic esters. The catalyst has been found to be recyclable.
Hydrophosphonylation Reactions
Chiral thiourea catalyst L12 has been used for highly enantioselective hydrophosphonylation of a wide range of N -benzyl imines (Scheme \(14\)). The hydrophosphonylated products can be readily deprotected by hydrogenolysis using Pd/C to provide chiral α-amino phosphonic acids with high enantioselectivity. This methodology provides general and convenient access for the synthesis of optically active α -amino phosphonates.
10.04: Problems and Reference
Problems
Complete the following reactions.
Complete the following reactions.
How will you carry out the following using thiourea based organocatalysis?
Complete the following reactions.
Reference/Text Book
• I. Ojima, Catalytic Asymmetric Synthesis , 3 rd ed., Wiley, New Jersey, 2010.
• M. B. Smith, Organic Synthesis , 2 nd edition, McGraw Hill, New Delhi, 2004. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/10%3A_Organocatalysis/10.03%3A_Thiourea_Based_Catalysis.txt |
Biocatalysis is a highly efficient and a powerful tool for organic chemists to prepare optically pure molecules. A broad range of biocatalytic methods has been already in use for large-scale manufacture of drug intermediates. This module covers some of the recent developments in the enzyme catalysis.
The enzymatic resolution of alcohols and amines affords an effective method to access optically active alcohols and amines from racemic or prochiral substrates.
Reactions with Alcohols
The use of lipase for the resolution of racemic alcohols is a widely known technology. However, this method gives the product with maximum up to 50% yield. This limitation can be overcome by coupling the lipase-catalyzed enantioselective resolution with a racemization of the alcohol substrate, thus obtaining a dynamic kinetic resolution process. The latter process can be pursued employing a nonchiral metal complex as a catalyst. For example, using the combination of Ru complex and CAL-B, the acylation of racemic alcohol can be accomplished with 78-92% yield and 99% ee (Scheme \(1\)).
This methodology has been subsequently utilized for the enantio- and diastereoselective synthesis of chiral polymers. For example, dimethyl adipate reacts with a mixture of racemic and meso -alcohols to give chiral polyester (Scheme \(2\)). Ru complex acts as a racemization catalyst in combination with lipase CAL-B as biocatalyst for the resolution.
Furthermore, the transformation has been demonstrated employing a cheap and readily available aluminium complex prepared from AlMe3 and BINOL as the racemization catalyst. For example, racemic 1-phenyl-1-propanol can be acylated with 99% yield and 98% ee (Scheme \(3\)).
11.1.2 Reactions with Amines
Optically pure amines serve as versatile intermediates in the manufacture of pharmaceuticals and agrochemicals. The lipase-catalyzed acylation of amines proceeds efficiently with excellent enantioselectivity (Scheme \(4\)). In this reaction, one of the enantiomer is converted into amide and the remaining amine enantiomer can be obtained in enantiomerically enriched form. The reaction functions in organic medium, MTBE as solvent, and E value exceeds 2000 (E = environmentally impact of the process.
11.1.3 Other Acylations
Enzymatic catalytic transformation of achiral amines and racemic acid components known as aminolysis affords elegant approach for the synthesis of enantioenriched acids. An interesting example is the reaction of dimethyl 3-(benzylamino)glutarate to give monoamides with excellent enantioselectivity (Scheme \(5\)). The monoamides are intermediates for the synthesis of unnatural β -amino acids.
A dynamic kinetic resolution with enzymatic aminolysis provides effective route towards the access of enantiomerically enriched acids. For example, in the presence of an immobilized phosphonium chloride for racemization of ethyl 2-chloropropionate and lipase, aminolysis can be carried out to give amides with up to 92% yield and 86% ee (Scheme \(6\)).
Hydrolytic Reactions
The enzymatic hydrolysis of racemic esters, amides, nitriles and epoxides affords effective methods for the synthesis of optically pure carboxylic acids, amines, amides, esters and alcohols. The reactions of a broad range of substrates have been well explored.
Ester Hydrolysis
Hydrolysis of racemic or prochiral ester using enzymes such as lipase, esterase and protease provides effective method for the resolution of broad range of substrates. Recently, the hydrolysis of indole ethyl ester has been shown using a lipase from Pseudomonas fluoresens (Scheme \(7\)). The process runs at a high substrate concentrate 100g/L and turned out to be technically feasible to perform successfully on a 40-kg scale.
Lipases are also suitable for the resolution of complex molecules having more than one additional functional group. For example, acyloin acetate can be hydrolyzed with E > 300 leading to diol in excellent enantioselectivity (Scheme \(8\)).
Hydrolases can also recognize “remote chiral centers”. For example, ester group separated from the stereogenic center by an aromatic group proceeds hydrolysis with enantioselectivity having the E value of 60 (Scheme \(9\)). The product, Lasofoxifene ( cis ), is a potent and selective estrogen receptor modulator.
The synthesis of an intermediate for a rhinovirus protease inhibitor has been accomplished by an impressive resolution employing a protease from Bacillus lentus (Scheme \(10\)).
Nitrile Hydrolysis
Nitrilases are used for the hydrolysis of racemic or prochiral nitriles to give carboxylic acids. For example, nitrilase from A. faecalis catalyzes the hydrolysis of α -hydroxy nitriles to give ( R )-mandelic acid with excellent enantioselectivity (Scheme \(11\)).
11.2.3 Hydantoin Hydrolysis
Hydantoinases and carbamoylases hydrolyses racemic hydantoins to give optically pure α -amino acids (Scheme \(12\)). In the beginning, the hydantoinase catalyzes the hydrolytic ring opening of the hydantoin to give an N -carbamoyl amino acid that proceeds cleavage to give the desired α -amino acid.
11.2.4 Epoxide Hydrolysis
Hydrolysis of racemic epoxide using epoxide hydrolase proceeds with high enantioselectivity. For example, the resolution of aliphatic epoxide having functional group can be accomplished using Methylobacterium sp. with good enantioselectivity (Scheme \(13\)).
11.02: Formation of Carbon-Carbon Bonds
Biocatalysts are turned out to be versatile catalysts for carbon-carbon bond forming and reduction reactions in organic synthesis.
Carbon-carbon bond formation belongs to the heart of organic synthesis. The biocatalyzed route provides effective tool for the construction of carbon-carbon with excellent enantioselectivity.
Hydrocyanation of Aldehydes
The biocatalytic hydrocyanation of aldehydes is one of the oldest methods in organic synthesis. One of the well-established technologies for the large-scale hydrocyanation of aldehydes is the oxynitrilase (Griengl process) catalyzed production of (S)-phenoxybenzaldehyde cyanohydrins, which is an important intermediate for the industrial pyrethroid manufacture (Scheme \(1\)). This method is turned out to be useful for the reactions of numerous aldehydes.
Benzoin Condensation
The development of an asymmetric cross-benzoin condensation via enzymatic cross-coupling reactions is a synthetically useful process. Highly enantiomerically enriched mixed benzoins can be obtained from two different substituted benzaldehdyes using benzaldehyde lyase as a catalyst (Scheme \(2\)). One of the aldehydes acts as acceptor, whereas the other one acts as donor.
Aldol Reaction
The biocatalytic aldol reactions are highly specific with respect to donor component, whereas a broad substrate scope is observed for the acceptor molecules. One of the examples is the reaction of glycine (donor) with substituted benzaldehyde (acceptor) employing threonine aldolases to give α-amino β -hydroxy acids with excellent enantioselectivity (Scheme \(3\)).
Nitroaldol Reaction
Enzymes are also useful for the non-natural reactions. For example, using (S)-oxynitrilase the reaction of nitromethane with a broad range of aldehydes can be accomplished with excellent enantioselectivity (Scheme \(4\)). Nitroalkane acts donor, whereas the aldehydes are acceptors. | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/11%3A_Enzyme-Catalyzed_Asymmetric_Reactions/11.01%3A_Acylation_of_Alcohols_and_Amines.txt |
The enantioselective reduction of C=X double bonds (X = O, NR, C) to C-XH single bonds plays a major role in asymmetric synthesis.
Reduction of Ketones
The enantioselective reduction of ketones represents an atom-economical approach towards optically active alcohols. The biocatalytic reduction of ketones is based on the use of an alcohol dehydrogenase (ADH) as a catalyst, and a cofactor as a reducing agent. For example, ADH from Leifsonia sp. catalyses the reduction of substituted acetophenone to give secondary alcohols with high enantioselectivity (Scheme \(1\)). In this process, 2-propanol acts as a reducing agent oxidizing into acetone.
The keto group of 2,5-diketo ester can be selectively reduced with excellent regio- and enantioselectivity using E. coli cells with overexpressed ADH from Lactobacillus brevis (Scheme \(2\)). In this process 2-propanol acts as a reducing agent oxidizing into acetone.
The reduction of a wide range of aliphatic and aromatic ketones can be accomplished employing R. ruber ADH to give the corresponding alcohols with excellent enantioselectivity in 2-propanol (Scheme \(7\)).
Whereas formate dehydrogenase (FDH) from C. boidinii catalyzes selectively the reduction of keto group of β -keto esters with high enantioselectivity. In this reaction, formate is oxidized into carbon dioxide (Scheme \(4\)).
The FDH-based whole-cell can be used for the reduction of ethyl 4-chloro-3-oxobutanoate with 99% ee (Scheme \(5\)).
The use of FDH from C. boidinii has limitation due to its inability to regenerate NADP+. This has been overcome by expanding the application range of FDH-based cofactor regeneration to NADP+ -dependent ADHs (Scheme \(6\)). This involves the integration of an additional enzymatic step within the cofactor-regeneration cycle that is exemplified in the reduction of acetophenone to (R)-phenylethanol. In this process, the pyridine nucleotide transhydrogenase (PNT)-catalyzes regeneration of NADPH from NADP+ under consumption of NADH forming NAD+.
Further, for recycling the cofactor NAD(P)H, the use of a glucose dehydrogenase (GDH) has been demonstrated. In this system, D-glucose is oxidized to D-gluconolactone, while the oxidized cofactor NAD(P+) is reduced to NAD(P)H. Since D-gluconolactone is then hydrolyzed into D-gluconic acid, the reaction is irreversible shifting the whole process towards the desired alcohol product formation. This GDH coupled cofactor-regeneration process has been used for the reduction of ketone to alcohol with high enantioselectivity (Scheme \(7\)).
This principle has been recently used for the reduction of ethyl 6-benzyloxy-3,5-dioxohexanoate to afford ethyl (3 R,5 S )-6-benzyloxy-3,5-dihydroxyhexanoate with 99% ee employing ADH from Acinetobacter calcoaceticus in combination with a GDH and glucose (Scheme \(8\)).
Reduction of Ketones
Recombinant whole-cell catalytic system having E. coli , co-expressing both the ADH from S. salmonicolor and the GDH from B. megaterium , has been developed for the asymmetric reduction of 4-chloro-3-oxobutanoate in a mixture of n -butyl acetate/water (Scheme \(9\)). It is an elegant approach toward tailor-made biocatalysts containing both of the desired enzymes, ADH and GDH, in overexpressed form (Scheme \(9\)).
The application of recombinant whole-cell biocatalytic system has been further demonstrated in pure aqueous media without the need of addition of external amount of cofactor (Scheme \(10\)). This method is economical and simple, and finds applications for the reduction of a wide range of ketones (Scheme \(10\)).
Reductive Amination of α -Keto Acids
Enzyme catalyzed asymmetric reductive amination of α -keto acids represents a straightforward method to access optically active α -amino acids. For example, L- tert- leucine, which serves as building block for the pharmaceutical industry, is obtained with high conversion and enantioselectivity using a leucine dehydrogenase for the reductive amination and an FDH from C.boidinii (Scheme \(11\)). The latter is required for an in situ recycling of the cofactor NADH.
Similarly, the synthesis of L-6-hydroxynorleucine can be accomplished from α -keto acid with complete conversion and >99% enantioselectivity (Scheme \(12\)). In this reaction, a beef liver glutamate dehydrogenase has been used as L-amino acid dehydrogenase and a GDH from B. megaterium has been used for the cofactor regeneration.
However, the need for the addition of expensive cofactor NAD+ as well as the isolation and cost of the enzymes make these approaches are limited. Thus, efforts have been made to address these aspects by employing a whole-cell catalyst, having both an amino acid dehydrogenase and FDH in overexpressed form. For example, the synthesis of L-allysine ethylene acetal has been shown using a whole-cell catalyst, Pichia pastoris cells having a phenylalanine dehydrogenase from Thermoactinomyces intermedius and an FDH from P. pastoris (Scheme \(13\)).
Reduction of Activated Carbon-Carbon Double Bonds
The reduction of carbon-carbon double bonds using the biocatalytic systems has high potential in organic chemistry. However, this process is less explored compared to the C=O reduction of ketones and keto esters. The reduction of the carbon-carbon double bond in ketoisophorone has been accomplished using whole-cell catalyst overexpressing an enolate reductase from Candida macedoniensis and a GDH (Scheme \(13\)). This study can be regarded as one of the pioneering works in the reduction of carbon-carbon double bonds using biocatalytic systems.
α,β -Unsaturated carboxylic acids can also be used as substrates. For example, α -chloroacrylic acid can be converted into α -chloropropionate using an enolate reductase from Burkholderia sp ., in high enantioselectivity (Scheme \(14\)).
Besides, enone and α,β -unsaturated carboxylic acid, nitroalkanes are also suitable substrates for enoate reductase. For example, the reduction of carbon-carbon double bond in Z -nitroalkenes proceed reaction to give 2-substituted 3-nitropropanoates with high conversion and in most cases with high enantioselectivity (Scheme \(15\)).
Transamination\(1\)
Depending on the nature of the transaminase, α -keto acids and ketones proceed reaction to give α-amino acids and amines with a stereogenic center in α -position, respectively. For example, a coupling of the transaminase process with an irreversible aspartate aminotransferase-catalyzed transamination process using cysteine sulfinic acid as an amino donor has been used for the synthesis of various types of non-natural 3- or 4-substituted glutamic acid analogues (Scheme \(16\)).
Furthermore, the highly efficient synthesis (S)-methoxyisopropylamine has been accomplished using a recombinant whole-cell catalyst overexpressing a transaminase. A key feature in this process is the high substrate concentration and the desired target molecule can be obtained with excellent enantioselectivity (Scheme \(17\)). | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/11%3A_Enzyme-Catalyzed_Asymmetric_Reactions/11.03%3A_Reduction_Reactions.txt |
Biocatalysts are also turned to be useful for asymmetric oxidations. A wide range of asymmetric oxidations using biocatalytic systems has been explored.
Baeyer-Villiger Oxidation
Baeyer-Villiger reaction is known for more than 100 years. However, the asymmetric version of this reaction remains as challenge for organic chemists. Depending on the nature of ketones the reaction can be carried out as a resolution of racemic ketones as well as an asymmetric desymmetrization reaction from prochiral ketones. The enzymes used for this reaction is known
as Baeyer-Villiger monooxygenases. These enzymes are cofactor dependant and are generally obtained from microbial sources. For example, 4-substituted monocyclic cyclohexanones can be oxidized into the lactones in good yield and with high enantioselectivities (Scheme \(1\)). In this process, the reduced form of the cofactor (NADPH) is needed under the formation of NADP+ that is in situ recycled using an enzymatic coupled cofactor reproduction.
The scale up of the process has also been explored. For example, the racemic bicyclo[3.2.0]hept-2-enone with input of 25g/L proceeds oxidation in the presence of a recombinant whole-cell biocatalyst to afford regioisomeric lactones with high enantioselectivity (Scheme \(2\)).
A further process improvement is the coupling of a cyclohexanone monooxygenase with an ADH from T. brockii , a cosubstrate-free “double oxidation” of an alcohol into lactones (Scheme \(3\)). In this system, the oxidized form of the cofactor (NADP+) is consumed in the initial ADH-catalyzed step, while the reduced form of the cofactor (NADPH) is then needed for the second, monooxygenase-catalyzed oxidation step. In the second step, the oxidized form of the cofactor (NADP+), which is then needed for the first step, is produced again.
Epoxidation
Optically active epoxides serve as versatile building blocks in organic synthesis. Besides metal and organocatalysts, cofactor dependent monooxygenase turned out to be valuable catalyst for the epoxidation of alkenes. For example, the epoxidation of styrene has been shown using a stable recombinant FAD/NADH-dependent styrene monooxygenase in aqueous-organic emulsions (Scheme \(4\)). The reaction condition is also effective for the oxidation of other styrene derivatives.
Oxidation of Amino Acids
The asymmetric oxidation of amine group in amino acids provides effective method for the synthesis unnatural amino acid which is important in drug synthesis. For example, racemic tert -leucine can be oxidized to D- tert -leucine using a leucine amino dehydrogenase and an NADH-oxidase from E-coli with excellent enantioselectivity (Scheme \(5\)).
Oxidation of Alcohols
The oxidation of secondary alcohols into ketones has also been investigated using biocatalytic systems. For example, the oxidation of racemic secondary alcohols proceeds in the presence of an ADH from R. ruber (Scheme \(6\)). The recycling of the cofactor NADPH is carried out in situ using acetone, which is reduced into 2-propanol under the formation of NADP+.
Sulfoxidation
Optically active sulfoxides play important role in organic synthesis as chiral auxiliary as well as intermediates for the construction of optically active molecules. Optically active sulfoxide is also present as structural unit in many biologically active compounds. The enzymatic oxidation of sulfides provides an effective method for the synthesis optically active sulfoxides. For example, cyclopentyl methyl sulfide undergoes oxidation in the presence of chloroperoxidase with excellent conversion and enantioselectivity.
11.05: Problems and Reference
Problems:
Complete the following reactions.
Describe enzyme-catalyzed amide hydrolysis
Complete the following reactions.
Complete the following reactions.
Complete the following reactions.
Describe enzyme catalyzed hydroxylation of alkanes and oxidation of amines.
Reference/Text Book
• I. Ojima, Catalytic Asymmetric Synthesis , 3 rd ed., Wiley, New Jersey, 2010.
• M. B. Smith, Organic Synthesis , 2 nd edition, McGraw Hill, New Delhi, 2004.
12.04: Carbonylation Reactions
not available | textbooks/chem/Organic_Chemistry/Catalytic_Asymmetric_Synthesis_(Punniyamurthy)/11%3A_Enzyme-Catalyzed_Asymmetric_Reactions/11.04%3A_Enantioselective_Oxidations.txt |
The challenge of synthetic planning is the identification of a set of available precursors that can be combined and manipulated by a series of chemical reactions to provide the synthetic target. Analysis does not a priori have to proceed from target to starting materials along the exact reverse of the actual synthesis (i.e. retrosynthetic analysis), but this protocol is highly effective for the analysis of structurally complex molecules because it provides a logical basis for the systematic recognition of potential synthetic pathways. For example, recognizable characteristics of the precursors predispose them toward chemical reactions that generate the target. These characteristics are the result of certain structural features of the precursors (e.g. functionality), the residue of which is often apparent in the target and from which the precursor can be inferred. The ⇒ symbol is used to indicate one or more backward steps, often referred to as dislocations or transforms of the target to a precursor. Bonds severed in a dislocation (i.e. generated during the synthesis) are indicated by drawing wavy lines through the appropriate bonds. Furthermore, the target will generally be shown to the left of the ⇒ symbol and the precursor(s) to the right.The dislocation may correspond to a single known chemical reaction, or a hypothetical reaction, or may be the result of a multistep retrosynthetic process. For example, the hydroxyl group in a secondary alcohol may be viewed as the residue of the carbonyl functional group that predisposes a precursor aldehyde toward reaction with a Grignard reagent to deliver the synthetic target. The C=C bond in a cyclohexene may be viewed as the residue of the pi system in 1,3-butadienediene that predisposes this precursor toward a Diels-Alder cycloaddition with methyl acrylate to deliver the synthetic target.
The following dislocations of some molecules that we will consider more thoroughly in subsequent chapters show only the targets and a set of starting materials, precursors that are readily available organic chemicals. Thus, the overall strategy of each total synthesis is summarized in a single dislocation of the target. The molecular numbering system of the synthetic target is adopted to designate the corresponding atoms of synthetic precursors. The examples in Charts 1-3 provide a glimpse of the diversity of solutions possible for a particular synthetic problem. The systematic procedures which guide the invention of such strategies are the focus of this book.
Three overall strategies are presented in Chart 1 for the total synthesis of prostaglandin $F_{2\alpha}$ ($PGF_{2\alpha}$) a fatty acid derivative. These examples constitute a tiny sample of the numerous strategies that have been applied to the total synthesis of this important natural product.1 These and other syntheses of prostaglandins will be considered in detail in chapter 3. Each strategy in chart 1 uses the same starting material 1 for carbons 1-5 of the upper side chain and similar starting materials 2 or 3 for carbons 14-20 of the lower side chain. But very different precursors are employed for the C6-7 and C8-13 portions of the target. Thus, the Woodward strategy involves ring contraction of a six- membered ring to generate the cyclopentane of C8-12 with C13 appended and glyoxalic acid to provide carbons 7 and 8.2 The Brown strategy3 uses α-chloroacrylonitrile for these carbons and acetoxyfulvene as precursor for the portion of the target which is provided by cyclohexanetriol in the Woodward synthesis. Turner's strategy carves the cyclopentane nucleus, C8-12, from the readily available Diels-Alder dimer of cyclopentadiene.4 Thus, carbons 9-11 are derived from one molecule of cyclopentadiene while carbons 6-8 and 12-13 are derived from a second molecule of cyclopentadiene.
Two strategies for total synthesis of the sesquiterpene longifolene are presented in Chart 2. The Corey synthesis5 builds the tetracyclic skeleton from a cyclohexan-1,3-dione precursor that provides carbons 1 and 7-11. The Johnson strategy6 builds the same carbon network from a cyclopentane precursor that provides carbons 1-3 and 9-11 of the target. The bonds formed in the two approaches are completely different.
While the choices of starting materials in the above examples may seem mysterious, consider the even more remarkable strategy for synthesis of these molecules in nature. As summarized in Chart 3, all of the carbon atoms of all natural products are derived from the same starting material, carbon dioxide. The biosynthesis of more complex biosynthetic building blocks, e. g., 3-phospho-D-glyceric acid and D-glucose from $\ce{CO2}$ will be our starting point for examining the logic that can be applied to designing total syntheses of organic molecules. The biosynthesis of natural products is a convenient framework for a systematic overview of the total synthesis of a variety of organic structural types. The logic of each biosynthesis will be considered and then compared with strategies employed in laboratory total syntheses of the same natural product.
First, however, in the remaining sections of this chapter, some basic principals of synthetic planning will be presented. The biosynthesis of glucose and other sugars from carbon dioxide in the dark reactions of photosynthesis will be examined in chapter 2. Sugars are not skeletally complex synthetic targets, but their functional and stereochemical complexity is a significant challenge for synthetic design. Chapter 2 concludes with a brief consideration of enantioselective total synthesis of sugars. Ensuing chapters examine the logic of biosyntheses and corresponding total syntheses of structurally complex natural products of the fatty acid, terpenoid, polyketide, and alkaloid families. An important feature of the discussion is the inclusion of unsuccessful plans that emerged from the work of leading practitioners of the art and science of organic total synthesis. These examples emphasize the practical limits of synthetic planning even by experts in the field.
Some previous books on the principles, logic, strategies, and tactics of synthesis design and surveys of total syntheses of complex organic molecules are described briefly in the following list.
A. A. Akhrem, A. A. Titov, A. Yu, Total Steroid Synthesis (Plenum, New York, NY, 1970): briefly discusses some principles of total synthesis and then exhaustively outlines total syntheses of steroids oganized according to topological categories of skeletal construction.
N. Anand, J. S. Bindra, and S. Ranganathan, Art in Organic Synthesis (Holden-Day, Inc., San Francisco, first edition, 1970): flow chart presentations of syntheses of complex organic molecules occaisionaly accompanied by brief discussions of strategic highlights.
N. Anand, J. S. Bindra, and S. Ranganathan, Art in Organic Synthesis (John Wiley, New York, second edition, 1987): updated flow chart presentations of syntheses of complex organic molecules occaisionaly accompanied by brief discussions of strategic highlights.
John ApSimon, Ed., The Total Synthesis of Natural Products, Vols. 1-9 (John Wiley & Sons, New York, 1973-1992): A collection of graphical surveys organized by biosynthetic families.
J. S. Bindra and R. Bindra, Creativity in Organic Synthesis (Academic Press, Inc., New York, 1975):
R. T. Blickenstaff, A. C. Gosh, G. C. Wolf, Organic Chemistry Vol. 30: Total Synthesis of Steroids (Academic Press, New York, 1974): exhaustively outlines total syntheses of steroids oganized according to topological categories of skeletal construction.
E. J. Corey and Xue-Min Cheng, The Logic of Chemical Synthesis (John Wiley & Sons, New York, 1989): duscusses the principles of synthetic design then provides specific examples by an exhaustive presentation of Corey's successful syntheses in outline format with little or no discussion.
Samuel E. Danishefsky and S. Danishefsky, Progress in Total Synthesis (Appleton-Century-Crofts, New York, 1971): graphical outlines of total syntheses of natural products organized by biogenetic families accompanied by a discussion of strategic highlights.
Ian Fleming, Selected Organic Syntheses (Wiley-Interscience, New York, 1973): discusses the key reactions in the total syntheses of more than two dozen complex organic molecules, the majority being natural products. It features multiple syntheses of several molecules, i. e. Cecropia Juvenile Hormone and Colchicine, providing an opportunity for comparison of different approaches.
J. Furhop, G. Penzlin, Organic Synthesis. Concepts, Methods, Starting Materials (Verlag Chemie: Weinheim, Fed. Rep. Ger., 1983): exhaustive systematic discussion of synthetic methods organized by synthons, difunctional relationships, and functional group interconversions followed by a consideration of the principles of retrosynthetic analysis and graphical summaries for syntheses of a wide variety of complex organic molecules.
S. Hanessian, Total Synthesis of Natural Products: The 'Chiron' Approach (Pergamon Press, London, 1983): concepts for designing total syntheses of natural products using readily available chiral nonracemic natural products as starting materials are discussed and extensively illustrated with examples.
Robert E. Ireland, Organic Synthesis (Prentice-Hall, Englewood Cliffs, New Jersy, 1969): A discussion of the principles of synthetic design is followed by a detailed consideration of specific examples of successful syntheses.
Thomas Lindberg, Ed., Strategies and Tactics in Orgainc Synthesis, Vols. 1-3 (Academic Press, Inc., New York, 1984-1991): anecdotal case histories of specific total syntheses illustrating the design and execution of synthetic plans and revealing the obstacles and failures commonly encountered even by experts.
Bradford P. Mundy, Concepts of Organic Synthesis (Marcel Dekker, New York, 1979): a review of synthetic methods organized according to specific goals or reaction types such as ring formation or rearrangements respectively. Also discussed are the biosynthesis of terpenes, concepts of stereocontrol and synthetic planning, and examples of complex syntheses.
Koji Nakanishi, Toshio Goto, Shô Itô, Shinsaku Natori, Shigeo Nozoe, Eds., Natural Products Chemistry, Vols 1-3 (Academic Press, Inc., New York, 1974-1983): information on the structural characterization and outlines of total syntheses organized by biogenetic families.
Fèlix Serrratosa, Studies in Organic Chemistry 41, Organic Chemistry in Action The Design of Organic Synthesis (Elsevier, Amsterdam, 1990): a textbook on the principles of synthesis design including the use of computers that concludes with several examples including several strategically different syntheses of twistane and lucidulene.
Stephen Turner, The Design of Organic Synthesis (Elsevier, New York, 1976): systematically discusses principles of synthesis planning with examples of considerable complexity. The focus is on concepts, and thorough discussion of specific total syntheses is not provided.
Stuart Warren, Organic Synthesis: The Disconnection Approach (John Wiley & Sons, New York, 1982): presents principles of synthesis planning on a very simple level. Concepts, especially retrosynthetic analysis, are defined and their applications systematically exemplified by the design of short syntheses of simple targets.
1. For a recent monograph, see: "New Synthetic Routes to Prostaglandins and Thromboxanes", Roberts, S.M.; Scheinmann, F., Academic Press, New York (1982).
2. Woodward, R.B.; Gosteli, J.; Ernest, I.; Friary, R.J.; Nestler, G.; Raman, H.; Sitrin, R.; Suter, C.; Whitesell, J.K. J. Am. Chem. Soc. 1973, 95, 6853.
3. Brown, E.D.; Lilley, T.J. Chem. Commun. 1975, 39.
4. Brewster, D.; Myers, M.; Ormerod, J.; Other, P.; Smith, A.C.B.; Spinner, M.E.; Turner, S. J. Chem. Soc. Perkin I, 1973, 2796.
5. Corey, E.J.; Ohno, M.; Vatakencherry, P.A.; Mitra, R.B. J. Am. Chem. Soc. 1964, 86, 478.
6. Volkmann, R.A.; Andrews, G.C.; Johnson, W.S. J. Am. Chem. Soc. 1973, 97, 4777. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/01%3A_Some_Principles_of_Synthetic_Planning/1.01%3A_Introduction.txt |
Exhaustive Retrosynthetic Analysis
Three things must be established to accomplish the total synthesis of an organic molecule. These are the appropriate (1) carbon network, (2) functionality, and (3) stereochemistry. The carbon network consists of carbon atoms and a set of connections between them. An exhaustive retrosynthetic analysis of the problem of synthesizing a complex organic molecule would include consideration of all possible strategies involving each C-C bond as the hypothetical last connection in the skeletal construction, a disconnection (DIS) in the retrosynthetic analysis. Furthermore, it may be advantageous to generate intermediates that contain bonds not present in the final target. These bonds must be severed at some stage in the synthesis. For example, consider a synthesis of the tetracarboxylic acid 4. This target could be obtained readily by oxidative cleavage of endo-dicyclopentadiene (5), itself readily available by dimerization of cyclopentadiene (6). In planning such a synthesis, these bond cleavages correspond to dislocations which generate connections (CON). Thus, an exhaustive analysis must also consider all possible bond cleavages that could generate the desired skeleton from a more highly connected precursor.
Besides establishing the requisite carbon skeleton from available precursors by the formation or cleavage of C-C bonds, the generation of a synthetic target may require manipulation of functional groups. Thus, synthetic targets may contain functionality that is different than that in a readily available precursor. For example, a well known synthesis of ketones 7 involves oxidation of alcohol precursors 8 that are, in turn, often assembled by the union of aldehydes 9 with Grignard reagents 10. Another example is provided by a strategy for the synthesis of cyclohexane 11. Cyclohexene 12, that is readily available from 13 and 14, is an excellent precursor that would deliver the cyclohexane 11 upon saturation of the C=C bond.
Finally, some reactions neither change the carbon network nor modify functionality, but merely alter stereochemistry. For example, a possible dislocation of the precursor 15 for $PGF_{2\alpha}$ is epimerization of the stereocenter at position 12 since this allows generation of 16 from a readily available cis fused bicyclic precursor 17.
An exhaustive logic centered retrosynthetic analysis would consider every possible disconnection, connection, functional group modification, and stereochemical modification as a potential last step of the synthesis. In so doing, a set of subtarget structures (e.g. T1, T2, T3 . . . Ti) is generated, which may be converted in a single synthetic operation, that is, chemical step, to the synthetic target. The same process is applied to each subtarget and so on until the molecule is reduced to several sets of readily available starting materials, and a complete tree of synthetic intermediates (sometimes referred to as a synthetic tree) is generated (Figure 1). It is often convenient during the planning process to generalize potential intermediates of a particular type. Such generalized intermediates or synthons may correspond to stable organic molecules or to hypothetical reactive fragments such as a "methyl cation", "acyl carbanion" or “α-keto carbocation”. The actual organic intermediates corresponding to various synthons are called synthetic equivalents. Thus, methyl iodide, methyl bromide, methyl chloride, methyl trifluoromethanesulfonate or methyl p-toluenesulfonate are all synthetic equivalents of the "methyl electrophile" synthon. Synthetic equivalents of acyl carbanions and α-keto carbocations will be discussed on page 17. Usually a synthetic tree of synthons is generated and possible synthetic equivalents are noted, but the final choice of a suitable synthetic equivalent for each synthon is often determined by experiment during the execution of the synthesis.
Boundary Conditions
Logic centered retrosynthetic analysis generating a tree of synthons7 is the basis of computer-assisted synthetic analysis.8 Even with the help of a computer, however, an indiscriminately exhaustive analysis would be impossibly cumbersome and of little use because much effort would be expended exploring pathways that have little or no likelihood of being useful. Rather, it is desirable to identify dislocations that are unlikely to be fruitful and abandon them, to prune the synthetic tree as it grows. The goals of reterosynthetic analysis are: (1) the identification of readily available starting materials and (2) an efficient pathway for their conversion into the synthetic target. Since the starting materials will usually have simple structures, dislocations that reduce molecular complexity are likely to lead to them. This recommends seven boundary conditions for the selection of desirable dislocations. Thus, a desirable dislocation (or transform) must (i) reduce internal connectivity by scission of rings, (ii) reduce molecular size by disconnection of chains or appendages, (iii) remove functionality, and/or (iv) simplify stereochemistry, for example, by removal of asymmetric centers. The synthetic pathways that emerge under the guidance of these boundary conditions will rapidly generate the requisite molecular complexity of the target and will, thus, involve a minimum number of steps. However, some dislocations that (v) increase molecular complexity may also be desirable if they facilitate a simplifying dislocation. For example, increasing the molecular complexity of 11 by adding unsaturation suggests a subtarget 12 that should be readily available by a 2π + 4π cycloaddition that generates two C-C bonds in a single step from the readily available starting materials 13 and 14. If the C=C bond in the subtarget 12 can be selectively hydrogenated in the presence of a C=O bond, then the final target 11 could be obtained from 12. Note that a hypothetical synthesis will be designated with dashed arrows in this book.
Another example of a potentially desirable dislocation that increases molecular complexity is provided by a strategy for preparing glyceraldehyde ketal 18. Thus, a dimeric subtarget 19 should provide 18 by oxidative cleavage of the vicinal diol functional array. Although 19 is structurally and functionally more complex than 18, it would be an excellent precursor if a method can be found to selectively ketalize the terminal vicinal diol arrays in D-mannitol, because the hexitol starting material is an inexpensive naturally derived product.
Another boundary condition is suggested by the need to (vi) avoid undesirable side reactions during the early stages of the total synthesis of a functionally complex target. Thus, side reactions are less likely if a sensitive functional array in the target is generated near the end of the synthesis. Reterosynthetically, this means that dislocations that modify (e. g. hide) or remove sites of unusually high chemical reactivity or instability are especially desirable. For example, the δ-hydroxy- β,γ-unsaturated aldehyde functional array in 20 is especially prone toward dehydration to give the dieneal 21. The aldehyde functional group can promote the dehydration. Therefore, generation of the aldehyde group in the last step of the synthesis is recommended. One possibility is to use a vicinal diol functional array in a subtarget 22 as a hidden aldehyde. Of course, the success of this strategy depends upon the feasibility of achieving oxidative cleavage of the structurally and functionally more complex subtarget 22 under suitably mild reaction conditions. This may be considered a risky strategy because the entire scheme would fail if the last step cannot be accomplished. However, the stability of the target to reaction conditions that are required to oxidatively cleave vicinal diols can be tested. However, other potential pitfalls can probably only be tested on the subtarget 22 itself. For example, will 22 tend to undergo intramolecular ketalization that cannot be easily and cleanly reversed? On the other hand, the benefits of finding a method of achieving the 22 to 20 conversion justify attempting the synthesis through this subtarget.
The ultimate goal of synthetic planning is to devise the most economical synthesis of the target. The suitability of a particular strategy must inevitably depend upon the state of the art (science?). As the availability of starting materials or methods (new or more effective) for uniting and manipulating them vary, so will the relative merits of different pathways. Put another way, a poor synthesis can become the method of choice if a method for improving a bad step can be discovered. Even a "logic centered" approach cannot produce absolute answers. What it can do is systematically generate a large number of alternative strategies for consideration in light of existing chemical knowledge.
Another concept that can guide the fruitful growth of a synthetic tree is the identification of target characteristics that direct special attention to a particular synthetic method or starting material and, thus, channel the choice of dislocations. For example, a six-membered ring invites consideration of a Diels-Alder cycloaddition as we have seen above in a strategy for the synthesis of 11 from 13 plus 14. Similarly, because of the stability associated with aromaticity, the presence of an aromatic ring in a synthetic target recommends consideration of aromatic precursors because: (1) their stability may prevent undesirable side reactions and (2) a great variety of aromatic compounds are readily available.
The facts that: (1) chemical reactions are the means of achieving skeletal construction, and (2) functionality facilitates chemical reactions, recommends a boundary condition that favors synthetic strategies that make (vii) maximum use of target-related functionality in precursors to pro- mote skeletal construction. "Target-related" refers to functionality in precursors that may be identical with or closely related to functionality in the final synthetic target.
The imposition of boundary conditions during the generation of a synthetic tree may eliminate the need for considering a large fraction of potential synthetic pathways. For example, in devising a synthesis of prostaglandin $F_2\alpha$ we would disfavor all pathways involving a final connection between any of the carbons 16-20 which constitute an n-pentyl group. This group of atoms is an unreactive nonfunctionalized moiety. Joining two synthons at any of these bonds would require extensive functional manipulation with no obvious justification. Such strategies do not make maximum utilization of functionality.
Direct Associative Strategies
Syntheses of some target molecules or subtargets do not require the logic centered rigorous analytical approach since the molecules may be recognized as arising from the union of a number of readily available undisguised subunits which can be brought together in the proper way using standard reactions. This is known as a direct associative approach to synthetic planning. Thus, for example, strategies for the synthesis of polypeptides, almost without exception, involve the union of amino acids or suitable derivatives by the creation of amide bonds.
Generally, synthetic planning for complex molecules is intermediate between a direct associative and a logic centered approach. The initial recognition process may use logic centered analysis until a number of potentially readily available subunits or key intermediates become apparent. The choice of a particular key intermediate as a starting point channels and simplifies the analysis. This is followed by careful, usually logic centered analysis of detailed sequences that lead to the desired subunits and from them to the synthetic target.
Thus, the practical goal of logic centered analysis is to reduce a complex molecule to a set of "readily available" or "recognizable" synthons. That is, to simplify the synthetic objective to the extent that a direct associative approach becomes feasible. A knowledge of what is readily available need not precede the logic centered simplification of the problem. The simplified structures generated by such analysis may, on the contrary, become the subject of a thorough search of the chemical literature. This search might begin with a computer database such as Chemical Abstracts Online or one of the following general references:
(a) H.O. House, "Modern Synthetic Reactions", 2nd ed, Benjamin, 1972.
(b) R.B. Wagner and H.D. Zook, "Synthetic Organic Chemistry", Wiley, 1953.
(c) C.A. Buehler and D.E. Pearson, "Survey of Organic Syntheses", Wiley, 1970.
(d) A.I. Vogel, "Practical Organic Chemistry", 3red ed, Wiley, 1956.
(e) I.T. Harrison and S. Harrison, "Compendium of Organic Sythetic Methods", Wiley, 1971.
(f) L.F. Fierser and M. Fierser, "Reagents for Organic Synthesis", Wiley.
(g) "Organic Reactions", Wiley.
(h) "Organic Syntheses", Wiley.
(i) "Newer Methods of Preparative Organic Chemistry", Academic Press.
Information gleaned from the literature on established synthetic approaches to similar structures may then be used to generate further refinements of the synthetic plan by logic centered analysis. This general procedure for synthetic planning is an interactive approach. Furthermore, synthetic planning generally does not end when work in the laboratory begins. Information on molecular reactivity gleaned in the laboratory may be exploited to modify or generate new strategies. The interactions between modes of analysis and sources of relevant information are summarized below. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/01%3A_Some_Principles_of_Synthetic_Planning/1.02%3A_Logic_Centered_Analysis.txt |
Exploitation of functionality in synthetic planning requires an understanding of the interrelationships between chemical reactions and functionality. This is most effectively achieved in terms of basic electronic reaction mechanisms that allow a very compact and systematic classification of hundreds of synthetic reactions. For example, let us systematically consider the relationships which inhere between molecular structure and functionality with respect to polar reactions.
Functionality Level Changes
For organic synthetic analysis it is often assumed that all carbon centers in a hydrocarbon are not activated toward polar C-C bond forming reactions, hence, the name paraffin (from the Latin parum affinis = little affinity) denotes relative unreactivity. The hydrocarbon skeleton of organic molecules is considered to be a homogeneous conglomeration of unreactive carbon atoms. It is useful to define the functionality level9 of an atom as f = the number of valence electrons in the neutral atom minus the number of electrons assigned to the atom by the following protocol: all bonding electrons are divided equally between C-C, C=C, C≡C, C-H, M-M or X-X, but all bonding electrons are given to the better nucleofuge (often but not always the more electronegative atom, vide infra) for C-X, C-M, or X-Y bonds, where X and Y are hetero atoms, and M is a metal. Thus, for example, the electrons taken or given to carbon when breaking the following bonds to carbon are assigned as follows: RO-, RS- (-1); O= (-2); F-, Cl-, Br-, or I- (-1); R2N-, R2P- (-1); RN= (-2); N≡ (-3); Li-, Na-, K-, R2Al-, R3Si- (+1).
The functionality level approximation emphasizes the similarity between similarly functionalized carbons. Thus, the functionality level of all carbons in a hydrocarbon is zero. That is, in a hydrocarbon all carbon atoms whether quaternary, tertiary, secondary, or primary, share a common functionality level (f = 0). Likewise, all carbinol carbon atoms share a common functionality level (f = +1) regardless of whether they are primary, secondary or tertiary. Aldehydes and ketones share a common functionality level (f = +2). To organic chemists these conclusions of similarity are tacitly accepted. The functionality level approximations differ from those made for defining the oxidation state x = the number of valence electrons in the neutral atom minus the number of electrons assigned to the atom by the following protocol: all bonding electrons are divided equally between C-C, C=C, C≡C, M-M or X-X, but all bonding electrons are given to the more electronegative element for bonds between different elements.10 It is of little significance to an organic chemist that the oxidation states of the carbonyl carbon in formaldehyde (x = 0), other aldehydes (x = +1), and ketones (x = +2) differ as do the oxidation states of primary (x = -1), secondary (x = 0), or tertiary (x = +1) carbinol carbons. The abovementioned contrasts between the oxidation state and functionality level approximations result from the fact that in effect, the functionality level approximation assigns an oxidation number of 0 for hydrogen when bound to carbon in contrast with the oxidation state approximation that assigns an oxidation number of +1.
As we shall see, the functionality level concept is useful in the context of polar reactions which are those that result in bond formation by electron pair donation from an electron rich synthon (nucleophile) to an electron deficient synthon (electrophile). In this context, for example, organic chemists generally consider all methyl halides, i. e. fluoride, chloride, bromide, iodide, to be similarly functionalized, and thus it is appropriate that they all share f = +1. It is of little significance (and probably not widely known) that the oxidation states of the carbons in methyl iodide (x = -4) and methyl bromide (x = -2) are different.
Interconversions of functional groups of different functionality level correspond to oxidations or reductions:
Heterolysis of the C-H bond is viewed as a special mode of C-H reaction that results in functionalization of a hydrocarbon. If hydride is abstracted the reaction is considered oxidation whereas proton abstraction is considered reduction.
All functional groups of the same functionality level are, in principle, interconvertable by metatheses or polar addition and elimination reactions such as in equations 1-3.
For organic synthetic analysis, it is important to recognize that polar carbon-carbon bond forming reactions are redox processes. The carbon nucleophile is oxidized, and the carbon electrophile is reduced. In terms of functionality levels of carbon in representative hypothetical polar reactions; nucleophilic substitution, nucleophilic addition, and nucleophilic acyl substitution are indicated in equations 4-6 respectively.
Thus, if we desire a product without functionality (f = 0) we must plan to react a (+1) electrophile with a (-1) nucleophile (equation 7). Alternatively, we may use reactants of other functionality level, but the functionality level of the initial product will have to be changed (oxidation or reduction) after C-C bond formation (e.g. equation 8).
Unsaturation Level Changes
If carbon functionality is defined as carbon for which f ≠ 0, then C=C and C≡C bonds are not considered to be functionality. Clearly, then, functionality is not the only molecular characteristic (structural feature) that facilitates bond forming reactions. In order to systematically consider the relationships which inhere between molecular structure and polar reactions, it is useful to define the unsaturation level of a specific atom as u = 0 for all singly bonded atoms, as u = 1 for all atoms involved in homonuclear double bonding, and as u = 2 for all atoms involved in homonuclear triple bonding. Thus, carbon-carbon and homonuclear multiple bonding in general does not change functionality levels. Introduction of C-C unsaturation is viewed as activation rather than oxidation (increased functionality level). Hydrogenation of C-C unsaturation is viewed as saturation rather than reduction of functionality level. These conventions find analogy in the concepts of coordinative unsaturation in organometallic chemistry. Thus, reactivity depends of f and u. Changes in f during chemical reactions are always balanced, i.e. an increase of f for one atom requires a decrease of f for another atom. For example, addition of bromine to C=C results in oxidation of both C's and reduction of both Br's (from f = 0 to f = -1).
Addition of HBr to C=C results in oxidation of one C (the one receiving Br) while \(H\oplus\) is reduced to H•. The functionality level concept corresponds well with experience for the most part. Although synthetically valuable differences in chemical reactivity are achievable for 1°, 2°, and 3° C-H bonds of hydrocarbons, it is useful to view these as different proclivities towards oxidation (hydride abstraction) or reduction (proton abstraction).
An increase of the functionality level of the carbon nucleophile also accompanies nucleophilic conjugate addition. But the carbon electrophile is not reduced. Rather, \(H\oplus\) is reduced to H• and the unsaturation level of the carbon electrophile is decreased. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/01%3A_Some_Principles_of_Synthetic_Planning/1.03%3A_Perception_of_Structure-Functionality_Relationships.txt |
The π-electron pair in a C=C bond may be unevenly distributed if the π-bond bears or is conjugated with a functional group. It is reasonable to approximate the electron pair distribution in, for example, the enol or enolate π-bond as having electron abundance on the β-carbon since a hydroxyl substituent activates the β-carbon toward bond formation with a carbon electrophile. Thus, functional groups stabilize neighboring centers of electron abundance (nucleophilic centers) and centers of electron deficiency (electrophilic centers). For example, the carbonyl carbon of a ketone is electrophilic while the carbon α- to a carbonyl is potentially nucleophilic. Actual nucleophilicity at this carbon is obtained when this carbon is conjugated with the carbonyl carbon as the corresponding enol or enolate. Similarly, the enone C-C π-bond is electrophilic at the β-carbon while the γ-carbon is potentially nucleophilic, actual nucleophilicity being available by conversion to the corresponding enol or enolate. Thus, the polar activation afforded by a functional group may be extended to remote carbon centers by conjugation. This possibility is indicated for 23. In the ensuing discussion, centers of actual or potential electrophilic or nucleophilic reactivity will be designated as (+) and (-) respectively in contradistinction to centers of positive or negative charge, which will be designated as \(\oplus\) and \(\ominus\).
Let us consider all possible synthetic strategies for direct synthesis of the butyryl moiety of butyrophenone (23) from two fragments by a polar reaction exploiting the polar activation afforded by the carbonyl group or any functional group precursor which confers electrophilicity to the same carbon atom. There are three possible C-C disconnections of the target 23. The three possible C-C connective strategies are summarized in equations 9-11. The strategies can be considered first in general terms by representing the required reactive polar precursors as synthons. The carbonyl group in 23 provides electrophilic reactivity at carbon 1 allowing a synthesis by polar creation of the 1- 2 bond by reaction with a three carbon nucleophile. The carbonyl group in 23 also potentially provides nucleophilic reactivity at carbon 2 allowing a synthesis by polar creation of the 2-3 bond by reaction with a two carbon electrophile. The carbonyl group in 23 also potentially provides electrophilic reactivity at carbon 3 allowing synthesis by polar creation of the 3-4 bond by reaction with a one carbon nucleophile. Usually the requisite synthons are recognized but only appropriate synthetic equivalents of these synthons are considered explicitly. For each of the above syntheses a large variety of alternative synthetic equivalents are possible. It is only necessary that the electrophilic precursor chosen has a functionality level one unit higher than the corresponding carbon in the target ( or has a C=C bond conjugated with an electrophilically activating functional group) and that the nucleophilic precursor has a functionality level one unit lower than the corresponding carbon in the target in order to achieve a direct synthesis of the target.
An indirect synthesis of the target may also be reasonable. For example, 23 could be prepared by addition of n-PrLi to benzaldehyde producing an intermediate 24 with the carbon skeleton of the target 23. Subsequent adjustment of functionality level by oxidation then delivers the ketone 23 (equation 12). Retrosynthetically such a strategy requires recognition of the possibility that benzaldehyde is a readily available electrophilic precursor of the benzoyl portion of 23. However, since the functionality level of this electrophile is the same at the incipient carbon 1 as in the target, the latter cannot be produced directly from benzaldehyde in a polar C-C bond forming process. Rather, the first dislocation of the target must be adjustment of its functionality level (FLA) prior to polar disconnection in the second dislocation (equation 13).
Topologically, the strategy of equation 13 is related to that of equation 9. An indirect synthesis of 23 by a strategy related topologically to that of equation 10 is outlined in equation 14. Retrosynthetically such a strategy requires recognition of the possibility that acetaldehyde is a readily available two carbon electrophile. However, since the functionality level of this electrophile is two units higher than the incipient carbon 3 in 23, a polar bond-forming reaction with a carbon nucleophile leads to a product in which the functionality level at this carbon is one unit higher than required for 23. Therefore, the first dislocation of the target must be adjustment of its functionality level (here functional group addition, FGA, a special case of FLA) prior to polar disconnection in the second dislocation (equation 15).
Regioselective Polar Reactions
It is important to recognize that all of the strategies considered above are hypothetical. The desired synthetic reaction between the chosen intermediates may not be the only reaction pathway available. For example, delocalized synthons are inherently ambident; they possess several centers of reactivity. Thus, the enolate in equation 14 is an ambident nucleophile that may react with an electrophile either at the carbonyl oxygen or α-carbon. Similarly, the conjugated electrophile 25 may react with a nucleophile either at the carbonyl carbon (1,2-addition) or the β-carbon (1,4- or Michael addition). Thus, 25 is an ambident electrophile. To be synthetically useful, bond formation must be accomplished at the desired position of an ambident nucleophile or electrophile, the reaction must be regioselective.
Reactivity Control Elements
We have now seen that indirect strategies, that involve dislocations of a target that do not directly reduce molecular complexity, may be desireable because: (1) they allow a subsequent dislocation of the target that efficiently simplifies molecular complexity, (2) they expliot readily available starting materials that have a high level of molecular complexity, or (3) they expliot certain readily available electrophiles or nucleophiles that have functionality levels that are inappropriate for direct C-C connective synthesis of a target. Indirect strategies may be desirable for other reasons. Thus, some atoms or groups of atoms may be exploited to control synthetic reactions by altering selectivity. We will refer to such molecular fragments as control elements.
For example, alkylation of ketones as in equation 10 often results in polyalkylation owing to rapid proton transfers from product ketone to starting enolate. The strong basicity of ketone enolates also can result in proton abstraction from alkyl halides (β-elimination) rather than nucleophilic substitution. The addition of a carboethoxy group provides a less reactive less basic nucleophile that can be alkylated in good yield (equation 16). Such a carboethoxyl group is often referred to as an activating group since it activates the molecule toward proton abstraction. It is perhaps more significant, however, that this group deactivates the resulting nucleophile making it a more selective reactant. After it has served its purpose, the control element must be removed. Retrosynthetically, the desirability of exploiting a control element requires addition of that element (CEA) in the first dislocation of the target prior to the reaction it is intended to control which then is the second dislocation of the target (equation 17).
Difunctional Targets
Polar syntheses of difunctional targets by strategies that exploit the polar activation provided by both functional groups to achieve C-C bond formation may be divided into two categories: those whose carbon skeleton can be assembled directly with the required functionality and those that cannot. C-C connective syntheses that directly generate difunctional targets with the required functionality are possible if both functional groups impart the same actual or potential polar reactivity to the atoms connecting the functional groups. We will refer to such functional groups and the atoms connecting them as consonant circuits. For example, 26 and 27 contain consonant circuits. Direct C-C connective synthesis of constant difunctional targets can be achieved by: (a) conjugate addition to an electrophile whose unsaturation level is one unit greater than that of the target, or (b) nucleophilic substitution or addition to an electrophile whose functionality level is one unit greater than that of the target. It should be noted that, while the carbon skeleton is assembled directly with the correct functionality level in the above strategies, it is not always possible to achieve a direct synthesis of consonant difunctional targets with the required unsaturation level. Thus, the reaction of 28 with 29 will generate a product with the carbon skeleton of 27 but with greater unsaturation. Thus, the 27 28 + 29 dislocation must be a two step process.
Indirect strategies are also possible for assembling consonant difunctional targets. Thus, during C-C bond formation, an intermediate may be generated that does not have the proper functionality level for the desired target. However, while the functionality levels of the precursors may be different than those of the target, the functionality in the synthetic equivalents of those precursors is electronically the same as the functionality of the consonant difunctional target. We shall refer to functionality in precursors whose nucleophilicity or electrophilicity is the same as that of the target -- but whose level may differ -- as target-related functionality.
Polar reactivity dissonance is present in difunctional targets if the polar reactivity imparted to the connecting atoms by one functional group is reversed by the other. We will refer to such functional groups and the atoms connecting them as dissonant circuits. For example, 30 contains a dissonant circuit. Syntheses of dissonant difunctional targets can never be achieved by C- C connective routes that directly exploit the polar activation afforded by both functional groups. For example, polar disconnection of 30 at the 2,3-bond must generate an acyl nucleophile synthon 32. But the carbonyl group usually provides electrophilic reactivity as in 31 and not nucleophilic reactivity at the carbonyl carbon. Synthetic equivalents such as 34 of such abnormal synthons, i.e. acyl carbanion equivalents, are known. They contain functionality that is related to that in the target but in which the usual polar reactivity of the target functionality is masked and the opposite polar reactivity is stabilized.
The normal polar reactivity of functional groups can be masked by conversion to unreactive derivatives.11 The functional group is said to be masked, blocked or protected in such derivatives The unreactive functional groups thus created are called masking or protecting groups. Such groups are examples of reactivity control elements. There is a subclass of masking groups which not only block the normal polar reactivity of a functional group but also facilitate the opposite polar reactivity. Such inversion of the polar reactivity of a functional group has been called umpölung.12 For example, the normal electrophilic reactivity of the carbonyl carbon in acetaldehyde can be transformed to nucleophilic reactivity by deprotonation of the derived thioacetal 35. The dithioacetal group not only masks the electrophilicity of the carbonyl precursor but also facilitates deprotonation of the carbonyl carbon by stabilizing the derived carbanion. Thus, the anion 34 is a synthetic equivalent of the acyl carbanion synthon 32. Acylation of 34 would deliver 36 from which the dissonant target 30 can be derived by hydrolysis. Note that the carbonyl group in the acetaldehyde starting material is exploited indirectly, i.e. after inversion of its usual polar reactivity, for the polar generation of a target C-C bond.
Polar disconnection of 37 at the 2,3-bond must generate a synthon 32 or 38 with inverted polar reactivity while disconnection at the 3-4 bond must generate a synthon 44 with inverted polar reactivity. It should be noted that synthetic equivalents of synthons with inverted polar reactivity, e.g. 34, 39, 41, and 45, by definition are dissonant molecules. Thus, for example, while the masked carbonyl carbon has nucleophilic reactivity in 41, the nucleofugacity of thiophenyl groups also makes this carbon potentially electrophilic. In this case the opposing polar reactivities are conferred by a single functional group, the dithioacetal, a functional group that can provide both nucleophilic and electrophilic activation at the same carbon.
An acyl carbanion equivalent 41 is available by deprotonation of the di(phenylthio)acetal derivative of acetaldehyde. Conjugate addition of carbanion 41 to methyl vinyl ketone might produce the thioketal 46 from which the dissonant target 37 would be obtained by hydrolysis.
A large variety of synthetic equivalents of "umpoled synthons" are available.13 Although they incorporate masked functionality with inverted reactivity, they are not necessarily prepared by umpolung of the target related functional group. For example, the synthetic equivalent 48 of the synthon 47 is an acetaldehyde enolonium ion equivalent. It reacts with cyclohexanone enolate to deliver 49 from which the dissonant target 50 is obtained upon hydrolysis.14
The acetaldehyde enolonium ion equivalent 48 can be obtained from methyl magnesium chloride and carbon disulfide by deprotonation of the intermediate dithioacetate followed by S-methylation and then by selective oxidation with m-chloroperbenzoic acid (MCPBA).14
Dissonant Targets from Dissonant Precursors
C-C connective polar syntheses of dissonant difunctional targets may also be achieved by multistep sequences employing polar reactions that exploit the polar reactivity provided by only one of the two functional groups in a dissonant precursor. For example, allylation of acetone enolate with 2-methoxyallyl bromide (51), a synthetic equivalent of the acetone enolonium synthon (43), followed by hydrolysis of the enol ether intermediate 52 could afford the dissonant difunctional target 37. Although 51 is prepared from acetone, the polar reactivity provided by the carbonyl group of the acetone precursor is not involved in the reaction of 51 with nucleophiles. Rather, the carbonyl group -- as an unreactive derivative -- is an innocent bystander. The polar reactivity required for C-C bond formation is provided by a target non-related second functional group, i.e. the bromo group. Also, it should be recognized that 51 is itself a dissonant difunctional molecule. The reaction of acetone enolate with 51 provides another example of a general principle: dissonant targets are available by polar C-C connective reactions of a dissonant precursor. Thus, 51 is a dissonant difunctional molecule.
As noted above for dithioacetals, some functional groups not only provide electrophilic reactivity at the carbon to which they are appended but also facilitate carbanion generation (i.e. reduction) at that carbon. Since this allows both electrophilic and nucleophilic reactivity at the functional carbon or any carbon conjugated with it, we shall refer to it as a biphilic functional group. For example, ≡N confers electrophilicity to carbon in a nitrile and also facilitates deprotonation of HC≡N to confer nucleophilicity to the same carbon. Thus, although the nitrile carbon in 53 is electrophilic and 53 is therefore a dissonant difunctional target, the cyanide ion is a stable nucleophilic equivalent of the nitrile carbanion synthon. The dissonant target 53 is available directly by the polar conjugate addition of cyanide to methyl vinyl ketone.
In summary, dissonant targets may be constructed by multistep sequences employing polar reactions that exploit: (a) inversion of the polar reactivity of one functional group in the target; (b) only one of the two functional groups in a dissonant precursor to provide polar reactivity; (c) a biphilic functional group.
Nonpolar Syntheses of Dissonant Targets
Dissonant difunctional targets are often prepared by direct C-C connective nonpolar reactions, such as oxidations, reductions, pericyclic bond-shift processes, or free radical additions. Thus, reductive coupling involves the union of two electrophilic centers accompanied by addition of an electron pair as in the pinacol reaction of acetone to produce the dissonant difunctional product pinacol.
Oxidative coupling involves the union of two nucleophilic centers accompanied by removal of one electron pair. The dissonant diketone 54 is obtained upon oxidative coupling of pinacolone enolate.
Generation of dissonant targets by pericyclic bond-shift processes is possible since the orientation of such reactions is controlled by p-orbital overlap which does not necessarily correspond with polar reactivity. For example, dissonant diester 57 is the major product from the cycloaddition of 55 with 56.
The free radical chain reaction between acetaldehyde and acetal 58 to generate 59 exemplifies another nonpolar C-C connective route to dissonant difunctional products.
Dissonant difunctional targets are also available by non-C-C connective processes such as addition of electronegative atoms X and Y to both carbons of a C=C bond. We shall refer to such reactions as dioxidative additions since both carbons are oxidized. Dioxidative additions can also occur with polyenes. Such reactions, which we shall call 1,n-dioxidative additions, always generate dissonant difunctionality. Thus, the conversion of 60 into 61 involves 1,2-dioxidative addition while the 62 to 63 conversion is a 1,4-dioxidative addition.
Disconnection of C=C Bonds
Retrosynthetic dislocations of a synthetic target involving disconnection of a carbon-carbon double bond, i.e. double disconnections, usually correspond to multistep synthetic sequences. There are no polar reactions that generate two bonds between two carbon atoms in a single step. (Note that dimerizations of carbenes are cycloadditions, that by definition, generate two bonds in a single step.) Therefore, if polar activation is to be exploited, a double connection during the synthesis must be made in two steps: the first, a polar union; the second, an elimination. The elimination step usually involves loss of HX, XY, or MX where X and Y are groups that are more electronegative than carbon while M is any group that is more electropositive than carbon. Thus retrosynthetically, disconnection across a C=C bond requires an addition as the first dislocation of the target.
The synthesis outlined in equation 18 is a representative example of the first approach. Here an electrophilic activating group of functionality level = 1 resides on each carbon. The syntheses outlined in equations 19-21 are representative examples of each of the last three strategies. In each case, the functionality level of the electrophilic synthon decreases by two on going to the C=C target. The functionality level of the nucleophilic synthon goes from -1, -2, or 0 for equations 19, 20, and 21 respectively in the precursors to 0 in the products. Also note that the second steps in equations 18 and 19 require oxidation of a hydrogen (deprotonation), and that the second step in equation 20 is a direductive elimination.
Strategic Flaws
The polar activation provided by a single functional group in a target can be exploited numerous times during a synthesis to facilitate several C-C connective steps. For example, the carbonyl group of the 2-cyclohexen-1-one 64 might be used to provide the requisite nucleophilic and electrophilic reactivity for generating two C-C connections in this target (bonds a and b) corresponding to dislocations #2 and #3 (synthetic steps 1 and 2) in a strategy for synthesis of 64 from methyl vinyl ketone and phenyl acetone. The first dislocation of the target, addition of water to the C=C bond shows the necessary intervention of an intermediate during the double connection (synthetic steps 2 and 3) corresponding to the 65 to 64 conversion. This synthetic plan also provides an example of a significantly flawed synthetic design since the intermediate δ-diketone 66 cyclizes in two different ways only one of which affords the desired product. The isomeric 2-cyclohexen-1-one 67 can even be the major product of this reaction.15
Theory and Practice
Besides failures to achieve the required regioselectivity during addition reactions of multidentate nucleophiles or electrophiles, or the reactions of molecules with several similar functional groups, the planned removal of activating functionality, or unsaturation, as well as the introduction, removal, or interconversion of functionality by oxidation, reduction, metathesis, etc., may not be feasible owing to limitations of known reactions and/or limitations imposed by the reactivity characteristic of a particular synthetic target. Polar reactivity analysis serves merely to systematically generate a set of synthetic strategies. These must be subsequently evaluated in terms of the availability of suitably selective reactions and appropriate starting materials. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/01%3A_Some_Principles_of_Synthetic_Planning/1.04%3A_Polar_Reactivity_Analysis.txt |
In summary, some principles of synthetic planning that can provide a logical basis for designing a synthesis include the following (additional principles will be introduced on pages 83-84):
1. Dislocate the target to precursor synthons by connections (CON), by disconnections (DIS), adjustment of functionality level (FLA) – such as oxidations and reductions, polar reactivity inversion (PRI), or functional group addition (FGA) – by interconversion of functional groups (FGI) without a change of functionality level, or by addition of control elements (CEA).
2. Devise synthetic equivalents of precursor synthons by appropriate functional group addition (FGA, a subclass of FLA, i. e. from f = 0 to f ≠ 0).
3. Construct a synthetic tree systematically generating sets of potential intermediates.
4. Prune the tree as it grows by eliminating schemes that do not follow logically imposed boundary conditions such as favoring dislocations that exploit target related functionality to facilitate the corresponding chemical reactions during synthesis.
5. Rank alternative strategies favoring efficient schemes that are most likely to deliver the desired target and synthetic intermediates by avoiding undesired side reactions. That is, disfavor schemes that probably incorporate flaws, especially ones that are fatal, i. e. will give 0% yield of the desired product.
1.06: Terminology
For definitions see the sections indicated.
(+), (-) (1.4)
\(\oplus\), \(\ominus\) (1.4)
activating group (1.4)
ambident electrophile (1.4)
ambident nucleophile (1.4)
biphilic functional group (1.4)
boundary condition (1.2)
CEA (1.4)
CON, DIS (1.2)
consonant circuit (1.4)
difunctional target (1.4)
dioxidative addition (1.4)
direct associative strategy (1.2)
direct synthesis (1.4)
dislocation (1.1)
electrophilic center (1.4)
FGA (1.4)
FLA (1.4)
functionality level (1.3)
indirect synthesis (1.4)
key intermediate (1.2)
logic centered analysis (1.2)
masking group (1.4)
nonpolar reaction (1.4)
nucleophilic center (1.4)
oxidation state (1.4)
polar reaction (1.4)
polar reactivity analysis (1.4)
polar reactivity dissonance (1.4)
polar reactivity inversion (PRI) (1.4)
protecting group (1.4)
reactivity control element (1.4)
retrosynthetic analysis (1.1)
strategic flaw (1.4)
subtarget (1.2)
synthetic equivalent (1.2)
synthetic tree (1.2)
synthon (1.2)
target-related functionality (1.2)
transform (1.1)
umpölung (1.4)
unsaturation level (1.3)
1.07: Study Questions
1. Indicate the functionality and unsaturation levels of the boldface atoms in the reactants and products of the following reactions.
(a)
(b)
(c)
(d)
2. Consider possible strategies for construction of the $PGF_{2\alpha}$ carbon skeleton exploiting the functional groups at the 9, 11, and/or 15 positions to activate formation of various bonds in the cyclopentane ring by polar reactions.
(a) Categorize each of the following circuits as consonant or dissonant:
Circuit Type
1-2-3-4-5-6-7-8-9
9-10-11
9-8-12-11
9-8-12-13-14-15
11-12-13-14-15
3. Perform a thorough polar analysis of cincassiol D1, a natural product of the "terpene" family.
For all circuits consisting only of carbon chains of 14 carbons or less, list the polar relationships between functional groups with a table in the following format:
Positions Circuit Relationship
1 + 6 1-5-6 consonant
1-2-3-4-5-6 dissonant
1-2-3-4-9-8-7-6 dissonant
4.
(a) Find the dissonant polar reactivity circuits, if any, between functional groups in the natural products hyperforin and cocaine. List them in the table format described above for question 4.
(b) Disconnection of one, and only one, C-C bond in usnic acid eliminates all dissonant circuits. Which is this unique bond in usnic acid that is incorporated in every dissonant circuit?
(d) What type of reaction could generate usnic acid directly from the subtarget identified in c?
5.
(a) With (+) and (-) next to appropriate atoms, indicate on structure 66 the polar activation provided to all atoms in a curcuit connecting the functional groups that could allow polar formation of the bond that is disected with a wavy line. Then draw structures for a synthon and a synthetic equivalent of the synthon for an immediate precursor of 66.
(b) Draw structures of three alternative monomeric products that might be formed during an attempt at converting the above synthetic equivalent into the synthetic target 1.
1.08: References
1. For a recent monograph, see: "New Synthetic Routes to Prostaglandins and Thromboxanes", Roberts, S.M.; Scheinmann, F., Academic Press, New York (1982).
2. Woodward, R.B.; Gosteli, J.; Ernest, I.; Friary, R.J.; Nestler, G.; Raman, H.; Sitrin, R.; Suter, C.; Whitesell, J.K. J. Am. Chem. Soc. 1973, 95, 6853.
3. Brown, E.D.; Lilley, T.J. Chem. Commun. 1975, 39.
4. Brewster, D.; Myers, M.; Ormerod, J.; Other, P.; Smith, A.C.B.; Spinner, M.E.; Turner, S. J. Chem. Soc. Perkin I, 1973, 2796.
5. Corey, E.J.; Ohno, M.; Vatakencherry, P.A.; Mitra, R.B. J. Am. Chem. Soc. 1964, 86, 478.
6. Volkmann, R.A.; Andrews, G.C.; Johnson, W.S. J. Am. Chem. Soc. 1973, 97, 4777.
7. For an introduction to retrosynthetic analysis on a simple level see: Warren, S. "Organic Synthesis: The Disconnection Approach", Wiley-Interscence, New York (1982).
8. For reviews see: (a) Wipke, W. T.; Howe, W. J. (Eds.) "Computer-Assisted Organic Synthesis", ACS Symposium Series volume 61, American Chemical Society, Washington, D. C. (1977); (b) Corey, E. J.; Long, A. K.; Rubenstein, S. D. Science 1985 228, 408.
9. Hendrickson defined functionality level differently, i. e., as f = π + z where π = number of C-C π- bonds (identical with u = unsaturation level as defined on page 12) and z = number of carbon- heteroatom attachments: Hendrickson, J. B. Topics Current Chem. 1976, 62, 49. This definition has the desirable feature of indicating an equivalence for tautomers, e. g. Hendrickon's f = 2 for both ketones and their enols. As with our definition, Hendrickson's concept also recognizes that organic chemists view all carbinols, whether 1°, 2°, or 3° as functionally equivalent (f = 1), and that "there exist functional families which are easily interconverted for synthetic purposes": Hendrickson, J. B. J. Am. Chem. Soc. 1971, 93, 6847. But Hendrickson's f does not incorporate the concept of negative functionality levels engendered by metals or other elements, e. g. silicon, that may serve as electrofuges when attached to carbon.
10. Pauling, L.
11. For compilations see: (a) McOmie, J. F. W. (Ed.), "Protective Groups in Organic Chemistry", Plenum, New York (1973); (b) Greene, T. W., "Protective Groups in Organic Synthesis, John Wiley & Sons, New York (1981).
12. For reviews see: (a) Seebach, Dieter Angew. Chem. 1979 91, 259: (b) Aakermark, B.; Baeckvall, J. E.; Zetterberg, K. Acta Chem. Scand., Ser. B 1982 B36, 577.
13. For a compilation see: Hase, T. A. (Ed.), "Umpoled Synthons", John Wiley & Sons, New Jersey (1987).
14. Kaya, R.; Beller, N. R. J. Org. Chem. 1981 46, 196.
15. Ross, N. C.; Levine, R. J. Org. Chem. 1964 29, 2341. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/01%3A_Some_Principles_of_Synthetic_Planning/1.05%3A_A_Protocol_for_Synthetic_Design.txt |
Strategies for Glucose Biosynthesis
Glucose is the ultimate organic starting material from which all other organic carbon compounds can be synthesized in nature. The single carbons of six carbon dioxide molecules are stitched together to form glucose by photosynthetic organisms. The energy for this reaction is provided by hydrolysis of adenosine triphosphate (ATP) to produce adenosine diphosphate (ADP) and phosphate (P). Hydrogen atoms are provided by the 1,4-dihydro derivative (NADPH) of nicotinamide-adenine dinucleotide phosphate (NADP+) and by protons. NADPH is a source of hydride, a "hydride transfer agent", that is stable in the aqueous environment of biosynthesis, i.e. at physiological pH it does not react with protons to generate molecular hydrogen. The high energy triphosphate ATP is produced by a photochemical phosphorylation of ADP to yield ATP. The reducing agent NADPH, a dihydropyridine, is produced in the same reaction by photochemical reduction of NADP+. Another important product of this reaction is molecular oxygen that is needed for the oxidative catabolism of natural products to provide energy in the form of ATP, i.e. by oxidative phosphorylation of ADP.
Elongation of a five carbon sugar chain to a six carbon chain by appending a molecule of the one carbon electrophile \(\ce{CO2}\) is an especially obvious strategy for a synthesis of glucose from \(\ce{CO2}\). Addition of a carbon nucleophile to \(\ce{CO2}\) (f = 4) would produce a carboxyl group (f = 3). This suggests that the first dislocation of the target might be oxidation of the aldehyde group (f = 2) to a carboxyl. There is a consonant circuit between the carboxyl group and the oxygen functionality in position 3 of the resulting gluconic acid subtarget. However, expression of the requisite polar reactivity at the 2-position requires conjugation as in the enol of ribulose. Therefore, adjustment of the functionality level at position 3 is a second logical second dislocation. Disconnection of the terminal carboxyl (a retro Claisen condensation) as the third dislocation of the target then suggests ribulose as a starting material.
Interestingly, the above strategy is not operative in the biosynthesis of glucose although it is used, albeit in reverse, for the generation of ribulose from glucose by the phosphogluconate pathway (vide infra). Rather, the biosynthesis of glucose involves a different strategy although the starting materials are indeed \(\ce{CO2}\) and ribulose. Glucose has ample functionality to facilitate its construction by C-C connective strategies involving generation of any of its C-C bonds by polar reactions. For example, the 3,4-bond could be generated by reaction of a nucleophilic synthon corresponding to carbons 1-3 with an electrophilic fragment corresponding to carbons 4-6. This suggests a first dislocation of the target involving adjustment of functionality level to allow conjugation of the C-2 oxygen with position 3 to facilitate generation of nucleophilic reactivity at C-3. By coupling oxidation at the 2-position with reduction at the 1-position, the first dislocation is simply an isomerization of the target glucose, an aldose, to fructose, a ketose. Polar disconnection of the subtarget (a retro aldol condensation) in the second dislocation has the important consequence of dividing the target into two similarly functionalized fragments with identical carbon skeletons. Such dislocations potentially reveal latent symmetry which is defined as the possibility of deriving two halves of a target from a common starting material. The precursors generated in the second dislocation, dihydroxyacetone and glyceraldehyde are readily interconverted by isomerization through an enediol intermediate.
Once again, we note that incorporation of \(\ce{CO2}\) into a precursor by a polar process will generate a carboxyl group. This suggests a carboxylic acid, glyceric acid, that can serve as a common precursor for both dihydroxyacetone and glyceraldehyde. Reterosynthetically this involves dislocation of dihydroxy acetone to glyceraldehyde (an isomerization) and dislocation of both molecules of glyceraldehyde to the same acid precursor (oxidation). Polar connection of two molecules of glyceric acid (a Claisen condensation) suggests a β-ketoacid subtarget from which a carboxyl group can be disconnected in the last dislocation of the target leading to the precursors \(\ce{CO2}\) and ribulose.
Biosynthesis of Glucose
In fact, the actual biosynthesis involves carboxylation of this five carbon sugar, albeit in the form of a bisphosphate derivative, ribulose-1,5-bisphosphate (RuBP). A strategy for biosynthesis of the subtarget RuBP might proceed in a stepwise fashion adding one \(\ce{CO2}\)-derived carbon at a time to a growing carbon chain. Such a process might require a different enzyme to catalyze fixation of each molecule of \(\ce{CO2}\) by addition to different subtargets. However, a much more ingenious strategy is adopted in nature. Carbon fixation occurs only by the reaction of \(\ce{CO2}\) with RuBP. Therefore, only a single enzyme is required to catalyze the process. Six molecules of \(\ce{CO2}\) are combined with six molecules of the five-carbon sugar derivative RuBP to produce twelve molecules of glyceric acid two of which are used to generate glucose by the above strategy. The thirty carbons of the remaining ten glyceric acid molecules are reshuffled to regenerate six five-carbon RuBPs. Thus, RuBP also functions as a catalyst for the bioconversion of \(\ce{CO2}\) into glucose.
The photosynthetic formation of glucose (actually in "the dark reactions of photosynthesis") involves an intricate series of reactions known as the Calvin cycle. In the accompanying reaction schemes, P is used to represent a phosphate ester [P = –\(\ce{PO3^2-}\)]. The carbon fixation cycle begins with carboxylation of RuBP (see below), a reaction that is catalyzed by ribulose bisphosphate carboxylase oxidase (RuBisCO) that is probably the most abundant protein on Earth. Thus, carboxylation of the enol of RuBP leads to a presumed b-keto acid intermediate that is readily cleaved by water in a retro Claisen condensation to give two molecules of 3-phosphoglyceric acid (3PG). Given the importance of this chemistry for the biosynthesis of organic molecules and the success of carbon-based life forms, it is noteworthy that RuBisCo catalysis of this reaction is barely viable. At ambient levels of carbon dioxide and oxygen, the catalyst consumes only a few molecules of \(\ce{CO2}\) per second in contrast with many enzymes that process thousands or tens of thousands of molecules of substrate per second. Furthermore, RuBisCO catalyzes another reaction that competes with carboxylation, the oxidative cleavage of RuBP to 3-PG plus 2-phosphoglycolate. This oxidative cleavage presumably involves electron transfer from than enolate intermediate to oxygen to produce superoxide and a cation radical. Bond formation between these two radicals then generates a hydroperoxy alkoxide. Fragmentation of this intermediate is driven by the exothermic generation of two carbonyl groups. The ratio of carboxylation versus oxidative cleavage is only about 4 to 1 and is even less favorable at higher temperatures. Thus, plants in high heat environments store carbon dioxide during the hot hours of intense sunshine, and generate glucose in the cooler hours in the absence of sunshine and its blistering heat.
The biosynthesis of all sugars, including glucose and the regeneration of RuBP, use 3PG as the common and only starting materisl. 3PG is first reduced to an aldehyde, glyceraldehyde-3-phosphate (G3P), by NADPH. ATP facilitates the reduction by converting the carboxyl into a more electrophilic derivative, a carboxylic-phosphoric anhydride. The remainder of the reactions of the Calvin cycle redistribute the thirty six carbon atoms of twelve G3Ps to yield one molecule of glucose (six carbon atoms) and regenerate six molecules of RuBP (thirty carbon atoms). The cycle will be summarized in Chart 1 below.
The aldose G3P is transformed to the ketose dihydroxyacetone phosphate (DHAP) under the influence of the enzyme isomerase. The six carbon atom skeleton of glucose is then assembled by an aldol condensation of G3P with DHAP. The initial product, fructose bisphosphate (FBP), is hydrolyzed (to F6P), isomerized (to G6P) which is hydrolyzed further to yield glucose.
Regeneration of Ribulose Bisphosphate
Retrosynthetic analysis reveals that a polar synthesis of Ru5P from G3P requires an umpoled synthon, the 2-hydroxyacetyl carbanion. A boundary condition, the aqueous reaction conditions of biosynthesis limit the choice of synthetic equivalents for this synthon. It is instructive to consider that a similar synthon 1 is required in the benzoin condensation, a cyanide ion- catalyzed polar coupling of two electrophilic benzaldehyde carbonyl groups that can be achieved in aqueous solution. Cyanide inverts the polar reactivity of a benzaldehyde carbonyl carbon by nucleophilic addition followed by a proton transfer that generates the carbanion 2, a synthetic equivalent of synthon 1. Anion generation at the former carbonyl carbon is favored by conjugation with the nitrile in 2. It is the biphilicity of cyanide that is the basis of its ability to invert the polar reactivity of an aldehyde carbonyl carbon. Condensation of 2 with a second molecule of benzaldehyde delivers alkoxide 3 which affords alkoxide 4 by proton transfer. Expulsion of cyanide from 4 then regenerates the catalyst and produces benzoin. Analogous cyanide-catalyzed reactions of other aldehydes are generically called benzoin condensations. All of the steps of the benzoin condensation are reversible. Therefore, the umpoled synthon 2 not only can be generated by reaction of cyanide with benzaldehyde, but also by retro benzoin condensation of benzoin.
A similar retro benzoin condensation of fructose 6-phosphate (F6P), an intermediate generated in the biosynthesis of glucose from glyceraldehyde 3-phosphate (G3P), could provide a synthetic equivalent of the 2-hydroxyacetyl carbanion required for biosynthetic regeneration of RuBP from G3P. In fact, the biosynthesis of RuBP from G3P involves the transfer of a 2-hydroxyacetyl group from F6P to G3P that is promoted by the enzyme transketolase.
Needless to say, cyanide is not the cocatalyst which masks the usual electrophilic reactivity of a carbonyl group and imparts nucleophilic reactivity to it in nature. The biological equivalent of cyanide ion is a carbanion generated by deprotonation of the thiazole ring in thiamine pyrophosphate (TPP).
The thiamine carbanion nucleophile condenses with the electrophilic carbonyl carbon of a ketose (e.g. F6P) to yield a 2-hydroxy iminium derivative. The latter readily undergoes a retro aldol-like reaction leading to an aldose, e.g. erythrose 4-phosphate (E4P), that has two carbons less than the original ketose. The resulting nucleophilic 2-hydroxyacetyl equivalent, 2-(1,2-dihydroxyethylidene)thiamine pyrophosphate (DETPP) can condense with a different aldose, e.g. G3P, to regenerate TPP and a ketose, e.g. xyulose 5- phopsphate (Xu5P) that has two carbons more than the aldose.
Further reactions in the Calvin cycle are aldolase promoted condensation of E4P with DHAP to yield sedoheptulose bisphosphate (SBP), hydrolysis of the latter to the monophosphate (S7P), transketolase promoted hydroxyacyl transfer from S7P to G3P to give Xu5P plus ribose 5-phosphate (R5P), isomerization of the latter to ribulose 5-phosphate (Ru5P), epimerization of Xu5P to give Ru5P, and phosphorylation of the latter to regenerate RuBP. The Calvin Cycle is summarized in chart 1.
Summary of Biosynthetic Carbon Fixation
(1) There is only one reaction that converts carbon dioxide into organic starting materials: the generation of two 3PGs from RuBP and \(\ce{CO2}\). This is step #1 in the biosynthesis of all natural products. (2) RuBP serves as a catalyst in a cycle that converts six \(\ce{CO2}\) into one molecule of glucose. (3) The RuBP consumed in step #1 is regenerated by a series of reactions, that reshuffle the atoms of ten molecules of the three-carbon sugar G3P into six molecules of the five- carbon RuBP. (4) All C-C bond formation and cleavage involves condensations (aldol, Claisen, benzoin) that are readily reversible. Furthermore, aldolase, the enzyme that catalyzes the formation of glucose from three-carbon sugars, also catalyzes their regeneration. As we shall see, further biosynthetic transformations of glucose into fatty acids, terpenes, or polyketides begin with cleavage of glucose (glycolysis) by this retro aldol reaction.
Ribulose from Glucose
Before proceding with an examination of strategies for the synthesis of glucose starting materials, let us first return to the simple strategy outlined above that is not used for the biosynthesis of glucose. Thus, rather than serving as a synthetic route to glucose from RuBP, this strategy in reverse is used in nature to produce five-carbon sugars from glucose. This pathway for glucose degradation is important for biosynthesis because it generates pentoses for the synthesis of nucleic acids. The pathway begins with oxidation of glucose 6-phosphate to 6-phosphogluconate. It is known as the phosphogluconate pathway, the hexose monophosphate shunt, or the pentose phosphate pathway. Many of the enzymes and reactions of this pathway are also involved in the biosynthesis of glucose from \(\ce{CO2}\) in the dark reactions of photosynthesis. The phosphogluconate pathway produces 2NADPH + CO2 + R5P from glucose and 2NADP+. Four enzymes are required: [1] 6-glucose phosphate dehydrogenase, [2] lactonase, [3] 6-phosphogluconate dehydrogenase, and [4] phosphopentose isomerase. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/02%3A_Sugars_-_Biosynthetic_Starting_Materials/2.01%3A_Carbon_Fixation-_Biosynthesis_of_Sugars.txt |
Retrosynthetic analysis reveals that a polar synthesis of glyceraldehyde can be achieved by condensation of a nucleophilic glycolaldehyde synthon with formaldehyde, a one-carbon electrophile of with f = 2. In fact, base-catalyzed aldol condensation of glycolaldehyde with formaldehyde not only generates glyceraldehyde but also dihydroxyacetone through tautomerization to an endiol and erythulose through aldol condensation with a second equivalent of formaldehyde.1 These reactions are believed to be involved in the base-catalyzed oligomerization of formaldehyde that generates the same products. A tiny amount of glycolaldehyde is sufficient to accelerate the oligomerization that otherwise has a long induction period, but eventually proceeds with the same kinetics as the glycolaldehyde-promoted process. Under certain conditions, as much as 50% of the formaldehyde is converted to glycolaldehyde, apparently through tautomerization of erythrulose to erythrose that then undergoes retro aldol cleavage to two molecules of glycolaldehyde. Thus, the induction period in the ologomerization of formaldehyde presumably corresponds to a slow process that generates the first traces of glycolaldehyde that then catalyzes further ologomerization. One hypothesis is that the formation of glycolaldehyde from two molecules of formaldehyde involves proton abstraction to generate a tiny concentration of acylcarbanion that condenses with a second molecule of formaldehyde.1 An alternative possibility is that a thermally allowed 2πs+2πa cycloaddition (see chapter 3, page 67) delivers a dioxetane intermediate that undergoes base catalyzed disproportionation to the hydroxyaldehyde.
The oligomerization of formaldehyde to provide a variety of sugars is a likely (pre)biosynthetic route for the generation of these molecules in a prebiotic world. In the prebiotic world, it is likely that the formation of glycolaldehyde occurred mainly through a cyanide catalyzed condensation that involves a cyanohydrin carbanion intermediate.
The major molecular complexity of sugars inheres in their abundance of functionality and stereochemistry. One strategy for the total synthesis of ribose exploits the prospect of stereospecific cis hydroxylation to introduce two hydroxyl groups with the requisite stereocontrol. Ribose exists predominantly in a cyclic hemiacetal form. The relatively rigid 5-membered ring can be expected to favor the appropriate stereocontrol. Disconnection of a cis alkene precursor at the carbinol carbon suggests the addition of a vinyl carbanion with glycolaldehyde.
Two refinements are required to implement this strategy. The glycolaldehyde hydroxyl must be masked to prevent protonation of the carbanion and one aldehyde group must be masked as an acetal. Rather than a vinyl carbanion, an acetylide was chosen as the nucleophile with the prospect of stereospecific cis partial hydrogenation of a disubstituted alkyne as a route to the requisite cis alkene.2
In the biosynthetic route to ketoses such as Ru5P from G3P, thiamine pyrophosphate serves as catalyst to provide an equivalent of a glycolaldehyde with inverted polar reactivity of the carbonyl group. An aldol condensation strategy for the C-C connective synthesis of ribulose is suggested by the latent nucleophilicity of the α-carbon enabled by the carbonyl group of dihydroxyacetone to react with a glycolaldehyde electrophile.
The biosyntesis of sugars generates single enantiomers owing to the asymmetry of the enzymes that catalyze their formation. The sugars generated by the hydroxide-catalyzed oligomerization of formaldehyde are a mixture of stereoisomers that are all racemic. However, asymmetric catalysis can be achieved in aldol C-C connective syntheses using chiral nonracemic (S)-proline as catalyst to promote the aldol condensation of dihydroxyacetone acetonide wih the benzyl ether of glyceraldehyde.3 | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/02%3A_Sugars_-_Biosynthetic_Starting_Materials/2.02%3A_Synthesis_of_Sugars.txt |
All of the carbon atoms of glucose are bound to oxygen. In contrast, many complex natural products are far less oxygenated. For example, fatty acids (Chapter 3) are long straight chains of often more than a dozen carbon atoms with no oxygen at all except for one terminal carbon that is fully oxidized to a carboxylic acid. Glucose catabolism (breakdown) can proceed anaerobically (doesn't require oxygen) producing biosynthetically useful small molecules in which some carbon atoms are less and some more highly oxidized. No net oxidation occurs. The oxygen atoms of glucose are merely reshuffled. The end product of the process is lactic acid, a molecule that is oxygen rich at one end and oxygen poor at the other. Perhaps most importantly for living organisms, anerobic catabolism of glucose also generates chemical energy in the form of ATP that can be used, inter alia, to power muscular contractions.
Glycolysis begins with phosphorylation of glucose followed by isomerization to fructose 6- phosphate (F6P) that is then phosphorylated further. Fructose bisphosphate is then cleaved under the influence of aldolase in a retero-aldol reaction to yield DHAP and G3P. Isomerization of DHAP then produces a second molecule of G3P.
The final transformation of G3P into lactic acid begins with the removal of hydride from the aldehyde portion of the molecules (oxidation) by nicotinamide-adenine dinucleotide (NAD\({}^\oplus\)). The reaction is catalyzed by the enzyme glyceraldehyde 3-phosphate dehydrogenase. The enzyme binds G3P as a hemithioacetal that readily transfers hydride to an enzyme-bound NAD\({}^\oplus\). The product, a reactive thioester of phosphoglyceric acid, readily acylates phosphate to yield bisphosphoglyceric acid (BPGA), a reactive mixed anhydride. BPGA then phosphorylates ADP. Hence, the chemical energy generated in this oxidation is stored in the phosphate bond energy of ATP.
For the biosynthesis of fatty acids (Chapter 3), terpenes (Chapter 4), or polyketides (chapter 5), phosphoglyceric acid is dismantled further to form a molecule of \(\ce{CO2}\) and a thioester of acetic acid with a structurally complex thiol, coenzyme A. This thioester, referred to as acetyl CoA, has one carbon that is completely reduced, a methyl group. Since the acetyl methyl is potentially nucleophilic and the carbon of \(\ce{CO2}\) is electrophilic, an obvious strategy for the biosynthesis of acetyl CoA and \(\ce{CO2}\) from 3PG uses malonyl CoA as the penultimate target and exploits polar cleavage of a C-C bond during decarboxylation. Adjustment of the functionality level of this subtarget suggests a precursor 5 which has the same overall functionality level as the desired starting material 3PG. Conversion of 3PG to 5 could be achieved by elimination of water followed by readdition and hydrolysis of the phosphate. Interestingly, this strategy is not used for the biosynthesis of acetyl CoA although the first dislocation is used, albeit in reverse, for generating malonyl CoA from acetyl CoA (vide infra).
An alternative strategy for biosynthesis of acetyl CoA from 3PG involves cleavage of \(\ce{CO2}\) from the incipient acyl carbon. But this requires umpolung of the normal electrophilicity of the carbonyl carbon in acetyl CoA. That is, polar cleavage would have to generate an umpoled acyl nucleophile synthon 6 from an umpoled synthon 7 of pyruvic acid. Generation of pyruvic acid from 3PG only requires redistribution of functionality. This is the actual biosynthetic strategy for acetyl CoA.
The biosynthesis of acetyl CoA uses many of the reactions involved in the anerobic catabolism of glucose. Therefore, let us resume our discussion of the biosynthesis of lactic acid from glucose (see above). The 3-phosphoglyceric acid (3PG) that results from oxidation of G3P (see above) undergoes a transfer of the phosphoryl group from the 3- to the 2-hydroxyl and subsequent dehydration to phosphoenolpyruvate (PEP). This enol ester is energy rich since its hydrolysis generates a relatively strong C=O bond at the expense of a relatively weak C=C bond. PEP readily phosphorylates ADP releasing pyruvic acid. The carbon atom of the ketone carbonyl group of this α-ketoacid is very electrophilic and readily accepts hydride from NADH under catalysis of the enzyme lactate dehydrogenase.
The biosynthesis of acetyl CoA from glucose involves decarboxylation of pyruvic acid that is regenerated by dehydrogenation of lactic acid. To allow a polar decarboxylation reaction, pyruvic acid mustistransformedbyumpolungoftheketonecarbonylintoamorereadilydecarboxylatedderivative. As in the transketolase reaction, the polar reactivity of this carbonyl group is temporarily inverted by the biphilic thiazole carbanion moiety of thiamine pyrophosphate (TPP). Thus, the nucleophilic thiazole ring carbon of TPP condenses with the highly electrophilic carbonyl carbon of pyruvic acid to give an adduct 8 that resembles a β-ketoacid. This undergoes decarboxylation by retro Claisen cleavage to deliver hydroxyethylidene TPP (9). The functionality level of the incipient carboxyl carbon is only f = 1 in 9. Therefore, oxidation of 9 is required to produce an acetyl functionality level (i. e. f = 3).
This oxidation is achieved by a polar process that concomitantly reduces a disulfide to a dithiol. Thus, 9 transfers an acetyl group to the disulfide of a lipoic acid residue bound to the enzyme dihydrolipoyl transacylase. The acetyl group is then transferred from the enzyme bound thiol to the thiol group of a coenzyme (CoA) to give acetyl CoA.
2.04: Terminology
For definitions see sections listed.
adenosine triphosphate (ATP) (2.1)
anerobic (2.3)
Calvin cycle (2.1)
catabolism (2.3)
coenzyme A (CoA) (2.3)
glycolysis (2.1)
latent symmetry (2.1)
NADP (2.1)
phosphogluconate pathway (2.1)
RuBisCo (2.1)
thiamine pyrophosphate (TPP) (2.1)
transketolase (2.1)
2.05: Study Questions
1. Different strategies are adopted in Nature for the disconnection of \(\ce{CO2}\) from acetylCoA during the biosynthesis of acetylCoA and for the connection of \(\ce{CO2}\) to acetylCoA during the biosynthesis of malonylCoA from acetylCoA.
(a) Indicate with (+) or (-) next to each C in the following retrosynthetic analysis to show the polar activation provided by the carboxyl functionality for the carboxylation of acetylCoA.
(b) Indicate the functionality levels of each atom in boldface type in the following strategy for the direct synthesis of malonylCoA from acetylCoA.
(c) Indicate with (+) or (-) next to each C in the synthon to the left the appropriate polar reactivity required for a strategy which generates acetylCoA by direct cleavage of \(\ce{CO2}\) (decarboxylation) of a precursor.
(d) Draw an intermediate, derived from pyruvic acid and thiamine pyrophosphate (TPP), that is a synthetic equivalent of the above synthon. With (+) and (-) next to the appropriate atoms, indicate the polar activation provided by functionality in the intermediate that allows the polar decarboxylation. Show the bond that cleaves in the biosynthesis with a wiggly line.
2. Tropinone is a key degradation product obtained during determination of the structure of atropine, a natural product of the "alkaloid" family.
(a) Perform a thorough polar analysis of tropinone. List the polar relationships between functional groups by completing the following table:
(b) Write a retrosynthetic analysis that provides a synthetic strategy for tropinone from acyclic symmetrical starting materials each containing no more than five contiguous carbons and using only polar bond-forming reactions. In your analysis show pertinent polar reactivity patterns with (+) and (-) and indicate disconnections with wavey lines through the bond to be severed in the dislocation of the target to its precursor. If you draw a synthon, label it as a "synthon" and also draw an appropriate synthetic equivalent and label it as a "synthetic equivalent". All of the starting materials must be symmetrical!
2.06: References
1. Breslow, R. Tetrahedron Lett. 1959, 22-26.
2. Iwai, I.; Iwashige, T.; Asai, M.; Tomita, K.; Hiraoka, T.; Ide, J. Chem Pharm Bull (Tokyo) 1963, 11,
188-
3. Enders, D.; Grondal, C. Angew. Chem. Int. Ed. Engl. 2005, 44, 1210-1212. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/02%3A_Sugars_-_Biosynthetic_Starting_Materials/2.03%3A_Acetyl_CoA-_a_Sugar-Derived_Starting_Material.txt |
In the previous chapter, two hypothetical biosynthetic strategies were presented that are not used biosynthetically. That the individual steps in each of these hypothetical strategies are reasonable, is indicated by the interesting fact that both strategies are exploited in reverse in Nature; one for the conversion of glucose into ribulose and the other for the conversion of acetyl CoA into malonyl CoA. The actual biosynthetic strategies for acetyl CoA and malonyl CoA were then presented. This format is intended not only to exemplify the numerous potential strategic options available, but also to provide foils that highlight the unique features of the actual biosynthetic strategies. These contrasting strategies encourage the reader to go beyond understanding the logic that governs the success of the biosynthetic sequence of reactions, and to ask: why does Nature choose this particular strategy?
In the ensuing chapters, a variety of strategies will be presented, compared, and contrasted for each natural product. Besides unimplemented hypothetical biosynthetic strategies, fatally flawed strategies, and often several topologically unique successful strategies will be considered with the goal of familiarizing the student with the options and pitfalls presented by the challenge of designing and executing the total synthesis of structurally and functionally complex organic molecules.
03: Fatty Acids and Prostaglandins
Fatty acids have larger carbon skeletons than sugars, but they are structurally simple. They have long unbranched chains of carbon atoms with much less functionality than sugars and no centers of asymmetry. Thus, they are more reduced (less oxygenated) than sugars. Higher animals have only limited capacity for storage of sugars as polysaccharides. Therefore, sugars are converted into fatty acids that may be stored as triesters of glycerol and used in the biosynthesis of the complex polar lipids of membranes and in the biosynthesis of prostaglandins and thromboxanes, two large groups of physiologically active substances.
A plausible strategy for the biosynthesis of stearic acid, which consists of an eighteen-carbon chain, involves reductive deoxygenation of a highly oxygenated precursor 1 that could be assembled by polar union of three six-carbon sugar molecules (see below). Such a strategy would economically utilize all of the carbon atoms in glucose to build the skeleton of the target. The carbonyl group in fructose 6-phosphate (F6P) activates position 1 toward alkylation by carbon 6 in F6P or glucose 6-phosphate (G6P). The nucleophilic substitution at position 6 would displace the activating oxygen from two precursor sugars delivering the precursor 1 that lacks oxygen at positions 6 and 12. Removal of twelve remaining hydroxyl and two carbonyl groups and oxidation of the terminal aldehyde in the precursor 1 to provide the carboxyl of stearic acid would require eighteen equivalents of hydride from e.g. NADPH. The only byproduct from such a synthesis would be eighteen molecules of water. But Nature not only uses glucose as the source of carbon but, except for the photosynthetic generation of NADPH, also uses glucose as the ultimate source of hydride for all organic biosynthesis.
The actual biosynthetic strategy is an ingenious process that co generates all the reducing agent, NADPH, required for deoxygenation, by oxidation (hydride abstraction) from an aldehyde intermediate derived from glucose. The byproducts from the biosynthesis are eighteen equivalents of water as well as nine equivalents of a byproduct \(\ce{CO2}\). Instead of three molecules of glucose, which would be required for the first strategy, the actual biosynthesis consumes four and a half molecules of glucose for every molecule of stearic acid produced. The carbons that are incorporated into the fatty acid product are almost all reduced while those in the \(\ce{CO2}\) byproduct have been oxidized.
A boundary condition governing the biosynthetic strategy for fatty acids is that the reagents and reactions should be readily adapted to the biosynthesis of a large selection of fatty acids with differing chain lengths. This suggests a repeatable chain-growing strategy: addition of a two-carbon carboxylic (acetic) acid to the growing fatty acid chain by a Claisen condensation. Thus, if the strategy is to be repeatable, a shorter chain carboxyl will serve as electrophile and become a keto group after C-C connection by polar bond formation with a two-carbon carboxyl-stabilized nucleophile on the α-carbon, then the functionality level of the electrophile (f = 3 for a carboxyl) will become (f = 2 for a ketone) in the resulting β-keto group derived from the carboxyl group in a precursor 2b that incorporates two less carbons.
Further refinement of this strategy recognizes the need for a better leaving group than hydroxyl, especially considering that most of the carboxyl group will be in the form of carboxylate at physiological pH. This suggests replacement of the hydroxyl, functional group interconversion (FGI), in 2a and 3a with a better leaving group indicated by X in 4a and 5a.
In the biosynthesis, all of the carbon atoms of a fatty acid are derived from acetyl CoA, that transfers its acetyl group to the thiol group of an a protein-bound acyl carrier protein (ACP). Both acetyl-S-ACP and acetyl-S-CoA are thioesters, acylating agents corresponding to \(\ce{H3C–COX}\) that are more electrophilic than their oxygen analogues because back donation of electron density of the nonbonding electrons from the large sulfur orbitals is far less important than back donation of nonbonding electrons from ester oxygen whose orbitals overlapp more effectively with those of the carbonyl π-bond.
A key feature in the biosynthesis of fatty acids is a requirement for carbon dioxide as bicarbonate ion, although the \(\ce{CO2}\) or \(\ce{HCO3-}\) is not incorporated into the fatty acids. This suggests a strategy in which \(\ce{CO2}\) is temporarily added to a precursor and then eventually removed after it has served its purpose. In fact, except for two carbon atoms at the alkyl terminus, acetyl-CoA is not the immediate precursor of the fatty acid carbon chain. Rather, an activated form of acetyl CoA, malonyl CoA, is generated by carboxylation of acetyl CoA. The electron deficiency of \(\ce{CO2}\) suggests that its function might be to remove electron density from an anionic intermediate, e.g., its function might be to stabilize a carbanion intermediate such as a carbanion on the α-carbon of an acetyl group. Thus, the nucleophile that reacts with acetyl-S-ACP might be a carbanion derived from malonate 7. Carboxylation of acetyl-S-ACP delivers malonyl-S-ACP.
For this refinement of the retrosynthetic analysis of the β-keto fatty acyl 5a would involve addition of an activating carboxyl group, reactivity control element addition (CEA), to a precursor 6a to facilitate carbanion formation (see page 44). Thus, the last carbon-carbon bond forming synthetic step is suggested by a dislocation of the precursor 6a involving carbon-carbon bond disconnection (DIS) suggesting a precursor 4b with two less carbons than 5a (three less than 6a). The synthetic strategy suggested by the above retrosynthetic analysis involves Claisen condensation of a malonate carbanion derived from 7 with a precursor 4b with two less carbons than the desired fatty acid 2a followed by decarboxylation of 6a to deliver 5a and accomplish net chain elongation by two carbons.
The carboxylation of acetyl-S-CoA is promoted by acetyl CoA carboxylase and involves transfer of a carboxyl group from an enzyme bound \(\ce{CO2}\) carrier, biotin. The role of carboxybiotin in thie biosynthesis deserves further consideration. It delivers anhydrous \(\ce{CO2}\) to an active site that, presumably encapsulates the reactants in a water-free environment. In a aqueous environment, \(\ce{CO2}\) is present as bicarbonate that is much less electrophilic than anhydrous \(\ce{CO2}\). Thus, the energy expended, in the form of ATP hydrolysis to ADP, results in the conversion of a weak electrophile into a stronger electrophile. Simultaneously, a base, the biotinyl anion, is produced that is strong enough to abstract a proton from acetyl-S-ACP. This proton abstraction also must occur in an aprotic environment because otherwise water would protonate both the biotinyl anion and the acetyl-S-ACP carbanion.
The fatty acid carbon chain is then assembled by a series of Claisen condensations starting with malonyl plus acetyl. In fact, the CoA derivatives of both synthons are first transformed into enzyme bound thioesters of the acyl carrier protein (ACP). The acyl groups are bound to the protein, located in the cytoplasm, by a 4'-phosphopantetheine ester of a serine residue. The acetyl group is then transferred to a specific cysteine residue of another enzyme of the fatty acid synthetase complex, β-ketoacyl-ACP synthetase (HS-synthetase). The activating carboxyl group in malonyl-S-ACP assures that the methylene of this acetyl synthon acts as the nucleophile. After condensation, the activating group is lost to give acetoacetyl-S-ACP.
There is another reasonable hypothesis for the role of the carboxyl group in malonyl-S-ACP in the condensation with acetyl-S-ACP. Rather than serving as an activating group to facilitate generation of a malonyl carbanion, it may serve as a latent carbanion. Driven by the energy released upon formation of a C=O bond, decarboxylation may generate an acetyl-S-ACP carbanion in an anhydrous environment in an active site of the fatty acid synthetase complex. This strong nucleophile would be acylated by acetyl-S- ACP to form acetoacetyl-S-ACP directly. Thus, the role of the carboxylate group is to allow the generation of a strongly basic carbanion without the requirement for a strong base, and in the absence of water that would protonate the carbanion or a strong base. This putative role of the carboxyl group is related to its role in the carboxylation of acetyl-S-ACP, except that instead of the decarboxylation generating a strong base that abstracts a proton from acetyl-S-ACP to produce the acetyl-S-ACP carbanion, the decarboxylation of malonyl-S-ACP generates the acetyl-S-ACP carbanion directly. In both scenarios, the generation of a strongly basic intermediate is driven by the energy released by the formation of a C=O bond in a water-free environment required to preclude destruction of the strongly basic intermediate.
The β-keto group is then reduced to a methylene group in a series of hydride reductions involving NADPH. The first reduction enantiospecifically gives D-β-hydroxy-butyryl-S-ACP under catalysis by β-ketoacyl-ACP-reductase. The β-hydroxy ketone is readily dehydrated under the influence of enoyl-ACP dehydratase to give the α,β-unsaturated thioester, crotonyl-S-ACP. Reduction of the latter occurs via 1,4-addition of hydride from NADPH to the electrophilic β-carbon of this D-2,3-unsaturated ester catalyzed by crotonyl-ACP reductase. The resulting butyryl-S-ACP then condenses with a second malonyl-S-ACP leading ultimately to hexanoyl-S-ACP and so on until seven molecules of malonyl-S-ACP have been combined with one acetyl-S-ACP. The process stops at palmityl-S-ACP from which palmitic acid is released by the action of a hydrolytic deacylase. Further elongation of the carbon chain occurs in the mitochondria by addition of acetyl-S-CoA rather than malonyl-S-CoA. The same enzymes in the mitochondria catalyze the reverse reaction, the catabolism (oxidative degradation) of fatty acids except that hydride reduction of the α,β-unsaturated ester involves NADPH; whereas, the corresponding dehydrogenation steps in the breakdown of fatty acids to acetyl CoA involve a flavoprotein as hydrogen acceptor. Catabolism of fatty acids also differs mechanistically from their anabolism in that acetyl CoA is produced directly in the thiolytic cleavage of a 3-keto fatty acyl-CoA by CoASH. That is, malonyl CoA is not involved in fatty acid catabolism.
Two different pathways exist for the biosynthesis of unsaturated fatty acids. One of these involves aerobic dehydrogenation of palmitic or stearic acid to give palmitoleic or oleic acids respectively. This reaction is remarkable because of its regiospecificity, its stereospecificity, and because the hydrogen atoms removed are remote from any functional group and, therefore, are not activated toward chemical reactions. An interesting feature of the dehydrogenation reaction is the concomitant oxidation of NADPH. The enzyme system is an example of a class of oxygenases which require a coreductant, such as NADPH, known as a mixed function of oxygenases.
A different pathway is operative in anaerobic bacteria. Thus, β-hydroxy-decanoyl- ACP is dehydrated by a specific enzyme, β-hydroxydecanoyl-ACP dehydratase that yields thecis-β,γ(or Δ3)-decanoyl ACP rather than the trans−α,β(or Δ2)-isomer formed in saturated fatty acid biosynthesis. Further elongation by malonyl-ACP then leads to palmitoleic acid. All polyunsaturated fatty acids biosynthesized in animals arise from palmitoleic or oleic acid by further chain elongations or dehydrogenations similar to those described above. Two of these precursor fatty acids, linoleic and linolenic acids, cannot be synthesized in mammals and must be obtained from plant sources; they are therefore called essential fatty acids.
Oxidative degradation (catabolism) of unsaturated fatty acids to acetyl-CoA follows much the same pathway as the corresponding saturated acids. Thus, successive C2 units are removed by thiolytic cleavage of β-ketothioesters.
When a cis-β,γ-unsaturated thioester results (e.g. 8), it is isomerized under catalysis by the enzyme enoyl-CoA isomerase to the trans-α,β-unsaturated isomer (e.g. 9) that is an intermediate in the biosynthesis. Further degradation then proceeds as usual. Since hydration of a cis-α,β-unsaturated thioester (e.g. 10), promoted by enoyl hydratase, gives a D-3-hydroxyacyl-CoA, epimerization, promoted by 3-hydroxyacyl CoA-epimerase, must occur before further degradation may occur. It is noteworthy that only the L-enantiomer is dehydrogenated to β-ketoacyl-S-CoA in oxidative degradation, while only the D-enantiomer is produced in the reduction of a β-ketoacyl-S-ACP during the biosynthesis of fatty acids. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/03%3A_Fatty_Acids_and_Prostaglandins/3.01%3A_Biosynthesis_of_Fatty_Acids.txt |
Prostaglandins are the skeletally most complex molecules we have yet considered. All prostaglandins are 1,3-dioxygenated cyclopentane derivatives with a 7-carbon carboxylic acid side chain and a vicinal 8-carbon γ-hydroxy- vinyl side chain. Three series of prostaglandins are known which are exemplified by prostaglandins F, F, and F. These are designated PGF, PGF, and PGF and respectively have one,two, or three C=C bonds in the side chains. The prostaglandins are appropriately considered at this point since their biosynthesis from tri-, tetra-, or pentaenoic fatty acids is very simple, involving the formation of only one new C-C bond. Moreover, the plethora of strategically different syntheses of prostaglandins which have been achieved in the laboratory offer a unique opportunity to gain an appreciation for the myriad solutions to the problem of planning a complex molecular synthesis.
With the exception of a bridge between carbons 8 and 12, the topology -- an unbranched chain of twenty carbons -- as well as the terminal carboxyl functionality of prostaglandins suggests fatty acids as biosynthetic precursors. Polar reactivity analysis of prostaglandin F (PGF) reveals that the 8,12-bond lies on a dissonant circuit between the hydroxyl groups on carbons 9 and 11 (the 9,8,12,11-circuit) and a dissonant circuit between the hydroxyl groups on carbons 9 and 15 (the 9,8,12,13,14,15-circuit). The 8,12-bond cannot be formed in a polar reaction involving polar activation by any two target related functional groups. The observed dissonant functionality pattern could be generated by 1,4-dioxidative addition of two hydroxyls to a 15-hydroxy fatty acid precursor or by 1,6-dioxidative addition of two hydroxyls to an 11-hydroxy fatty acid precursor. The requisite hydroxy fatty acid precursors might reasonably be produced by allylic oxidation, e.g. of arachiconic acid (AA), involving hydrogen removal from position 13 and hydroxyl addition at position 11 or 15.
In nature, prostaglandins arise by an oxidative cyclization of poly-unsaturated twenty-carbon fatty acids, which begins with enantiospecific removal of the L-hydrogen atom of the prochiral methylene group at C-13 coupled with enantiospecific introduction of oxygen at the allylic C-15 position. Subsequent cyclization and termination by addition of a second molecule of oxygen leads to a 15-hydroperoxy bicyclic peroxide (PGG), that is reduced to a 15-hydroxy bicyclic peroxide (PGH). These intermediates, known as prostaglandin endoperoxides, have been isolated and shown to yield prostaglandins. Reduction of the peroxy bridge gives PGF, while disproportionation gives β-hydroxy ketones PGE and PGD. The carbons in prostaglandins are numbered one to twenty starting at the carboxyl carbon and following the numbering system of the biosynthetic precursor fatty acids.
Important features of the biosynthesis of prostaglandins are its dia-stereo- and enantioselectivity. Consider the possible stereochemical relationships between the four substituents on the cyclopentane ring of PGF. There are 2n different possible arrangements for n stereocenters each having two possible configurations. Of the sixteen possible stereoisomeric arrangements, only 13' is found in the natural product. The isomers 11-18 are diastereomers. They possess unique stereochemical interrelationships of their four substituents. Thus, they are stereoisomers that have different configurations at one or more (but not all) of their stereocenters and, therefore, are not mirror images of each other. The remaining isomers 11'-18' are mirror images or enantiomers of the other isomers. Taking into account a fifth stereocenter at position 15 in the sidechain, there are 32 possible stereoisomers of PGF, two enantiomeric sets of 16 diastereomers. The biosynthesis is completely stereoselective. For any synthesis of a complex molecule, this is important because the less stereoselective a synthesis, the lower the yield of the desired product. Also, purification of the product is usually difficult if it is contaminated by stereoisomers since these often possess chemical and physical properties that are very similar to those of the desired isomer. In the biosynthesis of PGF2α, the first stereocenter, that at position 11, is introduced enantioselectively by the action of an asymmetric reagent (enzyme) on a prochiral precursor generating only one enantiomeric intermediate. Such a process, known as asymmetric induction, is inherently more efficient than a synthesis involving separation of a racemic mixture of enantiomeric products (resolution) since no starting materials are wasted in the generation of wrong isomers. The biosynthetic strategy for PGF involves a connection that ties the two ring hydroxyl groups together in a temporary bridge. The latter serves as a stereocontrol element assuring a cis relationship between the hydroxyls at positions 9 and 11, and allows the introduction of both cyclopentane oxygens atoms as a single molecule of oxygen.
There are three topologically unique strategic categories for the synthesis of prostaglandins: (a) syntheses from acyclic precursors, (b) syntheses from multicyclic precursors by cleavage of temporary bridges, and (c) syntheses from precursors containing an isolated cyclpentane ring. Examples of each strategic type will be considered in the following three sections. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/03%3A_Fatty_Acids_and_Prostaglandins/3.02%3A_Biosynthesis_of_Prostaglandins.txt |
As in the biosynthesis of prostaglandins, several total syntheses feature generation of the cyclopentane ring by cyclization of acyclic precursors. We will first compare the biosynthesis with three total syntheses involving cyclopentane ring formation by generation of the prostaglandin 8,12-bond. Since the 8,12-bond lies on dissonant circuits between the functionality at positions 9 and 11 or at positions 9 and 15, a polar connection cannot be achieved which depends on polar activation by either pair of functional groups. Therefore, each of these syntheses exploits the polar activation provided by only one target-related functional group to promote polar creation of the 8,12 bond. In Miyano's strategy1 (see below), polar disconnection of the lower side chain of PGE1 at the C=C bond suggests subtarget 19. Neither the aldehyde group nor functionality at C-11 in 19 can provide the requisite electrophilicity at C-12 for polar bond formation exploiting nucleophilicity at C-8 activated by the C-9 carbonyl. Therefore, a precursor of 19 must incorporate additional functionality to provide electrophilicity at the incipient C-12. This might be provided by a carbonyl group as in 20. However this strategy is flawed since the electrophilic aldehyde in 20 will compete with the carbonyl at the incipient C-12 in 20 for reaction with a C-8 nucleophile. This will produce an undesired benzoquinone byproduct derived from the intermediate 21 by dehydration.
To prevent undesired competition by an electrophilic aldehyde, this group is not introduced until it is needed. Instead, it is concealed in a pre-cursor 22 of 19 as a C=C bond from which it can be generated by oxidative cleavage. The C=C bond does not possess the high electrophilicity of an aldehyde. Yet an aldehyde group can be readily generated from the C=C bond. Polar disconnection of 22 suggests electrophilic functionality at the incipient prostaglandin C-12 in a precursor 23. Further disconnection of 23 to 24 and 25 exploits the polar activation provided by consonant functionality at the incipient C-9 and C-11 ignoring the carbonyl at C-12 in 23.
We shall refer to an unreactive direct precursor group with a different functionality level than the target as a latent functional group (see below for some examples).2 Thus, (1) an alkene (f = 0), as in 22 above, or a vicinal diol (f = 1) can serve as a latent equivalent of an aldehyde or ketone (f = 2). Although the alcohol is electrophilic at the incipient carbonyl carbon, its electrophilicity is considerably less than that of an aldehyde or ketone. (2) An arene (f = 0) is a latent carboxyl group (f = 3). (3) An enol ether (f = 1) provides a latent ester (f = 3) since oxidative cleavage of the latent precursor can be achieved to provide the desired functional group. (4) A ketone (f = 2) is a latent ester (f = 3) since Baeyer-Villiger oxidation of the former will deliver the latter; and (5) a terminal alkyne (f = 0) is a latent acetylide anion (f = -1) or terminal vinyl carbanion (f = -1) equivalent since alkynyl hydrogen is readily abstracted by strong bases and the alkyne products from coupling of acetylides with electrophiles can be selectively reduced to the corresponding alkene. Note that generation of a functional group from its latent equivalent, by definition, involves oxidation [O] or reduction [R], i.e., increase or decrease of functionality level. Also note that generation of a carbanion by proton abstraction from carbon or hydride addition to an α,β- unsaturated carbonyl compound corresponds to a reduction. In other words, proton abstraction from a “carbon acid”, i.e., an acidic C-H bond, corresponds to reduction in functionality level of the carbon from which a proton is abstracted and oxidation of the hydrogen that is abstracted as a proton. Also note that addition of a proton to a C=C bond results in reduction of the proton and and oxidation of the carbon that becomes a carbocation, and addition of \(\ce{Cl2}\) to a C=C bond corresponds to oxidation of both carbons with concomitant oxidation of both chlorines, a process that is called “dioxidative addition”.
A closely related concept is the masked functional group, which is an unreactive precursor group with the same functionality level as the target. For example, a ketal is a masked ketone (f = 2). Another example is provided by esters (f = 3) that serve as masked carboxyl groups (f = 3). Esterification blocks the proclivity of the acid toward decarboxylation when β to a carbonyl or toward deprotonation by bases. As we shall see in the Kojima-Saki synthesis of prostaglandins (see below), different masking groups for the same functional group, such as a benzyl and a methyl ester for two carboxylic acid groups in a molecule, may allow selective removal (unmasking) to convert one ester to an acid while the other remains masked.
In Miyano's synthesis of PGE1, β-ketoacid 26 rather than methyl ketone 24 (see above) is condensed with ketoaldehyde 25. This decarboxylative condensation regioselectively achieves nucleophilic activation at the incipient 10-position without competition from condensation at the incipient 8-position that also can be activated by the C-9 carbonyl. Thus, the carboxyl group appended to position 10 in 26 serves as an activating group. It is a reactivity control element and, consequently, a regiocontrol element. Intramolecular aldol condensation then generates the 8,12-bond delivering cyclopentenone 27. Selective oxidative cleavage of the more electron rich styryl C=C bond in 27 delivers an unsaturated aldehyde 28. Saturation of the remaining C=C bond affords 29 in which the aldehyde and carboxyheptyl groups adopt the required trans relative configurations owing to a thermodynamic preference and epimerizability at both positions 8 and 12. Condensation of 29 with ylide 30 then delivers PGE1 after selective reduction of the 15-carbonyl. Neither the stereocenter at position 15 nor that at position 11 is generated with high stereocontrol: thermodynamic control (TC). Furthermore, this synthesis produces a racemic mixture of PGE1 and its unnatural enantiomer since any synthesis which begins with nonasymmetric or racemic starting materials and employs racemic reagents will ultimately generate only racemic products.
A second strategy3 for prostaglandin synthesis involving cyclopentan-one annulationtion by formation of the 8,12-bond starts with polar disconnection of the lower side chain of PGF2α to suggest a subtarget 32. However, instead of using a C-8 nucleophile and C-12 electrophile as in the Miyano synthesis, the Kojima-Saki synthesis achieves polar 8,12-bond formation by reaction of a C-8 electrophile with a C-12 nucleophile. The C-12 aldehyde in 32 or an ester in a precursor 33 can activate carbanion generation at C-12. To preclude β-elimination of the C-ll oxygen and provide additional stabilization of a C-12 carbanion, the C-11 oxygen is present as a carbonyl group in the precursor 33 of 32. A possible β- elimination of the C-9 oxygen is precluded by concealing this functional group in a latent form as a benzyloxycarbonyl group in 33. Polar disconnection of 33 requires electrophilic reactivity at C-8 which could be provided by conjugation with the benzyloxycarbonyl or an additional carbonyl group at C-8 as in 34. This carbonyl group also can provide nucleophilic activation at C-9 for polar generation of the 9,10 bond. The benzyloxycarbonyl also can aid in formation of a carbanion at C-9 and prevent interference by carbanion generation at C-7. Thus, the benzyloxy-carbonyl also serves as an activating group and a regiocontrol element. The 9,10,11-circuit in 34 is dissonant. Therefore, polar disconnection at a nucleophilic C-9 requires electrophilic activation of the incipient C-10 in a precursor 36. The carbonyl at C-11 in 34 is ignored in the polar disconnection to 36 which is an umpoled synthon from methyl acetoacetate (37).
As in the 23 to 27 cyclization of the Miyano synthesis, cyclization of 34 produces a cyclopentanone 38. But now the roles of nucleophile and electrophile are reversed. Thus, in the Miyano synthesis the nucleophilic center is at position 8 and the electrophilic center at position 12 in 23.
In the Kojima-Saki synthesis, the nucleophilic center is at position 12 and the electrophilic center at position 8 in 34. This intermediate is stereoselectively converted to 33 by catalytic hydrogenation which saturates the C=C bond and also selectively converts the benzyl ester into a carboxylic acid without affecting the methyl or ethyl esters. Preferential generation of the α,α,β relative configurations at C-9, 8, and 12 respectively in 33 results from steric approach control followed by epimerization of the β-keto carbomethoxyl group. Conversion of 33 into PGF is straightforward.
Generation of the C-10 hydroxyl from the latent precursor, a C-10 benzyloxycarbonyl, is achieved by Baeyer-Villiger oxidation of an intermediate methyl ketone 39. Selective reduction of the carboxyl in 39 at C-12 is achieved by masking the electrophilic reactivity of the C-1 carboxyl as a potassium salt. To allow selective manipulation of the resulting alcohol, the hydroxyls at positions 9 and 11 in 40 are masked as tetrahydropyranyl (THP) ethers prior to reduction of the carbomethoxy group.
For a synthesis of PGE1 from 39, generation of the C-9 oxygen functionality from its latent precursor is delayed until after the C-11 acetoxy group in 39 is converted into a THP ether to allow differentiation from the C-9 acetoxy generated in a Baeyer-Villager oxidation of 43. The dithioketal protecting group in 41 can be selectively removed from 42 after introduction of the THP ether. Addition of the lower sidechain to 43 after oxidation to aldehyde 44 parallels the sequence described for the Miyano synthesis.
The β-hydroxycarbonyl array in PGE2 is sensitive toward dehydration. If the C-9 carbonyl is to be exploited to activate nucleophilic reactivity at C-8 in a precursor, this sensitivity must be addressed. In the Miyano synthesis, dehydration of the cyclization product 27 is disfavored by the instability of the antiaromatic cyclopentadienone that would result. In a third strategy for prostaglandin synthesis4 that also mimics the biosynthetic cyclopentane annulation involving 8,12-bond creation, the problem is circumvented by introducing the C-11 hydroxyl at the end of the synthesis. This suggests a key intermediate 45 in which the C-11 functionality is removed and an activating group is added at C-8 to aid in carbanion generation at this position. Polar disconnection of the upper side chain from the subtarget 45 suggests electrophilic functionality at C-7 as in the precursor 50. Polar disconnection of 46 at the 8,12- bond reveals the need for electrophilicity at C-12. However, rather than placing appropriate functionality at C-12 as in intermediate 23 of the Miyano synthesis (see above), a nucleofuge at C-14 in 47 provides the requisite activation by conjugation with C-12. An epoxide 47a provides the appropriate electrophilicity at C-12 and oxygen functionality at C-15. A chlorohydrin 47b is an alternative synthetic equivalent that is interconvertible with 47a. Polar analysis of 47b suggests disconnection to the electrophilic precursor 49 and 48 whose terminal acetylene serves as a latent vinyl nucleophile. The utility of terminal acetylenes as latent terminal vinyl nucleophiles also suggests a strategy for a C-C connective route to 50 via 51 from 52, cyanide, and a 1,3-propane dielectrophile. Although 47a and 47b are alternative synthetic equivalents, conversion of 47b to 47a during the synthesis would provide a more reactive electrophile.
A synthesis of 48 might have been achieved by propargylation of ethylacetoacetate dianion. However, the potential for abstraction of the acetylenic hydrogen, by the strongly basic dianion, recommended an alternative approach.
Thus, a malonic ester synthesis provided 4-pentynoic acid that was further elaborated to a β-ketoester by Claisen condensation.4 Enoletherification then masks the ketone in 48 and allows selective deprotonation at the terminal acetylene. Condensation of the resulting acetylide nucleophile with α-chloroheptanal (49) produces 53 stereoselectively and then cis vinyl trans epoxide 47a after partial hydrogenation and base promoted heterocyclization.
Cyclization of β-keto ester 47, generating the prostaglandin 8,12-bond, might have been accomplished by intramolecular alkylation of an intermediate enolate. However, an alternative nucleophile, enamine 55 was employed. Hydrolysis of an intermediate enamine derivative 56 followed by allylation of the resulting β-ketoester delivered 45. Especially noteworthy is the stereoselectivity of this synthesis of 45 with the correct relative stereochemistry at C-12 and C-15. This is the consequence of three consecutive stereoelectronically controlled (SEC) reactions.
First, addition of an acetylide nucleophile derived from 48 to the α-chloroaldehyde 49 occurs stereoselectively at the least hindered face of the carbonyl group in a conformation of 49 that achieves maximum separation of the C=O and C-Cl dipoles by an anti periplanar arrangement. Subsequent cyclization of the β-chloroalkoxide 54 with Walden inversion produces a trans disubstituted epoxide stereospecifically.
A stereoelectronically preferred mode of cyclization was expected to translate the stereochemical relationship between the chiral centers in the cis vinyl trans epoxide 55 into the requisite stereochemical relationship between the chiral centers at positions 12 and 15 in 56.4 Thus, anti SN2' displacement of alkoxide by the enamine nucleophile in 55 was expected to generate 56 after proton transfer in a presumed iminium alkoxide intermediate.
Introduction of a hydroxyl substituent at the 11-position in 45 is complicated by an absence of activating functionality adjacent to C-11. Reactivity can be provided by introducing unsaturation between carbons 10 and 11 taking advantage of the C-9 carbonyl to activate C-10 for introducing a leaving group. PGE2 could then be obtained by epoxidation of the α,β-unsaturated ketone PGA2 followed by reductive cleavage of the C-O bond adjacent to the carbonyl in 57. This suggests PGA2 as a synthetic precursor of PGE2.
While 45 (see above) might be converted to PGA2 by decarbethoxylation of the β-ketoester array and subsequent oxidative introduction of a leaving group at C-10, a more elaborate strategy was adopted. The process provides an example of a construction of the prostaglandin skeleton by generating the 9,10-bond of the cyclopentane ring as the last skeletal connection. Thus, a 10-carboethoxy precursor 58 would be well suited for the regioselective (α vs α’) nucleophilic activation (proton abstraction) of the 10-position required for the conversion of a 10,11-dihydro-PGA2 derivative into PGA2. Also, 58 is suitably functionalized for polar generation by reaction of a C-10 nucleophile with a C-9 electrophilic center in a precursor 59. Polar reconnection of 59 suggests the key intermediate 45 as a precursor of 58 via 59.
PGA2 is a naturally occuring dehydration product from PGE2, and the former has been prepared from the latter by an oxidation reduction sequence. Stereoselectivity during the epoxidation was achieved by employing a sterically demanding blocking group appended to the 15-hydroxyl in 60 to direct epoxidation to the α face of the cyclopentenone ring.5
The conversion of 45 into 58 was achieved by an ethoxide-catalyzed rearrangement presumably involving retro Dieckmann cleavage to 59 followed by Dieckman cyclization to 58. The carboethoxy transfer might also occur by decarboethoxylation and recarboethoxylation. In any event, the rearrangement is driven to 58 by formation of the corresponding enolate. The rearrangement allows regiocontrol in the formation of an enol ether 61, the subsequent introduction of bromine by 1,2-dioxidative addition to give 62, and ultimately in the introduction of unsaturation between carbons 10 and 11.
The previous three examples of prostaglandin synthesis illustrated polar synthesis of the 2,3-bond of a cyclopentanone ring corresponding to the 8,12-bond of the prostaglandin skeleton. In each case, this requried additional functionalization of a precursor because the 9,8,12,13,14,15 or 9,8,12,11-circuits are dissonant. Since the 9,10,11 circuit is consonant, either the 9,10 or 10,11- bond can be formed by a polar reaction that depends only on target-related functionality. As we shall see in section 3.7, seco prostaglandins (molecules lacking one C-C bond of the prostaglandin skeleton) are natural products for which the name levuglandin (LG) was coined to signify that they are derivatives levulinaldehyde with prostaglandin side chains. In theory, 13,14-dihydro-PGE1 (63) could be generated directly from dihydro-LGE1 by polar reaction of a C-10 nucleophilic enolate with the electrophilic carbonyl carbon of the aldehyde group at C-11, i.e an aldol condensation. However, although 11,13-dihydro-PGE1 is undoubtedly an intermediate in this cyclization, it is not stable and dehydrates under the basic aldol condensation reaction conditions to afford olefin 64, that must then be refunctionalized to deliver the target β-hydroxyketone 63.6
A Merck synthesis7 of PGE1 achieves cyclopentanone annulation by creating the 9,10-bond in a polar process. However, to avoid generation of a sensitive β-hydroxy ketone intermediate, only one target related functional group is exploited. Polar disconnection of the lower side chain suggests a precursor 65 (see below). The C-11 hydroxyl is concealed in latent form until the end of the synthesis to avoid β-elimination. Thus, subtarget 65 is dislocated to a penultimate precursor 66 in which the C-11 hydroxyl is replaced by a methyl ketone and the C-9 carbonyl is masked to allow selective Baeyer-Villiger oxidation of the methyl ketone to deliver 65. The reactive methyl ketone and carboxylic acid functionality in 66 can be internally masked as a lactone in a precursor 67. Although the ring juncture in 67 is necessarily cis, the substituents at both positions 11 and 12 in 66 and its stereoisomers are epimerizable allowing generation of the required all-trans relative configuration of the substituents in 66 that is favored thermodynamically.
To facilitate polar synthesis of the cyclopentanone ring in 67, a carboxyl group can be appended to the incipient C-10 in a precursor 69 to provide nucleophilic activation (CEA). This activating carboxyl will be removed readily from the cyclization product 68 by a polar cleavage. The two reactive carboxylic acid groups in 69 can be derived from a latent precursor 70 by oxidative cleavage. Finally, the cyclohexene moiety in 70 suggests a double disconnection to 71 and 72 that would provide the cyclohexene ring by a Diels-Alder cycloaddition. A preference for the required orientation of the cycloaddition is predicted owing to orbital overlap effects which favor an ortho relationship between the substituent on the diene and the electron withdrawing substituent on the dieneophile.
During the synthesis, it was discovered that opening of the lactone in 67, to allow oxidation of the secondary hydroxyl and deliver ketone 66, could not be achieved. To circumvent this flaw in the original plan, 67 was converted to an acetal 73 that could then be converted into a hemiacylal 74 by \(\ce{RuO4}\) oxidation. Transesterification replaced the carboxymethyl ester in 74 with a methyl ester in 66 that could then be converted to PGE1 as planned.
In the above synthesis, a cycloaddition was applied to generate a cyclohexene by a C-C double connective process. Cycloadditions generally provide a valuable nonpolar route to various cyclic products. Functionality is unnecessary for cycloadditions. Usually the targets contain unsaturation, but cyclobutanes, that can be generated by cycloaddition, do not even have unsaturation. A retro cycloaddition (RC) dislocation is feasible if a cyclic shift of two σ-bonds and n-2 π-bonds cleaves the ring into two poly and/or monoene precursors. Targets that are candidates for synthesis by cycloaddition of two poly and/or monoenes can be recognized by the presence of at least n-2 π-bonds in a 2n-atom closed circuit. If the precursors are bridged, the cycloaddition will be intramolecular. Cycloadditions may occur readily with thermal activation if n is an odd number but may require photochemical activation or transition metal catalysis if n is an even number. These rules are a consequence of the requirement for positive overlap between the lowest unoccupied molecular orbital (MO) of one reactant with the highest occupied molecular orbital (HOMO) of the other reactant. Sometimes this is only possible for the HOMO of the photoexcited π* state of one reactant and usually the interaction is suprafacial (on the same face of the π molecular orbitals. However, note that for 2π + 2π cycloadditions, a thermal reaction is favorable if one of the π-MOs interacts antarafacially (on opposite faces) and undergoes twisting of the two ends of the MO in opposite directions during the cycloaddition. For steric reasons, this is usually not feasible. However, it occurs readily for ketenes (see section 3.4).
Some examples of retro cycloaddition dislocations are presented below. The precursors of 75 and 76 may cycloadd with thermal activation while the precursors of 77 and 78 may require photoactivation, transition metal catalysis or involve antarafacial reaction of one π-bond, e.g., of a ketene.
The 2n atom circuit may contain more than n-2 π-bonds. For example, dislocation of 80 to 81 and 82 corresponds to a cycloaddition that will readily occur thermally. Shift of two σ-bonds and n-2 = 1 π-bond cleaves the ring into two polyenes and n = 3 is an odd number.
Since the 11,12,13,14,15-circuit in PGE1 is consonant, in theory annulation of the cyclopentanone ring by forming the 11,12-bond can be achieved by exploiting the polar activation provided by the functional groups at positions 11 and 15. For example, conjugation with the C-15 carbonyl in 84 should facilitate generation of a carbanion at C-12 that could couple with the aldehyde carbonyl in 84 to generate 83 directly. However, PGE1 contains a sensitive β-hydroxycyclopentanone array that readily dehydrates to give PGA1. Therefore, early strategies for the synthesis of PGE1 were dominated by efforts to mask the reactive β-hydroxy ketone array.
In the first total synthesis of PGE1, achieved by E. J. Corey8, the C-9 ketone carbonyl was carried along in latent form as a relatively unreactive formamide grouping which was transformed into a carbonyl group only at the end of the synthesis, vide infra. For the ultimate skeletal connection between carbons 11 and 12 in a precursor 87 of 85 in Corey's strategy for PGE1, nucleophilic reactivity at C-12 is provided by a carbonyl group added to C-13. This carbonyl would be removed after polar cyclization to 86. Furthermore, reduction followed by β-elimination fostered by a carbonyl group at C-15 would generate the required unsaturation between carbons 13 and 14. The two reactive carbonyl groups in 87 could be derived from a latent precursor, the C=C bond in a cyclohexene 88. A double disconnection of the latter intermediate suggests diene 90 and dienophile 89 as precursors that would provide 88 by a Diels-Alder cycloaddition. The use of a nitro group in 88 and 89 as precursor for the formamido group in 87 is dictated by the favorable reactivity of electron deficient dienophiles toward electron rich dienes such as 90. For the synthesis of diene 90, the polar union of an electrophilic isoprenoid synthon 91 with an acetal carbanion synthon 92 was chosen since isoprenyl bromide 93 is readily available. A dithiane-derived carbanion 94 would serve as the synthetic equivalent of the umpoled ketal carbanion synthon 92. The allylic bromide 93 was prepared by free radical allylic bromination of 95, a cycloadduct obtained from isoprene and sulfur dioxide. Free radical abstraction of allylic hydrogen is favored by delocalization of the resulting allylic radical. Benzylic hydrogen abstraction and bromination with N- bromosuccinimide (NBS) is simillarly favored. Both 95 and the derived allylic bromide are crystalline solids from which the correspond-ing dienes can be generated by cycloelimination of \(\ce{SO2}\). Allylation of 94 with 93 delivered a diene 96 that is a synthetic equivalent of 90 (see above).
Rather than first convert thioketal 96 into ketal 90, the former was reacted with dienophile 97 to produce cyclohexene 98. Then the dithioketal was replaced with an ethylene ketal protecting group. Revelation of the latent carbonyl groups by oxidative cleavage of the alkene 88 provided the ε-keto aldehyde 87. Base catalyzed aldol cyclization of 87 then delivered 86 stereoselectively. Thus, because the C-12 substituent is epimerizable in 86, the required thermodynamically favored trans relationship between the two bulky side chains was produced. Because no control was exerted during generation of the C-11 stereocenter, some of the wrong epimer was also formed.
Although the prostanoid carbon skeleton was generated in the aldol cyclization of 87 to give 86, completion of the synthesis required extensive adjustment of functionality and unsaturation level. The sensitive β-hydroxy ketone array was immediately acetylated and then the carbonyl group was reduced to avoid dehydration. After deprotection of the ketone and dehydration of the intermediate 99, the allylic carbonyl in an intermediate enone was reduced with \(\ce{Zn(BH4)2}\), a mild hydride reducing agent, to produce an allylic alcohol 100. Hydrolysis of the nitrile and acetate was followed by protection of the hydroxyl groups at positions 11 and 15 as tetrahydropyranyl ethers. Subsequent hydrolysis of the formamide required more vigorous conditions to deliver a THP protected derivative of 85.
Production of PGE1 by generation of the sensitive β-hydroxy ketone array under mild conditions was then accomplished in the key step of the synthetic plan. The strategy to use an amino group as a latent carbonyl in the immediate precursor 85 of PGE1 depended upon a precedented sequence of reactions. Thus, selective oxidation to an imine was accomplished by N-bromination with NBS followed by base promoted elimination. Finally, hydrolysis of both the imine and the tetrahydropyranyl (THP) ether protecting groups under mildly acidic conditions delivered PGE1.
The key oxidation process is based entirely on polar reactions. Thus, N-bromination oxidizes the amino nitrogen from f = -3 to f = -1. Elimination of \(\ce{HBr}\) then reduces the nitrogen to f = -3 while it oxidizes carbon and hydrogen. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/03%3A_Fatty_Acids_and_Prostaglandins/3.03%3A_Syntheses_of_Prostaglandins_from_Acyclic_Precursors.txt |
In the preceding syntheses of prostaglandins stereocontrol was achieved in several ways. For example, stereoselective generation of 33 from 38 depended on steric approach control (SAC) during catalytic hydrogenation to favor a cis relationship between substituents at positions 9 and 8. Subsequent thermodynamic control (TC) favored a trans relationship between the substituents at positions 9 and 12 by epimerization of a thermodynamically less stable cis intermediate to the more stable trans isomer. Stereoelectronic control (SEC) was adduced to account for the stereoselective generation of the correct relationship between the stereocenters at positions 12 and 15 in 56 during the cyclization of 55.
In this section, another technique for achieving stereocontrol will be considered. Thus, proximity of functional groups may be assured by the tactic of tying them together in a temporary ring which is ultimately cleaved. The biosynthesis of PGF involves such a temporary bridge (TB) that enforces a cis relationship between the oxygen atoms at the 9 and 11 positions. These oxygens are tied together with an O-O bond in the intermediate prostaglandin endoperoxide PGH2.
Often, temporary bridges contain functional groups in a latent form. We previously saw that cycloolefins may be oxidatively cleaved to yield dicarbonyl compounds. Creation of the PGF skeleton by generation of both C=C bonds from carbonyl precursors suggests a 1,5-dialdehyde subtarget 101. Since the aldehyde substituent at the C-12 stereocenter should be epimerizable, the less thermodynamically favored all cis aldehyde 102 can also serve as subtarget. The carbonyl groups in 102 can be concealed in latent form in the temporary unsaturated bridge of 103. By employing a second temporary unsaturated bridge, a highly stereocontrolled synthesis of PGF can be achieved. Thus, the cis-1,3-diol array found in PGF and in the proposed intermediate 103 can be obtained -- by Baeyer-Villiger oxidation of the derived methyl ketone - from the cis-diacid 104 that can be produced by oxidative cleavage of endo-dicyclopentadiene (DCPD). In this strategy for prostaglandin synthesis9, generation of the required cis relationship between the stereocenters at positions 8 and 9 ultimately depends upon a stereoelectronic preference for generation of the endo rather than exo isomer of DCPD during \(2 π + 4 π\) cycloadditive dimerization of 1,3-cyclopentadiene. This is favored by secondary orbital overlap between the "nonparticipating" C=C bond and the cycloadding diene.
This synthesis exploits selective cleavage of one temporary bridge, the more strained C=C bond, to produce a dialdehyde 105. After conversion to diketone 106, the remaining C=C bond is partially oxidized to deliver 107 after acetylation. Baeyer-Villiger oxidation then produces a tetraacetate. Saponification followed by oxidative cleavage provides dialdehyde 102 from its latent precursor, the vicinal diol array in 108. Epimerization of 102 at position 12 generates 101 that forms a hemiacetal in which one aldehyde carbonyl is adequately masked to allow chemoselective olefination of the remaining carbonyl to provide 109. To prevent reduction of the aldehyde carbonyl, 109 is converted to a mixed acetal before a nonstereoselective reduction of the ketone carbonyl. Reductive cleavage of the β-trichloroethyl acetal in 110 then allows olefination of the remaining aldehyde group to provide 111 and ultimately racemic PGF together with the racemic 15-epimer.
Corey's second strategy for total synthesis of prostaglandins10 exploits two temporary bridges to assure the proper stereochemical relationships between the stereocenters at positions 9, 8, and 11. The cis relationship between the substituents at positions 8 and 9 in 101 is assured by a temporary ring in the lactone precursor 112 that is generated by stereoselective functionalization of an olefin 113. Another temporary bridge, invloving the C-8 substituent, is used in the lactone 114 to assure a cis relationship with the hydroxyl at position 11. Since ketones are latent esters the cyclic ketone 115 can serve as a precursor of 114. The required regiospecificity in the Bayer-Villiger oxidation of ketone 115 can be expected since this reaction involves 1,2-migration to an electron deficient terminus. The group that most readily supports a partial positive charge migrates preferentially. Thus, in 115 the secondary alkyl group that is also allylic migrates in preference to the primary alkyl group. A trans relationship between the substituent at position 12 and the remaining stereocenters in the cyclopentane ring is ultimately the consequence of steric approach control during the cycloaddition of a 5-substituted 1,3-cyclopentadiene precursor 116 with ketene.
A potential flaw in this strategy arises from the instability of 5-substituted 1,3-cyclopentadienes that readily rearrange at room temperature, by [1.5]sigmatropic hydrogen migrations (see section 4.7), to generate mixtures of 1 and 2-substituted isomers. This isomerization was circumvented by using \(\ce{Cu(BF4)2}\) to catalyze the Diels-Alder reaction of 5-methoxymethyl-1,3-cyclopentadiene with α-chloroacrylonitrile at low temperature (to avoid rearrangement of the 5-substituted 1,3-cyclopentadiene). This chloronitrile -- a latent ketene -- undergoes 2π +4π cycloaddition with cyclopentadiene whereas ketene prefers to undergo 2πa + 2πs cycloaddition (see section 3.3). Another potential flaw, epoxidation of the C=C bond in 115 during Baeyer-Villiger oxidation, is apparently prevented by steric shielding of the C=C bond. Stereoselective (one configuration is generated preferentially at a new stereocenter) introduction of the C-9 hydroxyl results from the stereocontrolling influence of a temporary bridge. Thus, a nucleophile that is appended to C-8 in 113 is introduced intramolecularly (internal nucleophile) to an electrophilic center created at C-9 by the addition of I\({}^{\oplus}\) to the C-C π-bond to give 117. Deprotection and oxidation generate the aldehyde 118.
Appendage of the lower side chain to aldehyde 118 is achieved by olefination with a β-keto phosphonate. Reduction of an intermediate ketone followed by transesterification gives a lactone diol in which the hydroxyl at position 9 is differentiated from the remaining hydroxyls. The latter are then masked as tetrahydropyranyl (THP) ethers in 119. Partial reduction of the lactone and Wittig olefination of an intermediate aldehyde delivers a key intermediate 120 that can be converted into E or F prostaglandins of the "1" or "2" series by approptiate manipulation of protecting groups to allow selective adjustments of functionality and unsaturation levels. Thus, the hydroxyl at position 9 in 120 or the derived 122 can be selectively oxidized to afford PGE2 or PGE1 respectively while deprotection of 120 or 122 delivers PGF or PGF respectively.
A closely related strategy for synthesis of prostaglandins11 exploits exactly the same temporary bridges to enforce a cis relationship between the substituents at positions 9, 8, and 11 on the cyclopentane nucleus. However, a different order for generating the same skeletal connections obviates the necessity of using protecting groups. Thus, the upper side chain is added to a precursor 124. However the lower side chain is already present in a bicyclo[2.2.1]heptene intermediate 125 prior to Baeyer-Villiger cleavage of the temporary bridge. Also the necessity for a difficult low-temperature Diels-Alder cycloaddition is avoided by using a fulvene 127 instead of a 5-substituted cyclopentadiene to react with a ketene equivalent 128. The presence of an aldehyde enol acetate in 126 and 127 also avoids the requirement for a subsequent adjustment of functionality level after hydrolytic removal of the masking group.
The enol acetate in 129 is readily hydrolyzed selectively in the presence of the α-chloronitrile. The stereoselective generation of the requisite configuration at the incipient 12 position is undoubtedly the consequence of thermodynamic control. Thus, the aldehyde adopts the least sterically congested configuration. After olefination of this aldehyde with a β-ketophosphonate carbanion, the ketone carbonyl is reduced by a Meerwein-Pondorf-Verly reaction followed by hydrolysis of the α-chloronitrile delivering 130 in good overall yield. Since this ketone incorporates appreciable ring strain, an unusual Bayer- Villiger-like cleavage with hydroperoxide anion is possible. Peracids react with 130 to give epoxides, but the hydroperoxy anion reacts exclusively with the carbonyl group. The diol 131 can be masked to eventually allow selective oxidation of the 9-hydroxyl delivering PGE's while further elaboration to PGF closely follows the synthesis from 120 except that THP protecting groups are unnecessary. Because no steps involving introduction or removal of protecting groups are required, this synthetic strategy is remarkably efficient.
The strategies presented thus far all succeeded. Unfortunately, failed attempts are often not published. Sometimes they are described in doctoral theses. It would be a mistake to assume that synthetic planning for the total synthesis of complex molecules is so dependable, even by the undisputed superstars of organic synthesis. Therefore, to maintain a realistic perspective, we will consider some flawed strategies from time to time.
R. B. Woodward’s Flawed Strategy
The dialdehyde 101, that incorporates all the stereochemical information required for the cyclopentane ring of prostaglandins, might be derived from an enol ether 132 in which two functional groups are internally masked in a temporary bridge. The use of an epoxide 133 as a precursor of the alcohol 132 is recommended by the consequent possibility that 133 can be generated from a symmetrical precursor 134. This strategy requires the discovery of a method to achieve regioselective reductive cleavage of epoxide 133 to generate 132. The presence in 133 of a six-membered ring containing one C=C bond suggests the possibility of a 2π + 4π cycloaddition that would generate 133 from 134. The intramolecular hetero Diels Alder cycloaddition of an aldehyde dieneophile to an α,β-unsaturated aldehyde diene to generate the dihydropyran ring in 133 is precedented by the corresponding intermolecular dimerization of acrolein which, however, favors the wrong orientation. Generation of 134 might be feasible by selective oxidative cleavage of the most electron rich C=C bond in cyclooctatetraene monoxide 135. This strategy, devised by Woodward, is fatally flawed because the intermediate 134 undergoes a novel homo retro Claisen rearrangement producing 136 instead of the desired Diels-Alder cycloaddition.1
Ring Contraction Strategies
The mixed acetal 137 is another temporarily bridged precursor similar to Corey's aldehyde 118 (see above) except that the functionality level in 137 is identical with that in 101. Therefore, the temporary bridge in 137, like that in 132, is an internally masked derivative of two functional groups as opposed to a latent precursor. Woodward12,13 recognized that a potential precursor of 137 is 138 in which C-11 and the aldehyde carbonyl carbon are temporarily bridged by a C-C bond. The intermediates 137 and 138 are isomers with different connectivities and a different distribution of functionality but identical overall functionality level. The rearrangement of 138 to 137 involves oxidation to an aldehyde of a carbon bearing a hydroxyl and concomitant reduction of a carbon bearing an electronegative leaving group. Such a process, a pinacol rearrangement, is driven to completion by the energetically favorable generation of a C=O double bond at the expense of two C-O single bonds. The subtarget 138 can be simplified by dislocation to a less functionally substituted precursor 139 that might provide 138 by 1,2-dioxidative addition. Generation of the C=C bond in 139 from a ketone in 140 is suggested by the goal of disconnecting and functionally reorganizing this subtarget to a symmetrical precursor 141 by polar dislocation involving disconnection of an internal electrophile. The ketone carbonyl in 140 can provide nucleophilic reactivity to facilitate this C—C bond formation. A temporary bridge in 141 between the electrophile and nucleophile assure the necessary cis relationship between the masked hydroxyls in 141 and the newly created C-C bond in 140. Ultimately, 141 might reasonably be available by selective protection of two of the three identical hydroxyl groups in all cis 1,3,5- cyclohexanetriol and oxidation of the remaining hydroxyl.
Stereospecific (the stereochemical configuration of the product isomer is determined by that of the reactant isomer) generation of the stereochemical relationships required in 137 is expected during the pinacol rearrangement of 138. Thus, such rearrangements, i.e. 143 to 145, generally proceed with retention of configuration at the migrating carbon owing to a temporarily-bridged transition state 144.
Two Step Reterosynthetic Analysis of Polar Rearrangements
Dislocation of a pinacol rearrangement product 146 to a precursor 148 may be viewed as polar disconnection of the migrating carbon as nucleophile resulting in oxidation of the migration terminus. Subsequent connection of the nucleophilic migrating carbon results in reduction of the migration origin (note that this is an internal nucleophile). In fact, the disconnection and connection steps occur simultaneously in pinacol rearrangements. Synthetically the 148 to 146 rearrangement results in ring contraction. Pinacol rearrangements can also result in ring expansion. This is exemplified retrosynthetically by generation of a precursor 151 with a six-membered ring for a target 149 with a seven-membered ring by disconnection to 150 and subsequent connection to 151. This example, which also suggests that a vinyl carbon may serve as the migrating group, is a step in a strategy for total synthesis of the terpene longifolene that will be considered in chapter 4. Of course, pinacol rearrangements may also occur in acyclic systems. The Favorskii rearrangement of α-haloketones to generate ring-contracted or acyclic carboxylic acids is structrually and functionally related to the pinacol rearrangement. However, the Favorskii rearrangement involves a temporarily-bridged intermediate rather than transition state. Thus, 1,3-elimination from 152 generates a cyclopropanone intermediate 153 from which a ring-contracted product 154 is formed by nucleophile-induced cleavage. Retrosynthetically, Favorskii rearrangements generate a more connected precursor 156 from a carboxylic acid target 155. Disconnection of the precursor 156 then suggests the skeletally and functionally reorganized precursor 157 in which the functionality level of the carboxyl group (f = 3) equals the sum of the functionality levels of a ketone carbonyl (f = 2) and a carbon bearing an electronegative leaving group (f = 1). Thus, as in the pinacol rearrangement, the Favorski rearrangement results in no net change in molecular functionality level, i. e. no net oxidation or reduction. Rather, these processes involve redistribution of functionality by an intramolecular redox process. Thus, rearrangement dislocations are complex because they involve coupled connection and disconnection steps as well as an associated redistribution of functionality.
Although differentiation of the three hydroxyls in 142 was achieved by reaction with glyoxalic acid, the second Woodward strategy was also fatally flawed (see section 3.5). Reductive cleavage of 158 afforded diol 159 quantitatively, and the primary hydroxyl in 159 was readily activated selectively by tosylation. However, the ketone 160, obtained by oxidation of the monotosylate, failed to produce 140 upon treatment with a variety of bases. Instead, elimination of a β-alkoxy group to produce 161 occurred to the complete exclusion of intramolecular alkylation.
To obviate the necessity for enolate generation β to the alkoxy groups as in 141, 162 was recognized as a direct precursor to olefin 139. Polar disconnection of 162 suggests addition of a carbon electrophile to a C=C double bond as in 163. The two dislocations, 140 to 141 and 162 to 163 are isoelectronic (mechanisms with identical electron movement patterns). That is, they both involve the movement of two pairs of electrons and the cleavage of a C-C σ-bond. However, whereas cleavage of a C- O bond in a synthetic equivalent of 141 to give 161 is driven by the production of a C=O bond, the similar cleavage of a C-O bond in a synthetic equivalent of 163 would generate a relatively unstable intermediate, an allylic carbocation.
Synthetic equivalents of the unsymmetrical synthon 163 might be obtained from the available symmetrical diol 159 by β-elimination. Unfortunately, a precedent suggested that cyclization of 163 might not occur in the desired fashion. Thus, the carbocyclic analogue 164 produces the isomeric ring system 165 upon solvolysis. However, it could be argued that the allylic oxygen substituents in 163 might disfavor such a mode of cyclization that must generate an electron deficiency β to the alkoxy substituents.
This time the gamble payed off.13 The bismesylate 166 from 159 afforded olefin 167 upon selective elimination of the secondary mesyloxy group. Solvolysis of 167 produced a mixture that contained only 5-8% of the undesired product 168. Of course, the desired cyclization product 169 is racemic. It can be resolved. However, only one enantiomer leads to prostaglandins of natural configuration. Thus, while this synthesis (vide infra) solves "the main sterochemical problem inherent in prostaglandin F synthesis -- the alignment of the four contiguous chiral atoms in the cyclopentane moiety", the process is not enantioselective. Half of the intermediate 169 is the wrong enantiomer, that is not readily recyclable. Dehydration of the appropriate cyclization product 169 then provided 170. The requisite stereochemical preference during 1,2-dioxidative addition to 170 was best achieved with the perimidic acid generated in situ from benzonitrile and hydrogen peroxide. This reaction delivered a mixture of the exo epoxide 171 and the endo epoxide 172. The former epoxide could be recycled to 170. Stereoelectronically controlled nucleophilic opening of the epoxy ring in 172 delivered 173 stereospecifically. This isomer is mandatory for the subsequent pinacol-like ring-contracting rearrangement that ensues upon deamination of the bicyclic mixed acetal 174. Thus, migration of the incipient C-11 carbon is favored in 174 by an anti periplanar relationship (two bonds or groups lying in the same plane with a dihedral angle of 180°) with the leaving group. Rearrangement of 174 occurs not only with retention of configuration at the migrating carbon, but also stereospecifically generates the requisite configuration at C-12 in the product 175 owing to Walden inversion during the intramolecular SN2 reaction. Further elaboration of the key intermediate 175 into prostaglandins followed well-precedented reactions.
Corey devised an alternative route14 to key intermediates of the type 138. Thus, 138 might be available by cis-1,2-dioxidative addition to alkene precursor 176. Furthermore, a trans relationship between the incipient leaving group X and the newly introduced oxygen atoms might be anticipated on the basis of steric approach control. Steric approach control might also favor the required trans relationship between X and the lactone ring. This would be especially true if allylic oxidation were achieved by an ene mechanism which would involve a sterically demanding cyclic transition state. Furthermore, such a mechanism would assure the requisite regiocontrol, i.e., substitution with allylic rearrangement, during introduction of X. The lactone in 177 could be obtained from a latent precursor, the ketone in 178, available in turn by a 2π + 2π cycloaddition of ketene to a symmetrical precursor, 1,3-cyclohexadiene.
Structurally selective cycloaddition (see section 3.3) of dichloroketone to 1,3-cyclohexadiene delivered 179 from which the unsaturated lactone 177 was obtained by reductive dechlorination followed by Baeyer-Villiger oxidation (see section 3.5). Partial reduction followed by ketalization delivered 180 that stereoselectively afforded 181 upon ene reaction with N-phenyltriazolinedione. Hydroxylation of the derived 182 also proceeded stereoselectively. The latter reaction also involves a temporary ring, an osmate ester 185, that enforces a cis relationship between the newly introduced oxygen atoms. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/03%3A_Fatty_Acids_and_Prostaglandins/3.04%3A_Syntheses_of_Prostaglandins_from_Polycyclic_Precursors.txt |
Since the all trans stereochemistry of ring substituents should be thermodynamically preferred for cyclopentane derivatives such as PGE1, a method of stereocontrol less powerful than the use of temporary bridges would seem adequate for prostaglandin synthesis. Furthermore, the availability of simple cyclopentanoid precursors including cyclopentadiene, that was used in many of the syntheses described above, led to the formulation of a simple strategy for stereocontrolled total synthesis of prostaglandins. Furthermore, such strategies are well-suited to enantioselective total synthesis (see section 3.6). Polar reactivity analysis of PGE1 as in 186 suggests dislocation of this stereochemically complex target into two fragments 187 and 188 containing only one stereocenter each.15 Thus, steric approach control might favor ddition of the vinyl nucleophile 188 from the less congested face of the cyclopentanone ring, the face opposite a substituent at position 11.
Furthermore, 1,4-additions of lithium diorganocuprates such as 189 with α,β-unsaturated ketones are especially susceptible to such SAC. However, lithium diorganocuprates were also known to displace allylic oxygen such as that at the 11-position in the cyclopentenone 187 or at the 15-position in the lower prostaglandin side chain as in the hypothetical reaction of 190 to generate 191, a useless byproduct. Should such a potentially fatal flaw preclude further consideration of a synthetic strategy? The answer depends on the value of the possible discovery that the flaw is not fatal. This leads to another rule of thumb to be added to the list began in section 1.5:
(6) Favor potentially flawed strategies only if the effort involved in further examination of the possible flaw is offset by the potentially great reward of an especially elegant and efficient synthesis.
Woodward's strategy involving intramolecular cycloaddition of 134 to generate 133 is an example of this principle not paying off. Woodward's strategy involving intramolecular alkylation of ketone 160 and his ultimate success in achieving the required skeletal connection by a modification of the strategy is an example of yet another principle of synthetic planning:
(7) Devise backup strategies, especially for risky steps.
The 9,8,12,11-circuit in 187 is dissonant. One strategy for generation of this dissonant functional array (see page 88) involves 1,4-dioxidative addition (4πs + 2πs cycloaddition) of singlet oxygen to a monosubstituted 1,3-cyclopentadiene precursor 194 to generate an endoperoxide 192 that could undergo disproportionation to the required hydroxycyclopentenone in analogy with the disproportionation of PGH to PGE.15 Alkylation of cyclopentadienide anion with bromoester 195 would produce a 5-substituted 1,3-cyclopentadiene. However, the requisite 2-substituted isomer is readily available because monoalkyl 1,3-cyclopentadienes exist at room temperature as an equilibrium mixture of mainly 1 and 2-substituted isomers that are formed from the 5-substituted isomer by [1.5] sigmatropic hydrogen migrations.
Alternatively, a simple monosubstituted cyclopentenone 193 might be converted to 187 by allylic oxidation. A route to 193 is suggested by the possibility that the C=C bond in this enone can be produced from a cyclopentanone 196 by elimination of water. If the leaving group is a hydroxyl, the presence of such functionality at the 8-position in a precursor 196 invites further dislocation to a nucleophilic upper side chain synthon 197 and a carbonyl electrophile, 1,2-cyclopentanedione. The electrophilic carboxyl functionality in 193 is latent in 197 to avoid undesired intramolecular reaction with the nucleophilic center at position 7.
It is interesting to note that the two routes to 187 outlined above involve electronically complimentary polar strategies for generating the 7-8 bond. One route exploits an upper sidechain electrophile and a cyclopentyl nucleophile (i.e. 195 and cyclopentadienide anion) while the other route exploits an upper sidechain nucleophile and a cyclopentyl electrophile (i.e. 197 and 1,2-cyclopentanedione).
Bromoester 195 was prepared from tetrahydropyran and diethyl malonate. Singlet oxygen, generated chemically, reacts with the monosubstituted cyclopentadienes 198-200 under basic conditions to deliver hydroxycyclopentenone 201 and its isomer having a hydroxyl at the 9-position and a carbonyl at the 11-position. The latter isomer was readily converted to 201 by an oxidation and reduction sequence.
A Grignard reagent synthetic equivalent of nucleophilic synthon 197 was prepared by monohydroboration of 1,7-octadiene followed by iodo-deborination and reaction of the resulting iodide 202 with magnesium. Oxidation of cyclopentanone provides 1,2-cyclopentanedione whose methyl enol ether 203 delivered cyclopentenone 204 upon reaction with 7-octenyl-magnesium iodide followed by hydrolysis of the enol ether and dehydration. Generation of an ester from the latent precursor required selective oxidative cleavage of one C=C double bond in 204. This was readily achieved by epoxidation of the more electron-rich C=C bond with peracid followed by oxidative cleavage of 205 with periodate. Methylation delivered ester 190 that was allylically brominated to provide 207 after hydrolysis of an intermediate bromide 206.
A lower side chain vinyl nucleophile is prepared by hydroalumination of (S)-1-octyne-3-ol (208) followed by iododealumination of an intermediate vinyl alane to deliver optically pure vinyl iodide 209 of correct absolute configuration. This iodide is also available by chloroacylation of acetylene with valeryl chloride followed by iododechlorination of an intermediate vinyl chloride to deliver iodoketone 211 that affords racemic 209 upon borohydride reduction. Resolution of racemic 209 can be achieved with the phenethylamine salt of the hemiphthalate derivative. The hydroxyl group in 209 must be masked prior to lithium-iodine exchange. Reaction of 209 with ethyl vinyl ether affords an α-ethoxyethyl (EE) derivative 212 that provides a divinyl cuprate 213 by metal-halogen exchange with t-butyllithium followed by addition of \(\ce{CuI}\) and \(\ce{Bu3P}\).
The key 1,4-addition of optically pure divinylcuprate 213 to the THP derivative 214 of racemic hydroxycyclopentenone 201, followed by removal of THP and EE protecting groups, delivers an almost 1:1 mixture of (-)-PGE1 ethyl ester 215 with the absolute stereochemistry of the natural product and its diastereomer that is epimeric at positions 8, 12, and 11. Hydrolysis of the ester to produce PGE1 could be achieved under especially mild conditions by incubation with baker's yeast. Reaction of optically pure divinyl cuprate 214 with optically pure 214 (see section 3.6) delivers (-)-PGE1 exclusively.16
Another strategy for synthesis of prostaglandins from cyclopentane precursors17 exploits steric approach control during hydride reduction of a PGE2 derivative 216 to provide the correct configuration at the 9-position in PGF. Polar analysis of 216 suggests that the upper side chain can be appended by reaction of a cis vinyl nucleophile 218 with an α,β-unsaturated ketone 217. Polar analysis of 217 suggests a further dislocation to ketone enolate 219 and formaldehyde. A regioselective synthesis of the requisite enolate could be accomplished by reductive cleavage of α-bromo ketone 220. Appropriate functionalization of olefin 221 might be feasible through 1,2-dioxidative addition. That 221 might be obtained stereoselectively through regioselective nucleophilic opening of cyclopentadiene monoxide (223) by a vinyl nucleophile 222 is the reasonable consequence of an SN2 mechanism with attack at the weaker allylic C-O bond. Thus, cleavage of a temporary bridge, the epoxide, will proceed with inversion of configuration at one terminus leading to a trans relationship between the nucleophile and nucleofuge groups which become the substituents at positions 12 and 11 respectively.
The lithium acetylide from 3-(α-ethoxyethoxy)-1-octyne can serve as a terminal vinyl carbanion equivalent. Thus, reacts with epoxide 223 to afford 224 after benzylation of an intermediate alkoxide. Hydrolysis of the EE protecting group followed by trans stereoselective hydride reduction of an intermediate propargyl alcohol in the presence of methoxide followed by masking of the resulting allylic alcohol affords 225. That hydroxy bromination of 225 occurs stereo and regioselectively apparently results from a steric preference for the α-bromonium ion 226 that is attacked by water at the least sterically congested position, i. e. remote from the bulky substituent at position 12, delivering 227. That the cyclopentene C=C bond reacts in preference to the side chain C=C bond is a consequence of the electron withdrawing deactivating effect of the allylic oxygen substituent. Oxidation of 227 to the corresponding ketone followed by a Perkow reaction delivers the enol derivative 228 regiospecifically. Generation of an enolate from 228 by reaction with t-butyllithium regiospecifically activates the 8-position for nucleophilic reaction with formaldehyde delivering 229. This aldol condensation is promoted by a temporary bridge that is provided by a chelating zinc cation. Dehydration of 229 then affords enone 230 that adds a cis vinyl cuprate 231 to produce the upper side chain in 232 after selective hydrolysis of the EE protecting group and oxidation of the primary alcohol. Stereoselective, i.e. SAC, hydride reduction of 232 affords PGF2α after reductive removal of the benzyl and benzyloxymethyl ether protecting groups in 233.
Stereospecific opening of epoxides by carbon nucleophiles can be exploited to introduce both prostanoid side chains onto a cyclopentane nucleus. A remarkable strategy for the total synthesis of PGF from cyclopentadiene18 first simplifies the target by disconnection of the upper side chain in the usual manner at the C=C bond. The key step in the strategy involves the regioselective SN2 displacement of an electrophile at position 12 by a nucleophilic lower side chain trans vinyl carbanion synthon 222. The requisite trans relationship between the substituents at positions 11 and 12 is assured by a temporary epoxide bridge in 235 between the stereocenters at positions 11 and 12. This epoxide might be generated from the corresponding trans diol monotosylate 236. Introduction of a nucleophilic fragment of the upper side chain might also be achieved stereospecifically by an SN2 attack on an epoxide 237, a symmetrical electrophile containing a temporary bridge between the incipient 8 and 12-positions. Stereoselective generation of 237 might be achieved by steric approach control during epoxidation of a precursor cyclopentene 238. Finally, the cis relationship between the oxygen substituents in 238 can be assured by a third temporary bridge, this time between two oxygen atoms in an endoperoxide precursor 239 that is available from 1,3-cyclopentadiene by 2π + 4π cycloaddition of singlet oxygen.
Reductive cleavage of the temporary peroxide bridge in 239 delivers a cis diol. The regiocontrol during cleavage of the epoxide intermediate 242, that could be achieved with an aluminum acetylide, apparently results from a temporary bridge between nucleophile and electrophile. Thus, the hydroxy-ethyl substituent in 242 reacts with the organoalane nucleophile. The alkoxy alane then delivers the alkynyl nucleophile intramolecularly as in 243 to the desired position 12 and not position 11. The primary hydroxyl in the tetraol 238. Finally, the cis relationship between the oxygen substituents in 238 can be assured by a third temporary bridge, this time between two oxygen atoms in an endoperoxide precursor 239 that is available from 1,3-cyclopentadiene by 2π + 4π cycloaddition of singlet oxygen.
It was postulated that regiocontrol during nucleophilic attack on the epoxide intermediate 235 might be provided by a temporary bridge between the nucleophile and electrophile. Thus, the hydroxyethyl substituent in 235 would react with an organoalane nucleophile. The resulting alkoxy alane can deliver the alkynyl nucleophile intramolecularly as in 244 to the desired position 12 and not position 11. Indeed, this reaction gave the desired regioisomeric adduct 245a in 60% yield and no trace of the undesired regioisomer 245b. Further support for this mechanistic explanation is provided by the observation that silylation of 235 prior to reaction with the alane produced a regioisomeric mixture of adducts and even favored nucleophilic attack at the 11 position by 2.6:1. Also noteworthy is the fact that the bridge involving the hydroxyethyl group and the acetylide nucleophile in 244 is fused in a trans fashion with the cyclopentane ring, whereas the epoxide bridge is cis fused. Thus, while small rings prefer cis fusions, trans fusions may be unstrained and even favored thermodynamically for larger rings.
To complete the prostaglandin skeleton, the primary hydroxyl in the tetraol intermediate 242 was differentiated by tritylation. After acetylation of the remaining hydroxyls and detritylation, the resulting primary alcohol 243 was oxidized to an aldehyde before final addition of the remaining portion of the upper side chain in the usual manner.
In the foregoing strategy for synthesis of prostaglandins, polar activation that is potentially afforded by target-related functionality is not exploited for skeletal construction. Rather, electrophilicity at the 8 and 12-positions is provided by added functionality, the epoxides in 235 and 240. Economy of functionality is sacrificed in favor of incorporating temporarily bridged leaving groups that assure stereocontrol. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/03%3A_Fatty_Acids_and_Prostaglandins/3.05%3A_Syntheses_of_Prostaglandins_from_Cyclopentanes.txt |
All of the foregoing total syntheses of prostaglandins produced these natural products together with their unnatural enantiomeric isomers because each synthesis began with nonasymmetric or racemic starting materials and employed racemic or nonasymmetric reagents. In some instances racemic mixtures of enantiomeric precursors were separated by resolution and then converted to the enantiomerically pure natural product. But this approach to the total synthesis of chiral nonracemic natural products is usually inherently wasteful since half of the racemic precursor, the wrong enantiomer, must be discarded. Very rarely, the wrong enantiomer can be converted to the correct enantiomer or converted into the natural product in an enantio-convergent synthesis by a unique reaction sequence.
There are three tactics that allow enantioselective synthesis of natural products. They all depend on the chirality of natural products to provide asymmetric starting materials or to induce asymmetry during the generation of chiral intermediates from prochiral precursors. Presented in the ensuing discussion will be examples of syntheses that are enantiocontrolled by the use of: (1) chiral nonracemic reagents; (2) microbial metabolism -- a special case of category 1; or (3) chiral nonracemic starting materials.
Enantiocontrol by a Chiral Nonracemic Reagent
In the synthesis discussed above, the chirality of 235 is determined by an intermediate 246 that was generated by reaction of an allyl nucleophile with the prochiral epoxide 240. Since the allylating reagent employed was nonasymmetric, the chiral product was racemic. The intermediate 235 has also been prepared in another manner, one that generates only the correct enantiomer required for the total synthesis of natural optically pure prostaglandins.19 In this asymmetric synthesis, the chirality of 235 is determined by an intermediate 247 produced by hydroboration of the prochiral diene 248 with a chiral nonracemic dialkyl borane.
The 5-substituted 1,3-cyclopentadiene 248 was generated at -78° C by alkylation of sodium cyclopentadienide and treated in situ with (+)-di-3-pinanylborane, followed by alkaline hydrogen peroxide to yield hydroxy ester 247, that was at least 96% optically pure. Owing to steric approach control during the syn addition of boron hydride to 248 and subsequent stereospecific retention of configuration during oxidative replacement of boron with oxygen, the new stereocenter at position 9 (PG numbering) in 247 is generated stereoselectively with the unnatural configuration, opposite to that required for prostaglandins. However, the required cis configuration is readily generated by SN2 inversion of the hydroxyl, and lactonization delivers 249. The stereoselective generation of the cis epoxide in 235 depends upon the influence of a temporary bridge. Thus, the hydroxyl at C-9 directs the delivery of oxygen by hydrogen bonding with MCPBA as shown in 250. This temporary bridging in the transition state of a reaction is an example of a neighboring group effect.
Enantiocontrol by Microbial Metabolism
The enzymes which catalyze microbial oxidations and reductions are chiral nonracemic molecules that often promote highly enantioselective transformations of synthetic prochiral substrates.20 Several strategies have been explored for enantioselective microbial generation of hydroxycyclopentenone intermediates for syntheses of prostaglandins. For example, the chiral intermediate 207 might be available by microbial allylic oxidation of the prochiral precursor 190 or by microbial reduction of the prochiral precursor 251. The dione 251 should be readily available by oxidation of the hydroxycyclopentenone mixture obtained by base catalyzed disproportionation of a singlet oxygen 2π + 4π cycloadduct 252 with cyclopentadiene 253.
A flaw in the allylic oxidation strategy resulted from a general proclivity of fungi containing hydroxylases to degrade the carboxylic side chain of 190 by the β-oxidation-retro Claisen cleavage mechanism discussed in section 3.1. Thus, cleavage of one acetate unit produced 254 while 255 was generated upon loss of a second acetate.
A proclivity of dione 251 toward monoreduction is expected owing to the activating effect of opposed electron withdrawal by two conjugated carbonyl groups. Therefore enzyme-catalyzed monoreduction of 251 is anticipated to be readily achieved by microorganisms. However, two problems interfered with attempts to obtain a practical asymmetric bioorganic synthesis of enantiomerically pure 207 from the vinylogous α-diketone 251. First, reduction of the C=C bond often accompanied C=O reduction. Saturation of α,β-unsaturated ketones is a common microbiological transformation. This undesired side reaction was prevented by microbiological reduction of 251 in the presence of excess 2-cyclohexenone or methyl vinyl ketone as competitive substrates for the C=C bond reductases but not for the C=O reductases.16 Furthermore, with a wide variety of microorganisms, reduction of the incipient 9-keto group generating 256 competed with the desired reduction to generate 207 with a hydroxyl at the incipient 11-position.
A less direct alternative strategy for enantioselective synthesis of 207 by asymmetric carbonyl reduction exploits functionality and unsaturation level adjustment of a hydroxydione precursor 257 that might be available by enantioselective (generating a pure enantiomeric product from an achiral precursor) reduction of a trione 258. Polar analysis of 258 suggests a synthesis of this dissonant functional array by the condensation of a methyl ketone 259 with the dissonant diester, diethyl oxalate.
The trione 258 actually exists as an enol 258e that is a hydroxy derivative of 251. But this enol can be expected to have less proclivity than 251 toward saturation because the hydroxyl substituent will reduce the electrophilicity of the C=C bond by donation of a nonbonding electron pair. Furthermore, the carbonyl group at the incipient 11-position in 258e should be especially susceptible to nucleophilic attack by hydride owing to the dipole effect of a vicinal hydroxyl group. A synthesis of trione 258 began with azelaic acid (260) and its dimethyl ester to afford monomethyl azelate (261) by thermal equilibration. Condensation of the derived imidazolide with the magnesium enolate of lithium monomethyl malonate followed by decarboxylation, hydrolysis, and a second decarboxylation delivered methyl ketone 262. Claisen condensation with dimethyl oxalate and subsequent Dieckmann cyclization and methylation of the carboxyl group produced the key intermediate 258.
Trione 258 was cleanly and regioselectively reduced to hydroxydione 263 by a variety of microorganisms. Dipodascus uninucleatus catlayzed the completely asymmetric reduction of 258 to the 11(R) alcohol that is required for the total synthesis of prostaglandins. In contrast, Mucor rammanianus reduced 258 to the 11(S) alcohol. Conversion of optically pure hydroxydione 263 into the optically pure hydroxycyclopentenone 207 required selective reduction of the carbonyl at position 12. This was achieved by selectively masking the carbonyl at position 9 as an enol mesitylenesulfonate 264 followed by hydride reduction (see section 3.7). Subsequent hydrolytic allylic rearrangement of the intermediate allylic alcohol 265 delivered 207.16
Enantiocontrol by Exploiting Chiral Nonracemic Starting Materials
Instead of using the asymmetry of natural products, e.g. enzymes, to induce asymmetry during conversion of prochiral precursors into chiral synthetic intermediates, the asymmetry of readily available natural products, e.g. sugars, can be incorporated into synthetic targets by conversion into chiral nonracemic intermediates for total syntheses. For 207, the chiral center at position 11 might be derived from a chiral center in a sugar. Since every carbon in a sugar is oxygenated, polar disconnection of chiral nonracemic 207 with the boundary condition of uncovering a sugar-derived chiral segment suggests a trihydroxy precursor 266 (see section 3.7). Note that 266 is a nucleophilic umpoled synthon generated by polar reactivity inversion (PRI) at the incipient 9-position carbonyl. Further polar disconnection suggests an α-carbomethoxy- stabilized nucleophile 267 and D-glyceraldehyde as electrophile. D-Glyceraldehyde should be available by oxidative cleavage of any D-sugar. An especially efficient synthesis is suggested by a dislocation involving reductive coupling to connect two molecules of glyceraldehyde. The axially symmetrical precursor D-mannitol is available by reduction of D-mannose.
In an enantiospecific synthesis of optically pure 207 from D-mannitol, methyl oleate provided the nucleophile corresponding to 267.21 The C=C bond in methyl oleate comprises a latent carboxyl that is not unmasked until the end of the synthesis. Aldol condensation of methyl oleate with acetonide 269 of D-glyceraldehyde delivers 270. Deketalization unmasks a vicinal dihydroxyl array (see section 3.7) and subsequent lactonization differentiates the primary and secondary hydroxyls exploiting an internal masking group and the favorable stability of a temporarily bridged butyrolactone. The free primary hydroxyl in 271 is then activated by tosylation, and the α-ethoxyethyl (EE) ether of a cyanohydrin is generated from the lactone carbonyl by reduction, cyanohydrin formation, and O-alkylation with ethyl vinyl ether. Cyclization of 272 then completes the carbon skeleton. Removal of protecting groups, oxidative cleavage of the side chain C=C bond and methylation of the resulting carboxylic acid, hydrolysis of the cyanohydrin, and dehydration then delivers the optically pure hydroxy-cyclopentenone 207 from 273.
The abundant functional (oxygen on every carbon) and stereochemical information present in sugars suggests an even more ambitious synthesis of prostaglandins: incorporation of several sugar-related centers of chirality from a sugar starting material with a sugar-related hydroxyl at the incipient 10 position of PGF. Thus, polar disconnection of PGF with the boundary condition of uncovering a sugar-derived homochiral segment suggests a precursor 274 in which the target related polar reactivity implied by the hydroxyl at the 9-position in PGF must be inverted (PRI), e.g., as a nitrile-stabilized carbanion derived from an aldehyde cyanohydrin. Generalized representations 275 of 274, especially the Fischer projection 275c emphasize structural similarities with D-sugar precursors.
The necessity of deprotonating a cyanohydrin ether to generate 274 suggests replacement of the terminal carboxyl with a less reactive latent equivalent functional group such as an ether in 276 that also incorporates an ester as precursor for the cyanohydrin at the incipient 9-position with a view toward further polar disconnection of 276 to 278 is suggested by polar analysis which also reveals the possibility of disconnecting 278 to a methyl acetate nucleophile, or a malonic ester carbanion in which the added ester group serves as a reactivity control element (CEA), and a sugar derived electrophile 279. The required stereochemistry at the incipient 12-position in 278 would be generated by stereospecific inversion during the nucleophilic substitution of an oxygen electrofuge by a carbanion. This strategy may be derailed by an alternative possible SN2' nucleophilic substitution of the allylic nucleofuge in 2 7 9 . An alternative dislocation of subtarget 278 avoids this ambiguity. The sigma bond between incipient carbons 8 and 12 in 278 might replace a sigma bond between the incipient ester carbonyl oxygen and carbon 14 by a process involving allylic rearrangement of two π-bonds and a σ-bond in a precursor 280 by a cyclic three electron pair-shift. Such bond reorganizations, known generally as a [3.3] sigmatropic rearrangements, involve a temporary bridge in the transition state that, for the 280 to 278, conversion might be expected to adopt a chair-like conformation (SEC) as in 281. The rearrangement consequently involves predictable transfer of chirality from the migration origin at position 14 in 280 to the migration terminus at position 12 in 278. The driving force for sigmatropic rearrangements is a net increase in thermodynamic stability.
For the 280 to 278 conversion, an enol ester-Claisen rearrangement, this energetic advantage accrues from the generation of a C=O bond at the expense of a C=C bond. The ketene acetal 280 is a derivative of the allylic alcohol 282. A sugar-like progenitor 283 for 282 is suggested by 1,2-dioxidative addition. Such an intermediate might, for example, be produced by nucleophilic addition of an n-pentyl nucleophile to D-glucose.
The conversion of diol 283 into trans alkene 282 must surmount several hurdles. Since the vicinal diol is surrounded by hydroxyl groups or derivatives of hydroxyl groups as in 284, reductive cleavage generating an intermediate or transition state resembling carbanion 285 might lead to β-elimination of the wrong vicinal oxyanion producing 287 rather than 286.
A more certain outcome can be assured by employing an alternative reaction, a concerted cycloelimination of carbon dioxide from a carbene-bridged derivative 288, to generate the requisite trans alkene from a vicinal diol. Such a process involves the cyclic shift of three electron pairs -- two σ-bonds and a nonbonding electron pair on the carbene carbon -- and is driven by the creation of two C=O bonds. Since the cycloelimination is concerted, the carbene derivative generated from a threo diol necessairly fragments to a trans alkene while that derived from an erythro diol would fragment to give a cis alkene. Therefore, to be a precursor of a trans alkene, the intermediate 283 must incorporate a threo diol as in 289 and glucose.
However, generation of 289 need not necessairly proceed directly from glucose by addition of an n-pentyl anion. In fact D-glycero-D-guloheptose (290), that can be prepared from glucose and incorporates the requisite configuration at the incipient position 15, is commercially available.
An enantiospecific synthesis of chiral nonracemic PGF was executed that derives three centers of chirality from glucose.22 Thus, glucose is chain extended by one carbon by addition of \(\ce{HCN}\). Acid-catalyzed hydrolysis and lactonization of the intermediate cyanohydrin 291 produces D-glycero-D-guloheptono-1,4-lactone (290). The hydroxyl groups in this intermediate must be differentiated to allow selective manipulation. Four hydroxyl groups can be masked by ketalization with acetone. Subsequent partial reduction of the lactone group delivers a lactol 292 that affords 293 upon further reduction and selective acetylation of a primary hydroxyl in the presence of two secondary hydroxyls. The threo diol array which remains unmasked in 293 may now be stereospecifically eliminated to generate a trans alkene.
The requisite bridged carbene intermediate is generated by thermolysis of a dimethylformamide cyclic acetal derived from 293 in the presence of acetic anhydride. A concerted cycloelimination of this carbene then stereospecifically delivers the requisite trans alkene 294 in about 40% yield overall from 290. The masked allylic hydroxyl at the incipient 14-position must now be selectively unmasked to set the stage for an ortho ester-Claisen rearrangement. But both this hydroxyl and its vicinal neighbor are masked in 294 by the same acetonide. To selectively capture its neighbor after removal of the acetonide, the acetate in 294 was initially converted into a methyl carbonate that then intramolecularly acylates the neighboring hydroxyl in 295. One of two hydroxyls is thus protected by the temporary bridge of a carbonate. The remaining hydroxyl in 296 is then displaced with allylic rearrangement by a carbomethoxymethyl group. Thus, an orthoester Claisen reaction of 296 stereospecifically transfers the chirality of the hydroxyl substituted position 14 in 296 to a carbon substituted position 12 in 297. This intermediate incorporates three of the five chiral centers as well as the 13,14-trans C=C bond of the target PGF. Appendage of the carboxylic side chain, after masking the hydroxyls as α-ethoxyethyl (EE) ethers, was achieved by allylation of an ester enolate delivering 299. The stereochemistry at the incipient 8-position in 299 is a consequence thermodynamic control (TC) that favors a trans relationship between vicinal substituents on the five-membered lactone ring. Annulation of the cyclopentane ring required partial reduction of the lactone carbonyl, cyanohydrin formation, removal of the EE protecting groups, selective monotosylation of the primary hydroxyl and protection of the resulting triol as EE ethers. Finally treatment of 300 with base generated the corresponding nitrile stabilized carbanion which underwent intramolecular alkylation affording 301. A carboxyl was then generated after removal of the silyl protecting group. Removal of the EE protecting groups from the carboxylic acid 302 delivered a cyanohydrin that was cleaved to the corresponding ketone and reduced stereoselectively in situ to produce PGF. This efficient interception of the ketone carbonyl is a noteworthy tactic. The carbonyl was reduced in order to avoid loss of the hydroxyl at position 11 by dehydration of the base sensitive PGE2 intermediate. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/03%3A_Fatty_Acids_and_Prostaglandins/3.06%3A_Enantioselective_Syntheses_of_Prostaglandins.txt |
Water-induced rearrangement of PGH2 occurs rapidly under the conditions of its biosynthesis to generate PGE2, PGD2, and two seco-prosta-glandin levulinaldehyde derivatives known as levuglandins (see section 4.1). Thus, for example, intramolecular hydride migration from the 9 to the 10-position in PGH2 accompanied by cleavage of the 10,11-C-C bond and the peroxide O-O bond generates levuglandin (LG) E2. This levuglandin is formally related to PGE2 by aldol condensation, although interconversion of PGE2 with LGE2 has never been observed.
Enantiocontrol with a Chiral Auxiliary
The availability of abundant supplies for biological testing and confirmation of the structure of LGE2 depended on the development of an efficient asymmetric total synthesis. Another strategy for deriving asymmetry from chiral nonracemic natural starting materials is to use it as a chiral auxilliary (vide infra), as illustrated by a synthesis of LGE2 from L-arabinose.23 A dominant consideration in planning a total synthesis of LGE2 is its proclivity toward dehydration, epimerization at positions 8 and 12 (prostaglandin numbering) and allylic rearrangement of the 14-15 (prostaglandin numbering) C=C bond into conjugation with the aldehyde carbonyl. Many of these difficulties are circumvented by replacing the aldehyde carbonyl with a latent equivalent, a vicinal diol as in 303. Conversion of 303 into LGE2 should be achievable under exceptionally mild conditions by oxidative cleavage with periodate. Stereocontrol is a more difficult challenge in the total synthesis of LGE2 than it was for the total synthesis of PGE2 since LGE2 is acyclic and, therefore, more conformationally mobile than PGE2 that has three of its four stereocenters arranged in the thermodynamically preferred all-trans configuration around a relatively rigid cyclopentanone ring.
The tactic of using a vicinal diol as a latent aldehyde group apparently complicates rather than simplifies the synthetic target by adding a fourth stereocenter. On the contrary this additional center of chirality, that will not be incorporated in the final product, is the key to enantioselective generation of the correct absolute configuration at position 9 (levuglandin numbering). Furthermore, the correct configuration at position 8 should be available by epimerization of any 8-epi 303 that might be generated. Polar analysis of 303 suggests the possibility of exploiting electrophilicity at position 9 provided by the acetyl carbonyl as in 304 to allow polar bond formation with a chiral nonracemic nucleophilic vinyl synthon 305. Most importantly, such conjugate additions are highly diastereoselective. The neighboring alkoxy substituent is expected to foster generation of only the requisite absolute confuguration at position 9 during 1,4-addition of a vinyl cuprate nucleophile to 304. Further polar analysis of 304 suggests generation of this enone by aldol condensation of an enolate nucleophile with the aldehyde 307, L-glyceraldehyde acetonide. This chiral nonracemic starting material is readily available from L-arabinose (vide infra). Because its chiral center provides enantiocontrol but is not incorporated into the final product, 307 said to serve as a chiral auxiliary (a chiral unit that is incorporated into an intermediate to bias the stereoselectivity of one or more subsequent reactions after which it is cleaved from the substrate or its chiral center is removed). To activate enolate generation and control the regiochemistry of the aldol condensation, a diethylphosphono group is added to 306 as in 308. Further exploitation of the polar activation afforded by the acetyl carbonyl and phosphono groups should allow construction of 308 by allylation of 309 with the upper sidechain electrophile 310.
A synthesis of the chiral auxillary 307 from L-arabinose starts with interception of the acyclic aldose from its equilibrium with a pyranose form 311 by thioacetalization with benzylmercaptan. Selective ketalization of the resulting tetraol 312 delivers monoacetonide 313. Oxidative cleavage of the latter then produces 307 in admixture with 314 from which it is readily separated by distillation.24
A short, highly stereocontrolled, asymmetric total synthesis of LGE2 was executed23 from the commercially available 1-(diethylphosphono)-2-propan-one (309) that was allylated in good yield with bromoester 315. The main side reaction was diallylation. Horner-Emmons olefination of L-glyceraldehyde acetonide (307) with the carbanion derived from 308 delivers in excellent yield a mixture of geometric isomers E-304 and Z-304 in a 2.3:1 ratio. It is unnecessary to separate this mixture because either isomer reacts stereoselectively (i. e. SEC) with cuprate 316 to deliver an identical 7:3 mixture of 317 and its 8-epi diastereomer in excellent yield. This key reaction proved refractory. Little or no 1,4-addition could be achieved until it was discovered that anhydrous \(\ce{MgBr2}\) catalyzes the required reaction presumably by serving as a Lewis acid that enhances the electrophilicity of enone 304. Again separation of isomeric products is unnecessary because saponification of either diastereomeric ester 317 or 8-epi-317 generates an identical 7:3 mixture of the corresponding carboxylic acids. This is apparently the equilibrium ratio.
Most fortunately, separation of the diastereomeric acids was also unnecessary because either isomerically pure acid gave the same 13:1 mixture of LGE2 and its 8-epi diastereomer upon desilylation followed by acid-catalyzed hydrolysis of the acetonide and finally periodate cleavage of the resulting vicinal diol. The favorable diastereoselectivity of the acid-catalyzed epimerization that accompanied the deketalization of the vicinal diol was entirely unexpected. The vicinal diol also plays an important role in this serendipitous process. Thus, epimerization occurs in 318 but not in LGE2 or 8-epi-LGE2 under these conditions for hydrolysis and oxidative cleavage. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/03%3A_Fatty_Acids_and_Prostaglandins/3.07%3A_Levuglandins.txt |
[3.3]sigmatropic rearrangement (3.6)
aerobic dehydrogenation (3.1)
anti-periplanar (3.4)
asymmetric induction (3.2)
β-hydroxy decanoyl-ACP dehydratase (3.1)
chiral auxiliary (3.7)
competitive substrate (3.6)
diastereomer (3.2)
enantioconvergent (3.6)
enantiomer (3.2)
enantioselective (3.6)
enoyl-CoA isomerase (3.1)
essential fatty acid (3.1)
Favorskii rearrangement (3.4)
internal electrophile (3.4)
internal nucleophile (electrophile) (3.4)
isoelectronic (3.4)
latent carbanion (3.1)
latent functional group (3.3)
masked functional group (3.3)
masking group (3.3)
mixed function oxygenase (3.1)
neighboring group effect (3.6)
pinacol rearrangement (3.4)
regiocontrol element (3.3)
resolution (3.2)
retro cycloaddition (RC) (3.3)
ring contraction strategy (3.4)
ring expansion strategy (3.4)
stereocontrol element (3.2)
stereoelectronic control (SEC) (3.3)
stereoselective (3.4)
stereospecific (3.4)
steric approach control (SAC) (3.4)
temporary bridge (3.4)
thermodynamic control (TC) (3.4)
unmasking (3.4)
3.09: Study Questions
1. Turner’s synthesis of PGF uses endo dicyclopentadiene (2) as starting material and generates an intermediate 1.
Use one or more of the following terms to answer each of the following questions: thermodynamic control, stereoelectronic control, steric approach control, or temporary bridge. How is stereocontrol achieved:
(a) at the 11 position relative to the 9 position in 1?
(b) at the 8-position relative to the 9-position in 1?
(c) at the 12-position relative to the 8-position in 1?
2. Corey’s second synthesis of PGF exploited a lactone intermediate 3 that contains all of the cyclopentane ring stereochemical information present in PGF.
Use one or more of the following terms to answer each of the following questions: thermodynamic control, stereoelectronic control, steric approach control, or temporary bridge.
(a) Two factors favor the correct relative stereochemistry for the aldehyde substituent in 3 during its synthesis from 6 by way of 5 and 4. What are these two stereocontrolling factors?
(b) How is stereocontrol achieved at the 9-position relative to the 8-position in 3?
(c) How is stereocontrol achieved at the 11-position relative to the 8-position in 3?
3. In Corey’s first synthesis of PGE1, he uses a substituted cyclohexene precursor that is suggested by a polar disconnection of the subtarget and by his intention to use target-related functionality at the 15-position to stabilize a carbanion at that carbon during assembly of the lower side chain.
(a) What is the structure of Corey’s cyclohexene intermediate in his synthesis of 7?
(b) Why does Corey choose an \(\ce{-NO2}\) group in his cyclohexene intermediate to serve as a precursor of the \(\ce{NHCHO}\) group in 7?
4. Two syntheses of the PGF precursor 8 were described as outlined in the following retrosynthetic analysis:
(a) Why was the 10 to 9 conversion not achieved enantioselectively?
(b) How was the 12 to 11 conversion accomplished enantioselectively?
(c) What stereocontrolling factor is responsible for the configuration of the epoxy group relative to the other stereocenters in 8 when this epoxide is prepared from the alkene 11?
5. Woodward’s PGF synthesis generates the key intermediate 13, that is similar to Corey’s lactone 3, by a ring contraction of 14.
(a) In an attempt at preparing the precursor 15 of 14 by intramolecular alkylation of enolate 16, the desired ketone 17 was not obtained. Why?
(b) Woodward achieved the synthesis of 15 from 18 by a multistep sequence that began with a polar process closely related to the 16 to 17 reaction. How did he accomplish the 18 to 15 conversion?
3.10: References
1. Miyano, M.; Stealey, M. A. J. Org. Chem. 1975, 40, 1748.
2. For a review see: Lednicer, D. Advan. Org. Chem. 1972, 8, 179.
3. Kojima, M.; Sakai, K. Tetrahedron Lett. 1972, 3333; 1975, 2837.
4. Martel, J.; Toromanoff, E.; Mathieu, J.; Nomine, G. Tetrahedron Lett. 1972, 1491.
5. Corey, E. J.; Ensley, H. E. J. Org. Chem. 1973, 38, 3187.
6. Strike, D. P.; Smith, H. Tetrahedron Lett. 1970, 4393; Ann. N.Y. Acad. Sci. 1971, 180, 91.
7. Kuo, C. H.; Taub, D.; Wendler, N. L. Tetrahedron Lett. 1972, 5317.
8. Corey, E. J.; Anderson, N. H.; Carlson, R. M.; Paust, J.; Vedejs, E.; Vlattas, I.; Winter, R. E. K.
J. Am. Chem. Soc. 1968, 90, 3245.
9. Brewster, D.; Myers, M.; Ormerod, J.; Otter, P.; Smith, A. C. B.; Spinner, M. E.; Turner, S. J.
C. S. Perkin I 1973, 2796.
10. Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969, 91, 5675.
11. Brown, E. D.; Clarkson, R.; Leeney, T. J.; Robinson, G. E. J. C. S. Chem. Commun. 1974, 642.
12. Ernest, I. Angew. Chem. Int. Ed. Engl. 1976, 15, 207.
13. Woodward, R. B.; Gosteli, J.; Ernst, I.; Friary, R. J.; Nestler, G.; Raman, H.; Sitrin, R.; Suter,
C.; Whitesell, J. K. J. Am. Chem. Soc. 1973, 95, 6853.
14. Corey, E. J.; Snider, B. B. Tetrahedron Lett. 1973, 3901; J. Org. Chem. 1974, 39, 256.
15. Sih, C. J.; Salomon, R. G.; Price, P.; Sood, R.; Perruzzotti, G. J. Am. Chem. Soc. 1975, 97, 857.
16. Sih, C. J.; Heather, J. B.; Sood, R.; Price, P.; Peruzzotti, G.; Hsu Lee, L. F.; Lee, S. S. J. Am.
Chem. Soc. 1975, 97, 865.
17. Stork, G.; Isobe, M. J. Am, Chem. Soc. 1975, 97, 4745.
18. Kluge, A. F.; Untch, K. G.; Fried, J. H. J. Am. Chem. Soc. 1972, 94, 7827.
19. Partridge, J. J.; Chadha, N. K.; Uskokovic, M. R. J. Am. Chem. Soc. 1973, 95, 7171.
20. For reviews see: (a) Sih, C. J.; Shieh, W. R.; Chen, C. S.; Wu, S. H. Ann. N. Y. Acad. Sci. 1986,
471, 239. (b) Sih, C. J.; Rosazza, J. P. Tech. Chem. (N. Y.) 1976, 10, 69.
21. Stork, G.; Takahashi, T. J. Am. Chem. Soc. 1977, 99, 1275.
22. Stork, G.; Takahashi, T.; Kawamoto, I.; Suzuki, T. J. Am. Chem. Soc. 1978, 100, 8272.
23. Salomon, R. G.; Miller, D. B.; Raychaudhuri, S. R.; Avasthi, K.; Lal, K.; Levison, B. S. J. Am.
Chem. Soc. 1984, 106, 8296.
24. Baker, S. B. J. Am. Chem. Soc. 1952, 74, 827. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/03%3A_Fatty_Acids_and_Prostaglandins/3.08%3A_Terminology.txt |
A trivial pattern characterizes the structures of fatty acids: their carbon skeletons generally have even numbers of carbons. This is a consequence of their biosynthetic origins. They are oligomers of the two-carbon building block, acetyl CoA. Terpenes are a structurally and functionally diverse family of natural products. Nevertheless, a pattern that characterizes their structures is often discernible. They appear to be oligomers of isoprene. In the ensuing discussion, for clarity, we occasionally will represent bonds that that are not in these isoprene units with dashed lines as in the following examples.
The biosynthesis of some terpenes involves such intricate carbon skeletal transmogrifications that the terpenoid biosynthetic origin is not at all obvious. Moreover, the intricate multicyclic skeletons of some terpenes are devoid of functionality. For such molecules, polar reactivity analysis is of little value. Instead, it is the topology of these molecules that must be analyzed in order to perceive potentially effective dislocations to generate precursors, and ultimately, to identify starting materials.
04: Terpenes
Terpenes have a large variety of carbon skeletons characterized by branched chains, and often complex multicyclic ring systems. They are oligomers of the biological isoprene unit, Δ3-isopentenol, which is a relatively reduced hydrocarbon comprised of five carbons. It is produced in nature from three molecules of a relatively oxidized two carbon starting material, acetic acid in the form of acetyl CoA. A likely candidate for the byproduct containing the carbon atom lost from three molecules of acetic acid during the biosynthesis of Δ3-isopentenol is carbon dioxide. Polar analysis suggests a more highly oxidized precursor, mevalonic acid, that could be decarboxylated by polar fragmentation of a \(\ce{CO2}\) electrofuge and a hydroxide nucleofuge. Such a fragmentation can benefit from the thermodynamic advantage of generating a C=O bond and produces easily disposable highly oxidized byproducts, \(\ce{CO2}\) and water. Further retrosynthetic analysis of mevalonic acid suggests polar disconnection to two acetic acid carbanion synthons which would condense with an acetyl electrophile.
A very large variety of lipids are derived in nature from the oligomerization of Δ3-isopentenyl pyrophosphate (5). This five carbon biosynthetic building block is produced by condensation of three molecules of acetyl CoA. Acetoacetyl CoA (1), produced by Claisen condensation of two molecules of acetyl CoA, reacts at the ketone carbonyl with a second equivalent of acetyl CoA as nucleophile. This condensation is enantioselective. The asymmetry of the enzyme, hydroxymethylglutaryl CoA synthetase, directs the attack of the acetyl CoA nucleophile to one side of the prochiral acetoacetyl CoA electrophile. The product is symmetrical. Nevertheless, the condensation is accompanied by the enantioselective hydrolysis of the CoA-SH ester derived from the acetyl group. The monothioester 2 is then reduced by hydride attack at the more electrophilic thioester carbonyl to give L-mevalonic acid (3). Phosphorylation of 3 leads, via a 5-monophosphate and 5-pyrophosphate, to an unstable intermediate phosphorylated at the C- 3 hydroxyl. This tertiary phosphate readily undergoes decarboxylative elimination to give Δ3-isopentenyl pyrophosphate that readily isomerizes to Δ2-isopentylpyrophosphate.
A head to tail dimer, geranyl pyrophosphate (E-7), is formed by addition of the allylic electrophile 6 to the terminal olefin 5 accompanied by proton loss. The resulting ten carbon allylic pyrophosphate E-7 readily alkylates a second molecule of 5 to give a trimer, the fifteen carbon allylic pyrophosphate farnesyl pyrophosphate (E-8). The monoterpenes are C10 compounds biogenetically derived from geranyl pyrophosphate (E-7), its Z-isomer neryl pyrophosphate (Z-7), or from a cyclopropyl dimer, chrysanthemyl pyrophosphate (9), that is formed directly from two molecules of Δ2-isopentenyl pyrophosphate. Isoprene units are often discernable embeded in the skeletons of terpenes. However, some terpenes, e.g. derivatives of the santolinyl cation, are not composed entirely of intact isoprene units owing to rearrangements during their biosynthesis (vide infra). These are called irregular terpenes.
Intramolecular nucleophilic attack by a C=C π-bond on the electrophilic pyrophosphate generates various isomeric carbocationic intermediates such as menthane, pinane, carane, camphane, or thujane carbenium ions.
The monoterpene loganin is the biosynthetic precursor of secologanin, a natural product whose terpenoid origin is unobvious. Secologanin, whose isoprene units are not intact, is derived biosynthetically by a polar cleavage of the cyclopentane ring of loganin exploiting the polar activation afforded by the cyclo pentane hydroxyl substituent.
Polar analysis of loganin shows that the hydroxyl substituent is not essential for facilitating generation of the cyclopentane ring by a polar C-C bond formation since adequate functionality is located in the proximity of the key bond. In the biosynthesis of loganin, this hydroxyl group is introduced at the end of the synthesis by a remote oxidation. The dihydropyran is simply a derivative of a 1,5-dialdehyde whose structure is simplified by polar disconnection of a ring C-C bond located between two consonant functional groups. This dislocation represents a retro Michael addition. The requisite nucleophile could be generated by deprotonation of a saturated precursor. An alternative precursor for this nucleophile, the one involved in the biosynthesis, is an unsaturated aldehyde. Thus, conjugate addition of hydride to an a,b-unsaturated aldehyde provides the nucleophile which will be Michael alkylated. The highly oxidized cyclization substrate is derived from geraniol by multiple allylic oxidations, and geraniol is a dimer of two isopentenol precursors, Δ2 and Δ3-isopentenol.
Loganin (13), the glucoside (a mixed acetal of glucose and an alcohol) of a monoterpene, is a key intermediate, which affords secologanin (14), the immediate precursor of the non-tryptamine portion of the corynanthe, aspidosperma, iboga, ipecacuanha and cinchona groups of indole alkoloids (see chapter 7). Loganin is produced from geraniol (10), which is first oxidized to a trialdehyde (11). Reductive cyclization of 11 to 12 is followed by further oxidations. Hydroxy loganin (14) gives secologanin (15) by a retro-Prins cleavage. The origin of secologanin from isoprenoid precursors is not immediately obvious from a cursory examination of its structure. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/04%3A_Terpenes/4.01%3A_Biosynthesis_of_Monoterpenes-_Loganin.txt |
Total syntheses of loganin, that invole polar connection as the first step in the retrosynthetic analysis, have been described. Thus, dislocation of the monocyclic target to a bicyclic target recognizes the potential of retroaldol cleavage of a cyclobutane ring for generation of the required vicinal cis relationship of the malonyl and carboxaldehyde substituents of the target. The cyclobutane can be generated in a two bond-forming cycloaddition process, which, owing to the strain expected for the alternative trans-fused bicyclic product, can be expected to favor the required cis-fused bicyclic intermediate.
Loganin was synthesized in the laboratory by an ingenious scheme involving photochemical cycloaddition to a preformed symmetrical cyclopentene synthon 16.1 The desired cis ring fusion is assured by a temporary bridge in the intermediate 17.
An asymmetric total synthesis of loganin was achieved2 by an overall strategy for skeletal construction which is similar to, although shorter than, the previous approach. The asymmetric intermediate 18 was produced in high optical purity (at least 98%) by hydroboration of the prochiral symmetrical substrate, 5-methyl-cyclopentadiene, with (+)- or (-)-di-e-pinanylborane.
Since this involves stereospecific addition of the borane to the least hindered face of 18, the configuration at the carbinol carbon had to be inverted during the preparation of the acetate 19. The regioselective formation of the isomer 20 results from the steric approach control during the photoannealation. The enol (21) attacks the less hindered face of 19.
4.03: Biosynthesis of Sesquiterpenes- Longifolene
The sesquiterpenes are C15 compounds derived biogenetically from E,E-farnesyl-PP (8), the allylic isomer nerolidyl-PP (22), or the geometric isomer Z,E-farnesyl-PP (23). Nucleophilic attack by a C=C π-bond on the electrophilic pyrophosphate generates various isomeric cationic intermediates such as 24-31 which undergo proton loss, nucleophilic capture by external nucleophiles (especially water) or by another C=C π-bond to generate a wide variety of carbon networks.
Retrosynthetic analysis of the biosynthesis of the sesquiterpene longifolene (32) is channeled by the boundary condition that the starting material most probably is a head-to-tail-head-to-tail trimer of isopentenyl pyrophosphates. The longifolene skeleton is an intricate network of carbon. The analysis must simplify the tricyclic topology by disconnections which generate or lead to an acyclic precursor such as Z,E-farnesyl-PP (23). Three isoprene units are clearly discernable embeded in the skeleton of longifolene. Unmasking of the acyclic trimeric starting material requires disconnection of some bonds between these isoprene units. A series of disconnections of C=C π-bond nucleophiles from carbocationic electrophiles can be achieved by proton addition to 32 to give 33. Retropolyene cyclization of 33 disconnecting a nonisoprenoid bond suggests the precursor 34. Similar disconnection of this carbocationic intermediate suggests a precursor 35, but further disconnection of nonisoprenoid bonds cannot proceed from this carbocationic precursor. Therefore, hydride migration producing an isomeric carbocation must follow the cyclization that generates the carbon skeleton of 35. The isomeric carbocation 36, on the other hand, can be generated by addition of a carbon electrophile to a C=C bond in 37 which has the carbon skeleton of a head-to-tail-head-to-tail isoprenoid trimer. Intermediate 37 could be generated from Z,E- farnesyl-PP (23) by elimination of pyrophosphoric acid and subsequent addition of a proton to an intermediate tetraene 38.
The actual biosynthetic strategy for longifolene (1) is similar to that inferred above but avoids generating relatively unstable 1° carbenium ions such as 33 or 37 by exploiting a skeletal rearrangement step. Such carbenium ion rearrangements are a common occurrence during the biological construction of carbon networks, particularly those of many terpenes. Addition of the allylic electrophile to a nucleophilic trisubstituted C=C π-bond in 23 generates 29 or 31 that can rearrange to a more stable 2° allylic carbenium ion 39 by 1,3-hydride shift. Cationic polyene cyclization then delivers a bicyclic 3° carbocation 40 and then tricyclic 2° carbocation 41 that undergoes [1.2] sigmatropic rearrangement of carbon, a Wagner-Meerwein rearrangement, to produce a more stable 3° carbocation 43 with the longifolane skeleton. The 41 to 42 rearrangement is readily reversible (vide infra). Deprotonation of 42 delivers longifolene.
The biosyntheses of all the multicyclic sesquiterpenes involve similar carbocationic polyene cyclizations. Channeling the cyclization to specific structures is undoubtedly influenced by the folding of the acyclic pyrophosphate substrate by various protein catalysts (enzymes) promote the reactions and also limit the access of water to the carbocationic intermediates. Otherwise, the carbocationic intermediates would be captured by water to produce various alcohols resulting from interception of the numerous intermediates. It is also possible that folding causes juxtapositions of p-bonds that favor a concerted formation of several sigma bonds without the generation of numerous discrete carbocationic intermediates such as those shown in the above scheme for the biosynthesis of longifolene. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/04%3A_Terpenes/4.02%3A_Syntheses_of_Loganin.txt |
Polar Analysis of Functionalized Precursors
Polar reactivity analysis is not very helpful for dislocaton of longifolene because it has no polar functionality. However, functionalized precursors are suggested by considering possible syntheses of the exocyclic methylene. Thus, an alcohol could produce 32 by dehydration, and the alcohol could arise by addition of a methyl nucleophile to ketone 43.
For a direct polar C-C connective synthesis of 43, any additional polar activating functionality in a precursor must be lost during C-C bond formation. Thus, 44-47, precursors for a direct synthesis of 43, result from the four possible disconnections that exploit the potential nucleophilicity of carbon a to a carbonyl, whereas 48 and 49 result from the two possible disconnections that exploit the electrophilicity of a carbonyl carbon. However, it may be advantageous to use an indirect strategy, one that incorporate additional functionality in the penultimate intermediates of skeletal construction (eq. 50 or 51).
That functionality must then be removed after the completion of the carbon network. For example, because the exocyclic methylene of 32 might reasonably be derived from an ester 52, another set of intermediates that has a different reactivity pattern than the first set may be generated by polar reactivity analysis (e.g. 53 and 54). A great many additional precursors may be generated by considering dislocations involving additional activating groups or unsaturation.
Topological Analysis
For molecules like 32, that have minimal functionality and complex skeletons, another approach has been suggested for identifying useful dislocations. Thus, attention is first directed to "an exhaustive analysis of the topological properties of the carbon network to define the range of possible precursors...from which the desired skeleton can be produced by the establishment of one or two connecting bonds."3 Possible reactions, appropriate activating functionality, etc., are only considered after the topological analysis.
In many cases, the most synthetically useful dislocations result from removing one bond between ring-member atoms, called common atoms, that are bonded to three or four other ring members (but not two). For longifolene (32), in which the common atoms are numbered 1-4, this generates three topologically simplified structures 55-57.
Another useful series is generated by removing one bond between a common atom and a noncommon atom. Two members of this series are 58 and 59. Since some reactions generate two new bonds, e.g. Diels-Alder cycloaddition, structures generated by removing two bonds of the original network 32, especially which join two adjacent atoms to one or more common atoms as in 60, should be considered. However, intermediates suggested by dislocations involving removal of a bond between noncommon atoms cannot be disregarded a priori.
After the topological analysis, specific reactions and appropriate functionality to permit bond formation are considered. The process is repeated until a series of potential precursors is generated for each penultimate intermediate and so on until the synthetic tree is complete. As functionality is added to intermediates, topological analysis becomes less relevant. “Maximum utilization of (sub)target-related functionality” (see section 1.2), and hence polar reactivity analysis (see section 1.4), becomes a major factor in synthetic planning. Compounds 61-66 are possible functionalized derivatives corresponding to structures 55-60, respectively.
At some point, a choice between a broad range of possibilities is made. It must necessarily be "very much a function of the methodology of synthetic chemistry available at the time, of certain practical considerations such as the availability of the necessary materials and reagents, and of certain subjective judgments relating to the feasibility of key reactions or the existence of alternatives."3
Fatally Flawed Strategies
To illustrate the pitfalls of designing a complex molecular synthesis, we will first consider some unsuccessful strategies for the synthesis of longifolene. One strategy4 was based on the interconvertibility by rearrangement of longifolene (32) and its hydrochloride 67.
An intermediate 69, related to 65, was prepared in ten steps from D-α-bromocamphor (68), that is readily available from a natural product. However, 69 gave aldol product 71 rather than the desired product 70 under Michael reaction conditions. Thus, the ready availability of the starting material notwithstanding, the ambident electrophilicity of the enone moiety in 69 derailed the synthetic plan.
Removal of a bond between two noncommon atoms in the first dislocation from 32 led to consideration of the potential intermediate 73 for the synthesis of longifolene.5 This route is especially attractive since 73 is easily prepared in a few steps from readily available starting materials. The key cyclization of 73 to 74 failed upon treatment of 73 with acids.
Other modes of cyclization should be examined, such as 73 75 76. But preferential initial hydroboration of the monosubstituted C=C bond will preclude the required orientation for the addition to the tetrasubstituted C=C bond and lead to 77. Alternatively, an intermediate 79, related to 65, may be available from the Diels-Alder adduct 72 and may undergo intramolecular alkylation delivering 76. Steric approach control should favor the requisite stereochemistry at position 7 in 78.
The first successful synthesis of longifolene (32) involves the key cyclization 61 80 as the last step of skeletal construction.3 Incidentally, 61 is suggested not only by topological considerations (i.e. structure 55), but also by polar reactivity analysis (i.e. structure 44). After much experimentation, only a 10-20% yield could be achieved in this crucial step. Conversion of 80 to 32 then involved final addition of a methyl and methylene group and removal of the carbonyl groups.
The synthesis of the key intermediate 61 illustrates a strategy that is useful for carbon skeletal construction, namely ring size modification (RSM). Thus, 61 was prepared from the readily available Wieland-Miescher ketone (81) by expansion of a six to a seven membered ring. The selective ketalization of the saturated carbonyl group in 81 is possible owing to deactivation of the unsaturated carbonyl by the adjacent $\pi$-electron system.
Exposure of diol 82 to the usual acidic conditions for pinacol-pinacolone rearrangement would result in ionization of the tertiary allylic alcohol and produce an acetyldecalin derivative. It was, therefore, necessary to devise a modified procedure to direct the rearrangement of the diol 82 along the desired pathway by facilitating ionization of the secondary hydroxyl. Therefore, the secondary hydroxyl was selectively tosylated. Ionization of the labile tosylate leaving group was accompanied by migration of the vinyl group. The saturated carbon chain is less prone to migrate than the unsaturated one because p- electron participation is possible in the latter but not the former rearrangement.
The Ring Size Modification Tactic
The logic of a synthetic route can be used as a tool for devising a strategy or, ex post facto, as a framework to achieve a fundamental understanding of a known synthesis. The decision to employ ring size modification in the above synthesis of 61 is a logical consequence of topolgical and polar analysis of this target. Topological analysis suggests disconnection of the bicyclic ring system at bonds to the bridgehead carbons which are common atoms. Double disconnection of the seven-membered ring suggests a symmetrical precursor, a 2-substituted 2-methylcyclohexan-1,3-dione. Polar analysis reveals the possibility of a polar annealation for construction of the cyclohexandione that exploits the activation provided by two consonant carbonyl groups. However, one of the desired disconnections of 61 lies on a dissonant circuit. Removal of one atom of this dissonant circuit (ring contraction) produces a consonant circuit in 82 and the possibility of skeletal construction by polar annelation; i.e the Robinson annelation producing 81.
It is important to note that a dissonant circuit in 61 is produced from a dissonant precursor 82. Also, as noted in the previous chapter (see section 3.4), the ring expanding rearrangement of 82 is equivalent to a hypothetical two stage dislocation of the target, disconnection followed by connection. It is also instructive to note the changes in fs that accompany the 82 61 rearrangement. Polar disconnection raises f (from +1 to +2) for the electrophilic center undergoing polar disconnection from 82 and lowers f (from +1 to 0) for the electrophilic center undergoing polar connection. The requisite polar reactivity dissonance is created by a nonpolar reaction, oxidative vicinal hydroxylation of an alkene (dioxidative addition). This alkene is obviously derivable from dione 81 by selective Wittig olefination. 81 is entirely consonant. It can be constructed by polar reactions from 2-methylcyclohexan-1,3-dione and methyl vinyl ketone. Had the Robinson annelation process and Wieland-Miescher ketone (81) not been known, the above retrosynthetic analysis would have led to their invention.
Check for Flaws
Having devised the above strategy, it is mandatory to apply step 4 of the "Protocol for Synthetic Design" outlined on page 23. We must examine the strategy for possible flaws. In fact, polar rearrangment of 82 under acid catalysis is expected to follow an alternative pathway involving hydride migration to a tertiary carbenium ion that would be formed more readily than the requisite secondary carbenium ion. Therefore, the strategy was modified to provide selective activation of the secondary hydroxyl. Thus, tosylation enhanced its nucleofugacity.
Also note that the concerted hydride migrating rearrangement is equivalent to a two stage dislocation of the target, disconnection followed by connection of H${}^\ominus$. Furthermore, polar disconnection of hydride raises f (from +1 to +2) for the electrophilic carbon center undergoing polar disconnection (the migration origin) in 82 and lowers f (from +1 to 0) for the electrophilic carbon center undergoing polar connection (migration terminus).
Similar changes in fs accompany polar rearrangements involving nucleophilic carbon at the migration origin and terminus as, for example, in the rearrangement of G3P to DHAP (see section 2.1). This process is actually a two-stage dislocation of the target DHAP: disconnection of H${}^\oplus$ from C-1 followed by connection of H${}^\oplus$ at C-2.
Ring size modification can be applied at any stage of skeletal construction. In the following synthesis, ring expansion is applied after completion of a skeletal network that is topologically equivalent to that in longifolene (32).6 Although the skeletal network in 86 has bridges of different lengths than those in 32, it has the same connectivity as 32. Expansion of one of the bridges in 86 leads to the longifolene ring system (see below). The synthesis of 86 has several important features. As in the previous synthesis of 32, the present appraoch begins with the Wieland-Miescher ketone (81). Catalytic hydrogenation proceeds with stereoselective formation of the cis-decalone 83 owing to steric approach controlled addition of hydrogen to the convex side of the folded ring system of 81. Similarly, epoxidation of 84 occurs with stereoselective delivery of oxygen from the convex side. The stereochemistry of epoxide 85 is ideally suited for nucleophilic attack during intramolecular SN2 alkylation of the corresponding enolate anion. This key cyclization in Mc Murray's longifolene synthesis proceeds in excellent yield (92%).
The longifolene ring system was then generated from 86 by a ring expansion involving pericyclic opening of a cyclopropyl carbenium ion that is generated during solvolysis of 87. The required nucleophilic 1,4-addition of a methyl nucleophile to an enone 88 was accompanied by two undesired reactions. One, the replacement of a vinyl bromo substituent with methyl, generated a useless byproduct. However, the other, an intramolecular aldol condensation, was not a fatal flaw because the extra ring thus formed could be cleaved by a fragmentation reaction (89 90).
Ring Expansion as a Three Step Process
Again, let us perform a retrosynthetic analysis ex post facto to achieve a more fundamental understanding of the longifolene synthesis via key intermediates 81-90. We will consider some alternatives that were not adopted, and examine strategic considerations that underlie the pathway that was chosen. In this analysis, we will presume the boundary conditions of using 81 as starting material and generating a tricyclic carbon network by formation of a bond between the incipient common atoms 1 and 2 (numbered as in 55 on page 116) in a bicyclic precursor. Also, functionality will be introduced by presuming a ketone as the progenitor of the exocyclic methylene group. However, instead of forming the tricyclic skeleton at the end of the synthesis after expansion of a 6 to a 7-membered ring, we will first form the tricyclic skeleton and then perform a ring expansion. We could presume that the quaternary carbon bearing the gem dimethyls is inserted into the six-membered ring of a precursor 92 to generate 91. That 91 might contain a second carbonyl adjacent to the bridgehead is the suggested by the fact that this carbon in 92 corresponds to a carbonyl carbon in the starting material 81 (vide infra). The bond to be disconnected between two common atoms in 92 lies on a dissonant circuit between the carbonyls. Therefore, additional functionality, i.e., a nucleofuge, is required in a precursor, X in 93, to allow polar bond formation.
Ring expansion involves insertion of a carbon atom between two ring members. One bond must be formed between the new carbon and each ring member while the bond between ring members must be severed. There are two topologically different ways to accomplish a ring expansion. One possibility for generating 91 from 92 is analogous to the ring expansion of 81 via 82 (see above). Thus, a retro pinacol dislocation of 91 is achieved by disconnecting the bridgehead carbon (as nucleofuge) in 91 from the quaternary carbon and reconnecting it (as nucleophile) to the neighboring carbonyl carbon. This suggests a synthon 94 and synthetic equivalent 95 as precursors of 91. In this strategy, ring expansion is achieved by a connection-disconnecion-connection (CDC) sequence that starts with connection of the nucleophilic carbon of 2-diazopropane to an electrophilic carbonyl carbon of 92.
A topologically different strategy, connection-connection-disconnection (CCD), necessarily involves a cyclopropane intermediate that might be formed by cycloaddition to an alkene 98. Thus, 91 could be derived from a cyclopropane 97 that could isomerize to a cycloheptene precursor 96. Necessarily, only one of the gem methyl groups of 91 can be present in 96 because the carbon bearing this methyl is quaternary in the cyclopropyl precursor 97. Thus, provision must be made for introducing the last methyl group. This might be done by adding functionality to 96, as in 99 that has a carbonyl group conjugated with the carbon center to which a methyl must be added. If the ring expansion that will produce 99 is to involve a polar fragmentation of the ring fusion bond in a cyclopropane intermediate, then retrosynthetic polar analysis suggests two routes to 99. In both routes, the ring fusion bond is provided by retrosynthetic connection to a carbon bearing electropohilic subtarget-related functionality, a carbonyl in 99 or a hydroxyl in 100. The electrons for this connection are provided by an incipient nucleofuge (Nu) through addition to the C=C bond.
The less direct route via 100 is compatible with an alkene precursor 98. Both routes revealed by this analysis involve the cycloadditon of a carbene to which is appended a nucleofuge (Nu). Although departure of the nucleofuge could occur after fragmentation of the ring-fusion bond, alternative timing is possible. The solvolysis of the dibromocyclopropane derived from 98 probably would be a concerted process.
Polar dislocation of 98 to an allylic electrophile and enolate may provide a flawed strategy because the C=C bond in 99 introduces ambident electrophilicity. Thus, cyclization might generate 102 by an SN2' reaction.
Therefore, the C=C bond in 98 is best introduced after cyclization, e.g. by dehydration of alcohol 86. The bond to be disconnected between two common atoms in 86 lies on a dissonant circuit between the carbonyl and hydroxyl groups. Therefore, additional functionality is required in a precursor, e.g. 85, to allow polar bond formation. This epoxide would be obtainable by dioxidative addition to an alkene 84. Generation of 84 from starting ketone 81 is trivial.
Fragmentation of Fused Bicyclics: A Tactic for Generating Larger Rings
During the Mc Murray synthesis of longifolene, an undesired connection formed by intramolecular aldol condensation of enolate 103 generated in the conjugate addition of a methyl nucleophile to intermediate 88. Owing to a proclivity of enolate 105 toward aldol condensation, retro aldol fragmentation of the pentacyclic product 104 could not provide the requisite ring system. This problem was circumvented by an isoelectronic (see page 80) fragmentation after lowering the functionality level of the ketone in 104 to an alcohol. Thus, retro Prins fragmentation of mesylate 89 generated 90 in which the weakly nucleophilic alkene, in contrast with the more strongly nucleophilic enolate in 105, showed no proclivity toward condensation with a carbonyl group.
The Mc Murray synthesis of longifolene provides two examples of fragmentation of a bond shared by two fused rings to generate a single larger ring. The first example exploited fragmentation of the cyclopropane 87 as part of a ring expansion tactic, while the second, an unplanned step in the synthesis, involved fragmentation of 89.
Another synthesis of longifolene was designed to exploit the fragmentation of a fused cyclobutane. This strategy recognizes the possibility of using carbonyl functionality in 43 to provide polar reactivity for introducing the methylene and a-methyl groups, and another carbonyl group to allow introduction of the gem dimethyl array into a precursor 106. Dislocation of this subtarget by a polar connection suggests that dione 106 might be generated by the retroaldol fragmentation of a β-hydroxyketone 107. In contrast with the equilibrium between aldol 104 and dione 109 that favors the former, the equilibrium between aldol 107 and dione 106 is expected to favor the latter owing to relief of ring strain associated with cleavage of a cyclobutane.
An exceptionally efficient synthesis of longifolene resulted from the application of this strategy.7a Only 10 steps are used to convert enamine 110 and acyl halide 111 into longifolene in 26% overall yield. Phototolysis of an enol ester derivative of dione 112 folowed by hydrogenolytic removal of the benzyloxycarbonyl (BOC) group generated dione 106 via 107. Selective methylenation of the less sterically congested carbonyl in 106 followed by cyclopropanation, hydrogenolysis of 1 1 3 , and methylation delivered ketone 43, an intermediate in both the Corey and McMurray longifolene syntheses.
A Polyene Cyclization Route
Another efficient synthesis of longifolene (32) is based on a structural simplification suggested by topological analysis. Thus, dislocation to a subtarget 60 (see page 116) by removal of two bonds involving common atoms suggests a precursor containing only one ring. In the synthesis, these two bonds were generated in a key acid-catalyzed polyene cyclization (114 115).7b The conversion of 115 to 32 requires reductive removal of the hydroxyl. This was accomplished by an SN1 replacement of hydroxyl by hydride through an intermediate carbenium ion 116. To provide polar activation that could be exploited for introducing the angular methyl group, the C=C bond in 117 was isomerized to an exocyclic methylene in 118. Oxidative cleavage then delivered ketone 119.
A synthesis of 114 from a methylenecyclopentanone electrophile 120 and nucleophilic side chain synthon 121 is suggested by polar analysis. Two extra steps were added to the synthesis to allow purification of the enolate 122 produced by the 1,4-addition of 120 to 121. Thus, 122 was trapped by O-acylation. After purification of the enol acetate 123, the enolate 122 was regenerated and then brominated. Dehydrobromination and reduction completed the synthesis of 114. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/04%3A_Terpenes/4.04%3A_Syntheses_of_Longifolene.txt |
The Cecropia juvenile hormones are biogenetic close relatives of farnesol that contain one or two extra carbon atoms in their sesquiterpenoid carbon skeletons. These terpenoid homologues are referred to as homo and bishomo sesquiterpenes respectively. The extra carbon atoms arise through the incorporation of one or two molecules of propionate in place of acetate during a biosynthetic skeletal construction that is otherwise identical to that of farnesol. Thus, propionyl CoA condenses with two molecules of acetyl CoA to give homomevalonic acid (124) after reduction with NADPH. Conversion of 124 to 125 via decarboxylative elimination and isomerization to 126 is followed by addition of the allylic electrophile 126 to the terminal C=C bond in Δ3-isopentenyl-PP (5) or to its six carbon homologue (125). The allylic electrophiles 127 or 128 then alkylate Δ3-isopentenyl-pyrophosphate to deliver homo and bishomo farnesylpyrophosphates 129 or 130, respectively. These are oxidized to the corresponding acids by hydride donation to NAD+. Enantio-selective epoxidation, and O-methylation of the carboxyl by methyl transfer from S-adenosyl-methionine (SAM, 133) gives optically active epoxyesters 131 and 132 which are known as C17 and C18 juvenile hormones respectively.
Stereocontrolled Generation of Trisubstituted Alkenes
The primary synthetic challenge presented by the Cecropia juvenile hormones is stereocontrol during the construction of trisubstituted C=C double bonds. Temporary rings may be effectively utilized to control alkene geometry. A variety of different applications of this tactic have been employed to achieve stereocontrolled syntheses of juvenile hormones. These syntheses generally involve stereocontrolled construction of methyl bishomo farnesoate (134), that is converted into C18-JH (132) by regioselective epoxidation as in the biosynthesis of 132. Polar analysis of 134 suggests a synthesis from the phosphono ester-stabilized carbanion 136 and dienone 135.
A Temporary Bridge Strategy
One tactic for stereocontrolled synthesis of 135 employs temporary thioether bridges in 137 to enforce the 5-E and 9-Z configurations.8 The sulfur bridges are reductively cleaved after the carbon skeleton of 135 is complete. Both of dihydrothiapyran fragments in 137 were derived from a common intermediate, tetrahydro-1,4-thiapyrone (138). Sulfur serves a dual strategic role in this scheme. Besides enforcing the required configuration at the carbon-carbon p-bonds (stereocontrol), sulfur stabilizes a neighboring nucleophilic center (reactivity control) in the carbanions 139 and 140. The mercapto and sulfide functional groups readily provide activation for either nucleophilic or electrophilic reactivity. They are biphilic functional groups, and, as previously encountered for the biphilic nitrile functional group (see pages 19 and 31), they can be used to produce polar reactivity inversion. We encountered this phenomenon previously in the conversion of an electrophilic carbonyl into a nucleophilic dithiane carbanion, an acyl carbanion equivalent.
In the present synthesis of JH, the electrophilic β-carbon of methyl acrylate is transformed by the thioether functional group into a nucleophilic center in 139 and 140.
Another instance of biphilic activation by sulfur is found in the reaction of the electrophilic carbonyl carbon of 138 with dimethyloxosulfonium methylide (141), a sulfur stabilized nucleophile, to produce epoxide 143. Sulfur then provides electrophilic activation at the same carbon by serving as a nucleofuge in the intermediate betaine 142.
SEC in Fragmentations
Another stereocontrolled synthesis of 135 exploits reversible stereospecific, anti-periplanar addition to a carbon-carbon π-bond to transpose the stereochemical relationships in monocyclic and bicyclic intermediates into those of acyclic products.9 The anti-periplanar arrangement allows continuous overlap during a concerted fragmentation. Thus, the E configuration of the 5,6-π-bond in 135 is preserved in latent form in the cyclic intermediate 144 by a dislocation involving anti-periplanar addition of a carbon electrophile and hydroxyl nucleophile to 1 3 5 . A new electrophilic carbonyl carbon is generated by the dislocation 144 fi 145. The Z configuration of the C=C bond in 145 is preserved in latent form by a dislocation involving antiperiplanar addition of a carbon electrophile and hydroxyl nucleophile to the C=C bond in 145. Thus, all of the stereochemical information in the acyclic intermediate 135 is contained in latent form in the bicyclic precursor 146. Control of alkene geometry in an acyclic carbon skeleton is thereby transposed to control of relative stereochemistry in a multicyclic carbon network. Since the conformations of multicyclic carbon networks are more rigid than acyclic ones, the influences of steric and neighboring group effects are more easily predicted and usually more pronounced.
Fragmentation of bonds a and b in 146 was promoted by converting hydroxyl into toluenesulfonate leaving groups. The triol 146 was readily selectively monotosylated at the least sterically congested secondary hydroxyl. Fragmentation of the resulting b-tosyloxy 3° alcohol delivering the Z-alkene 145 proceeded stereospecifically upon treatment with \(\ce{NaH}\). Addition of \(\ce{MeLi}\) to the tetrahydropyranyl derivative of 145 occurred stereoselectively (57%). After deprotection and selective tosylation of the secondary hydroxyl in the resulting diol, fragmentation of an intermediate β-tosyloxy 3° alcohol occurred smoothly to afford 135 stereospecifically (80%).
Since the functionality in 146 was introduced by polar reactions, it is a foregone conclusion that the functional groups are connected by consonant circuits. Polar analysis of 146 shows that all circuits in the cyclohexane ring are consonant. This allows disconnection of bonds to the ring fusion common atoms. However, activation of nucleophilic reactivity vicinal to the secondary hydroxyls requires conjugation that is only afforded by carbonyl groups as in 147. Polar disconnection of 147 then suggests propyl vinyl ketone and 2-ethylcyclopentan-1,3-dione as starting materials.
A synthesis of 146 based on the strategy outlined above began with Robinson annelation of 2-ethylcyclopentane-1,3-dione with propyl vinyl ketone. Steric approach controlled hydride delivery to the resulting dione provided 148 after protection of the hydroxyl. Steric approach control also resulted in stereoselective methylation from the less sterically congested α-face of the enolate from 148. Similarly, hydride delivery to the less sterically congested face of 1 4 9 gave 1 5 0 stereoselectively. The stereochemistry of the final hydroxyl group required for the triol 146 was dictated by the effect of the neighboring hydroxyl in 150 on the epoxidation of this alkene. The hydroxyl group hydrogen bonds with MCPBA thereby enforcing oxygen delivery cis to the neighboring hydroxyl as for 250 in section 3.6.
SEC Through Preferred Conformations
Conformational effects in cyclic transition states can also result in substantial, as well as predictable, stereoselectivity in the generation of acyclic alkenes. In another stereocontrolled synthesis of C18-JH (132), Claisen rearrangement of the allyl vinyl ether 153 from transketalization of 152 with 151, followed by elimination, generates the γ,δ-unsaturated ketone 154 stereoselectively.10 A chair transition state with an equatorial carbomethoxyl substituent is preferred for this [3.3] sigmatropic rearrangement. Borohydride reduction of 154 gives an allylic alcohol 155, which was again homologated stereoselectively with 152 to give allylic alcohol 158 via 156 and 157. A cyclic transition state is also the key to a stereocontrolled conversion of 158 to the allylically transposed chloride 159. Thus, the chlorosulfite ester 160 of 158 gives 159 via SNi' rearrangement involving a chair conformation with the bulky substituent in an equatorial position.
Another synthesis of C18-JH (132) that exploits a Claisen rearrangement to generate the 6,7-trisubstituted double bond stereoselectively is outlined below.11 An interesting step in this synthesis is the selective destruction of an undesired byproduct 162. This allylic chloride is more reactive than the isomers 161 and 163 and, therefore, selectively forms a water soluble pyridinium salt. Claisen rearrangement occurs via a transition state conformation 164 with an equatorial chloroethyl group. The 2,3-double bond is generated stereoselectively by cis-1,4-addition of an organocuprate derived from 165 to methyl 2-butynoate.
In this synthesis, the epoxide is produced by base-induced cyclization of a chlorohydrin rather than epoxidation of an olefin. Stereoselective HO generation of the Z-epoxide is possible because the reaction of chloroketone 166 with methyl magnesium chloride leads predominately to one diastereomer, the threo chlorohydrin 167.
This stereoselectivity is not the consequence of a cyclic transition state. Rather, for acyclic ketones which contain polar α-substituents (e.g. halogens) that are unlikely to coordinate with metal atoms, a combination of torsional strain, steric interactions, and electrostatic interactions must be considered. Two models have been formulated to explain such stereoselectivity. One model presumes that the reactive conformation of such ketones is a structure (e.g., 168) in which the carbonyl group and the polar α substituent are anti-periplanar to minimize dipole-dipole repulsion. Alternatively, the transition state may resemble 169 that allows maximum separation of the electronegative a substituent and the negatively charged nucleophilic reagent. Another example of such stereoelectronically controlled stereoselection is provided by the 48 + 49 53 conversion presented in Chapter 3 (section 3.3).
Other TB Strategies
Two tactics for stereoselective construction of trisubstituted C=C bonds not encountered in the previous examples are exploited in a strategy for synthesis of C18-JH that was devised by Corey.12 The 2,3-E configuration in 134 can be assured by a temporary ring during pseudo-intramolecular hydroalumination of a propargyl alcohol 171 that produces an intermediate vinyl alane 170 which is subsequently alkylated. This tactic can also produce the 6,7-E configuration by a similar hydroalumination-alkylation sequence applied to 172. The fact that a terminal alkyne is a latent carbanion suggests a polar dislocation of 172 to a propargyl alcohol-derived acetylide nucleophile and an electrophilic precursor 173. The E configuration of 173 can be assured by a temporary bridge that is suggested by dislocation to a more highly functionalized precursor 174 with differentiated carbonyl groups. Thus, reductive coupling of these two carbonyl groups provides a bridged latent dicarbonyl precursor 175.
Especially noteworthy is the synthetic role of the aldehyde carbonyl group in 174. This functional group is exploited solely to facilitate stereocontrol.
The substituents in the acyclic product 176, from selective oxidative cleavage of 175, are necessarily cis since only a cis double bond can be accommodated in a six membered ring. The cis relationship between the aluminum and hydroxymethyl substituent enforced in the intermediate 177 by a temporary bridge is preserved in the subsequent halogenolysis of the C-Al bond and alkylation of the resulting vinyl iodide delivering 178. Both transformations occur with retention of configuration. A similar sequence delivers 180 stereoselectively from 179. Conversion of the allylic alcohol 180 into key intermediate 134 requires oxidation followed by O-methylation.
SEC Through Preferred Conformations
Highly stereoselective formation of trisubstituted alkenes can sometimes be achieved by processes not involving intermediates with temporary bridges or cyclic transition states. Thus, occasionally, a combination of conformational and stereoelectronic effects may produce high stereoselectivity in reactions of acyclic molecules. For example, the 6,7-C=C bond of JH can be generated stereoselectively during transformation of the cyclopropyl carbinyl bromide 181 into the homoallylic bromide 182.13
Stereoselectivity arises from a stereoelectronic preference for an anti-periplanar arrangement of cleaving bonds that leads to generation of the new carbon-carbon double bond in a concerted stereocontrolled fashion. That is, a coplanar arrangement of the breaking C-C and C-Br bonds allows coupling of these bond cleavages with carbon-carbon double bond formation. Either transition state conformation 183 or 184 satisfies this requirement, but 183 is clearly preferred because the cyclopropyl group eclipses only hydrogen. Thus, a conformational bias, coupled with a stereoelectronic preference, favors a transition state 183, that leads to E-olefin 182.
The preparation of an early intermediate, 188, for the C1 to C4 segment of 181 illustrates a useful tactic for the synthesis of pure stereoisomers: selective destruction of one of two isomeric products from a nonstereoselective reaction. Thus, N-bromosuccinimide brominates dimethyl acrylic acid (185) nonselectively to give a mixture of bromoacids 186 and 187.
The undesired Z-isomer 187 undergoes spontaneous lactonization, leaving the desired E-isomer 186 as the only acidic organic product, that can be extracted into mild base and subsequently methylated to provide the intermediate 188 for the synthesis of JH. This is combined with a nucleophile derived from ketoester 190 that is available, in turn, from 1-acetyl-γ-buryrolactone 189. Symmetry was exploited during completion of the JH carbon skeleton by alkylation of the enolate of 3,5-heptanedione with 182. Chlorination of the product gave 191. The extra propionyl group was cleaved in a retro Claisen reaction by \(\ce{Ba(OH)2}\). The resulting chloroketone 166 reacted stereoselectively with MeMgCl to give 167 with less than 8% of the unwanted diastereomer (see section 4.6). Base-induced heterocyclization of the threo chlorohydrin 167 delivered racemic C18-JH.13 | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/04%3A_Terpenes/4.05%3A_Homo_and_Bishomo_Sesquiterpenes_ii_Cecropia_Juvenile_Hormones.txt |
Biosynthesis
As for all natural products, a successful synthetic strategy for spatol existed before any human endeavor. It is always interesting to examine Nature's strategy because an analogous approach, a biomimetic strategy (mimicing Nature), may be effective in the laboratory. Thus, the diterpenes are C20 compounds derived biogenetically from E,E,E-geranylgeranyl-PP (192) or its geometrical isomers.
These acyclic tetramers of Δ3-isopentenyl-PP (5) arise from reaction of 5 with a trimer such as E,E-farnesyl-PP (8). Subsequent intramolecular electrophilic addition of the allylic pyrophosphate to the trisubstituted C=C bonds can lead to various mono and multicyclic carbocations such as 193. Another general route to carbocationic electrophiles involves protonation of C=C bonds. A hypothetical pathway for the biosynthe- sis of spatol (196) involves protonation of a C=C bond and intramolecualr electrophilic addition of the resulting carbocation to produce a cyclobutane (195) by proton loss from 194. This hypothesis derives support from the natural occurrence of 195.14 The oxygen functionality in 196 is presumed to arise from oxidative metabolism of 195 by the marine organisms that produce this tricyclic diene and a wide variety of oxygenated metabolites with the spatane carbon skeleton.
Topological Analysis of Spatol
Ex post facto topological retrosynthetic analysis of the biosynthetic strategy reveals an important feature. The tricyclo[5.3.0.02,6]decane nucleus of the spatane diterpenes incorporates 4 common atoms (circled in 196), the four atoms of the B-ring. The biosynthetic strategy benefits from the powerful topological simplification that accrues from removing bonds between two sets of common atoms, 4-8 and 9-10. This suggests a monocyclic topological synthon 197. For this synthon, one synthetic equivalent, 198, is suggested by our biogenetic hypothesis.
Another synthetic equivalent, 199, is suggested by the possibility of an intramolecular 2π + 2π cycloaddition. An expeditious synthesis15a of the sesquiterpene b-bourbonene ( 2 0 1 ) exploits intramolecular photocycloaddition of germacrene D (200) an intermediate analogous to 199. UV evidence (λmax = 259 mm, ε = 4500 in n-hexane) indicates a significant transannular interaction between the two endocyclic C=C bonds in the sesquiterpene 200. Thus, 200 probably prefers a conformation in which the two endocyclic C=C bonds are situated parallel and face to face with each other, and the isopropyl substituent occupies the less sterically hindered equatorial configuration. Thermodynamic control of the conformation of 200 assures the proper configuration at the isopropyl bearing carbon while stereoelectronic control (syn periplanar = suprafacial addition) assures the correct cis,anti,cis configurations at the cyclobutane stereocenters. An analogous photocyclization to generate a precursor 202 for spatol is not favorable since a substituent R which is to become the side chain must occupy a more sterically encumbered axial position as in 202a rather than the more thermodynamicaly favorable conformation 202e.
A Topological and Stereochemical Strategy
A different topological disection of the cis-anti-cis-tricyclo[5.3.0.02,6]decane nucleus of β-bourbonene (201) has also been exploited for its synthesis. Thus, removing two bonds between pairs of common atoms can generate two cyclopentene precursors, 203 and 204, that could be united by a 2πs + 2πs photocycloaddition (see section 3.3). In fact, UV irradiation of 2-cyclopenten-1-one with 204 results in a photocycloaddition that is orientationally nonselective, producing a 1:1 mixture of structural isomers 205 and 206.15b However, the cycloaddition is favorably stereoselective owing to a steric approach controlled preference for cycloadddition to the face of the cyclopentene ring opposite the isopropyl substituent. This stereoselectivity detracts from the utility of a similar synthesis for spatol because the allylic diepoxide side chain in spatol (196) is cis to the cyclobutane rather than trans as is the isopropyl group in 201 or 205.
Thus, the allylic diepoxide side chain or its precursor in a cyclopentene intermediate 207 can be expected to favor the wrong stereoselectivity in a photocycloaddition with 2-cyclopenten-1-one, i.e., favoring 208 or 209 rather than the desired adduct 210 or its structural isomer 211.
One strategy to surmount this shortcoming of cyclopentene photocycloadditions for the total synthesis of spatol uses a temporary bridge to shield one face of a cyclopentene ring to preclude addition to that face.16 Thus, such a bridge can be provided by linking the hydroxyl group at the 5-position with a carboxymethyl group that also serves as a progenitor of the sidechain at position 7 as in lactone 213. Furthermore, the lactone can be derived from a latent precursor, ketone 214, by a Baeyer-Villiger oxidation. Double disconnection of 214 by a cycloelimination suggests photocycloaddition of a norbornenone 215 with cyclopent-2-en-1-one. Thus, in 214 a temporary oxoethano bridge shields the α-face of the incipient C-ring enforcing stereoselective cycloaddition of the A-ring precursor cyclopent-2-en-1-one trans to the incipient 5-hydroxyl group.
This strategy has one obvious flaw. The strained bicyclic homoallylic ketone 215 was expected to readily undergo photoinduced cleavage to diradical 216. However, masking of the carbonyl in 215 would circumvent this problem and facilitate differentiation between the two carbonyl groups in the photocycloadduct 214. Also, the configuration at the 7-position in 212 would have to be inverted to provide the requisite configuration at this stereocenter in spatol. A synthesis of 6-methylbicyclo[2.2.1]hept-5-ene-2-one (215) from vinyl acetate and methyl-1,5-cyclopentadiene is possible through a Diels-Alder reaction of these starting materials. Although the reaction produces a mixture of structural isomers, saponification followed by oxidation gives a mixture of isomeric ketones from which 215 can be isolated by distillation.
Masking a Sensitive Ketone
Masking of the carbonyl group in 215 proved unexpectedly difficult. Only a moderate yield of the ethylene ketal 217 was available by acid-catalyzed ketalization of 215 under conditions which give an excellent yield of ketal from the 6-unsubstituted analogue, bicyclo-[2.2.1]hept-5-en-2-one, owing to a competing fragmentation to 218. The proclivity of 215 toward this fragmentation undoubtedly arises from the relative stability of the tertiary carbocation 220 and the relief of ring strain attending conversion of 219 to 220.
An unusual choice for the masking group was developed during a search for a group that could be introduced under nonacidic conditions. Thus, ketone 215 is converted quantitatively into an epimeric mixture of cyanohydrin silyl ethers 221 by reaction with trimethylsilyl cyanide. While the use of an unsymmetrical masking group might seem unwise since this leads to epimeric mixtures of several intermediates, this is a small price to pay for the otherwise ideal characteristics of the cyanohydrin silyl ether masking group. Thus, photocycloaddition with cyclopent-2-en-1-one delivered two epimeric adducts 222x and 222n with high stereo (cis,anti,cis ring fusions and exo addition to the bicyclohept[2.1.1]ene) and orientational (cyclopentane carbonyl remote from the bridgehead methyl group) selectivity. Serendipitously, the major adduct 222x crystallized from the photoreaction mixture together with the dimer of cyclopentenone from which it was readily separated by trituration with hot hexane leaving behind pure dimer. Pure 222x was then obtained in 51% yield, based on 2 2 1 , by elution of the partially purified product through a column of silica gel with ethyl acetate- hexane. Column chromatography of the hexane soluble photoproduct afforded a fraction from which nearly pure minor cycloadduct 222n crystallized together with a little 222x. This mixture is suitable for Wittig olefination to produce methylidene ketone 224, vide infra. The combined isolated yield of 222x plus 222n exceeds 60%. A sample of pure 222n was obtained by HPLC. The epimeric relationship between 222x and 222n was demonstrated by production of the same diketone 223 upon hydrolysis of the cyanohydrin silyl ether masking group and also by production of the same methylidene ketone 224 upon reaction with methylenetriphenylphosphorane followed by hydrolysis of the cyanohydrin silyl ether. The conversion of 222 into 224 was performed as a one-pot procedure affording pure 224 in 89% overall yield. The utility of the cyanohydrin silyl ether masking group in the above transformations is noteworthy. It is introduced under mild neutral reaction conditions. It is sufficiently robust to survive UV irradiation, chromatography on silica gel, and Wittig olefination; but it is readily converted to a carbonyl group by the aqueous base generated upon addition of water to the Wittig reaction mixture.
Amplifying SAC
Catalytic hydrogenation of 224 favored the required epimer 228 over the useless byproduct 229 by 10:1 owing to steric approach control by the methyl group in 224 that shields the α-face of the A-ring. However, separation of 228 from the mixture could not be achieved by any method except fractional crystallization, and this only allowed isolation of the desired epimer in only fair yield. To circumvent this separation problem, 224 was isomerized to the endocyclic alkene 227 by \(\ce{SO2}\). This clean, quantitative isomerization presumably involves ene addition of \(\ce{SO2}\) to 224 producing 225. Subsequent [1.3] sigmatropic rearrangement of sulfur affords 226 that undergoes retro ene fragmentation delivering 227. Catalytic hydrogenation of 227 delivers 228 cleanly and quantitatively. Apparently the closer proximity of the endocyclic C=C bond to the methyl group in 227 than the exocyclic C=C to the methyl group in 224 results in greater steric hindrance to α hydrogen delivery in 227 than in 224.
Resolution
Efficient, virtually quantitative resolution of ketone 227 was readily achieved by flash chromatography and crystallization of the 1,2-adduct with chiral lithiosulfoximine 230. Retro ene elimination of the less soluble dextrorotatory diastereomer (+)-232 delivered ketone (+)-227 that was correlated with (+)-spatol by conversion to a degradation product from natural spatol (vide infra). The sulfoximine (+)-(S)-231 was recovered in 96% yield.
A Temporary Bridge During Hydride Delivery
Catalytic hydrogenation of (+)-227 provided ketone (+)-228. Introduction of oxygen at position 5, cleavage of the temporary bridge, and inversion of configuration at the 7-position were then addressed. Thus, Baeyer-Villiger oxidation to give lactone (+)-233, saponification, and methylation of the resulting acid provided alcohol (+)-234. Masking of the 5-hydroxyl provided (-)-235 that was carboxylated to give malonic ester (-)-236. Epimerization at the 7-position was initiated by selenenylation followed by oxidative deselenenylation of the resulting 237 to deliver alkylidene malonic ester 238. Reduction of 238 with \(\ce{NaBH4}\) followed by removal of the MEM protecting group with \(\ce{TiCl4}\) afforded a 2:1 mixture respectively of the cis hydroxy malonic ester 240 and its C-7 epimer, the desired trans hydroxy malonic ester 241. This disappointing result suggested that the 2-methoxyethoxymethoxy (OMEM) substituent at the 5-position sterically hinders hydride delivery to the α- face of the C=C bond in 238.
A remote hydroxyl group was found to foster pseudointramolecular syn hydride delivery via an alkoxyborohydride intermediate 242. Thus, treatment of the derived hydroxy alkylidene malonate (+)-239 with \(\ce{NaBH4}\) delivered the desired trans hydroxy malonic ester (-)-241 completely stereoselectively. The overall yield was 9% from C-ring precursor 215 in 21 steps including the resolution.
Enantiospecific Synthesis with a Chiral Auxillary
A different synthesis18 of a homochiral tricyclodecylmalonic ester intermediate 245 (an analogue of 241) was designed with a focus on exploiting butenolide 243 as a chiral auxiliary to establish the correct absolute configuration during generation of the B-ring by a 2π + 2π photocycloaddition with A-ring precursor 244. Homochiral butenolide 243 is readily available from L-glutamic acid. An allylic oxygen substituent in 244 provides a point of attachment for the malonic ester side chain and activation for the introducing oxygen at the 5-position.
In a retrosynthetic format, the strategy envisions attachment of the malonic ester last by a stereospecific SN2 alkylation with 246. Since the chiral auxiliary 243 does not provide the cyclopentane ring required for the A-ring of 245, this ring will have to be generated after the photocycloaddition of 250.
The A-ring might be created by an intramolecular aldol condensation of a bis methylketone precursor 248. This step is potentially flawed because an undesireable alternative aldol condensation is possible. However, an excellent precedent is provided by a similar step in a total synthesis of the sesquiterpene α- bourbonene (F). Thus, intramolecular aldol condensation of A delivers cyclopentenone E and none of the isomeric cyclopentenone C. Apparently, cyclization to the aldol condensation product B is disfavored by steric hinderance by the angular methyl substituent in the alternative aldol condensation product D. Steric approach control (SAC) should favor β-delivery of hydrogen during reduction of 247 to give the requisite configuration at position 1 in 246. The proper orientation during generation of the B-ring can be assured by a temporary bridge, an ester, between 243 and the C-ring precursor 244.
Intramolecular photocycloaddition of the ester 250 from the chiral auxiliary 243 delivered cyclobutane 251. Addition of a methyl group, the one carbon needed to complete the A-ring required 4-10 steps depending on the configuration of the C-7 substituent in 251. Reduction of the remaining ester in 252 then provided the methyl group at position 4 in 253 which had been functionalized solely to allow construction of the temporary bridge in 250. Functional group manipulation then provided dione 254 which underwent completely selective aldol condensation affording 255. Stereoselective hydrogenation of 255 created the stereocenter at position 1 and removed the benzyl protecting group. Wolff-Kishner reduction of the resulting saturated ketone delivered 256. Introduction of the 5-hydroxyl and 7-malonic ester substituents then required oxidation to 257, reduction and Mitsunobu inversion to give 258, stereoselective epoxidation followed by hydride reduction, protection, and deprotection to deliver 259 and nucleophilic substitution which provided malonic ester 245 in 0.6% yield overall from 243 in 29-35 steps.
Convergent and Linear Strategies
The overall yield of homochiral malonic ester (-)-241 from racemic (±)-215 in the first synthesis was 9%, more than an order of magnitude higher than the 0.6% overall yield of homochiral malonic ester 245 from homochiral 243 in the second synthesis. The success of the first synthesis, that relies upon resolution to introduce asymmetry, is especially noteworthy because resolution is inherently inefficient -- it provides at best as 50% yield of the correct enantiomer. Two factors diminish the penalty for using resolution. First, the resolution is performed very early in the first synthesis and, therefore, the effort wasted by discarding half of the racemic product is minimized. Second, Johnson’s sulfoximine method is spectacularly effective. Furthermore, the advantages of the clever plan to exploit the readily available chiral auxiliary 243 to introduce asymmetry into the second synthesis cannot overcome the penalty arising from the absence of a methyl group at position 4 or a hydroxyl group at position 5, and the lack of an A-ring in the photocycloadduct 251 from 243. The first synthesis is more convergent than the second. Thus, two large fragments are constructed that contain most or all of the skeletal atoms and functionality of the target and these fragments are then united. Such an approach has several advantages over a linear synthesis, that is one in which the molecule is constructed by sequentially uniting many small fragments or introducing functionality after skeletal construction is complete. A convergent synthesis is more efficient as measured by overall yield. If the average yield of an n-step synthesis is Ψ%, then the overall yield will be 100(Ψ/100)n%. A 21-step linear synthesis with an average 95% yield will have an overall 34% yield, or an overall 11% with an average 90% yield, or an overall 0.9% with an average 80% yield. In contrast for a convergent synthesis that combines two intermediates each prepared by 10-step syntheses (i.e. a total of 21 steps), the overall yield will be 56% with an average 95% yield, or an overall 31% with an average 90% yield, or an overall 9% with an average 80% yield. In effect the convergent synthesis is only 11 steps. The two abovementioned syntheses are a case in point. The average yield per step, 84-87%, in the second synthesis was almost as high as the 89% average per step yield in the first synthesis. The 15 fold lower overall yield for the second synthesis is almost entirely the consequence of its greater length, 29-35 steps versus 21 steps.
Stereocontrolled Sidechain Construction
Two strategic challenges must be met for completion of a total synthesis of spatol (196). First, the unique allylic vicinal diepoxide in 196 was presumed to be highly electrophilic because epoxide ring opening by chloride, a weak nucleophile, accompanies esterification upon treatment of 196 with p-bromobenzoyl chloride and pyridine. Second, the three stereocenters of the flexible sidechain must be assembled with the correct configurations relative to those in the rigid tricyclic nucleus.
The malonic ester group in the intermediates (-)-241 and 245 could provide a three-carbon allylic precursor of the spatol side chain. Koga converted 245 into allylic alcohol 260 by a modified Marshall reduction.
However, attempted one-step conversion of (-)-241 into the allylic alcohol 263 by the Marshall reduction, i.e. LAH reduction of the sodium enolate, failed completely. Therefore, this transformation was accomplished by monosaponification to 261 and decarboxylative aldol condensation with formaldehyde to provide acrylic ester (+)-262. Hydride reduction then delivered allylic alcohol (+)-263 that was selectively oxidized with \(\ce{MnO2}\) to the aldehyde (+)-264. To correlate this synthetic intermediate with the natural product, (+)-264 was acetylated. The totally synthetic acetate showed [α]D22 +25.1° that compares well with the naturally derived acetate which showed [α]D22 +26.5°.1
An Absolute Asymmetric Strategy
Disconnection of both a nucleophilic oxygen and an electrophilic carbon from carbon 15 of spatol suggests a precursor 266 in which the sulfonium functional group provides the requisite biphilic reactivity at carbon 15.19 The correct relative configurations for the stereocenters in the tricyclic nucleus and at position 17 are assured in an absolute asymmetric synthesis by using building blocks 266 and 267 with the correct absolute configurations. Although very short, this convergent strategy provides no control over the configurations at positions 15 and 16.
Ylide 266 was prepared from allyic alcohol 260 through sulfonium salt 268. Reaction of ylide 266 with aldehyde 267 produced spatol in only 3% yield together with the isomeric allylic cis diepoxide 270 (1.5%) and a mixture of trans diepoxides 271 (8%). Moreover, 266 exists in equilibrium with an alternative ylide 269 that underwent [2.3] sigmatropic rearrangement producing the homoallylic sulfide 272 (35%) as the major product of the reaction.
A Stereospecific Epoxydiol Rearrangement Strategy
The last step in the reaction of ylide 266 with aldehyde 264 involves vicinal alkylation of an alkoxide during cyclization of 273. The reaction of aldehyde 277 with ylide 276 is a related strategy. The epoxy aldehyde 277 might be available from aldehyde (+)-264 by Corey-Fuchs alkynylation to give 278, homologation with formaldehyde, Lindlar reduction of the resulting propargyl alcohol, asymmetric epoxidation of the derived allylic alcohol, and Swern oxidation of the resulting epoxy alcohol. Alternatively, 278 might be homologated to 275. Then, after assymmetric reduction of this propargyl ketone, Lindlar reduction, and VO(acac)2-catalyzed epoxidation, heterocyclization of the resulting 274 might deliver (+)-spatol. However, these strategies are too long, and ring closures of intermediates such as 274 may be derailed considering the potential, inter alia, for E-1 elimination and transepoxidation. Thus, intramolecular attack of the alkoxide in 280 at the 2° 16-position to give 281 rather that at the 3° 18-position to give spatol might even be favored. Such transepoxidation reactions (Payne rearrangements) are well known. However, the rearrangement to 281 is reversible while heterocyclization of 280 would be irreversible. Nevertheless, E1 elimination to give 279 seemed a reasonable concern.
An alternative strategy is possible involving an epoxy alkoxide similar to 281 but with the positions of the nucleofuge and alkoxide exchanged. Thus, Payne rearrangement should produce 283 but the trans stereochemistry of the epoxide in 282 should virtually preclude direct attack of the alkoxide at the 15-position to produce a tetrahydrofuran. The allylic electrophile at position 15 in 283 should be particularly effective in alkylating the neighboring alkoxide producing an allylic diepoxide 284.
Furthermore, an efficient strategy for assembling an epoxydiol precursor 285 for 282 seemed feasible. Thus, 285 should be available by regioselective epoxidation of 286 which should, in turn, could be prepared by the union of a C15 electrophile (+)-264 with a C5 nucleophile 287.
In model studies, a method was sought to produce the allylic diepoxide array of the spatol side chain from appropriately activated derivatives of epoxydiol 285. Initial results were disappointing. Thus, activation of erythro-288 as a mesylate, erythro-289, followed by treatment with solid \(\ce{K2CO3}\) in boiling isopropanol delivered threo-290 by intermolecular SN2 displacement rather than the desired vicinal diepoxide by Payne rearrangement followed by heterocyclization. Since the tertiary hydroxyl group in erythro-289 appeared not to be sufficiently nucleophilic to displace the epoxy leaving group, conditions were sought that would generate an alkoxide from the tertiary hydroxyl. Treatment with t-BuOK in t-BuOH promoted a clean, stereospecific rearrangement and heterocyclization to deliver the diepoxide trans,erythro-292. A route from the erythro-288 to an activated derivative of the threo epoxy alcohol requires activation with concomitant inversion of configuration. This was accomplished by the Still modification of the Mitsunobu reaction. Thus, reatment of erythro-288 with \(\ce{Zn(OTs)2}\), diethyl azodicarboxylate, and triphenylphosphine, gave tosylate threo-291 that, upon treatment with t-BuOK in DMF, afforded the allylic diepoxide cis,erythro-292 in 82% yield.
The substitution reaction of mesylate erythro-289 with isopropanol to give threo-290 suggested that a similar substitution with tetrabutylammonium hydroxide might provide a route to the inverted alcohol. Instead, however, a high yield of diepoxide trans,erythro-292 was obtained. The unexpected stability of this allylic diepoxide toward hydroxide is especially interesting in view of the epoxide-cleaving substitution reaction of spatol with the less nucleophilic chloride anion that gives a chlorohydrin (vide supra). Apparently, the latter reaction is an acid-catalyzed epoxide opening induced by pyridinium hydrochloride, a byproduct of the acylation with p-bromobenzoyl chloride in the presence of pyridine.
In a first attempt to implement the plan, addition of vinyllithium 287 to aldehyde (+)-264 provided a 1:6 mixture of triols 295 and 296 respectively after desilylation of the intermediate monosilyl ethers 293 and 294. To control the regioselectivity of epoxidation, the triol 296 was selectively disilylated. Vanadium-catalyzed epoxidation of 297 was then directed to the 15,16-C=C bond by the remaining allylic hydroxyl. Since the major epoxide product was the erythro derivative 298e, selective activation of the less hindered 15-hydroxyl in the corresponding triol 298e was performed with inversion of configuration. However, treatment with base produced an allylic diepoxide 300 with a cis,anti,cis- tricyclo[5.3,0,02,5]decane nucleus. Thus, Wagner-Meerwein rearrangement of the cis,anti,cis-tricyclo[5,3,0,02,6]decane nucleus of 298e to give 300, apparently owing to an unintended activation of the 5-hydroxyl that accompanied the desired activation of the hydroxyl at the 15-position.
These results suggested that derivatives of epoxy triols 299e and 299t in which the hydroxyl at position 5 is masked were needed for generation of the spatol side chain without accompanying rearrangement of the tricyclic nucleus. The lability of the allylic diepoxide array in spatol (196) under acidic conditions limited the choice of derivatives to those with masking groups that would be removable under neutral or basic reaction conditions. The further requirement for stability towards a vinyllithium reactant and the presence of unsaturation in the synthetic target recommended p-methoxybenzyl (MBn) ether derivatives. The MBn masking group is removable under mild conditions by oxidative cleavage with DDQ. Therefore, the MBn derivatives erythro-308b and threo-308b of 298e and 298t were prepared from diol (+)-263.
The assignment of an S absolute configuration at the 15-position to the major epimer (-)-305b was based on correlation with natural (+)-spatol (vide infra). Epoxidation of the derived silyl ether (-)-307 provided a 2:7 mixture of threo and erythro epoxides 308b. The major isomer, erythro-308b, was converted into a cis, erythro diepoxide (-)-310 by conversion to a threo tosylate with inverted configuration at the 15-position followed by base-induced Payne rearrangement, heterocyclization, and finally by deprotection of the 5-hydroxyl. That (-)-310 was not spatol (196) was evident from its optical activity, [α]D = -10.0° in contrast with [α]D = +45.6° reported for the natural product. Small chemical shift differences, e.g. vinyl 1H NMR resonances at δ5.14 and 5.09, confirmed that (-)-310 is epimeric at positions 15, 16, and 17 with (+)-spatol which exhibits vinyl resonances at δ5.13 and 5.02.
The minor isomer, threo-308b, was converted into (+)-spatol (196) by monomesylation followed by base-induced Payne rearrangement, heterocyclization, and deprotection of the 5-hydroxyl. Each resonance in the 1H NMR spectrum of synthetic (+)-spatol coincided within 0.01 ppm with a spectrum of an authentic sample of natural spatol.
An Absolute Asymmetric Stereoconvergent Strategy
Both of the aforementioned strategies for the spatol allylic diepoxide suffer from inadequate stereocontrol. Thus, while the correct absolute configuration at position 17 in 273 is assured by using the correct enantiomer of 267, generation of the stereocenters at positions 15 and 16 in 273 is not selective. Similarly, although either epimer at position 15 in 308 can provide an activated derivative with the correct configuration, i. e. by activation with retention or inversion of configuration, generation of the stereocenters at positions 16 and 17 in 308 is not favorably selective.
Since either epimer of epoxydiol 312 can be converted stereospecifically into spatol, the synthesis is stereoconvergent, and stereocontrol at the 15-position is unnecessary for an efficient total synthesis.. The correct stereochemistry at positions 16 and 17 could be assured by an absolute asymmetric strategy that combines the homochiral C15 aldehyde (+)-304 and a homochiral C5 α-epoxy nucleophile 313.
Because α-silyl epoxides are readily hydrodesilylated by moist fluoride with complete retention of configuration, a possible synthetic equivalent of synthon 313 is the silyl-stabilized α-lithioepoxide 314. However, a serious flaw could sabotage this strategy. Thus, although α-lithioepoxides are generally configurationally stable, the α-lithioepoxide 316, a close analogue of 314, exhibits an unusual configurational instability rearranging completely to 317 owing, no doubt to steric strain that is relieved upon trans-cis isomerization. A similar isomerization of 314 to 315 would derail the synthesis. This pitfall was circumvented by a temporary bridge between the C-silyl substituent and neighboring oxygen in 321. Thus, intramolecular O-silylation precludes isomerization of the carbanion 321 obtained by metallation of 320. Racemic 321 was prepared through epoxidation of a vinylsilane 319 that was generated by a novel hydrogenation-dehydrogenative-heterocyclization of 318.
In a model study, reaction of α-lithioepoxide 321 with 2-(i-propyl)acrolein delivered an epimeric mixture of adducts 322 favoring the erythro diastereomer by 7:3. Desilylation of erythro-322 gave epoxydiol erythro-323. Thus, the racemic intermediate 321 provides a two-step synthesis of epoxydiol precursors of the spatol allylic diepoxide. However, only conjunction of aldehyde (+)-304 with the correct enantiomer of 321 will provide the correct absolute configurations at positions 16 and 17 in 312 that are required to accomplish an efficient construction of natural spatol (196). A route to optically pure epoxide 321 must yet be found. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/04%3A_Terpenes/4.06%3A_Biosynthesis_and_Total_Syntheses_of_Diterpenes-_Spatol.txt |
Biosynthesis of Lanosterol
Lanosterol (324) is a member of steroid family of natural products. The isoprenoid origin of this triterpene, biogenetically a C30 hexamer of isopentenyl pyrophosphate, is not entirely evident from its structure. Thus, while two isoprene units are discernable in the right hand portion of 324 and two in the leftand portion, the ten carbon atoms in the central region of the molecule do not show isoprenoid connectivity. If, however, a methyl group were appended at position 8 or 9 of the four carbon 7,8,9,11-chain an isoprene unit would be formed. Since generation of the multicyclic carbon networks of terpenes occurs by electrophile-induced polyene cyclizations, the 8,9-C=C bond in 324 might arise by elimination of a proton from a carbocation precursor. A carbocation at the 8 position could have been generated by 1,2-migration of a methyl group from position 8 to a carbocation at position 14. Two more isoprene units are discernable in the central portion of the putative precursor 325. Topological analysis of 325 reveals six common atoms. Two disconnections between common atoms and two between a common and a noncommon atom greatly simplifies the structure suggesting an acyclic triterpene precursor 326 that might arrise by the head to head union of a diterpene pyrophosphate 327 with a monoterpene pyrophosphate 328. The strategy inferred above is close to that involved in the biosynthesis of lanosterol.
The actual biosynthetic strategy does indeed involve a head to head union of terpenoid pyrophosphates. However, a more efficient construction is achieved through a symmetrical acyclic triterpene intermediate, squalene (333), formed by the union of two molecules of a sesquiterpene precursor, E,E-farnesyl pyrophosphate (8). Since both carbons to be joined are electrophilic, polar formation of the central C-C bond of squalene cannot be direct. Rather, only the electrophilic activation provided by the functional group of one molecule of farnesyl-OPP is utilized to form a C-C bond with the nucleophilic C=C bond of a second molecule of farnesyl-OPP. Proton loss from the putative intermediate 3° carbocation 329 (or, possibly, the corresponding adduct with a nucleophilic moiety of the enzyme that catalyzes the process) produces a cyclopropylcarbinyl intermediate, presqualene pyrophosphate (330), that can be isolated from biosyntheses conducted in vitro in the absence of NADPH. In the presence of NADPH, 330 undergoes a reductive rearrangement formally involving a rearranged cyclopropyl 3° carbinyl cationic intermediate 331 and an allylic cation 332 that is captured by hydride to deliver squalene (333). The σ-bond in the cyclopropyl- carbinyl pyrophosphate 330 serves as nucleophile that displaces a pyrophosphate nucleofuge. The σ-bond electrons in cyclopropanes are especially accessible.
Asymmetric epoxidation converts the prochiral acyclic triterpene precursor 333 into a homochiral epoxide, squalene oxide (334). Generation of the four fused rings of lanosterol is then initiated by intramolecular alkylation of a C=C bond by a tertiary electrophile provided by protonation of the epoxide. A total of four consecutive alkylations, known as a polyene cyclization, deliver the putative intermediate 335 that rearranges by a series of two 1,2-hydride and two 1,2-methyl shifts to give lanosterol (324) after proton loss from the 9 position.
Especially interesting are the stereochemical details of the polyene cyclization and subsequent rearrangement of 335 to deliver 324. The polyene cyclization involves stereospecific anti-periplanar addition across three C=C bonds in 334 (see below). The folded conformation of 334, required for cyclization to 335, is probably imposed by the enzyme involved since appreciable steric congestion is present in both 334 and the intermediate 335. Relief of steric strain provides a large driving force for the rearrangement of 335 to 324 that involves stereospecific inversion of configuration at each stereocenter during 1,2-hydrogen or methyl shifts. Thus, each 1,2-hydride or 1,2-methyl shift occurs to the backside of the orbital connected to the departing nucleofuge in what can be viewed as a series of nucleophilic substitution reactions – where σ-bonding electron pairs serve as the nucleophiles. Instead of proton loss to give 324, the rearrangement of 334 in some higher plants and algae ends with proton migration from the 9 to the 8 position and proton loss from the methyl group at position 10 forming a cyclopropane ring in cycloarteneol (336). This mechanism for the generation of a cyclopropane is analogous to that for the production of presqualene pyrophosphate (330) from 329.
Nor and Seco Steroids. Although lanosterol (324) and cycloarteneol (336) are irregular triterpenes, i.e. their carbon skeletons are not composed of intact isoprene units, these triterpenes possesses the expected thirty carbons. Many steroids, that are derived biologically from lanosterol, contain fewer than thirty carbons and are referred to as nor triterpenes. Thus, for example, formation of cholesterol (337) from lanosterol (324) occurs by oxidative conversion of three methyl groups into formyl or carboxyl substituents that are lost as formate or cabon dioxide to give a tris nor triterpene after saturation of the side-chain C=C bond and migration of the Δ8,9 C=C bond to the Δ5,6 position. The biosynthesis of some steroids from cholesterol, such as the insect molting hormone α-ecdysone (338), simply involves oxidative introduction of functionality and C=C bond migrations. The loss of six carbons from the sidechain of cholesterol (337) leads to pregnenolone (339) the biosynthetic precursor of the female reproductive hormone progesterone (340) and the adrenocortical hormones such as cortisone (341) that is generated by oxidative functionalization of 340. The biosynthesis of the cardiac steroids such as digitoxigenin (342), that occurs in plants, creates the butenolide moiety by addition of a two carbon nucleophile from acetylCoA to the electrophilic side-chain carbonyl of 340.
Addition of a carbon atom as an electrophilic methyl group from S-adenosylmethionine (SAM) occurs during the biosynthesis of ergosterol (343). A pericyclic rearrangement of 343 to 344 followed by a thermally allowed antarafacial [1.7]-sigmatropic rearrangement of hydrogen from the methyl at position 10 to the 9 position leads to the generation of vitamin D2 (345). Sigmatropic shifts of hydrogen necessarily involve positive overlap, i.e., with the same phase, of the hydrogen half-occupied σ-orbital with the ends of the highest occupied pentadienyl π-orbital Both 344 and 345 are seco steroids, i.e. their carbon skeletons lack one of the ring C-C bonds of the tetracyclic steroid skeleton.
The entire cholesterol sidechain is removed during biosynthesis of the male sex hormones androsterone (346) and testosterone (347) and biosynthesis of the female reproductive hormone estrone (348) even requires loss of the angular methyl substituent from position 10. Noteworthy is the fact that the biosynthetic strategy for 348 is exceptionally circuitous and lengthy considering the structural simplicity (only four centers of chirality) of this target. The justification, of course, is the availability of the starting material, the ubiquitous biological steroid precursor, cholesterol. Furthermore, Nature has at its disposal a vast armementarium of selective reagents (enzymes) to achieve surgically clean removal of unwanted carbon atoms or groups by activation of C-H bonds, even those that are remote from functionality.
Total Syntheses of Estrone. All circuits between the oxygen functionality in the A and D rings of estrone are consonant except those involving carbons 15 and 16. Therefore, activating functionality is essential to allow polar C-C bond formation between the D ring carbonyl carbon and carbon 16. Disconnection of this bond in 349 suggests a diester 350 which still has functional dissonance, e.g. between the two carboxyl groups. All dissonance is removed by shortening the propionic to an acetic sidechain as in 351. Polar disconnection of an ester stabilized nucleophile sugggests a β-keto ester 352 and further polar disconnections then suggest 353 and a methyl electrophile, as precursors. Finally, polar disconnection of 353 suggests a monocyclic aromatic precursor 354 with an entirely consonant side chain in which the added carbonyl at the incipient 9 position can facilitate further polar disconnections to 355, an ester stabilized nucleophile, and a glutaryl electrophile. The foregoing retrosynthetic analysis provides a linear strategy for the synthesis of estrone that starts with an intact A ring and then builds the B, C, and D-rings in succession by polar reactions.
The first total synthesis of estrone, was completed21 in 1948. It assembled a methyl ether 357, related to 354, from the bromoethylanisole (356) by alkylation and then acylation of diethyl malonate. Cyclialkylation of the resulting ketotriester 357 makes use of the polar activation provided by target related functionality at position 3 that is conjugated through the aromatic ring with position 10. Hydrolysis and decarboxylative elimination then delivered alkene 35822 that upon hydrogenation, O-methylation, Dieckman cyclization, and C-methylation delivered an epimeric mixture from which the required ketoester 360 was isolated by fractional crystallization. Once again target related functionality, here the incipient carbonyl at position 17, facilitates polar bond formation. It is also noteworthy that target unrelated functionality, a carbonyl group on the carbon that will become position 9, serves as a lynchpin for connecting major segments in the 356 to 357 conversion and for generating the last connection for the B-ring in the 357 to 358 conversion. Reformatsky condensation followed by dehydration and hydrogenation provided diester 362 and an epimer from which it was separated by fractional crystallization. The lack of stereocontrol in this synthesis of 362 necessitated tedious isolations from isomer mixtures and resulted in a low overall yield.
Chain elongation of the consonant 1,5-diester 362 generated a dissonant 1,6-diester precursor 365 of the dissonant D-ring cyclopentanone in 367. The creation of a dissonant product by polar reactions requires a dissonant reactant. In the present case this role is played by diazomethane that is dissonant by virtue of the presence of a biphilic activating group. Thus, the diazonium group stabilizes an α carbanion providing nucleophilicity for C-C bond formation with an acyl chloride and subsequently serves as a nucleofuge promoting migration of a nucleophilic alkyl group from the carbonyl carbon in 363 to the neighboring carbon in 364.
An alternative construction of the dissonant D-ring cyclopentanone in 367 from the consonant 1,5-diester 365 generates a C-C bond between the two electrophilic ester carbons by a nonpolar process, reductive coupling.23 Thus, an acyloin condensation provides 368 from which the unneeded carbonyl is removed by reductive desulfurization of the derived thioacetal 369.
Topological Analysis of Estrone. The topological strategy for a synthesis can be summarized in a diagram that shows the starting material with bold outline and bonds formed in completing the skeleton with dashed lines. The two previous estrone syntheses illustrate strategies featuring late construction of the dissonant D-ring as in diagram A which allows the sequence of C-C connections employed. Greater efficiency can be accomplished by incorporation of the dissonant D-ring as a preformed unit as in B. Almost as efficient is the use of a dissonant precursor from which the D-ring is readily generated immediately after assembling an intermediate containing all the carbon atoms required for the skeleton as in C. A highly convergent and, therefore, exceptionally short synthesis is achievable by joining a preformed AB-ring unit with a D-ring unit as in D. The strategies summarized by A-D use aromatic starting materials for the aromatic moiety in the synthetic target. This tactic benefits from the relative stability of aromatic systems by avoiding potential yield-decreasing side reactions that might occur during manipulation of nonaromatic intermediates containing more reactive functionality. Interestingly, some efficient modern syntheses, summarized by E and F, generate the A-ring after assembly of a nonaromatic precursor containing all the skeletal carbons of the final target. Further discussion of the strategies B-F is deferred to a full consideration of each synthesis.
A strategy summarized topologically by B introduces nontarget related functionality, carbonyl groups in 370 on the carbons that will become positions 9 and 14, to activate the polar union of two pairs of common atoms and polar union of a symmetrical D-ring nucleophile with 371. Dislocation of this enone to a saturated ketone 372 with a nucleofuge (Nu) β to the carbonyl and the latter to an alkyne 373, reveals the possibility of exploiting a terminal alkyne nucleophile to assemble 373 from an arylpropyl electrophile 374.
The use of a preformed D-ring in the dissonant building block 380 makes the synthesis24 more convergent. Greater efficiency is also provided by the consecutive formation of two connections, between the 8 and 14 and then between the 9 and 10 positions, in a single reaction that produces 382 from 381. Noteworthy is the regioselectivity of the 377 to 378 conversion. Clearly the diethylamino group provides a regiocontrolling influence, perhaps owing to a coordinative interaction with the \(\ce{Hg^2+}\) catalyst or to inductive destabilization of the development of a vinyl cation β to the electronegative nitrogen. Generation of the requisite stereochemical relationships is achieved by SAC during the delivery of hydrogen to 382 and TC during protonation of the preferred conformations of anionic intermediates in the reduction of 383.
Another more recent synthesis,25 summarized topologically by C , is closely related to the B topological approach discussed above. Thus, the topology and polar reactivity involved in the 381 to 382 conversion is the same as that in the 387 to 388 conversion. However, a preformed D-ring is not exploited. Rather, this moiety is present in latent form in 386 that contains a dissonant circuit between masked 1,4-dicarbonyl groups. The dissonance derives from a latent 1,4-dicarbonyl array that protected by the aegis of aromaticity in the furan ring of 384 that is readily prepared by lithiation and then alkylation of α-methylfuran.
Stereoselective generation of the trans disubstituted C=C bond in 387 is accomplished by the Schlosser modification of the Wittig olefination. Thus, the β-oxidophosphonium intermediate 390, that is the major product from the addition of ylide 385 to an aldehyde, is converted to an epimeric β-oxidophosphonium intermediate 393 by protonation of a β-oxido ylide 392. This carbanion is thermodynamically favored over the epimeric carbanion 391. Subsequent syn elimination (perhaps through 2πs + 2πa cyclo- elimination of \(\ce{Ph3P=O}\) from a betaine intermediate) delivers the trans alkene stereospecifically.
Although 387 has no polar functionality at position 9, the 9-position participates as electrophile and the 8 position as nucleophile during polar cyclization to 388 in analogy with the 381 to 382 bis annelation. The stereoselectivity of this cyclization derives from a stereoelectronic preference for anti periplanar addition to the C=C bond in 387 and steric approach control during bond formation between positions 8 and 14. Stereoselective introduction of the angular methyl is accomplished by generation of the α-epoxide 389. Here SAC favors β attack by \(\ce{Cl^+}\) on the C=C bond. This is followed by stereospecific configurational inversion during intramolecular SN2 displacement. Finally, 1,2-migration of methyl during a pinacol rearrangement generates the required β-methyl configuration and a trans CD ring junction.
The most efficient strategy for total synthesis of estrone is also the most convergent, joining a preformed AB-ring unit 394 with a D-ring unit 380 as in D. This, the Velluz synthesis26, provides an industrial source of estrone that is more economical than biosynthesis. The polar union of 395 with 380 epitomizes the efficient use of functionality to facilitate skeletal construction. Interestingly, 380 is a vinylogous carboxylic acid sufficiently acidic to protonate 395. The resulting carbocation 396 is stabilized by target related functionality at position 3 while nucleophilicity at position 13 is stabilized by the target related oxygen functionality at position 17 in the enolate 397. Target related functionality at position 3 also facilitates generation of the 8-14 C-C bond during acid catalyzed cyclization of 400 to 382. A stereoselective route from 382 to estrone methyl ether (367) was described above.
An Enantioselective Synthesis. The foregoing strategies all produce racemic estrone that must be resolved to provide the natural enantiomer. An enantioselective synthesis of natural (+)-estrone was reported in 1975.27 The key step converts prochiral trione 404 into enantiomerically enriched dione 405 by an enantioselective aldol condensation. Except for the use of a pyridine ring as a nonnucleophilic latent 1,5-dicarbonyl precursor of the estrone A ring, the topological and polar strategy is identical with that described above involving Michael condensation of 379 with 380. In the present synthesis, all the carbons required for the final target are united in a Michael condensation of 403 with 380. After the crucial enantioselective generation of ring C, the required trans CD ring junction is established by steric approach control during catalytic hydrogenation of an unsaturated alcohol derived from 405 by selective hydride reduction of the more electrophilic unconjugated carbonyl. Completion of the last two skeletal connections required unmasking of a latent 1,5-dicarbonyl array by Birch reduction of 406 followed by base catalysed hydrolysis of the resulting 1,4-dihydropyridine intermediate and aldol condensation. Hydrolysis of the ketal at position 9 then allows equilibration of the C8 stereocenter, and generation of the final skeletal connection by another aldol condensation. Aromatization of 408 delivers crude estrone. A single recrystallization gave optically pure (+)-estrone (13% from 380) as well as racemic estrone (3% from 380) from the mother liquor.
Estrone Synthesis by Cycloadditions. Since the B ring of estrone (348) contains one C=C bond in a six-membered ring, a thermal cycloaddition synthesis is possible. An intramolecuar Diels-Alder reaction could provide estrone from 409. Furthermore, another pericyclic rearrangemant can be employed for the synthesis of 409. Thus, the 1,3-diene array in 409 can be generated by electrocyclic rearrangement of a cyclobutene 410.
One particularly striking application28 of this strategy29 generates a benzocyclobutene intermediate 416 in an intramolecular cobalt(I)-catalyzed alkyne cyclotrimerization involving 1,5-diyne 412 with a synthetic equivalent 413 of the ketene enol 411. The trimerization is actually a stepwise process involving oxidative addition to cobalt(I) to generate a cobalt(III) cyclopentadiene 414. Diels Alder cycloaddition of 413 with 414 then produces 415 from which the cobalt(I) catalyst is regenerated by a reductive elimination that delivers 416.
The correct relative configurations at positions 13 and 14 were established by steric approach control during alkylation of an enolate that was produced regiospecifically by 1,4-addition to 417 and regenerated from 418. Cycloaddition of 419 with bis(trimethylsilyl)acetylene in the presence of cyclopentadienylcobalt dicarbonyl generated an intermediate benzocyclobutene 420. Heat promoted generation of the derived ortho xylelene followed by intramolecular cycloaddition afforded 421 in 71% yield overall from 419. The stereoselective generation of the correct configurations at positions 8 and 9 arises from a preference for an exo transition state in the Diels-Alder cycloaddition. Steric congestion destabilizes the alternative endo transition state that would otherwise be favored by secondary orbital overlap. Mono protodesilylation of 421 removed the 2-silyl group with a 9:1 preference over the 3-silyl group. Oxidative desilylation generated the 3-hydroxyl and delivered estrone in 24% overall yield from 2-methyl-2-cyclopenten-1-one (417) in seven steps.
Total Synthesis of Cortisone. The strategy for the first total synthesis30 of cortisone (341) focused on the problem of assembling a trans fusion between the C and D rings. The challenge was to overcome the thermodynamic preference for a cis fusion between a five and a six-membered ring. Since a trans fusion is favored thermodynamically between two six-membered rings, an attractive solution seemed to be to create an intermediate with a six-membered D ring and to contract the six to a five-membered ring. With this goal in mind, an aldehyde group at position 17 in a cyclopentene precursor 422 ought to provide a starting point for building the sidechain found at this position in cortsone. Polar disconnection between carbons 16 and 17 of the D ring suggests a dialdehyde precursor 423 that would provide 422 by intramolecular aldol condensation. Connection of the two reactive aldehyde groups in 423 suggests a latent dialdehyde precursor 424 containing a six-membered trans-fused D ring.
Disconnection of two bonds in the A ring at the ring fusion results in a major topological simplification. The ring fusion carbons in the A ring of 424 are common atoms, and disconnection of these two bonds, each between a common and a noncommon atom, completely removes the A ring. All circuits between the two carbonyl groups in 424 are dissonant. Therefore, both carbonyls cannot be used simultaneously to provide polar activation for generating C-C bonds. Rather, additional functionality, e.g. a carbonyl group at position 5, must be added to a precursor 425 to provide electrophilic activation at position 5 and nucleophilic activation at position 10 that can be exploited in conjunction with target related functionality at position 3 to assemble the A-ring. Such a polar cyclohexenone annelation process, the "Robinson annelation", had recently been devised in which an alkyl vinyl ketone serves first as an electrophile at the β-position of the vinyl group and then as a nucleophile at the α' position. Thus, two- step polar condensation of 425 with methyl vinyl ketone could be expected to provide the A ring in 424. A similar process could also be used to add the B ring to a bicyclic precursor 426. Because the carbonyl group at the 11 position in cortisone cannot provide the polar reactivity required for the annelation described above, its introduction can be delayed until the latter stages of the synthesis.
The cyclohexene unit in 427 suggests a cycloaddition synthesis involving a Diels-Alder reaction between a C ring precursor dienophile and 1,3-butadiene. However, generation of a trans ring fusion would require a C ring precursor containing a severely strained trans C=C bond in a six-membered ring. A more reasonable strategy would be to generate the thermodynamically favored trans ring fusion by epimerization of a cis fused precursor that would be produced, in turn, by a Diels-Alder reaction of a cis C=C bond in a dienophile. The carbonyl at the 9-position in 427 could be present in latent form in a precursor 428. A carbonyl group at position 8 in 428 could provide the polar activation required for epimerization of a cis ring fusion in 429 into a trans ring fusion. This carbonyl would also activate the conjugated C=C bond in 430 toward Diels-Alder reaction with a relatively electron rich diene. However, this strategy is fatally flawed because 430 can be expected to aromatize by enolization to afford 431. To block aromatization and provide additional activation of the dienophile, a second carbonyl can be added at position 12. This suggests a p-quinone dienophile 434 that would deliver a cis fused adduct 433 by Diels Alder reaction with 1,3-butadiene, and a trans fused intermediate 432 by epimerization.
The more electron deficient methyl-substituted C=C bond in 434 is expected to be a more reactive dienophile towards 1,3-butadiene than the more electron rich methoxy-substituted C=C bond.
After having provided activation for epimerization at position 14 in 433, the carbonyl substituent at position 8 in 432 is removed by reduction to a hydroxyl, acetylation, and reductive cleavage. Simultaneously, the blocking carbonyl group at position 12 is removed by reduction and dehydration affording 427. Nucleophilic activation at position 8 is then enhanced by adding a formyl group that exists in the enol form in 435. Robinson annelation with ethyl vinyl ketone (EVK) then creates the B ring in 437. Thus, after facilitating the Michael alkylation, the activating formyl group is removed by a retro Claisen condensation upon treatment with \(\ce{KOH}\). Simultaneously, \(\ce{KOH}\) catalyzes an intramolecular aldol condensation in 436 generating the B ring in 437.
The stereoselectivity of this annelation can be ascribed to a thermodynamic preference for the requisite configuration at position 8 that is epimerizable owing to conjugation with the carbonyl group at position 5. Selective dioxidative addition to the unconjugated C=C bond in triene 437 is feasible because the electrophilic \(\ce{OsO4}\) is less reactive toward the electron deficient conjugated C=C bonds. Selective saturation of the sterically less encumbered, less substituted C=C bond in 438 is followed by installation of an enamine derivative of a formyl substituent as a blocking group at position 6 in 439. The contrasting applications of formyl substituents in 436 and 439 is noteworthy. Of the three remaining acidic hydrogens in 439, proton abstraction from position 11 is least sterically encumbered. The resulting ambident dienolate nucleophile, as expected, is selectively Michael alkylated α to the carbonyl group owing to greater electron density at the central compared with the terminal carbon atom of the 1-oxa-pentadienyl array in the intermediate carbanion. In other words, the resonance form 448b is more important than 448a of 448c.
Unfortunately, alkylation of 448 is nonstereoselective producing carboxylic acid 440 and an epimer after hydrolysis of an intermediate nitrile. The final carbon required for the A ring of cortisone was to be provided by \(\ce{MeMgBr}\). However, to prevent addition to the ketone carbonyl in 440, the latter group was masked as an enol lactone in 441. The methyl ketone produced by addition of \(\ce{MeMgBr}\) to 441 delivered 442 by intramolecular aldol condensation. The poor yield for the 440 to 442 conversion would be improved, no doubt, by modern methods. Thus, a chemoselective reaction of the acid chloride from 440 with \(\ce{LiMe2Cu}\) would provide a high yield of the corresponding methyl ketone.
Contraction of the D-ring was accomplished by oxidative cleavage to dialdehyde 443 that gave 444 by a remarkably regioselective aldol condensation. Saturation of the two least sterically encumbered C=C bonds in the derived ester 445 gave a mixture of epimers 446 (at the 5 position) separation of which was best achieved after conversion to the 3-hydroxy derivative that then provided 447 by acetylation.
At this point the total synthesis intersected with "extensive prior investigations by many groups on the partial synthesis, from natural sources, of cortisone." Thus, introduction of the 11 carbonyl group was accomplished by epoxidation of alkene 447, hydrolysis of the epoxide to triol 449, and oxidation to dione hemiketal 450. Nucleophilic replacement of the oxygen at position 9 by Br proceeded with allylic rearrangement upon treatment of 450 with \(\ce{HBr}\). Selective generation of a trans A-B ring fusion and the required configuration at position 9 in 451 is a consequence of thermodynamic control. Reductive debromination of bromoketone 451 followed by reduction to a diol, selective acetylation of the less sterically encumbered hydroxyl at position 3, and oxidation delivered the 11-keto steroid 452.
Assembly of the dissonant cortisone side chain was accomplished by polar condensation of the acid chloride from 452 with a dissonant building block, diazomethane, and reaction of an intermediate diazoketone with acetic acid. Saponification of the resulting diacetate 453 and selective reacetylation of the primary hydroxyl delivered 454. Introduction of a hydroxyl group at position 17 was then accomplished by 1,2-dioxidative addition to 455. Steric approach control favored the requisite configuration at the 17 position. Finally, introduction of unsaturation between carbons 4 and 5 was accomplished by bromination followed by dehydrobromination of 456. Dehydrobromination of α-bromoketones can be complicated by α' proton abstratction that leads to a Favorskii reaction through the formation of a cyclopropanone. The mild Mattox-Kendall method avoids this pitfall because α-bromo hydrazones readily eliminate bromide to generate intermediate α,β-unsaturated hydrazones, e.g. 457. Pyruvic acid effects removal of the hydrazine while hydrolysis of the side chain acetate occurred upon treatment with \(\ce{HCl}\) completing the first total synthesis of cortisone (341) by R. B. Woodward in 1952.
As a practical source of supply for medicinal applications, Woodward's synthesis could not compete with partial syntheses from other natural steroids that are readily available from plants. A major shortcomming of the total synthesis is the generation of a racemic product. The natural enantiomer was available by resolution of the intermediate 445, but at least half of this precious advanced intermediate was discarded, i.e. the wrong enantiomer. Although the biosynthesis of cortisone is circuitous, it produces only one enantiomer owing to an entirely enantioselective epoxidation of squalene.
An Enantioselective Strategy for Cortisone. The achievement of an industrially viable total synthesis of cortisone depended on the development, in 1966, of an enantioselective strategy.31 Interestingly, the strategy evolved from methods and intermediates developed during a synthesis of cortisone that employs methoxytetralone (394) as a BC ring precursor32 in contrast to the Velluz estrone synthesis mentioned earlier (see section 5.3) that used this starting material for the AB ring moiety. But the key development in the evolution of an enantioselective strategy was the conception of a prochiral starting material and a route for its elaboration into a steroid.33 Thus, extensive research on the partial synthesis of cortisone from naturally derived 17-ketosteroids had established methods that allow the elaboration of the cortisone sidechain from precursors like 458.
Polar analysis of this subtarget, ignoring the 11-keto group, reveals that all circuits between the oxygen functionality in the A and D rings are consonant except those involving carbons 15 and 16. Introduction of the 11-keto group by addition to a C ring C=C bond in a precursor 459 is precedented by the similar functionalization of 447 (see section 5.4) in the Woodward synthesis.
Polar disconnection of the 4,5-C=C bond in 459 suggests intramolecular aldol condensation of 460 for generating the A ring. In the Woodward synthesis, a similar intermediate, i.e., 440, was generated by alkylation of 439. Methylation of the analogue 461 of 439 might similarly provide 460. Further polar disconnections of the B and C rings suggests a monocyclic precursor 462 that is achiral. We saw a similar intermediate in Danishefsky's enantioselective synthesis of estrone. Thus, 404 (see above) contains two of the carbonyl groups of 462 in latent form. In the estrone synthesis, asymmetry was introduced by an enantioselective aldol condensation of 404 to give 405. Also, in that synthesis, 404 was prepared from an intact D-ring precursor 380 by Michael addition to enone 403.
A similar strategy was employed a decade earlier to prepare an analogous prochiral precursor for cortisone. However, as we shall see, a different enantioselective transformation of the prochiral precursor 467 (see below) was used to introduce asymmetry into this synthesis of cortisone by Velluz.
A symmetrical starting material 463 is converted to the Michael acceptor 466 through Friedel-Crafts acylation of ethylene with the acid chloride 464 and dehydrochlorination of the intermediate β-chloro ketone 465. Although the yield of 466 is poor, it is readily available in kilogram quantities from inexpensive starting materials. Condensation of 466 with the intact D ring precursor 380 delivers 467. Enantioselective microbiological reduction provides the optically pure mono reduction product 468 in good yield as a single diastereomer.
Acid-catalyzed intramolecular aldol condensation then creates the C ring in 469. Stereoselective saturation of the C=C bond in 470 creates the requisite trans CD ring fusion, without a need for the lengthy ring contraction process of the Woodward construction of the trans CD ring fusion. To achieve selective polar connection at the carboxyl carbon in 470 of a nucleophilic fragment containing the remaining carbons required for the A and B rings, the ketone carbonyl must be masked. This is accomplished intramolecularly by enol esterification to give 471.
Grignard reagent 472 reacts with 471 to deliver 473 that is cyclized by intramolecular aldol condensation to provide the B ring in 474. The correct configuration at position 8 is assured by thermodynamic control because this center is conjugated with the carbonyl at position 5. Nevertheless, proton abstraction from 474 occurs primarily at the 11 position leading upon angular methylation to 475 completely stereoselectively with the requisite configuration for cortisone. The stereoselectivity of this alkylation contrasts sharply with the lack of stereoselectivity observed in the corresponding 384 to 385 conversion in the Woodward synthesis. The contrasting stereochemical behavior of these two alkylations are a consequence of mechanistic differences. Thus, the alkylation of 439 is a reversible, thermodynamically controlled, Michael reaction whereas the methylation of 474 is a kinetically controlled process. Axial methylation from the β face of the enolate is stereoelectronically preferred because it leads directly to the chair conformer of 475.
Generation of the A ring is then accomplished with a third intramolecular aldol condensation providing 476 after hydrolysis of the 17 benzoate. Oxidation of the 17 hydroxyl, and introduction of oxygen at the 11 position by addition of \(\ce{HOBr}\) provides 477 that, upon oxidation and reductive debromination, delivers 478 stereoselectively with the thermodynamically preferred configuration at position 9 which is α to the carbontyl at position 11. Finally, elaboration of the cortisone side chain was accomplished by ethynylation of the more electrophilic unconjugated 17 carbonyl. Catalytic hydrogenation then provided the tertiary allylic alcohol 4 7 9 . Bromodehydroxylation of 4 7 9 occurred with allylic rearrangement, presumably through an allylic cation intermediate, while replacement of \(\ce{Br}\) in 480 with \(\ce{OAc}\) proceded by a direct SN2 substitution. The unusual oxidizing agent, phenyliodosodiacetate and a catalytic quantity of \(\ce{OsO4}\), converted the more nucleophilic C=C bond in 481 directly into the α hydroxy ketone 482. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/04%3A_Terpenes/4.07%3A_Biosynthesis_and_Total_Synthesis_of_Steroids.txt |
absolute asymmetric synthesis (4.6)
bishomo terpene (4.5)
CCD (4.4)
CDC (4.4)
convergent synthesis (4.6)
decarboxylative elimination (4.1)
glucoside (4.1)
head-to-tail dimer (4.1)
homo terpene (4.5)
irregular terpene (4.1)
isoprene unit (4.1)
linear synthesis (4.6)
mevalonic acid (4.1)
monoterpene (4.1)
nor terpene (4.7)
oxidative addition (4.7)
RSM (4.4)
reductive elimination (4.7)
seco steroid (4.6)
stereoconvergent (4.6)
topological analysis (4.4)
4.09: Study Questions
1. Circle the "common atoms" in cincassiol D1, a diterpene, and then draw wavy lines through each C-C bond that involves at least one common atom and that lies on a consonant circuit (refer to your answer to question 4 in chapter 1 for a polar reactivity analysis of cincassiol D1). You may wish to use the structures below as templates for some of your drawings. Simply "white out" unwanted bonds.
(a) For each of the dislocations suggested by your topological analysis and refering to your previous polar analysis, draw a synthon that could theoretically provide the target skeleton by polar C-C bond-forming reactions.
(b) For some of these synthons draw a functionalized precursor (synthetic equivalent) that could be used in a direct polar syntheses of the target or that could be used in a polar synthesis requiring addition of a methyl group and/or formation of a a heterocyclic C-O bond after completion of the multicyclic carbon skeleton by polar C-C bond formation.
(c) For the remaining synthons which contain consonant circuits that are blocked by quaternary centers, synthetic equivalents exploiting the polar activation afforded by target-related functional groups are not available since conjugation of these functional groups with one or both of the reacting carbon centers is not readily achieved without prior cleavage of additional carbon-carbon bonds. Label these synthons as "BLOCKED".
2. The deduction of likely biosyntheses of terpenes provides an excellent opportunity to practice retrosynthetic analysis with a set of boundary conditions: (a) isopentenyl pyrophosphate as starting material, (b) head to tail acyclic oligomer as an intermediate, (c) carbocationic electrophile and C=C π-bond nucleophile for C-C bond formation, (d) all of the reactions of carbocation intermediates as potential steps, e. g. β-proton loss, and rearrangements by 1,2-C shifts or hydride shifts.
(a) Deduce likely biosyntheses for the following regular sesquiterpenes:
Hint: notice and think about any similarities in the structures of α-acorenol and α-cedrene.
(b) Cincassiol D1 is a regular diterpene. In the following structure: (a) circle the isoprene units, (b) draw wavey lines through all C-C bonds that are not bonds within the isoprene units, (c) for those nonisoprene bonds that would be present in the acyclic geranylgeranyl pyrophosphate precursor of cincassiol D1, label the ends with h or t to indicate a head or tail atom of an isoprene unit.
(c) Draw a circle around each of the “common atoms” (as defined by Corey) in the following structure of lanosterol (1).
(d) Describe the topological strategy of the biosynthesis of lanosterol (1) from squalene oxide (2).
(e) Write a mechanism for the polyene cyclization and rearrangement involved in the biosynthesis of lanosterol (1) from squalene oxide (2). Show the flow of electrons with arrows pointing from electron pairs in the reactants to their impending location in the incipient products. Show the polyene cyclization as a single concerted process involving several electron pairs and leading to an intermediate cation. Then show the rearrangement of that intermediate to lanosterol as another concerted process involving the movement of several electron pairs.
3. By drawing the appropriate resonance forms of a key cationic and a key anionic intermediate, write a mechanism that shows how the C-C bond forming reaction between 3 and 4 generates 5 by a process that relies upon the stabilizing influence of functionality in 3 and 4 that is related to the 3-hydroxyl and 17-keto groups in the final synthetic target, estrone (6).
Hint: 4 is a vinylogous carboxylic acid.
4. For each of the following reactions that generate a trisubstituted alkene stereoselectively, what is the driving force and why is it stereospecific?
(a)
(b)
(c)
5. A remarkable reaction occurs upon UV irradiation of 7 and 8. A product 9, that contains the loganin skeleton is generated stereoselectively.
(a) Write a mechanism for this reaction. Show the flow of electrons with arrows pointing from electron pairs in the reactants to their impending location in the incipient products.
(b) Use one or more of the following terms to answer each of the following questions: thermodynamic control, stereoelectronic control, steric approach control, or temporary bridge. How is stereocontrol achieved: (i) at the 3 position relative to the 2 position in 9? (ii) at the 7-position relative to the 2-position in 9?
6. In the Kojima-Saki synthesis of PGF, the relative stereochemistry at positions 8, 9, and 12 is set in the conversion of 10 into 11.
How is stereocontrol achieved: (i) at the 12 position relative to the 9 position in 11? (b) at the 8- position relative to the 9-position in 11?
7. Each of the following reactions fails because of a fatal flaw. For each reaction draw the structure of the actual product.
(a)
(b)
(c)
(d) | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/04%3A_Terpenes/4.08%3A_Terminology.txt |
1. Buchi, G.; Carlson, J. A. J. Am. Chem. Soc. 1970, 92, 2165; ibid. , 1973, 95, 540.
2. Partridge, J. J.; Chada, N. K.; Uskokovic, M. R. J. Am. Chem. Soc. 1973, 95, 532.
3. Corey, E.J.; Ohno, M.; Mitra, R. B.; Vatakencherry J. Am. Chem. Soc. 1964, 86, 478.
4. Scherrer, R. A., Ph.D. Thesis (E. J. Corey, Advisor), University of Illinois, 1958; Diss. Abstr. 1958, 19, 960.
5. Grant, J. E., Jr., Ph.D. Thesis, Pennsylvania State University, 1969; Diss. Abstr. B, 1969, 29, 3653.
6. McMurry, J. E.; Isser, S. J. J. Am. Chem. Soc. 1972, 94, 7132.
7. (a) Oppolzer, W.; Godel, T. J. Am. Chem. Soc. 1978, 100, 2583. (b) Volkmann, R. A.; Andrews, G. C.; Johnson, W. S. J. Am. Chem. Soc. 1975, 97, 4777.
8. (a) Kondo, K.; Negishi, A.; Matsui, K.; Tsunemoto, S.; Masamune, S. J. Chem. Soc., Chem. Commun. 1972, 1311. (b) Stotter, P. L.; Hornish, R. E. J. Am. Chem. Soc. 1973, 95, 4446.
9. Zurfluh, R.; Wall, E. N.; Siddall, J. B.; Edwards, J. A. J. Am. Chem. Soc. 1968, 90, 6224.
10. Johnson, W. S.; Brocksom, T. J.; Loew, P.; Rich, D. H.; Werthemann, L.; Arnold, R. A.; Li, T.; Faulkner, D. J. J. Am. Chem. Soc. 1970, 92, 4463.
11. Henrick, C. A.; Schaub, F.; Siddall, J. B. J. Am. Chem. Soc. 1972, 94, 5374.
12. Corey, E. J.; Katzenellenbogen, J. A.; Gilman, N. W.; Roman, S. A.; Erickson, B. W. J. Am. Chem. Soc. 1968, 90, 5618.
13. Johnson, W. S.; Li, T.; Faulkner, D. J.; Campbell, S. F. J. Am. Chem. Soc. 1968, 90, 6225.
14. Ravi, B. N.; Wells, R. J. Aust. J. Chem. 1982, 35, 129.
15. White, J. D.; Gupta, D. N. J. Am. Chem. Soc. 1968, 90, 6171.
16. Salomon, R. G.; Sachinvala, N. D.; Raychaudhuri, S. R.; Miller, D. B. J. Am. Chem. Soc. 1984106, 2211.
17. Carrupt, P. -A.; Vogel, P. Tetrahedron Lett. 1982, 23, 2563.
18. Tanaka, M.; Tomioka, K.; Koga, K. Tetrahedron Lett. 1985, 26, 3035.
19. Tanaka, M.; Tomioka, K.; Koga, K. Tetrahedron Lett. 1985, 26, 6109.
20. Salomon, R. G.; Basu, B.; Roy, S.; Sharma, R. B. Tetrahedron Lett. 1989, 30, 4621.
21. Anner, G.; Miescher, K. Helv. Chim. Acta 1948, 31, 2173.
22. Bachmann,W. E.; Kushner, S.; Stevenson, A. C. J. Am. Chem. Soc. 1942, 64, 974.
23. Sheehan, J. C.; Coderre, R. A.; Cruickshank, P. A. J. Am. Chem. Soc. 1953, 75, 6231.
24. Douglas, G. H.; Graves, J. M. H.; Hartley, D.; Hughes, G. A.; McLoughlin, B. J.; Siddall, J.; Smith, H. S. J. Chem. Soc. 1963, 5072.
25. Bartlett, P. A.; Johnson, W. S. J. Am. Chem. Soc. 1973, 95, 7501.
26. Ananchenko, S. N.; Torgov, I. V. Tetrahedron Lett. 1963, 1553.
27. Danishefsky, S.; Cain, P. J. Am. Chem. Soc. 1975, 97, 5282.
28. Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1979, 101, 215.
29. Kametani, T.; Nemoto, H.; Ishikawa, H.; Shiroyama, K.; Matsumoto, H.; Fukumoto, K. J. Am. Chem. Soc. 1977, 99, 3461.
30. Woodward, R. B.; Sondheimer, F.; Taub, D.; Heusler, K.; McLamore, W. M. J. Am. Chem. Soc. 1952, 74, 4223.
31. Bellet, P.; Nominé, G.; Mathieu, J. Compt. Rend. Acad. Sci. 1966, 263C, 88.
32. Velluz, L.; Nominé, G.; Mathieu, J. Angew. Chem. 1960, 72, 725.
33. Velluz, L.; Nominé, G.; Amiard, G.; Vesperto, T.; Cérède, J. Compt. Rend. Acad. Sci. 1963, 257, 3086. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/04%3A_Terpenes/4.10%3A_References.txt |
The polyketides, a diverse family of highly oxygenated natural products, are characterized by the presence of many β-dihydroxy or β-hydroxycarbonyl consonant polar functional relationships. Some polyketides have carbon skeletons comprized of a long straight chain of carbon atoms that is often crosslinked into one or more six-membered rings. Thus, a variety of aromatic compounds is produced in nature from acetate-derived (poly-β-keto)carboxylic acids through dehydrocyclization, i.e. intramolecular aldol condensation. For example, orselenic acid is topologically and functionally related to a mono crosslinked 3,5,7-triketo octanoic acid.
Some polyketides are further modified by oxidative coupling, as in the conversion of griseophenone into griseofulvin. Other modifications include alkylations at the nucleophilic carbon atoms, reduction of carbonyl groups, and electrophilic aromatic substitutions. For example, tetracycline is topologically related to a tetra crosslinked 3,5,7,9,11,13,15,17-octaketo octadecanoic acid. However a dimethylamino and two hydroxyl groups are present that do not fit the otherwise entirely consonant polar reactivity pattern of the remaining functionality. Also a methyl and carboxamido group are also present that are not deriveded from a (poly-β-keto)carboxylic acid precursor.
A large family of polyoxygenated macrolide antibiotics, that contain 12-, 14-, or 16-membered lactone rings, share a polyketide biogenesis. For example, erythromycin B is a diglycoside of erythronolide B, a propionate-derived aglycone.
05: Polyketides
Formation of the intermediate polyacetyl or propionyl chains in the biosynthesis of polyketides is closely related to fatty acid biosynthesis. Thus, for example, acetyl CoA acylates an enzyme-bound malonylthioester to yield an enzyme bound acetoacetylthioester. In fatty acid biosynthesis, this would then be reductively deoxygenated prior to undergoing Claisen condensation with a second molecule of malonyl-S-ACP (see section 3.1). In polyketide biosynthesis, repeated aldol condensations yield an enzyme bound polyacetyl chain in which many acetyl carbonyls are retained or only partially reduced to hydroxyls. The name acetogenin, a synonym for polyketides, arises from their poly- acetyl biogenesis. Cyclization of the polyacetyl chain occurs completely, or at least partially, prior to its release from the polyacetyl synthetase enzyme surface. For example, orselenic acid is constructed biosynthetically from acetyl CoA and three molecules of enzyme-bound malonyl-thioester.
A total synthesis of orselenic acid was achieved by a biomimetic strategy, that is, by a strategy that mimics the biosynthesis of this acetogenin.1 Thus, the trianion of 2,4,6-heptanetrione was carboxylated to yield 3,5,7-triketo octanoic acid (1) that readily underwent intramolecular aldol condensation and dehydration to give orselenic acid (2).
5.02: Griseofulvin
Polar reactivity analysis of griseofulvin (3) reveals dissonant circuits involving the chloro substituent and furan oxygen. A dislocation cleaving these dissonant circuits suggests an entirely consonant precursor 4 or the aromatic close relative 5. This disconnection -- between a common atom, the spiro carbon, and a non common atom, the furan oxygen -- also leads to major topological simplification. Disconnection of the rings ring in 5 to generate an acyclic precursor must be preceded by conversion of ring C=C bonds into C-C bonds. Thus, addition of water or tautomerization gives a precursor 6 in which polar disconnection of C-C single bonds is feasible. The functionality level at the electrophilic centers in the acyclic precursor 7 suggested by this polar disconnection must be one unit higher than in the intermediate 6 if the cyclization of 6 is to yield 7 directly.
The biosynthesis of griseofulvin (3) illustrates the involvement of electrophilic aromatic substitution and oxidative coupling in the transformation of a poly-β-ketomethylene chain into a functionally and skeletally complex acetogenin. Thus, intramolecular aldol condensations of an enzyme- bound 3,5,7,9,11,13-hexaketohexadecanoic acid thioester followed by hydrolysis, O-methylation with S-adenosylmethionine (SAM) and electrophilic aromatic chlorination generates an intermediate, griseophenone A (8). A dissonant connection in the furan ring of griseofulvin is created by an oxidative coupling that generates dehydrogriseofulvin (9) from 8. Stereo-selective reduction of 9 with NADH then delivers griseofulvin (3).
A Biomimetic Synthesis of Griseofulvin
A ferricyanide-induced oxidative coupling of griseophenone A (8) to dehydrogriseofulvin (9) with was exploited in a biomimetic total synthesis of racemic griseofulvin.2 The symmetrical starting materials, phloroglucinol (10) and orcinol (12) were elaborated into the intermediates 11 and 13 by well precedented electrophilic aromatic substitutions. Acylation of 11 with 13 occurred mainly at carbon. The O-acylation product was readily rearranged to the C-acylation product, thus affording griseophenone A (8) in good overall yield. Conversion of 8 to d,l-griseofulvin (3) closely paralleled the biosyn-thetic pathway.
Polar Cyclohexenone Annelation Strategies for Griseofulvin
A strategy for the total synthesis of griseofulvin is suggested by a polar analysis that ignores the polar activation afforded by the furan oxygen. Disconnection of two bonds to a common atom, the spiro carbon, in 3 leads to major topological simplification, and suggests a nucleophilic precursor synthon 14 and a biselectrophilic precursor synthon 15. The eneyne 16 is a synthetic equivalent of 15 that should provide 3 directly because 1,4-addition of a nucleophile will decrease the unsaturation level of each electrophilic center by one unit.
The biselectrophile 16 was prepared from methoxyacetylene and crotonaldehyde, and the precursor 14 of the requisite dissonant nucleophile was obtained from phloroglucinol (10) via 18 produced by acylation of 11 with chloroacetyl chloride. It should be noted that the dissonance in the furan ring of 14 is derived from the dissonant precursor chloroacetyl chloride. Treatment of a mixture of 14 and 16 with base delivered 3 via anions 19 and 20.3
A different strategy is also suggested by a polar analysis that ignores the polar activation afforded by the furan oxygen. Disconnection of two bonds of the cyclohexenone ring as in 3 suggests a well precedented annelation of cyclohexanediones that is similar to a Robinson annelation (see section 4.7). In contrast to the previous strategy, a methyl enol ether is not produced directly. The enone 23 serves as synthetic equivalent for the synthon 22.
Condensation of 21 with 23 gives two diastereomeric cyclohexanediones 25 and 26. This synthesis is less efficient than the previous one because the major diastereomer 25 is epimeric with the natural product 3 and methyletherification of the minor diastereomer 26 occurs with unfavorable regioselectivity.4
A Cycloaddition Strategy for Griseofulvin
Danishefsky's strategy for a total synthesis of griseofulvin5 was designed around his method for cyclohexenone annelation through Diels-Alder reaction of highly oxygenated dienes, e.g., 27.
This boundary condition guides and channels the retrosynthetic analysis to seek a two-bond disconnection of the cyclohexenone ring to a butadiene and dienophile precursor. Furthermore, the stereoselective conversion of 9 to give 3 established previously2 was adopted to simplify the stereochemistry of the target. The dislocation to 9 removes one asymmetric center, that can be introduced at the end of the synthesis by stereoselective hydrogenation. For the desired Diels-Alder reaction, a C=C bond between carbons 3' and 4' is required. Therefore, the 2',3' and 5',6' C=C bonds in 9 must be generated after the key Diels-Alder step. The requisite 3',4' C=C bond is provided by dislocation of 9 to the enol-keta1 derivative 26. The 5',6' C=C bond could be introduced in 26 by a variety of elimination processes. The choice of a sulfoxide as leaving group is dictated by the additional utility of the sulfoxide group for activating the dienophile 28 toward Diels-Alder reaction with the diene 27 which is necessarily electron-rich. The sulfoxide can also be expected not to control the structural selectivity of the Diels-Alder reaction, that will be controlled instead by the carbonyl group of the furanone ring in 28. The electron withdrawing sulfoxide group is dissonant with respect to the furanone carbonyl in 28, but it can be obtained by oxidation of the corresponding electron donating sulfide group in 29. This consonant vinyl sulfide is simply an enol sulfide derivative of the dione precursor 30. This dione might be available by acylation of the furanone 14 that was used in a previous synthesis of griseofulvin. Alternatively, construction of the dissonant C-O bond in 30 could be achieved after completion of the carbon skeleton but a nucleofuge would be required in 31 because the carbonyl groups can not provide the requisite electrophilicty. Ignoring the chloro group in 31, the 1,3-dicarbonyl array is consonant and can be constructed by Claisen acylation of the ketone 18 that was also used in the previous stereoselective synthesis discussed above.
In fact, O-acylation of the enolate anion from 14 occurs to the complete exclusion of carbon acylation required to produce 30. On the other hand, an intramolecular delivery of the acetyl electrophile in 32 served to unmask Intramolecular O-alkylation of the intermediate phenolate 33 delivered the desired dione 30 that exists as an enol tautomer. Conversion of the enol sulfide 29 from 30 into the corresponding sulfoxide was accomploshed by selective oxidation of the sulfide in the presence of a C=C bond with MCPBA at low temperature. Diels-Alder addition of the resulting vinyl sulfoxide 28 to the 1,3-diene 27 was followed, in situ, by thermal elimination of phenylsulfenic acid and methoxytrimethylsilane from an intermediate cyclohexene 26 to deliver cyclohexadienone 9. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/05%3A_Polyketides/5.01%3A_Orselenic_Acid.txt |
Acetyl CoA is not the only thioester that may initiate the enzyme matrix oligomerization of malonyl CoA. Thus, for example, a biosynthesis has been postulated for tetracycline (44) involving condensation of malonamoyl CoA (34) with eight molecules of malonyl CoA to produce an enzyme bound polyketoamide thioester 35, that is partially dehydrocyclized after methylation of one methylene and reduction of one carbonyl.6 The final ring of the tetracycline ring system is formed by Dieckmann cyclization of 36 to 37 after release of the partially cyclized polyketide from the polyketide synthetase. Two aromatic hydroxylations increase the functionality after completion of the carbon skeleton. These hydroxylations may involve intermediate arene oxides, e.g. 37 38 39. The reductive amination of 40 via 41 and 42 to yield 43 is accompanied by oxidative deamination of glutamic acid.
Topological Analysis of Fused-Ring Systems.7
A ring pair is a fused-ring system if two rings share one and only one common bond, the fusion bond. The steroid and tetracycline ring systems are examples of multicyclic structures containing only fused-ring pairs, as opposed to spirocyclic or bridged-ring pairs. Besides fusion bonds (marked f), the diagrams below indicate common atoms (shown as •), and exendo bonds (marked e) which are exo to one ring and endo to another, and bonds (indicated as dashed lines) that are formed during the biosyntheses of these ring systems from acyclic precursors.
There is an interesting contrast between the topological strategies of tetracycline and steroid biosyntheses. Both strategies involve key acyclic intermediates that incorporate all of the skeletal carbon atoms. However, the biosynthesis of the tetracycline skeleton involves formation of all of the ring fusion bonds, whereas only exendo bonds are formed during the biosynthesis of the steroid skeleton. Another contrast is found in the biosynthetic generation of the peripheral ring, i. e. the ring that remains after cleavage of all fusion bonds. Thus, only one peripheral bond is generated during the biosynthesis of the tetracycline skeleton, whereas four bonds of the peripheral ring are generated during steroid biosynthesis.
Also noteworthy is the fact that, in both biosyntheses, bonds between pairs of common atoms are strategic bond, i.e., strategically important in achieving rapid reduction of molecular complexity by disconnection during dislocation of the synthetic target. The dislocations of the tetracycline biosynthetic strategy are recommended both by topological and polar reactivity analysis. Topologically, the strategy disconnects all bonds between pairs of common atoms. Polar reactivity analysis reveals ample functionality. If the activation provided by several functional groups is ignored, numerous functional groups remain with solely consonant connecting circuits that can be generated by exploiting target related functionality in precursors in conjunction with several added consonant functional (carbonyl) groups.
A Linear Strategy for Tetracyclines
The first synthesis of a biologically active (though unnatural) tetracycline derivative was achieved by Woodward and collaborators.8 These workers simplified the synthetic goal by not including the labile tertiary 6-hydroxyl as well as the 6-methyl of tetracycline (44). Ring A of 45 is functionally and stereochemically the most complex portion of this simplified target. This ring is so highly functionalized that polar analysis is ambiguous. It contains a plethora of polar reactivity dissonances. If this ring is severed from 45, a tremendous simplification of the synthetic target results. Not only is an abundance of reactive functionality removed, but a topological simplification is also realized. Thus, by cleaving a pair of exendo bonds that are vicinal and cocyclic (in the same primary ring, i. e. one that is not disected into a pair of smaller rings by a transanular bridge), all vestiges of the A-ring are removed. The remaining BCD synthon is a relatively chemically stable, structurally simple fragment 46. A possible synthetic intermediate, i. e. appropriately functionalized molecular fragment, that corresponds to 46 is 47. The carbonyl group in ring B in 47 provides activation for elaboration of ring A. The methyl ether in ring D blocks deprotonation of the phenol. Polar analysis of the nonaromatic portion of 47 suggests a dislocation to 48 and dimethyloxalate, a symmetrical dissonant biselectrophile. Annelation of 48 by Friedel-Crafts acylation of 49 would exploit the nucleophilic reactivity of the aromatic D-ring in 49, that is activated by a target-related methoxy group, and the electrophilic reactivity of a carbonyl.
However, this strategy is potentially flawed because electrophilic substitution that must occur ortho to the methoxy substituent in the D ring of 49 during conversion to 48, could also occur at the nucleophilic position para to the activating methoxy group. To preclude para acylation, a chloro substituent in the precursor 50 could be used as a blocking group (a substituent introduced to control reactivity and subsequently removed).
Topologically, a dislocation of 49 to 51 + 52 is desireable because all vestiges of the sidechain are removed from the aromatic ring. However, polar analysis of 49 shows that electrophilic alkylation or acylation of an anisole precursor would favor ortho or para substitution rather than the meta substitution required to generate 49.
The dislocation 49 53 + 54 is recommended by the ready availability of benzylic organometallics corresponding to 53. A nucleophilic synthon such as 53 might afford a diester of 49 by 1,4-addition to 54. In fact, a general synthesis of β-substituted alkanedioic acids such as 49 is known that is related to this approach.9 Dislocation to more connected, cyclic β-ketoester intermediates 55 reveals the possible utility of readily available cycloalkenone precursors for the synthesis of β-substituted alkanedioic acids by retro Dieckman cleavage.
In practice, C-acylation of enolate intermediates such as 56 is accompanied by O-acylation of the resulting β-keto esters. However, no additional steps are required because the resulting enol esters are hydrolyzed to β-keto esters under the reaction conditions required for retro Dieckman cleavage of the latter to generate the target β-substituted alkane dioic acids.
Instead of a benzylic nucleophile as starting material, Woodward's strategy was based on the choice of a readily available benzylic electrophile, methyl m-anisate (57), as starting material. This choice channels retrosynthetic analysis to a precursor 58 with an activating functional group, the benzylic carbonyl, that must be removed subsequently to provide 49. Although conjugation with the remote carbomethoxyl in 58 could provide the nucleophilic activation required to unite a hexanedioic ester starting material with 57, Woodward chose to exploit a classical synthetic method for ketones, alkylation of a β-keto ester followed by hydrolysis and decarboxylation (an acetoacetic ester synthesis), to assemble the carbon skeleton of 49. This choice mandates the inclusion of a carboxylic ester activating group in 58.
Woodward examined three different strategies to discover which route actually provides the best overall yields of 58 from 57. Each pathway exploits readily available starting materials. Interestingly, the longer (less convergent) route, using methyl acetate and methyl chloroacetate as building blocks, gave better overall yields than the other two routes that exploit symmetrical diester precursors. It is also significant that, in each route, a dissonant starting material is used to provide the dissonant circuit in 58.
Conversion of 58 to the key tricyclic intermediate 61 was then achieved by hydrolysis, decarboxylation, hydrogenolysis, chlorination, Friedel-Crafts acylation, Claisen condensation-Dieckmann cyclization, and then another hydrolysis and decarboxylation. The interesting selective demethylation that produced 60 results from intramolecular transesterification of an intermediate benzyl alcohol followed by hydrogenolysis of the resulting benzylic ester. Methylation of 60 was performed solely to facilitate purification.
Woodward anticipated different properties for the three carbonyl groups in 61. Thus, the β-dicarbonyl array (C-11 and 12) is "a stabilized vinylogous carboxylic acid system, while the third, like that in simple α-keto acids, should be both highly susceptible to addition reactions and readily enolizable. The latter property should confer high nucleophilic reactivity upon the adjacent methylene." This reactivity was exploited to append to 61 a precursor fragment for ring A, and then the dimethylamino group by polar reactions. The third carbonyl, having served its purpose, was then removed by reduction to α-hydroxy-ketone 63, activation by intramolecular transesterification, and reductive cleavage of the resulting lactone.
A fully functionalized acyclic precursor was then elaborated for ring A by acylation of a methyl malonamate carbanion with the mixed anyhdride 64. Dieckman cyclization, exploiting the nucleophilic reactivity conferred to the adjacent methylene by the carbonyl at position 12, produced ring A. The required stereochemistry at position 4a in 64 is produced during addition of dimethylamine to 62, which favors the more stable equatorial epimer of 63. Installation of the last functional group, the hydroxyl at position 12a was then accomplished oxidatively to deliver 45.
A More Convergent Strategy for Tetracyclines.
In another strategy for the total synthesis of 6-desmethyl-6-desoxytetracycline (45), as in the previous synthesis by Woodward, the target is simplified by removing the C-12a hydroxyl. Then, except for the polar activation afforded by the C-4 dimethylamino substituent, the polar reactivity provided by the remaining functional groups is entirely consonant along any circuit as shown in 65. The polar disconnection 65 66 separates the molecule into two large fragments united by a simple methylene bridge. Further bond disconnections disect the A ring into two straight chain precursors 67 and 68, that can be reunited by polar reactions. The synthetic equivalents that Muxfeldt utilized for the synthons 67 and 68 were 69 and 70a, respectively.9
The highlight of the Muxfeldt synthesis is the ingenious reaction that produces the tetracyclic intermediate 71 in one step from the bicyclic precursor 69 in 82% yield! Final adjustment of functionality readily affords 45 from 71. The strategy benefits from a high degree of convergence. Moreover, 69 is readily available by an azalactone synthesis from 72 and 73. Finally, the intermediate CD-ring aldehyde 72 was prepared in good overall yield from 4-chloro-3-methylanisole.
The first total synthesis of a natural tetracycline, the 5-hydroxy derivative terramycin, was achieved by Muxfeldt.10 The A and B rings were assembled by the same strategy used above to generate 45. Thus, a CD-ring aldehyde 74, analogous to 72, was condensed with a preformed azathio lactone 75 analogous to an azalactone intermediate involved in the reaction of 73 with 72. The resulting Michael acceptor 76, analogous to 69 was then condensed with the unprotected amide 70b corresponding to 70a to generate the tetracycline ring system in one synthetic step. Subsequent deprotection of the masked hydroxyls and oxidative introduction of the last hydroxyl at position 12a was followed by removal of the thiobenzoyl masking group under exceptionally mild conditions upon treatment with methyl iodide. This reaction involves the generation and subsequent hydrolysis of a methyl thioimidic ester intermediate. Finally, controlled dimethylation of the primary amine gave terramycin.
The strategy employed for generating the key intermediate 74 exploits a temporary bridge in 78 to mask the aldehyde in latent form as an alkene and to create a folded tricyclic precursor that is expected to add a methyl nucleophile to the carbonyl at position 6 from the least sterically congested convex face. This assures a cis relationship between the methyl group and the neighboring bridgehead proton. The vinylogous α-diketone array in 77 is expected to be especially electrophilic, sufficiently activated that competition from addition to the acetate carbonyl can be avoided. Selectivity favoring addition to the carbonyl at position 6 rather than 11 may result from decreased electrophilicity owing to conjugation of the 11- but not the 6-carbonyl with the oxygen at postion 10. The presence of a cyclohexene in 77 recommends a cycloaddition synthesis involving a doubly activated electron-deficient quinone dienophile and relatively electron rich 1-acetoxy-1,3-butadiene.
In fact, the Diels-Alder reaction of acetoxybutadiene with juglone acetate (78) gave the diacetate 79 regioselectively, and addition of a methyl Grignard reagent to 79 is regio- and stereoselective. The cyclohexene ring, having served its purpose, was then oxidatively cleaved to generate an aldehyde from its latent equivalent, the carbon-carbon double bond. An unneeded two-carbon fragment was then removed by a sequence involving aldol condensation, oxidative cleavage, and finally retro Claisen cleavage of an intermediate β-diketone array in 80.
Because of a stereoelectronic preference for an endo transition state in the Diels-Alder reaction of 78, 79 is generated with the correct configuration at position 5. However, the oxidative cleavage that generates 80 produces a mixture of epimers at position 5. During replacement of the acetyl protecting group with a methoxymethyl, piperidine is used as a nucleophile to cleave the acetate and as a masking group to hide the sensitive aldehyde during alkylation of the phenol. Fortunately, hydrolysis of the enamine 82, by treatment with moist silica gel, generated epimerically pure 74 with the requisite configuration at position 5. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/05%3A_Polyketides/5.03%3A_Tetracyclines.txt |
An enzyme promoted reaction of propionylCoA with methylmalonylCoA generates 83 enantioselectively. Diastereoselective reduction then delivers the b-hydroxy thioester 84. In contrast with fatty acid biosynthesis, dehydration and conjugate reduction of the resulting α,β-unsaturated thioester does not preceed Claisen condensation with a second equivalent of methylmalonylCoA during the biosynthesis of the seco acid precursor 87 of the macrolide 6-deoxyerythronolide B.
The resulting β-ketothioester 85 is reduced to a β-hydroxyester 86 that reacts with additional methylmalonylCoA and NADPH to generate 87. Lactonization then provides 6-deoxyerythronolide B from which erythronolide is formed by oxidation. Generation of only 1 of the 2048 possible diastereomers of the acyclic intermediate 87 is the remarkable consequence of the asymmetry of the homochiral catalysts (enzymes) that promote the condensations and reductions responsible for producing ten asymmetric centers.
A Relay-directed Strategy for Total Synthesis of Erythronolide B.
In a feasibility study, naturally derived erythronolide B was converted into an acyclic hydroxy acid 88 that was used to work out the final steps for a total synthesis.12 The synthetic design process was then channeled by the choice of this naturally derived precursor, a relay compound. The two stereocenters at positions 12 and 13 in 88 are remote from those at positions 2-6 and 8. Therefore, it would be difficult to generate one set of stereocenters under the stereo-controlling influence of the other. Rather, building blocks containing these stereocenters with the correct absolute configurations can be assembled and then united to provide the relay compound 88. The first total synthesis of Erythronolide B1 3 adopted a convergent absolute asymmetric (see section 4.6) strategy designed to provide 88 by the union of two homochiral segments, a nucleophile 89 and an electrophile 90.
To provide a more conformationaly rigid platform for generating and confirming the relative configurations of stereocenters, a cyclic temporarily-bridged precursor 91 was envisioned for the acyclic subtarget 90. Even greater rigidity is provided by the smaller ring of a six-membered ketone 92 that incorporates the lactone functionality in latent form. Stereoelectronically favored axial delivery of hydrogen to the isomeric cyclohexanone 94 can be expected to generate an equatorial hydroxyl at position 3. Furthermore, dislocation of 93 to 94 allows a carbonyl at position 3 to promote a thermodynamically favored equatorial disposition for the methyls at positions 2 and 4, and sets the stage for uncovering a symmetrical precursor, vide infra. Another temporary bridge, a six-membered lactone can be exploited to favor generation of the required configuration at the relatively remote stereocenter at position 8 in 92 during a methylation of 95 that can be expected to favor an equatorial methyl in 94. Lactone bridges can also be exploited to assure the proper stereo and regiochemical orientation during introduction of oxygen substituents at positions 1 and 6 by polar additions to the C=C bonds in a symmetrical dienone precursor 96. A search of the literature for available starting materials with the carbon skeleton of 96 can be used to identify the allyl cyclohexadienone 97 that is readily prepared from the trimethylphenol 98.
Reaction with allyl bromide of a phenolate from 98 provides 100 by Claisen rearrangement of the initial O-allylation product 99. An acid-catalyzed Cope rearrangement of 100 delivers the symmetrical dienone 97 that is selectively hydroborated at the terminal vinyl group and then oxidized to produce the carboxylic acid 96. Stereo and regioselective delivery of oxygen to position 5 is accomplished by intramolecular addition of a carboxylate to a C=C bond in 96. Capture of the reversibly formed enolate carbanion intermediate with electrophilic bromine produces 101. To repeat this process on the remaining C=C bond, the lactone is saponified to regenerate a carboxylic acid. This also generates an epoxide by intramolecular displacement of the bromo substituent by alkoxide. A second stereo and regioselective delivery of oxygen, this time to position 1, is again accomplished by intramolecular addition of a carboxylate to a C=C bond. Subsequent reductive removal of unneeded heteroatom functionality at positions 1 and 4 provides 103.
The nucleophilic activation afforded by the lactone carbonyl in 103 could now be exploited to introduce a methyl group at position 8. However, prior adjustment of functionality level at position 3 avoids nucleophilic activation adjacent to the ketone carbonyl. Methylation of 104 then afforded 105 stereoselectively. The lactone in 103 differentiates the hydroxyl substituents at positions 1 and 5. To maintain this diferentiation after saponification of the lactone, the other hydroxyls in 105 had to be suitably masked. The choice of benzoate ester masking group is particularly subtle. The feasibility of selective saponification of the lactone in the presence of benzoate esters relies upon the diminished electrophilicity of the benzoate carbonyl group owing to conjugation. Oxidation of the alcohol 106 to a ketone and then a lactone 107 followed by activation of the carboxylic acid as a thioester provided an electrophilic C1-9 segment equivalent to 90 where the masking groups R1 and R4 are replaced by a lactone bridge.
The synthesis outlined above provides racemic compounds. Resolution of an early intermediate, the carboxylic acid 102, by fractional crystallization of diastereomeric 1-α-naphthylethylamine salts, was employed to generate intermediates with the absolute configurations shown above that are required for natural erythronolide B.
Resolution of an early intermediate was also employed to prepare the requisite enantiomer of a precursor 115 (see section 6.3) for the nucleophile 89. Thus, the epoxy carboxylic acid 110, that is readily available by a one-step oxidation of trans-crotyl alcohol (109), was resolved by fractional crystallization of diastereomeric 1-α-naphthylethylamine salts. Stereospecific nucleophilic substitution on 110 generated the absolute configuration required at position 12. The regioselectivity of this epoxide opening is controlled by the bulky ether substituent in 111. Use of the corresponding epoxy alcohol in the displacement showed much inferior regioselectivity. Replacement of the terminal hydroxyl in 112 by a methyl group to give 113 could be accomplished without masking of the secondary hydroxyl by using an excess of \(\ce{Me2CuLi}\). The completely regioselective conversion of acetylene 114 into vinyl iodide 115 depended upon the outstandingly high regioselectivity that had recently been reported for hydrozirconation of unsymmetrically disubstituted acetylenes. This step in the Corey erythronolide B synthesis is a poignent example of the impact of developments in synthetic methodology on our ability to achieve efficient syntheses of complex organic molecules.
Although both building blocks 108 and 115 were available in homochiral form with the correct absolute configurations for erythronolide B, the synthesis was actually carried out by coupling the correct enantiomer of 115 with racemic 108. Thus, a Grignard reagent 116 derived from 115 was acylated with thioester 108 to produce ketone 117 and a diastereomer in 90% total yield. The mixture was caried through several additional steps before separation by preparative thin layer chromatography.
Thus, reduction of the ketone carbonyl in 117 proved unexpectedly difficult owing to suprisingly similar reactivity of the keto and lactone carbonyls toward most reducing agents and also because of a proclivity toward conjugate reduction of the enone. Reduction with zinc borohydride was accompanied by two unexpected phenomena, a very welcomed complete stereoselectivity and an essentially irrelevant translactonization that generated a 10-membered lactone 118 after removal of the silyl protecting group at position 13. Saponification of this lactone was most effectively accomplished with \(\ce{LiOH}\) and aqueous \(\ce{H2O2}\) which presumably benefits from the supernucleophilicity of the hydroperoxide anion. Hydrolysis of the less reactive benzoate esters in 119 was then accomplished with aqueous \(\ce{KOH}\). Subsequent methyl- ation delivered 120 together with a diastereomer from which it was sepatated by TLC on silica gel.
The relay compound 88 was obtained from 120 by ketalization with 2-methoxypropene, selective hydrolysis of 2-methoxy-2-propyl ethers that were also formed, and saponification of the methyl ester. Macrolactonization was accomplished by the "double activation method" that involves simultaneous activation of the hydroxyl and carboxyl functions. Presumably, a doubly activated intermediate 123 collapses to a tetrahedral carbonyl adduct 124 from which the lactone 126 is formed by elimination of 125. Thus, heating the thioester 122 at reflux in dry toluene provided erythrololide B in 50% yield.
Erythronolide B from Sugar-derived Homochiral Building Blocks.
A strategy for an enantiospecific total synthesis of erythronolide B evolved from the recognition that the C2-4 and C10-12 segments are identically substituted but have different absolute stereochemistries. Such segments, differentially substituted at each end, i.e. 127 and 128, might be elaborated and joined to generate the natural product. Therefore, studies were launched to define synthetic routes to such intermediates. Since (R)-2,3-O-isopropylideneglyceraldehyde (129) is a readily available homochiral building block (see section 3.7), it's possible utility as a starting material for the enantiospecific synthesis of such segments was explored.14
The addition of a crotylchromium reagent to aldehyde 129 showed virtually no diastereofacial selectivity for addition to the aldehyde but a high preference for generating an anti relationship at the two newly formed stereocenters owing to a stereoelectronic preference for chair-like transition state structures 130 and 131 that lead to 132 and 133. These diastereomers were readily separable by preparative column chromatography on a large scale. Conversion of 132 to an intermediate of type 127 and of 133 to an inter- mediate of type 128 requires inversion of the free secondary hydroxyl and substitution of the other secondary oxygen substituent by methyl with inversion of configuration. Inversion of the free hydroxyl was accomplished by activation as a tosylate followed by intramolecular SN2 displacement by a vicinal hydroxyl. This stereospecifically produced 135 from 134 and 138 from 137. Reaction of these epoxides with \(\ce{Li2Me2CuCN}\) accomplished the second configurational inversion during replacement of an oxygen substituent with methyl. The diols 136 and 139 correspond to the fragments 127 and 128 respectively, where FG1 and FG3 are both latent aldehydes while FG2 and FG4 are both hydroxymethyl groups.
The availability of the homochiral building blocks 136 and 139 channeled a second phase of strategic planning.15 Polar disconnection of erythronolide B at the C6-C7 and C8-C9 generates two precursors, 140 and 142, both with terminal carbonyl functions. Polar union of these fragments would require a "vicinally dianionic two-carbon (C6/C7) synthon" 141 with a pendant methyl group. Although the identification of a synthetic equivalent for 141 was postponed, it was recognized that "the methyl branching excluded the straightforward application of some acetylenic derivative."
Further polar disconnection of 142 to generate an aldehyde 143, that should be available from the building block 139, requires an acetyl carbanion synthon for which isopropenylmagnesium bromide is a latent synthetic equivalent. The alkene 144 is a latent equivalent of aldehyde 140. Further polar dislocation of 144 suggests an ethyl nucleophile and aldehyde electrophile 145 that should be available by oxidation of 136.
A masked derivative 147 of 142, containing the carboxylic acid functionality in latent form as a benzyloxy ether, was prepared from the homochiral building block 139 (see below). The addition of a Grignard reagent to an aldehyde intermediate generated the stereocenter at position 5 nonstereoselectively, leading to 146 as a 2:1 mixture of diastereomers. However, the requisite configuration at this carbon could be established by equilibration of the epimeric ketones 147 and 148. The equatorial ketone was favored over the axial epimer 148 by 94:6 at equilibrium.
A masked derivative 149 of aldehyde 140 was prepared from the homochiral building block 136. Although a polar union of the two carbonyl containing fragments 147 and 149 might exploit a dissonant dianionic fragment corresponding to 141, a synthetic equivalent of 141 was not devised. Rather, a nucleophilic reagent that was nucleophilic at C6 and contained an electrophilic carbon at position 7 was joined with aldehyde 151, and then the polar reactivity of C7 was inverted by conversion to an allylic thioether that could be deprotonated to provide nucleophilic reactivity at C7.
The carbon skeleton of erythronolide B was completed by joining ketone 147 with the allylic carbanion 152 produced by deprotonation of sulfide 151 with n-BuLi in the presence of TMEDA. Initial results were disapointing because the major product was the γ-adduct 153 rather than the desired α-adduct 154. By addition of HMPA, the formation of 153 could be suppressed almost completely. However, under these conditions, the main product was an epimeric α-adduct 155. Finally, it was discovered that precomplexation of the ketone 147 with \(\ce{BF3}\) strongly favored the required regio and stereoselecivity.
Having served its purpose as a polar reactivity inversion operator, the allylic phenylthio substituent was removed reductively. Differentiation of the hydroxyl groups was then accomplished by acetylation followed by selective deacetylation of 156 to unmask the primary hydroxyl. Oxidation followed by exhaustive deacetylation delivered the trihydroxy acid 157. Macrolactonization was accomp- lished in very good yield by conversion to a mixed anhydride that was cyclized in dilute toluene solution. Apparently a strain-free conformation that is ideally suited for cyclization is available to 157, whereas serious congestion is present in conformations suitable for forming a 12-membered lactone by acylation of the 11-OH.
Completion of the synthesis required introduction of oxygen at position 9. Anti Markovnikov hydration of the 8,9-C=C bond in 158 by hydroboration-oxidation accomplished this functionalization, and apparently owing to macrocyclic conformational effects, generation of the correct configuration at position 8 was favored by 9:1. Conformational effects also fostered selective oxidation of the secondary hydroxyl at position 9 in the presence of another secondary hydroxyl at position 11. Thus, the accumulation of many favorably selective steps owing to subtle, unanticipated consequences of molecular shape -- i. e. the remarkably effective macrolactonization, and favorably stereo and regioselective processes - - resulted in a total synthesis that rivals the Corey strategy that was more meticulously planned by thorough reterosynthetic analysis. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/05%3A_Polyketides/5.04%3A_Erythronolide_B.txt |
acetogenin (section 5.2)
biomimetic strategy (section 5.2)
cocyclic bond (section 5.3)
dehydrocyclization (section 5.1)
exendo bond (section 5.3)
fused-ring (section 5.3)
fusion-bond (section 5.3)
peripheral ring (section 5.3)
primary ring (section 5.3)
relay compound (section 5.4)
strategic bond (section 5.3)
5.06: Study Questions
1. Biosynthetic Strategies
(a) Draw a circle around each of the “common atoms” (as defined by Corey) in the carbon skeleton in the following structure of cercosporin (160).
(b) What is the polar reactivity relationship between the two functional groups at the ends of the circuits that are highlighted in 161 with respect to the bond indicated with a wavy line?
(c) What are the polar reactivity relationships between all of the functional groups with respect to all bonds along the circuit that is highlighted in 162?
(d) Presuming that this symmetrical molecule is generated in Nature by dimerization of a precursor, write a structure for that precursor of cercosporin (160).
(e) Name one type of reaction that could generate the bonds which unite two molecules of the biosynthetic precursor of cercosporin (160) that you proposed in d above.
(f) On the basis of a biogenetic hypothesis, the correct structure of eleutherinol was postulated to be 164 and not 163. In the space provided, write the structure of an acyclic precursor of 164 that is suggested by the biogenetic hypothesis.
2. Tactics in Polyketide Synthesis
(a) In his total synthesis of terramycin, Muxfeldt utilized 166 as a precursor for 165. Two of the carbons in 166, the ones that are highlighted, are not needed in the skeleton of 166. Explain all of the benefits of incorporating these two carbons in 166.
(b) In his total synthesis of 6-desmethyl-6-desoxytetracycline, Woodward exploits chloroester 168 as a precursor for 167. Neither the cholro nor the carbomethoxyl groups in 168 are incorporated into the final product, 6-desmethyl-6-desoxytetracycline. Explain the strategic roles of these two groups in the synthesis.
5.07: References
1. Harris, T. M.; Murphy, G. P.; Poje, A. J. J. Am. Chem. Soc. 1976, 98, 7733.
2. (a) Kuo, C. H.; Hoffsommer, R. D.; Slates, H. L.; Taub, D.; Wendler, N. L. Tetrahedron, 196319, 1. (b) Day, A. C.; Nabney, J.; Scott, A. I. J. Chem. Soc. 1961, 4067.
3. Stork, G.; Tomasz, M. J. Am. Chem. Soc. 1962, 84, 310; ibid. 1964, 86, 471.
4. Brossi, A.; Baumann, M.; Getecke, M.; Kyburz, E. Helv. Chim. Acta 1960, 43, 1444, 2071.
5. Danishefsky, S.; Walker, F. J. J. Am. Chem. Soc. 1979, 101, 7018.
6. Ranganathan, D.; Ranganathan, S. "Art in Biosynthesis" Academic Press, New York, 1976, pp. 167-172.
7. Corey, E. J.; Cheng, X.-M. "The Logic of Chemical Synthesis" Wiley, Interscience, New York, 1989, pp. 33-46.
8. (a) Woodward, R. B. Pure Appl. Chem. 1963, 6, 651. (b) Korst, J. J.; Johnston, J. D.; Butler, K.; Bianco, E. J.; Conover, L. H.; Woodward, R. B. J. Am. Chem. Soc. 1968, 90, 439.
9. Salomon, R. G.; Salomon, M. F. J. Org. Chem. 1975, 40, 1488.
10. Muxfeldt, H.; Rogalski, W. J. Am. Chem. Soc. 1965, 87, 933.
11. Muxfeldt, H.; Hardtmann, G.; Kathawala, F.; Vedejs, E.; Moobery, J. B, J. Am. Chem. Soc. 1968, 90, 6534.
12. Corey, E. J.; Nicolaou, K. C.; Melvin, Jr., L. S. J. Am. Chem. Soc. 1975, 97, 654.
13. (a) Corey, E. J.; Trybulski, E. J.; Melvin, Jr. , L. S.; Nicolaou, K. C.; Secrist, J. A.; Lett, R.; Sheldrake, P. W.; Falck, J. R.; Brunelle, D. J.; Haslanger, M. F.; Kim, S., Yoo, S. J. Am. Chem. Soc. 1978, 100, 4618. (b) Corey, E. J.; Kim, S.; Yoo, S.; Nicolaou, K. C.; Melvin, Jr. , L. S.; Brunelle, D. J.; Falck, J. R.; Trybulski, E. J.; Lett, R.; Sheldrake, P. W. J. Am. Chem. Soc. 1978, 100, 4620.
14. (a) Mulzer, J.; de Lasalle, P.; Freiβler, A. Liebigs Ann. Chem. 1986, 1152. (b) Mulzer, J.; Autenrieth-Ansorge, L.; Kirstein, H.; Matsuoka, T.; Münch, W. J. Org. Chem. 198752, 3784.
15. Mulzer, J.; Kirstein, H. M.; Buschmann, J.; Lehmann, C.; Luger, P. J. Am. Chem. Soc. 1991, 113, 910. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/05%3A_Polyketides/5.05%3A_Terminology.txt |
The alkaloids are a diverse family of nitrogen-containing natural products that generally are produced from amino acids in plants. Phenyl rings derived from aromatic amino acids may often be discerned embedded in the skeletons of some alkaloids. For example, the A ring of colchicine is derived from L-phenylalanine and the A rings of cephalotaxine and morphine are derived from L-tyrosine. Interestingly, the remaining carbons of the above mentioned alkaloids are also derived exclusively from L- phenylalanine or L-tyrosine. The loss of aromaticity that is common during such biosyntheses is an example of the unusual synthetic strategies that must be adopted in Nature owing to a limited selection of available starting materials.
The aromatic rings of polyketides (see chapter 5) arise from acetyl-CoA by a linear route culminating in dehydrocyclization of intermediate poly-β-ketoalkanoic acids. In the biosynthetsis of the aromatic amino acids L-phenyl-alanine, L-tyrosine, and L-tryptophan, the aromatic rings are assembled by a more convergent route starting with an aldol condensation of phosphoenol pyruvate (PEP) and erythrose 4-phosphate (E4P). These starting materials are available from glucose metabolism (see chapter 2).
Cyclization of the enol tautomer 2 of the resulting 3-deoxy-D-arabinoheptulosonic acid 7-phosphate (1) is reminiscent of the polyene cyclizations that are initiated by allylic pyrophosphates which are encountered in the biosynthesis of terpenes (see chapter 4). Dehydration and reduction then provide shikimic acid (3), the intermediate for which this biosynthetyic pathway is named. Phosphorylation of 3 and transetherification with a second molecule of PEP leads to a pivotal intermediate, chorismic acid (4). Appendage of the final three carbons of tyrosine and phenylalanine is achieved by a Claisen, i.e. [3.3] sigmatropic, rearrangement of 4 that produces prephenic acid (5). Decarboxylative elimination generates phenylpyruvic acid from 5 while oxidation and decarboxylation of the resulting vinylogous b-keto acid affords p- hydroxyphenylpyruvic acid. Transamination of the arylpyruvic acids (see 40 43 on section 5.3) delivers the corresponding α-amino acids L-phenylalanine (6) and L-tyrosine (7).
Amino acids are not the only building blocks incorporated into alkaloids. Thus, for example, some alkaloids incorporate starting materials of terpenoid origin. Quinine is assembled in Nature by the union of L-tryptophan with secologanin, a monoterpene. Interestingly, neither the tryptophane origin of the aromatic portion of quinine nor the terpenoid biogenisis of secologanin are at all obvious.
Much more obvious is the presence of L-tryptophan and an isopentenyl group embedded in the skeleton of lysergic acid. Polyketide fragments and nonaromatic amino acids may also serve as building blocks for alkaloids. For example, lycopodine is derived in nature from two molecules of L-lysine and one of acetoacetyl CoA.
06: Amino Acids and Alkaloids
Biosynthetic Strategy
The use of aromatic amino acids, i.e. phenylalanine or tyrosine, as the sole starting materials for colchicine (8) requires preparing the seven-membered C-ring by expansion of an aromatic six-membered ring in a precursor such as 9. How the ring expansion is accomplished will considered later. Since the starting amino acids do not have benzylic amino groups, it is likely that the bond between the C ring and the benzylic carbon is formed by electrophilic aromatic substitution. Since the starting amino acids are aryl propionic acid derivatives, the electrophile could be derived from an aryl propionic amide such as 10. Clearly the bond between the A and C rings in 10 would be formed by oxidative coupling of electron rich aryl precursors 11 and 12. Since the nitrogen in 11 probably comes from an amino group in the C ring amino acid precursor, and since 12 should also be derived from an a-amino arylpropionic acid, it is likely that the structure 12 must be revised so that the R group in 11 incorporates 12 as in the amide 13 (see below). A cinnamic acid 14, generated by elimination of ammonia from phenylalanine (6) could be the progenitor of the arylpropionic acid portion of the amide 13.
Generation of a phenylethyl amine 15 by decarboxylation of tyrosine (7) requires cleavage of a bond lying on a dissonant circuit. Such a cleavage is achieved biosynthetically by a polar process which converts the amino group temporarily into a derivative that can stabilize electronic excess on the amino carbon. The decarboxylation of tyrosine (7) to give p-hydroxy-b-phenthyl amine (15) is an example of a general reaction of amino acids that is promoted by the coenzyme pyridoxal phosphate (16). The process is initiated by the formation of a Schiff base 17. The pyridine nitrogen is conjugated with the carbon a to the carboxyl and can stabilize electronic excess at that carbon. The imine nitrogen does not provide polar activation; it serves merely as a linking atom. Schiff base 17 readily undergoes acid catalyzed decarboxylation to form 18. Protonation of 181 leads to rearomatization delivering the Schiff base 19. Hydrolysis delivers the phenylethyl amine 15 and regenerates 16. Thus, pyridoxal phosphate (16) acts as a polar reactivity-inverting catalyst.
We encountered polar ring expansion strategies in the total synthesis of longifolene (see section 4.4). There, a fused bicyclic intermediate, generated by cyclopropanation of a cyclohexene, underwent cleavage of the fusion bond in conjunction with departure of a nucleofuge to deliver a cycloheptenyl array (eq 1). An analogous process, involving departure of an electrofuge in conjunction with cleavage of the fusion bond in a similar intermediate, depends on a cyclopropyl carbinyl to homoallyl carbocation rearrangement (eq 2). The presence of oxygen substituents in the colchicine C ring suggests the possibility that such a ring expansion mechanism may transpire during the biosynthetic conversion of a six-membered C ring precursor into the seven-membered C ring.
One carbon of the phenethyl sidechain in 13, the benzylic carbon, could be incorporated in an aromatic precursor to generate the seven-membered C ring. The remaining carbon of the sidechain must be disconnected. Disconnection of this carbon as a carbocation can be stabilized by the amino group as in 20. Retrosynthetic analysis of the colchicine biosynthetic ring expansion, presuming 20 as electrofuge, suggests cyclopropyl carbinyl and homoallyl carbocation intermediates 21 and 22. The carbon that is inserted into the aromatic ring of the starting material 24 corresponds to the dication synthon 23 for which an aldehyde might serve as a synthetic equivalent.
Biosynthesis
In the biosynthesis of colchicine (8), \(\ce{NH3}\) is eliminated from phenylalanine (6), and tyrosine (7) is decarboxylated, before an amide 26 is formed by joining the resulting intermediates 25 and 15. The seven-membered B ring is created by an enantioselective intramolecular electrophilic aromatic substitution that gives 27 and an oxidative coupling of 28 that delivers 29. Functionalization of an apparently unactivated methylene in 29 is accomplished by a sequence involving polar hydrolytic fragmentation to 30 followed by oxidation to an aldehyde suitable for insertion into the six-membered C ring progenitor in 31. Expansion of the aryl ring to generate a seven-membered tropolone is initiated by intramolecular electrophilic aromatic substitution. Intramolecular alkylation of 32 followed by a fragmentation of an intermediate cyclopropane 33 produces the ring expanded skeleton in 34 of the biosynthetic target. Final hydrolysis of the imminium group, N-demethylation and N-acetylation delivers colchicine (8).
Molecular Characteristics
The stability of aromatic derivatives is often exploited in synthesis by strategies that incorporate preformed aromatic moieties. Thus, in the biosynthesis of colchicine (8), the aromatic A-ring is derived from the preformed aromatic ring of phenylalanine (6). The four different total syntheses of colchicine to be considered in this section all adopt this same strategy. In contrast with the biosynthesis, however, the total syntheses all employ fully functionalized aromatic starting materials. This is because the regioselective hydroxylations, that are acheived enzymatically in the biosynthesis, are not so readily achieved in the laboratory.
It should also be noted that the C ring of colchicine (8) contains two functional groups that provide electrophilic activation on adjacent carbon atoms, a polar reactivity dissonance. Thus, these functional groups cannot be exploited directly in a polar reaction (i.e. without umpölung) to create the C-C bond of the dissonant circuit between these carbon atoms. In each of the following syntheses, the seven- membered C ring is added to an AB-ring precursor. In each case, a different strategy is exploited for annelation of the C ring.
Key Intermediate-Directed Strategies for Conchicine
Two syntheses of colchicine exploited a readily available key intermediate, purpurogallin (34), for the AB ring moiety of 8 and formed the seven-membered C-ring by nonpolar reactions. Polar reactivity analysis of 34 suggests a synthesis from an aromatic precursor 36. Thus, appendage to 36 of the B-ring in 34 can be facilitated by addition of an activating carboxyl as in 35 that could be generated from 36 and 37 by two polar bond-forming reactions. In fact, the aromatic starting material 36 can also be the precursor of a temporarily-bridged synthetic equivalent 39 (vide infra) of the synthon 37.
Purpurogallin (34) was a well-known product from the oxidation of pyrogallol (36). It is probably formed by dimerization of 3-hydroxy-o-quinone (38). An initial Michael addition of the enolate 39 to 38 to give 40 followed by an intramolecular aldol condensation leads to a tricyclic intermediate 41 (see below). This is cleaved in a retro Dieckman reaction, typical for β-diketones, to produce a bicyclic carboxylic acid 37, which can be isolated. This vinylogous β-keto acid readily undergoes decarboxylation to deliver 28.
Both syntheses employing 34 for the A and B rings simplified the target by neglecting the acetamido group. This could be introduced by benzylic oxidation after completion of the carbon skeleton of the target 8. Both syntheses construct the simplified target 43 from benzosuberone derivative 44, in which the carbonyl functional group provides activation for annelation of the C ring. Eschenmosher1 prepared 39a by reducing the trimethyl ether 45 of purpurogallin (34) via 46, 47, and 48.
A Cycloaddition-Pericyclic Rearrangement Strategy for the C Ring
Eschenmosher's strategy1 for annelation of the seven membered ring C was to build a diene onto 44a, then construct a six membered carbocycle by a Diels-Alder reaction of the diene and finally expand the six to a seven membered ring by pericyclic rearrangement of a norcaradiene. Facile interconversion of cycloheptatrienes such as 49 with norcaradienes such as 50 is a well-known [3.3] sigmatropic (Cope) rearrangement that is driven to favor cycloheptatrienes by the relief of ring strain associated with cleavage of the cyclopropane. It is doubtful that the strategy was concieved by rigorous retrosynthetic analysis since conversion of 49 to 43 would certainly require extensive functional group manipulations. The decision to employ 49 as a precursor for 43 almost certainly evolved as a consequence of the decisions to employ: (1) a Cope rearrangement of a norcaradiene.
Therefore, chloromethylmaleic anhydride (52) is ideally suited to cycloadd to the reletively electron rich diene 53. Perhaps a more obvious dislocation of 50 would be to 53 and the cyclopropene 55. This branch of the retrosynthetic tree would, most probably, be considered first because it would provide a more convergent synthesis. Thus, reaction of 55 with α-pyrone 53 would deliver 50 directly by a Diels alder cycloaddition, followed in situ by a retro Diels Alder cycloelimination of carbon dioxide from an intermediate 56.
The alternative precursor, dienophile 52 with a chloromethyl substituent, is suggested by polar disconnection of 50 to 51 that can be derived from 53 by a Diels-Alder-retro Diels-Alder sequence. Dienophile 52 rather than 55 was chosen because it is more readily available than 55. A Diels-Alder addition of 52 to 53 followed by a retro Diels-Alder elimination of \(\ce{CO2}\) from an intermediate adduct, a carbonyl-alkene exchange process, will provide the cyclohexadiene 51. The driving force for the process is the generation of a relatively stable C=O bond in exchange for the C=C bond of the dienophile 52. The diene 53 is an enol lactone derivable from the acid 54. Polar analysis of 54 suggests construction from 44a and methyl propiolate by a polar 1,4-addition. Apparent Michael alkylation of 44a with methyl propiolate provided pyrone 57. Though 44a could give 57 via direct Michael addition to the yneone, in fact the reaction was more complex. It involved participation by the phenolate anion. Thus, the electrophile was delivered intramolecularly to the rather hindered benzylic carbon of 44a.
After methylation of phenol 57, the annelation of a cyclohexadiene 58 was achieved by the well- known cycloaddition-cycloelimination reaction of α-pyrones. Base-catalyzed intramolecular alkylation of the diester 51 from 58 led, via the norcaradiene 50, to the cycloheptatriene 49. The least hindered ester in 49 was readily hydrolyzed selectively, and the resulting acid afforded a tropolone 61 via osmium catalyzed vicinal hydroxylation-decarboxylation, saponification of the remaining ester in 60 and a second decarboxylation.
Unfortunately, the sequence leads to an oxygen function on C-11 rather than C-9 as required for colchicine. Transposition of the functional group was achieved by a well-precedented sequence of nucleophilic displacements on the tosylate derivative 62 of 61 first with \(\ce{NH3}\) to give 63 then with -OH to deliver 64. The tropolone 64 was then methylated and functionalized at C-7 by allylic bromination with N-bromosuccinimide to provide 65. Nucleophilic displace-ment of bromide by ammonia gave the required C-7 amine accompanied by ammonolysis of the tropolone, a vinylogous ester. Saponification of the resulting vinylogous amide 66 gave 67, that afforded colchicine upon methylation and acetylation.
An Acyloin Strategy for the C Ring
Van Tamelen's strategy for annelation of the C-ring with vicinal oxygen functionality recognizes the applicability of an intramolecular acyloin reaction for creation of the dissonant circuit between vicinal electrophilic activating groups.2 Further polar analysis suggests a synthesis of the requisite diester intermediate 68 by exploiting the polar activation provided by a carbonyl group in an AB-ring precursor 44. Thus, appendage of acetic and a propionic acid side chains should be feasible respectively by a Reformatsky reaction and Michael alkylation.
A pair of isomeric hydroxy diacids 69c and 69t was obtained by Michael alkylation of 44b with acrylonitrile, Reformatsky reaction of the intermediate ketonitrile and hydrolysis. The hydroxyl group was masked intramolecularly as a lactone, and the remaining carboxyl group was methylated. Only one of the isomeric lactone esters 70 underwent an acyloin reaction which provided 71. Unfortunately, this was the minor isomer 70t, with an axial carbometh-oxymethyl substituent. The ester groups in the major isomer 70c could not readily attain juxtaposition suitable for intramolecular acyloin reaction. The acyloin product 71 was oxidized to 72 with Cu(II) and further oxidized with NBS to provide tropolone 64. Methylation and bromination delivered the bromide 65, an intermediate also prepared by Eschenmosher. Substitution of an amino group for the bromo substituent in 65 followed by hydrolysis, remethylation of the vinylogous carboxylic acid, and N-acetylation produced colchicine 8.
Extensive functional group manipulations after completion of the carbon skeleton were required in the Eschenmosher synthesis because an annelation strategy for the C ring was adopted that ignored target related functionality. Van Tamelen could complete his synthesis with less functional group manipulations because more target related functionality, that had been exploited to facilitate skeletal construction, was present after completion of the C ring.
A Target-related Functionality-promoted Polar Bond Formation Strategy
Another synthesis of colchicine (8), also involving annelation of ring C on a preformed AB-ring intermediate, was devised by R. B. Woodward.3 The strategy is unique in incorporating the 7-amino substituent early and in its extensive use of target related functionality to facilitate carbon skeletal construction. Dislocation of the target 8 to derivative 74 in which the 8-position is also blocked allows selective introduction of oxygen at C-10. In the synthetic equivalent 75 of the synthon 74, an aromatic isothiazole ring masks both the amino substituent and C-8. Annelation of the C-ring can be achieved by a Dieckman cyclization 77 76 exploiting the polar activation provided by the C-9 carbonyl and an activating carbomethoxyl group appended to C-10 in a precursor 77. The polar activation provided by this carbomethyl group in 77 suggests an electrophilic aromatic substitution 78 77 for annelation of the B- ring. Of course, for the appropriate electrophilicity to be expressed, the carbomethoxyl group in 77 must be conjugated with the γ-position as in 78. The isothiazole also serves as a temporary bridge in 78, that assists entropically in the 78 77 cyclization. The carbomethoxyl in 78 also allows a polar elaboration of the dienoic ester array from an isothiazole aldehyde precursor 79 by stabilizing a carbanion in the ylide fragment 80. The sulfur atom in the isothiazole ring even provides activation for carbanion generation a to sulfur in 78 allowing polar connection of the carbomethoxyl required in 77. The extensive strategic utilization of the isothiazole unit in Woodward's strategy is a hallmark of this synthetic plan.
After Dieckman cyclization of 81, the C-9 monoketone 75 is selectively oxidized at the C-10 by a polar reaction exploiting the nucleophilic activation at C-10 provided by the C-9 carbonyl group. Nucleophilic attack by the C-10 carbanion on a sulfur electrophile leads to oxidation of C-10 (and concomitant reduction of sulfur). The resulting thioketal 82 is hydrolyzed to 83, that affords the enol acetylation product 84. The enediolate obtained by saponification of the diacetate 84 is readily oxidized to deliver 85. Desulfurization of 85 with Raney nickel removes the isothiazole masking group. Reduction of the resulting imine 86 followed by acetylation provides 87 that is N-methyl-ated to deliver colchicine (8).
Woodward's synthesis of the key intermediate 81 is centered around the novel aromatic isothiazole ring. The starting material, an isothiazole 88, is readily available from methyl β-aminocrotonate, an enamine derived from methyl acetoacetate. The conjugated methyl group in 88 is readily brominated with NBS. Alkylation of \(\ce{Ph3P}\) affords a phosphonium bromide 89, that gives ylide 90 upon deprotonation. Wittig olefination of 3,4,5-trimethoxybenzaldehyde (91) with ylide 90 produces alkene 92 that was selectively hydrogenated with diimide. Catalytic hydrogenation of 92 was precluded by the susceptibility of the isothiazole ring to hydrogenolysis. Hydride reduction of the ester 93 and partial oxidation of an intermediate conjugated carbinol gave the aldehyde 94. Wittig olefination of 94 with ylide 95 followed by saponification and cis-trans isomerization provided 96.
This diene underwent intramolecular electrophilic aromatic substitution upon treatment with perchloric acid. The temporary bridge provided by the isothiazole ring undoubtedly facilitates this cyclization by favorably juxtaposing the reacting carbon centers. Selective reduction of the cyclization product 99 with diimide gave 100. The final carbon required for the C ring was introduced by carbonylation of an organolithium derivative 102 from the thiazole 100. Thus, selective metallation in the presence of a carboxylate was achieved with the relatively non nucleophilic, sterically encumbered aryl lithium 101. The lithiated thiazole 102 gave the key intermediate 81 upon carbonation followed by methylation.
A Hypothetically Biomimetic Strategy
A fourth synthesis of colchicine, devised by Scott4, differs from the previous three in its strategy for skeletal constuction. Scott assembled an intermediate containing the A and C rings and then created the B ring by an intramolecular oxidative coupling. This strategy was based on a hypothetical mechanism for colchicine biosynthesis, that is now know not to be operative. In this mechanism, in contrast with the actual biosynthetic mechanism (see above), generation of a tropolone C-ring by ring expansion of an aromatic precursor preceeds the oxidative coupling that creates the B-ring.
The tactic of introducing the colchicine amino group at the end of the synthesis was well-precedented. Thus, the Scott strategy begins with dislocation of the target 8 to a precursor 103. The bond between aryl and tropolone rings lies along a dissonant circuit between the oxygen functionality at positions 1 + 9, 1 + 10, 3 + 9, or 3 + 10. Thus, polar analysis reveals that formation of this bond cannot be achieved by a polar process using these functional groups to provide activation since union of two nucleophilic centers would be required. Such a process can be achieved oxidatively, suggesting dislocation of 103 to a precursor 104 with two monocyclics joined by a simple trimethylene bridge. The polar reactivity afforded by the carbonyl group in 104 can be reinforced by activating carboxyl groups in a precursor 105 allowing polar bond formation between an electrophilic intermediate 106 and a nucleophile derived from 107 by deprotonation. The unobvious choice of 107 as a precursor for 104 was undoubtedly dictated by its ready availability from purpurogallin 34 by selective oxidative cleavage of the relatively electron rich aryl ring.
Thus, oxidation of 34 with hydrogen peroxide followed by dehydration gave the enol anhydride 107. It is interesting that Scott utilized purpurogallin (34) as a precursor for the C ring of colchicine in contrast to Eschenmosher and Van Tamelen who built the A and B rings of colchicine from 34.
An A-ring synthon, 3,4,5-trimethoxy acetaldehyde (106) was obtained by Arndt-Eistert homologation of 3,4,5-trihydroxybenzoic acid (108). Union of the electrophilic A ring synthon 106 with the nucleophilic C-ring synthon 107 was best achieved thermally without base catalysis by a process that starts with an aldol condensation. At 100°C, a lactone 110 was formed, presumably by decarboxylation of an intermediate vinylogous β-keto acid 109. Further heating of 110 at 190°C gave 112, presumably by decarboxylation of an intermediate β-keto acid 111. Reduction and demethylation gave the A+C ring intermediate 104. The electron rich product 103 from the desired oxidative coupling of 104 was highly susceptible to undesirable further oxidation. Nevertheless, the mild oxidant, \(\ce{FeCl3}\), in a two phase system gave 103 after paper chromatography in an inert atmosphere albeit in low yield (5%).
It has been suggested that the annelation may involve an ionic process rather than the radical coupling originally envisioned.5 Thus, utilizing the aryl oxygen functionality at position 2, that was ignored in the polar analysis of 103 above, it can be seen that the bond between the aryl and tropolone rings lies on a consonant circuit between positions 2 and 10. This allows Michael addition of a tropolone nucleophile to an enone electrophile as shown in 113 to deliver 114. Final adjustment of functionality gave 8 from 103 through 73 as discussed previously. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/06%3A_Amino_Acids_and_Alkaloids/6.01%3A_Colchicine.txt |
The biosynthesis of cephalotaxine (115) involves a convergent strategy that assembles an intricate multicyclic skeleton from two aromatic amino acid precursors, phenylalanine (6) and tyrosine (7). As in the biosynthesis of colchicine (8), one aromatic ring is incorporated intact while the other is extensively modified. Thus in the biosynthesis of colchicine (8) the seven-membered C-ring is elaborated by a one- carbon expansion of a tyrosine-derived aromatic ring. In contrast, the biosynthetic strategy for cephalotaxine (115) exploits a one-carbon ring contraction to produce a five-membered C-ring from a phenylalanine-derived six-membered ring. The logic of the strategy is based on: (1) the ready availability of highly oxygenated cyclohexyl derivatives such as 119 by oxidative metabolism of aromatic precursors and (2) the possibility of extruding a carbon atom as carbon dioxide from an α-diketone by a benzylic acid rearrangement to an α-hydroxy acid. This suggests the α-hydroxy acid 116 as precursor to 115.
Retrosynthetically, dislocation of a benzylic acid rearrangement product 116 to a precursor 119 corresponds to polar disconnection of the migrating carbon as nucleophile resulting in oxidation of the migration terminus. Subsequent connection of the nucleophilic migrating carbon in 117 results in reduction of the migration origin in the precursor 118. Polar analysis of 119 suggests polar disconnection of nitrogen as nucleophile from an electrophilic carbon β to a carbonyl group. Polar analysis of the precursor 120 suggests that the aromatic rings of two precursors 6 and 7 might be joined by an oxidative coupling.
The connection-disconnection sequence of the benzylic acid rearrangement, generalized in the 121 to 125 conversion, is mechanistically analogous to the pinacol rearrangement discussed in chapter 4 (see section 3.4). The rearrangement of 122 into 124, involved in the benzylic acid rearrangement, is isoelectronic with the 126 to 128 conversion of the pinacol rearrangement, i. e. the same electronic movements in identical arrays of atoms, bonds, and nonbonding electrons are involved. Nucleophilic addition of hydroxide to an α-diketone 121 initiates the benzylic acid rearrangement, that proceeds through a temporarily-bridged transition state 123, and ultimately produces an α-hydroxy acid 125. The pinacol rearrangement proceeds through a temporarily-bridged transition state 127. In both the benzylic acid and pinacol rearrangements, the migrating group acts as an internal nucleofuge-nucleophile that adds to an electrophilic migration terminus. In both rearrangements the functionality level of the migration origin increases while the functionality level of the migration terminus decreases.
The biosynthesis of cephalotaxine (115) is believed to involve oxidative coupling of two electron rich aromatic rings in a phenethylisoquinoline6 intermediate 128 delivering a tetracyclic δ-amino-α,β- unsaturated ketone 129. The polar formation and subsequent polar cleavage of a temporary six-membered nitrogen heterocycle in 128, facilitates the oxidative coupling by making it an entropically more favorable intramolecular cyclohexannelation rather than a cyclodecannelation that must generate 130 directly. It is reasonable to postulate the presence of a methoxyl group at position 7 in 128 since this could account for the regioselective oxidative coupling at position 8a which is para to the hydroxyl group presumed to be present at position 6. This regioselectivity contrasts with that observed in the oxidative coupling of autumnaline (28) at position 4a (see section 6.1). Thus, the O-methyl groups in 28 and 128 serve as regiocontrol elements in the oxidative couplings of these phenethylisoquino-lines. Reduction and regioselective methylation of 130 set the stage for regioselective electrophilic activation by oxidation of the ortho hydroquinone 131 to an ortho quinone 132
Nucleophilic Michael addition of the secondary amine then delivers 133 whose keto tautomer 134 is an α-diketone. Benzylic acid rearrangement initiated by conversion to 135 delivers α-hydroxy acid 136 in which the carboxyl carbon is derived from a meta carbon of the phenylalanine (6) starting material. Loss of this carbon as carbon dioxide then generates cephalotaxine (115) after conversion of the ortho methoxy-phenol array into a methylenedioxy group. This conversion, i.e. 137 to 139, is common in Nature and presumably involves oxidative generation of an electrophile 138.
B Ring Annelation by Electrophilic Aromatic Substitution
As in the biosynthesis of cephalotaxine (115), the stability of aromatic derivatives recommends the utilization of an aromatic precursor for ring A. The Weinreb strategy for construction of the cephalotaxine skeleton7 recognizes the potential utility of the amino group and dissonant C-ring functionality for activating polar reactions that could append the C-ring onto an ABD-ring precursor. Synthetic equivalents 142 and 143 correspond to the polar synthons 140 and 141. A carbonyl group in 143 is added to facilitate generation of a precursor 145, the amide of prolinol (146) and the arylacetic acid 147. The enamine in 143 could be produced by dehydration of a β-hydroxy amine precursor 144 that, in turn, should be available directly by polar union of an aromatic nucleophile and aldehyde electrophile in 145.
The enamine 143 was constructed by annelation of ring B between an aromatic ring A precursor 147 and a preformed ring D precursor 146. Masking of the hydroxyl group in 146 is unnecessary since acylation occurs at the more nucleophilic nitrogen to give amide 148 rather than at the less nucleophilic oxygen to produce an ester. The final bond of ring B was formed by electrophilic aromatic substitution which occurred exclusively at the less congested aryl position in 145. Having served its purpose, the amide carbonyl was reductively removed from 143 to deliver 149. The polar activation afforded by the acyl group in 142 is first exploited to unite 142 and 149 to give 150. Then the polar activation afforded by both carbonyl groups is exploited to complete the annelation of ring C. An intramolecular Michael addition of an enolate anion to the electrophilic β-carbon atom of an α,β-unsaturated carbonyl system leads to 153. The required cis-ring fusion of ring C is undoubtedly the most stable. The methyl carbonate anion leaving group in 142 is especially noteworthy. Decarboxylation of this anion generates methoxide in situ that then deprotonates an intermediate iminium ion 150 to produce the Michael acceptor 151 under exceptionally mild conditions. Also noteworthy is the use of magnesium methoxide as base to generate the enolate 152 in the Weinreb synthesis of cephalotaxine. Magnesium can assist the cyclization by chelation that enforces a favorable cisoid conformation. Final adjustment of functionality involved enol etherification and hydride reduction. Delivery of hydride occurs from the less sterically congested convex face of 154 producing 115 with the correct relative configuration at the third asymmetric center in ring C. A regioisomeric enol ether was obtained together with 154. This isomer could be recycled by acid catalyzed equilibration.
B Ring Annelation by Nucleophilic Aromatic Substitution
Whereas annelation of ring B in the Weinreb synthesis of cephalotaxine (115) was achieved by electrophilic aromatic alkylation, Semmelhack's synthesis creates the same connection by nucleophilic aromatic alkylation.8 Semmelhack's strategy exploits a C-ring carbonyl to provide the requisite nucleophilicity in a final intermediate 155. As in the biosynthesis and the Weinreb strategy, an aromatic precursor is exploited for ring A. N-alkylation of a CD-ring amine fragment 157 with the A-ring fragment 156 provides 155. The same A-ring starting material 147 is used for both total syntheses. Ring C in 157 contains two oxygen functionalities that provide electrophilic activation at their respective carbon atoms. Thus, these functional groups cannot be exploited directly to create the bond between those carbon atoms by a polar reaction. In the Weinreb synthesis of cephalotaxine (115), ring C was constructed by polar reactions by using a starting material 142 that incorporates the dissonant circuit between the two oxygen functionalities in the C-ring. The Semmelhack strategy recognizes that this dissonant circuit in 157 can be formed by a nonpolar reaction, reductive coupling of the two electrophilic carbonyl carbons in a precursor 158. Although 158 might be available directly by polar addition of two carbomethoxymethyl nucleophiles to an electrophilic D-ring precursor 160, Semmelhack opted for the alternative strategy of adding two allyl nucleophiles to 160 followed by oxidative revelation of the latent carboxyl groups in an intermediate 159.
The CD-ring intermediate 157 was prepared from pyrrolidinone. The reaction of an imino ester 160 with an allyl nucleophile gave 159. Masking of the amino group as an acid labile amide 161 was required prior to oxidative cleavage of the C-C π-bonds in 159 which ultimately provided the diester 158. Intramolecular acyloin coupling of 158 in the presence of chlorotrimethyl silane (the Rühlmann modification) produced 162, that was oxidized directly to 163 by a one-pot addition of bromine and elimination of TMSBr. Methylation of this symmetrical dione delivered 157. Alkylation of this amine with the nitrosylate 164 provided 155. Cyclization of 155, vide infra, followed by reduction of the intermediate 154 delivered cephalotaxine (115). This synthetic strategy leads directly to the correct enol ether 154 without formation of the regioisomeric enol ether that is a byproduct in the Weinreb synthesis.
The key cyclization of 155 to 154 was achieved by a variety of reactions all involving nucleophilic aromatic substitution. Of course, direct nucleophilic attack on the electron rich A ring aryl iodide does not occur when an enolate nucleophile is generated from 155. However, net nucleophilic substitution could be accomplished by photolysis of the enolate 165 or by treatment of 165 with Na/K or a nickel(0) catalyst. Best yields of the cyclization product 154 (94%) were obtained by a photostimulated SRN1 reaction presumably involving the chain carrying anion radicals 166 and 167. The SRN1 reaction could also be achieved (45%) by reaction of the enolate 165 with Na/K. A nickel(0)-catalyzed reaction of 165 provided 154 in 30% yield presumably by oxidative addition of the aryl halide to Ni(O) and nucleophilic substitution of iodide by a carbanion producing a σ-aryl-nickel(II) intermediate 168, that undergoes reductive elimination of 154 to regenerate the Ni(0) catalyst. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/06%3A_Amino_Acids_and_Alkaloids/6.02%3A_Cephalotaxine.txt |
Biosynthesis of Benzylisoquinoline Derived Alkaloids
The biosyntheses of colchicine and cephalotaxine involve phenylethylisoquinoline progenitors 28 and 128. Many alkaloids, that are derived biologically from two molecules of tyrosine, share benzylisoquinoline progenitors of general structure 169 (see below). In addition, both six membered rings derived from the aryl nuclei are often retained. Both may be aromatic as in berberine (170), or one may be nonaromatic as in morphine (171). The biogenetic strategy for berberine (170) involves a simple dislocation to a benzylisoquinoline precursor by disconnection of a one-carbon electrophile from the nucleophilic nitrogen and D-ring arene. An intact benzylisoquinoline structure is less evident in the convoluted multicyclic skeleton of morphine (171). If an electron rich aromatic precursor is presumed for the highly oxygenated C-ring, then polar disconection of a furan C-O bond suggests that oxidative coupling of aromatic A and C-rings of a benzylisoquinoline precursor can generate the B-ring of 171. The key benzylisoquinoline intermediates 169 could be produced by Mannich reactions. These condensations might involve polar bond formation between a phenylacetaldehyde electrophile 173 and dopamine (172) as bisnucleophile.
The biosynthesis of berberine (170) from two molecules of tyrosine (see below) commences with pyridoxal-catalyzed decarboxylation and electrophilic hydroxylation that produces dopamine (172). Replacement of the α-amino group of tyrosine with a carbonyl by transamination and electrophilic hydroxylation produces 3,4-dihydroxyphenylpyruvic acid (174). This highly reactive ketone, rather than a phenylacetaldehyde, serves as the electrophile in a Mannich reaction with dopamine (172). Polar condensation of the highly electrophilic carbonyl in 174 with 172 as bisnucleophile generates the benzylisoquinoline ring system in 175. Oxidative decarboxylation of this α-amino acid followed by reduction of the intermediate 176 delivers norlaudanosoline (177) from which reticuline (178) is produced by O and N-methylation. The N-methyl group is incorporated into the berberine skeleton by a Mannich condensation of iminium derivative 180 produced by dehydration of an intermediate protonated N-oxide 179. Conversion of an o-methoxyphenol array in the product 181 to a methylenedioxy group in 182, methylation and aromatization of the product 183 delivers berberine (170).
The more topologically complex skeleton of the morphine alkaloids is also produced from reticuline (178). Thus, oxidative ortho-para coupling delivers salutaridine (184). Generation of the benzofuran ring of thebaine (186) occurs after adjustment of functionality level resulting in loss of functionality from position 7 of 185. Interestingly, although simple hydroly-sis of enol ether 186 could produce ketone 188, the oxygen of the methoxyl group is retained in 188. Therefore, a different mechamism must be involved. Perhaps demethylation of 186 occurs through an oxidized intermediate 187 that undergoes retroene fragmentation. Allylic isomerization, reduction, and demethylation then deliver morphine (171).
The demethylation of codeine (190) and of the enol ether 187, as well as the conversion of ortho methoxy phenols 137 into methylenedioxy derivatives 139 (see section 6.2) may all be related mechanistically by the initial oxidative conversion of a methyl ether into an α-oxygen-stabilized carbocationic intermediate. Demethylation would occur upon nucleophilic capture by water and fragmentation of the resulting formaldehyde hemiacetal.
A Biomimetic Synthesis of Morphine
Morphine has been assembled in the laboratory by a biomimetic strategy involving oxidative coupling of reticuline (178).9 Oxidative coupling of 178 was accomplished by treatment with manganese dioxide. Salutaridine (184) was obtained, albeit in miniscule yield. Hydride reduction provided the allylic alcohol 185. With mild acid catalysis, 185 underwent intramolecular SN2' displacement of the allylic hydroxyl by the phenolic hydroxyl to afford thebaine (186) from which morphine (171) can be produced (vide infra).
The bridged multicyclic skeleton of morphine has considerable topological complexity. A topological analysis (see section 4.4) may, therefore, be useful for synthetic planning. Considering only the carbocyclic skeleton of 171, there are four common atoms, a-d, and three possible disconnections between them. Of these disconnections, only one, removal of the bond between common atoms b and c, leads to a structural simplification. If the heterocyclic skeleton is also considered, there are also three more common atoms, x, y, and z. Disconnection of bonds between these latter common atoms and a heteroatomic ring member are generally trivial because the heteroatoms are reactive functionality. Disconnection of the b-c bond (and the bond between common atom y and oxygen) suggests a precursor such as 178 (reticuline), the biosynthetic progenitor of morphine alkaloids. Interestingly, this is the only cleavage of a bond between a pair of common atoms that leads to simplification of the morphine carbon skeleton. Thus, cleavage of the bond between common atoms a and b leads to an intermediate with two fused ten membered rings, that would be a redoubtable synthetic challenge. Because it does not lead to reduction of molecular complexity, this dislocation is probably not useful. Cleavage of the π-bond between common atoms c and d disrupts an aromatic system and creates a ten membered ring. The stability of aromatic systems usually disfavors synthetic strategies involving annelation of aromatic rings in the final stages of a synthesis. Therefore, this dislocation is also probably not useful.
A Diels Alder Strategy for C Ring Annulation
The presence of a cyclohexene array in the C ring of morphine (171) recommends consideration of a Diels-Alder reaction to generate two vicinal exendo bonds, each involving one common atom (i. e. a or b) and one noncommon atom. This topological simplification was exploited in the first total synthesis of morphine.10 However, the C=C bond in the C ring of 171 is in the wrong location. Therefore, with the use of a Diels-Alder tactic as a boundary condition, dislocation of 171 to an amide 190 sets the stage for a retro Diels Alder dislocation. To allow the incorporation of a C=C bond for a dienophile, 190 is first dislocated to 191 by cleavage of carbon-heteroatom bonds to the common atoms x and y. The carbonyl at position 9 in 191 provides activation for a Diels-Alder construction of the C-ring from an AB-ring dienophile 192 and 1,3-butadiene, a relatively electron-rich diene. However, this strategy is fatally flawed because 192 is expected to exist almost exclusively in the aromatic enol form 193 that would not be a reactive dienophile. To block this undesirable enolization, a carbonyl group can be exploited at position 10 (morphine numbering) in a precursor 194. The cyanomethyl sidechain can be appended by the polar union of a nitrile-stabilized nucleophile with the electrophilic β carbon of the α,β-unsaturated carbonyl array in 195. The C-10 carbonyl in 195 also would facilitate this Michael addition of the sidechain nucleophile by preventing enolization of the enone in conjunction with aromatization.
The scheme used for the synthesis of 195 exploits the symmetry of 2,6-dihydroxynaphthalene (196) that readily undergoes electrophilic substitution at the α-position. The electron withdrawing effect of the benzoyl group in the monobenzoate 197 diminishes the electron donating ability of the benzoylated hydroxyl. Therefore, nitrosation occurs regiospecifically at the α-position next to the free hydroxyl. Reduction of the nitroso group affords an amine 198, that is oxidized to an ortho quinone 199. Reduction, methylation, and saponification then delivers phenol 200 that affords 195 by regioselective nitrosation, reductive N-O cleavage and oxidation.
The carbon skeleton of the dienophile 194 is completed by Michael addition of ethyl cyanoacetate carbanion to 195. After saponification, decarboxylation and aromatization, an intermediate hydroquinone 201 is oxidized to give the ortho quinone 194. The carbocyclic skeleton of morphine is completed by a Diels-Alder cycloaddition that provided 191. Elaboration of a piperidine ring began with a reduction that gave the lactam 202 directly. This lactam is epimeric with the morphine skeleton at position 14 presumably owing to steric approach control during delivery of hydrogen to the enolic 9-14 C=C bond in 191.
The resulting alcohol presumably adds to the C≡N bond producing an iminoether intermediate that rearranges to the lactam 202. Remarkably, the sterically far more congested 9-14-C=C bond is reduced while the 6,7-C=C bond remains unreduced under these conditions.
The C-10 carbonyl in 202, having served its purpose was then removed by Wolff-Kishner reduction. After N-methylation of 203, the amide carbonyl was removed by hydride reduction. Hydration of the isolated π-bond in 204 proceeded completely regio and stereoselectively to give 205 in "yields up to 28%". This fortunate selectivity is understandable in terms of a stereoelectronic preference for anti periplanar diaxial addition to the C=C bond with addition of the nucleophile preferentially syn to the protonated amino substituent. The original intention had been to demethylate both ether groups of 205 and to attempt a selective remethylation of the less sterically congested 3-hydroxyl. The action of pyridinium hydrochloride, however, not only cleaved both phenolic ether groups but also dehydrated the secondary alcohol. Fortunately some demethylation of the C-4 methyl ether had been observed during the 202 to 203 conversion. This discovery was exploited by developing conditions that afforded 206 in 54% yield upon heating with KOH in ethylene glycol. Presumably releif of steric congestion fosters demethylation of the 4-methoxy group by an SN2 displacement of phenolate by hydroxide. Completion of the morphine skeleton by generating a furan ring required considerable adjustment of functionality and stereochemistry in 206. A carbonyl at position 6 could be exploited both to allow activation of the 5-position toward intramolecular nucleophilic attack by the C-4 hydroxyl and to allow epimerization at the 14 position. Thus, oxidation of the C-6 hydroxyl in 206 by a variation of the Oppenauer reaction gave ketone 207. To provide the conjugation with the C-6 carbonyl needed to allow epimerization at C-14, a C=C bond was introduced between carbons 7 and 8. Thus, bromination followed by Mattox-Kendall de-hydrobromination (see section 5.4) provided the epimerized tosylhydrazone 198.
After hydrolysis to an enone 210 and reduction to a ketone 211, activation at the 5-position was achieved by bromination with two equivalents of bromine. It is not clear why 207 could not be converted directly into 212 without the intermediacy of 210 and 211. Subsequent monodehydrobromination of an intermediate α,α'-dibromo ketone with DNPH delivered 212. This underwent cyclization in pyridine to yield benzofuran 213 after hydrolysis of the hydrazone. During the 207 to 208 conversion an adventitious bromo group was introduced into the A ring. This was conveniently removed during the reduction of the C-6 carbonyl with lithium aluminum hydride to give codeine (190), the monomethyl ether of morphine (171). Hydride delivery to 213 occurred stereoselectively from the more sterically accessible convex face. Demethylation of 190 was achieved by nucleophilic displacement by chloride of phenol from the protonated ether.
A Friedel-Crafts B Ring Annelation Strategy
Another strategy for synthesis of morphine (171) is channeled by the decision to generate the B ring by electrophilic substitution of an electron-rich A ring nucleophile.11 This tactic requires temporary carbonyl functionality at the incipient 10 position that would have to be removed in the final steps, e. g. by reduction of a precursor 214. Target- related oxygen functionality at position 5 can be exploited to facilitate introduction of the remaining C-ring functionality and unsaturation and to facilitate generation of the nitrogen heterocycle by alkylation of a carbon nucleophile at position 13. This requires activation of the incipient carbon 15, i.e. α to the amide carbonyl in 214, with a nucleofuge. Appendage of an amino nucleophile to position 11 in a precursor 216 for 215 cannot be achieved by a polar process since neither keto group in 216 can provide electrophilic activation at the 11 position. On the other hand, a nitrogen electrophile could be added to an intermediate that is nucleophilic at position 11 because of activation by the neighboring ketone carbonyl, e.g. by nitrosation of ketone 216. The ABC-ring carbocyclic skeleton of morphine can be assembled by intramolecular Friedel-Crafts aromatic substitution of an electron rich AC-ring precursor 217. Polar analysis of 217 recommends an a,b-unsaturated enone electrrophile 218 that would provide 217 by addition of a carboxy activated nucleophile.
A precursor 219 of 218 might be generated by electrophilic aromatic substution of 220 by a carbonyl activated electrophile, 1,2-cyclohexanedione. However, steric congestion would favor the alternative regioisomeric product 222. The use of an alternative nucleophile, the regioselectively ortho lithiated aromatic diether 221 as nucleophile, avoids this ambiguity. Alternative routes to 218 are recommended by the possibility of employing cyclohexanone as a more readily available C ring starting material. Thus, the arylcyclohexene 224 could be functionalized by a dihydroxylation-oxidation sequence to give 218 through 219 and 223. The possibility of generating 218 directly from 224 by allylic oxidation suffers from the ambiguity of an alternative regiochemical course leading to 225.
An arylcyclohexene 224 is readily available by ortho lithiation of veratrole (220) with butyllithium and reaction of the resulting aryllithium 221 with cyclohexanone followed by acid-catalyzed dehydration. Allylic bromination (with NBS) or chlorination (with t-butylhypochlorite) followed by hydrolysis and oxidation did deliver the requisite enone 218. But this intermediate was more readily available (overall yields of 40 - 50%) by addition of nitrosyl chloride (from amyl nitrite, acetic acid, and 30% HCl), dehydrochlorination of the intermediate nitrosochloride 226 as the oxime tautomer 227 to the unsaturated oxime 228 and hydrolysis.
The two carbons required to complete the B-ring were appended by Michael addition of dibenzyl malonate carbanion to the enone 218, hydrogenolysis of the resulting 229, and decarboxylation. Friedel-Crafts cyclization of 217 provided the B-ring in 216. Differentiation of the carbonyls in 216 could be accomplished by selective ketalization of the more electrophilic carbonyl. An amino substituent was introduced by nitrosation of an enolate. Reduction of the oxime 230 under acidic conditions was accompanied by deketalization. N-acylation delivered α-acetoxyacetamide 231. Intramolecular alkylation and selective ketalization (now of the less sterically congested carbonyl) occurred upon treatment of 231 with acid. Transposition of the C-ring carbonyl was initiated by nitrosation of the enolate of 232. Deketalization followed by Wolff-Kishner reduction of the intermediate diketo oxime 233 delivered oxime 234 removing two carbonyl groups but not the oxime-masked carbonyl. Hydrolysis of the oxime, reductive removal of the amide carbonyl, reductive methylation of the resulting amine, and oxidation of an intermediate secondary alcohol delivered the ketone 235. Conversion of an analogous intermediate 208 to morphine (171) was described above.
A Conjugate Addition-Alkylation Strategy for B Ring Annulation
Both of the foregoing syntheses of morphine involve: (1) extensive functional group manipulation after construction of the ABC and piperidine rings, (2) generation of the furan ring last, and (3) a dependence on carbonyl groups to activate or control reactivity. A completely different strategy was employed to achieve a more convergent synthesis of morphine.12 This strategy involves: (1) generation of the piperidine ring last, (2) minimal functional group manipulation after completion of skeletal construction, and (3) exploitation of a sulfonyl group to provide polar activation. As for the biosynthesis and previous syntheses of morphine, the aromaticity of the A-ring recommends an aromatic starting material for this ring. A consonant circuit between C-ring oxygen and B-ring nitrogen substituents in morphine (171) suggests a construction of the piperidine ring, that exploits the polar reactivity provided by target-related functionality in an α,β,γ,δ-unsaturated ketone precursor 236. A polar double disconnection of the B-ring, between a pair of common atoms and between a common and a noncommon atom, is made possible by a strategically placed phenylsulfonyl activating group in a precursor 238 of 237. Polar disconnection of 238 suggests A and C-ring precursors 239 and 240 that should be available from isovanillin (241) and the symmetrical 2-allylcyclohexane-1,3-dione (242) by functional group additions and interconversions.
The key A-ring intermediate 239 is available on a large scale from isovanillin (241) in 40% overall yield as outlined below. Substitution of the enolic hydroxyl in 2-allylcyclohexane-1,3-dione (242) by a phenylsulfonyl group is accomplished through the vinylogous acyl chloride 243 to provide 244 by addition of phenylsulfinate and elimination chloride, respectively, in 74% yield overall. Oxidative functionalization of 244 was accomplished by a Rubottom reaction, i.e. treatment of the corresponding enol silyl ether with m-chloroperbenzoic acid. Neither the electron deficient α,β-unsaturated sulfone nor the terminal C=C bond are oxidized in competition with the more electron rich silyl enol ether. Steric approach control in a hydride reduction of 245 delivers the allylic alcohol 246 stereoselectively.
O-alkylation of 246 with 239 provides the key intermediate 247, that undergoes a remarkable cyc- lization upon halogen-metal exchange. Intramolecular Michael addition of the intermediate aryllithium 238 leads via sulfone-stabilized carbanion 248 to 237. Construction of the piperdine ring requires conversion of the allyl group in 237 into an ethylamino sidechain and conjugation of C-11 with the oxygen functionality at position 6 in 237. Oxidation and enol etherification delivers 250 from 249. Elimination of phenylsulfinate to give 251, and hydrolysis to deliver 252 sets the stage for the completion of the morphine ring system by generation of the piperidine ring. Thus, neutralization of the ammonium salt 252 generates an amino group that undergoes spontaneous intramolecular 1,6-Michael addition to the dienone to deliver a mixture of neopinone (188) and codeinone (189) in 63% yield. Conversion of this mixture via codeine (190) to morphine (171) was accomplished as described previously by Rapoport. The required configuration of the hydroxyl at position 6 is established during a steric approach controlled delivery of hydride to the carbonyl carbon in 189. The correct configuration at the 15-position in 190 arises from equilibration through the common enol derivative of ketones 188 and 189. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/06%3A_Amino_Acids_and_Alkaloids/6.03%3A_Morphine.txt |
Biosynthesis of Tryptophan and Lysergic Acid
The carbon skeleton of anthranilic acid (254) is constructed in nature from two molecules of phosphoenol pyruvate and one of erythrose 4-phosphate via chorismic acid (see section 5.1). The two-component enzyme complex of anthranilate synthetase (AS) then promotes the transfer of \(\ce{NH3}\) from glutamine to chorismic acid (4) affording amino acid 253 by conjugate displacement of a hydroxyl group. During the strategically intricate biosynthesis of tryptophan (259), the carboxyl carbon of 254 is ultimately lost. A five-carbon unit from ribose is appended to the amino group of 254, but suprisingly all five carbons of phosphoribosyl pyrophosphate (PRPP) are not retained to complete the tryptophan skeleton (vide infra). Deprotonation of the imine derived from 255 delivers an enamine 256 that is also the enol tautomer of ketone 257. Intramolecular Friedel-Crafts cyclization of the latter delivers a β-iminocarboxylic acid 258 that, being the nitrogen analogue of a β-keto acid, readily decarboxylates producing indole-3-glycerol phosphate. While the biosynthesis of tryptophan might be completed by simple functionality adjustments, Nature adopts a different, more convoluted, strategy. Thus, tryptophan synthetase catalyzes a remarkable Friedel-Crafts alkylation with L-serine coupled with a dealkylation that cleaves glyceraldehyde-3-phosphate (G3P) and delivers L-tryptophan (259).
So far, we have seen that complex alkaloids may be assembled in Nature by a convergent strategy involving the union of two large fragments derived from aromatic amino acids. Alkaloids may also be constructed in Nature by the conjugation of amino acid-derived intermediates with terpenoid starting materials. Thus, as outlined below, lysergic acid (270) is forged from tryptophan (259) and Δ2-isopentenyl pyrophosphate. Later, we shall see how indole 259 is united in a variety of ways with secologanin, a terpene, to generate a vast array of structurally complex tryptophan-derived alkaloids. The carbons of these starting materials remain connected in the product, although the carboxyl carbon is lost. Thus, the biosynthetic strategy is simple.
The biosynthesis of lysergic acid commences with the prenylation of tryptophan. Thus, Δ2-isopentenyl pyrophosphate is a potent electrophile that readily alkylates the nucleophilic benzene ring of tryptophan 259 to afford 4-prenyltryptophan (260). The cyclization of 260 to lysergic acid requires addition of functionality to the Δ2-isopentenyl (prenyl) group by oxidations. The process is accompanied by a remarkable odyssey of the allylic carbon marked with an asterisk in the intermediates 260 - 265. Allylic hydroxylation and dehydration provide 261. The diene 261 has free rotation, that allows interconversion of the E and Z-methyl carbons during the 260 to 263 conversion. Formation of the D-ring is believed to occur by a decarboxylative SN2' alkylation in the allylic epoxide 262. Oxidation of the cyclization product, chanoclavine-I (263), to an E allylic aldehyde 264 is followed by cis-trans isomerization to the Z-isomer 265. Condensation to the Schiff base 266 completes the lysergic acid skeleton. Final adjustment of functionality by reduction to agroclavine (267), allylic oxidation to elymoclavine (268), further oxidation to Δ8-lysergic acid (269), and isomerization gives lysergic acid (270).
Dihydrogen as a Masking Group for an Alkene
Lysergic acid is thermodynamically unstable. Acids, base, or noble metals readily catalyze the irreversible rearrangement of lysergic acid (270) into a naphthalene isomer 271 by migration of a D-ring and a B-ring C=C bond into the C ring. Therefore, the stability of aromatic derivatives, that may often be advantageously exploited in complex molecular synthesis, was seen by Woodward as a major obstacle for the synthesis of lysergic acid (270). A central tactic in the first successful synthetic strategy,13 was the scrupulous avoidance of aromaticity in ring C. On the other hand, the crucial last step of the scheme, dehydrogenation of an indoline 272, ingeniously exploits the aromaticity of the indole array in 270. What is remarkable about this strategy is Woodward's recognition that, although it might seem unlikely that a way could be found to dehydrogenate 272 without also inducing isomerization of 270 to 271, the search for a method to achieve such a selective reaction could provide an excellent solution to the central challenge of the synthesis, and, therefore, was well worth the effort.
The Woodward strategy was channeled by the decision to use an intramolecular Friedel-Crafts acylation of the electron-rich A ring in 274 to generate the C ring in 273. This approach is recommended by the ready availability of 274 as starting material, and by the potential utility of the carbonyl group in 273 to activate bond forming reactions required to add the D ring. However, construction of 272 from 273 can be achieved by polar reactions only if polar reactivity inversions are employed, because the polar reactivity patterns of 272 and 273 are opposed.
The ABC-ring intermediate 273 is readily available from 275 by selective catalytic hydrogenation followed by intramolecular Friedel-Crafts acylation of 274. The carbonyl group in 273 provides activation at the adjacent methylene position that may be exploited for the attachment of the requisite nitrogen atom. However, an amino group is a nucleophile. To allow polar C-N bond formation, the potential nucleophilic reactivity of the methylene α to a ketone carbonyl must be inverted. This was achieved by bromination to afford 276 in excellent yield. An early attempt at alkylation of the amine 277 with 276 was unsuccessful. After exploring a very large number of alternative approaches for annelation of the D ring and developing an eleven stage sequence for preparing 278 from 273, it was discovered that a nonpolar solvent was uniquely effective for the alkylation of 277 with 276. Under these reaction conditions, the ketone ketal 278 was produced in excellent yield. This scenario is a poignant epitome of the vicissitudes of organic synthesis. It serves to underscore a caveat mentioned earlier (see section 1.2) that is worth repeating: as the availability of starting materials or methods (new or more effective) for uniting and manipulating them vary, so will the relative merits of different pathways. A poor synthesis can become the method of choice if a way to improve a bad step can be discovered.
It is instructive to examine the alternative strategy for the synthesis of 278 from 273, and to keep in mind that this alternative sequence was one of a great many that were painstakingly explored. The alternative route involves a strategy analogous to the 276 278 conversion, except that the carbonyl group of 276 and 278 is present in latent form as a vicinal diol in the corresponding key intermediates 280 and 279 respectively. Thus, the carbonyl is generated in the last step of the synthesis by oxidative cleavage.
The synthesis of 279 involves a novel sequence in which the enol 283 from decarboxylation of the glycidic acid 282 is intercepted by bromine (\(\ce{Br2}\) is in equilibrium with \(\ce{Br3^-}\)) delivering α-bromoaldehyde 284 from the Darzens condensation product 281. Dehydrohalogenation of the α-bromoaldehyde 284 was effected by the mild Mattox-Kendall procedure via semicarbazone 285 and unsaturated semicarbazone 287, that afforded the unsaturated aldehyde 288 by transfer of the semicarbazide residue to pyruvic acid. Nucleophilic epoxidation delivered the key intermediate 280. The latent carbonyl in 279 was deblocked by oxidative cleavage with periodate. This cumbersome route to 278 was abandoned when conditions for achieving the direct preparation of 278 from the bromoketone 276 were discovered.
Completion of ring D was straightforward via intramolecular aldol condensation of the diketone 289. The carbonyl group in the resulting enone 290 then provided reactive functionality in an alcohol 291 and the derived chloride for attachment of cyanide (a carboxy carbanion equivalent) as the final carbon atom of lysergic acid. After hydrolysis of 292 to 272, the two hydrogen atoms, placed at the outset by design at C-5 and C-5a to mask a rearrangement-prone C=C bond, needed only to be removed to afford lysergic acid (270).
A Polar D Ring Annelation Exploiting Target-related Functionality
The D-ring ester and amino functionality provide entirely consonant polar reactivity patterns in the derivative 293 of Woodward's carboxylic acid intermediate 272. An alternative strategy14 for annelation of the D-ring of lysergic acid exploits the polar activation provided by these functional groups that suggests a dislocation to 294. Dislocation of 294 to the aldehyde 288, prepared previously by Woodward, suggests an ylide precursor 295 in which a t-butyl ester serves as a latent amine. A more direct approach using an α-amino ylide seemed inadvisable in view of a possible β-elimination.
Introduction of the amino substituent was initiated by selective hydrolysis of the t-butyl ester in 296 under acidic conditions. The carboxylic acid 297 was then transformed into the corresponding chain shortened primary amine 301 in 80% yield by a Curtius degradation. Cyclization, i.e. of 294, accompanied the reductive amination of formaldehyde with primary amine 301 to afford a 3:1 mixture of the desired ester 293 and its C-8 epimer.
C-Ring Annulation by Nucleophilic Aromatic Substitution
Another synthesis of the key ester intermediate 302 involves annelation of ring C in a preformed ABD-ring precursor by intramolecular nucleophilic substitution with a carbanion 303 that is conjugated with the carboxyl functionality found at position 8 in the target.15 The same carboxyl also provides nucleophilic activation at position 4. Thus, polar analysis of 304 suggests a polar dislocation to two aromatic starting materials that can be joined by an aldol condensation between ketone 305 and carbanion 306. However, this strategy is fatally flawed owing to a preference for ketone 305 to exist as an enol. The addition of another carbonyl group at position 2, as in 309, precludes enolization (blocking group), enhances the electrophilicity of the ketone carbonyl, in 309, and activates the C=C bond in 308 toward dissolving metal reduction.
Actually, generation of an isomer of 309, i.e. 310 with the bromo group para to nitrogen, is favored during a synthesis by electrophilic aromatic substitution owing to the powerful activating influence of the nitrogen substituent. However, this is not a flaw because a mecahanism exists for nucleophilic aromatic substitution with rearrangement. Thus, elimination of the nucleofuge leads to a benzyne intermediate 315 to which the nucleophile then adds regioselectively at the required position to give 316. Having served its roles as a reactivity control element, the carbonyl group in 311 is then selectively removed by reduction with diborane. The pyridine ring of the product 312 is activated toward hydride reduction by N-methylation after acetylation of the indole nitrogen. Unfortunately, hydride reduction of the D-ring in 313 produces two epimers only one of which, i.e. 314, cyclizes upon treatment with base delivering 302 in only 15% yield. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/06%3A_Amino_Acids_and_Alkaloids/6.04%3A_Lysergic_Acid.txt |
Biosynthesis of Alkaloids from Secologanin
A comparison of the structures of polycyclic alkaloids with a variety of topologically different skeletons, such as preakuammicine (317), catharanthine (318), and tabersonine (319), suggests a biosynthetic strategy which assembles these heteromulticycles by the union of an aminoethyl indole starting material 400 with ten additional skeletal carbons. The aminoethyl indole, tryptamine (400), is reasonably derived from decarboxylation of the amino acid L-tryptophan (259) by a process analogous to the decarboxylation of tyrosine (7) discussed in section 6.4.
The origin of the remaining ten skeletal carbons is less obvious. The remarkable fact that these remaining carbons have a common origin is nicely illustrated by studies on the time evolution of alkaloid production in germinating seedlings of Vinca Rosea.16 Thus, the alkaloids 317 - 326, and 328 are all isolable from this plant while 327 is a putative common intermediate for the generation of 318 and 319 by two different 2$\pi$ + 4$\pi$ cycloadditions.
In the early intermediate vincoside (321), there is a consonant circuit that connects the two nitrogens. Two polar disconnections in this circuit reveal an aldehyde precursor that bears little resemblence to a monoterpene besides its ten skeletal carbon atoms. Nevertheless, this aldehyde is secologanin whose terpenoid origin was discussed in chapter 4 (see section 4.4).
The biosynthesis of over 1,000 indole alkaloids from tryptophan (259) begins with a Mannich reaction between tryptamine (320) and secologanin to produce vincoside (321). Hydrolysis of the glucoside 321 and deketalization of the resulting hemiketal 329 affords amino-aldehyde 330. Cyclization of the latter gives an iminium derivative 331. Intramolecular Michael addition of an oxygen nucleophile followed by reduction affords another isolable product, ajmalicine (332). Alternatively, reduction of 331 affords 322.
Generation of the other skeletal types from 322 involves rearrangements that are enabled by oxidative introduction of a vicinal diol array to produce 333. This vicinal hydroxylation is accomplished by a stepwise process through the hydration of an isolable intermediate, the β-hydroxyindolenine 323. A pinacol rearrangement of 333 produces 324. Conversion to an imino ester would endow 324 with the reactivity required to form preakuammicine (317) by cyclization and reduction. Retero-aldol-like fragmentation of 317 followed by the reduction of the resulting immine affords stemmadenine (326). A second fragmentation of the enamine isomer 334 of 326 apparently produces an acrylic ester intermediate 335. The dienamine tautomer 327 of 335 provides the iboga alkaloid skeleton of catharanthine (318) by an intramolecular Diels-Alder reaction (not necessarily concerted). Alternatively, the aspidosperma alkaloid skeleton of tabersonine (319) arises from the acrylic ester 335 via polyene cyclization to 336 and subsequent aldol-like cyclization of the latter followed by proton loss to afford tabersonine (319).
Biosynthesis of Quinine
Even more cryptic is the biosynthesis of several alkaloids containing the quinoline heterocyclic ring system such as quinine (337). The surprising fact that the carbon skeletons of these alkaloids are also derived from tryptophan and secologanin further illustrates the lengths to which Nature must go to achieve the biosynthesis of some natural products owing to a limited inventory of available starting materials. It is an instructive exercise to infer the biosynthetic pathway by retrosynthetic analysis. Given the boundary condition of an indole precursor, the pyridine ring of the quinoline ring system in 337 must be generated. This might be accomplished by dehydrogenation of the imine produced from an amino aldehyde precursor 338. The alcohol functionality in 338 could be the residue of electrophilic activating functionality in a precursor that was involved in a connection with the nucleophilic amino group in a pyrrole ring, as in the tryptophan 339. Referring to the boundary condition of tryptophan as the biosynthetic starting material, the aldehyde in the precursor 339 could be generated by hydrolytic cleavage of an imine derivative 340 of the ethylamine sidechain of tryptamine. A concomitant disconnection of one bond to the tertiary amino group in 339 is required to make room for the connection. Referring to the boundary condition of vincoside as starting material, 340 could arise from acarboxy dialdehyde 341 by polar decarboxylation and heterocyclization.
The biosynthesis of the quinuclidine portion of quinine (337) from the secologanin portion of vincoside (321) involves hydrolysis of the glucoside to give a dialdehyde 330, followed by intramolecular reductive alkylation and decarbomethyoxylation to give 342, that is in equilibirum with a hemiaminal 343. Hydrolytic fragmentation of the latter accompanied by oxidation of a primary alcohol to an aldehyde and reduction of the hemiaminal to an amine affords 344. The rearrangement of the indole portion of 344 to a quinoline skeleton is initiated by an oxidation to 345 followed by ring cleaving hydrolysis and recyclization of the resulting amino aldehyde 346. Arene oxidation, methylation, and then reduction of the resulting quinoline derivative 347 delivers quinine (337).
A Relay Synthesis of Quinine
A major topological simplification of the quinine skeleton arises by disconnection of a bond between atoms 1 and 8. Atom 1 is a common atom of the multicyclic quinuclidine portion of 337. Though atom 8 is a noncommon atom, its role as a link between the two major portions of 337 recommends removal of skeletal connections to this atom. This disconnection was actually achieved by Rabe during degradative studies on the structure of 337.17 The fragmentation of 337 to 348 depends upon the polar activation provided by the quinoline and quinuclidine amino groups (ignoring the activation provided by the C-8 hydroxyl).
Polar Redox Reactions
Rabe also demonstrated that the reverse process, a synthesis of 331 from 347, can be achieved by exploiting the polar activation of C-8 in 347 (quinine numbering).17 This approach requires a nitrogen electrophile and involves oxidation via polar intermediates. Thus, the nucleophilic secondary amino group in 348 is converted into an electrophile in 349 by appending a more electronegative atom, i.e. bromine. This constitutes oxidation of the amino group. Electrophilic attack on carbon in 349 to give 350 produces a bond between carbon and a more electronegative atom (i.e. nitrogen). This constitutes oxidation of carbon coupled with reduction of the amino group. We shall refer to such reactions as polar redox reactions. An example of this reaction type occurs in the biosynthesis of acetyl CoA (see section 2.3) during nucleophilic attack by hydroxyethylidene TPP (351) on the the disulfide 352. Thus, the nucleophilic carbon is oxidized from f = 1 in 351 to f = 2 in 353 while a sulfur atom in 352 is reduced from f = -1 to f = -2 in 353. This reaction is complex because another carbon in 351 is concurrently oxidized from f = 2 to f = 3 in 353 in conjunction with reduction of the second sulfur in 352 from f = -1 to f = -2 in 353.
Another polar redox reaction, again with sulfur as electrophile, was encountered in the Woodward synthesis of colchicine (see section 6.1). In fact, the introduction of a dithioketal at the nucleophilic carbon α to a cabonyl group involves two successive oxidations of the α carbon, first of 354 to 356 then of the latter into 358, coupled with two reductions of sulfur, first in the conversion of 355 to 356 then in the conversion of the latter, via 357, into 358. This reaction is also complex because another carbon in 354, α to the enolic hydroxyl, is concurrently oxidized from f = 1 to f = 2 in 356 in conjunction with reduction of a second sulfur in 355, and a second carbon is oxidized from f = -1 in 357 to f = -2 in 358 (the carbonyl carbon) in conjunction with reduction of a second sulfur.
A Convergent Strategy for Key Intermediate 348
It should be noted that 350 (see above) is a mixture of epimers at C-8, and the reduction that produces 337 introduces another asymmetric center (at C-9). Fortunately, 337 was a major component of the isomeric mixture produced by this nonstereocontrolled conversion of 348 to 337. This conversion makes quinotoxine (348) an attractive subtarget for the total synthesis of quinine (337). The subtarget 348 is further simplified by a dislocation, that breaks the molecule into two large fragments by severing one of the four bonds connecting the quinoline and piperidine rings. The dislocation chosen by Woodward and Doering for the first total synthesis of quinine (337) was dictated by the fact that the reverse process, synthesis of 348 from 359 and 360, had excellent precedent. A dihydro derivative of 348 (with an ethyl instead of a vinyl group) was prepared by Rabe from 359 and a dihydro derivative of 360 which had been obtained from degradation of natural quinine (337).
Total syntheses of the subtarget ethyl quininate (359) were also known when the total synthesis of 337 was undertaken. A particularly effective route introduces the carboxyl group in latent form as a benzylic methyl group, and constructs the nitrogen heterocycle on a preformed aromatic precursor 361 by polar reactions. Cyclodehydration of 362 affords 363, that is reduced to 364. Benzylic oxidation of 364 is achieved by oxidative cleavage of a latent carboxylic acid, a C=C bond in the precursor 365, that is available by a polar condensation of 364 with benzaldehyde. The condensation exploits the nucleophilic activation of the benzylic methyl, that is provided by the nitrogen in 364.
The only remaining synthetic objective was, thus, ethyl N-benzoylhomomeroquininate (360). The two side chains in 360 could be generated stereospecifically cis by oxidative cleavage of a temporary bridge in 366. The cis ring fusion in 366 could be produced, in turn, by catalytic hydrogenation of an aromatic isoquinoline precursor 367.
Several potential flaws must be avoided in designing a detailed scheme for the 366 to 360 conversion. For example, cleavage of the temporary bridge in 366 by a Baeyer-Villiger oxidation followed by an elimination to generate the vinyl group in 360 must avoid generating the alternative, thermodynamically favored, ethylidene derivative 368.
Interestingly, the reaction chosen to achieve the ring cleavage was a reaction used earlier in degradation studies for determining the structure of quinine. Thus, Rabe effected cleavage of quininone (369) into ethylquininate (359) and an oximino compound 370 by treatment with amyl nitrate and sodium ethoxide. This cleavage is analogous to a retro-Claisen reaction, that occurs especially readily for nonenolizable β-keto esters.
Application of this cleavage process to the N-acetyl analogue 371 of 366 generates oxime 372. A potential flaw, epimerization of the cis-1,2-disubstituted product 372 into the thermodynamically more stable trans isomer 373, was not a problem. In contrast to what would be expected for the corresponding acetyl derivative, the oxime 372 is not prone toward epimerization. Thus, the hydroxyl proton rather than an α-proton is preferentially abstracted upon treatment of oximes with base. Reduction and methylation of 372 readily affords a quaternary ammonium derivative 374, that affords the requisite terminal vinyl group in 360 by base promoted Hofmann elimination involving regioselective abstraction of hydrogen from the less substituted β carbon.
As noted above, an aromatic precursor 367 was chosen for the synthesis of ethyl N- benzoylhomomeroquininate (360). A monocyclic aromatic precursor for 367 could be either a pyridine derivative or a benzene derivative. Choosing the latter allows exploitation of electrophilic aromatic substitution on an electron-rich precursor to accomplish annelation of the pyridine ring. This annelation requires carbon-carbon bonds meta and para to the hydroxyl group. Formation of the para bond by electrophilic aromatic substitution is favored over meta by the strong electron donating activating effect of the hydroxyl group. Formation of this para carbon-carbon bond in the last step of annelation suggests a phenolic precursor 375 with the four atoms of the incipient pyridine ring appended to the meta position. The bond between this meta substituent and the phenol ring can not be generated by electrophilic aromatic subsitution because ortho and para rather than meta substitution is favored. However, disconnection of this substituent by removal of the bond between nitrogen and the benzylic carbon suggests a dissonant carbonyl-masked amino acetaldehyde 376 and a benzaldehyde derivative 377. The methyl substituent in 377 might also be introduced by electrophilic aromatic substitution on the readily available m-hydroxy-benzaldehyde (378). However, achieving the requisite regiocontrol in such an alkylation might be difficult.
In fact, a different order of steps was adopted. Introduction of the ortho methyl substituent was postponed until after annelation of the pyridine ring was completed because introduction of a methyl group can be readily achieved regioselectively by electrophilic aromatic substitution on the β-hydroxy isoquinoline 379. Thus, aminomethylation with piperidine and formaldehyde produced the benzylic amine 380 that was reduced to 367 upon heating in the presence of sodium methoxide. This unusual reduction involves hydride transfer from methoxide. Technical difficulties arose in the hydrogenation of 367 to 371. Thus, because the amine poisoned the catalyst, the hydrogenation stopped after only the nitrogen containing ring had been reduced. The amine had to be blocked as an amide before reduction of the benzene ring could be achieved. The desired cis-stereospecificity in the reduction of 381 to 371 could not be achieved. Fortunately, however, this was not a fatal flaw because the required isomer could be isolated from the trans-fused hydrogenation reaction product 383. Thus, catalytic hydrogenation is not entirely reliable for stereoselective delivery hydrogen to one face of an aromatic ring. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/06%3A_Amino_Acids_and_Alkaloids/6.05%3A_Quinine.txt |
The availability of an appropriate starting material dictates a biosynthetic strategy for alanine (383). Pyruvic acid (384) is a key intermediate in the biosynthesis of acetyl CoA. A functional group interchange (FGI) coupled with functionality level adjustment (FLA), i. e. reductive amination, can provide the α amino substituent of 383 from the carbonyl group in pyruvic acid.
Adopting a similar strategy for the biosynthesis of aspartic acid (385) suggests oxaloacetic acid (386) as a precursor. The consonant circuit in the β-keto acid array of 386 suggests a polar synthesis from pyruvic acid and carbon dioxide.
In the biosynthesis of 386, carboxylation does not involve the direct reaction of pyruvic acid with \(\ce{CO2}\). Rather, the carboxylating agent is an enzyme-bound N-carboxy biotin derivative that is generated by a series of reactions that begin with the activation of carbonate by phosphorylation with ATP. The resulting carbonic phosphoric anhydride acylates the biotinyl nitrogen of N-carboxybiotin which is bound to an enzyme, pyruvate carboxylase, as N-carboxybiocytin. Pyruvate carboxylase catalyzes the transfer of a carboxy group to pyruvate from N-carboxybiotin. Alternatively, in some plant cells phosphoenol pyruvate is carboxylated producing oxaloacetic acid directly.
The biosynthetic strategy for glutamic acid (387) is more intricate. Thus, the potential precursor α-ketoglutaric acid (388) contains dissonant circuits in both the g and the α-keto acid arrays precluding a direct polar synthesis by a C-C connective route from smaller precursors. One way to invert the polar reactivity pattern generated by a functional group is 1,2-transposition of the functionality. Thus, the transposed precursor 389 has consonant β-hydroxy acid arrays that could be created by polar condensation of an acetate C-nucleophile with malonaldehydic acid as a carbonyl electrophile.
This polar strategy is adopted by Nature except that oxaloacetic acid (386) rather than malonaldehydic acid is used as the electrophile. This starting material has an extra carboxyl group that must be removed during the construction of 388. The 1,2-oxygen transposition also creates a polar pathway for the requisite decarboxylation. The biosynthetic strategy also has other idiosyncrasies. Thus, besides a plan for assembling the carbon skeleton, the biosynthetic strategy for glutamic acid includes cogeneration of a reducing agent. We encountered a similar tactic in the biosynthesis of fatty acids from glucose (see section 3.1) where the conversion of glucose to the starting material, acetyl CoA, cogenerates all the reducing agent, NADPH, required for deoxygenation of β-ketoacyl intermediates. Nature's remarkable strategy for the biosynthesis of glutamic acid simultaneously generates a starting material, α-ketoglutaric acid 388, and the requisite reducing agent, NADPH, for the subsequent reductive amination of 388 to produce 387.
The biosynthesis begins with condensation of an acetyl CoA nucleophile with the highly electophilic carbonyl carbon of oxaloacetic acid to form citric acid (390). The reaction is catalyzed by the enzyme, citrate synthetase (or condensing enzyme). Dehydration of citric acid gives cis-aconitic acid (391) that is then hydrated to isocitric acid (392). Dehydrogenation of the latter is coupled with decarboxylation of a presumed β-ketoacid intermediate 393 to yield α-ketoglutaric acid (388). The hydrogen is transferred to NADP+ generating the NADPH needed for the nitrogen-fixing reductive amination of 388. Thus, the protonated imine 394, that is produced by reaction of the ketone carbonyl with \(\ce{NH3}\), is reduced by hydride transfer from NADPH to deliver L-glutamic acid (387) with enzyme-induced enantioselectivity. This is an example of asymmetric induction by a homochiral reagent (the enzyme) during the reaction of a prochiral intermediate, the imine 394.
Interestingly, an oxidative pathway exists in Nature for conversion of α-ketoglutaric acid (388) back into oxaloacetic acid (386). Thus, oxidative decarboxylation of α-ketoglutaric acid occurs by the same thiamine pyrophosphate-catalyzed mechanism as for the pyruvate-acetate conversion (see section 2.3) that cogenerates NADH from NAD+. The initial product, succinyl CoA (385), is a high energy thioester. Its hydrolysis is coupled with phosphorylation of ADP, through an indirect process involving phosphorylation of a histidine residue of the hydrolyzing enzyme (see 399), transfer of phosphate to guanosyl diphosphate (390, GDP), and finally, transfer of phosphate from the resulting GTP to ADP. Dehydrogenation of succinic acid (396) is then catalyzed by succinate dehydrogenase producing fumaric acid (397). The hydrogen is transferred to flavin adenine dinucleotide (401, FAD) producing FADH2. The reversible hydration of fumaric acid to give L-malic acid (398) is catalyzed by fumarase, that promotes enantioselective stereospecifically trans addition of water to the symmetrical prochiral olefin. This is another example of asymmetric induction by a homochiral reagent, the enzyme fumarase. Finally, L-malate dehydrogenase catalyzes the oxidation of L-malic acid to oxaloacetic acid by transfer of hydride to NAD+.
The overall process, generation of α-ketoglutaric acid from acetyl CoA plus oxaloacetic acid and regeneration of oxaloacetic acid from α-ketoglutaric acid also produces two molecules of \(\ce{CO2}\), four molecules of reducing agent (2 x NADH, NADPH, and FADH2), and one molecule of ATP. This cycle of reactions, known as the Krebs cycle or the tricarboxylic acid cycle (citric acid is a tricarboxylic acid) results in the aerobic oxidative catabolism of acetyl CoA. Besides providing a source of useful reagents for biosynthesis from fatty acids or sugars (via acetyl CoA), it also generates a variety of biosynthetically useful intermediates, e.g., α-keto glutaric acid) that can be diverted from the cycle. If Krebs cycle intermediates are to be removed from the cycle for biosynthesis, then other cycle intermediates must be generated somehow to replace them. The most important anaplerotic (filling up) reaction is the pyruvate carboxylase-catalyzed carboxylation of pyruvate to form oxaloacetate. Another modification of the Krebs cycle, known as the glyoxylate cycle, is important in plants and microorganisms for production of biosynthetic starting materials from acetyl CoA. Acetyl CoA condenses with oxaloacetic acid giving isocitric acid by way of citric and cis aconitic acids. But, rather than being oxidized to α-ketoglutaric acid, isocitric acid is cleaved to succinic and glyoxalic acids in a retro-aldol reaction that is catalyzed by isocitrase. Succinic acid may then be used for biosynthesis, while glyoxalic acid (392) reenters the Krebs cycle by malate synthetase-catalyzed condensation with aceyl CoA to form L-malic acid.
Glutamic acid is the direct biosynthetic precursor of glutamine (404) and proline (406). Activation of one carboxyl as a mixed phosphoric carboxylic anhydride (403) followed by acylation of \(\ce{NH3}\) delivers 404. Selective partial reduction of one carboxyl and intramolecular reductive amination of the resulting γ-amino aldehyde 405 delivers 406.
The biosynthesis of glutamic acid from α-ketoglutaric acid by reductive amination with ammonia is not typical. Generally, the conversion of α-keto acids into the corresponding amino acids involves transfer of an amino group from glutamic acid, a process called transamination. Pyridoxal phosphate (407) and divalent metal cations are cocatalysts for the transfer that occurs by a polar process. Thus, the imine from 4 0 7 and glutamic acid undergoes prototropic shift to generate the tautomer 4 0 9 . Rearomatization by another prototropic shift generates a new imine 410 that is hydrolyzed to pyridoxamine phosphate (411) and α-keto glutaric acid. Transamination is then completed by the reaction of an α-keto acid with 411 to produce the corresponding α-amino acid and regenerate pyridoxal by a process that is analogous to the reverse of the reaction that generates 411 plus α-keto glutarate from 407 plus glutamic acid.
Thus, transamination of pyruvic and oxaloacetic acids yields alanine (384) and aspartic acid (385), respectively. The biosynthesis of asparagine (412) from 385 parallels that of glutamine from glutamic acid (see above). Serine (414) is produced in Nature from 3-phosphoglyceric acid via oxidation to 3-phosphopyruvic acid (413), followed by transamination with glutamic acid.
The consonant circuit between the carboxyl and hydroxyl groups of serine (414) suggests a polar strategy for the biosynthesis of glycine (415) involving retroaldol cleavage. The α-amino group is in a dissonant relationship with the other functional groups in 415 and, therefore, cannot assist in the polar cleavage. However, Nature adopts a strategy that allows the desired cleavage to occur under mild conditions by prior umpölung of the α-amino group as in 416 that has two functional groups stabilizing the buildup of electron density at the α-carbon.
Pyridoxal phosphate (407) is the reagent, a polar reactivity inversion operator, that converts the amino group by a polar process into a derivative in 417 which stabilizes an anion at the α-carbon. It is instructive to consider how this process works. The key feature of the reagent 417 is a dissonant relationship between the aldehyde and pyridinium nitrogen. The electrophilic reactivity of the aldehyde carbon is used to form a C=N bond with the nucleophilic amino nitrogen in serine. The polar reactivity of this C=N bond is then ignored, and it is the dissonant pyridinium nitrogen in 417 that stabilizes the buildup of electron density on the serine α-carbon. The C=N bond derived from the serine amino group serves only to conjugate the pyridinium nitrogen with the serine α-carbon. Retroaldol fragmentation of 417 produces 418 and formaldehyde. The latter is captured by tetrahydrofolic acid (vide infra) while 418 is rearomatized and protonated to produce an imine 419 of glycine. Hydrolysis produces glycine and regenerates pyridoxal phosphate that is, thus, a true catalyst for the retroaldol fragmentation.
The formyl group lost in the conversion of 417 to 418 is transferred to tetrahydrofolic acid (420, FH4). The product, N5,N10-methylene FH4 (421), is one member of a family of folic acid coenzymes that carry one-carbon groups, such as methyl, formimino, and formyl in 422, 423, and 424, respectively.
The major portion of these one-carbon transfers is achieved via methyl transfer to homocysteine (425) from N5-methyltetrahydrofolate (422), which yields methionine (426) and, hence, S-adenosylmethionine (SAM+). Hence, serine and, ultimately, 3-phosphoglyceric acid is the source of the ubiquitous methyl groups donated by SAM+ to a wide variety of acceptors.
One biosynthetic strategy for L-lysine (427) is closely related to that involved in the biosynthesis of glutamic acid (see above). Thus, double reductive amination of a precursor α-keto diacid 428 could provide the two amino groups in 427. A precursor 429 containing a consonant β-hydroxy acid array is suggested by 1,2-transposition of oxygen functionality in 428. The precursor 429 could be created by polar condensation of an acetate C-nucleophile with succinaldehydic acid as a carbonyl electrophile.
This is the biosynthetic strategy for lysine that is adopted by most fungi except that α- ketoglutaric acid (388) rather than succinaldehydic acid is used as the electrophile. The biosynthesis proceeds via α-aminoadipic acid (430) by a scheme commencing with a Claisen-Schmidt condensation between α-ketoglutaric acid (388) and acetyl CoA. Rearrangement, oxidation, and decarboxylation occur in reactions analogous to the conversion of oxaloacetic acid into α-ketoglutaric acid (see above). Transamination of the resulting a-ketoadipic acid (428) enantioselectively produces the L isomer of α-aminoadipic acid (430). Reduction of 430 to 431 followed by reductive alkylation of glutamic acid by 431 affords 433. Oxidation followed by hydrolysis gives L-lysine (427). Note that the iminium group in 434 is stabilized relative to that in 432 owing to conjugation with the carboxyl in 434.
An alternative strategy for the biosynthesis of L-lysine (427) generates the ε-amino array by decarboxylation of an α-amino acid group in a symmetrical precursor 435, a process which can be catalyzed by pyridoxal phosphate (see below). As is common in α-amino acid biosynthesis, 435 could be derived from an α-keto acid precursor 436. The carbon skeleton of this ketone can be assembled by an aldol condensation between a pyruvic acid enolate and an aldehyde electrophile 437 derived from L-aspartic acid (385).
The primary route for biosynthesis of L-lysine in bacteria and higher plants generates a seven carbon diacid intermediate 438 from the three carbons of pyruvic acid and four carbons of aspartic acid (385). Reduction of 385 to the aldehyde 437 with concomitant hydrolysis of ATP is analogous to the reduction of 3-phosphoglyceric acid (3PG) to glyceraldehyde-3-phosphate (G3P) (see section 2.1) and the production of 431 from 430. Aldol condensation of 437 with pyruvic acid delivers 438. Intramolecular imine formation and dehydration produces 439 that is reduced and then hydrolyzed and succinoylated to produce a masked (N-succinylated) derivative 440 of 2-amino-6-ketopimelic acid. Transamination and hydrolysis of the resulting amino amide 441 delivers diamine 435. Monodecarboxylation of this α-amino acid, catalyzed by pyridoxal phosphate, then delivers L-lysine (427). As in the pyridoxal phosphate-catalyzed retro-aldol cleavage of serine to glycine (see above), pyridoxal serves as a polar reactivity inversion operator that temporarily converts the amino group by a polar process into a derivative in 442 which stabilizes electronic excess at the α-carbon. The consonant circuit between the pyridinium nitrogen and carboxyl carbon in 442 (ignoring the polar reactivity of the imine group) facilitates polar cleavage of a C-C bond generating the imine 443. Aromatization by prototropic shift then produces 444. Finally, the polar reactivity of the imine is utilized to achieve hydrolysis, releasing the amine 427 and regenerating the aldehyde catalyst 407.
Note that both the α-amino acid array in 435 and the amino aldehyde array in 407 incorporate dissonant circuits. It is the polar union of one functional group in each dissonant reactant (407 and 435) that creates a consonant relationship between the remaining functional groups in these molecules. Thus, umpölung of the amino group in α-amino acids is accomplished by a dissonant difunctional reagent, pyridoxal pyrophosphate. Previously umpölung of the ketone carbonyl group in α-keto acids was encountered in the cyanide ion catalyzed benzoin condensation (section 2.1), in the thiamine pyrophosphate (TPP) catalyzed transketolase reaction (section 2.1), and in the TPP catalyzed decarboxylation of pyruvic acid (section 2.2). It is now instructive to note that both HC≡N and TPP contain biphilic functionality. They are both readily metallated (i.e. deprotonated). This introduces a nucleophilic functional group (the carbanion) in a dissonant relationship with other functionality in these molecules, and allows them to serve as catalytic polar reactivity inversion operators. One of the functional groups, the nucleophilic carbanion, is exploited to link the catalyst to the ketol or aldehyde carbonyl, in the transketolase or benzoin reactions respectively, or the α-keto acid carbonyl in the pyruvate decarboxylation reaction. The other functionality in the catalyst then stabilizes electronic excess at the formerly electrophilic ketone or aldehyde carbonyl carbon. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/06%3A_Amino_Acids_and_Alkaloids/6.06%3A_Biosynthesis_of_Nonaromatic_Amino_Acids.txt |
Biosynthesis of Alkaloids from L-Lysine
A variety of topolgically complex saturated nitrogen heterocycles are constructed in nature from simple acyclic precursors. The incisive logic of these biosyntheses is especially striking when viewed either from a topological or a polar reactivity standpoint. For example, the efficiency with which the intricate multicyclic skeleton of sparteine (445) is assembled, exclusively from three molecules of a symmetrical synthon, is remarkable. Topological analysis of 445 reveals the presence of six common atoms a-f. Cleavage of two bonds between two pairs of common atoms, b-c and d-e, simplifies the topology to two piperidine rings joined by a straight chain in 446. This intermediate is readily derived from two five carbon synthons 447 and 448. Polar reactivity analysis of 445 reveals that polar reactions, activated by the amino groups in 445 should readily allow its construction from 447 and 448.
In fact, functionalized synthetic equivalents for both 447 and 448 are prepared in nature from L-lysine (427). Thus, pyridoxal catalyzed decarboxylation of 427 produces the symmetrical diamine 449. Oxidation and hydrolysis of 449 via 451 afford pentanedial, which provides iminium derivative 452 by reaction with 450. Intramolecular aldol condensation then affords 453. The iminium derivative 454 from dehydration of 453 yields an iminium derivative 455 by reaction of the corresponding enamine with a second equivalent of the imine 450. A second intramolecular aldol condensation affords 456. Dehydration and reduction provides sparteine (445).
Biosynthesis of Lycopodine
We have seen that many natural products are formed from a single starting material, such as (a) many polyketides, fatty acids, or prostaglandins from acetyl CoA, (b) many alkaloids from shikimic acid, or (c) terpenes from mevalonic acid. However, some natural products are formed by mixed biosyntheses from combinations of these starting materials. Thus, lysergic acid (see section 6.4) arises from chorismic acid plus the mevalonic acid-derived isopentenyl pyrophosphate plus a sugar, D-ribose. Similarly, indole alkaloids (see section 6.5) arise from chorismic acid plus a mevalonic acid-derived terpene, secologanin, plus a sugar, D-ribose.
Now we shall see that the bridged multicyclic skeleton of the alkaloid lycopodine (457) arises from acetoacetyl CoA plus L-lysine (427). As for sparteine above, both topological and polar analysis of the biosynthetic strategy for 457 reveal its incisive logic. The carbonyl group in 457 is generated in nature by solvolytic cleavage of a temporary bridge. In the process, a propyl substituent with electrophilic activation at the end is generated, that is then used to construct the final ring of 457. Retrosynthetically, this involves disconnection to 458, followed by reconnection to 459. A considerable simplification of this subtarget results from disconnection of two bonds between pairs of common atoms in 459 to afford 460. Polar analysis of 460 reveals that reconnection of these bonds could be achieved by exploiting the polar activation provided by the nitrogen atoms in 460. Furthermore, 460 could be assembled from two large fragments by a polar reaction forming any of the bonds in the carbon chain connecting the two nitrogen heterocycles.
In nature, the two piperidine rings in 460 are derived from L-lysine (427), and the connecting chain is assembled from two three carbon units derived from actetoacetyl CoA (461). Aldol condensation of 461 with 450 affords 462. Note that alkylation of 461 occurs at the less acidic δ carbon. Perhaps this involves an enzyme-bound enamine derivative 470 (see below) of 461. Oxidation and deprotonation of 462 provides 465, while 462 also yields pelletierine (463) by hydrolysis and decarboxylation. Aldol condensation between 464 and 465 then provides 466, that is hydrolyzed to 467. Decarboxylative elimination gives 468, that is reduced to provide 469, a synthetic equivalent of the synthon 460 generated in the strategic analysis presented below.
Cyclization of 469 by intramolecular enamine alkylation, followed by intramolecular aldol-like condensation, produces the intermediate 459 suggested in the strategic analysis. Hydrolysis of the imine in 459 generates the carbonyl group required for lycopodine. Oxidation of the resulting propyl amine 471 to an aldehyde 472 followed by intramolecular reductive alkylation then produces lycopodine (457) in which one lysine derived piperidine ring is clearly discernable while the two polyketide derived acetonyl units and a five carbon unit from a second molecule of lysine are intricately interwoven.
A Fatally Flawed Strategy for Lycopodine Synthesis
We have seen that both topological and polar analysis of the biosynthetic strategy for lycopodine (457) illuminate the logic of the process. The two functional groups in 457 can be exploited in a variety of strategies to facilitate construction of the skeletal network using polar reactions. There are five common atoms in 457, four carbon atoms that are all in ring B, and the nitrogen. We will first consider a fatally flawed strategy that only generates an epimer rather than the natural product itself.
Polar analysis of ring B reveals that polar reactions, exploiting the polar activation afforded by the amino and carbonyl functionalities in 457, could be used to construct any bond of this ring. In the Wiesner approach to lycopodine,19 the final skeletal bond formed is between common atom 7 and noncommon atom 6, corresponding to the dislocation of 457 to 473. The penultimate bond formed is that between common atoms 4 and 13, corresponding to the dislocation of 473 to a bicyclic precursor 474. The elegance of the strategy lies in the plan to accomplish cyclization of the bicyclic intermediate 474 to the tetracyclic skeleton of the target 457 in a single step. The synthetic equivalent 475 of 474 has additional carbonyl groups at the 7 and 9 positions. The former provides additional electrophilic activation at C-7, while the latter deactivates the nucleophilicity of the amino group. The bicyclic intermediate 475 might be available from a symmetrical monocyclic precursor 476. The incipient amino group of 457, the nitrile nitrogen in 476, even provides polar activation for the construction of 476 from acrylonitrile and dihydroresocinal.
In fact, acid-catalyzed hydrolysis of 476 leads directly to the enamide 477 that afforded 475 by N- alkylation with the alkyl bromide 467 and subsequent hydrolytic removal of the masking ketal group. Base-catalyzed intramolecular Michael reaction of 475 could generate two stereoisomers at position 13 which result from addition of the carbanion to either face of the D-ring in 479. However, as expected, steric approach control fosters stereoselective addition on the side of the D-ring opposite the methyl substituent to afford an intermediate 481 rather than undesired stereoisomer 480. Nevertheless, the synthesis is fatally flawed because the subsequent aldol reaction gave exclusively 484, whose skeleton is epimeric with lycopodine at a C12. Thus, C-12 in the intermediate 481 is epimerizable, and the epimer 482 apparently cyclizes in complete preference to 481. This produces 484 rather than 483, that is required for the synthesis of lycopodine (457) . Reductive removal of the amide carbonyl and tertiary hydroxyl groups from 484 delivered 12-epi-lycopodine (485).
A Relay Strategy and a Symmetrical Precursor for Lycopodine
A second strategy for lycopodine synthesis generates ring D by cyclization of a tricyclic synthon 486 with preformed AB and C rings.20 This strategy was channeled by the prospect of exploiting a symmetrical fused tricyclic ketone 487 as a starting material. Thus, topological analysis of 457 recommends disconnection of two bonds between a common (circled) and a noncommon atom, the 7-8 and 13-14 bonds, to entirely remove the D-ring. A concomitant transposition of the carbonyl group from C-5 in 457 to C-6 is required to generate a symmetrical precursor 487. Furthermore, this transposition in 486 allows formation of the 7-8 C-C bond of the lycopodine skeleton by an intramolecular alkylation that exploits the polar activation afforded by a carbonyl at position 6. Whereas, the nitrogen in 486 can provide electrophilic activation for C-C bond formation at position 13 in 487. An amide carbonyl at C-9 in 486 is included as a deactivating group to decrease the nucleophilicity of the amino group disfavoring an undesired quaternization that might compete with alkylation of a carbanion nucleophile at C7.
Intramolecular alkylation of the ketone 486 would yield 488. It would be reassuring if the final steps in the synthesis could be worked out with a sample of 488 that might be readily prepared from the natural product 457, perhaps via the diol 489, that had already been prepared from 457 during structural studies on the lycopodium alkaloids. This sample of compound 488 could then be used, instead of the synthetic material, to work out the details of the conversion of 488 to 457. This is another example of the strategem known as the relay approach, that we saw employed in syntheses of erythronolide B (see section 5.4) and quinine (see section 6.5). The advantage of this approach is that a valuable key intermediate can be obtained readily in quantity. The relay compound (e.g. 488) becomes the target of the synthesis.
Let us first consider the interconversion of the relay compound 488 and 457 before examining the total synthesis of the relay compound. To differentiate the hydroxyls at positions 5 and 6, the diol 489 from natural lycopodine (457) was monoacetylated at the sterically most accessible C-6 hydroxyl. Dehydration followed by hydrolysis afforded 490. Oxidation of the allylic hydroxyl followed by reduction of the resulting α,β-unsaturated ketone and permanganate oxidation α to the tertiary amine gave the proposed relay compound, amide 488, in 13% overall yield from natural lycopodine (457).
Reconversion of the relay compound 488 into lycopodine (457) was then achieved by removal of the amide carbonyl, by reduction with LAH, and oxidation of the resulting C-6 epimeric alcohols. The amino ketone 491 was then oxidized to the diosphenol 492, that was reduced selectively by a Wolff-Kishner reaction with hydrazine hydrate to afford lycopodine (457).
As noted above, a synthesis of 486, and hence the relay compound 488, from a symmetrical starting material was envisioned (see above). In particular, 486 might be prepared from 487 by reaction with a nucleophilic side chain synthon. With a provision for masking the electrophilicity of the carbonyl group, this strategy proved viable. Thus, 494 was prepared from thalline (493) by alkylation with 1-bromo-3-chloropropane followed by dissolving metal reduction and ketalization. Reaction of 494 with the nucleophilic fragment 495 followed by hydrolysis gives the cis,cis-fused tricyclic amine 496. Ring closure of this epimer is impossible. Epimerization to the trans,cis isomer 485 must precede ring closure. Therefore, epimerization was accomplished by exploiting the carbonyl functionality in 496 by bromination followed by Mattox-Kendall dehydrobromination and dissolving metal reduction. Demethylation of the product 497 then afforded a mixture of racemic diastereomeric ketones 498 and 499. These were separated by chromatography on alumina. The minor isomer 498 possessed the natural relative configuration of the methyl substituent. Thus, the present synthesis is nonstereospecific, and a near fatal major loss of valuable material occurs owing to the formation of an unwanted stereoisomer 499.
Before intramolecular alkylation of the tricyclic ketone could be accomplished, the nucleophilicity of the amino group had to be attenuated by conversion of the amino group in 498 into an amide 500 to avoid N-alkylation. Saponification, mesylation, and intramolecular alkylation then provided the relay compound 488 in racemic form. Since 476, albeit homochiral, derived from natural lycopodine (457) had already been converted to 457 as discussed above, the total synthesis was complete.
An Unintentionally Biomimetic Strategy
In the two strategies for lycopodine (457) discussed above, one generated ring B last and one generated ring D last. Now we shall consider a strategy that generates ring C last as found in the biosynthesis of 457. Moreover, in further analogy with the biosynthetic strategy, the three carbon chain substituent on ring B of 501, that is the used to complete ring C, is incorporated into a temporary ring in a precursor 502 by attachment at the (latent) carbonyl carbon at C-5. Finally, the consonant circuit between the amino and methoxy groups in the aromatic precursor 503 suggests a polar construction from 504 of the 4-13 C-C bond, again in analogy with the biosynthetic strategy, by attack of a C-13 electrophile on a nucleophilic center at the incipient C-4. However, this strategy was conceived before the biosynthesis of lycopodine had been elucidated. In the words of the author of the strategy, "although the particular synthetic plan followed for the construction of the tetracyclic system had no particular basis in biogenetic considerations, very recent work has suggested a biogenetic pathway in which the crucial cyclization step is strikingly similar to the one we devised."21
Before we consider the successful implementation of this plan, it is instructive to note that it was developed with the aid of lessons learned during attempts to achieve a synthesis using other, fatally flawed, strategies. One unsuccessful early plan for a transformation analogous to the generation of 503 from 504 was supported by successful model studies. Thus, a carbocyclic model 505 readily underwent an analogous cyclization to 506 on heating with polyphosphoric acid. It was anticipated that the methyl substituent at position 15 on the D-ring of 504 could be introduced subsequently by exploiting the nucleophilic activation afforded by a carbonyl group at position 8. Furthermore, the inclusion of this carbonyl group could enhance the general utility of the synthesis because oxygen substitution is found at position 8 in many lycopodium alkaloids. However, in contrast to the carbocyclic model 505, cyclization of the heterocyclic analogue 507 to give 508 could not be achieved. Rather 507 was apparently prone toward elimination leading to aromatization.
Nevertheless, an encouraging observation emerged from this model study. Thus, the dialkylated derivative 509, a byproduct in the synthesis of 507, underwent the desired type of cyclization. The success of this cyclization seemed attributable to two factors, an axial orientation of a benzyl substituent and blocking of the elimination pathway.
A modified strategy was then devised in which the methyl substituent required at position 15 was introduced prior to the annelation of ring B and the carbonyl group at position 8 was deleted. Moreover, the stereochemistry of this methyl substituent in lycopodine dictated a trans relationship of the methyl and m-methoxybenzyl groups in the new subtarget. The functionalized derivative chosen to embody these requirements was 511. It was further recognized that the trans methyl subtituent in 511 should virtually eliminate the energy barrier to achieving the axial orientation of the benzyl substituent required for cyclization to 510.
Several strategies were explored for synthesis of the subtarget 511, that is obviously derivable from 512. An approach to 512 via conjugate addition of a methyl nucleophile to 513 followed by oxidative cleavage of the cyclohexenone 514 was precluded by the proclivity of 514 to isomerize into the β,γ-unsaturated isomer 515.
A second approach to 511 exploits the consonant circuit between the carbonyl carbon and enamide nitrogen in 511 or the related consonant circuit between the two carbonyl groups in keto amide 516. Disconnection of the three carbon side chain suggests a cyclohexanone precursor 517 that can be generated by polar connections activated by the carbonyl group.
Cyclohexanone 517 was prepared by polar reactions between an acrylic ester and acetoacetic ester. Thus, a symmetrical dione 519 was generated from β,γ-unsaturated ester 518 by prototropic allylic rearrangement, followed by Michael addition of ethyl acetoacetate, Dieckmann cyclization, hydrolysis, and decarboxylation. Selective reduction of only one carbonyl group in 519 was facilitated by masking the second carbonyl of this dione as a vinylogous ester. Acid-catalyzed dehydration then provided a cyclohexenone that delivered 517 upon stereoselective 1,4-addition of a methyl nucleophile.
The original strategy for construction of key intermediate 511 from cyclohexanone 517 had one major shortcoming. Thus, conversion of 517 into 511 requires regioselective Michael alkylation. However, alkylation of 517 occurred nonregioselectively at both carbons α to the carbonyl producing a mixture of 511 and 520.
An improved, completely structurally specific synthesis of the subtarget 511 was finally devised that exploited regiospecific generation and electrophilic trapping of the enolate 522. This was achieved by Michael addition of a benzyl nucleophile to the cyclohexenone 521. The resulting regiospecific enolate was then alkylated with allyl bromide. The process is also highly stereoselective owing to a preference for axial attack in Michael additions of organocopper nucleophiles and a preference for an equatorial disposition of the methyl substituent in 521. Furthermore, the required trans relationship between the allyl and benzyl substituents is assured by thermodynamic control owing to epimerizability α to the ketone carbonyl. Hydroboration and oxidation of the allyl side chain, esterification, and reaction of the resulting ketoester with ammonia afforded the key intermediate 511.
Intramolecular electrophilic aromatic substitution gave mainly the desired para substituted cyclization product 510 (55%) together with some ortho substitution product (29%). The amide carbonyl was then removed by reduction with LAH, and the protective aromaticity of the aryl ring was removed by Birch reduction. A plan to effect ring cleavage by oxidation of an α,β-unsaturated cyclohexenone failed owing to a thermodynamic preference for the required enone 502 to exist as the corresponding β,γ- unsaturated tautomer 524.
Once again, therefore, an alternative strategy had to be formulated. The original plan for generating 489 from 497 was fatally flawed. Indeed, while the each step in the original plan was well precedented, so was the likelihood that 502 would be in equilibrium with a substantial amount of 524. Indeed, this same problem derailed an attempted synthesis of 512 from 514 (see above). As is so often the case, a shortcoming of well-known methodology for achieving an important synthetic goal, especially if it impedes the conclusion of an ambitious total synthesis, inspires the application of novel chemistry to provide a solution to the dillema. Necessity is the mother of invention! Thus, generation of 501 from 523 required oxidative cleavage of two bonds, "a" and "b", in the cyclohexadiene ring. The original plan called for cleavage of bond "a" first after an isomerization that placed a readily cleavable C=C bond in this position. In the alternative strategy, bond "b" is cleaved first after an isomerization that placed a readily cleavable C=C bond in this position.
Thus, the 1,4-cyclohexadiene 523 was isomerized to a conjugated 1,3-diene, and the amino group was masked to protect it from oxidation. Selective ozonolysis of the more electron rich C=C bond in 525 then afforded the aldehydo methyl ester 526. An unusual Baeyer-Villager oxidation of 526 gave the enol formate 527 that afforded keto amide 528 after methanolysis of the enol ether, removal of the carbamate protecting group from the amino nitrogen, and lactamization. The amide carbonyl was then removed to provide lycopodine (457) by reduction with LAH followed by reoxidation of the C-5 hydroxyl to the required C-5 carbonyl group.
6.08: Terminology
For definitions see the sections listed.
deactivating group (section 6.7)
polar reactivity inversion operator (section 6.6)
polar redox reaction (section 6.5)
pyridoxal phosphate (section 6.6)
transamination (section 6.6)
6.10: References
1. Schreiber, J.; Leimgruber, W.; Pesaro, M.; Schudel, P.; Threlfall, T.; Eschenmosher, A. Helv. Chim. Acta 1961, 44, 540.
2. van Tamelen, E. E.; Spencer, F. A.; Allen, O. S.; Orvis, R. L. Tetrahedron 1961, 14, 8.
3. Woodward, R. B. The Harvey Lectures 1963, 31.
4. (a) Scott, A, I,; McCapra, F.; Buchanan, R. L.; Day, A. C.; Young, D. W. Tetrahedron 1965, 21, 3605. (b) Scott, A, I,; McCapra, F.; Nabney, J.; Young, D. W.; Day, A. C.; Baker, A. J.; Davidson, T. AS. J. Am. Chem. Soc. 1963, 85, 3040.
5. Fleming, I. "Selected Organic Syntheses", p. 201, Wiley Interscience, New York, 1973.
6. Ranganathan, D.; Ranganathan, S. "Art in Biosynthesis" pp. 36-9, Academic Press, New York, 1976.
7. Auerbach, J.; Weinreb, S. M. J. Am. Chem. Soc. 1972, 94, 7172.
8. Semmelhack, M. F.; Chung, B. P.; Jones, L. D. J. Am. Chem. Soc. 1972, 84, 8629.
9. (a) Barton, D. H. R.; Kirby, G. W.; Steglich, W.; Thomas, G. M. Proc. Chem. Soc. 1963, 203. (b) Barton, D. H. R.; Bhakuni, D. S.; James, R.; Kirby, G. W.; J. Chem. Soc. (C) 1967, 128.
10. Gates, M.; Tschudi J. Am. Chem. Soc. 1952, 74, 1109 and 1956, 78, 1380.
11. Elad, D.; Ginsburg, D. J. Am. Chem. Soc. 1954, 76, 312 and J. Chem. Soc. 1954, 3052.
12. Toth, J. E.; Hamann, P. R.; Fuchs, P. L. J. Org. Chem. 1988, 53, 4694.
13. (a) Kornfeld, K. C.; Fornefeld, E. J.; Kline, G. B.; Mann, M. J.; Jones, R. G.; Woodward, R. B. J. Am. Chem. Soc. 1954, 76, 5256. (b) Kornfeld, K. C.; Fornefeld, E. J.; Kline, G. B.; Mann, M. N.; Morrison, D. E.; Jones, R. G.; Woodward, R. B. J. Am. Chem. Soc. 1956, 78, 3987.
14. Lysergic Acid Synthesis
15. Julia, M.; LeGoffic, F.; Igolen, J.; Baillarge, M. Tetrahedron Lett. 1969, 1569.
16. (a) Scott, A. Ian; Reichardt, P. B.; Slaytor, M. B.; Sweeny, J. G. Bioorg. Chem. 1971, 1, 157. (b) Qureshi, A. A.; Scott, A. I. Chem. Commun. 1968, 948.
17. Rabe,
18. Woodward, R. B.; Doering, W. von E. J. Am. Chem. Soc. 1945, 67, 860.
19. ? Wiesner, K.; Valenta, Z.; et al. Tetrahedron Lett. 1965, 1279; 1967, 4931; 1968, 5643.
20. Ayer, W. A.; Bowman, W. R.; Joseph, T. C.; Smith, P. J. Am. Chem. Soc. 1968, 90, 1648.
21. (a) Stork, G.; Kretchmer, R. A.; Schlessinger, R. H. J. Am. Chem. Soc. 1968, 90, 1647. (b) Stork, G. Pure and Appl. Chem. 1968, 17, 383. | textbooks/chem/Organic_Chemistry/Complex_Molecular_Synthesis_(Salomon)/06%3A_Amino_Acids_and_Alkaloids/6.07%3A_Lycopodine.txt |
Objective
After completing this chapter, you should be able to
• fulfill all of the detailed objectives listed under each individual section.
• define, and use in context, the key terms introduced in this chapter.
• have an understanding of how spectroscopy works in a general sense.
Throughout organic chemistry, one needs to think about the structure of a molecule because structure informs reactivity. This connection between structure and reactivity is central to organic chemistry. By looking at a structure, experienced organic chemists can already begin to gather information about the properties of a molecule. However, structure determination has not always been as quick and easy to potentially determine as it can be today, but modern spectroscopic techniques have reduced the time it once took. Spectroscopic techniques are based on the absorption of radiation from the electromagnetic spectrum. The different spectroscopic techniques can give different snapshots of the molecule's structure and lend insight to properties the molecule may have. When combining different techniques, one can get a more complete picture of the molecule, which allows one to deduce the structure of a molecule. This chapter will discuss spectroscopy in general before moving into different spectroscopic techniques and the information you can gather from the technique.
1.02: The Nature of Radiant Energy and Electromagnetic Radiation
Learning Objectives
After reading this section, you should be able to
• Understand the nature of light
• Explain what it meant by wave and particle duality
• Write a brief paragraph discussing the nature of electromagnetic radiation.
• Explain the equations that relate energy to frequency, frequency to wavelength and energy to wavelength, and perform calculations using these relationships.
Key Terms
Make certain that you can define, and use in context, the key terms below.
• electromagnetic radiation
• electromagnetic spectrum
• hertz (Hz)
• photon
• wavelength
• constructive interference
• destructive interference
As you read the print off this computer screen now, you are reading pages of fluctuating energy and magnetic fields. Light, electricity, and magnetism are all different forms of electromagnetic radiation. Electromagnetic radiation, as you may recall from a previous chemistry or physics class, is composed of electrical and magnetic waves which oscillate on perpendicular planes as shown in the diagram below. These electric and magnetic waves travel at 90 degree angles to each other and have certain characteristics, including amplitude, wavelength, and frequency. Electron radiation is released as photons, which are bundles of light energy that travel at the speed of light as quantized harmonic waves. This radiation can travel through empty space. Most other types of waves must travel through some sort of substance. For example, sound waves need either a gas, solid, or liquid to pass through in order to be heard.This energy is then grouped into categories based on its wavelength into the electromagnetic spectrum.
Waves and their Characteristics
Just like ocean waves, electromagnetic waves travel in a defined direction. While the speed of ocean waves can vary, however, the speed of electromagnetic waves – commonly referred to as the speed of light (2.99 x 108 m/s) – is essentially a constant, approximately 300 million meters per second. This is true whether we are talking about gamma radiation or visible light. Obviously, there is a big difference between these two types of waves – we are surrounded by the latter for more than half of our time on earth, whereas we hopefully never become exposed to the former to any significant degree.
Amplitude
Amplitude as shown above is the distance from the maximum vertical displacement of the wave to the middle of the wave. This measures the magnitude of oscillation of a particular wave. In short, the amplitude is basically the height of the wave. Larger amplitude means higher energy and lower amplitude means lower energy. Amplitude is important because it tells you the intensity or brightness of a wave in comparison with other waves.
Wavelength
The different properties of the various types of electromagnetic radiation are due to differences in their wavelengths, and the corresponding differences in their energies: shorter wavelengths correspond to higher energy. Wavelength ($\lambda$) is the distance of one full cycle of the oscillation (measured between the distance of either crest to crest as shown above or trough to trough). Longer wavelength waves such as radio waves carry low energy; this is why we can listen to the radio without any harmful consequences. Shorter wavelength waves such as x-rays carry higher energy that can be hazardous to our health. Consequently lead aprons are worn to protect our bodies from harmful radiation when we undergo x-rays. This wavelength frequently relationship is characterized by:
$c = \lambda\nu$
where
• c is the speed of light,
• $\lambda$ is wavelength, and
• $\nu$ is frequency.
Shorter wavelength means greater frequency, and greater frequency means higher energy. Wavelengths are important in that they tell one what type of wave one is dealing with. You can see this depicted in the image below.
Remember, wavelength tells you the type of light and amplitude tells you about the intensity of the light.
Frequency
Frequency is defined as the number of cycles per second, and is expressed as sec-1 or Hertz (Hz). Frequency is directly proportional to energy and can be express as:
$E = h\nu$
where
• E is energy,
• h is Planck's constant, (h= 6.62607 x 10-34 J), and
• $\nu$ is frequency.
Period
Period (T) is the amount of time a wave takes to travel one wavelength; it is measured in seconds (s).
Velocity
The velocity of wave in general is expressed as:
$velocity = \lambda\nu$
Remember for an electromagnetic wave, the velocity in vacuum is $2.99 \times 10^8\;m/s$ or $186,282$ miles/second.
Electromagnetic spectrum
The notion that electromagnetic radiation contains a quantifiable amount of energy can perhaps be better understood if we talk about light as a stream of particles, called photons, rather than as a wave. (Recall the concept known as ‘wave-particle duality’: at the quantum level, wave behavior and particle behavior become indistinguishable, and very small particles have an observable ‘wavelength’). If we describe light as a stream of photons, the energy of a particular wavelength can be expressed as:
$E = \dfrac{hc}{\lambda} \tag{12.5.1}$
where E is energy in J, λ (the Greek letter lambda) is wavelength in meters, c is 3.00 x 108 m/s (the speed of light), and h is 6.626 × 10−34 J · s, a number known as Planck’s constant.
Because electromagnetic radiation travels at a constant speed, each wavelength corresponds to a given frequency, which is the number of times per second that a crest passes a given point. Longer waves have lower frequencies, and shorter waves have higher frequencies. Frequency is commonly reported in hertz (Hz), meaning ‘cycles per second’, or ‘waves per second’. The standard unit for frequency is s-1.
When talking about electromagnetic waves, we can refer either to wavelength or to frequency - the two values are interconverted using the simple expression:
$\lambda \nu = c \tag{12.5.2}$
where ν (the Greek letter ‘nu’) is frequency in s-1. Visible red light with a wavelength of 700 nm, for example, has a frequency of 4.29 x 1014 Hz, and an energy of 2.84 x 10-19 J per photon or 171 kJ per mole of photons (remember Avogadro’s number = 6.02 × 1023 mol−1). The full range of electromagnetic radiation wavelengths is referred to as the electromagnetic spectrum (below).
Example $1$
Visible light has a wavelength range of about 400-700 nm. What is the corresponding frequency range? What is the corresponding energy range, in kJ mol−1 of photons?
Solution
For light with a wavelength of 400 nm, the frequency is 7.50 × 1014 Hz:
In the same way, we calculate that light with a wavelength of 700 nm has a frequency of 4.29 × 1014 Hz.
To calculate corresponding energies using hc/λ. We find for light at 400 nm:
Using the same equation, we find that light at 700 nm corresponds to 171 kJ mol−1.
As a wave’s wavelength increases, the frequency decreases, and as wave’s wavelength decreases, the frequency increases. When electromagnetic energy is released as the energy level increases, the wavelength decreases and frequency decreases. Thus, electromagnetic radiation is then grouped into categories based on its wavelength or frequency into the electromagnetic spectrum. The different types of electromagnetic radiation shown in the electromagnetic spectrum consists of radio waves, microwaves, infrared waves, visible light, ultraviolet radiation, X-rays, and gamma rays. The part of the electromagnetic spectrum that we are able to see is the visible light spectrum.
Electromagnetic Spectrum with Radiation Types
How are the types of radiation related to me? Radio waves are transmitted by radio broadcasts, TV broadcasts, and even cell phones. They are also used in radar systems, where they release radio energy and collect the bounced energy back. Microwaves can be used to broadcast information through space, as well as warm food. Infrared radiation can be released as heat or thermal energy and is most commonly used in remote sensing as infrared sensors collect thermal energy, providing us with weather conditions. Visible light is the only part of the electromagnetic spectrum that humans can see with an unaided eye. This part of the spectrum includes a range of different colors that all represent a particular wavelength. Rainbows are formed in this way; light passes through matter in which it is absorbed or reflected based on its wavelength. Thus, some colors are reflected more than other, leading to the creation of a rainbow. The typical wavelengths of each color region is listed below.
Color Region
Wavelength (nm)
Violet 380-435
Blue 435-500
Cyan 500-520
Green 520-565
Yellow 565-590
Orange 590-625
Red 625-740
Ultraviolet, Radiation, X-Rays, and Gamma Rays are all related to events occurring in space. UV radiation is most commonly known because of its severe effects on the skin from the sun, leading to cancer. X-rays are used to produce medical images of the body. Gamma Rays can used in chemotherapy in order to rid of tumors in a body since it has such a high energy level. Out this huge spectrum, the human eyes can only detect waves from 390 nm to 780 nm.
Exercise $1$
Calculate the energies for the following;
A. Gamma Ray λ = 4.0x10-11 m
B. X-Ray λ = 4.0x10-9 m
C. UV light υ = 5.0x1015 Hz
D. Infrared Radiation λ = 3.0x10-5 m
E. Microwave Radiation υ = 3.0x1011 Hz
Answer
A. 4.965x10-15 J
B. 4.965x10-17 J
C. 3.31x10-18 J
D. 6.62x10-21 J
E. 1.99x10-22
Note: You should not try to memorize the relationship between energy and wavelength in the form in which it is given here. Instead, you should be prepared to work from first principles using:
E = hv, where h = Plank's constant = 6.626 × 1034J · s.
c = λv, where c = the speed of light = 3.00 × 108m · s−1.
Avogadro’s number = 6.02 × 1023 mol
Exercise $2$
What is the frequency of a wave with a wavelength of 200 cm?
Answer
1.5 × 108 Hz
Exercise $3$
Which of the following frequencies/wavelengths are higher energy?
A. λ = 2.0x10-6 m or λ = 3.0x10-9 m
B. υ = 3.0x109 Hz or υ = 3.0x10-6 Hz
Answer
A. λ = 3.0x10-9 m
B. υ = 3.0x109 H
Exercise $4$
A radio transmits a frequency of 100 Hz. What is the wavelength of this wave?
Answer
2.998 × 106 m | textbooks/chem/Organic_Chemistry/Introduction_to_Organic_Spectroscopy/01%3A_Introduction_to_Organic_Spectroscopy/1.01%3A_Chapter_Objectives_and_Preview_of_Spectroscopy.txt |
Objectives
After completing this section, you should be able to
• Understand how an organic molecule interacts with electromagnetic radiation.
• Understand how different frequencies affect organic molecules.
Now that we we have discussed electromagnetic radiation and what it is, let's look at how it can interact with organic molecules. As was discussed in the last section, electromagnetic radiation can either acts as a wave or a particle, a photon. As a wave, it is represented by velocity, wavelength, and frequency. Light is an electromagnetic wave since the speed of electromagnetic waves is the same as the speed of light. As a particle, electromagnetic radiation is represented as a photon, which transports energy. When a photon is absorbed, the electron can be moved up or down an energy level. When it moves up, it absorbs energy, when it moves down, energy is released as is shown in the diagram below. Thus, since each atom has its own distinct set of energy levels, each element emits and absorbs different frequencies. Photons with higher energies produce shorter wavelengths and photons with lower energies produce longer wavelengths.
Electromagnetic radiation is also categorized into two groups based, ionizing and non-ionizing, on the severity of the radiation. Ionizing radiation holds a great amount of energy to remove electrons and cause the matter to become ionized. Thus, higher frequency waves such as the X-rays and gamma-rays have ionizing radiation. However, lower frequency waves such as radio waves, do not have ionizing radiation and are grouped as non-ionizing.
Molecular spectroscopy – the basic idea
In a spectroscopy experiment, electromagnetic radiation of a specified range of wavelengths is allowed to pass through a sample containing a compound of interest. The sample molecules absorb energy from some of the wavelengths, and as a result jump from a low energy ‘ground state’ to some higher energy ‘excited state’. Other wavelengths are not absorbed by the sample molecule, so they pass on through. A detector on the other side of the sample records which wavelengths were absorbed, and to what extent they were absorbed.
Here is the key to molecular spectroscopy: a given molecule will specifically absorb only those wavelengths which have energies that correspond to the energy difference of the transition that is occurring. Thus, if the transition involves the molecule jumping from ground state A to excited state B, with an energy difference of ΔE, the molecule will specifically absorb radiation with wavelength that corresponds to ΔE, while allowing other wavelengths to pass through unabsorbed.
By observing which wavelengths a molecule absorbs, and to what extent it absorbs them, we can gain information about the nature of the energetic transitions that a molecule is able to undergo, and thus information about its structure. If a sample is irradiated with energy of many wavelengths and determine which are absorbed and which are transmitted, the absorption spectrum of the compound can be measured. The energy the molecule gains when it absorbs radiation must be distributed over the molecule in some way. The different types of radiation cause different ways of interacting with the electromagnetic radiation. With infrared radiation, the energy absorbed by a molecule causes bonds to bend and stretch. With ultraviolet radiation, the energy absorbed causes an electron to jump from a lower energy orbital to a higher energy orbital. With these different frequencies interacting differently with the molecule, different types of structural information can be gleaned as you interpret the results of absorption spectra.
These generalized ideas may all sound quite confusing at this point, but things will become much clearer as we begin to discuss specific examples. In the upcoming chapters, ultraviolet spectroscopy, infrared spectroscopy, and nuclear magnetic resonance spectroscopy will be discussed in greater detail.
Exercise \(1\)
Knowing that infrared radiation causes bonds to bend and stretch more vigorously. Would you expect this type of radiation to be ionizing or non-ionizing?
Answer
The photons of infrared radiation absorbed do have enough energy to cause an increase in the amplitude of bond vibrations (bending/stretching), but not enough energy to break a covalent bond.
Exercise \(2\)
The ΔE (energy gap) has in inverse dependance on wavelength.
E=hc/λ
Therfore, a smaller gap leads to a longer or shorter wavelength?
Answer
The smaller the energy gap, the longer the wavelength of light that will be absorbed in the electronic transition. | textbooks/chem/Organic_Chemistry/Introduction_to_Organic_Spectroscopy/01%3A_Introduction_to_Organic_Spectroscopy/1.03%3A_Introduction_to_Spectroscopy.txt |
Learning Objectives
• Understand how spectroscopic measurements are taken.
• Explain frequency resolution vs time resolution.
Spectroscopic measurements are typically taken in one of two domains: frequency or time. These measurements are given the terms frequency-resolved or time-resolved. Frequency-resolved measurements are the most familiar forms of spectroscopy. UV/Visible, IR, Raman, and X-ray spectroscopy are typically done in the frequency domain. This type of spectroscopy acquires data across a range of frequencies (or wavelengths). The data acquired is typically in the form of an light intensity which can in turn be interpreted as absorbance, transmittance, reflectance, or photon scattering depending on the instrument and technique being used.
The less familiar time-resolved spectroscopy includes Ultrafast laser spectroscopy and florescence. In this form of spectroscopy data is acquired over a range of time. This data can be at a single wavelength or at multiple wavelengths, depending on the specific technique. Some spectroscopic techniques, such as Ultrafast laser spectroscopy, FT-NMR and FT-IR, span both frequency and time domains. In the case of Ultrafast laser spectroscopy, useful data is acquired in both the time and frequency domains. FT-NMR and FT-IR acquire data in the time domain. That data is then converted into a signal in the frequency domain using a process called Fourier Transform (FT). This is covered in more detail in the next section.
Frequency Resolution
Frequency is defined as inverse time. The unit is typically given in inverse seconds (s-1) or hertz (Hz). Frequency is used to represent the number of cycles occurring in a given time period. These cycles could be any repetitive process including: the periodic motion of a harmonic oscillator, the sinusoidal propagation of electromagnetic radiation, or the rotation of a rigid rotator. The most relevant for spectroscopy is the propagation of electromagnetic radiation or light. This is often represented in many different forms that, though not technically frequency, are related to frequency, and therefore fall into the frequency domain. These include representing frequency as wavelength (nm), wavenumber (cm-1), and photon energy (eV). These are all connected by a few simple equations given below. (c=speed of light, E=energy, v=frequency, w=wavenumber, h=Planck's constant,lambda=wavelength)
$\lambda = \dfrac{c}{\nu}$
$E = h\nu$
$w = \dfrac{1}{\lambda}$
The frequency domain is the most familiar domain in spectroscopy. UV/visible, infrared, photoelectron, microwave, and X-ray spectroscopy all have applications in the frequency domain. The results of these spectroscopic techniques are typically given in some form of intensity versus wavelength. The most familiar is likely the steady state ultraviolet/visible absorption spectrum (an example is shown below).
Frequency Resolved Visible Absorption Spectrum
The energy of absorbed light corresponds to the energy of transition between two eigen states of the system. In the case of visible spectroscopy these states are electronic states.
Time Resolution
Spectra can also be acquired in the time domain. Rather than acquiring spectra by averaging data over a relatively long time range, data is acquired over discrete time intervals or, in some cases, continuously. This may be done over one or many wavelengths. Time resolved spectroscopy observes the change in eigen states with respect to time. In order for data from time-resolved spectroscopy to be useful, the spectroscopy must be suited to the time scale of the process of interest. Below is a table of the approximate time scales and spectral ranges of physical processes that may be interesting.
Process Time Applicable Spectral Range
Singlet Electronic Excited State Lifetime femto-nanoseconds Visible
Triplet Electronic Excited State Lifetime nanoseconds-minutes Visible
Molecular Vibration Excited State Lifetime pico-milliseconds Infrared
Nuclear Rotation pico-microseconds Radio
Molecular Reaction Kinetics eons-picoseconds Varies
If a spectroscopy with suitable spectral region and time resolution is available, time resolved spectroscopy can be used to study kinetics, reactions, and lifetimes. Common applications of time-resolved spectroscopy include ultrafast laser spectroscopy and time-resolved florescence.
Fourier Transform
The process of Fourier Transform is a mathematical process used to move from one set of coordinates to another. The most spectroscopically relevant fourier transform is from the time domain to the frequency domain. In this case, a signal originally measured in the time domain can be converted into a signal in the frequency domain. This is done via the mathematical process shown below.
$\displaystyle F(v) = \int_{-\infty}^{\infty} f(t)e^{-2i\pi vt}dt$
$\displaystyle f(t) = \int_{-\infty}^{\infty} F(v)e^{-2i\pi vt}dv$
A mathematical relation known as Euler's Formula is an important identity when using Fourier Transform, particularly with sine and cosine functions. This is shown below.
$e^{\pm ix} = cos(x) \pm isin(x)$
A simple graphic representation of Fourier Transform is shown below.
Original Signal in Time Domain
Fourier Transformed: Signal in Frequency Domain
Fourier Transformed Again: Signal in Time Domain (The Components of the Original Signal)
Sum of the Components(Equivalent to the Original Signal)
An example fourier transform with sine is given in the links section and more information in The Power of the Fourier Transform for Spectroscopists.
Common Application of Fourier Transform
Some fields of spectroscopy use measurements taken in the time domain to gain information about the frequency domain. These spectroscopies include Nuclear Magnetic Resonance, Fourier Transform Ion Cyclotron Resonance Mass Spectroscopy(FT-ICR MS) and Fourier Transform Infrared spectroscopy(FT-IR). Unlike the above graphic representation of Fourier Transform, these systems yield transforms that are impossible to compute by hand. Computer algorithms must be used.
The initial signal typically forms a beat pattern. This can be in the form of an interferogram or a free induction decay(FID), in the cases of FT-IR and NMR, respectively. Graphic representations of an interferogram and FID are shown below alongside IR and NMR spectra.
FT-IR Spectra
Interferogram(X-axis: Time|Y-Axis:Amplitude) Infrared Spectrum(X-axis: Wave Number (cm-1)|Y-axis: Percent Transmission)
FT-NMR Spectra
Free Induction Decay(X-axis: Time|Y-axis: Amplitude) NMR Spectrum(X-axis: Chemical Shift (ppm)|Y-axis: Amplitude)
Spectroscopy in Both Time and Frequency Domains
Some spectroscopies yield data in both time and frequency domains. The most prominent of these techniques is time-resolved laser spectroscopy. By measuring complete spectra at discrete time intervals, spectral evolution with respect to time can be monitored. This technique is unique in it's ability to collect data in multiple domains with femtosecond time resolution. This allows electronic states to be monitored both as they evolve over time and statically at any particular time along the time scale of the instrument. Below is an example of a typical ultrafast spectrum, notice both wavelength and time domains. This three-dimensional spectrum can be deconstructed to yield either time or frequency dependent results in two-dimensions. This is also shown below.
Time Resolved Visible Absorbance Spectrum
(X-axis:Wavelength(nm)|Y-axis:Time(ps)|Z-axis:(ABS)[Shown as color])
The time resolved spectrum shown above is plotted as a contour plot showing the Z-axis as a color gradient from red(low signal) to blue(high signal). This contour plot contains a multitude of information, but is by itself not terribly useful. It is most easily analyzed by taking crossections at a single wavelength or time. Each is shown below.
Frequency Domain Signal (A crossection of the Time Resolved Spectrum constant time)
The above spectrum is a crossection of the complete time resolved spectrum. This particular crossection is the frequency domain signal at 56.75 picoseconds after the sample has been excited by a laser pulse.
Time Domain Signal (A crossection of the Time Resolved Spectrum at a single Wavelength)
The above spectrum is a crossection of the complete time resolved spectrum. This crossection is the time resolved signal at 618 nanometers. This crossection contains kinetic data on the eigen state that absorbs at 618nm.
Exercise $1$
What types of spectroscopy are done using the frequency domain?
Answer
UV/Visible, IR, Raman, and X-ray spectroscopy are typically done in the frequency domain. This type of spectroscopy acquires data across a range of frequencies (or wavelengths).
Exercise $2$
How is data acquired in the time domain?
Answer
Data is acquired over discrete time intervals or, in some cases, continuously. | textbooks/chem/Organic_Chemistry/Introduction_to_Organic_Spectroscopy/01%3A_Introduction_to_Organic_Spectroscopy/1.04%3A_Time-resolved_vs._Frequency_Resolved.txt |
Learning Objectives
• Understand what the Fourier transform does to allow spectroscopists to observe spectra.
• Describe the important components of Fourier transform.
• Explain the benefits and limitations to Fourier transform.
Fourier transform is a mathematical technique that can be used to transform a function from one real variable to another. It is a unique powerful tool for spectroscopists because a variety of spectroscopic studies are dealing with electromagnetic waves covering a wide range of frequency. In Fourier transform term $\ e^{ - 2\pi ixy} \$, when x represents frequency, the corresponding y is time. This provides an alternate way to process signal in time domain instead of the conventional frequency domain. To realize this idea, Fourier transform from time domain to frequency domain is the essential process that enable us to translate raw data to readable spectra. In short, this mathematical technique takes the raw data and translates the raw data to the spectra typically seen. Recent prosperity of Fourier transform in spectroscopy should also attribute to the development of efficient Fast Fourier Transform algorithm.
Introduction
The nature of trigonometric function enables Fourier transform to convert a function from the domain of one variable to another and reconstruct it later on. This is a robust mathematical tool to process data in different domains under different circumstances. Taking this principal idea and applying it in spectroscopy showed many impressive results in the early stage, which in other ways are very difficult to resolve. These benefits triggered a wide exploration of Fourier transform based methodology in a variety of spectroscopic techniques. At the same time, Fourier transform spectroscopic instruments are developed with great efforts by physicists and engineers. All these factors give rise to the wide use of Fourier transform spectroscopy.
In the following topics, the relevant mathematical background, the implementation of Fourier transform in spectroscopy and a brief overview of various Fourier transform Spectrometers will be addressed in sequence.
Fourier Series
The motivation of Fourier transform arises from Fourier series, which was proposed by French mathematician and physicist Joseph Fourier when he tried to analyze the flow and the distribution of energy in solid bodies at the turn of the 19th century. He claimed that the temperature distribution could be described as an infinite series of sines and cosines of the form shown in equation (1):
$f(x)= \dfrac{a_{0}}{2} + \displaystyle \sum_{n=1}^{\infty} \left(a_{n}\cos\dfrac{n\pi x}{L}+b_{n} \sin \frac{n \pi x}{L}\right) \tag{1}$
It turns out that this combination of sines and cosines series can be used to express any periodical function. As $n$ increases, the series will approach to the original function more closely.
If we use Euler's Identity (equation 2), as well as the exponential representations of sine (equation 3) and cosine (equation 4) in our Fourier Series, we will find a natural redefinition of our coefficients $a_n$ and $b_n$ into a single complex coefficient C_n (equation 5).
$e^{i\theta}=\cos{\theta}+ i\sin{\theta} \tag{2}$
$\cos{\theta}=\dfrac{1}{2} (e^{i\theta} + e^{-i\theta}) \tag{3}$
$\sin{\theta}=\dfrac{1}{2i} (e^{i\theta} - e^{-i\theta}) \tag{4}$
$C_n =\dfrac{1}{2}(C_n-ib_n) \tag{5}$
Using a bit of clever mathematics (complex conjugation, properties of odd function, rearranging summation set) we can represent our original Fourier series in terms of a complex exponential, shown as equation (6).
$f(x) = \sum_{n=-\infty}^{\infty} C_n e^{i\theta} \tag{6a}$
$\theta = \dfrac{2\pi n x}{L} \tag{6b}$
Writing the Fourier series in this exponential form helps to simplify many formulas and expressions involved in the transformation.
Fourier Transform
Then we can consider an extreme case, when L in equation (1), the summation becomes an integral as shown in equation (4)
$f(x) = \sum\limits_{-\infty} ^\infty c_n e^{n\frac{i\pi x}{L}} = \int_{ -\infty}^\infty c_n e^{n\frac{i\pi x}{L}} dn = \int_{-\infty}^\infty c_n e^{\frac{i\pi xn}{L}} dn \tag{7}$
This naturally gives the Fourier transform pair of f(x) and F(y). The relationships are shown below :
$F(y) = \int_{ -\infty }^{ +\infty } {f(x)e^{ - i2\pi yx} dx} \tag{8a}$
$f(x) = \int_{ -\infty }^{ +\infty } {F(y)e^{ i2\pi xy} dx} \tag{8b}$
In other cases, it is used to simplify the integral in the Fourier transform based on the symmetry of the function. But so far, all these are just about mathematics. Its story with spectroscopy should start from the mathematical description of electromagnetic waves.
Mathematical description of electromagnetic waves
Maxwell–Faraday equation and Ampère's circuital law give us electromagnetic wave equations to describe the characteristics of an electromagnetic wave.[1] Using the linearity of Maxwell's equations in a vacuum, the solutions of the equation can be decomposed into a superposition of sinusoids as shown below[3]:
$E(r,t) = \overrightarrow {E_0 } \cos (2\pi ft - \overrightarrow k \cdot r + \phi _0 ) \tag{9a}$
$B(r,t) = \overrightarrow {B_0 } \cos (2\pi ft - \overrightarrow k \cdot r + \phi _0 ) \tag{9b}$
Where t is time, f is the frequency, k=(kx,ky,kz) is the wave vector and $\phi$ is the phase angle.
This indicates that electromagnetic wave can be written as the sum of trigonometric functions with specific frequencies. Scientists already discovered the fact that frequency and time is a classic Fourier transform pair in Fourier transform relationship. All the Fourier transform pairs are connected by the Fourier transform term $e^{ - i2\pi yx}$. Regarding this case, we can use the term to transform between two variables in this pair, namely time and frequency. In this way, we can measure the properties of the electromagnetic wave in both conventional frequency domain and somehow more robust time domain.
Applying Fourier Transform-Fourier Transform Spectroscopy
Fourier transform are widely involved in spectroscopy in all research areas that require high accuracy, sensitivity, and resolution. All these spectroscopic techniques using Fourier transform are considered Fourier transform spectroscopy. By definition, Fourier transform spectroscopy is a spectroscopic technique where interferograms are collected by measurements of the coherence of an electromagnetic radiation source in the time-domain or space-domain, and translated into frequency domain through Fourier transform.
Interferometer-What it is used for and how it works?
How to introduce a time-domain or space-domain variable in the spectrometer is the primary question that needed to be addressed when we consider constructing a Fourier transform spectrometer. In the experimental set-up, a Michelson interferometer is commonly used to solve this problem. Different from the classical Michelson interferometer with two fixed mirrors (Figure 1.a), the interferometer used in Fourier transform spectrometer has a moving mirror at one arm (Figure 1.b).
Figure 1. Scheme for Michelson interferometer [components: coherent light source; half-silvered beam-splitting mirror; two highly polished reflective mirrors; detector] (a) Stationary version [two fixed mirrors] (b) Movable version [One movable mirror and one movable mirror]
As shown in Figure 1.b, when a parallel beam of coherent light hits a half-silvered mirror, it is divided into two beams of equal intensities by partial reflection and transmission. After being reflected back, the two beams meet at the half-silvered mirror and recombine to produce an interference pattern, which is later detected by the detector. Manipulating the difference between these two paths of light is the core of Michelson interferometer. If these two paths differ by a whole number of wavelengths, the resulting constructive interference will give a strong signal at the detector. If they differ by a whole number and a half of wavelengths, destructive interference will cancel the intensity of the signal.
Measuring Interferograms
With a Fourier transform spectrometer equipped with an interferometer, we can easily vary the parameter in time domain or spatial domain by changing the position of the movable mirror. But how data are collected by a Fourier transform spectrometer? A quick comparison between a conventional spectrometer and a Fourier transform Spectrometer may help to find the answer.
• Conventional spectrometer:
Monochromator is commonly used. It can block off all other wavelengths except for a certain wavelength of interest. Then measuring the intensity of a monochromic light with that particular wavelength becomes practical. To collect the full spectrum over a wide wavelength range, monochromator needs to vary the wavelength setting every time.
• Fourier transform spectrometer:
Rather than allowing only one wavelength to pass through the sample at a time, an interferometer can let through a beam with the whole wavelength range at once, and measure the intensity of the total beam at that optical path difference. Then by changing the position of the moving mirror, a different optical path difference is modified and the detector can measure another intensity of the total beam as the second data point. If the beam is modified for each new data point by scanning the moving mirror along the axis of the moving arm, a series of intensity versus each optical path length difference are collected.
So instead of obtaining a scan spectrum directly, raw data recorded by the detector in a Fourier transform spectrometer is less intuitive to reveal the property of the sample. The raw data is actually the intensity of the interfering wave versus the optical path difference (also called Interferogram). The spectrum of the sample is actually encoded into this interferogram.
Extracting the spectrum from raw data
Based on the previous discussion, it is predictable that, without further translation, the raw data collected on a Fourier transform spectrometer will be quite difficult to read. A Fourier transform needs to be performed to decode interferogram and extract actual spectrum I($\overline v$) from it. The following shows how to conduct a Fourier transform to decode:
The intensity collected by the detector is a function of the path length differences in the interferometer p and wavenumber $\overline v$[3]:
$I(p,\overline v ) = I(\overline v )[1 + \cos (2\pi \overline v p)] \tag{9}$
Thus, the total intensity measured at a certain optical path length difference (for each data point at a certain optical pathlength difference p) is:
$I(p) = \int_0^\infty {I(p,\overline v ) = I(\overline v )[1 + \cos (2\pi \overline v p)]} \cdot d\overline v \tag{10}$
It shows that they have a cosine Fourier transform relationship. So by computing an inverse Fourier transform, we can resolve the desired spectrum in terms of the measured raw data I(p) (10):
$I(\overline v ) = 4\int_0^\infty {[I(p) - \frac{1} {2}I(p = 0)]} \cos (2\pi \overline v p) \cdot dp \tag{11}$
An example to illustrate the raw data and the resolved spectrum is also shown in Figure 2.
Figure 2. Fourier transform between interferogram and actual spectrum[4]
The Fast Fourier Transform (FFT)
Fast Fourier Transform (FFT) is a very efficient algorithm to compute Fourier transform. It applies to Discrete Fourier Transform (DFT) and its inverse transform. DFT is a method that decomposes a sequence of signals into a series of components with different frequency or time intervals. This operation is useful in many fields, but in most cases computing it directly from definition is too slow to be practical. Fast Fourier Transform algorithm can help to reduce DFT computation time by several orders of magnitude without losing the accuracy of the result. This benefit becomes more significant when the number of the components is very large. FFT is considered a huge improvement to make many DFT-based algorithms practical. In Fourier transform spectrometer, signals are often collected by a series of optical or digital channels at the detector. Then FFT is of great importance to quickly achieve the following signal processing and data extraction based on DFT method.
Combining all these steps together, we can take a look at how the data from the sample are processed. The diagram is shown in Figure 3.
Figure 3. Data processing in FTIR
(Figure from ThermoNiolet at mmrc.caltech.edu/FTIR/FTIRintro.pdf)
Different operating modes in Fourier Transform Spectrometer
• Continuous/Scanning FTS
Continuous Fourier transform spectroscopy refers to the scanning form of FTS, in which by step moving one mirror, the whole range of optical path difference is measured. This is the most widely used mode in FTS, like most absorption spectra and emission spectra obtained by FTS.
• Pulsed FTS
In some Fourier transform spectrometers, depending on the feature of the involved spectroscopic technique and purpose of measurement, a pulsed Fourier transform technique may be applied instead of the scanning mode.
Pulsed FTS is different from conventional continuous FTS. It is not based on the transmittance technique, which is widely used in the absorption spectra, like FTIR. Instead, in pulse FTS, the idea is that the sample is first exposed to an energizing event, and this pulse induces a periodic response. The frequency of this response relative to the field strength is determined by the properties of the sample. Using Fourier transform to resolve the frequency will tell the information about the targeted analyte.
Pulse FTS is a relatively new improvement of FTS. Some examples are from pulse-Fourier Transform-Nuclear Magnetic Resonnance (FT-NMR), pulse-Fourier Transform-Electron Paramagnetic Resonnance (FFT-EPR) and Fourier Transform-Mass Spectrometry (FT-MS). Please refer to the following topics for more details about how they work.
• Stationary FTS
In addition to the continuous/scanning mode of FTS, a number of stationary Fourier transform spectrometers are also available to meet special needs.
The principle of the interferometer and the analysis of its output signal is similar to the typical scanning FTS. But the signal is collected at certain optical path length differences rather than scanning over the whole range of the path difference.
An overview of various FTS techniques
Fourier transform spectroscopy can be applied to a variety of regions of spectroscopy and it continues to grow in application and utilization including optical spectroscopy, infrared spectroscopy (IR), nuclear magnetic resonance, electron paramagnetic resonance spectroscopy, mass spectrometry, and magnetic resonance spectroscopic imaging (MRSI). Among them, Fourier Transform Infrared Spectroscopy (FTIR) has been most intensively developed, which uses scanning Fourier transform to measure the mid-IR absorption spectra. .
Nuclear Magnetic Resonance (NMR) and Electron Spin Resonance Spectroscopy (EPR) are two magnetic techniques that use pulse Fourier transform mode. A Radio Frequency Pulse (RF Pulse) in a strong ambient magnetic field background is used as the energizing event. This RF Pulse directs the magnetic particles at an angle to the ambient strong magnetic field, causing gyration of the particle. Then the resulting gyrating spin induces a periodic current in the detector coil. This periodic current is recorded as the signal. Each gyrating spin has a characteristic frequency relative to the strength of the ambient magnetic field, which is also governed by the properties of the sample.
Fourier Transform Mass Spectrometry (MS) is also operated at pulse Fourier transform mode. Different from NMR and EPR, the injection of the charged sample into the strong electromagnetic field of a cyclotron acts as the energizing event in MS. The injected charged particles travel in circles under the strong electromagnetic field. The circular pathway will thus induce a current in a fixed coil at one point in their circle. Each traveling particle exhibits a characteristic cyclotron frequency relative to the field strength, which is determined by the masses in the sample.
Exercise $1$
Search literatures to find the advantages and the limitations of Fourier transform spectroscopic techniques.
Answer
Advantages
Firstly, Fourier transform spectrometers have a multiplex advantage (Fellgett advantage) over dispersive spectral detection techniques for signal, but a multiplex disadvantage for noise; Moreover, measurement of a single spectrum is faster(in the FTIR technique) because the information at all frequencies is collected simultaneously. This allows multiple samples to be collected and averaged together also resulting in an improvement in sensitivity; In addition, FT spectrometers are cheaper than conventional spectrometers because building of interferometers is easier than the fabrication of a monochromator (in the FTIR technique). So most commercial IR spectrometers are built based on FTIR techniques.
Limitations: practical frequency regions limited (FT UV-vis is not quite practical)
Exercise $2$
Perform a Fourier transform to show how to extract spectrum, equation (11), from the raw data in equation (10).
Answer
Exercise $3$
Compare interferometer with monochromator (at least two aspects).
Answer
Interferometer vs. Monochromator
Interometer: a. Collect signal in time or spatial domain; b. Measure all frequencies in the incident beam at one time; c. Determined by the interferometer, raw data from FT spectrometer is an interogram, which needs to be Fourier Transform back to get spectrum.
Monochromator: a. Collect signal in frequency domain; b. Scan each wavelength and measure the intensity for each single wavelength at a time; c. Determined by the feasure of monochromator, spectrum can be directly collected from the spectrometer
Exercise $4$
What are the important components to make Fourier transform spectrometer practical? What are they used for?
Answer
Interferometer and Fast Fourier Transform Data Analyzer
Interferometer: to generate continuous optical path length difference and enable the idea to collect data in the time or spatial domain;
Fast Fourier Transform Data Analyzer: to quickly transform the raw data (interferogram) to spectrum by using fast Fourier transform algorithm
Exercise $5$
Based on the information introduced in this module, design any one of the Fourier transform spectrometers mentioned in the context.
Answer
FT IR:
A FTIR Spectrometer Layout (Figure from ThermoNiolet at mmrc.caltech.edu/FTIR/FTIRintro.pdf)
FT NMR:
A modern high resolution liquid FT-NMR instrumentation is shown:
A schematic diagram of liquid FT-NMR[5]
Outside Links
• Please visit the free source for a consice introductory liquid pulse FT-NMR textbook[5] : www.analytik.ethz.ch/praktika...nmr/ft-nmr.pdf
• Fourier Series en.Wikipedia.org/wiki/Fourier_series
• Electromagnetic wave equation en.Wikipedia.org/wiki/Electro..._wave_equation
• Fourier Transform en.Wikipedia.org/wiki/Fourier_transform
• Fourier Transform Spectroscopy en.Wikipedia.org/wiki/Fourier...m_spectroscopy
• Fast Fourier Transform en.Wikipedia.org/wiki/Fast_Fourier_transform
• Discrete Fourier Transform en.Wikipedia.org/wiki/Discret...rier_transform
Contributor
• Jing Zhao, Chemistry, University of California, Davis | textbooks/chem/Organic_Chemistry/Introduction_to_Organic_Spectroscopy/01%3A_Introduction_to_Organic_Spectroscopy/1.05%3A_The_Power_of_the_Fourier_Transform_for_Spectroscopists.txt |
Learning Objectives
• Have a brief introduction to each of the techniques to be discussed in upcoming chapters
• Understand what type of information each technique gives to help with structure determination
To "see" a molecule, we must use light having a wavelength smaller than the molecule itself (roughly 1 to 15 angstroms). Such radiation is found in the X-ray region of the spectrum, and the field of X-ray crystallography yields remarkably detailed pictures of molecular structures amenable to examination. The chief limiting factor here is the need for high quality crystals of the compound being studied. The methods of X-ray crystallography are too complex to be described here; nevertheless, as automatic instrumentation and data handling techniques improve, it will undoubtedly prove to be the procedure of choice for structure determination. The spectroscopic techniques described below do not provide a three-dimensional picture of a molecule, but instead yield information about certain characteristic features. A brief summary of this information follows:
• Ultraviolet-Visible Spectroscopy: Absorption of this relatively high-energy light causes electronic excitation. The easily accessible part of this region (wavelengths of 200 to 800 nm) shows absorption only if conjugated $\pi$ electron systems are present.
• Infrared Spectroscopy: Absorption of this lower energy radiation causes vibrational and rotational excitation of groups of atoms. within the molecule. Because of their characteristic absorptions, identification of functional groups is easily accomplished.
• Nuclear Magnetic Resonance (NMR) Spectroscopy: Absorption in the low-energy radio-frequency part of the spectrum causes excitation of nuclear spin states. NMR spectrometers are tuned to certain nuclei (e.g. 1H, 13C, 19F & 31P). For a given type of nucleus, high-resolution spectroscopy distinguishes and counts atoms in different locations in the molecule.
1.S Summary of Organic Spectroscopy
Concepts & Vocabulary
1.1: Chapter Objectives and Preview of Spectroscopy
• Modern spectroscopic techniques have reduced the time it once took for structure determination.
• Spectroscopic techniques are based on the absorption of radiation from the electromagnetic spectrum.
• The different spectroscopic techniques can give different snapshots of the molecule's structure and lending insight to properties the molecule may have.
1.2 The Nature of Radiant Energy and Electromagnetic Radiation
• Electromagnetic radiation is composed of electrical and magnetic waves which oscillate on perpendicular planes.
• Electron radiation is released as photons, which are bundles of light energy that travel at the speed of light as quantized harmonic waves.
• The amplitude is basically the height of the wave. Larger amplitude means higher energy and lower amplitude means lower energy.
• Amplitude is important because it tells you the intensity or brightness of a wave in comparison with other waves.
• The different properties of the various types of electromagnetic radiation are due to differences in their wavelengths, and the corresponding differences in their energies: shorter wavelengths correspond to higher energy.
• Longer waves have lower frequencies, and shorter waves have higher frequencies.
• The full range of electromagnetic radiation wavelengths is referred to as the electromagnetic spectrum.
• The different types of electromagnetic radiation shown in the electromagnetic spectrum consists of radio waves, microwaves, infrared waves, visible light, ultraviolet radiation, X-rays, and gamma rays.
1.3 Introduction to Spectroscopy
• As a particle, electromagnetic radiation is represented as a photon, which transports energy.
• When a photon is absorbed, the electron can be moved up or down an energy level.
• When it moves up, it absorbs energy, when it moves down, energy is released.
• Since each atom has its own distinct set of energy levels, each element emits and absorbs different frequencies.
• Electromagnetic radiation is also categorized into two groups based, ionizing and non-ionizing, on the severity of the radiation.
• In spectroscopic techniques, electromagnetic radiation of a specified range of wavelengths is allowed to pass through a sample containing a compound of interest. The sample molecules absorb energy from some of the wavelengths, and as a result jump from a low energy ‘ground state’ to some higher energy ‘excited state’.
• Here is the key to molecular spectroscopy: a given molecule will specifically absorb only those wavelengths which have energies that correspond to the energy difference of the transition that is occurring.
• By observing which wavelengths a molecule absorbs, and to what extent it absorbs them, we can gain information about the nature of the energetic transitions that a molecule is able to undergo, and thus information about its structure.
1.4 Time-resolved vs. Frequency-resolved
• Spectroscopic measurements are typically taken in one of two domains: frequency or time.
• Frequency is used to represent the number of cycles occurring in a given time period.
• The frequency domain is the most familiar domain in spectroscopy.
• UV/visible, infrared, photoelectron, microwave, and X-ray spectroscopy all have applications in the frequency domain.
• The results of these spectroscopic techniques are typically given in some form of intensity versus wavelength.
• Rather than acquiring spectra by averaging data over a relatively long time range, data is acquired over discrete time intervals or, in some cases, continuously. This may be done over one or many wavelengths.
• Time resolved spectroscopy observes the change in eigen states with respect to time.
• In order for data from time-resolved spectroscopy to be useful, the spectroscopy must be suited to the time scale of the process of interest.
• Time resolved spectroscopy can be used to study kinetics, reactions, and lifetimes.
• Some spectroscopies yield data in both time and frequency domains. The most prominent of these techniques is time-resolved laser spectroscopy.
1.5 The Power of the Fourier Transform for Spectroscopists
• Fourier transform is a mathematical technique that can be used to transform a function from one real variable to another.
• Fourier transform from time domain to frequency domain is the essential process that enable us to translate raw data to readable spectra.
• The nature of trigonometric function enables Fourier transform to convert a function from the domain of one variable to another and reconstruct it later on.
• This is a robust mathematical tool to process data in different domains under different circumstances.
• Fourier transform are widely involved in spectroscopy in all research areas that require high accuracy, sensitivity, and resolution.
• By definition, Fourier transform spectroscopy is a spectroscopic technique where interferograms are collected by measurements of the coherence of an electromagnetic radiation source in the time-domain or space-domain, and translated into frequency domain through Fourier transform.
• With a Fourier transform spectrometer equipped with an interferometer, we can easily vary the parameter in time domain or spatial domain by changing the position of the movable mirror.
• An interferometer can let through a beam with the whole wavelength range at once, and measure the intensity of the total beam at that optical path difference.
• If the beam is modified for each new data point by scanning the moving mirror along the axis of the moving arm, a series of intensity versus each optical path length difference are collected.
• Fourier transform spectroscopy can be applied to a variety of regions of spectroscopy and it continues to grow in application and utilization including optical spectroscopy, infrared spectroscopy (IR), nuclear magnetic resonance, electron paramagnetic resonance spectroscopy, mass spectrometry, and magnetic resonance spectroscopic imaging (MRSI).
1.6 Upcoming Spectroscopy Techniques
• Ultra-violet spectroscopy shows absorption only if conjugated $\pi$ electron systems are present.
• Infrared spectroscopy allows for the identification of functional groups present in a molecule.
• Nuclear magnetic resonance distinguishes and counts atoms in different locations in the molecule.
Skills to Master
• Skill 1.1 Be able to manipulate the equations to calculate frequency or energy.
• Skill 1.2 Determine which frequency or wavelength is a higher energy.
• Skill 1.3 Understand how an organic molecule interacts with electromagnetic radiation.
• Skill 1.4 Determine how an energy gap will lead to longer or shorter wavelength.
• Skill 1.5 Know why some spectrometers use frequency domain and others use time domain.
• Skill 1.6 Perform a Fourier transform to show how to extract spectrum from the raw data.
• Skill 1.7 Compare an interferometer with a monochromator.
• Skill 1.8 Know the important components to make Fourier transform spectrometer practical and what are they used for. | textbooks/chem/Organic_Chemistry/Introduction_to_Organic_Spectroscopy/01%3A_Introduction_to_Organic_Spectroscopy/1.06%3A_Upcoming_Spectroscopy_Techniques.txt |
Learning Objectives
After completing this chapter, you should be able to
• fulfill all of the detailed objectives listed under each individual section.
• solve fragmentation problems which may require the interpretation of mass spectrometry.
• define, and use in context, the key terms introduced in this chapter.
Every time a reaction is run, the products must be identified. Every time a new molecule is found in nature, its structure must be determined. After reading this chapter and the following chapters, you will have an idea of what techniques are used to elucidate structures as well as how and when to use them. The powerful techniques used for structure determination are mass spectrometry (MS), ultraviolet spectroscopy (UV), infrared spectroscopy (IR), and nuclear magnetic spectroscopy (NMR). Want to know the size and formula of the molecule - use mass spectrometry. Does the molecule have a conjugated pi-system? Ultraviolet spectroscopy will help identify those. Need to determine the functional groups present, then turn to infrared spectroscopy. Looking to piece together the framework of the molecule, then look no further then nuclear magnetic spectroscopy.
In this chapter, the focus will be on mass spectrometry. In short, mass spectrometry is a way to determine the molecular weight of a molecule. In the process, it can give insight into the structure of the molecule by the fragment sizes formed. This chapter will begin to introduce the techniques used to determine the structure of organic molecules, starting with mass spectrometry.
2.02: Instrumentation
Learning Objectives
• Understand how mass spectrometer works
• Learn about the different parts of a mass spectrometer
Principles of Mass Spectrometry
Mass spectrometry (MS) is a powerful characterization technique used for the identification of a wide variety of chemical compounds. At its minimum, MS is merely a tool for determining the molecular weight of the chemical species in a sample. However, with the high resolution obtainable from modern machines, it is possible to determine structural information from the fragments. There are libraries of mass spectra have been compiled which allow rapid identification of most known compounds, including proteins. MS relies on the ability of a compound to be ionized, so the limitations of this technique are when the compound of interest is not readily ionized or if it decomposes upon ionization.
There are many mass spectrometers on the market, but they all have the same basic parts. There is an ionization source, where the molecules are broken into fragments. The mass analyzer is where the ions are separated into their mass/charge ratios before moving to the detector to be observed and counted. Collisions force the fragments to move forward. Consider if something is moving and you subject it to a sideways force, instead of moving in a straight line, it will move in a curve - deflected out of its original path by the sideways force. Suppose you had a cannonball traveling past you and you wanted to deflect it as it went by you. All you've got is a jet of water from a hose-pipe that you can squirt at it. Frankly, its not going to make a lot of difference! Because the cannonball is so heavy, it will hardly be deflected at all from its original course. But suppose instead, you tried to deflect a table tennis ball traveling at the same speed as the cannonball using the same jet of water. Because this ball is so light, you will get a huge deflection. The amount of deflection you will get for a given sideways force depends on the mass of the ball. If you knew the speed of the ball and the size of the force, you could calculate the mass of the ball if you knew what sort of curved path it was deflected through. The less the deflection, the heavier the ball. You can apply exactly the same principle to atomic sized particles.
Atoms can be deflected by magnetic fields - provided the atom is first turned into an ion. Electrically charged particles are affected by a magnetic field although electrically neutral ones aren't.
The sequence is :
• Stage 1: Ionization: The atom is ionised by knocking one or more electrons off to give a positive ion. This is true even for things which you would normally expect to form negative ions (chlorine, for example) or never form ions at all (argon, for example). Mass spectrometers always work with positive ions.
• Stage 2: Acceleration: The ions are accelerated so that they all have the same kinetic energy.
• Stage 3: Deflection: The ions are then deflected by a magnetic field according to their masses. The lighter they are, the more they are deflected. The amount of deflection also depends on the number of positive charges on the ion - in other words, on how many electrons were knocked off in the first stage. The more the ion is charged, the more it gets deflected.
• Stage 4: Detection: The beam of ions passing through the machine is detected electrically.
A full diagram of a mass spectrometer is below.
Let's break down the stages in more detail. In order for the ions to have free run of the machine, a vacuum is created in the ionization chamber to avoid air molecules getting in the way. The vaporized sample passes into the ionization chamber. The electrically heated metal coil gives off electrons which are attracted to the electron trap which is a positively charged plate.
The particles in the sample (atoms or molecules) are therefore bombarded with a stream of electrons, and some of the collisions are energetic enough to knock one or more electrons out of the sample particles to make positive ions. Most of the positive ions formed will carry a charge of +1 because it is much more difficult to remove further electrons from an already positive ion. These positive ions are persuaded out into the rest of the machine by the ion repeller which is another metal plate carrying a slight positive charge. The positive ions are repelled away from the very positive ionization chamber and pass through three slits, the final one of which is at 0 volts. The middle slit carries some intermediate voltage. All the ions are accelerated into a finely focused beam.
Different ions are deflected by the magnetic field by different amounts. The amount of deflection depends on:
• the mass of the ion. Lighter ions are deflected more than heavier ones.
• the charge on the ion. Ions with 2 (or more) positive charges are deflected more than ones with only 1 positive charge.
These two factors are combined into the mass/charge ratio. Mass/charge ratio is given the symbol m/z (or sometimes m/e). For example, if an ion had a mass of 28 and a charge of 1+, its mass/charge ratio would be 28. An ion with a mass of 56 and a charge of 2+ would also have a mass/charge ratio of 28. In the diagram below, ion stream A is the most deflected - it will contain ions with the smallest mass/charge ratio. Ion stream C is the least deflected - it contains ions with the greatest mass/charge ratio.
It makes it simpler to talk about this if we assume that the charge on all the ions is 1+. Most of the ions passing through the mass spectrometer will have a charge of 1+, so that the mass/charge ratio will be the same as the mass of the ion. Assuming 1+ ions, stream A has the lightest ions, stream B the next lightest and stream C the heaviest. Lighter ions are going to be more deflected than heavy ones.
Only ion stream B makes it right through the machine to the ion detector. The other ions collide with the walls where they will pick up electrons and be neutralized. Eventually, they get removed from the mass spectrometer by the vacuum pump.
For those ions that make it to the detector, the ion hits the metal box and its charge is neutralized by an electron jumping from the metal on to the ion (diagram below). That leaves a space amongst the electrons in the metal, and the electrons in the wire shuffle along to fill it. A flow of electrons in the wire is detected as an electric current which can be amplified and recorded. The more ions arriving, the greater the current.
How might the other ions be detected - those in streams A and C which have been lost in the machine?
Remember that stream A was most deflected - it has the smallest value of m/z (the lightest ions if the charge is 1+). To bring them on to the detector, you would need to deflect them less - by using a smaller magnetic field (a smaller sideways force). To bring those with a larger m/z value (the heavier ions if the charge is +1) on to the detector you would have to deflect them more by using a larger magnetic field. If you vary the magnetic field, you can bring each ion stream in turn on to the detector to produce a current which is proportional to the number of ions arriving. The mass of each ion being detected is related to the size of the magnetic field used to bring it on to the detector. The machine can be calibrated to record current (which is a measure of the number of ions) against m/z directly. The mass is measured on the 12C scale.
The output from the chart recorder is usually simplified into a "stick diagram". This shows the relative current produced by ions of varying mass/charge ratio. The stick diagram for molybdenum looks like this:
You may find diagrams in which the vertical axis is labeled as either "relative abundance" or "relative intensity". Whichever is used, it means the same thing. The vertical scale is related to the current received by the chart recorder - and so to the number of ions arriving at the detector: the greater the current, the more abundant the ion.
As you will see from the diagram, the commonest ion has a mass/charge ratio of 98. Other ions have mass/charge ratios of 92, 94, 95, 96, 97 and 100. That means that molybdenum consists of 7 different isotopes. Assuming that the ions all have a charge of 1+, that means that the masses of the 7 isotopes on the carbon-12 scale are 92, 94, 95, 96, 97, 98 and 100.
Coupling Mass Spectrometry to Other Instruments
Mass spectrometry is a powerful tool for identification of compounds, and is frequently combined with separation techniques such as liquid or gas chromatography for rapid identification of the compounds within a mixture. Typically, liquid chromatography systems are paired with ESI-quadrupole mass spectrometers to take advantage of the solvated sample. GC-MS systems usually employ electron impact ionization and quadrupole or ion trap mass analyzers to take advantage of the gas-phase molecules and fragmentation libraries associated with EI for rapid identification.
Mass spectrometers are also often coupled in tandem to form MS-MS systems. Typically the first spectrometer utilizes a hard ionization technique to fragment the sample. The fragments are passed on to a second mass analyzer where they may be further fragmented and analyzed. This technique is particularly important for studying large, complex molecules such as proteins.
Exercise \(1\)
Does a mass spectrum show the results from just one molecule?
Answer
A mass spectrum does not show the results from one molecule, but from millions of molecules. Because it is displaying results for a population of molecules, more than one mass is shown
Exercise \(1\)
Where would you expect to find the molecular weight of the molecule?
Answer
A mass spectrum is a bar graph showing the weights of entire molecules as well as smaller pieces of molecules. The entire molecule must have the largest mass, the one farthest to the right, because if a molecule falls into pieces the pieces would be smaller than the whole. | textbooks/chem/Organic_Chemistry/Introduction_to_Organic_Spectroscopy/02%3A_Mass_Spectrometry/2.01%3A_Chapter_Objectives_and_Preview_of_Mass_Spectrometry.txt |
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