EnantioselectiveOrganoSOMOCascadeCycloadditionsARapidApproachtoMolecu - PDF document

1 EnantioselectiveOrgano-SOMOCascadeCycloa
EnantioselectiveOrgano-SOMOCascadeCycloadditions:ARapidApproachtoMolecularComplexityfromSimpleAldehydesandOleÞnsNathanT.Jui,EstherC.Y.Lee,andDavidW.C.MacMillan*MerckCenterforCatalysisatPrincetonUniersity,Princeton,NewJersey08544ReceivedMay18,2010;E-mail:dmacmill@princeton.edu Ahighlyselective,radical-mediated(42)couplingreactionofaldehydesandconjugatedoleÞnshasbeenachievedthroughasymmetricSOMO-catalysis.Aradical-polarcrossovermechanismisproposedwhereinoleÞnadditiontoatransientenamineradicalcationandoxidationoftheresultingradicalfurnishesacationwhichisvulnerabletonucleophilicaddition.Arangeofaromaticaldehydesareshowntocouplewithstyrenesanddienestoprovidecyclicproductswithhighchemicalef-Þciency,regioselectivity,andstereoselectivity. TheidentiÞcationofnewtransformationsthatallowtherapidandselectiveproductionofmolecularcomplexityfromsimplestartingmaterialsremainsapreeminentgoalforthechemicalsciences.TheDielsAlderreactionremainsperhapsthearchetypalexample(eq1),apowerfultechnologythatbuildsstereochemicallydensecyclohexenylringsfromsimpledienesanddienophilesinaroutineandpredictablefashion.Recently,wequestionedwhetherthemechanisticelementsofSOMO-catalysis(singlyoccupiedmolecularorbital)mightbetranslatedintoanovelring-formingprotocolthatwouldexhibitmanyofthevaluablecharacteristicsfoundintheDielsAlderreaction.Herein,wedescribetheÞrstSOMO(42)cascadecycloaddition,atransformationthat(1)allowsdirectandselectiveaccesstocomplexcyclohexylmotifs,(2)employssimplealdehydeandoleÞnsubstrates,(3)iscatalystmediated,(4)isoperationallytrivial,and(5)ishighlypredictablewithrespecttoregio-,diastereo-,andenantiocontrol.Weexpectthatthisnew,stereoselectiveapproachtocarbocycleconstructionwillbeofsigniÞcantutilitytopractitionersofbothnaturalproductandmedicinalagentsynthesis.DesignPlan.Withinthepastthreeyears,ourlaboratoryhasintroducedanewmodeofactivationtermedSOMO-catalysisthathasenabledtheÞrstdirectenantioselectiveallylicalkylation,andcarbo-oxidationofalde-hydes,allofwhichwerepreviouslyunknowninasymmetricformat.Inthelatterreaction,wedemonstratedthatstyrenyloleÞnsreadilycouplewithtransientlygenerated3-electronsystemstogeneratehighlyreactivebenzyliccationsunderoxidativeconditionsthatrapidlytrapNOtoafford-oxy-homobenzylicaldehydes.Recently,wehypothesizedthatthisradical-polarcrossoverandtheputativebenzyliccationmightprovidethedesignelementsforanovelSOMO-cycloadditionreaction.Asdetailedineq2,wehopedthatexposureofaaldehydetoSOMO-activationusingimidazolidinonecatalystanoxidantwouldgeneratetheradicalcation,whichshouldrapidlyengageanoleÞnicsubstrateinanenantioselectivealkylationsteptoproducethealkylradical.Oxidativeradical-polarcrossoverwouldthenfurnishacarbocationthatshouldtriggerastereoselective-nucleophileringclosuretodeliveracomplexcyclohexylmotif.InaccordwithpreviousSOMO-studies

2 ,wepresumedthathighlevelsofenantioinduct
,wepresumedthathighlevelsofenantioinductionshouldbepossibleusingcatalystthebasisof3-electrongeometrycontrolandselectivemethylgroupshieldingoftheradicalcation-face.Furthermore,wepresumedthatthecyclizationstepshouldbestereoselectivebasedonthekineticpreferenceforchairliketransitionstateswhereinpseudoringsubstituentsarelocatedinequatorialorientations.Afterexaminingvarioussingle-electronoxidants,foundthatthetrisphenanthrolinecomplexesofiron(III)bearingnon-nucleophiliccounterions(e.g.,PF,AsF,andSbF,Table1)doindeedpromotethedesiredcyclizationreactionbetween3-aryl-propionaldehydesandstyrene(3equiv)withexcellentlevelsofenantiocontrol.Furthermore,thediastereoselectivityofthecycliza-tioneventappearstovaryasafunctionoftheoxidantcounterion(withthelargestcounterion,SbF,beingthemostselective).Apossibleexplanationforthistrendisthatthestereodeterminingchairliketransitionstate()ismoreordered(orlater)whentheintermediatecarbocationispairedwithamorepolarizableorstabilizingcounterionsuchasSbFHavingdevelopedoptimalconditionsforthisnewcascadeoleÞn-Craftssequence,wenextexaminedthescopeofthealdehydiccomponent.AsshowninTable2,awiderangeofelectron-richbenzenesandheteroarenes(indoles,anisoles,catechols,benzofurans)canfunctionassuitablenucleophilicterminatorstofurnishthedesiredcyclohexylringswithexcellentstereoselectivity(entries16,620:1dr,92%ee).Interestingly,substratesthat PublishedonWeb07/01/20102010AmericanChemicalSocietyJ.AM.CHEM.SOC.2010,10015Ð10017 cangenerateeithersix-orseven-memberedcyclo-adductsleadexclusivelytothesmallerring(entries35),regardlessofthe-densityofthetetherednucleophile.AshighlightedinTable3,thisnewcouplingisalsotoleranttoabroadarrayofoleÞnicreactionpartners.Forexample,styrenesofvaryingelectronicpropertiesreadilyparticipateinthisformalformal+2]reactionwithoutlossinyieldorenantiocontrol(entries3,7990%yield,9194%ee).-substitutedstyrenesreactsmoothlytoconstructquaternarybenzyliccenterswithgoodtoexcellentdiastereo-control(Table3,entries613:1dr,88%ee).VinylheteroaromaticsalsocoupleefÞcientlyinthisprotocoltoincorporateelectron-deÞcientringsystems,achemotypethatshouldbeofvaluetopractitionersofmedicinalchemistry(Table3,entries5,6).Importantly,thistranformationisnotrestrictedtostyrenyloleÞnsaswehavefoundthatdienesreadilyparticipateinthiscascadecycloaddition,albeitwithlowerlevelsofenantiocontrol(entry9,70%ee).Finally,wesoughttodetermineifothercarbogenicphilesmightbeemployedinlieuofaromaticterminatorsinthecation-trappingcyclizationevent.Indeed,asshownineqs3and4,formyltetheredallylsilanesreadilyundergo(32)and(4cascadecycloadditionstoproducebothcyclopentylandcyclohexylringswithgoodenantiocontrolandusefuldiastereoselectivities68%yield,4:1dr,88%ee).Insummary,afundamentallynewapproachtothedirectconstructionofsix-andÞve-memberedcarbocyclesfromaldehydesandconjugated

3 oleÞnshasbeenachievedusingenantioselecti
oleÞnshasbeenachievedusingenantioselectiveSOMO-catalysis.Furtherstudiesdirectedtowardtheapplicationofthistechnologytotheconstructionofheterocyclicadductswillbeoutlinedinduecourse.FinancialsupportwasprovidedbyNIHGMS(R0101GM093213-01)andkindgiftsfromMerck,Amgen,andSupportingInformationAvailable:Experimentalprocedures,structuralproofs,andspectraldataforallnewcompoundsareprovided.ThismaterialisavailablefreeofchargeviatheInternetathttp://Table1.SOMO-Cascade(42)Cycloaddition:Counterion entryCounterion%conv%ee1PF827:1902AsF828:1903SbF11:190DeterminedbycrudeHNMRanalysisusinganinternalstandard.Isolatedyield.DeterminedbychiralHPLCanalysisofalcohol;absolutestereochemistryassignedbyX-raycrystalstructureorbyTable2.EnantioselectiveSOMO-Cycloaddition:AreneScope Resultslistedasproduct,yield,diastereomericratio(dr),enantiomericexcess(%ee).Diastereomericratio,%eedeterminedasinTable1.Yieldcontains7%-coupledisomer.conductedat Table3.EnantioselectiveCascadeCycloaddition:OleÞnScope Resultslistedasproduct,yield,diastereomericratio(dr),enantiomericexcess(%ee).Diastereomericratio,%eedeterminedasinTable1.ReactionconductedatReactionperformedwithasoxidant.Reactionconductedat10016J.AM.CHEM.SOC.VOL.132,NO.29,2010 (1)Diels,O.;Alder,K.JustusLiebigsAnn.Chem.,98.ForreviewsontheDielsAlderreaction,see:(a)Corey,E.J.Angew.Chem.,Int.Ed.,1650.(b)Nicolaou,K.C.;Snyder,S.A.;Montagnon,T.;Vassilikogiannakis,G.Angew.Chem.,Int.Ed.,1668.(2)Cascadecycloadditionreferstoareactionthatunitesmultiplereactionpartnerstoformacyclicproductviaacascademechanism,whichisinaccordwiththeIUPACGoldBookdeÞnitionofcycloaddition.(3)Beeson,T.D.;Mastracchio,A.;Hong,J.-B.;Ashton,K.;MacMillan,D.W.C.,582.(4)Jang,H.-Y.;Hong,J.-B.;MacMillan,D.W.C.J.Am.Chem.Soc.,7004.(5)Kim,H.;MacMillan,D.W.C.J.Am.Chem.Soc.,398.(6)(a)Nicolaou,K.C.;Reingruber,R.;Sarlah,D.;Bra¬se,S.J.Am.Chem.,2086.Correction:J.Am.Chem.Soc.,6640.(b)Conrad,J.C.;Kong,J.;Laforteza,B.N.;MacMillan,D.W.C.J.Am.Chem.Soc.,11640.(7)Graham,T.H.;Jones,C.M.;Jui,N.T.;MacMillan,D.W.C.J.Am.Chem.,16494.(8)Murphy,J.A.TheRadical-PolarCrossoverReaction.InRadicalsinOrganic;Renaud,P.,Sibi,M.P.,Eds.;Wiley-VCH:Weinheim,Germany,2001;Vol.1,p298.(9)(a)Zimmerman,H.E.;Traxler,M.D.J.Am.Chem.Soc.,1920.(b)Yang,J.Six-MemberedTransitionStatesinOrganicSynthesis;Wiley-Interscience:Hoboken,NJ,2008.andreferencestherein.(10)Theuseofcericammoniumnitrateasoxidant(asinpreviousstudies)was,forthiscascadecycloaddition,unsuccessfulasitresultedinselectiveformationofbenzylicnitrates(seeref7).(11)(a)Wong,C.L.;Kochi,J.K.J.Am.Chem.Soc.,5593.(b)Connelly,N.G.;Geiger,W.E.Chem.Re,877,andreferences(12)Olah,G.A.;Prakash,G.K.S.;Molna«r,A.;Sommer,J.;JohnWiley&Sons,Inc.:Hoboken,NJ,2009.Foranillustrativeexampleofcounterioneffectsoncarbocationstability,see:Reed,C.A.Chem.Commun.,1669.J.AM.CHEM.SOC.VOL.132,NO.29,2010