text:
Todd:Catalytic, Asymmetric Pictet-Spengler Reaction
The Catalytic, Asymmetric Pictet-Spengler Reaction
Katrina A. Badiola, School of Chemistry, The University of Sydney, NSW 2006, Australia
Murray N. Robertson, School of Chemistry, The University of Sydney, NSW 2006, Australia
Michael A. Tarselli, Biomedisyn Corp., Woodbridge, CT, United States of America
Matthew H. Todd, School of Chemistry, The University of Sydney, NSW 2006, Australia
Additional authors - add alphabetically if you contribute something substantial (e.g., the summary of a paper with a scheme). Please include some public place you can be contacted, e.g. a G+ account.
The licence for this page is CC BY 3.0
How this works:
0. Background described in this blog post.
1. This article will be a stand-alone review. It will be written openly in January and February 2012. Once it is complete and well-written, it will be submitted to an open access journal for publication. This will provide a citation - a static object to which others may refer. Until that time this page is a work in progress and is not to be taken as complete.
2. The article is open source, like Wikipedia. Anyone can add and edit. To contribute you will need to get an account on OWW (quick and easy). People contributing something lasting and substantial will be named authors. Final arbitration on what qualifies as authorship lies with Mat Todd, who is the corresponding author for this paper.
3. References for the papers described here may be found in full at the Mendeley page. Chemdraw files for the schemes are currently held in a Dropbox folder we can share with anyone who needs it. PNG files are hosted on this wiki site.
4. The review incidentally acts as background to the open science project to find a catalytic, asymmetric route to praziquantel. That project is currently active in the lab. A catalytic, enantioselective synthesis of this drug is an alternative to the resolution approach that was discovered, also by open science.
5. If you want to get in touch to ask questions (e.g. if you want to ask "what can I do to help?") please do not use email. The current to-do list is on the talk page (click on the tab above). Questions should go there with your initials. You can also discuss via Google+ pages: Mat, Kat, (please add other public places where you can be contacted if you contribute as an author by inserting links along with your name, above).
6. When editing remember to include a reason for your edit, to make it easier to revert back to an original version if needed.
Important note on simultaneous edits: If you are intending to work for some time on editing the page, we'd recommend writing text elsewhere then pasting it in here, since there is a small but non-zero chance that you might simultaneously edit the same section as someone else, resulting in the chance of the loss of some information.
Schemes: Use Wiley/Angewandte settings for the .cdx files and add below as 300 dpi .png files.
References: Please use the citation style below (click to see the page source for formatting details) and include a link to the DOI of the paper to that it may be checked easily.
The Pictet-Spengler (PS) reaction is just over a century old.Pictet, Spengler 1911 The reaction is a cyclization between an amine that carries an aromatic ring, and an aldehyde, usually catalyzed by acid (Scheme 1911 Pictet Spengler 2). The original reaction employed formaldehyde and phenethylamine, to give the tetrahydroisoquinoline scaffold. Several years after the original report tryptamine was found to be perform well in the reaction permitting access to a range of tetrahydrocarbolines.[ref] A wide range of variations on these original themes have been investigated.Stöckigt 2011, Whaley, Govindachari[Youn 2006][Larghi 2011] such as cases where the amine component is acylated or alkylated, those where ketones are employed rather than aldehydes so as to generate quaternary centres adjacent to the aromatic ring, and reactions employing alcohols rather than amines - the so-called oxo-PS reaction.
The reaction is important for two reasons. Firstly, Nature uses this chemistry. Enzymes ("pictet spenglerases") carry out the PS cyclization to produce important intermediates which feed into many biological pathways that result in bioactive small molecules, such as strychnine, morphine, vinblastine and reserpine.
All monoterpene indole alkaloids are thought to be made via this route, the key intermediate of which is strictosidine, formed from a PS reaction between tryptamine and secologanin.
Secondly, and probably consequently, the general structures one can access through the PS reaction - alkaloids with a stereocentre adjacent to an aromatic ring - are often highly bioactive, and are of interest for the development of new medicines. This has led to a great deal of interest in controlling the stereochemical outcome of PS reactions. Most of this work has involved understanding diastereoselective PS reactions, where an existing stereocentre in the molecule, often derived from an amino acid, directs the ring closure.Cook 1995(Need: What was the first diastereoselective example? Cook 1992 Cook[Larghi 2005, review, no DOI][Youn 2006] This approach has been used in several notable total syntheses, among them (-)-suaveoline (Cook, 1992) and (-)-phalarine (Danishefsky, 2010). (Need: combine the two structures below with the general scheme for this part)
Several important pharmaceuticals may be synthesized with the PS reaction, for example the widely-used anthelmintic praziquantel, tadalafil (Cialis(TM)) used for erectile disfunction, the painkiller Etodolac and the promising new antimalarial compound NITD609 (Scheme Intro - Relevant Drugs). The biological activity of these compounds typically arises from one enantiomer: for example the (S) enantiomer of Etodolac (10.1021/jm00366a025) and the (R)- enantiomer of praziquantel (10.1371/journal.pntd.0000357); ent-NITD609 is inactive (10.1126/science.1193225). The potency of this class of compounds leads to great market value: $1.7 Bn for tadalafil alone in 2010.(Need: full reference inserting at end)(Eli Lilly Annual Report 2010, available at http://investor.lilly.com/annuals.cfm) Efficient enantioselective methods for the PS reaction would be very desirable, and progress to date in this field is the subject of this review. It is now certainly possible to carry out some PS reactions to give products with high enantiomeric excess. However, the scope of these processes is limited (as we shall see) reducing their impact on the preparation of bioactive compounds industrially. The PS reaction has been used in the racemic industrial synthesis of X, for example, but the enantiopure material is obtained through a resolution.(Need: example here - someone please check http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107522/)
Enantioselective approaches, where the stereocontrol of the cyclization is not governed by a stereocentre already in the cyclization precursor, have received much less attention than the diastereoselective, racemic or achiral version of the PS reaction. It was shown in 1996 that the PS reaction could be effected with superstoichiometric Lewis acid - in this case the cyclization of the (Z)-nitrone derived from Nb-hydroxytryptamine using diisopinocampheylchloroborane (Ipc2BCl) to give the corresponding tetrahydro-β-carboline products (Scheme Nakagawa 1998).(10.1016/0957-4166(96)00134-6 and 10.1021/jo980810h) The racemic cyclization could be effected with Bronsted acid and a number of achiral Lewis acids, but it was found that Ipc2BCl gave high yields and ee with reduced temperatures. Lowering the quantity of Ipc2BCl to 0.5 eq. caused a significant reduction of yield, while attempts to alter the Lewis acidity by substitution of the chloride (with e.g. fluoride or triflate) did not improve yield or ee. The proposed reaction mechanism involved the formation of an iminium ion with coordination of the nitrone oxygen to the Ipc2BCl boron centre, and preliminary modeling confirmed a difference in transition state energies for approach of the indole from the re- and si-faces of the iminium ion. It was found that iminium ions derived from electron-deficient aldehydes gave poor enantioselectivity, but that these cyclizations were effective (with 74% ee in the case of the nitrone derived from 4-nitrobenzaldehyde) when a different reagent was added, a boronate incorporating two BINOL ligands (X) that had been previously described by Yamamoto for aldol-type reactions of imines.(10.1021/ja00102a019) The mechanism of action of such a boronate was suggested to involve replacement of one of the coordinating BINOL oxygen atoms with that on the nitrone, and it is not clear why such a mechanism could not operate catalytically. Nevertheless this was the first report of a reagent-controlled enantioselective PS reaction; earlier work by Nakagawa employing a similar approach had led to cyclization, but to give enantioenriched spiroindoline products.Paper Chiral Bronsted acids were ultimately successfully applied to the catalytic, enantioselective PS reaction through the use of a phosphoric acid, rather than a boronate, as described below.
A chiral Lewis acidic silane reagent (X, Scheme Leighton 2009) was shown to be effective in promoting highly enantioselective PS reactions.(Leighton 2009 10.1002/anie.200806110) The substrates (e.g., X) contained α-ketoamide ketimines: NMR studies suggested that following O-silylation the proton from the NH group transfers to the reagent's nitrogen atom and activates the complex (X) to cyclization. Electron-withdrawing groups on the N-aryl ring improved the reaction rate. The quaternary stereocentre could be generated even with sterically demanding aryl groups appended to the imine, such as 1-naphthyl (product ee 87%). A one-pot procedure was also developed in which the initial amine and a-ketoamide were allowed to react, followed by the addition of the reagent. The process was shown to be effective on a 5 mmol scale with 1.3 equivalents of silane, and the pseudoephedrine ligand could be recovered and crystallised following work-up of the reaction. It was subsequently shown that the same (now commercially-available) reagent could be used with similar effectiveness in the synthesis of the more ususual PS reaction products X and X, derived from the less common indole amines X and X.[Leighton 2012 10.1021/ol300922b] These
It is perhaps surprising that there are still no examples of Lewis acid-catalyzed asymmetric PS reactions. In a recent study (10.1016/j.tetlet.2011.08.071) a small number of chiral Lewis acidic complexes were shown to effect conversion in a PS reaction between tryptamine and isatins, but there was negligible enantioinduction; high product ee was ultimately achieved with Bronsted acid catalysis, to which we now turn.
Brønsted Acid Organocatalysis
(Note - consider a diagram section at start which includes the structures of all the BINOL-derived catalysts so we don't have to include in the individual schemes). i.e. we draw them at start and then number them then just include the numbers in the schemes.
Chiral Brønsted acids have been shown to be effective in the catalytic, asymmetric PS reaction, which builds on earlier work demonstrating the ability of such compounds to catalyze the reaction between nucleophiles and iminium ions.
Akiyama (10.1002/anie.200353240) reported chiral phosphoric acids prepared from arylated BINOLs in the enantioselective Mannich-type coupling of silyl enolates with aldimines (Scheme Akiyama 2004). High yields and enantio- (as well as, in appropriate cases, diastereo-) selectivities were observed with a variety of substituted aldimines and enolates (What's "high" for this reaction? Akiyama reports 81-96% ee, and given that the group reports several "100% yields" I'm inclined towards suspicion -MAT). Limitations to the methodology were that an ortho hydroxy group was required on the N-aryl ring of the aldimine (Why? Mechanistic raionale? - MAT), and that aldimines derived from aliphatic aldehydes did not participate effectively. Typical catalyst loading was 10 mol%. The structure of the catalyst itself may be thought of as a chiral proton, i.e., a proton surrounded by a chiral environment, particularly given the aromatic rings of the BINOL and the 3-substituents are non-coplanar. However, the proposed mechanism operates via an ion pair of phosphate and iminium ion. The bond-forming event would naturally disrupt such an ion pair, ensuring catalytic turnover. (ultimately need a scheme of this very general idea [nice example in the Akiyama paper here] but may go in mechanism section)
At the same time Terada (10.1021/ja0491533) reported similar catalysts in the enantioselective Mannich reaction for the synthesis of β-aminoketones (Scheme Terada 2004a), utilizing acetylacetonate nucleophiles in place of silyl enolates. Terada, like Akiyama, notes the important influence of the 3,3'-position of the naphthyl rings on the enantioselectivity of the reaction. A followup paper later that same year incorporates furan nucleophiles (10.1021/ja046185h).
Since these early examples, several reactions have been reported that can be catalysed by these or related structures (reference reviews of chiral bronsted acid catalysts here).(Terada 2010 Bull Chem Soc Jpn 10.1246/bcsj.20090268)
List reported the first Brønsted acid-catalyzed enantioselective Pictet-Spengler reaction in 2006 (10.1021/ja057444l). Chiral, substituted phosphoric acids were shown to be effective in the PS cyclization of tryptamines with a number of aliphatic and aromatic aldehydes (Scheme List 2006). The diester functionality was found to be necessary, presumably due to promotion of a clean reaction through the Thorpe-Ingold effect (and an aldol side reaction was observed when the esters were absent). Lower yields were typically observed when the methoxy group was absent from the tryptamine aromatic ring.
In 2007, Hiemstra reported the enantioselective synthesis of tetra-β-carbolines via the in situ formation of N-sulfenyliminium ions (10.1002/anie.200701808). Stabilization of the intermediate iminium by the N-tritylsulfenyl group was effective at promoting the acid-catalyzed PS reaction by substituted enantiopure binaphthyl-derived phosphoric acids. Several substitutions were assayed in the 2-position of the catalyst, with no clear trend being observed in the ee of product obtained. The N-S bond in the N-tritylsulfenyl product was found to be susceptible to homolytic cleavage, but this could be suppressed by the addition of a radical scavenger. A one-pot process was developed that allowed precipitation of the product as a salt, and this was applied to the synthesis of a variety of substituted tetra-β-carbolines with high yield and high ee. The reaction was also demonstrated on a multi-gram scale.
An extension to this methodology was developed that allowed the synthesis of enantioenriched N-benzyl-protected versions of similar products from the relevant protected tryptamines and diverse aldehydes (10.1021/jo8010478). During optimization it was found that removal of water was essential for high enantioinduction presumably because water prevents effective association between catalyst and cyclization precursor. Several control reactions were performed under the optimized conditions that suggested this PS reaction was irreversible. The best-performing catalyst was the triphenylsilyl-substituted binaphthyl system, delivering up to 100% conversion and high ee values (78-85%). The ee obtained was sensitive to the aldehyde employed. Of the aliphatic aldehydes, no product was observed with the enolizable phenylacetaldehyde and low ee (8%) was obtained with 3-phenylpropanal. While electron-deficient aromatic aldehydes generally gave products with high ee as expected, there were exceptions that performed poorly; 3-chlorobenzaldehyde gave near-racemic product, for example.
This methodology has been employed in the syntheses of three natural products. The PS reaction employed in the synthesis of (-)-arboricine (10.1021/ol900888e) (Scheme Hiemstra 2009) involved an aldehyde containing a dioxolane-protected ketone group, preventing an aminal formation that was observed when the ketone was used unprotected, but it is notable that this protecting group withstands the PS cyclization, and that the yield and ee of the cyclization were both dramatically improved by the use of the protecting group. The partially saturated (and slightly more sterically crowded) (R)-H8-Binol-PA catalyst was also shown to be effective. This catalyst was subsequently used for the key step in the synthesis of (+)-yohimbine (Scheme Hiemstra 2011).(10.1021/jo201657n). The natural product was to be synthesized via a Diels-Alder precursor that could itself be made using an enantioselective PS reaction. However, the aldehyde required for the PS reaction was β,γ-unsaturated and this was likely to result in the unproductive formation of an enamine from the initially-formed iminium ion. This substrate limitation necessitated use of a latent double bond, in this case a phenylselenide; this group survived the successful PS cyclization and could be eliminated to the double bond via oxidation to the selenoxide. A similar synthetic strategy was employed in the synthesis of the related corynanthe alkaloid family. (10.1002/chem.201103150)
Dixon included a chiral phosphoric acid as part of a reagent cocktail effecting a cascade sequence involving a Pictet-Spengler-like cyclization (Scheme Dixon 2009).(10.1021/ja9024885) Tryptamines and lactones formed ketoamides with an appended π-nucleophile that underwent enantioselective cyclizations in the presence of chiral phosphoric acids, and it was again shown that aromatic substitution of the BINOL ring system was essential for high ee. The method could be used with more substituted lactones to effect high levels of diastereocontrol: the combination of a disubstituted enol lactone with tryptamine gave isolable intermediates, the structures of which implied that the formation of the reactive iminium ion was fast and reversible, and that final ring closure occurred with one matched catalyst/substrate pair. The mechanism of the enantiodetermining cyclization is presumed to be via a tight ion pairing between iminium ion and catalyst conjugate anion. High yields and stereoselectivities could be obtained for diverse products using this methodology, which was shown to be compatible with a one-pot cascade process that also included a gold(I)-catalyzed step to generate the initial lactone.
The method was broadened to allow the use of racemic keto acids and esters in place of the enol lactones, again with polycyclic products being produced in high yield and ee (79-98%). (10.1021/ol101651t). If the reaction time was reduced, enamides could again be isolated, one achiral and the other chiral with an ee of only 7%. Either enamide gave the intended product with an ee of 83% when resubjected to the reaction conditions, supporting the fast, reversible formation of iminium ions which are trapped by an enantioselective cyclization event controlled by the chiral acid. Possibly mention the racemic oxo acid.
Franz (10.1016/j.tetlet.2011.08.071) screened a number of catalysts in the search for a means of creating medicinally-relevant spirocyclic structures from tryptamine and isatin. Lewis acidic complexes were ineffective, and though thioureas gave some enantioinduction, it was found that Bronsted acid catalysts were the most effective, giving products in sometimes excellent ee in often near-quantitative yields. Interestingly the 3,3'-substituents on the BINOL ring system strongly influenced the enantioinduction, to the extent that changing this substituent (from e.g., anthracenyl to triisopropylphenyl) reversed the sense of enantioinduction (strictly, the (S)-enantiomer of one catalyst gave the same enantiomer of product as did the (R)-enantiomer of the other catalyst.) Unsurprisingly the outcome of the reaction was dependent on the choice of solvent as well as the electronic and steric substitution pattern of both coupling partners. (Citations done, but leads to 10.1002/adsc.201100050 - MHT doing Jan 23 - very similar, which may require a proper merge here)
Thiourea Organocatalysts
In 2004, Jacobsen reported his initial work on asymmetric catalysis of the acyl-Pictet-Spengler reaction using chiral thioureas. Jacobsen realised the inherent challenge of developing an asymmetric Pictet-Spengler catalyst involved low reactivity of the imine substrate. Additionally, previously reported racemic efforts had involved Lewis acid catalysts paired with highly reactive agents at high temperatures. Jacobsen enhanced the reaction by increasing the electrophilicity of the iminium intermediate through formation of the corresponding N-acyliminium ion (MAT - Why? We need to explore this concept a bit...) Early screening experiments showed cyclization occuring at -30 °C in 59% ee. While screening individual reaction parameters, Jacobsen discovered that product chirality exhibited a strong dependence upon the structure of the acylating agent, reaction solvent, and temperature.
Under optimized conditions (-30 °C, ether, 5 mol% catalyst), Jacobsen's thiourea delivered enriched tetrahydro-B-carbolines in 65-81% yields, and up to 95% ee.
A proposed mechanism for the thiourea-catalysed enantioselective Pictet-Spengler-Type cyclization was published by Jacobsen in 2007. Interestingly, key experimental observations, supported by DFT computational analyses, pointed towards an SN1-type pathway in these cyclizations, with catalysis via a previously unprecedented anion-catalyst hydrogen bonding mechanism.
An extensive screen of acidic additives revealed that either chlorotrimethylsilane or the combination of HCl and 3 Å molecular sieves afforded high levels of conversion and enantioselectivity, but that water had a deleterious effect on catalyst activity. Furthermore, a quite significant inverse correlation between conversion and reaction concentration was observed, with reactions run at lower concentrations affording substantially improved yields.
As a direct demonstration of the applicability of this new methodology, Jacobsen applied the enantioselective hydroxylactam cyclization to the total synthesis of (+)-harmicine with the cyclization proceeding in 97% ee followed by subsequent LiAlH4 reduction affording the natural product in only four steps from tryptamine. (Note - picture reads "Hermicine" - MAT)
Variable temperature 1H NMR studies of reaction mixtures indicated that formal dehydration and formation of the corresponding chlorolactam is rapid and irreversible. Further observation of enhanced reactivity of alkylated versus reduced derivatives suggests that an SN2-type displacement of chloride is not operative in the cyclization reaction, which points instead to an SN1-type mechanism. Since the enantio-determining step is likely either the addition of the indole to the N-acyliminium ion (b → c or b → d), or alkyl migration of the spiroindoline intermediate (c → d), catalyst interaction with at least one of these species is required. However, there is no viable Lewis basic site for catalyst binding to substrate in c or d.
Therefore, Jacobsen proposed that the thiourea catalyst promotes enantioselective cyclization by inducing dissociation of the chloride counterion and forming a chiral N-acyliminium chloride-thiourea complex. Noticeable halide counterion effects and solvent effects on enantioselectivity lend proof to this theory. Furthermore, it was suggested that catalysis and enantioinduction may result from initial abstraction of a chloride anion from a in an SN1-type rate determining step (a → b) and subsequent cyclization mediated by the resulting anion-bound thiourea. This mode of catalytic generation of cationic intermediates was previously reported in the well-established anion-binding properties of ureas and thioureas. Further, the possibility of high levels of enantioinduction induced through counterion interactions is well precedented in chiral phase-transfer catalysis and has recently been demonstrated in the context of asymmetric counterion-directed catalysis.
In 2007, Jacobsen published a review titled "Small-Molecule H-Bond Donors in Asymmetric Catalysis" identifying chiral hydrogen-bond donors used for enantioselective synthesis. The area regarding to the PS reaction referred to previous work reported by Jacobsen. Concluding, Jacobsen stated his surprise at both phosphoric acids and thiourea derivatives being capable of mediating enantioselective transformations of prochiral iminium and N-acyliminium ion intermediates as they exist in opposite ends of the spectrum of the pKa scale of known H-bond donor catalysts.
In 2008, Jacobsen put his previously discovered enantioselective thiourea-acyl-Pictet-Spengler catalyst to use in the total synthesis of (+)-yohimbine. The synthesis was achieved in 11 steps and 14% overall yield with the absolute configuration of the molecule being established through the highly enantioselective thiourea-catalyzed acyl-Pictet-Spengler reaction at the start of the synthesis.
In 2009 Jacobsen reported asymmetric Pictet-Spengler reactions cocatalyzed by a chiral thiourea and benzoic acid. A number of optically active tetrahydro-β-carbolines were obtained in high ee.
The catalytic cycle for this was proposed where imine protonation is induced by a thiourea catalyst via H-bonding to the conjugate base of a weak Bronsted acid additive. The highly reactive protioiminium ion then cyclizes and aromatizes to generate the desired product and Bronsted acid cocatalyst. Examples also show that this thiourea catalyst promotes highly enantioselective Pictet-Spengler reactions on electronically and structurally diverse substrates.
In 2011, Jacobsen, Lee, and Klausen published further work on a thiourea/benzoic acid cocatalyzed "iso-Pictet-Spengler" reactions, so named due to the alternate connectivity of the 2-substituted isotryptamine starting material. This altered substrate permits synthesis of optically pure tetrahydro-γ-carbolines. Jacobsen reports a straightforward procedure for upgrading the produced tetrahydro-γ-carbolines' enantiopurity through Boc protection of the free amine, followed by crystallization or trituration. This simple preparative step elevates the ee to >99% in nearly all published examples. The group's optimized conditions are applied to a single aromatic ketone, generating a quaternary center with high ee (98% post-trituration), albeit with reduced yield (53%, 2 steps). Jacobsen cautions that one limitation of the method is the need for a slight excess of the thiourea catalyst relative to BzOH, to avoid a deleterious racemic background reaction.
What is Known of the Mechanisms of Existing Systems
Terada (10.1021/ja0491533) mentions (wrt Bronsted acids) "1) Tetradentate structure around the phosphorus(V) atom would prevent free rotation at R of the phosphorus center by formation of a ring structure. This characteristic feature cannot be found in other possible Brønsted acids, such as carboxylic and sulfonic acids, etc. 2) Their appropriate acidity16 should catch up the imine through hydrogen bonding without loose ion-pair formation. 3) Their phosphoryl oxygen should function as a Lewis basic site, and thus a phosphoric acid could function as a bifunctional catalyst."
Interesting --> Cook et al, "Study of the Cis to Trans Isomerization of 1-Phenyl-2,3-disubstituted Tetrahydro-β-carbolines at C(1). Evidence for the Carbocation-Mediated Mechanism" Paper - Proposes mechanism for the racemisation via retro Pictet-Spengler of enantioenriched tetrahydro-β-carbolines synthesised from tryptamines and aldehydes.
For binaphthyl-derived phosphoric acids are there any trends in the nature of the substituents vs. ee obtained? In Hiemstra 2007 no clear trend is visible in Table 1. Franz noticed strong effect of 3,3'-substituents, with similar sterically-demanding groups reversing enantioinduction.
Limitation: avoiding β,γ-unsaturated aldehydes, which tend to tautomerise from the intermediate iminium ion to the unreactive, conjugated enamine, e.g. in Hiemstra 2011.
Dixon 2010 (10.1021/ol101651t). Both isolated enamide intermediates (epimers?) gave the same ee on treatment with the chiral BINAP (to drive rxn to completion). The proposed mechanism was that both reactions underwent rapid epimerisation through a common prochiral enamide intermediate (steady state?). Also, suggested enantioselectivity arose from facial differentiation imposed by the tight ion pair between the binol phosphoric acid conjugate base and the iminium ion.
Terada Review (10.1246/bcsj.20090268): Phosphoric acids as stronger Bronsted acids than thioureas or than TADDOL (used in the Rawal Nature paper). Considered other possible acids including sulfonic (too strong), carboxylic and sulfuric (free rotation problem), and phosphoric - just right, and chiral info is closer to proton. (When deprotonated, the O minus and P=O sites interconvert, right, but this is unimportant?) Phosphoric acids not expected to form loose ion pairs. Expected to be H-bonding etc that keeps components together. Ring system employed in the BINOL derivatives makes more rigid. Good? Mechanistic proposal in Figure 4. H-bonding network, not ion pair. Developed phosphorodiamidic acid in Synlett 2006, 133. Figure 11 has mechanistic cycle that may be of interest to PZQ. Do all the enecarbamate reactions known to function have N-H's?
Solvents: toluene found to be a good solvent for a number of these reactions, e.g. 10.1021/ja9024885. No clear trend observed in Franz 2011; DCM happens to be the best, but...
Thiourea mechanism: Franz 2011 has Jacobsen ligands as giving good conversion but moderate ee, but the Takemoto ligand giving no conversion.
Clearly the main issue with regards the mechanism is the need for an electron-rich ring for the PS reaction to occur. Franz 2011 looked at this a little, though there are two steps in the mechanism - imine formation and cyclization, so one needs to be careful interpreting results.
Strictosidine Synthase Mechanism: O'Connor 2008 compares acid-base effects of non-enzymatic aqueous solution vs. enzyme-catalysed reactions (using kinetic isotope effects). The rate-determining step appears to be the same for both systems. O'Connor also discusses the pH dependence of enzymatic catalysis, but not for binding of substrate, and proposes an enzyme mechanism involving key residue Glu309; deprotonation of tryptamine increases its nucleophilicity for aldehyde attack (emphasis on proximity of the Glu residue to the substrate). Lack of significant conformational change on binding of the substrate.
O'Connor 2010 TL - A computational model was generated for the OpSTS active site, which determined that a reversible mixture of diastereomeric intermediate carbolines were formed, but that only the 2(R)3(S) diastereomer was capable of subsequent deprotonation by key Glu309, a carboxylate residue in the active site.
Enzymatic Catalysis
(Aim of this section should be to describe preparative uses of these enzymes, and whether they are able to do reactions we can't with small molecules. Mechanistic insights (crucial here) should go in the mechanism section, to provide a comparison with what's known of small molecule systems.)
Stockigt and Waldmann's 2011 ACIEE review on the Pictet-Spengler reaction eloquently opens with discussion of the two known families of "Pictet-Spenglerases" - enzymes that take as their substrates an electron-rich aromatic, appended to an ethylamine, and an aldehyde - and transform them into asymmetric tetrahydroisoquinoline or tetrahydro-β-carboline motifs. Strictosidine synthase (STR1), first isolated in 1975 by Scott and Lee, cyclizes natural product precursors belonging to the strychnos and ajmaline alkaloid pathways. Norcoclaurine synthase (NCR), isolated in 1981 by Nagakura from plant cell cultures, which condenses tyrosine-derived aldehydes and dopamine to form a variety of benzoisoquinoline precursors.
A variety of different halogenated and alkylated tryptamine precursors have been incorporated into final alkaloid structures utilizing a multi-enzyme cascade. First, the group transferred the genes encoding tryptamine halogenase RebH (from soil bacteria) into C. roseus hairy root culture. They then developed a modified STR enzyme, STRvm, capable of recognizing and turning over halogenated Trp precursors. The group used MS and 2D NMR methods to confirm detection of downstream halogenated alkaloids. (O'Connor, Nature 2010, 461)
In 2010, O'Connor and coworkers reported 3 strictosidine synthase homologs, isolated from R. serpentina (RsSTS), C. roseus (CrSTS), and O. pumila (OpSTS). Previous research by O'Connor and Stockigt had shown that variations to the tryptamine synthon (electron-rich, electron-deficient) were tolerated by the enzymes, but that aldehydes other than secologanin were not turned over. The O. pumila isolate, a lower homolog (~60% sequence identity to RsSTS or CrSTS) was capable of catalyzing the PS reaction between tryptamine and various non-native aldehydes. Tetrahydro-B-carbolines thus formed had >98% ee.
The substrate tolerance of strictosidine synthase was further extended by Stockigt and a multi-institutional team in a JACS 2012 paper. Strictosidine synthase (STR1), after substrate-directed mutagenesis, was able to turn over heteroatom-containing tryptamines such as 7-N tryptamine (indazole ethanamine). The resulting secologanin conjugate was detected by HRMS.
Miscellaneous Related Systems, or Known Catalysts not yet used for the PS
This is a very important section where we describe some obvious things that can be tried next in the field. Reviews are not proposals, but making maps gives you a clear sense of what has not yet been explored.
Non-BINOL derived Bronsted acids (other relevant, perhaps tartrate-derived, biologically relevant?)
Internal Lewis-acid assisted urea catalysis (see: Mattson, OL 2011 and 2012)
Enzyme mutagenesis to accept varied heterocyclic precursors (thiophenes, furans, pyrroles), extension of Stockigt 2012 work
"Interrupted" Pictet-Spengler reactions, perhaps to start cascade synthesis
Merge Denmark and Leighton work, see if "base-assisted silicon catalysis" might turn over the PS
Lewis acids for Friedel-Crafts-type reactions: http://www.sciencedirect.com/science/article/pii/S0040402009009302
PS of non-activated phenethylamine with aldehydes to give THIQs: One-step preparation of 1-substituted tetrahydroisoquinolines via the Pictet–Spengler reaction using zeolite catalysts, Adrienn Hegedus and Zoltan Hell, TetLett 2004 45, 8553–8555. DOI: 10.1016/j.tetlet.2004.09.097 Paper
PS of non-activated phenethylamine to give THIQ (clay): Pictet-Spengler condensation reactions catalyzed by a recyclable H+-montmorillonite as a heterogeneous Brønsted acid, DOI: 10.1007/s11426-010-0073-4
Achiral LA-catalysed PS to give THIQs: Catalytic Pictet-Spengler reactions using Yb(OTf)3, Manabe, K., D. Nobutou, et al. Bioorganic & Medicinal Chemistry 2005 13(17): 5154-5158. DOI: 10.1016/j.bmc.2005.05.018 Paper
- Development of the Pictet-Spengler Reaction Catalyzed by AuCl3/AgOTf, S. W. Youn, The Journal of Organic Chemistry 2006 71(6), 2521-2523. DOI: 10.1021/jo0524775 Paper
- Calcium-Promoted Pictet-Spengler Reactions of Ketones and Aldehydes, M. J. V. Eynden, K. Kunchithapatham, J. P. Stambuli, Journal of Organic Chemistry 2010, 75, 8542. DOI: 10.1021/jo1019283 Paper
Conclusions, and what's needed in this field
We will write this section last. Conclusions to address advantages and disadvantages of known systems, wrt temp, recoverability, ee, substrate scope.
Currently no examples of catalytic, asymmetric oxa-PS reaction? Review of oxo-PS is Larghi 2011, and has no cat. enantioselective examples
There might be, but if so, they're covered under different names...like Prins cyclizations, Friedel-Crafts, or anomeric (sugar) arylation. It might require a lot of digging! - MAT
Design of "mini-proteins" (think Marcey Waters, Manfred Reetz, or Scott Miller) to accomplish PS reaction in non-biological environment
Substrate limitations: all known examples are based on tryptamine. No examples with original PS system of an activated benzene ring. No examples with other Ar rings such as furans, thiophenes? One with pyrroles (Jacobsen). One iso-PS reaction (Jacobsen). Recent example of cat asymm on ISQ ring system - first reported: Monitoring On-Chip Pictet-Spengler Reactions by Integrated Analytical Separation and Label-Free Time-Resolved Fluorescence, Ohla Stefan; Beyreiss Reinhild; Fritzsche Stefanie; et al. Source: CHEMISTRY-A EUROPEAN JOURNAL 2012, Volume: 18, 1240-1246 DOI: paper
Papers discussed in the review should ONLY be listed here when the summary of the science in the review is complete. The papers may be found in full at the Mendeley page)
- Ueber die Bildung von Isochinolin-derivaten durch Einwirkung von Methylal auf Phenyl-aethylamin, Phenyl-alanin und Tyronsin, A. Pictet and T. Spengler, Ber. Dtsch. Chem. Ges. 1911, 44, 2030-2036. Paper
- Tatsui, G. J. Pharm. Soc. Jpn. 1928, 48, 92 (may be 453-459). Need to find this paper!
- The Pictet-Spengler Condensation: A New Direction for an Old Reaction, E. D. Cox and J. M. Cook, Chem. Rev. 1995, 95, 1797- 1842 Paper
- Asymmetric Synthesis of Isoquinoline Alkaloids, M. Chrzanowska and M. D. Rozwadowska, Chem. Rev. 2004, 104, 3341-3370 Paper
- The Pictet-Spengler Reaction in Nature and in Organic Chemistry, J. Stoeckigt, A. P. Antonchick, F. Wu and H. Waldmann, Angew. Chem. Int. Ed. 2011, 50, 8538-8564 Paper
- The Pictet-Spengler Synthesis of Tetrahydroisoquinolines and Related Compounds, W. M. Whaley and T. R. Govindachari, Organic Reactions 1951, 6, 151-190 Paper
- Enantiospecific Total Synthesis of the Ajmaline Related Alkaloids (-)-Suaveoline, (-)-Raumacline, and (-)-Nb-Methylraumacline, X. Fu and J.M. Cook, J. Am. Chem. Soc. 1992, 114, 6910-6912 Paper
- Resolution of etodolac and anti-inflammatory and prostaglandin synthetase inhibiting properties of the enantiomers, C. A. Demerson, L. G. Humber, N. A. Abraham, G. Schilling, R. R. Martel and C. Pace-Asciak, J. Med. Chem 1983, 26, 1778-1780. Paper
- The Pictet-Spengler Reaction: Efficient Carbon-carbon Bond Forming Reaction in Heterocyclic Synthesis, S. W. Youn, Org. Prep. Proc. Int. 2006, 38, 505-591 [Paper]
- Taste, A New Incentive to Switch to (R)-Praziquantel in Schistosomiasis Treatment, T. Meyer, H. Sekljic, S. Fuchs, H. Bothe, D. Schollmeyer, C. Miculka, PLoS Negl Trop Dis 2009, 3, e357 Paper
- Spiroindolones, a Potent Compound Class for the Treatment of Malaria, M. Rottmann, C. McNamara, B. K. S. Yeung, M. C. S. Lee, B. Zou, B. Russell, P. Seitz, D. M. Plouffe, N. V. Dharia, J. Tan, S. B. Cohen, K. R. Spencer, G. E. González-Páez, S. B. Lakshminarayana, A. Goh, R. Suwanarusk, T. Jegla, E. K. Schmitt, H.-P. Beck, R. Brun, F. Nosten, L. Renia, V. Dartois, T. H. Keller, D. A. Fidock, E. A. Winzeler, T. T. Diagana, Science 2010, 329, 1175-1180 Paper
- The Total Synthesis of Enantiopure Phalarine via a Stereospecific Pictet-Spengler Reaction: Traceless Transfer of Chirality from L-tryptophane, J.J. Trzupek, D. Lee, B.M. Crowley, V.M. Marathias, S.J. Danishefsky, J. Am. Chem. Soc. 2010, 132, 8506-8512 Paper
- Synthesis of Oxacycles Employing the Oxa-Pictet-Spengler Reaction: Recent Developments and New Prospects, E. L. Larghi and T. S. Kaufman, Eur. J. Org. Chem. 2011, 5195-5231 Paper
Diastereoselective Intro Section:
- Enantiospecific Formation of Trans 1,3-Disubstituted Tetrahydro-β-carbolines by the Pictet-Spengler Reaction and Conversion of Cis Diastereomers into Their Trans Counterparts by Scission of the C-1/N-2 Bond, E. D. Cox, L. K. Hamaker, J. Li, P. Yu, K. M. Czerwinski, L. Deng, D. W. Bennett and J. M. Cook, J. Org. Chem. 1997, 62, 44-61. Paper
- The Intermolecular Pictet-Spengler Condensation with Chiral Carbonyl Derivatives in the Stereoselective Syntheses of Optically-active Isoquinoline and Indole Alkaloids, E. L. Larghi, M. Amongero, A. B. J. Bracca and T. S. Kaufman, ARKIVOC 2005 (xii) 98-153. [Link here: http://www.arkat-usa.org/arkivoc-journal/browse-arkivoc/2005/12/]
Lewis Acid Intro Section:
- A New Evidence for the Presence of a Spiroindolenium Species in the Pictet-Spengler Reaction, T. Kawate, M. Nakagawa, K. Ogata, and T. Hino, Heterocycles, 1992, 33, 801-811. [Need DOI]
- A New Chiral BLA Promoter for Asymmetric Aza Diels-Alder and Aldol-Type Reactions of Imines, K. Ishihara, M. Miyata, K. Hattori, T. Tada and H. Yamamoto, J. Am. Chem. Soc. 1994, 116, 10520–10524. Paper
- Enantioselective Asymmetric Pictet-Spengler Reaction Catalyzed by Diisopinocampheylchloroborane, T. Kawate, H. Yamada, T. Soe and M. Nakagawa, Tetrahedron: Asymmetry 1996, 7, 1249-1252 Paper
- Chiral Lewis Acid-mediated Enantioselective Pictet-Spengler Reaction of N-b-Hydroxytryptamine with Aldehydes, H. Yamada, T. Kawate, M. Matsumizu, A. Nishida, K. Yamaguchi and M. Nakagawa, J. Org. Chem. 1998, 63, 6348-6354. Paper
- Highly Enantioselective Pictet–Spengler Reactions with α-Ketoamide- Derived Ketimines: Access to an Unusual Class of Quaternary α-Amino Amides, F. R. Bou-Hamdan and J. L. Leighton, Angew. Chem. Int. Ed. 2009, 48, 2403-2406 Paper
- Direct and Highly Enantioselective Iso-Pictet Spengler Reactions with α-Ketoamides: Access to Underexplored Indole Core Structures, Heike Schönherr and James L. Leighton, Org. Lett. 2012, 14, 2610-2613 Paper
Brønsted Section:
- Enantioselective Mannich-Type Reaction Catalyzed by a Chiral Brønsted Acid, T. Akiyama, J. Itoh, K. Yokota and K. Fuchibe, Angew. Chem. Int. Ed. 2004, 43, 1566-1568. Paper
- Chiral Brønsted Acid-Catalyzed Direct Mannich Reactions via Electrophilic Activation, D. Uraguchi and M. Terada, J. Am. Chem. Soc. 2004, 126, 5356-5357. Paper
- Catalytic Asymmetric Pictet-Spengler Reaction, J. Seayad, A. M. Seayad and B. List, J. Am. Chem. Soc. 2006, 128, 1086-1087. Paper
- Catalytic Asymmetric Pictet-Spengler Reactions via Sulfenyliminium Ions, M. J. Wanner, R. N. S. van der Haas, K. R. de Cuba, J. H. van Maarseveen and H. Hiemstra, Angew. Chem. Int. Ed. 2007, 46, 7485-7487. Paper
- Enantioselective BINOL-phosphoric Acid Catalyzed Pictet-Spengler Reactions of N-benzyltryptamine, N. V. Sewgobind, M. J. Wanner, S. Ingemann, R. de Gelder, J. H. van Maarseveen and H. Hiemstra, J. Org. Chem. 2008, 73, 6405-6408. Paper
- Organocatalytic Enantioselective Total Synthesis of (-)-Arboricine, M. J. Wanner, R. N. A. Boots, B. Eradus, R. de Gelder, J. H. van Maarseveen and H. Hiemstra, Org. Lett. 2009, 11, 2579-2581. Paper
- Enantioselective Brønsted Acid-Catalyzed N-Acyliminium Cyclization Cascades, M. E. Muratore, C. A. Holloway, A. W. Pilling, R. I. Storer, G. Trevitt and D. J. Dixon, J. Am. Chem. Soc. 2009, 131, 10796-10797. [1]
- Chiral Phosphoric Acids as Versatile Catalysts for Enantioselective Carbon-Carbon Bond Forming Reactions, M. Terada, Bull. Chem. Soc. Jpn. 2010, 83, 101-119. Paper
- Direct Enantioselective Brønsted Acid Catalyzed N-Acyliminium Cyclization Cascades of Tryptamines and Ketoacids, C. A. Holloway, M. E. Muratore, R. I. Storer and D. J. Dixon, Org. Lett., 2010, 12, 4720-4723 Paper
- Total Synthesis of (+)-Yohimbine via an Enantioselective Organocatalytic Pictet-Spengler Reaction, B. Herle, M. J. Wanner, J. H. van Maarseveen and H. Hiemstra, J. Org. Chem. 2011, 76, 8907-8912. Paper
- Enantioselective Syntheses of Corynanthe Alkaloids by Chiral Brønsted Acid and Palladium Catalysis, M. J. Wanner, E. Claveau, J. H. van Maarseveen and H. Hiemstra, Chem. Eur. J. 2011, 17, 13680-13683. Paper
- Enantioselective Pictet-Spengler Reactions of Isatins for the Synthesis of Spiroindolones, J. J. Badillo, A. Silva-Garcia, B. H. Shupe, J. C. Fettinger and A. K. Franz, Tetrahedron Lett. 2011, 52, 5550-5553. Paper
Organocatalysis Section:
- Highly Enantioselective Catalytic Acyl-Pictet-Spengler Reactions, M. S. Taylor and E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 10558-10559. Paper
- Small-Molecule H-Bond Donors in Asymmetric Catalysis, A. G. Doyle and E. N. Jacobsen, Chem. Rev. 2007, 107, 5713-5743. Link? <-- (MHT, Jan 22) - has this paper been read and relevant mechanistic ideas incorporated?
- Enantioselective Pictet-Spengler-Type Cyclizations of Hydroxylactams: H-Bond Donor Catalysis by Anion Binding, I. T. Raheem, P. S. Thiara, E. A. Peterson and E. N. Jacobsen, J. Am. Chem. Soc. 2007, 129, 13404-page?. Paper
- Catalytic Asymmetric Total Synthesis of (+)-Yohimbine, D. J. Mergott, S. J. Zuend and E. N. Jacobsen, Org. Lett. 2008, 10, 745-748. Paper
- Weak Brønsted Acid-thiourea Co-catalysis: Enantioselective, Catalytic Protio-Pictet-Spengler Reactions, R. S. Klausen and E. N. Jacobsen, Org. Lett. 2009, 11, 887-890. Paper
- Thiourea-Catalyzed Enantioselective Iso-Pictet-Spengler Reactions, Y. Lee, R. S. Klausen and E. N. Jacobsen, Org. Lett. 2011, 13, 5564-5567. Paper
Enzyme Section:
- Strictosidine Synthase: Mechanism of a Pictet-Spengler Catalyzing Enzyme, J.J. Maresh, L-A. Giddings, A. Friedrich, E.A. Loris, S. Panjikar, B.L. Trout, J. Stockigt, B. Peters, S.E. O'Connor. J. Am. Chem. Soc. 2008, 130, 710-723.
- Integrating carbon-halogen bind formation into medicinal plant metabolism, W. Runguphan, X. Qu, S.E. O'Connor. Nature 2010, 468, 461-467.
- Biocatalytic Asymmetric Formation of Tetrahydro-B-carbolines, P. Bernhardt, A.S. Usera, and S.E. O'Connor, Tetrahedron Lett. 2010, 51, 4400-4402.
- Scaffold Tailoring by a Newly Detected Pictet-Spenglerase Activity of Strictosidine Synthase: From the Common Tryptoline Skeleton to the Rare Piperazino-indole Framework, F. Wu, H. Zhu, L. Sun, C. Rajendran, M. Wang, X. Ren, S. Panjikar, A. Cherkasov, H. Zhou, and J. Stockigt, J. Am. Chem. Soc. 2012, 134, 1498-1500.
Papers we're not including, and why (arranged by date)
Insert details of papers here if they are not being used, and explain why.
- Asymmetric Pictet-Spengler Reactions Employing N,N-Phthaloyl Amino Acids as Chiral Auxiliary Groups, H. Waldmann, G. Schmidt, H. Henke and M. Burkard, Angew. Chem., Int. Ed. Engl. 1995, 34, 2402-2403. Paper - Diastereoselective. Use of stoichiometric chiral auxiliaries.
- Asymmetric Control in Pictet-Spengler Reaction by Means of N-Protected Amino Acids as Chiral Auxiliary Groups, G. Schmidt, H. Waldmann, H. Henke and M. Burkard, Chem. Eur. J. 1996, 2, 1566-1571. Paper - Diastereoselective. Use of stoichiometric chiral auxiliaries.
- Enantiopure Tetrahydro-β-carbolines via Pictet−Spengler Reactions with N-Sulfinyl Tryptamines, C. Gremmen, B. Willemse, M. J. Wanner, G.-J. Koomen, Org. Lett. 2000, 2, 1955-1958. [Paper]- Use of chiral auxiliary.
- Enantiopure tetrahydroisoquinolines via N-sulfinyl Pictet–Spengler reactions, C. Gremmen, M. J. Wanner, G Koomen, G.-J. Tetrahedron Lett. 2001, 42, 8885-8888. Paper - Use of chiral auxiliary and excess acid.
- Enantioselective Addition of Amines to Ketenes Catalyzed by a Planar-Chiral Derivative of PPY: Possible Intervention of Chiral Brønsted-Acid Catalysis, B. L. Hodous, G. C. Fu, J. Am. Chem. Soc., 2002, 124, 10006-10007, Paper - Reaction of pyrroles with ketenes catalysed by a PPY planar-chiral 4-(pyrrolidino)pyridine (PPY), which is Fe π-bonded complex. Not Pictet-Spengler.
- A Chiral Acrylate Equivalent for Metal-Free Diels-Alder Reactions: endo-2-Acryloylisoborneol, C. Palomo, M. Oiarbide, J. M. Garcia, A. Gonzalez, A. Lecumberri, A. Linden, J. Am. Chem. Soc. 2002, 124, 10288 Paper - Not relevant. Not chiral acid, use of chiral aux. in Diels-Alder.
- General Approach for the Synthesis of Sarpagine Indole Alkaloids. Enantiospecific Total Synthesis of (+)-Vellosimine, (+)-Normacusine B, (-)-Alkaloid Q3, (-)-Panarine, (+)-Na-Methylvellosimine, and (+)-Na-Methyl-16-epipericyclivine, J. Yu, T. Wang, X. Liu, J. Deschamps, J. Flippen-Anderson, X. Liao and J. M. Cook, J. Org. Chem. 2003, 68, 7565-7581. Paper - diastereoselective
- Organocatalytic Asymmetric Aza-Friedel-Crafts Alkylation of Furan, D. Uraguchi, K. Sorimachi and M. Terada, J. Am. Chem. Soc. 2004, 126, 11804-11805. Paper - Maybe include, but non-PS, simple extension of previous paper.
- Organocatalytic Asymmetric Direct Alkylation of α-Diazoester via C−H Bond Cleavage, D. Uraguchi, K. Sorimachi and M. Terada, J. Am. Chem. Soc. 2005, 127, 9360-9361. Paper - extension to a system too far removed from PS reaction.
- Chiral Brønsted Acid Catalyzed Enantioselective Hydrophosphonylation of Imines: Asymmetric Synthesis of α-Amino Phosphonates, T. Akiyama, H. Morita, J. Itoh and K. Fuchibe, Org. Lett. 2005, 7, 2583–2585. Paper - simple extension to other nucleophile.
- Stereocontrolled Total Synthesis of (-)-Eudistomin C, T. Yamashita, N. Kawai, H. Tokuyama and T. Fukuyama, J. Am. Chem. Soc. 2005, 127, 15038-15039. Paper - Diastereoselective.
- An Improved Total Synthesis of (+)-Macroline and Alstonerine as Well as the Formal Total Synthesis of (-)-Talcarpine and (-)-Anhydromacrosalhine-methine, X. Liao, H. Zhou, J. Yu and J. M. Cook, J. Org. Chem. 2006, 71, 8884-8890. Paper - presumed diastereoselective, but relevant chemistry is actually in J. Org. Chem. 2000, 65, 3173.
- Total Synthesis of the Opioid Agonistic Indole Alkaloid Mitragynine and the First Total Syntheses of 9-Methoxygeissoschizol and 9-Methoxy-Nb-methylgeissoschizol, J. Ma, W. Yin, H. Zhou and J. M. Cook, Org. Lett. 2007, 9, 3491-3494. Paper - diastereoselective.
- The Asymmetric Pictet-Spengler Reaction, M. Lorenz, M. L. van Linn and J. M. Cook, Curr. Org. Synth. 2010, 7, 189-223 Paper - this is a recent review, but persistently difficult to get hold of, so I suggest we do not include a link it. Waldmann's is I think more available and covers relevant material.
- K. Pulka, Curr. Opin. Drug Discov. Devel. 2010, 13, 669–684 - referenced from Franz 2011 but not easily available (MHT Feb 2) - ignore?
- Synthesis of beta-Carbolines from Aldehydes and Ketones via the alpha-Siloxy alpha,beta-Unsaturated Esters, S. He, Z. Lai, D. X. Yang et al. Tetrahedron Lett, 2010, 51, 4361-4364 paper - syntheses are rac.
- Intra- and Intermolecular Oxa-Pictet–Spengler Cyclization Strategy for the Enantioselective Synthesis of Deoxy Analogues of (+)-Nanomycin A Methyl Ester, (+)-Eleutherin, (+)-Allo-Eleutherin, and (+)-Thysanone, R. T. Sawant, S. G. Jadhav and S. B. Waghmode, Eur. J. Org. Chem. 2010, 4442-4449 Paper - diastereoselective
- Electrochemical Deallylation of alpha-Allyl Cyclic Amines and Synthesis of Optically Active Quaternary Cyclic Amino Acids, P. G. Kirira, M. Kuriyama and O. Onomura, Chem. Eur. J. 2010, 16, 3970-3982 paper - electrochemical generation of iminium ions - not relevant.
- Total Synthesis of (–)-Corynantheidine by Nickel-Catalyzed Carboxylative Cyclization of Enynes, T Mizuno, Y. Oonishi, M. Takimoto, and Y. Sato, Eur. J. Org. Chem. 2011, 2606-2609. Paper - diastereoselective PS as part of longer synthesis.
- Highly Enantioselective Mannich Reactions with alpha-Aryl Silyl Ketene Acetals and Imines, G. T. Notte, J. M. B. Vu and J. L. Leighton, Org. Lett. 2011, 13, 816-818 paper - adaptation of Leighton's methodology to Mannich reactions.
- A Straightforward Synthesis of N-Monosubstituted Alpha-keto Amides via Aerobic Benzylic Oxidation of Amides, J. Shao, X. Huang, S. Wang et al. Tetrahedron 2012, 68, 573-579 paper - not relevant - just synthesis of ketoamides.
- Lipase-Catalyzed Kinetic Resolution of 2-Phenylethanol Derivatives and Chiral Oxa-Pictet–Spengler Reaction as the Key Steps in the Synthesis of Enantiomerically Pure Tricyclic Amines, C. Ketterer and B. Wünsch, Eur. J. Org. Chem. 2012, 2428. [2] - diastereoselective


text:
For more on the role fitness professionals play in reversing the obesity epidemic, join registered dietitian Natalie Digate Muth for our recorded one-hour webinar.
I get tired of people who say, 'It's simple; just eat less and move more," wrote Tara Parker Pope, a New York Times Well blogger on her struggles with weight. "We don't do dieters any favors by telling them that it's easy and simple."
Every day, efforts to control weight and body size permeate the lives of most Americans. That struggle is demonstrated in the 25 percent of men and 40 percent of women on a diet at any given time, the $35 billion spent on weight-loss products annually and the devastating health consequences that result from excess weight and obesity. Fitness professionals on the front line in the war against obesity struggle every day too; they struggle to develop tips, strategies and programs to help their clients achieve a healthier weight.
While the mantra of "eat less and move more" works in practice, the struggles that clients face are much more complicated, ingrained and difficult to change. However, an emerging body of science combined with increased motivation to improve on multiple levels has invigorated the effort to reverse the obesity epidemic within the next generation. Fitness professionals are in a unique position to significantly contribute to reversing the weight problem in the U.S. and across the world. With that said, in order to be effective, they must stay on top of the latest research and scientific advances, emerging trends, and community collaborations and partnerships.
The Science
Much of what we thought we knew about weight loss may not be accurate, such as the common teaching that to lose a pound a week you should create a 500 calorie deficit each day, which will add up to 3500 calories - about the number of calories in a pound of fat. In the long term, this never plays out. While initial weight loss may more or less follow this principle, subsequent loss is frequently stalled despite large caloric deficits. A group of scientists at the National Institutes of Health developed a mathematical model to account for changes in metabolism that occur with weight loss. The study estimates that for every 10-calorie decrease in intake, the average overweight adult will lose about 1 pound with half of the weight lost by one year and 95% of the weight change by three years. For example, a woman who decreased her daily caloric consumption from 2,200 calories to 2,000 calories per day would lose about 10 pounds in one year and about 10 more pounds by the end of three years. If she had created a 500-calorie deficit each day, she would lose 25 pounds in the first year and about 25 more pounds by the end of three years. This is a lot slower weight loss than one would expect from the simple calculation of 3,500 calories in a pound. The research concludes that we don't do dieters any favors by telling them weight loss is easy and simple.
Emerging Trends and Collaborations
Despite an intensive physical activity regimen, nutrition changes or behavioral rewiring, many struggle to achieve their weight loss goals. While individuals are responsible for their behaviors, community and policy-level factors can greatly influence eating and activity patterns. Earlier this year the Institute of Medicine released a report titled "Accelerating Progress in Obesity Prevention: Solving the Weight of the Nation." In the report, authors outlined several goals that, if implemented collectively, would make significant strides in obesity prevention. They included:
- Make physical activity an integral and routine part of daily life.
- Create environments that ensure healthy food and beverage options are the routine, easy choice.
- Transform messages about physical activity and nutrition, making healthier options more desirable and accessible.
- Expand the roles of health care providers, insurers and employers to better support physical activity and nutrition.
- Make schools a national focal point by increasing physical activity opportunities and strong nutritional standards.
Clearly, most communities, states and even the nation as a whole have a long way to go in achieving these objectives. Fitness professionals can serve as powerful leaders in their communities by transforming many of these ideals into reality. For example, they can play an integral role in the development of:
- Community programs designed to increase physical activity (objective 1)
- Community task forces that develop and disseminate nutrition and activity recommendations to influential community members and decision makers (objective 2)
- Awareness-building and social marketing efforts to increase knowledge of healthy physical activity and nutrition choices (objective 3)
- Initiatives to increase access to and quality of work-based activity programs (objective 4)
- High-quality physical education programs that effectively increase the physical fitness level of students (objective 5)
These are just a few examples of the many collaborations and initiatives that can play a prominent role in the broad-scale effort to reverse the obesity epidemic by creating optimal nutrition and fitness opportunities, and choices for community members.
Finding the Solution
Ultimately, the price of obesity is very high for not only individuals and families but communities and the nation as a whole. With the exorbitant number of overweight and obese Americans, and the importance of exercise in reversing the epidemic, fitness professionals must take a leading role as exercise experts. With the most up-to-date knowledge and the right tools, they can each day make small steps to promote weight loss, ensure weight loss maintenance and prevent weight gain through both one-on-one coaching and community interventions.

subset: commoncrawl


text:
When a business wants to make progress and grow then it is very important for that business to use the right strategies and techniques for marketing itself. There are a number of ways through which the businesses can be advertised and promoted. Among many of the other things and ways, the use of the signs is also very important and effective.
It is considered to be a very effective way of communicating the thoughts and ideas of a business to the people and customers. They are considered to be a really powerful mode of communication. It creates a great impact on the minds of people and you would be greatly surprised to see their influence on people.
You can easily create a mood or feeling of the environment which you like to do. They can simply change the moods of people and can attract them towards the business in a great manner.
For most of the Medias of communication which are used for advertising, a directed attention is needed but this is not the case with the use of the signs and sign boards.
The people would not have to give full attention to the boards in order to get some meaning out of it. They would be a great way of depicting the meaning of the business to the people. The people would take your business just the way they would take your signs.
The role of the sign maker in Mulvane, KS is very important in this regard. sign maker in Mulvane, KS. sign maker in Mulvane, KS. You should be careful while choosing the company or individual for this task. He would be the one who can make or break the image of your business in the minds of others.
When you want to be known everywhere then you should give enough importance to your boards. These companies have a number of dedicated and skilled people who have the expertise of designing and making the best and most attractive boards.
They put a lot of emphasis on the better design as it is the first thing which is noticed by the people passing by. The use of the right colors and the schemes is very much important. The colors can easily change the moods and feelings of people and this is why special emphasis is put on it.
The next very important thing is what is written on these signs. The sign making is an art which requires a lot of skill. There are many wonderful writers who take a lot of time in writing catchy and attractive texts on these boards. The next thing noticed by the people after the design and coloring schemes are the texts written.
It would attract the attention of the customers and would help your business to grow. With the help of consulting the right company for making and designing your signs, you would actually be promoting your business and helping it to move forward. The people would get to know about you and your services through them and would make you more prominent and noticeable.


text:
US gun control advocates must show they like guns
NEW YORK (AP) -- Lobbying for gun control in the United States often means proving how much you like firearms. By ALEXANDRA OLSON Associated Press NEW YORK (AP) -- Lobbying for gun control in the United States often means proving how much you lik...
NEW YORK (AP) -- Lobbying for gun control in the United States often means proving how much you like firearms.
By ALEXANDRA OLSON
Associated Press
NEW YORK (AP) -- Lobbying for gun control in the United States often means proving how much you like firearms.
New York Gov. Andrew Cuomo, whose state recently passed some of the strictest gun control measures in the country, often reminds people he is a hunter. Former Rep. Gabrielle Giffords, who founded a gun control advocacy group after surviving a gunshot wound to the head, says she and her husband keep two guns in a safe at home. Vice President Joe Biden boasts that he owns two shotguns. And the White House recently released a photo of President Barack Obama skeet shooting at the Camp David presidential retreat, trying to silence skeptics of his claim in an interview that he has actually shot a gun.
The message is obvious: They, too, are a part of America's gun culture. In a country where at least a third of households have firearms, it's hard to impose stricter arms rules without support from gun owners. That means reassuring Americans that nobody is going to take away the guns they have legally acquired.
Gun rights groups scoffed at what they called clumsy and obvious attempts by Biden and Obama to ingratiate themselves with firearm owners even while trying to limit their rights.
"It's transparent, cynical and hollow and gun owners see right through it," said Lawrence Keane, senior vice president of the National Shooting Sports Foundation, an association that represents gun manufacturers.
But gun control proponents have pressed on with such efforts ahead of a crucial Senate vote on legislation backed by the Obama administration in response to the Dec. 14 shooting of 20 children and six educators at a Connecticut school.
A recent $12 million ad campaign, bankrolled by billionaire New York City Mayor Michael Bloomberg, urged moderate Republican and Democratic senators to support expanding federal background checks for gun sales, a system that currently applies only to federally licensed dealers. Advocates want to include gun show sales.
Far from criticizing guns, the ad shows a scruffy-faced man holding a shotgun in the back of a pickup truck. He argues that background checks don't infringe on the Second Amendment of the Constitution, which guarantees the right of citizens to bear arms and is often cited by gun rights defenders.
"For me, guns are about hunting and protecting my family," the man says, as two children play on tire swings in the background. "I believe in the Second Amendment, and I'll fight to protect it. But with rights come responsibilities. That's why I support comprehensive background checks, so criminals and the dangerously mentally ill can't buy guns."
Broader background checks face an uphill battle in Congress, along with proposals for a ban on military-style assault rifles and limits on ammunition capacity. Many Republicans and some Democrats represent states where citizens have vocally expressed fears that their gun rights will be taken away in the wake of the Connecticut shooting.
Gun sales nationwide surged after the school attack as people rushed to buy weapons they feared would be banned. Some communities have voted to allow teachers to carry firearms in schools, arguing that guns make people safer. A handful of small towns have even issued ordinances requiring their residents arm themselves.
The powerful National Rifle Association, which spent at least $24 million during the last U.S. election cycle, has stoked those fears, suggesting that the White House's real intention to eventually to ban all firearms. "It's about banning your guns ... PERIOD!" NRA leader Wayne LaPierre wrote in January email to the group's 4 million members.
But gun control advocates see evidence that, since the Connecticut shooting, many firearms owners are more open to stricter laws than the NRA contends.
Recent polling shows that more than 80 percent of Americans support extending federal background checks to include gun show sales and private purchases. Colorado, a state with a strong frontier tradition of gun ownership, passed legislation last month that expanded background checks to apply to personal and online sales and limited magazine capacity to 15 bullets. Connecticut followed suit with an even stronger bill to ban more than 100 previously legal weapons. In Maryland, legislators have approved a measure that, among other things, requires people who buy a handgun to submit fingerprints to state police.
Obama and others are touting such efforts as signs that the country can bridge one of its deepest cultural divides: The split between mostly rural Americans who cherish guns for hunting and self-defense and urban citizens who equate them with gang violence, drive-by shootings and young lives lost.
"I'm 100 percent for expanded background checks, because if you have something to hide, we don't want you to have a gun," said Jaci Turner, a gun owner who lives in a suburb of Denver, Colorado. "I don't have anything to hide, so I'll answer all your questions."
Turner, a dog trainer, grew up around guns in Minnesota. Weekends were often spent hunting or on the shooting range with her father. She and her husband, a big animal veterinarian, have shotguns, a rifle, a handgun and are in the process of acquiring a semi-automatic gun. She plans to take her 6-year-old daughter to the shooting range for the first time this year. Like many people from Colorado, Turner considers guns a normal part of enjoying the great outdoors.
"One of the biggest reasons for carrying a handgun is we spend a lot of time in the back country, so it's protection from wild animals," Turner said. "It's a whole lot easier to carry in a backpack than a different type of gun."
But Turner was unfazed when Colorado passed new gun control legislation. She said she doubted hunting groups would follow through on threats to boycott the state.
"I think they'll come here under the radar because if you are a hunter, you are a hunter," she said. "I don't have a huge problem with controlling large high-capacity or even high-caliber firearms because they were made for a reason, and we don't have that reason in our lives. I'm not walking around Afghanistan."
Giffords, the former congresswoman who was left partially blind and struggling to talk in a January 2011 shooting that killed six other people in Arizona, tried to reach people like Turner in a recent ad campaign promoting extended background checks.
"There are solutions we can agree on, even gun owners like us," Giffords said in the commercial.
Biden tried to strike a similar tone in a recent online video as part of a Facebook town hall. Reminiscing about learning firearm safety from his father, a hunter, the vice president said he has told his wife, Jill, to take one of their shotguns and "fire two blasts outside the house" if she ever felt threatened by an intruder. His point was that nobody needs a semi-automatic weapon to protect their home. "Buy a shotgun, buy a shotgun," Biden urged listeners.
But for some gun defenders, Biden only proved that the gap remains wide between his side of the debate and theirs.
Keane, the vice president of the gun association, which is based in the Connecticut town where the school shooting occurred, said many people prefer semi-automatic guns for protection because it gives them a better chance to hit their target.
Turner said she wants to add a semi-automatic to her collection for that very reason.
"Well, good luck, Joe," she said, referring to the vice president. "When someone walks in the house and you're freaked out, you're only going to give her two chances? Good luck."


text:
No Bomus Comic Strips
1 Results for No Bomus
View 1 - 1 results for no bomus comic strips. Discover the best "No Bomus" comics from Dilbert.com.
Top Dilbert Searches
marketing, project, cloud, catbert, leadership, budget, birthday, engineer, time sheet, sales, wally, strategy, dogbert, powerpoint, project management, topper, leader, boss, change, meeting, data, management, mordac


text:
We not only stock new Hyundai vehicles, but also maintain an extensive inventory of high-quality used cars. Each used car at Vandergriff Hyundai has been through a detailed inspection by our auto technicians to ensure the superiority of our pre-owned vehicles.
If you value extraordinary service, great prices, and high quality used cars, Vandergriff Hyundai is the place to shop for a used cars by Hyundai in Arlington. Browse our used car inventory using the Power Search tools below. You can filter by Year, Model, and Body Style. If you are not finding the specific used car, truck, SUV or Van you want, we can track it down for you with our CarFinder system.


text:
|Click here to make a booking - use minutes anytime.
|Connect instantly call: 0906 539 1430 (£1.50/per minute)
|Call a receptionist on: 0207 111 6162 (+442071116162)
|Click here to use the Email-a-Psychic Service.
Click here ...
First 3 messages are FREE for new users (UK,18+)
YOUR LIBRA YEAR AHEAD HOROSCOPEClick for Yesterday's Horoscope | Click for Tomorrow's Horoscope
LIBRA - September 24th - October 23rd
More Horoscopes- Lovescope
- Monthly Horoscope
- Week Ahead
- Holiday Horoscope
- Daily Horoscope
Horoscope Articles
- Your Sign and Debt
- Zodiac Love Signs
- Zodiac Teenagers
- Zodiac Angels
- Zodiac Health
- Zodiac Kitchens
Check your 2019 Year Ahead horoscope for Libra by CLICKING here, and get your free trial personal daily horoscopes for 2019!
Aries | Taurus | Gemini | Cancer | Leo | Virgo
Libra | Scorpio | Sagittarius | Capricorn | Aquarius | Pisces
[Your Sign and Debt] [Zodiac Love Signs] [Zodiac Teenagers] [Zodiac Angels] [Zodiac Health] [Zodiac Kitchens] [Past Lives] [Star Mums] [Starsign Magic] [Zodiac Bathrooms] [Sign Secrets] [Bedrooms by Sign] [Zodiac Friends] [Best Foods for your Sign] [Eating Habits for your Sign] [Stress of the Zodiac] [Dog Starsigns] [Zodiac Goddess] [Zodiac Partners] [Ups and Downs of the Zodiac] [Lovescope] [Monthly Horoscope] [Week Ahead] [Holiday Horoscope] [Daily Horoscope]


text: What It Is A scoliosis X-ray is a relatively safe and painless test that uses a small amount of radiation to create detailed images of the spine. During the examination, an X-ray machine sends a beam of radiation through the back, and an image is recorded on a computer or special film. The scoliosis X-ray includes the thoracic spine (upper back) and the lumbar spine (lower back). The X-ray image is black and white. Dense body parts that block the passage of the X-ray beam through the body, such as bones, appear white on the X-ray image. Softer body tissues, such as muscles, allow the X-ray beams to pass through them and appear darker. X-rays are performed by an X-ray technician in the radiology department of a hospital, a freestanding radiology center, or a health care provider's office. Two pictures are usually taken of the spine, one from the back (posteroanterior or PA view) and one from the side (lateral view). Sometimes other views are taken in which the person is bending to the side. Why It's Done Children with scoliosis have a spine that curves from side to side, like an S or a C. Although small curves generally don't cause problems, bigger curves can be visible and cause discomfort. A curved spine can cause the body to tilt to the left or right. One shoulder blade may be higher than the other, or the waist may be uneven, with a tendency to lean to one side. If a curve is severe, it can even affect breathing and heart function and lead to damage in the joints of the spine and pain during adulthood. Doctors routinely check kids for scoliosis during regular physical exams, and some schools also test for scoliosis. If scoliosis is suspected, the doctor may order X-rays to measure the curvature of the spine. The angle of the curve, measured in degrees on the X-ray, will help the doctor decide whether it needs to be treated and, if so, how. X-rays also help determine the type of scoliosis and how mature the child's skeleton is, which helps the doctor to predict if the scoliosis may progress. The scoliosis X-ray might be repeated at regular intervals (sometimes every 3-12 months) to check whether the curve is getting bigger or to monitor the effects of treatment. The doctor might refer your child to a specialist for further evaluation. If a neurological abnormality is suspected, the doctor may order a magnetic resonance imaging (MRI) study to look at the spinal cord. Preparation A scoliosis X-ray doesn't require any special preparation. Your child may be asked to remove some clothing and jewelry and change into a hospital gown because buttons, zippers, clasps, or jewelry might interfere with the image. If your daughter is pregnant, it's important to tell the X-ray technician or her doctor. X-rays are usually avoided during pregnancy because there's a small chance the radiation may harm the developing baby. But if the X-ray is necessary, precautions can be taken to protect the fetus. Procedure Although the procedure may take about 15 minutes, actual exposure to radiation is usually less than a few seconds. Your child will be asked to enter a special room that will most likely contain a table and a large X-ray machine hanging from the ceiling or wall. Parents are usually able to accompany their child to provide reassurance. If you stay in the room while the X-ray is being done, you'll be asked to wear a lead apron to protect certain parts of your body. Your child's reproductive organs will also be protected with a lead shield. A scoliosis X-ray is usually performed in a standing position, but may be done while the child is sitting or laying down. Sometimes, this will depend on the condition of your child. The technician will position your child, then step behind a wall or into an adjoining room to operate the machine. Two X-rays are usually taken (from the back and from the side), so the technician will return to reposition your child for each X-ray. Sometimes doctors will request additional views. Older kids will be asked to hold their breath and remain still for 2-3 seconds while each X-ray is taken; infants may require gentle restraint. Keeping still is important to prevent blurring of the X-ray image. What to Expect Your child won't feel anything as the X-rays are taken. The X-ray room may feel cool due to air conditioning used to maintain the equipment. The position required for the X-rays can feel uncomfortable, but they need to be held for only a few seconds. If your child is in pain and can't stay in the required position, the technician might be able to find another position that's more comfortable. Babies often cry in the X-ray room, especially if they're restrained, but this won't interfere with the procedure. After the X-rays are taken, you and your child will be asked to wait a few minutes while the images are processed. If they are blurred or unclear, the X-rays may need to be redone. Getting the Results The X-rays will be looked at by a radiologist (a doctor specially trained in reading and interpreting X-ray images). The radiologist will send a report to your doctor, who will discuss the results with you and explain what they mean. In an emergency, the results of an X-ray can be available quickly. Otherwise, results are usually ready in 1-2 days. In most cases, results can't be given directly to the patient or family at the time of the test. Risks In general, X-rays are very safe. Although any exposure to radiation poses some risk to the body, the amount used in a scoliosis X-ray is small and not considered dangerous. It's important to know that radiologists use the minimum amount of radiation required to get the best results. Developing babies are more sensitive to radiation and are at more risk for harm, so if your daughter is pregnant, inform her doctor and the X-ray technician. Helping Your Child You can help your child prepare for a scoliosis X-ray by explaining the test in simple terms before the procedure. It may help to explain that getting an X-ray is like posing for a picture. You can describe the room and the equipment that will be used, and reassure your child that you'll be right there for support. For older kids, be sure to explain the importance of keeping still while the X-ray is taken so it won't have to be repeated. If You Have Questions If you have questions about why the scoliosis X-ray is needed, speak with your doctor. You can also talk to the X-ray technician before the procedure. Back to Articles Related Articles Word! Scoliosis Scoliosis is an abnormal curve of the spine, also known as the backbone. Read More Getting an X-ray (Video) You'll get an X-ray if your doctor thinks you might have a broken bone. Find out how X-rays are done in this video for kids. Read More X-Ray (Video) This video shows what it's like to get an X-ray. Read More Kyphosis Your spine, or backbone, normally curves forward gently as it runs up your back. Sometimes, though, someone's back can be rounded too far forward, which is a condition known as kyphosis. Read More Scoliosis Scoliosis makes a person's spine curve from side to side. Large curves can cause health problems like pain or breathing trouble. Health care providers treat scoliosis with back braces or surgery when needed. Read More Scoliosis Scoliosis makes a person's spine curve from side to side. Large curves can cause health problems like pain or breathing trouble. Health care providers treat scoliosis with back braces or surgery when needed. Read More Kyphosis Everyone's spine is slightly rounded forward at a gentle angle. If this angle is too pronounced, more than 50 degrees or so, it's called kyphosis, also known as roundback or hunchback. Read More Note: All information is for educational purposes only. For specific medical advice, diagnoses, and treatment, consult your doctor. © 1995-2021 KidsHealth®. All rights reserved. Images provided by The Nemours Foundation, iStock, Getty Images, Veer, Shutterstock, and Clipart.com.


text:
After last night's episode in which the Oriole bird tackled Teddy Roosevelt, our 26th president wasn't going to leave anything to chance.
Today at Nationals Park, Teddy spotted the orioles mascot right out of the starting gate, ran after him and promptly slammed The Bird into the outfield wall, taking him down and out of the action. We've rarely seen Teddy so motivated.
In fact, the Bull Moose acted with such efficiency that he was able to spin around and rejoin the race, giving the other presidents a run for their money and almost catching George. Washington took his second presidents race of the series, pulling him into a tie for 2nd with Thomas Jefferson to finish the homestand.
The racing presidents are back in action June 2 when the Giants come to town.
Photo courtesy of James Littlefield.
Video by YouTube member DCSportFan