page:  = Nazarov cyclization reaction = 
   
   The Nazarov cyclization reaction ( often referred to as simply the Nazarov cyclization ) is a chemical reaction used in organic chemistry for the synthesis of cyclopentenones . The reaction is typically divided into classical and modern variants , depending on the reagents and substrates employed . It was originally discovered by Ivan Nikolaevich Nazarov ( 1906 – 1957 ) in 1941 while studying the rearrangements of allyl vinyl ketones . 
   As originally described , the Nazarov cyclization involves the activation of a divinyl ketone using a stoichiometric Lewis acid or protic acid promoter . The key step of the reaction mechanism involves a cationic 4π @-@ electrocyclic ring closure which forms the cyclopentenone product ( See Mechanism below ) . As the reaction has been developed , variants involving substrates other than divinyl ketones and promoters other than Lewis acids have been subsumed under the name Nazarov cyclization provided that they follow a similar mechanistic pathway . 
   The success of the Nazarov cyclization as a tool in organic synthesis stems from the utility and ubiquity of cyclopentenones as both motifs in natural products ( including jasmone , the aflatoxins , and a subclass of prostaglandins ) and as useful synthetic intermediates for total synthesis . The reaction has been used in several total syntheses and several reviews have been published . 
   
   = = Mechanism = = 
   
   The mechanism of the classical Nazarov cyclization reaction was first demonstrated experimentally by Shoppe to be an intramolecular electrocyclization and is outlined below . Activation of the ketone by the acid catalyst generates a pentadienyl cation which undergoes a thermally allowed 4π conrotatory electrocyclization as dictated by the Woodward @-@ Hoffman rules . This generates an oxyallyl cation which undergoes an elimination reaction to lose a β @-@ hydrogen . Subsequent tautomerization of the enolate produces the cyclopentenone product . 
   As noted above , variants that deviate from this template are known ; what designates a Nazarov cyclization in particular is the generation of the pentadienyl cation followed by electrocyclic ring closure to an oxyallyl cation . In order to achieve this transformation , the molecule must be in the s @-@ trans / s @-@ trans conformation , placing the vinyl groups in an appropriate orientation . The propensity of the system to enter this conformation dramatically influences reaction rate , with α @-@ substituted substrates having an increased population of the requisite conformer due to allylic strain . Coordination of an electron donating α @-@ substituent by the catalyst can likewise increase the reaction rate by enforcing this conformation . 
   Similarly , β @-@ substitution directed inward restricts the s @-@ trans conformation so severely that E @-@ Z isomerization has been shown to occur in advance of cyclization on a wide range of substrates , yielding the trans cyclopentenone regardless of initial configuration . In this way , the Nazarov cyclization is a rare example of a stereoselective pericyclic reaction , whereas most electrocyclizations are stereospecific . The example below uses triethylsilyl hydride to trap the oxyallyl cation so that no elimination occurs . ( See Interrupted cyclizations below ) 
   Along this same vein , allenyl vinyl ketones of the type studied extensively by Marcus Tius of the University of Hawaii show dramatic rate acceleration due to the removal of β @-@ hydrogens , obviating a large amount of steric strain in the s @-@ cis conformer . 
   
   = = Classical Nazarov cyclizations = = 
   
   Though cyclizations following the general template above had been observed prior to Nazarov 's involvement , it was his study of the rearrangements of allyl vinyl ketones that marked the first major examination of this process . Nazarov correctly reasoned that the allylic olefin isomerized in situ to form a divinyl ketone before ring closure to the cyclopentenone product . The reaction shown below involves an alkyne oxymercuration reaction to generate the requisite ketone . 
   Research involving the reaction was relatively quiet in subsequent years , until in the mid @-@ 1980s when several syntheses employing the Nazarov cyclization were published . Shown below are key steps in the syntheses of Trichodiene and Nor @-@ Sterepolide , the latter of which is thought to proceed via an unusual alkyne @-@ allene isomerization that generates the divinyl ketone . 
   
   = = = Shortcomings = = = 
   
   The classical version of the Nazarov cyclization suffers from several drawbacks which modern variants attempt to circumvent . The first two are not evident from the mechanism alone , but are indicative of the barriers to cyclization ; the last three stem from selectivity issues relating to elimination and protonation of the intermediate . 
   Strong Lewis or protic acids are typically required for the reaction ( e.g. TiCl4 , BF3 , MeSO3H ) . These promoters are not compatible with sensitive functional groups , limiting the substrate scope . 
   Despite the mechanistic possibility for catalysis , multiple equivalents of the promoter are often required in order to effect the reaction . This limits the atom economy of the reaction . 
   The elimination step is not regioselective ; if multiple β @-@ hydrogens are available for elimination , various products are often observed as mixtures . This is highly undesirable from an efficiency standpoint as arduous separation is typically required . 
   Elimination destroys a potential stereocenter , decreasing the potential usefulness of the reaction . 
   Protonation of the enolate is sometimes not stereoselective , meaning that products can be formed as mixtures of epimers . 
   
   = = Modern variants = = 
   
   The shortcomings noted above limit the usefulness of the Nazarov cyclization reaction in its canonical form . However , modifications to the reaction focused on remedying its issues continue to be an active area of academic research . In particular , the research has focused on a few key areas : rendering the reaction catalytic in the promoter , effecting the reaction with more mild promoters to improve functional group tolerance , directing the regioselectivity of the elimination step , and improving the overall stereoselectivity . These have been successful to varying degrees . 
   Additionally , modifications focused on altering the progress of the reaction , either by generating the pentadienyl cation in an unorthodox fashion or by having the oxyallyl cation " intercepted " in various ways . Furthermore , enantioselective variants of various kinds have been developed . The sheer volume of literature on the subject prevents a comprehensive examination of this field ; key examples are given below . 
   
   = = = Silicon @-@ directed cyclization = = = 
   
   The earliest efforts to improve the selectivity of the Nazarov cyclization took advantage of the β @-@ silicon effect in order to direct the regioselectivity of the elimination step . This chemistry was developed most extensively by Professor Scott Denmark of the University of Illinois , Urbana @-@ Champaign in the mid @-@ 1980s and utilizes stoichiometric amounts of iron trichloride to promote the reaction . With bicyclic products , the cis isomer was selected for to varying degrees . 
   The silicon @-@ directed Nazarov cyclization reaction was subsequently employed in the synthesis of the natural product Silphinene , shown below . The cyclization takes place before elimination of the benzyl alcohol moiety , so that the resulting stereochemistry of the newly formed ring arises from approach of the silyl alkene anti to the ether . 
   
   = = = Polarization = = = 
   
   Drawing on the substituent effects compiled over various trials of the reaction , Professor Alison Frontier of the University of Rochester developed a paradigm for " polarized " Nazarov cyclizations in which electron donating and electron withdrawing groups are used to improve the overall selectivity of the reaction . Creation of an effective vinyl nucleophile and vinyl electrophile in the substrate allows catalytic activation with copper triflate and regioselective elimination . In addition , the electron withdrawing group increases the acidity of the α @-@ proton , allowing selective formation of the trans @-@ α @-@ epimer via equilibration . 
   It is often possible to achieve catalytic activation using a donating or withdrawing group alone , although the efficiency of the reaction ( yield , reaction time , etc . ) is typically lower . 
   
   = = = Alternative cation generation = = = 
   
   By extension , any pentadienyl cation regardless of its origin is capable of undergoing a Nazarov cyclization . There have been a large number of examples published where the requisite cation is arrived at by a variety of rearrangements . One such example involves the silver catalyzed cationic ring opening of allylic dichloro cylopropanes . The silver salt facilitates loss of chloride via precipitation of insoluble silver chloride . 
   In the total synthesis of rocaglamide , epoxidation of a vinyl alkoxyallenyl stannane likewise generates a pentadienyl cation via ring opening of the resultant epoxide . 
   
   = = = Interrupted cyclization = = = 
   
   Once the cyclization has occurred , an oxyallyl cation is formed . As discussed extensively above , the typical course for this intermediate is elimination followed by enolate tautomerization . However , these two steps can be interrupted by various nucleophiles and electrophiles , respectively . Oxyallyl cation trapping has been developed extensively by Fredrick G. West of the University of Alberta and his review covers the field . The oxyallyl cation can be trapped with heteroatom and carbon nucleophiles and can also undergo cationic cycloadditions with various tethered partners . Shown below is a cascade reaction in which successive cation trapping generates a pentacyclic core in one step with complete diastereoselectivity . 
   Enolate trapping with various electrophiles is decidedly less common . In one study , the Nazarov cyclization is paired with a Michael reaction using an iridium catalyst to initiate nucleophilic conjugate addition of the enolate to β @-@ nitrostyrene . In this tandem reaction the iridium catalyst is required for both conversions : it acts as the Lewis acid in the Nazarov cyclization and in the next step the nitro group of nitrostyrene first coordinates to iridium in a ligand exchange with the carbonyl ester oxygen atom before the actual Michael addition takes place to the opposite face of the R @-@ group . 
   
   = = = Enantioselective variants = = = 
   
   The development of an enantioselective Nazarov cyclization is a desirable addition to the repertoire of Nazarov cyclization reactions . To that end , several variations have been developed utilizing chiral auxiliaries and chiral catalysts . Diastereoselective cyclizations are also known , in which extant stereocenters direct the cyclization . Almost all of the attempts are based on the idea of torquoselectivity ; selecting one direction for the vinyl groups to " rotate " in turn sets the stereochemistry as shown below . 
   Silicon @-@ directed Nazarov cyclizations can exhibit induced diastereoselectivity in this way . In the example below , the silyl @-@ group acts to direct the cyclization by preventing the distant alkene from rotating " towards " it via unfavorable steric interaction . In this way the silicon acts as a traceless auxiliary . ( The starting material is not enantiopure but the retention of enantiomeric excess suggests that the auxiliary directs the cyclization . ) 
   Tius 's allenyl substrates can exhibit axial to tetrahedral chirality transfer if enantiopure allenes are used . The example below generates a chiral diosphenpol in 64 % yield and 95 % enantiomeric excess . 
   Tius has additionally developed a camphor @-@ based auxiliary for achiral allenes that was employed in the first asymmetric synthesis of roseophilin . The key step employs an unusual mixture of hexafluoro @-@ 2 @-@ propanol and trifluoroethanol as solvent . 
   The first chiral Lewis acid promoted asymmetric Nazarov cyclization was reported by Varinder Aggarwal and utilized copper ( II ) bisoxazoline ligand complexes with up to 98 % ee . The enantiomeric excess was unaffected by use of 50 mol % of the copper complex but the yield was significantly decreased . 
   
   = = Related Reactions = = 
   
   Extensions of the Nazarov cyclization are generally also subsumed under the same name . For example , an α @-@ β , γ @-@ δ unsaturated ketone can undergo a similar cationic conrotatory cyclization that is typically referred to as an iso @-@ Nazarov cyclization reaction . Other such extensions have been given similar names , including homo @-@ Nazarov cyclizations and vinylogous Nazarov cyclizations . 
   
   = = = Retro @-@ Nazarov reaction = = = 
   
   Because they overstabilize the pentadienyl cation , β @-@ electron donating substiuents often severely impede Nazarov cyclization . Building from this , several electrocyclic ring openings of β @-@ alkoxy cyclopentanes have been reported . These are typically referred to as retro @-@ Nazarov cyclization reactions . 
   
   = = = Imino @-@ Nazarov reaction = = = 
   
   Nitrogen analogues of the Nazarov cyclization reaction ( known as imino @-@ Nazarov cyclization reactions ) have few instances ; there is one example of a generalized imino @-@ Nazarov cyclization reported ( shown below ) , and several iso @-@ imino @-@ Nazarov reactions in the literature . Even these tend to suffer from poor stereoselectivity , poor yields , or narrow scope . The difficulty stems from the relative over @-@ stabilization of the pentadienyl cation by electron donation , impeding cyclization . 
   
   