cyclic 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
cycl ic Ġring Ġclosure Ġto Ġan Ġoxy ally l Ġc ation Ġ. ĠIn Ġorder Ġto Ġachieve Ġthis Ġtransformation Ġ, Ġthe Ġmolecule Ġmust Ġbe Ġin Ġthe Ġs Ġ@ - @ Ġtrans Ġ/ Ġs Ġ@ - @ Ġtrans Ġcon formation Ġ, Ġplacing Ġthe Ġvinyl Ġgroups Ġin Ġan Ġappropriate Ġorientation Ġ. ĠThe Ġpropensity Ġof Ġthe Ġsystem Ġto Ġenter Ġthis Ġcon formation Ġdramatically Ġinfluences Ġreaction Ġrate Ġ, Ġwith ĠÎ± Ġ@ - @ Ġsubstituted Ġsubstr ates Ġhaving Ġan Ġincreased Ġpopulation Ġof Ġthe Ġrequisite Ġcon former Ġdue Ġto Ġally lic Ġstrain Ġ. ĠCoord ination Ġof Ġan Ġelectron Ġdonating ĠÎ± Ġ@ - @ Ġsubstit u ent Ġby Ġthe Ġcatalyst Ġcan Ġlikewise Ġincrease Ġthe Ġreaction Ġrate Ġby Ġenforcing Ġthis Ġcon formation Ġ. Ġ Ġ ĠSimilarly Ġ, ĠÎ² Ġ@ - @ Ġsubstitution Ġdirected Ġinward Ġrestricts Ġthe Ġs Ġ@ - @ Ġtrans Ġcon formation Ġso Ġseverely Ġthat ĠE Ġ@ - @ ĠZ Ġis omer ization Ġhas Ġbeen Ġshown Ġto Ġoccur Ġin Ġadvance Ġof Ġcycl ization Ġon Ġa Ġwide Ġrange Ġof Ġsubstr ates Ġ, Ġyielding Ġthe Ġtrans Ġcycl op ent en one Ġregardless Ġof Ġinitial Ġconfiguration Ġ. ĠIn Ġthis Ġway Ġ, Ġthe ĠNaz arov Ġcycl ization Ġis Ġa Ġrare Ġexample Ġof Ġa Ġstere ose lect ive Ġper icy cl ic Ġreaction Ġ, Ġwhereas Ġmost Ġelectro cycl izations Ġare Ġstere os pe cific Ġ. ĠThe Ġexample Ġbelow Ġuses Ġtri ethyl s ily l Ġhy dr ide Ġto Ġtrap Ġthe Ġoxy ally l Ġc ation Ġso Ġthat Ġno Ġelimination Ġoccurs Ġ. Ġ( ĠSee ĠInter rupted Ġcycl izations Ġbelow Ġ) Ġ Ġ ĠAlong Ġthis Ġsame Ġvein Ġ, Ġall en yl Ġvinyl Ġket ones Ġof Ġthe Ġtype Ġstudied Ġextensively Ġby ĠMarcus ĠT ius Ġof Ġthe ĠUniversity Ġof ĠHawaii Ġshow Ġdramatic Ġrate Ġacceleration Ġdue Ġto Ġthe Ġremoval Ġof ĠÎ² Ġ@ - @ Ġhyd rogens Ġ, Ġob vi ating Ġa Ġlarge Ġamount Ġof Ġster ic Ġstrain Ġin Ġthe Ġs Ġ@ - @ Ġcis Ġcon former Ġ. Ġ Ġ Ġ= Ġ= ĠClassical ĠNaz arov Ġcycl izations Ġ= Ġ= Ġ Ġ ĠThough Ġcycl izations Ġfollowing Ġthe Ġgeneral Ġtemplate Ġabove Ġhad Ġbeen Ġobserved Ġprior Ġto ĠNaz arov Ġ' s Ġinvolvement Ġ, Ġit Ġwas Ġhis Ġstudy Ġof Ġthe Ġrearr ang ements Ġof Ġall yl Ġvinyl Ġket ones Ġthat Ġmarked Ġthe Ġfirst Ġmajor Ġexamination Ġof Ġthis Ġprocess Ġ. ĠNaz arov Ġcorrectly Ġreasoned Ġthat Ġthe Ġally lic Ġo le fin Ġis omer ized Ġin Ġsitu Ġto Ġform Ġa Ġdiv inyl Ġket one Ġbefore Ġring Ġclosure Ġto Ġthe Ġcycl op ent en one Ġproduct Ġ. ĠThe Ġreaction Ġshown Ġbelow Ġinvolves Ġan Ġal ky ne Ġoxy mer c uration Ġreaction Ġto Ġgenerate Ġthe Ġrequisite Ġket one Ġ. Ġ Ġ ĠResearch Ġinvolving Ġthe Ġreaction Ġwas Ġrelatively Ġquiet Ġin Ġsubsequent Ġyears Ġ, Ġuntil Ġin Ġthe Ġmid Ġ@ - @ Ġ1980 s Ġwhen Ġseveral Ġsynthes es Ġemploying Ġthe ĠNaz arov Ġcycl ization Ġwere Ġpublished Ġ. ĠSh own Ġbelow Ġare Ġkey Ġsteps Ġin Ġthe Ġsynthes es Ġof ĠTr ich odi ene Ġand ĠNor Ġ@ - @ ĠSt ere pol ide Ġ, Ġthe Ġlatter Ġof Ġwhich Ġis Ġthought Ġto Ġproceed Ġvia Ġan Ġunusual Ġal ky ne Ġ@ - @ Ġall ene Ġis omer ization Ġthat Ġgenerates Ġthe Ġdiv inyl Ġket one Ġ. Ġ Ġ Ġ= Ġ= Ġ= ĠShort comings Ġ= Ġ= Ġ= Ġ Ġ ĠThe Ġclassical Ġversion Ġof Ġthe ĠNaz arov Ġcycl ization Ġsuffers Ġfrom Ġseveral Ġdrawbacks Ġwhich Ġmodern Ġvariants Ġattempt Ġto Ġcircumvent Ġ. ĠThe Ġfirst Ġtwo Ġare Ġnot Ġevident Ġfrom Ġthe Ġmechanism Ġalone Ġ, Ġbut Ġare Ġindicative Ġof Ġthe Ġbarriers Ġto Ġcycl ization Ġ; Ġthe Ġlast Ġthree Ġstem Ġfrom Ġselect ivity Ġissues Ġrelating Ġto Ġelimination Ġand Ġpro ton ation Ġof Ġthe Ġintermediate Ġ. Ġ Ġ ĠStrong ĠLewis Ġor Ġprot ic Ġacids Ġare Ġtypically Ġrequired Ġfor Ġthe Ġreaction Ġ( Ġe . g . ĠTi Cl 4 Ġ, ĠBF 3 Ġ, ĠMe SO 3 H Ġ) Ġ. ĠThese Ġpromoters Ġare Ġnot Ġcompatible Ġwith Ġsensitive Ġfunctional Ġgroups Ġ, Ġlimiting Ġthe Ġsubstrate Ġscope Ġ. Ġ Ġ ĠDespite Ġthe Ġmechan istic Ġpossibility Ġfor Ġcat alysis Ġ, Ġmultiple Ġequivalents Ġof Ġthe Ġpromoter Ġare Ġoften Ġrequired Ġin Ġorder Ġto Ġeffect Ġthe Ġreaction Ġ. ĠThis Ġlimits Ġthe Ġatom Ġeconomy Ġof Ġthe Ġreaction Ġ. Ġ Ġ ĠThe Ġelimination Ġstep Ġis Ġnot Ġreg i ose lect ive Ġ; Ġif Ġmultiple ĠÎ² Ġ@ - @ Ġhyd rogens Ġare Ġavailable Ġfor Ġelimination Ġ, Ġvarious Ġproducts Ġare Ġoften Ġobserved Ġas Ġm ixtures Ġ. ĠThis Ġis Ġhighly Ġundesirable Ġfrom Ġan Ġefficiency Ġstandpoint Ġas Ġardu ous Ġseparation Ġis Ġtypically Ġrequired Ġ. Ġ Ġ ĠElim ination Ġdestroys Ġa Ġpotential Ġstere oc enter Ġ, Ġdecreasing Ġthe Ġpotential Ġusefulness Ġof Ġthe Ġreaction Ġ. Ġ Ġ ĠPro ton ation Ġof Ġthe Ġen olate Ġis Ġsometimes Ġnot Ġstere ose lect ive Ġ, Ġmeaning Ġthat Ġproducts Ġcan Ġbe Ġformed Ġas Ġm ixtures Ġof Ġep im ers Ġ. Ġ Ġ Ġ= Ġ= ĠModern Ġvariants Ġ= Ġ= Ġ Ġ ĠThe Ġshortcomings Ġnoted Ġabove Ġlimit Ġthe Ġusefulness Ġof Ġthe ĠNaz arov Ġcycl ization Ġreaction Ġin Ġits Ġcanonical Ġform Ġ. ĠHowever Ġ, Ġmodifications Ġto Ġthe Ġreaction Ġfocused Ġon Ġremed ying Ġits Ġissues Ġcontinue Ġto Ġbe Ġan Ġactive Ġarea Ġof Ġacademic Ġresearch Ġ. ĠIn Ġparticular Ġ, Ġthe Ġresearch Ġhas Ġfocused Ġon Ġa Ġfew Ġkey Ġareas Ġ: Ġrendering Ġthe Ġreaction Ġcataly tic Ġin Ġthe Ġpromoter Ġ, Ġeffect ing Ġthe Ġreaction Ġwith Ġmore Ġmild Ġpromoters Ġto Ġimprove Ġfunctional Ġgroup Ġtolerance Ġ, Ġdirecting Ġthe Ġreg i ose lect ivity Ġof Ġthe Ġelimination Ġstep Ġ, Ġand Ġimproving Ġthe Ġoverall Ġstere ose lect ivity Ġ. ĠThese Ġhave Ġbeen Ġsuccessful Ġto Ġvarying Ġdegrees Ġ. Ġ Ġ ĠAdditionally Ġ, Ġmodifications Ġfocused Ġon Ġaltering Ġthe Ġprogress Ġof Ġthe Ġreaction Ġ, Ġeither Ġby Ġgenerating Ġthe Ġpent ad ien yl Ġc ation Ġin Ġan Ġunorthodox Ġfashion Ġor Ġby Ġhaving Ġthe Ġoxy ally l Ġc ation Ġ" Ġintercepted Ġ" Ġin Ġvarious Ġways Ġ. ĠFurthermore Ġ, Ġen anti ose lect ive Ġvariants Ġof Ġvarious Ġkinds Ġhave Ġbeen Ġdeveloped Ġ. ĠThe Ġsheer Ġvolume Ġof Ġliterature Ġon Ġthe Ġsubject Ġprevents Ġa Ġcomprehensive Ġexamination Ġof Ġthis Ġfield Ġ; Ġkey Ġexamples Ġare Ġgiven Ġbelow Ġ. Ġ Ġ Ġ= Ġ= Ġ= ĠSilicon Ġ@ - @ Ġdirected Ġcycl ization Ġ= Ġ= Ġ= Ġ Ġ ĠThe Ġearliest Ġefforts Ġto Ġimprove Ġthe Ġselect ivity Ġof Ġthe ĠNaz arov Ġcycl ization Ġtook Ġadvantage Ġof Ġthe ĠÎ² Ġ@ - @ Ġsilicon Ġeffect Ġin Ġorder Ġto Ġdirect Ġthe Ġreg i ose lect ivity Ġof Ġthe Ġelimination Ġstep Ġ. ĠThis Ġchemistry Ġwas Ġdeveloped