 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
Ġmost Ġextensively Ġby ĠProfessor ĠScott ĠDenmark Ġof Ġthe ĠUniversity Ġof ĠIllinois Ġ, ĠUr b ana Ġ@ - @ ĠChamp aign Ġin Ġthe Ġmid Ġ@ - @ Ġ1980 s Ġand Ġutilizes Ġsto ichi ometric Ġamounts Ġof Ġiron Ġtr ich lor ide Ġto Ġpromote Ġthe Ġreaction Ġ. ĠWith Ġbicycl ic Ġproducts Ġ, Ġthe Ġcis Ġis omer Ġwas Ġselected Ġfor Ġto Ġvarying Ġdegrees Ġ. Ġ Ġ ĠThe Ġsilicon Ġ@ - @ Ġdirected ĠNaz arov Ġcycl ization Ġreaction Ġwas Ġsubsequently Ġemployed Ġin Ġthe Ġsynthesis Ġof Ġthe Ġnatural Ġproduct ĠSil ph in ene Ġ, Ġshown Ġbelow Ġ. ĠThe Ġcycl ization Ġtakes Ġplace Ġbefore Ġelimination Ġof Ġthe Ġbenz yl Ġalcohol Ġmo iety Ġ, Ġso Ġthat Ġthe Ġresulting Ġstere ochemistry Ġof Ġthe Ġnewly Ġformed Ġring Ġarises Ġfrom Ġapproach Ġof Ġthe Ġs ily l Ġalk ene Ġanti Ġto Ġthe Ġether Ġ. Ġ Ġ Ġ= Ġ= Ġ= ĠPolar ization Ġ= Ġ= Ġ= Ġ Ġ ĠDrawing Ġon Ġthe Ġsubstit u ent Ġeffects Ġcompiled Ġover Ġvarious Ġtrials Ġof Ġthe Ġreaction Ġ, ĠProfessor ĠAlison ĠFrontier Ġof Ġthe ĠUniversity Ġof ĠRochester Ġdeveloped Ġa Ġparadigm Ġfor Ġ" Ġpolarized Ġ" ĠNaz arov Ġcycl izations Ġin Ġwhich Ġelectron Ġdonating Ġand Ġelectron Ġwithdrawing Ġgroups Ġare Ġused Ġto Ġimprove Ġthe Ġoverall Ġselect ivity Ġof Ġthe Ġreaction Ġ. ĠCreation Ġof Ġan Ġeffective Ġvinyl Ġnucle ophile Ġand Ġvinyl Ġelect roph ile Ġin Ġthe Ġsubstrate Ġallows Ġcataly tic Ġactivation Ġwith Ġcopper Ġtr if late Ġand Ġreg i ose lect ive Ġelimination Ġ. ĠIn Ġaddition Ġ, Ġthe Ġelectron Ġwithdrawing Ġgroup Ġincreases Ġthe Ġacid ity Ġof Ġthe ĠÎ± Ġ@ - @ Ġpro ton Ġ, Ġallowing Ġselective Ġformation Ġof Ġthe Ġtrans Ġ@ - @ ĠÎ± Ġ@ - @ Ġep imer Ġvia Ġequ ilib ration Ġ. Ġ Ġ ĠIt Ġis Ġoften Ġpossible Ġto Ġachieve Ġcataly tic Ġactivation Ġusing Ġa Ġdonating Ġor Ġwithdrawing Ġgroup Ġalone Ġ, Ġalthough Ġthe Ġefficiency Ġof Ġthe Ġreaction Ġ( Ġyield Ġ, Ġreaction Ġtime Ġ, Ġetc Ġ. Ġ) Ġis Ġtypically Ġlower Ġ. Ġ Ġ Ġ= Ġ= Ġ= ĠAlternative Ġc ation Ġgeneration Ġ= Ġ= Ġ= Ġ Ġ ĠBy Ġextension Ġ, Ġany Ġpent ad ien yl Ġc ation Ġregardless Ġof Ġits Ġorigin Ġis Ġcapable Ġof Ġundergoing Ġa ĠNaz arov Ġcycl ization Ġ. ĠThere Ġhave Ġbeen Ġa Ġlarge Ġnumber Ġof Ġexamples Ġpublished Ġwhere Ġthe Ġrequisite Ġc ation Ġis Ġarrived Ġat Ġby Ġa Ġvariety Ġof Ġrearr ang ements Ġ. ĠOne Ġsuch Ġexample Ġinvolves Ġthe Ġsilver Ġcataly zed Ġc ation ic Ġring Ġopening Ġof Ġally lic Ġdich lor o Ġcyl op rop anes Ġ. ĠThe Ġsilver Ġsalt Ġfacilitates Ġloss Ġof Ġchloride Ġvia Ġprecipitation Ġof Ġinsol uble Ġsilver Ġchloride Ġ. Ġ Ġ ĠIn Ġthe Ġtotal Ġsynthesis Ġof Ġro c ag lam ide Ġ, Ġep ox idation Ġof Ġa Ġvinyl Ġalk oxy all en yl Ġst ann ane Ġlikewise Ġgenerates Ġa Ġpent ad ien yl Ġc ation Ġvia Ġring Ġopening Ġof Ġthe Ġresultant Ġep oxide Ġ. Ġ Ġ Ġ= Ġ= Ġ= ĠInter rupted Ġcycl ization Ġ= Ġ= Ġ= Ġ Ġ ĠOnce Ġthe Ġcycl ization Ġhas Ġoccurred Ġ, Ġan Ġoxy ally l Ġc ation Ġis Ġformed Ġ. ĠAs Ġdiscussed Ġextensively Ġabove Ġ, Ġthe Ġtypical Ġcourse Ġfor Ġthis Ġintermediate Ġis Ġelimination Ġfollowed Ġby Ġen olate Ġt aut omer ization Ġ. ĠHowever Ġ, Ġthese Ġtwo Ġsteps Ġcan Ġbe Ġinterrupted Ġby Ġvarious Ġnucle oph iles Ġand Ġelect roph iles Ġ, Ġrespectively Ġ. ĠOxy ally l Ġc ation Ġtrapping Ġhas Ġbeen Ġdeveloped Ġextensively Ġby ĠFred rick ĠG . ĠWest Ġof Ġthe ĠUniversity Ġof ĠAlberta Ġand Ġhis Ġreview Ġcovers Ġthe Ġfield Ġ. ĠThe Ġoxy ally l Ġc ation Ġcan Ġbe Ġtrapped Ġwith Ġheter oat om Ġand Ġcarbon Ġnucle oph iles Ġand Ġcan Ġalso Ġundergo Ġc ation ic Ġcycl oad d itions Ġwith Ġvarious Ġtet hered Ġpartners Ġ. ĠSh own Ġbelow Ġis Ġa Ġcascade Ġreaction Ġin Ġwhich Ġsuccessive Ġc ation Ġtrapping Ġgenerates Ġa Ġpent acy cl ic Ġcore Ġin Ġone Ġstep Ġwith Ġcomplete Ġdi ast ere ose lect ivity Ġ. Ġ Ġ ĠEn olate Ġtrapping Ġwith Ġvarious Ġelect roph iles Ġis Ġdecidedly Ġless Ġcommon Ġ. ĠIn Ġone Ġstudy Ġ, Ġthe ĠNaz arov Ġcycl ization Ġis Ġpaired Ġwith Ġa ĠMichael Ġreaction Ġusing Ġan Ġir idium Ġcatalyst Ġto Ġinitiate Ġnucle oph ilic Ġconj ug ate Ġaddition Ġof Ġthe Ġen olate Ġto ĠÎ² Ġ@ - @ Ġnit rost y rene Ġ. ĠIn Ġthis Ġtandem Ġreaction Ġthe Ġir idium Ġcatalyst Ġis Ġrequired Ġfor Ġboth Ġconversions Ġ: Ġit Ġacts Ġas Ġthe ĠLewis Ġacid Ġin Ġthe ĠNaz arov Ġcycl ization Ġand Ġin Ġthe Ġnext Ġstep Ġthe Ġnit ro Ġgroup Ġof Ġnit rost y rene Ġfirst Ġcoordinates Ġto Ġir idium Ġin Ġa Ġlig and Ġexchange Ġwith Ġthe Ġcarb ony l Ġes ter Ġoxygen Ġatom Ġbefore Ġthe Ġactual ĠMichael Ġaddition Ġtakes Ġplace Ġto Ġthe Ġopposite Ġface Ġof Ġthe ĠR Ġ@ - @ Ġgroup Ġ. Ġ Ġ Ġ= Ġ= Ġ= ĠEn anti ose lect ive Ġvariants Ġ= Ġ= Ġ= Ġ Ġ ĠThe Ġdevelopment Ġof Ġan Ġen anti ose lect ive ĠNaz arov Ġcycl ization Ġis Ġa Ġdesirable Ġaddition Ġto Ġthe Ġrepertoire Ġof ĠNaz arov Ġcycl ization Ġreactions Ġ. ĠTo Ġthat Ġend Ġ, Ġseveral Ġvariations Ġhave Ġbeen Ġdeveloped Ġutilizing Ġch iral Ġaux ili aries Ġand Ġch iral Ġcataly sts Ġ. ĠDi ast ere ose lect ive Ġcycl izations Ġare Ġalso Ġknown Ġ, Ġin Ġwhich Ġextant Ġstere ocent ers Ġdirect Ġthe Ġcycl ization Ġ. ĠAlmost Ġall Ġof Ġthe Ġattempts Ġare Ġbased Ġon Ġthe Ġidea Ġof Ġtor qu ose lect ivity Ġ; Ġselecting Ġone Ġdirection Ġfor Ġthe Ġvinyl Ġgroups Ġto Ġ" Ġrotate Ġ" Ġin Ġturn Ġsets Ġthe Ġstere ochemistry Ġas Ġshown Ġbelow Ġ. Ġ Ġ ĠSilicon Ġ@ - @ Ġdirected ĠNaz arov Ġcycl izations Ġcan Ġexhibit Ġinduced Ġdi ast ere ose lect ivity Ġin Ġthis Ġway Ġ. ĠIn Ġthe Ġexample Ġbelow Ġ, Ġthe Ġs ily l Ġ@ - @ Ġgroup Ġacts Ġto Ġdirect Ġthe Ġcycl ization Ġby Ġpreventing Ġthe Ġdistant Ġalk ene Ġfrom Ġrotating Ġ" Ġtowards Ġ" Ġit Ġvia Ġunfavorable Ġster ic Ġinteraction Ġ. ĠIn Ġthis Ġway Ġthe Ġsilicon Ġacts Ġas Ġa Ġtr ac eless Ġauxiliary Ġ. Ġ( ĠThe Ġstarting Ġmaterial Ġis Ġnot Ġen ant iop ure Ġbut Ġthe Ġretention Ġof Ġen anti omer ic Ġexcess Ġsuggests Ġthat Ġthe Ġauxiliary Ġdirects Ġthe Ġcycl ization Ġ. Ġ) Ġ Ġ ĠT ius Ġ' s Ġall en yl Ġsubstr ates Ġcan Ġexhibit Ġax ial Ġto Ġtet ra hedral Ġch ir ality Ġtransfer Ġif Ġen ant iop ure Ġall enes Ġare Ġused Ġ. ĠThe Ġexample Ġbelow Ġgenerates