紫杉醇合成

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J.Am.Chem.Soc.1996,118,2843-28592843

TotalSynthesisofBaccatinIIIandTaxol

SamuelJ.Danishefsky,*,1aJohnJ.Masters,1bWendyB.Young,1cJ.T.Link,1a,dLawrenceB.Snyder,1eThomasV.Magee,1fDavidK.Jung,1g

RichardC.A.Isaacs,1hWilliamG.Bornmann,CherylA.Alaimo,1iCraigA.Coburn,1handMartinJ.DiGrandi1i

ContributionfromtheLaboratoryforBio-OrganicChemistry,Sloan-KetteringInstituteforCancerResearch,MemorialSloan-KetteringCancerCenter,1275YorkAVenue,NewYork,NewYork10021ReceiVedAugust8,1995X

Abstract:AnintramolecularHeckreaction(90f91)servesasthekeystepinthetotalsynthesisofthetitledcompounds.ThesyntheticrouteisbasedonutilizingtheWieland-Miescherketone(5)asamatrixtoprovidetheCandDringsofthetargetsandtoprovidefunctionalityimplementsforjoiningthissectortoanAringprecursor(6).Catalyticallyinducedenantiotopiccontrolandearlyemplacementoftheoxetaneareotherfeaturesoftheroute.

Background

In19,Wallandco-workersdiscoveredthatextractsfromthebarkofTaxusbreVifoliaexhibitedsignificantcytotoxicityagainstKBcells.Fromtheseextractswasisolatedaparticularlyactiveprinciplewhichwastermedtaxol.Itwasdeduced,againbyWallandco-workers,thattaxolcorrespondstostructure32(seeFigure1).Taxol(3)faredwellinearlypreclinicalcytotoxicitychallengesagainstavarietyofcelllines,andintime,emergedasacandidatecompoundforclinicalevaluation.Anotherstepintheascensionoftaxol(3)arosefromadisclosureofHorwitzandcolleagueswhereinthedrugwasdescribedtobeapromoterofmicrotubuleassembly.3Theidentificationofsuchamechanismofactionfortaxol(andputativeanalogs)atthecellularlevelwouldfacilitatebiochemi-calandpharmacologicalinvestigationtogoalongwithclinicallyorientedinvestigations.

Relentlessly,taxol(3)anditsanalogtaxotere(4)4advancedfromthestatusofesotericresearchcuriositiestocompoundsofseriousclinicalvalue.Atthepresenttime,taxol(3)hasbeenapprovedforuseagainstmetastaticovarianandbreastcancersandisundergoingevaluationagainstavarietyofotherindica-tions.Thestatusoftaxotereasanactivedrugisnotasyetasadvancedasisthatoftaxol.5

Earlyon,itappearedthatclinicalapplicationsoftaxolwouldbehinderedbyalackofavailabilityofthedrug.Thephy-AbstractpublishedinAdVanceACSAbstracts,February15,1996.(1)Currentaddresses:(a)DepartmentofChemistry,ColumbiaUniver-sity,HavemeyerHall,NewYork,NY10027.(b)EliLillyandCo.,Indianapolis,IN46285.(c)ArrisPharmaceuticals,385OysterPt.Blvd.,Suite3,SouthSanFrancisco,CA94080.(d)AportionofthisworkwassubmittedbyJ.T.LinkaspartofhisPh.D.dissertation,ColumbiaUniversity,August1995.Currentaddresses:(e)BristolMyersSquibb,S.ResearchPkwy,Wallingford,CT092-7660.(f)PfizerCentralResearch,EasternPt.Rd.,Groton,CT06340.(g)GlaxoPharmaceuticals,FiveMooreDrive,P.O.Box13358,ResearchTrianglePark,NC27709.(h)Merck&Co.,SumneyTownPike,WestPoint,PA19486.(i)ScheringPloughResearch,2015GallopHillRd.,Kenilworth,NJ07033.(j)WyethAyerst,401N.MiddletonRd.,PearlRiver,NY10965.

(2)Wani,M.C.;Taylor,H.L.;Wall,M.E.;Coggon,P.;McPhail,A.T.J.Am.Chem.Soc.1971,93,2325.

(3)Horwitz,S.B.;Fant,J.;Schiff,P.B.Nature1979,277,665.

(4)Mangatal,L.;Adeline,M.T.;Guenard,D.;Gueritte-Voegelein,F.;Potier,P.Tetrahedron19,45,4177.

(5)Forreviews,see:(a)Georg,G.I.;Chen,T.T.;Ojima,I.;Vyas,D.M.TaxaneAnticancerAgents;AmericanCancerSociety:SanDiego,1995.(b)Kingston,D.G.I.;Molinero,A.A.;Rimoldo,J.M.ProgressintheChemistryofOrganicNaturalProducts61;Springer-Verlag:NewYork,1993.

Figure1.StructuresofbaccatinIII(1),10-deacetylbaccatinIII(2),taxol(3),andtaxotere(4).

tochemicalroutetotaxolitselfis,evenatthiswriting,complicated.Thus,inmosttaxol-containingplants,thefullyfunctionaldrugtendstobelocalizedinnonrenewabledomains.Ontheotherhand,baccatinIII(1)and10-deacetylbaccatinIII(2),themselvesbereftofusefulbiologicalfunction,constituterathermoreaccessiblerawmaterials.Theyareisolableinquantityfromrenewableregionsofavarietyofplants.Intenseeffortstoachievethesemisynthesisoftaxol(3)from1or2havebeensuccessfulinamelioratingthedrugavailabilityproblem.Particularlycriticalinthisregardweremajorsemi-synthesiscontributionsfromHolton,Ojima,andGreene.6

Interestinthetotalsynthesisoftaxol(3)(viaatotalsynthesisofbaccatinIII(1))wastriggeredbyseveralfactors.Thenovelconfluenceoffunctionalityofthetetracyclicringsystemof1constitutesachallengewhichmustbeaccommodatedinanysuccessfuleffort.Itseemedlikelythatsolutionsofthistotalsynthesisproblemwouldbringwiththemcollateraladvancesinthetheoryandpracticeoforganicchemistry.Needlesstosay,thefavorableclinicalfindingspertinenttotaxol(sincegiventhetrademarknameofPaclitaxel)addedtothegeneralinterestinthetotalsynthesisgoal.Duringtheerawheretheavailabilityoftaxolwasfearedtobeaseriouslylimitingfactorinitsoncologicalapplications,totalsynthesiswasseenbyaheartyfewasapossiblesourceofthedrug.

ConsiderationofthechemicalcomplexityofbaccatinIII(1),whichinsuitablyprotectedform(atC7)wouldbethelikelysyntheticintermediateenroutetotaxol(3),shouldhave

(6)(a)Denis,J.N.;Greene,A.E.;Guenard,D.;Gueritte-Voegelein,F.;Mangatal,L.;Potier,P.J.Am.Chem.Soc.1988,110,5917.(b)Holton,R.A.Eur.Pat.Appl.EP400,971,1990;Chem.Abstr.1990,114,1568q.(c)Holton,R.A.WorkshoponTaxolandTaxus,1991.(d)Ojima,I.;Habus,I.;Zhao,M.;Georg,G.I.;Jayasinghe,L.R.J.Org.Chem.1991,56,1681.(e)Ojima,I.;Habus,I.;Zhao,M.;Zucco,M.;Park,Y.H.;Sun,C.M.;Brigaud,T.Tetrahedron1992,48,6985.(f)Ojima,I.;Sun,C.M.;Zucco,M.;Park,Y.M.;Duclos,O.;Kuduk,S.TetrahedronLett.1993,34,4149.

2844J.Am.Chem.Soc.,Vol.118,No.12,1996

engenderedconsiderableskepticismandevendisbeliefthattotalsynthesiswouldsupplantnaturalsourcesasaroutetothedrug.Moreplausible,thoughasyetunrealizedinpractice,istheprospectthatmasteryofthesynthesisofbaccatinIII(1)willbringwithitnewnucleiwhich,uponsuitableconjugationwithbiologicallycriticalsidechains,mightprovidemedicallypromisingvariantsoftaxol.

Indeedmuchinterestingchemistryhasbeendevelopedfollowingsyntheticexplorationspertinenttotaxol.7Manyfascinatingconstructionsandproposedconstructionshavebeenadumbratedanddisclosed.However,uponcriticalexamination,veryfewhavecarriedwiththemrealisticprospectsformaturingintocomprehensivetotalsynthesesspracticalorotherwise.ThebaccatinIII(1)totalsynthesisproblemhasservedasastarkbutusefulreminderofthedistinctionbetween“regionalcontributions”asopposedtoprogramswhichtakeaccountofthefullscopeofacomplexprobleminsynthesis.

Thefirsttotalmolecularsolutionstothetaxolproblem,againvia7-protectedbaccatinIII,wereprovidedinvirtuallyconcur-rentdisclosuresbytheresearchgroupsofNicolaou8andHolton.9Giventhedifficultyofthechallenge,andthemultipleop-portunitiesforfailure,thesetwosuccesseswereclearlyimpor-tanteventsinthefield.Inthispaper,wedocumentthetotalsynthesisofbaccatinIIIandthencetaxolwhichwereachievedinourlaboratory.10SyntheticPlanning

Ourplanningandthinkingaboutatotalsynthesisoftaxol(3)(whichinrealitymeantatotalsynthesisofbaccatinIII(1)ora7-protectedderivativethereof)wasguidedfromthebeginningbyacentralperceptionfromwhichweneverdeviated.ItseemedthatasuitableconfluenceoftheWieland-Miescherketone11ab(5)withtheknownandeasilyprepared(thoughnotcommerciallyavailable)trimethylcyclohexane-1,3-dione(6)11cmighteventuallyleadtobaccatinIII(Scheme1).Thisprospectushadseveralalluringfeatures.Thesumofthetwoeminentlyaccessiblecomponentscontainmorethananamplenumberofcarbons(11+9)20)toreachthecoreABCsector(19carbons)of1.Ofgreatersignificancethanthistypeofcarboncountwastherecognitionthatthefunctionalitiesfordevelopmentofthecomponentsandsuitablemeldingwere,in

(7)Forreviews,see:(a)Swindell,C.S.StudiesinNaturalProductsChemistry,Vol.12;ElsevierSciencePublishers:NewYork,1993;pp179-231.(b)Nicolaou,K.C.;Dai,W.M.;Guy,R.K.Angew.Chem.,Int.Ed.Engl.1994,33,15.

(8)(a)Nicolaou,K.C.;Zang,Z.;Liu,J.J.;Ueno,H.;Nantermet,P.G.;Guy,R.K.;Claiborne,C.F.;Renaud,J.;Couladouros,E.A.;Paulvannan,K.;Sorensen,E.J.Nature1994,367,630.(b)Nicolaou,K.C.;Nantermet,P.G.;Ueno,H.;Guy,R.K.;Coulandouros,E.A.;Sorensen,E.J.J.Am.ChemSoc.1995,117,624.(c)Nicolaou,K.C.;Liu,J.J.;Yang,H.;Ueno,H.;Sorensen,E.J.;Claiborne,C.F.;Guy,R.K.;Hwang,C.K.;Nakada,M.;Nantermet,P.G.J.Am.ChemSoc.1995,117,634.(d)Nicolaou,K.C.;Yang,Z.;Liu,J.J.;Nantermet,P.G.;Claiborne,C.F.;Renaud,J.;Guy,R.K.;Shibayama,K.J.Am.ChemSoc.1995,117,5.(e)Nicolaou,K.C.;Ueno,H.;Liu,J.J.;Nantermet,P.G.;Yang,Z.;Renaud,J.;Paulvannan,K.;Chadha,R.J.Am.Chem.Soc.1995,117,653.

(9)(a)Holton,R.A.;Somoza,C.;Kim,H.B.;Liang,F.;Biediger,R.J.;Boatman,D.;Shindo,M.;Smith,C.C.;Kim,S.;Nadizadeh,H.;Suzuki,Y.;Tao,C.;Vu,P.;Tang,S.;Zhang,P.;Murthi,K.K.;Gentile,L.S.;Liu,J.H.J.Am.Chem.Soc.1994,116,1597.(b)Holton,R.A.;Kim,H.B.;Somoza,C.;Liang,F.;Biediger,R.J.;Boatman,D.;Shindo,M.;Smith,C.C.;Kim,S.;Nadizadeh,H.;Suzuki,Y.;Tao,C.;Vu,P.;Tang,S.;Zhang,P.;Murthi,K.K.;Gentile,L.S.;Liu,J.H.J.Am.Chem.Soc.1994,116,1599.

(10)Forapreliminaryaccountofthiswork,see:Masters,J.J.;Link,J.T.;Snyder,L.B.;Young,W.B.andDanishefsky,S.J.Angew.Chem.1995,34,1723.

(11)(a)Wieland,P.;Miescher,K.HelV.Chim.Acta1950,33,2215.(b)Ramachandrin,S.;Newman,M.S.OrganicSyntheses;Wiley:NewYork,1973;Collect.Vol.V,p486.(c)Hargreaves,J.H.;Hickmott,P.W.;Hopkins,B.J.J.Chem.Soc.C1968,2599.

Danishefskyetal.

Scheme1

principle,inplace.Thus,in5,thefutureangular(C19)methylgroupandtheoxygenatedC7ofbaccatinIII(1)arereadilydiscernedasisthe6-memberedCring.AwealthofprecedentfromterpenoidchemistrycouldbedrawnupontoallowforfashioningthenecessarystereochemistryatC3andC7(baccatinIIInumbering)fromcarbons4aand1of5.Furthermore,ifoneimaginesaneminentlyplausibledeconjugationoftheconjugatedenonedoublebond,originallypresentincompound5,functionalityemergesatC4ofbaccatinIII(1)(correspondingtocarbon4oftheWieland-Miescherketone).SuchaketoneatC4mightbefurtherexploitabletointroducearequiredoxygenatC3(Wieland-Miescherketonenumbering)correspondingtoC5ofbaccatinIII(1).

LeftunspecifiedforthemomentisthetimingforintroductionofoxygenationatC9ofthebaccatin(correspondingtoC8oftheWieland-Miescherketone).Onecouldeasilyimagineusingthematrixofthebicyclicsystemofcompound5toachieveorderlyfunctionalizationatC8.However,therewasconcern,asthesynthesisbegantounfold,thatearlyinclusionofanoxygen-basedfunctionalgroupatthiscentercouldleadtointermediateswhoseadditionalcomplexitycouldprovetobeunmanageable.

WenowconsidertheAringsubstructure6.The1,3-diketonesystemcorresponds,overall,tofunctionalitysitesatC1andC11ofbaccatinIII(1)andcontainstherequiredC-methylpattern(seeScheme1).Twopossibilitieswereentertainedforbringingtogetherfragmentsderivedfrom5and6inausefulway.ForthispurposeweparticularlyconcentrateonC9andC10ofbaccatinIII(1).Clearly,C9istobederivedfrombuildingblock5.Nopossibilityforbonding6toafragmentderivedfromWieland-Miescherketone,inwhichC8of5weredissipated,wasevergivenseriouscredence.SuchanexcisionwouldplaceC8a(cf.5)atgreatriskfromastereochemicalstandpointandwouldopenupmajorhazardsinherentinreconstruction.Inshort,C9ofbaccatinIII(1)mustbederiVedfromC8ofcompound5.

TwoformulationsforderivingC10ofthebaccatingoalpresentedthemselves(Scheme2).Inoneplan,anincisionintothematrixderivedfrom5wouldbemadebetweenC7andC8aswellasbetweenC6andC5(seecleavagemodeA).Inthisview,aone-carbonfragment,destinedtobecomeC10ofbaccatinIII(1),wouldbeappendedto6(atitscarbonslatedtoemergeatC11)andabondestablishedbetweenC10andC9(baccatinnumbering).Alternatively,bothC10andC9wouldbederivedfrom5.Thefragmenttobepresentedforcouplingwith6couldhavearisenfromexcisionofC6oftheoriginalWieland-Miescherketoneconstruct,withemergenceofsuitablydif-ferentiatedfunctionalityfragmentspresentedatitserstwhileC7andC5(seecleavagemodeB).Wenotethatcompelling

TotalSynthesisofBaccatinIIIandTaxolScheme2

Scheme3

arguments(similartothoseadvancedaboveastoC8of5)dictatedthatC5couldnotbesacrificedtothedegradation.Anyschemetoexcisethiscarbonfromaconstructderivedvia5wouldagainunderminetheotherwisesecurablestereochemistryatC4a(slatedtobecomeC3ofbaccatinIII(1)).WewereunderstandablyapprehensiveaboutconfrontingtheseriousquestionswhichwouldberaisedbyattemptstoreattachC4aofadegradedversionof5toanAringderivedintermediate.WefavoredschemesanticipatingformationoftheC10-C11baccatinbondongroundsofsyntheticfreshness.Thus,aC9-C10closurehadalreadybeeninvestigatedinKende’sground-breakingassemblyoftheskeleton.12Furthermore,asdescribedbytheRochesterworkers,suchacouplingcarriedwithititsownrisksandseriouscomplications.Leftunspecifiedatthisplanningstage,isthematterofthesequencingoftheC1-C2andC10-C11attachments.OnecouldimagineestablishingtheC10-C11bondintheintermolecularstep,reservingformationoftheC1-C2bondforcyclization(Scheme3).Alternatively,thereverseordercouldbeconsidered,whereintheC1-C2bondwouldbeformedfirstthroughintermolecularmeans,delayingC10-C11bondconstructionforthecyclization(Scheme4).Inpractice,bothsequenceswereexplored,andweshallreturntothismatterasthesynthesisunfolds.Atthisstage,however,itiswelltoemphasizethattheconceptoftheWieland-MiescherketonematrixgainedparticularfavorfromthefactthattheenantiomericallypurecompoundcouldbeobtainedinquantitybyL-proline-inducedaldolizationoftheprochiraltrione7(Scheme5).13ThusallstereochemistryofbaccatinIII(1)wouldflowfromasinglestereogeniccenter(C8aoftheWieland-Miescherketone,correspondingtoC8ofthebaccatin),whichwasitselfinducedbycatalyticmeans.

(12)Kende,A.S.;Johnson,S.;Sanfillipo,P.;Hodges,J.C.;Jungheim,L.N.J.Am.Chem.Soc.1986,108,3513.

(13)Harada,N.;Sugioka,T.;Hisashi,U;Kuriki,T.Synthesis1990,53andreferencestherein.

J.Am.Chem.Soc.,Vol.118,No.12,19962845

Scheme4

Scheme5

Theexploratorystudieswereconductedonracemicmaterial.Actually,thesynthesisoftheappropriateC8aS-enantiomerisnomoredemandingthanisthatoftheracemate.However,theracemateiscommerciallyavailable,andwedrewonthisconvenienceduringthereconnaissancephasesof,whatwaslikelytobe,anarduousjourney.14Aftervalidationintheracemicseries,thechemistrywastranslatedtothesingleenantiomerregimearisingfromcompound5,C8a)S.

Weconcludethesectiononanalysisbyconsiderationofthetimingofoxetaneinstallation.Theoxetaneis,byallindications,ratherimportantforbiologicalactivity.15Maximizationoftheprospectsthatthetotalsynthesisexercisemightproducesignificantlytruncated,butstillactive,versionsoftaxol(3)constitutedastrongargumentforearlyemplacementoftheoxetane.Moreover,suchastrategywouldavoidtheneedforelaborateprotectingdevicestocontainthe“accesshandles”whichwouldbeneededforalatestagefashioningoftheoxetane.

Weweremindfulthatthepresenceoftheoxetaneringfromnearlytheoutsetmightrestrictthescopeoffeasibleoperationsfortheorchestrationofthesynthesis.However,wehopedthatsuccessfulmanagementoftheproblemsengenderedbytheresidentoxetanemight,inthelongrun,reducethenumberofsteps.Furthermore,wewouldlearnmuchaboutthe“chemicalpersonality”oftheoxetane.Thisknowledgecouldbehelpfulindevelopingananalogprogram.Thoughatseveralstagesoftheexpeditionweweredestinedtofaceseriousconsequencesfromthishigh-riskcourse,itwouldintimebeshowntobesound(Videinfra).ResultsandDiscussion

Compound5wasreducedwithsodiumborohydrideaccordingtoknownprotocols,16affording8andthencethedeconjugatedketal9(Scheme6).Thesecondaryalcoholof9,targetedtoemergeatC7ofthebaccatin,wasprotectedasitstert-butyldimethylsilylether.

Treatmentof10withdiboranewasfollowedbyoxidationwithhydrogenperoxide.Oxidationofthealcohol,thusob-(14)TheRversionof5isequallyaccessibleandcouldbeusedtosynthesizeent-baccatinIII.Wehave,infact,preparedlatestageentintermediatesbythismethod.

(15)TheChemistryandPharmacologyofTaxol;Farina,V.,Ed.;ElsevierPress:NewYork,1995.

(16)Heathcock,C.H.;Ratcliffe,R.J.Am.Chem.Soc.1971,93,1746.

2846J.Am.Chem.Soc.,Vol.118,No.12,1996Scheme6a

Reagents:(a)NaBH4,EtOH,0°C,97%;(b)Ac2O,DMAP,pyr,CH2Cl2,0°C,99%;(c)(HOCH2)2,PhH,naphthalenesulfonicacid,reflux,70%;(d)NaOMe,MeOH,THF,98%;(e)TBSOTf,2,6-lutidine,CH2Cl2,0°C,97%.

Scheme7a

Reagents:(a)(i)BH3‚THF,THF,0°Cfroomtemperature;(ii)H2O2,NaOH,H2O;(iii)PDC,CH2Cl2,0°Cfroomtemperature;(iv)NaOMe,MeOH,62%;(b)(i)KHMDS,THF,-78°C;(ii)PhNTf2,81%;(c)Pd(OAc)2,PPh3,CO,Hunig’sbase,MeOH,DMF,73%;(d)DIBAL,hexanes,-78°C,99%;(e)Me3S+I-,KHMDS,THF,0°C,99%;(f)Al(OiPr)3,PhMe,reflux,99%.

tained,withPDCfollowedbyequilibrationoftheresultantcrudeketonemixture16affordedhomogeneous,trans-fused11(Scheme7).HavingsecuredtheRconfigurationatC3(baccatinnumbering),wedirectedourattentiontothefashioningoftheoxetanelinkage.

Wesetasournextinterimgoalcompoundtheallylicalcohol15.Itwashopedthatatriolderivedfrom15mightbetransformedintothedesiredoxetane.Inpractice,twoprotocolswerepursuedforadditionofthemethylenegroupdestinedtobecomeC20oftheoxetane.Inone,theketone11wasconvertedtoitsvinyltriflate12.17Thelatter,uponpalladium-mediatedcarbonylation-methoxylationgaverisetoR,󰀃unsaturatedester13which,uponreduction,ledtothedesiredallylicalcohol15.However,asthesynthesisprogressedandlargequantitiesofintermediateshadtobegenerated,thisprotocolwaslessthanoptimal.Rather,wetookrecoursetoCorey’ssulfoniumylidemethodology.18Conversionofketone11tospiroepoxide14occurredinhighyieldundertheconditionsshown.Lewisacid-inducedepoxideopeningfollowingprecedentsgaverisetothedesiredallylicalcohol15.19

Manypossibilitieswereexploredtoconvertallylicalcohol15tothenextgoalsystem,oxetane22.17Treatmentoftheallylicalcohol15withosmiumtetroxidegaverisetotriol16(Scheme8).Inlightofthelineupofresident󰀃-facefunctional-ity,weweresurprisedthatthisreactionwasnotstereospecific.Approximately15%of17whereinosmylationhadoccurredfromthemorehindered󰀃facewasalsoobtained.Fortunately,evenonlargescale,theseparationofthetwodiolswasastraightforwardmatterandweproceededtoadvancetriol16towardthedesiredoxetane.Itwouldhavebeenpossible,in

(17)Magee,T.V.;Bornmann,W.G.;Isaacs,R.C.A.;Danishefsky,S.J.J.Org.Chem.1992,57,3274.Thisexploratoryeffortwasconductedintheracemicseries.

(18)Corey,E.J.;Chaykovsky,M.J.Am.Chem.Soc.1965,87,1353.(19)Waddell,T.G.;Ross,P.A.J.Org.Chem.1987,52,4802.

Danishefskyetal.

Scheme8a

Reagents:(a)OsO4,NMO,acetone,H2O,66%;(b)TMSCl,pyr,CH2Cl2,-78°Cfroomtemperature;(c)Tf2O,-78°Cfroomtemperature;(d)(HOCH2)2,40°C,69%;(e)NaH,THF,45°C,74%.

principle,tofollowtheleadofBerkowitz,20towardthisobjective.Indeed,suchatransformationwasaccomplishedinourlaboratoryonthecloselyrelatedhydrindenone-derivedsystem18enrouteto19.21

However,inthecaseathand,anewapproachwasfeasible.Theprimaryalcoholof16wasreadilydifferentiatedbysilylationwithTMSchloride(seecompound20).Thesecondaryalcoholwasthenactivatedbytriflation(seestructure21).Remarkably,treatmentof21withethyleneglycolatrefluxgaverisetothedesiredoxetane22.WepresumethatthistransformationentailsahypervalentsiliconetherspeciesonC20,triggeringdisplace-mentofthetriflate.Anotherproduct,23,arisingfromapinacol-likerearrangementwasalsodetectedinthisreaction.17

WenotethattheformationoftheoxetanebyinversionofC5bearingaleavinggrouphassubsequentlybeenemployed,thoughwithdifferentexperimentalprotocols,inboththeNicolaou8andHolton9syntheses.Duringthepreparationofourinitialdisclosureofthisstrategy,17thereappearedasimilaroutcomeinasemisyntheticsetting.22However,thePotierchemistrywasconductedonasubstratewhichlackedfunctionalityatC7.Thedemonstrationshownhereforbuildingtheoxetaneontoaringsystembearingfourdifferentiatedalcoholcentershadsignificantimplicationsfortotalsynthesisandfororganizingananalogprogram.

Considerablethoughtandexperimentationwasdevotedtoselectingtheproperblockinggroupforthetertiaryhydroxylcenterofcompound22.Muchwouldbeexpectedfromthisblockinggroup,nottheleastdemandingpropertybeingitssusceptibilitytoremovalatalatestageofthesynthesis.Itwasalsonecessarytodifferentiate,inasecureway,theC4sitefromtheotheralcoholcentersatC1,C7,andC10oftheemergingbaccatinIII.Onthebasisoftheseconsiderations,andaftersurveyingseveralotherpossibilities(Videinfra),weinstalledabenzylprotectinggrouponthetertiaryalcohol.Thistransfor-mationwasaccomplishedinhighyieldoncompound22giving

(20)Berkowitz,W.F.;Amarasekara,A.S.;Perumattam,J.J.J.Org.Chem.1987,52,3745.

(21)Isaacs,R.C.A.;DiGrandi,M.J.;Danishefsky,S.J.J.Org.Chem.1993,58,3938.

(22)Ettouate,L.;Ahond,A.;Poupat,C.;Potier,P.Tetrahedron1991,47,9823.

TotalSynthesisofBaccatinIIIandTaxolScheme9a

Reagents:(a)BnBr,NaH,TBAI,THF,0°Cfroomtemperature,98%;(b)TsOH,acetone,H2O,70°C,84%.

Scheme10

Scheme11

risetobenzylether24(Scheme9).Itwasfurtherpossibletocleavetheketallinkageofcompound24withoutdamagingtheoxetanemoietyandwithoutcleavingthesilyletherprotectinggroup(seecompound25).

Withketone25inhand,avarietyofefficientdegradationsequencesweredeveloped.23Someofthesetransformationswereconductedbeforethebenzylblockinggroupwassettledupon(seegeneralsystem26,Scheme10).AkeyfeaturewhichopeneduparangeofdegradativeoptionswasthehighlyselectiveenolizationoftheC6ketoneinthedirectionofC7(seeScheme1forWieland-Miescherketonenumbering).Thatbeingthecase,itwaspossiblebywell-precedentedchemistytoprepareenonetype27,aswellasaldehyde-ester29(derivedfromtheenonedihydroxylationproduct28).

Anothertypeofdegradationproductavailablefromenonetype27wastheR-oxygenatedaldehydoester31(Scheme11).ThiscompoundwasderivedbySchreibertypedirectedozo-nolysis24ofallylicalcoholderivatives(30).Thelatterarosefrom27byaWhartontypetransposition.25

Theuseofcompound6asanucleophiliccouplingpartnerwithfragmentsobtainedfromsystemtype26wasfacilitatedbytheselectivechemistrywhichthis󰀃-diketoneundergoes.Forinstance,monoketalizationof6gaveriseto32whichcouldbeconvertedtovinyliodide33(Scheme12).ThelattercouldbelithiatedtogiverisetoaC11-basednucleophile34,whichwascoupledtoaromaticaldehydesaspreviouslydocumented.26Weshallreturntolithiosystem34indiscussingattemptstoreduceScheme3topractice.

(23)DiGrandi,M.J.;Coburn,C.A.;Isaacs,R.C.A.;Danishefsky,S.J.J.Org.Chem.1993,58,7728.

(24)Schreiber,S.L.;Claus,R.E.;Reagan,J.TetrahedronLett.1982,23,3867.

(25)(a)Wharton,P.S.;Bohlen,D.H.J.Org.Chem.1961,26,3615.(b)Maas,D.D.;Blagg,M.;Wiemer,D.F.J.Org.Chem.1984,49,853.(26)DiGrandi,M.J.;Jung,D.K.;Krol,W.J.;Danishefsky,S.J.J.Org.Chem.1993,58,49.

J.Am.Chem.Soc.,Vol.118,No.12,19962847

Scheme12

Scheme13

PrototypeC1nucleophileswerealsodevelopedearlyinourinvestigations.SomewerefashionedinsystemsinwhichthefutureC10wasalreadypreinstalledontheAring(seediscussionaboveappropriatetoScheme1).Forinstance,wedemonstratedthefeasibilityofaShapiroreactionontrisylhydrazone36derivedfromketone35(Scheme13).Thelithioderivative37wascoupledtoavarietyofaromaticaldehydesandtothehighlyfunctionalizedaldehyde47(Videinfra)derivedfromanotherfragmentationstrategydiscussedbelow.Inthisway,wegainedconfidencethatcompound6couldbeconvertedtoeffectivenucleophilescorrespondingtoeitherC1orC11ofbaccatinIII(1).Itwasourhopetoexploitthesecapabilitiesforbondformationwithfragmentationproductsderivedfromasuitableversionof26.

Aftermanyoftheoptionswereexplored,theoneshowninScheme14wasadoptedowingtoitsamenabilitytolarge-scalework.Takingadvantageofselectiveenolizationoftheketogroupinsystemsofthetype26towardC7(Wieland-Miescherketonenumbering)specificketone25wasconvertedtosilylenolether38.ThelatterwashydroxylatedviaamodifiedRubottomtypeprotocol,27awith3,3-dimethyldioxirane,followedbytreatmentwithcamphorsulfonicacid(seecompound39).Ringfragmentationwasaccomplishedwithleadtetraacetate,40.Thecarboxylcarbonemergedasamethylester(seecompound40)sincethefragmentationwasperformedinmethanol.Thealdehydefunctionin40wasconvertedtothedimethylacetal(seecompound41).Lithiumaluminumhydridereductionoftheestergaverisetocarbinol42,whichwasconvertedinaGriecoprotocoltotheo-nitrophenylselenide43.27bOxidationwithhydrogenperoxidethenprovidedalkene44.Ozonolysisof44gavealdehyde45whichwasdestinedtoserveasakeyintermediateenroutetobaccatinIII.

Thepreviouslymentionedaldehyde47waspreparedfrom46whichwasinturnpreparedbyasequenceidenticaltothatdescribedfor44,startingwithcompound26a(the4-OTBS

(27)(a)Rubottom,G.M.;Vazquez,M.A.;Pelegrina,D.R.TetrahedronLett.1972,3375.(b)Grieco,P.A.;Gilman,S.;Nishizawa,M.J.Org.Chem.1976,41,1485.

2848J.Am.Chem.Soc.,Vol.118,No.12,1996Scheme14a

Reagents:(a)TMSOTf,Et3N,CH2Cl2,-78°C;(b)3,3-dimeth-yldioxirane,CH2Cl2,0°C;CSA,acetone,roomtemperature,%;(c)Pb(OAc)4,MeOH,PhH,0°C,97%;(d)MeOH,CPTS,70°C,97%;(e)LiAlH4,THF,0°C,100%;(f)o-NO2C6H4SeCN,PBu3,THF,roomtemperature,88%;(g)30%H2O2,THF,roomtemperature,90%;(h)O3,CH2Cl2,-78°C;PPh3,79%.

versionof26).Cleavageofthedimethylacetalof46followedbyreductionwithlithiumaluminumhydride,protectionoftheresultantcarbinolasitsOTBSether,andozonolysisofthevinylgroupaffordedaldehyde47.

BeforediscussingoursuccessfulroutetobaccatinIII(1)viainitialC1-C2bondformation(Scheme4),wesummarizeoureffortsinthedirectionoffirstestablishingaC9-C10bondandpostponingtheC1-C2mergerforthecyclizationstep(Scheme15).Actuallywehadpreferredthisplan.Reductivecyclizationofaketoaldehydeprecursor(cf.48)wasofparticularinterestbecauseitofferedtheprospectofdeliveringtheC1-C2functionality,configuredinitsrequiredsense(see49).28Weachievedthecouplingoflithiumreagent34withseveralrelevantaldehydes.Forthemostpart,thesestudieswerecarriedoutwithcholestanone-derivedaldehydesofthetype50.Thereadyaccessibilityofsuchsteroid-basedsubstratesgreatlyfacilitatedthereconnaissancephaseofourinvestigations.Thetranslat-abilityofsteroidmodelstoactualpre-taxolconstructswasexcellentsaveforthoseinitiativesinthelatterserieswhereintheoxetaneringprovedtobeunstable.

Whilecouplingof34andaldehydesofthetype50couldbeachieved,wehavenotatthiswritingsucceededintraversingallofthestepsrequiredtoreachaketoaldehydecorrespondingto51inthesteroidseries,or52intheoxetanecontainingseries.Theproblemswereencounteredwhentryingtoconstrain(throughanacetallinkage)ortootherwiseprotecttheoxygensatC9andC10(futurebaccatinnumbering).Evenprotectionofthesecondaryalcoholinsecosystem52(X)H)wasproblematic.Furthermore,therevealingoftheC1-C2keto

(28)Fortwoexamplesdescribingthereductionofthisschemetopractice,albeitinmuchsimpler(ringCaromatic)settings,see:(a)Swindell,C.S.;Chander,M.C.;Heerding,P.G.;Rahman,L.T.;Raman,V.;Venkataraman,H.TetrahedronLett.1993,34,7005.Swindell;(b)C.S.;Fan,W.andKlimko,P.G.TetrahedronLett.1994,35,4959.

Danishefskyetal.

Scheme15

Scheme16

aldehydeensemble(cf.51or52)fromitsprecursorguardinggroupaddedfurtherdifficultiestoanalreadycomplicatedprogram.Whilevariouspotentialsolutionstothisproblemremaintobeexplored,ourpreferencescametobefocusedonaplanwhichcalledforestablishingtheC1-C2bondfirst.OurfirstdemonstrationthatitwouldbepossibletoestablishtheC1-C2bondbythecouplingstrategywhichweenvisioned,arosefromthereactionofvinyllithiumagent37(describedabove)withaldehyde47(Scheme16).A60%yieldof53wasobtainedasasinglestereoisomer.Whilethiswasakeyadvance,itscontextdidnotfittheformulationimplicitinScheme4.Inparticular,thepresenceofaone-carbonunitatC11(whichwenumberasC10′)deviatedfromtheplancallingforaC10-C11closure.

Actually,wewouldhavebeenwillingtodepartfromourplan.However,seriousdifficultiessoonsurfaced.Attemptstoprotectthesecondaryalcohol(C2ofsecobaccatinsystem53)inthiscongestedenvironmentwereunsuccessful.Failuretoprotectthisalcoholunderminedeffortstodevelopthefunctionalgroupsalongthe“northernrim”.Again,whileotherpossibilitiesremainedtobeinvestigated,theresultsoftheseexpeditionsweresufficientlydiscouragingtoobligeareturntothebasicScheme4prospectus.

Forthisprogramtobeimplemented,amethodologicaladvancehadtobeachieved.TheprobleminvolvedthestatusofC11asweexploitedtheC1vinylnucleophile.Inthecaseof37,thisissuehadbeenobviatedbyemploymentofacarbon-carbonbond(C11-C10′).ThisbondservedtostabilizeC11duringlithiation.Intheconductoftheactualsynthesis,however,wecouldnotemploysuch“protection”.

TotalSynthesisofBaccatinIIIandTaxolScheme17

Scheme18a

Reagents:(a)H2NNH2,Et3N,EtOH,72%;(b)I2,DBN,THF,52%;(c)I2,DBN,THF,%;(d)TMSCN,cat.KCN,18-crown-6,CH2Cl2,%.

TwooptionsforthestatusofC11atthestageofcyclizationtoC10wereconsidered(Scheme17).Inonecase,thiscarbonwouldhaveemergedastheC11-C12vinyliodideof54.Alternatively,itmightbepresentedasavinyltriflateasshowninstructure55.RecoursetoacarbonappendageatC11wouldcomplicatereachingeither54or55.

Mucheffortwasexpendedgenerating1,4-cyclohexadienyl-lithiumreagentsofthetype56.Theseeffortswereunsuccessful.SincewecouldnotstoretheimplementeventuallyneededatC11ofthehypotheticalvinyllithiumreagent56,itwouldbenecessarytocreatethisfunctionalityaftercouplingofC1andC2.Toeventuallyreach54or55,aC11ketoneseemedtoberequired.Thus,theexactstatusofthe“pro-ketonic”C11duringthevinyllithiumformationhadtobedetermined.Thepossibilityofgeneratinganagentofthetype58withtheC11ketonealreadyinplacefromaprecursorofthetype57wasshowntobefeasibleinoneinstance,26butwassubsequentlyabandonedforlackofgenerality.

WealsodidnotpursuesolutionswhereC11wascarriedasaprotectedalcoholatthestagewhenthevinlylmetalnucleophile(cf.59)wasgenerated.ThedisentanglementofthefateofsuchaC11alcoholfromtheotherresidenthydroxyls(cf.C1,C2,C4,andC7)duringthemanipulationspriortocyclizationwouldbeverycomplicated.

Thedilemmawhichwenowfacedcouldbeformulatedbytheneedtogenerateasyntheticequivalentofhypotheticalconstruct60.Asolutionwasdiscovered(Scheme18).29Itwasdecidedthatthealdehydeacetal61,whichwasderivedbythe

(29)Masters,J.J.;Jung,D.K.;Danishefsky,S.J.;Snyder,L.B.;Park,T.K.;Isaacs,R.C.A.;Alaimo,C.A.;Young,W.B.Angew.Chem.Int.Ed.Engl.1995,34,452.

J.Am.Chem.Soc.,Vol.118,No.12,19962849

Scheme19a

Reagents:(a)tBuLi,THF-78°C;(b)add61,THF,-78°C,90%;(c)TBAF,THF,0°C,100%;(d)VO(acac)2,tBuOOH,CH2Cl2,0°C,91%;(e)H2,Pd/C,EtOH,0°C,90%;(f)e,thenHOAc0°Ctoroomtemperature,56%fromepoxide;(g)Cl2CO,pyr,CH2Cl2,0°C,100%.

degradationofcholestanone,wouldserveasamodelforaldehyde45(whichwasdestinedtobeadvancedtobaccatinIII(1)).Thesequencestartedwithdione6,whichwasconvertedtoitsmonohydrazone62.Thelatter,ontreatmentwithiodineinaBartonreaction,30gaverisetoiododienone.Thissubstancepresumablyarosefromiodineinduceddehydroge-nationoftheexpectedmonoeneiodideintermediate63.Compoundcouldbeconvertedtoitscyanohydrin65inracemicform.Thecomplicationsassociatedwiththecouplingofracemicintermediateswithopticallypureagentswouldnotbeofconsequencesincethesp3hybridization,introducedforpurposesofmetalation,wouldbedischargedduringworkup.Akeyfindingwasthatcompound65could,infact,belithiatedtogiveriseto66(Scheme19).Thelatterreactedwithaldehyde61togive,afterdecyanation,asinglestereoisomerformulatedas67.Whiletheconfigurationatthesecondaryhydroxylgroupinthissubstancewasnotprovenatthisstage,itwasestablishedthroughcrystallographicanalysisofsubse-quentreactionproducts(Videinfra).ItwasthenfoundthatdirectedepoxidationoftheC14-C1olefinproducedasingleepoxide.Furthermore,thisepoxidecouldbecleavedbypalladium-inducedhydrogenolysistogeneratediol68orfurtherreducedtothesaturateddiol69bytheadditionofaceticacid.Compound69couldbeconvertedtocycliccarbonate70undertheconditionsshown.Itwasinthiswaythattheproblem,capturedinthehypotheticalexpression60,wassolved.

Weshallreturntoketone70andtoitsutilityinvariouscyclizationpossibilitiesshortly.However,firstwedescribetheapplicationofthesefindingstotheoxetane-bearing45(Scheme20).Compound45andlithiumreagent66,again,gaverisetoasinglecarbinol71afterdeprotectionoftheC11ketone.At

(30)Barton,D.H.R.;Bashiardes,G.;Fourrey,J.-L.Tetrahedron1988,44,147-162.

2850J.Am.Chem.Soc.,Vol.118,No.12,1996Scheme20a

Danishefskyetal.

Reagents:(a)(i)THF,-78°C,93%;(ii)TBAF,THF,-78°C,80%;(b)mCPBA,CH2Cl2,roomtemperature,80%;(c)H2,Pd/C,-5°C,EtOH,65%;(d)CDI,NaH,DMF,81%;(e)L-Selectride,THF,-78°C,93%.

Scheme21Scheme22

thisjuncture,itwasnecessarytodevelopmildprotocolstopreservetheoxetaneringduringthecourseofthetransforma-tionstobedescribed.Invariousconstructsandatvariousstages,thehydoxylgroupatC2tendedtodisplacethecarbon-oxygenlinkatC20withformationofproductsofthetype72.Directedepoxidationof71produced73whichunderwenthydrogenationtoproducediol74,whereintheC1andC2hydroxylgroupscouldbeprotectedasacycliccarbonate(seecompound75).Withthecycliccarbonateinplace,theketone76couldbeobtainedbyconjugatereductionof75.

Thesteroidderivedketone70wasusedtoexploreringclosureswhichwehopedtoemployinclosingtheC10-C11bondenroutetobaccatinIII(1).Manypermutationswereinvesti-gated.Onesetbackwasourinabilitytoconvertketonetype77(derivedfrom70)tothecorrespondingvinyliodide(Scheme21).Eventually,wewereabletoreachavinyliodideviaacircuitousroute(Videinfra).Unfortunately,wewereunabletoeffectBarbier31orNozaki-Kishi32typeringclosuresof78or79inthemodelsteroid-derivedseries.

WethenturnedtothepossibilityofanintramolecularHecktypeolefinationreaction33,34toconstructtheC10fC11baccatinbond.Thefeasibilityofsuchapalladium-catalyzedinternalHeckreactionwasfirstdemonstratedinourlaboratorywitharomaticCringsubstrates(seetransformations80f81and82f83,Scheme22).35

ItwaswellappreciatedthatthesuccessfulHeckreactionofsubstrates80and82couldnotbetakenassecureprecedentsforproducingC-saturatedderivatives.Forinstance,inthecase

(31)Forareview,see:BlombergandHartog.Synthesis1977,18-30.(32)Kress,M.H.;Ruel,R.;Miller,W.H.;Kishi,Y.TetrahedronLett.1993,34,5999-6003.

(33)Heck,R.F.PalladiumReagentsinOrganicSyntheses;AcademicPress:NewYork,1985;p179.

(34)Forareview,see:Meijere,A.;Meyer,F.E.Angew.Chem.,Int.Ed.Engl.1994,33,2379.

(35)(a)Masters,J.J.;Jung,D.K.;Bornmann,W.G.;Danishefsky,S.J.TetrahedronLett.1993,34,7253.(b)Young,W.B.;Masters,J.J.;Danishefsky,S.J.J.Am.Chem.Soc.1995,117,5228.

ofthesteroid-baccatinIIIhybrid,cyclizationwouldinvolvecreationofapotentiallyseriousC17-C19methyl-methylabutment.Ofcourse,justsuchaconditionwouldhavetobemetforsuchareactiontobeofvalueinthebaccatinIII(1)directedenterprise.

ToinitiatetheplanfortheHeckreactionweneededtoextendthelinkerarmprovidingC9andC10ofthebaccatintarget(Scheme23).Thiswasaccomplishedasfollows.Theketone70underwentconversiontovinyltriflate84undercarefullyspecifiedconditions.Thedimethylacetalwascleaved,andtheresultantaldehydeunderwentWittigolefinationtoproduce85.Thekeyadvanceintheprogramwasrealizedwhen85under-wentintramolecularHeckclosure.Inthiscase,however,addi-tionofstochiometrictetrakis(triphenylphosphine)palladiumoverseveralhourswasrequiredanda50%yieldof86wasrealized.29ItseemedthattheoxidativeadditionsteptothehinderedC11vinyltriflatebondwasnotthelimitingfeatureofthereaction.Indeed,afterseveralhoursitwaspossibletoisolateapalladium-

TotalSynthesisofBaccatinIIIandTaxolScheme23a

J.Am.Chem.Soc.,Vol.118,No.12,19962851

Reagents:(a)KHMDS,PhNTf2,THF,-78°C,90%;(b)pTsOH,acetone,H2O,75°C,80%;Ph3PCH3Br,KOtBu,THF,0°C,95%;(c)Pd(PPh3)4,K2CO3,CH3CN,85°C,50%;(d)Pd(PPh3)4(1.1equiv),K2CO3,CH3CN,85°C,2h;I2,Et2O.

Scheme24

Reagents:(a)PhNTf2,KHMDS,THF,-78°C,98%;(b)PPTS,acetone,H2O,96%;(c)Ph3PdCH2,THF,-78°Cf0°C,77%;(d)Pd(PPh3)4,K2CO3,CH3CN,85°C,49%.

Scheme25

containingproductwhosestructurecouldnotbespecifiedindetail.Treatmentofthisentitywithiodineledtocompound87.36(Thelatterwasusedtoproducethepotentialcyclization

(36)Masters,J.J.Unpublishedresults.

substrates78and79,discussedabove.)ThemaindifficultyintheHeckreactionseemedtoarisefromtheolefininsertion-eliminationphases.Theprolongedreactiontimemayreflectthestrainofthebridgeheadolefinandtheclosemethyl-methylcontactinthecyclizedbaccatin-steroiddiene86.Afurthercomplicationarisingfromprecipitationofpalladiumblackduringthereactionbroughtwithittherequirementofstoichio-metricamountsofthepalladiummediator.

Theimportantpoint,however,wasthatapathwayhadbeendiscoveredwhichwaspotentiallyrelevanttosynthesizingbaccatinIII(1).Ofcourse,itwasnotclearthatcorrespondingstepscouldbereducedtopracticeinthemorefunctionalizedoxetane-containingseries(Scheme24).Thepreviouslydis-cussedketone76wasconvertedtovinyltriflate88.Hydrolysisoftheacetalafforded.Thelatter,uponWittigolefination,providedsubstrate90.TheintramolecularHeckreactionproceededinafashionsimilartoourfindingsinthecholestanone-deriVedseries(cf.85f86)andthetetracyclic91wasinhand!Ithadbeenhopedthatthenowextraneouscarbon(C10′)oftheexocyclicmethylenegroupattachedtoC10wouldbeeasilyexcisedbyoxidativecleavage(cf.95).Unfortunately,theconcludingphaseofthesynthesisprovedtobeverydifficult.Harbingersofdifficultieswerealreadypresentfromourmodelstudies.SeveralattemptstoachieveselectivecleavageoftheC10-C10′doublebondinHeckproducts81,83,and86wereunsuccessful.Thematterwasprobedindetailinthecaseof86(Scheme25).Bothozoneandosmiumtetroxideattackedthetetrasubstituteddoublebondfirst.Inthecaseofozonolysis(cf.86)thiswasfollowedbycleavageoftheexocyclicolefintoproducecompound92.Itseemedthatoxidantsweredirectedtothetetrasubstituteddoublebondfirst.Theonlyoxidizingagentwhichselectivelyattackedtheexocyclicdoublebondwasdimethyldioxirane.Thisreactiongaverisetocompound93.

2852J.Am.Chem.Soc.,Vol.118,No.12,1996Scheme26a

Danishefskyetal.

Reagents:(a)TBAF,THF,roomtemperature,92%;(b)TESOTf,Et3N,CH2Cl2,-78°C,92%;(c)MCPBA,NaHCO3,CH2Cl2,roomtemperature,45%;(d)H2,Pd/C,EtOH,roomtemperature,82%;(e)Ac2O,DMAP,pyr,roomtemperature,66%;(f)PhLi,THF,-78°C,93%;(g)OsO4,pyr,105°C;(h)Pb(OAc)4,PhH,MeOH,0°C,61%;(i)SmI2,Ac2O,THF,-78°C,92%;(j)KOtBu,(PhSeO)2O,THF,-78°C;KOtBu,THF,-78°C,81%;(k)Ac2O,DMAP,pyr,76%.

Unfortunately,attemptstotransformtheepoxideofcompound93toasystemwhereC10′couldbeexcisedwereunsuccessful.Forinstance,compound93wasresistanttoconversiontoasystemofthetype94.

Itisoursensethattheunusualchemistryencounteredduringexplorationsdirectedatoxidationoftheexocyclicmethylgroupofcompound86canbeaccommodatedinacommonrationale.Thussp3hybridizationatC10wouldcauseasignificantabutmentofitsRgroup(ifthisgroupisnotaproton)withthevinylicC18methylgroup(baccatinnumbering).Theacutebondanglesoftheepoxide,ofcourse,lessenthisimpact.Intheseterms,therewouldbesignificantresistancetotheattackofanyagentsattheexocyclicdoublebondwhichinvolvetransitionstatesleadingtohighermemberedringswithsp3-hybridizedbonds(cf.ozonolysis,osmiumtetroxide,rutheniumtetroxide).

Aftersignificantimprovisation,iteventuallyprovedtobepossibletocleavetheC10′methylenegroupinthesteroidalhybrid,resultinginconversionof86toenone95.Anaccountoftheseexperimentswasrecentlyprovidedelsewhere.37Here,wereturntocompound91anddescribeitsconversiontobaccatinIII(1)(Scheme26).

ThefirststepinthisconcludingphaseinvolvedchangingthestabilizingarrangementatC7.TherobustTBSgrouphadsuccessfullyprotectedthatfuturealcoholfunctionfromvariouschemicalincursions.However,inmodelprobestobedescribedshortly,itwasdiscoveredthattheremovaloftheTBSgroupwouldbeproblematicinsubstrateswhichcarrysignificantfunctionalitybeyondthatpresentin91.Hence,theTBSgroupwasremovedatvirtuallythelastfeasiblestage,andthealcoholatC7wasreprotectedwithamorelabileTESgroup(seeconversionof91f96).

Inthissubstrate,epoxidationofthetetrasubstituteddoublebondtoproducecompound97couldbeaccomplished,albeitinonly45%yield.Thecomplicationherewasthetendencyforadditionaloxidationattheexocyclicmethylenetoprovideanunwantedbis-epoxide.ThenextstepinvolvedadjustmentofthestatusofthemaskedalcoholatC4.Throughoutthejourneyfromcompound24,wehadbenefitedfromthestabilityofthebenzylprotectinggroup.However,itwasdeterminedthatthebenzylgroupwasnowgoingtobevulnerabletosomeoftherequiredoxidizingagents.Modelprobesalsosuggested

(37)Young,W.B.;Link,J.T.;Masters,J.J.;Snyder,L.B.;Danishefsky,S.J.TetrahedronLett.1995,36,4963.

thatitmaybedifficulttoconductdebenzylationinthelaterstagesofthesynthesis.

Theissueofwhenthebenzylgroupwouldbedischargedcausedmuchconcern.Eventually,thecouragewasmusteredtoattemptitsremovalatthestageof97byhydrogenolysis.Remarkably,theexocyclicmethylene(C10′)group,truetoits“tradition”ofstabilitytowardmanychemicalreactions,survivedthishydrogenolysisunscathed!TheresultantC4alcoholwasconvertedtoitsacetate,99.

Inthenextphaseofthesynthesis,thecycliccarbonatewascleavedwithphenyllithiumtogivetheC2benzoate(seecompound100a)38asprecedentedintheexperimentsofbothNicolaou8,39andHolton9oncloselyrelatedsubstrates.Itwasatthisstagethattheexocyclicmethylenegroupwastobecleaved.Thecampaignstartedwiththeformationofputativeosmateester101obtainedbytreatmentwithosmiumtetroxideunderforcingconditions.Thissubstancewastreatedwithleadtetraacetate,wherebyketone102wasobtainedina61%yield.Thenowextraneousepoxideoxygenwasremovedthroughtheactionofsamariumiodideinthepresenceofaceticanhydride(seecompound103).40WewerenowobligedtofacethepossibleconsequencesofhavingkeptC9underfunctionalizedthroughoutthecourseofthesynthesis.Fortunately,wecoulddrawuponthepowerfulchemistryoftheHoltongrouptorectifytheproblem.9Thus,treatmentof103withpotassiumtert-butoxideandphenylseleninicanhydrideled,afteracetylation,totheacetoxyketone105.

Inouroriginalconceptionsaboutsynthesizingtaxol(3),wehadenvisionedalatestageoxidationofC13.Indeed,in1992wereportedtheearliestexperimentsonthematterwhichindicatedthatsuchanoxidationcouldwork.41However,acloserandstillmorereassuringanalogywasreportedbyNicolaouandco-workers.8TheLaJollateamhadshownthat

(38)Thestereochemistryoftheepoxidationreactionwasestablishedthroughacrystalstructureoncompound100b.ThelatteristheC7-TBS,C4-Bnversionofcompound100aformedthroughanalogouschemistryvia91.

(39)Nicolaou,K.C.;Renaud,J.;Nantermet,P.G.;Couladouros,E.A.;Guy,R.K.;Wrasidlo,W.J.Am.Chem.Soc.1995,117,2409.Nicolaou,K.C.;Nantermet,P.G.;Ueno,H.;Guy,R.K.J.Chem.Soc.,Chem.Commun.1994,295.

(40)Forareviewontheusesofsamariumdiiodide,see:Molander,G.A.Chem.ReV.1992,92,29.

(41)Queneau,Y.;Krol,W.J.;Bornmann,W.G.;Danishefsky,S.J.J.Org.Chem.1992,57,4043.

TotalSynthesisofBaccatinIIIandTaxolScheme27a

J.Am.Chem.Soc.,Vol.118,No.12,19962853

Reagents:(a)PCC,NaOAc,PhH,reflux,%;(b)NaBH4,MeOH,79%;(c)HF‚pyr,THF,85%;(d)refs8,9,and42.

theoxidationcouldbeperformedontheVerysubstrateinquestion.Indeed,informalterms,ourexpeditioncouldhavebeenterminatedbythesynthesisof105sincethiscompoundwasdescribedasanintermediateintheNicolaoutotalsynthesis.8Itwas,however,ourintentiontocompleteafullyself-containedindependentsynthesisofbaccatinIII(1)itself.Forthatpurpose,anallylicoxidationwithPCCwascarriedoutonourfullysyntheticmaterialtogive106(Scheme27).Thisproduct,inturn,wasreducedwithsodiumborohydridetoprovide7-OTESbaccatinIII(107).Compound107,aswell,hadbeenanintermediateintheNicolaoutotalsynthesis.8Forourpurposes,however,weremovedthetriethylsilylgroupwithHF‚pyr.Insodoingwecompletedourrelay-freetotalsyn-thesisofbaccatinIII(1).Thematerial,thusobtained,wasidenticalwithanaturalsampleinallrespects,includingopticalrotation.

Asindicatedearlier,baccatinIII(1)hasbeenconvertedtotaxol(3)bynumerousgroups.Indeed,thistransformationiscurrentlypracticedonacommercialscale.Thus,therewouldseemtobelittleneedtoexecutesuchaconversionaspartofourownprogram.However,forsentimentalreasons,wecarriedouttheformalitiesinvolved.Forthatpurpose,wesubstantiallyfollowedtheregimenofOjimaandco-workers42toreach󰀃-lactam108a.Thiswasconvertedto108bwhichservedtoacylate7-TES-baccatinIII(107obtainedfromnatural10-deacetylbaccatinIII(2)).Byfollowingthesepreviouslyde-scribedprotocols8,9,42wecompletedatotalsynthesisoftaxol(3),identicalwiththenaturalproductinallrespects,includingopticalrotation.Conclusions

ThetotalsynthesisofbaccatinIII(1)hasbeenachieved.FrombaccatinIII(1),followingknownprotocols,taxol(3)itselfwasobtained.ThemostrewardingaspectofthesynthesiswastheabilitytostartwithWieland-Miescherketone,itselfavailablethroughcatalyticasymmetricinduction,andtoinstallallofthestereochemistryrequiredtoreachbaccatinIIIinasequentialfashion.Oursynthesis,thougharduous,involvesnorelays,noresolutions,andnorecoursetoawkwardlyavailableantipodesofthe“chiralpool”.

InthesestudieswehavediscoveredavarietyofefficientdegradativeschemesbywhichdifferentiatedappendagesmountedtoopticallypureCDfragmentscouldberetrieved.Anoriginalprotocolfordeliveringasyntheticequivalentof60wasdevelopedandfoundtobecompatiblewithanoxetane-containingCDfragment.Fromhere,aftercouplingvinyllithiumreagent66toCDconstruct45,andappropriatefunctionalgroupmanipulations,thevinyltriflate90wasprepared.ThedefiningbondconstructioninthesynthesiswastheHeckreactiontoproduce91.Theabilitytocarryoutthisreactioninsuchacomplicatedsettingcouldnothavebeenanticipatedinadvance.Thecapacitytocarrytheoxetanefromtheearlieststagesof

(42)Cf.:Ojima,I.;Sun,C.M.;Zucco,M.;Park,Y.H.;Duclos,O.;Kuduk,S.TetrahedronLett.1993,34,4149.Ojima,I.;Habus,I.;Zucco,M.;Park,Y.M.;Sun,C.M.;Brigaud,T.Tetrahedron1992,48,6985.

thesynthesistoandthroughthisstepalsohastaughtusmuchaboutthestability,aswellasthevulnerability,ofthisfascinatingstructuralelement.Unfortunately,theprocedureforcleavingtheextraneousC10′exo-methylenegroupprovedtobeunexpect-edlycomplicated.Thesetbackssustainedonthisfronterodedtheefficiencyofthetotalsynthesis.

Nonetheless,muchhasbeenlearnedaboutthechemicalnatureofbaccatin-likestructuresandaboutbicyclicandtricyclicanaloguesenroutetothebaccatinskeleton.Wearecurrentlydevelopinganoxetane-containinganalogsynthesisprogramwhichdrawsheavilyfromthechemistryusedinthetotalsynthesis.Resultsofthiseffortwillbedisclosedshortly.ExperimentalSection

GeneralProcedures.1HNMRand13CNMRspectrawererecordedonaBrukerAMX-400.InfraredspectrawererecordedonaPerkin-Elmer1600SeriesFTIR.OpticalrotationsweremeasuredonaJASCODIP-370polarimeter.MassspectrawereobtainedonaJOELJMS-DX-303HFmassspectrometer.AnalyticalchromatographywasperformedonE.Mercksilicalgel60F254plates(0.25mm).FlashchromatographywasperformedonMallinckrodtsilicagel60(230-400mesh).Tetrahydrofuran(THF)wasdistilledfromsodiummetal/benzophenoneketyl.Dichloromethane(CH2Cl2),acetonitrile,benzene(PhH),triethylamine,andpyridineweredistilledfromcalciumhydride.N,N-Dimethylformamide(DMF)waspurchasedfromAldrichinsuresealcontainers.Allothercommerciallyobtainedreagentswereusedasreceived.

Ketone11.Asolutionof1043(30.9g,91.3mmol)in300mLofTHFat0°CwastreateddropwisewithBH3(1MsolutioninTHF,93.0mL,93.0mmol).Aftercompleteaddition,themixturewasslowlyallowedtowarmtoroomtemperatureandstirfor13h.Themixturewascooledto0°CandtreateddropwisewithH2O(7.1mL),followedby3MNaOH(50mL)and30%H2O2.After1h,themixturewaswarmedtoroomtemperature,stirredfor3h,andconcentratedunderreducedpressure.Theresiduewasdissolvedether(600mL)andH2O(300mL).Theaqueouslayerwaswashedwithether(4×200mL)andthecombinedextractswerewashedwithsaturatedNaCl(2×200mL),dried(MgSO4),andconcentratedunderreducedpressure.Asolutionofthecrudecarbinolin300mLofCH2Cl2at0°CwastreatedwithPDC(66.7g,177mmol)and4Åsieves(66.5g)inportionsoveraperiodof1h.Themixturewasallowedtostirat0°Cfor0.5handthenwarmedtoroomtemperatureandstirredfor10h.Themixturewasdilutedwithether(500mL),treatedwithCelite(50g),andfilteredthroughapadofCelite.Thefiltratewasconcentratedunderreducedpressure,affordingthecrudeketoneasabrownoil.Asolutionofthecrudeketonein250mLofMeOHatroomtemperaturewastreatedwithNaOMe(25wt%inMeOH,28mL).After10h,themixturewasconcentratedunderreducedpressureandtheresiduewasdissolvedinether(500mL)andH2O(300mL).Theaqueouslayerwaswashedwithether(2×150mL),andthecombinedextractswerewashedwithH2O(200mL)andsaturatedNaCl(200mL),dried(MgSO4),filteredthroughCelite/MgSO4,andconcentratedunderreducedpressure,affording30.0g(93%)ofthetrans-fusedketone11asanorangeoil:1HNMR(400MHz,CDCl3

)δ3.97-3.83(m,4H),3.78(dd,J)11.1,5Hz,1H),2.46(dd,J)12.3,3.7Hz,1H),2.41-2.27(m,2H),2.00-1.58(m,7H),1.42(dt,J)13.4,4.9Hz,1H),0.88(s,9H),0.78(s,

(43)Enantiomericallypure10wasgeneratedviathesameproceduresasdescribedforracemic10;seeref17.

2854J.Am.Chem.Soc.,Vol.118,No.12,1996

3H),0.07(s,6H);13CNMR(100MHz,CDCl3)δ210.4,109.0,77.3,.3,.2,52.2,46.7,42.4,38.8,35.1,30.7,30.5,29.6,25.8,18.0,10.5,-4.1,-4.8;IR(film)2952,2857,1716,1110,1093,1051,869,837cm-1;[R]20D11.1°(c)1.8,CHCl3).

Spiroepoxide14.AsolutionMe3S+I-(25.9g,127mmol)in275mLofTHFat0°CwastreatedwithKHMDS(23.1g,110mmol)inportionsoveraperiodof0.5h.After1h,asolutionof11(30.0g,84.6mmol)in100mLofTHFwasaddedviacannulaoveraperiodof0.5h.After0.5h,themixturewastreatedwithH2O(25mL)andconcentratedunderreducedpressure.Theresiduewasdissolvedinether(500mL)andH2O(300mL).Theaqueouslayerwaswashedwithether(150mL),andthecombinedextractswerewashedwithH2O(150mL)andsaturatedNaCl(150mL),dried(MgSO4),andconcen-tratedunderreducedpressure,affording31.1g(99%)of14asalightyellowoil:1HNMR(400MHz,CDCl3)δ3.93-3.(dd,J)10.8,4.4Hz,1H),3.30(m,4H),2.63(d,J)4.4Hz,1H),2.23(d,J)4.4Hz,1H),1.99-1.92(m,1H),1.87-1.76(m,3H),1.-1.58(m,3H),1.48(t,J)13.2Hz,1H),1.24-1.19(m,3H),0.94(s,3H),0.85(s,9H),0.01(s,6H);13CNMR(100MHz,CDCl3)δ109.6,78.8,.3,.1,58.4,47.1,41.0,40.1,35.3,32.9,30.5,30.4,28.6,25.8,18.0,10.7,-4.0,-4.8;IR(neat)2950,2856,1471,1252,1106,872,836cm-1;[R]20D-0.7°(c)2.5,CHCl3).

AllylicAlcohol15.Asolutionof14(31.1g,84.5mmol)andAl-(iPrO)3(50.0g,245mmol)in300mLoftoluenewasheatedatrefluxfor38h.Themixturewascooledtoroomtemperature,dilutedwithether(1100mL),andtreatedwithsaturatedNa+K+tartrate(500mL).Thelayerswereseparated,andtheaqueouslayerwastreatedwith1MNaOH(500mL)andwashedwithether(3×300mL).ThecombinedorganicextractswerewashedwithsaturatedNaCl(500mL),dried(MgSO4),filteredthroughCelite,andconcentratedunderreducedpressure,affording30.9g(99%)of15asalightyellowsolid:mp72-73°C;1HNMR(400MHz,CDCl3)δ5.57(m,1H),4.03-3.92(m,6H),3.53(dd,J)9.8,6.5Hz,1H),2.49(brd,1H),2.23(brd,1H),2.02(m,1H),1.90(dt,J)12.9,2.5Hz,1H),1.83(dq,J)13.0,2.5Hz,1H),1.75(dd,J)13.7,4.7Hz,1H),1.67(dq,J)13.8,2.5Hz,1H),1.56(t,J)13.2Hz,1H),1.21(dt,J)12.8,4.5Hz,1H),0.87(s,9H),0.79(s,3H),0.02(s,6H);13CNMR(100MHz,CDCl3)δ137.8,123.0,109.4,75.8,65.0,.23,.17,41.6,37.4,33.3,33.2,32.1,30.8,25.8,18.0,8.9,-4.1,-4.8;IR(film)3416,2951,2856,1472,1360,1250,1106,1072,872,836,774cm-1;[R]20D25.4°(c)1.4,CHCl3).

Triol16.44Asolutionof15(30.9g,84.5mmol)andNMO(19.8g,170mmol)in1300mLofacetoneand170mLofH2OatroomtemperaturewastreatedwithOsO4(5wt%iniPrOH,42.0mL,4.23mmol).After15h,themixturewastreatedwithsaturatedNaHSO3(400mL)andstirredfor0.5h.ThemixturewasthenpouredintoEtOAc(400mL)andsaturatedNaCl(400mL).TheaqueouslayerwaswashedwithEtOAc(3×300mL),andthecombinedextractswereconcentratedunderreducedpressure.TheresiduewasdissolvedinEtOAc(750mL)andwashedwithsaturatedNaCl(300mL),dried(MgSO4),andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,EtOAc),affording15.3g(45%)of16asanoff-whitesolid:mp157-158°C;1HNMR(400MHz,CDCl3)δ3.98-3.90(m,5H),3.77(dd,J)11.5,5.5Hz,1H),3.56(m,2H),3.10(s,1H),2.62(d,J)2.4Hz,1H),2.31-2.29(m,1H),2.06(dd,J)14.7,2.7Hz,1H),1.87(m,2H),1.80-1.70(m,2H),1.62(m,2H),1.52(t,J)13.2Hz,1H),1.29(td,J)12.6,6.4Hz,1H),0.87(s,9H),0.82(s,3H),0.06(s,3H),0.04(s,3H);13CNMR(100MHz,CDCl3)δ109.3,73.8,73.7,69.3,.2,.18,62.0,42.4,38.8,37.9,34.8,30.8,30.1,25.8,18.0,12.3,-4.1,-4.8;IR(film)3441,2950,2856,1256,1102,8,835cm-1;[R]20D32.3°(c)1.1,CHCl3).

Oxetane22.45Asolutionof16(8.70g,21.6mmol)andpyridine(19.2mL,238mmol)in540mLofCH2Cl2at-78°Cwastreatedwithchlorotrimethylsilane(2.8mL,22.0mmol).Themixturewasallowedtowarmtoroomtemperature,andchlorotrimethylsilane(280µL,2.2mmol)wasaddedeveryhouruntilstartingmaterialwasconsumedasdeterminedbyTLC.After3h,themixturewascooled

(44)Formationofsideproduct17hasbeendescribedpreviously;seeref17.

(45)Formationofsideproduct23hasbeendescribedpreviously;seeref17.

Danishefskyetal.

to-78°C,treatedwithtrifluoromethanesulfonicanhydride(14.5mL,86.4mmol),andthenallowedtowarmtoroomtemperature.After1.5h,ethyleneglycol(90.0mL,1.62mol)wasaddedandthemixturewasheatedatrefluxfor14.5h.ThemixturewasthencooledandpouredintosaturatedNaCl(400mL)andsaturatedNaHCO3(400mL).TheaqueouslayerwaswashedwithCH2Cl2(3×250mL),andthecombinedextractswerewashedwith1:1H2O:saturatedCuSO4(400mL),saturatedNaHCO3(250mL),andsaturatedNaCl(250mL),dried(MgSO4),andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,3:2to1:1hexane:EtOAc),affording5.5g(66%)of22asawhitesolid:mp152-153°C;1HNMR(400MHz,CDCl3)δ4.78(dd,J)9.1,2.2Hz,1H),4.46(d,J)7.6Hz,1H),4.26(d,J)7.6Hz,1H),3.96-3.(m,4H),3.44(dd,J)10.6,7.2Hz,1H),2.40(s,1H),2.27(ddd,J)16.3,9.2,7.1Hz,1H),1.88(ddd,J)15.1,10.7,2.4Hz,1H),1.83-1.72(m,2H),1.68-1.55(m,5H),1.21(s,3H),0.87(s,9H),0.02(s,6H);13CNMR(100MHz,CDCl3)δ108.9,88.2,77.1,76.4,73.9,.3,.2,46.6,37.5,36.5,30.9,30.1,25.8,18.0,9.5,-4.1,-4.8;IR(film)3416,1094,859,836,774cm-1;[R]20D19.0°(c)3.65,CHCl3).

Benzyloxetane24.Asolutionof22(7.40g,19.2mmol)in100mLofTHFat0°CwastreatedwithNaH(2.3g,96mmol).After0.5h,themixturewastreatedwithbenzylbromide(3.0mL,25mmol)andTBAI(2.13g,5.76mmol)andallowedtowarmtoroomtemperature.After4h,themixturewascooledto0°C,andsaturatedNH4Clwasaddeduntilahomogeneousbiphasicmixtureresulted.Themixturewaspouredintoether(700mL)andsaturatedNaCl(300mL).Theaqueousphasewaswashedwithether(2×200mL),andthecombinedextractswerewashedwithsaturatedNa2S2O3(2×150mL)andsaturatedNaCl(150mL),dried(MgSO4),andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,9:1to17:3hexane:EtOAc),affording8.90g(98%)of24asawhitesolid:mp110-111°C;1HNMR(400MHz,CDCl3)δ7.38-7.24(m,5H),4.95(dd,J)9.0,1.6Hz,1H),4.55(d,J)11.6Hz,1H),4.42-4.38(m,3H),3.95-3.(m,4H),3.41(dd,J)10.4,7.4Hz,1H),2.22-2.20(m,1H),2.00-1.91(m,2H),1.85-1.79(m,2H),1.68-1.58(m,3H),1.30-1.25(m,1H),1.25(s,3H),0.87(s,9H),0.02(s,3H),0.01(s,3H);13CNMR(100MHz,CDCl3)δ138.3,128.4,127.6,127.3,109.0,82.8,79.0,76.7,74.6,65.0,.3,.2,41.3,38.1,37.5,36.9,31.1,29.5,25.8,18.0,9.9,-4.0,-4.8;IR(film)2951,2856,1471,1360,1256,1095,837cm-1;[R]20D33.3°(c)6.3,CHCl3).

Ketone25.Asolutionof24(8.90g,18.8mmol)in950mLof15:1acetone:H2OwastreatedwithpTsOH(4.g,24.4mmol),andthemixturewasheatedatrefluxfor2.5h.Themixturewascooledtoroomtemperature,treatedwithsaturatedNaHCO3,andconcentratedwithastreamofnitrogen.Theresiduewasdissolvedinether(800mL)andpouredintosaturatedNaHCO3(300mL).Theaqueousphasewaswashedwithether(150mL)andCH2Cl2(200mL).ThecombinedextractswerewashedsaturatedNaHCO3(2×200mL)andsaturatedNaCl(150mL),dried(MgSO4),andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,3:1:1hexane:CH2Cl2:EtOAc),affording6.80g(84%)of25asawhitesolid:1HNMR(400MHz,CDCl3)δ7.36-7.28(m,5H),5.04(dd,J)9.2,2.1Hz,1H),4.59(d,J)11.6Hz,1H),4.49(d,J)11.7Hz,1H),4.50-4.44(m,2H),3.43(dd,J)10.6,7.2Hz,1H),2.48(ddd,J)15.6,14.0,6.5Hz,1H),2.39-2.38(m,1H),2.34(s,1H),2.32(s,1H),2.30-2.24(m,1H),2.15(ddd,J)13.2,6.3,2.0Hz,1H),2.03-1.94(m,2H),1.42(s,3H),1.36(dt,J)14.1,5.0Hz,1H),0.(s,9H),0.03(s,3H),0.02(s,3H);13CNMR(100MHz,CDCl3)δ210.4,137.9,128.5,127.7,127.2,82.4,79.1,76.3,73.2,65.1,45.1,38.9,37.9,37.7,37.6,36.6,25.8,18.0,10.0,-4.0,-4.9;IR(film)2948,1707,1455,1255,1098,940,734cm-1;[R]20D27.4°(c)6.3,CHCl3).r-HydroxyKetone39.Asolutionof27(7.20g,16.7mmol)andtriethylamine(23.3mL,167mmol)in450mLofCH2Cl2at-78°Cwastreatedwithtrimethylsilyltrifluoromethanesulfonate(16.7mL,83.5mmol).After4h,themixturewastreatedwithsaturatedNaHCO3(25mL)andallowedtowarmfor10min.Themixturewaspouredintohexane(900mL)andsaturatedNaHCO3(250mL).Theaqueousphasewaswashedwithhexane(200mL),andthecombinedextractswerewashedwithsaturatedNaHCO3(2×250mL)andsaturatedNaCl(150mL),quicklydried(MgSO4),andconcentratedunderreducedpressure.ThecrudeenoletherwasdissolvedinCH2Cl2(300mL),

TotalSynthesisofBaccatinIIIandTaxol

cooledto0°C,andrapidlytreatedwith3,3-dimethyldioxirane(0.1Msolutioninacetone,180mL,18.0mmol).After10min,themixturewasconcentratedunderreducedpressure.Theresiduewasdissolvedinacetone(350mL)andtreatedwithCSA(106mg).After0.5h,themixturewasconcentratedunderreducedpressureandtheresiduewaspurifiedbyflashchromatography(SiO2,6.5:2:1.5to6:2:2hexane:CH2-Cl2:EtOAc),affording6.60g(%)of39asawhitesolid:mp115-116°C;1HNMR(400MHz,CDCl3)δ7.37-7.25(m,5H),5.04(dd,J)9.0,1.6Hz,1H),4.59(d,J)11.6Hz,1H),4.51(m,1H),4.42(d,J)7.9Hz,1H),4.33(dd,J)6.9,12.4Hz,1H),4.33(dd,J)12.4,6.9Hz,1H),3.50-3.60(brs,1H),3.44(dd,J)10.3,7.4Hz,1H),2.58(dd,J)10.3,7.0Hz,1H),2.52-2.46(m,2H),2.27-2.26(m,1H),2.01-1.96(m,2H),1.51(s,3H),1.20(t,J)12.6Hz,1H),0.88(s,9H),0.03(s,6H);13CNMR(100MHz,CDCl3)δ210.1,137.7,128.6,127.8,127.2,82.3,78.9,76.1,73.0,72.5,65.2,48.7,46.5,39.4,37.7,34.6,25.8,17.9,11.3,-4.0,-4.9;IR(film)3446,1719,1471,1251096,838cm-1;[R]20D37.2°(c)1.95,CHCl3).

Aldehyde40.Asolutionof39(3.90g,8.72mmol)in170mLof1:1C6H6:MeOHat0°Cwastreatedwithlead(IV)acetate(5.05g,11.4mmol).After10min,themixturewasdilutedwithether(600mL),affordingayellowslurrywhichwasthenfilteredthroughSiO2(300mL)usingetheraseluent.Theclearfiltratewasconcentratedunderreducedpressure.Theresiduewasdissolvedinether(800mL),washedwithsaturatedNaHCO3(2×150mL)andsaturatedNaCl(150mL),dried(MgSO4),andconcentratedunderreducedpressure,affording4.4g(97%)of40asaclearoil:1HNMR(400MHz,CDCl3)δ9.78(s,1H),7.37-7.26(m,5H),4.(dd,J)9.2,3.5Hz,1H),4.61(d,J)11.2Hz,1H),4.54(d,J)7.8Hz,1H),4.53(d,J)7.8Hz,1H),4.37(d,J)11.2Hz,1H),3.99(dd,J)11.2,6.1Hz,1H),3.48(s,3H),2.80(dd,J)9.9,7.8Hz,1H),2.62(d,J)17.1Hz,1H),2.41(dd,J)14.8,5.0Hz,1H),2.36-2.21(m,3H),1.96-1.94(m,1H),1.22(s,3H),0.87(s,9H),0.04(s,3H),0.03(s,3H);13CNMR(100MHz,CDCl3)δ201.3,173.1,137.9,128.4,127.60,127.55,81.8,80.5,75.9,71.8,.9,51.8,50.4,41.9,40.6,36.9,31.0,25.8,18.0,14.4,-3.8,-4.7.

Acetal41.Asolutionofcrude40in1100mLofMeOHwastreatedwithcollidiniump-toluenesulfonate(910mg,3.10mmol),andthemixturewasheatedatreflux.After10h,themixturewasconcentratedunderreducedpressureandtheresiduewasdissolvedinether(600mL).Theresultingwhiteslurrywasthenfilteredthroughbasicalumina(150mL)usingetheraseluent.Thefiltratewasconcentratedunderreducedpressure,affording4.40g(97%)of41asaclearoil:1HNMR(400MHz,CDCl3)δ7.37-7.23(m,5H),4.83(dd,J)9.2,3.8Hz,1H),4.66-4.62(m,2H),4.58(d,J)11.1Hz,1H),4.51(d,J)7.7Hz,1H),4.31(d,J)11.1Hz,1H),3.78(dd,J)10.9,6.0Hz,1H),3.43(s,3H),3.33(s,3H),3.32(s,3H),2.58-2.53(m,2H),2.28(ddd,J)9.3,5.9,14.9Hz,1H),2.20(dd,J)10.5,13.8Hz,1H),2.05-1.95(m,2H),1.50(dd,J)14.8,5.6Hz,1H),1.07(s,3H),0.(s,9H),0.09(s,3H),0.06(s,3H);13CNMR(100MHz,CDCl3)δ173.5,138.2,128.3,127.49,127.46,101.6,81.8,81.1,76.1,71.2,.5,52.5,51.6,39.9,39.7,38.8,37.3,31.1,25.8,18.1,15.6,-3.7,-4.9;IR(film)2952,2856,1737,1255,1.,991,837cm-1;[R]20D18.4°(c)2.25,CHCl3).

Alcohol42.Asolutionof41(6.60g,12.6mmol)in20mLofTHFwastransferredviacannulatoa0°CsolutionofLiAlH4(623mg,16.4mmol)in180mLofTHF.After1h,themixturewastreatedwithEtOAc(20mL)followedbysaturatedNH4Cl(2mL).After0.5h,themixturewasdilutedwithEtOAc(500mL),treatedwithSiO2(100mL),andfilteredthroughCeliteandMgSO4usingEtOAcaseluent.Thefiltratewasconcentratedunderreducedpressure,affording2.78g(quant.)of42asaclearoil:1HNMR(400MHz,CDCl3)δ7.38-7.28(m,5H),4.90(dd,J)9.6,4.6Hz,1H),4.65-4.(m,2H),4.57-4.49(m,3H),3.72(dd,J)11.8,5.6Hz,1H),3.56(q,J)5.9Hz,2H),3.30(s,3H),3.28(s,3H),2.98(t,J)6.4Hz,1H),2.29(ddd,J)5.7,9.7,14.8Hz,1H),2.19(d,J)9.4Hz,1H),1.99-1.90(m,2H),1.82-1.79(m,1H),1.(dd,J)14.7,6.7Hz,1H),1.47-1.46(m,1H),1.05(s,3H),0.88(s,9H),0.08(s,3H),0.07(s,3H);13CNMR(100MHz,CDCl3)δ137.4,128.6,127.9,127.6,101.5,82.0,81.6,76.2,70.8,.9,61.8,52.5,51.8,40.2,39.7,38.1,37.1,29.1,25.8,18.1,15.4,-3.5,-4.9;IR(film)3460,2953,2856,1463,1362,1254,1156,1086,984,837,775,734cm-1;[R]20D6.2°(c)2.7,CHCl3).

J.Am.Chem.Soc.,Vol.118,No.12,19962855

o-NitrophenylSelenide43.Asolutionofcrude42and(2-nitrophenyl)selenylcyanide(3.15g,13.9mmol)in130mLofTHFatroomtemperaturewastreatedwithtributylphosphine(3.73mL,15.2mmol).After0.25h,themixturewasconcentratedunderreducedaspiratorpressureinawell-ventilatedhood.Theresiduewasslurriedin17:3hexane:EtOAcandpurifiedbyflashchromatography(SiO2,17:3hexane:EtOAc),affording7.20g(88%)of43asayellowfoam:1HNMR(400MHz,CDCl3

)δ8.24(d,J)8.0Hz,1H),7.39-7.24(m,8H),4.90(dd,J)9.6,4.4Hz,1H),4.69(d,J)4.3Hz,1H),4.66(s,1H),4.57-4.50(m,3H),3.72(dd,J)11.6,5.7Hz,1H),3.33(s,3H),3.32(s,3),3.04(dt,J)11.6,4.6Hz,1H),2.85-2.78(m,1H),2.34-2.27(m,2H),2.04-1.93(m,2H),1.90(d,J)3.5Hz,1H),1.74-1.60(m,2H),1.03(s,3H),0.88(s,9H),0.09(s,3H),0.07(s,3H);13CNMR(100MHz,CDCl3)δ146.8,138.0,133.7,133.4,129.0,128.5,127.7,127.4,126.5,125.1,101.5,81.9,76.3,70.9,.6,53.2,51.5,41.7,40.4,38.6,37.1,25.9,25.6,25.2,18.1,15.6,-3.4,-4.9;IR(film)2952,2855,1513,1332,1087,984,837,730cm-1;[R]20D2.7°(c)0.85,CHCl3).

Olefin44.Asolutionof43(7.20g,11.1mmol)in140mLofTHFatroomtemperaturewastreatedwith11.5mLof30%H2O2.After12h,themixturewaspouredintoether(800mL)and10%NaOH(200mL).Theaqueouslayerwaswashedwithether(250mL),andthecombinedextractswerewashedwith10%NaOH(3×150mL)andsaturatedNaCl(200mL)anddried(MgSO4).Concentrationunderreducedpressureafforded4.72g(90%)of44asalightyellowoil:1HNMR(400MHz,CDCl3)δ7.38-7.24(m,5H),6.00-5.91(m,1H),5.18(d,J)17.2Hz,1H),5.15(dd,J)17.3,10.2Hz,1H),4.90(dd,J)8.0,3.4Hz,1H),4.63(d,J)7.4Hz,1H),4.59(t,J)5.3Hz,1H),4.55(d,J)11.8Hz,1H),4.51(d,J)11.6Hz,1H),4.45(d,J)7.4Hz,1H),3.72(dd,J)9.2,5.4Hz,1H),3.26(s,6H),2.77(d,J)9.3Hz,1H),2.28(ddd,J)3.2,9.4,13.4Hz,1H),2.00-1.93(m,1H),1.71(dd,J)14.4,4.7Hz,1H),1.61(dd,J)14.3,4.7Hz,1H),1.12(s,3H),0.90(s,9H),0.78(s,6H);13CNMR(100MHz,CDCl3)δ138.5,135.0,128.4,127.5,127.2,119.5,102.1,82.9,79.7,77.2,75.9,71.9,65.0,52.5,52.3,48.7,39.8,39.2,36.2,25.9,18.1,16.9,-3.7,-4.8;IR(film)2948,2929,2850,1461,1250,1078,985,832,774cm-1;[R]20D15.9°(c)3.1,CHCl3);FABHRMSm/ecalcdfor(M+K)C27H44K1O5Si1515.2586,found515.2595.

Aldehyde45.Asolutionof44(3.40g,7.15mmol)and5.25gofsolidNaHCO3in525mLofCH2Cl2at-78°Cwastreatedwithozoneuntilalightbluesolutionresulted.Theexcessozonewasremovedbypassingastreamofnitrogenthroughthesolutionfor5min,andthemixturewasthentreatedwithPPh3(1.87g,7.15mmol)andallowedtowarmtoroomtemperature.After0.5h,themixturewasconcentratedunderreducedpressureandtheresiduewaspurifiedbyflashchroma-tography(SiO2,9:1to4:1hexane:EtOAc),affording2.7g(79%)of45asaclearoil:1HNMR(400MHz,CDCl3)δ9.99(d,J)2.6Hz,1H),7.34-7.32(m,5H),4.92(dd,J)7.6,2.4Hz,1H),4.65(d,J)8.0Hz,1H),4.56-4.49(m,3H),4.44(d,J)11.2Hz,1H),3.72(dd,J)6.4,4.8Hz,1H),3.25(s,3H),3.24(s,3H),2.96(d,J)2.8Hz,1H),2.25-2.18(m,1H),2.00-1.94(m,1H),1.77(dd,J)12.4,4.8Hz,1H),1.69(dd,J)14.4,6.0Hz,1H),1.20(s,3H),0.090(s,9H),0.09(s,3H),0.08(s,3H);13CNMR(400MHz,CDCl3)δ203.9,138.0,128.4,127.6,127.4,101.9,83.1,77.4,77.2,76.0,71.7,65.5,56.7,52.7,52.4,39.6,39.3,34.1,25.8,19.1,18.1,-4.0,-4.9;IR(film)2929,2856,1708,1471,1387,1254,10,837,775,697cm-1;[R]20D9.4°(CHCl3,c)0.51);FABHRMSm/ecalcdfor(M+K)C26H42K1O6-Si1517.2388,found517.2379.

Monohydrazone62.Asolutionof611(34.5g,224mmol)in250mLofEtOHwastreatedwithtriethylamine(93.3mL,669mmol)andhydrazinemonohydrate(21.7mL,447mmol).After1.5h,thereactionmixturewasconcentratedunderreducedpressureandtheresiduewaspurifiedbyflashchromatography(SiO2,ether),affording27.0g(72%)of62asacolorlessoil:1HNMR(400MHz,CDCl3)δ5.05(brs,2H),2.59(ddd,J)9.3,6.3,3.0Hz,1H),2.49dd,J)11.2,6.8Hz,1H),2.42(m,1H),2.05(m,1H),1.62(m,1H),1.29(s,3H),1.25(s,3H),1.10(d,J)6.8Hz,3H);IR(film)3385,2973,2933,1708,1635,1459cm-1;CI(NH3)MSm/ecalcdfor(M+H)C9H16N2O1169,found169.

VinylIodide63.Asolutionof62(13.5g,80.4mmol)andDBN(98mL,793mmol)in2.7LofetherwastreateddropwisewithasolutionofI2(40.8g,161mmol)in1Lofetherover40min.After

2856J.Am.Chem.Soc.,Vol.118,No.12,1996

0.75h,themixturewasfilteredthroughSiO2usingetheraseluent.Concentrationofthefiltrateunderreducedpressureandpurificationoftheresiduebyflashchromatography(SiO2,9:1to4:1hexane:EtOAc)afforded11.0g(52%)of63asacolorlessoiland4.1g(19%)ofasayellowoil.

IodoDienone.Asolutionof63(11g,41.6mmol)in500mLofTHFat0°CwastreatedwithDBN(103mL,825mmol).ThreeportionsofI2(53g,209mmoltotal)wereaddedover30min,andthereactionmixturewasallowedtowarmtoroomtemperature.After8h,themixturewaspouredintoether(750mL)andH2O(500mL).TheorganiclayerwaswashedwithH2O(2×500mL),saturatedNa2S2O3(2×300mL),andsaturatedNaCl(400mL),dried(Na2-SO4),andconcentratedunderreducedpressure.Purificationoftheresiduebyflashchromatography(SiO2,4:1hexane:EtOAc)afforded9.8g(%)ofasayellowoil:1HNMR(400MHz,CDCl3)δ6.81(d,J)6.7Hz,1H),6.54(dd,J)7.9,0.2Hz,1H),1.83(s,3H),1.27(s,6H);13CNMR(100MHz,CDCl3)δ202.7,138.1,132.7,131.9,120.9,53.7,28.5,15.3;IR(film)2971,1655,1560,1456,1374,1361,1033cm-1;CI(NH3)MSm/ecalcdfor(M+H)C9H12O1I1263,found263.

Cyanohydrin65.Asolutionof(9.8g,37mmol)in150mLofCH2Cl2at0°CwastreatedwithTMSCN(6.0mL,45mmol),KCN(0.24g,3.7mmol),and18-crown-6(1.0g,3.8mmol).Thereactionwasallowedtowarmtoroomtemperatureandstirfor8h.Aftercoolingto0°C,thereactionwasquenchedbytheadditionofsaturatedNaHCO3(200mL).ThemixturewaspouredintoCH2Cl2(250mL)andwashedwithsaturatedNaHCO3(200mL).Theorganiclayerwasconcentratedunderreducedpressureinafumehood.Theresiduewaspurifiedbyflashchromatography(SiO2,19:1hexane:ether),affording12.0g(%)of65asayellowoil:1HNMR(400MHz,CDCl3)δ6.61(d,J)6.0Hz,1H),5.52(ddd,J)6.0,3.3,1.6Hz,1H),1.95(s,3H),1.23(s,3H),1.17(s,3H),0.23(s,9H);IR(film)2975,1590,1463,1254,1141,1099,844cm-1;CI(NH3)MSm/ecalcdfor(M+H2O)C13H22N1O1Si1I1379,found379.

Carbinol71.Asolutionofdiene65(3.93g,10.9mmol)in130mLofTHFat-78°CwastreateddropwisewithtBuLi(1.7Msolutioninpentane,12.5mL,21.2mmol).After0.5h,asolutionofaldehyde45in40mLofTHFwasaddeddropwisetothemixtureviacannula.Anadditional20mLofTHFwasusedtotransferanyremainingaldehyde.After0.25h,themixturewastreatedwithsaturatedNH4Cl(50mL),dilutedwithether(200mL),andallowedtowarmtoroomtemperature.Themixturewaspouredintoether(400mL)andsaturatedNH4Cl(150mL).Theaqueouslayerwaswashedwithether(200mL),andthecombinedextractswerewashedwithsaturatedNaCl(200mL),dried(Na2SO4),andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,9:1to4:1hexane:EtOAc),affording5.57gofamixtureofdiastereomers(whitefoam).Thismixtureofdiastereomers(3.04g,4.26mmol)in26mLofTHFat-78°Cwasthentreateddropwisewithtetrabutylammoniumfluoride(1.0MsolutioninTHF,25.6mL,25.6mmol).After0.25h,themixturewasdilutedwithhexane(26mL)anddirectlypurifiedbyflashchromatography(SiO2,hexaneto9:1to4:1hexane:EtOAc),affording2.11g(75%from45)of71asasinglediastereomer(whitefoam):1HNMR(400MHz,CDCl3)δ7.35-7.16(m,5H),6.74(d,J)6.6Hz,1H),6.27(d,J)6.6Hz,1H),5.61(d,J)8.1Hz,1H),4.98(d,J)6.9Hz,1H),4.90(s,1H),4.81(d,J)11.7Hz,1H),4.74(d,J)11.6Hz,1H),4.68(d,J)8.1Hz,1H),4.53(s,1H),4.43(t,J)4.9Hz,1H),3.75(t,J)4.0Hz,1H),3.26(s,3H),3.18(s,3H),2.38(d,J)2.4Hz,1H),2.34-2.25(m,1H),2.01(d,J)15.8Hz,1H),1.85(s,3H),1.42-1.40(m,2H),1.31(s,3H),1.30(s,3H),1.27(s,3H),0.97(s,9H),0.19(s,3H),0.18(s,3H);13CNMR(100MHz,CDCl3)δ206.2,157.9,138.5,137.2,130.6,128.3,127.3,127.2,117.7,102.4,82.2,81.2,77.2,76.0,74.7,69.6,.5,53.1,52.6,51.2,50.8,42.9,40.4,34.8,29.6,25.9,21.7,20.5,18.3,15.6,-4.4,-4.6;IR(film)3378,2929,2856,1654,1471,1376,1256,1050,837cm-1;[R]20D29.3°(c)0.7,CHCl3);FABHRMSm/ecalcdfor(M+)C35H54O7Si1614.3639,found614.3623.

Epoxide73.Asolutionof71(1.49g,2.43mmoles)andNaHCO3(2.97g)in69mLofCH2Cl2atroomtemperaturewastreatedwithmCPBA(95%,1.04g,6.05mmol).After11h,themixturewastreatedwithMe2S(0µL,12.1mmol)anddilutedwithH2O(40mL)andether(200mL).Themixturewaspouredintoether(400mL)and

Danishefskyetal.

saturatedNaHCO3(200mL),andtheaqueouslayerwaswashedwithether(200mL).ThecombinedextractswerewashedwithsaturatedNaHCO3(200mL)andsaturatedNaCl(200mL),dried(Na2SO4),andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,4:1to3:1to2:1petroleumether:ether),affording1.21g(80%)of73asawhitefoam:1HNMR(400MHz,CDCl3)δ7.35-7.24(m,5H),6.27(dd,J)3.1,1.4Hz,1H),5.39(d,J)9.0Hz,1H),4.97(d,J)11.4Hz,1H),4.86(appt,J)7.4Hz,1H),4.77(d,J)11.3Hz,1H),4.68(d,J)9.0Hz,1H),4.(t,J)5.0Hz,1H),4.52(s,1H),3.59(dd,J)11.8,4.3Hz,1H),3.51(d,J)4.5Hz,1H),3.27(s,6H),2.(s,1H),2.34-2.28(m,1H),2.17-2.10(m,2H),1.76(d,J)6.4Hz,1H),1.62(s,3H),1.44(s,3H),1.26(s,3H),1.15(s,3H),0.92(s,9H),0.11(s,6H);13CNMR(100MHz,CDCl3)δ201.2,138.5,137.5,135.5,128.3,127.9,127.6,102.2,82.7,81.7,77.5,77.2,72.7,67.4,66.7,.9,53.9,52.7,52.3,48.0,47.4,41.8,41.2,35.9,25.9,24.1,19.9,18.1,17.3,16.4,-3.6,-4.6;IR(film)3493,2952,2856,1683,1471,1384,1254,1082,837,775cm-1;[R]20D-36.0°(c)5.8,CHCl3);FABHRMSm/ecalcdfor(M+H)C35H55O8Si1631.3666,found631.3672.

Diol74.Asolutionof73(936mg,1.49mmol)and10%Pd/C(1.016g)inEtOH(87mL)at-5°Cwasplacedunderanatmosphereofhydrogen.After1.25h,themixturewasdilutedwithEtOAc,filteredthroughCeliteusingEtOAcaseluent,andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,3:1to7:3to3:2petroleumether:ether),affording610mg(65%)of74asawhitefoam:1HNMR(400MHz,CDCl3)δ7.37-7.30(m,5H),6.12(brs,1H),5.48(d,J)9.2Hz,1H),5.05(d,J)11.4Hz,1H),4.96(d,J)11.4Hz,1H),4.85(appt,J)7.4Hz,1H),4.59(d,J)9.0Hz,1H),4.52(appt,J)5.4Hz,1H),4.06(d,J)5.6Hz,1H),3.59(dd,J)10.6,4.4Hz,1H),3.37(s,1H),3.28(s,3H),3.23(s,3H),3.12(brs,1H),2.58-2.44(m,2H),2.38-2.32(ddd,J)13.2,8.4,4.4Hz,1H),2.22-2.17(m,1H),2.12(s,1H),1.69(d,J)1.2Hz,3H),1.63-1.60(m,1H),1.56(s,1H),1.20(s,3H),1.16(s,3H),1.06(s,3H),0.90(s,9H),0.11(s,3H),0.10(s,3H);13CNMR(100MHz,CDCl3)δ203.6,137.3,132.8,128.8,128.0,127.8,102.1,83.6,82.0,78.6,77.2,71.8,70.5,65.7,53.1,52.1,51.4,41.4,41.3,36.1,34.2,25.9,18.2,16.7,16.1,-3.5,-4.6;IR(film)3438,2947,14,1383,1255,1078,1046,837cm-1;[R]20D35.2°(c)0.27,CHCl3);FABHRMSm/ecalcdfor(M+H)C35H57O8Si1633.3823,found633.3835.

Carbonate75.Asolutionof74(0.76g,1.20mmol)andcarbonyldiimidazole(4.88g,30.1mmol)in40mLofDMFwastreatedwithNaH(48.6g,1.92mmol,95%)inportionsover20min.ThereactionwasquenchedbyadditionofsaturatedNH4Cl(200mL),andthemixturewaspouredintoether(500mL).TheorganiclayerwaswashedwithNaHCO3(300mL),H2O(300mL),andsaturatedNaCl(300mL),dried(Na2SO4),andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,4:1hexane:EtOAc),affording0.g(81%)of75asawhitesolid:mp249-250°C;1HNMR(400MHz,CDCl3)δ7.40-7.24(m,5H),6.13(brs,1H),5.21(d,J)9.9Hz,1H),4.95(d,J)10.3Hz,1H),4.88(d,J)10.1Hz,1H),4.87-4.78(m,3H),4.49(appt,J)5.3Hz,1H),3.60(dd,J)11.7,4.4Hz,1H),3.25(s,3H),3.23(s,3H),3.07-3.02(m,1H),2.69-2.65(m,1H),2.41-2.39(m,1H),2.24-2.16(m,2H),1.70(s,3H),1.58-1.55(m,2H),1.27(s,3H),1.19(s,3H),1.13(s,3H),0.(s,9H),0.11(s,3H),0.81(s,3H);13CNMR(100MHz,CDCl3)δ200.0,154.0,137.8,137.4,129.1,128.4,127.8,102.1,91.3,83.4,81.8,78.8,77.2,76.8,71.8,65.8,53.6,53.0,51.5,46.4,41.9,41.4,36.7,29.8,25.9,18.1,16.0,14.9,-3.3,-4.6;IR(film)2952,1794,1677,13,1047,838cm-1;[R]20D15.3°(c)0.66,CHCl3);FABHRMSm/ecalcdfor(M+Na)C36H54Na1O9Si1681.3434,found681.3467.

Ketone76.Asolutionof75(984mg,1.50mmol)in30mLofTHFat-78°CwastreateddropwisewithasolutionofL-Selectride(1.0MsolutioninTHF,4.50mL,4.50mmol).After1.25h,themixturewastreatedwithsaturatedNH4Cl(5mL),dilutedwithether(300mL),andallowedtowarmtoroomtemperature.Themixturewaspouredintoether(100mL),andsaturatedNH4Cl(75mL).Theaqueousphasewaswashedwithether(100mL)andthecombinedextractswerewashedwithsaturatedNH4Cl(75mL)andsaturatedNaCl(75mL),dried(K2CO3),andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,7:1.5:1.5to5:3:2

TotalSynthesisofBaccatinIIIandTaxol

hexane:CH2Cl2:ether),affording920mg(93%)of76asawhitesolid:mp272-273°Cdec;1HNMR(400MHz,CDCl3)δ7.39-7.24(m,5H),5.18(d,J)9.8Hz,1H),4.97-4.81(m,4H),4.75(s,1H),4.52(t,J)5.2Hz,1H),3.58(dd,J)12.4,4.8Hz,1H),3.28(s,3H),3.27-3.25(m,1H),3.25(s,3H),2.58-2.39(m,2H),2.34(s,1H),2.22-2.16(m,1H),1.97-1.86(m,1H),1.67(d,J)14.8,5.2Hz),1.54(d,J)14.8,5.6Hz,1H),1.28(s,3H),1.24(s,3H),1.10(s,3H),0.95(d,J)6.4Hz,3H),0.90(s,9H),0.11(s,3H),0.09(s,3H);13CNMR(100MHz,CDCl3)δ211.3,153.8,137.4,129.1,128.3,127.8,102.3,93.5,83.1,82.0,78.9,77.2,72.2,65.7,53.9,53.6,53.0,46.2,41.9,41.4,39.1,37.0,29.0,27.0,25.9,23.5,18.2,16.8,14.7,14.6,-3.3,-4.6;IR(film)2950,1786,1709,1115,1049,840cm-1;[R]20D8.1°(c)0.27,CHCl3);FABHRMSm/ecalcdfor(M+Na)C36H56-Na1O9Si1683.3591,found683.3620.

VinylTriflate88.Asolutionof76(920mg,1.39mmol)andN-phenylbis(trifluoromethanesulfonimide)(1.25g,3.49mmol)in47mLofTHFat-78°CwasrapidlytreatedwithKHMDS(0.5Msolutionintoluene,3.34mL,1.67mmol).After10min,themixturewastreatedwithsaturatedNH4Cl(5mL),dilutedwithether(300mL),andallowedtowarmtoroomtemperature.Themixturewaspouredintoether(100mL)andsaturatedNH4Cl(75mL).Theaqueousphasewaswashedwithether(100mL),andthecombinedextractswerewashedwithsaturatedNH4Cl(75mL)andsaturatedNaCl(75mL),dried(K2CO3),andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,9:1to17:3petroleumether:ether),affording1.08g(98%)of88asawhitefoamcontaminatedwith<5%ofN-phenyltrifluoromethanesulfonimide:1HNMR(400MHz,CDCl3)δ7.42-7.31(m,5H),5.22(d,J)12.4Hz,1H),4.94-4.84(m,4H),4.75(s,1H),4.49(appt,J)6.0Hz,1H),3.61(dd,J)11.6,4.4Hz,1H),3.22(s,3H),3.21(s,3H),2.45-2.33(m,3H),2.25-2.18(m,1H),1.75(dd,J)16.8,5.6Hz,1H),1.(s,3H),1.66-1.47(m,3H),1.26(s,3H),1.25(s,3H),1.13(s,3H),0.09(s,9H),0.11(s,3H),0.09(s,3H);13CNMR(100MHz,CDCl3)δ154.2,144.4,137.3,129.4,128.4,127.8,126.5,101.8,90.3,82.9,82.2,78.7,77.2,71.5,65.7,53.2,52.8,45.8,45.0,41.5,41.4,36.8,30.9,27.4,25.9,23.8,23.1,18.1,17.4,17.3,15.4,-3.3,-4.6;IR(film)2947,1797,1400,1211,1137,1077,991,853cm-1;[R]20D-19.5°(c)0.59,CHCl3);FABHRMSm/ecalcdfor(M+Na)C37H55Na1O11S1-Si1815.3084,found815.3125.

Aldehyde.Asolutionof88(1.39mmol)andPPTS(1.75g,6.97mmol)in60mLof9:1acetone:H2Owasheatedat75°Cfor9h.Themixturewascooledtoroomtemperature,treatedwithsaturatedNaHCO3(10mL),andconcentratedwithastreamofnitrogen.Theresiduewasdilutedwithether(200mL)andpouredintosaturatedNaHCO3(50mL).Theaqueousphasewaswashedwithether(2×50mL),andthecombinedextractswerewashedwithsaturatedNaHCO3(2×50mL)andsaturatedNaCl(75mL),dried(K2CO3),andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,9:1to3:1petroleumether:ether),affording998mg(96%)ofasawhitefoam:1HNMR(400MHz,CDCl3)δ9.5(s,1H),7.50-7.29(m,5H),5.15(d,J)10.2Hz,1H),4.95-4.(m,3H),4.82(d,J)9.8Hz,1H),4.62(s,1H),3.96(dd,J)12.6,4.9Hz,1H),2.87(d,J)18.0Hz,1H),2.69(s,1H),2.52-2.44(m,1H),2.35(dd,J)13.6,6.0Hz,1H),2.24-2.14(m,2H),1.80(dd,J)18.0,6.4Hz,1H),1.(s,3H),1.60-1.41(m,2H),1.32(s,3H),1.13(s,6H),0.88(s,9H),0.08(s,3H),0.02(s,3H);13CNMR(100MHz,CDCl3)δ200.9,153.8,143.9,136.9,129.4,128.4,127.9,127.0,90.2,82.6,81.8,77.9,77.3,77.2,70.2,65.7,50.2,44.9,44.7,43.1,37.0,27.2,25.8,23.3,23.0,18.0,17.6,17.3,15.3,-3.7,-4.8;IR(film)2938,1796,1722,1403,1211,1137,1083,995,881,852cm-1;[R]20D-19.4°(c)0.,CHCl3);FABHRMSm/ecalcdfor(M+H)C35F3H50O10S1Si1747.2847,found747.2857.

CyclizationPrecursor90.Asolutionof(998mg,1.34mmol)in45mLofTHFat-78°CwastreateddropwisewithasolutionofPh3P‚CH2(0.10MsolutioninTHF,13.5mL,1.35mmol).Aftercompleteaddition,themixturewasstirredat-78°Cfor10minandat0°Cfor15min.ThemixturewasthentreatedwithsaturatedNH4-Cl(5mL),dilutedwithether(150mL),andallowedtowarmtoroomtemperature.Themixturewaspouredintoether(150mL)andsaturatedNH4Cl(75mL).Theaqueousphasewaswashedwithether(100mL),andthecombinedextractswerewashedwithsaturatedNH4Cl(75mL)andsaturatedNaCl(75mL),dried(K2CO3),andconcentratedunder

J.Am.Chem.Soc.,Vol.118,No.12,19962857

reducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,9:1to17:3petroleumether:ether),affording771mg(77%)of90asawhitefoam:1HNMR(400MHz,CDCl3)δ7.43-7.30(m,5H),5.66-5.56(m,1H),5.22-5.20(d,J)9.9Hz,1H),5.10-5.00(m,2H),4.96-4.80(m,4H),4.70(s,1H),3.(dd,J)11.6,4.4Hz,1H),2.50-2.37(m,3H),2.24-2.15(m,1H),2.08(s,1H),1.87(dd,J)16.0,7.2Hz,1H),1.80-1.72(m,1H),1.(s,3H),1.59-1.41(m,1H),1.24(s,3H),1.19(s,3H),1.14(s,3H),0.88(s,9H),0.09(s,3H),0.02(s,3H);13CNMR(100MHz,CDCl3)δ154.0,144.2,137.2,131.9,129.5,128.4,127.9,126.6,120.2,119.4,90.0,83.0,82.2,78.1,77.2,69.4,65.8,44.9,44.6,42.2,41.1,36.6,27.2,25.8,23.4,23.3,18.1,17.4,17.3,15.9,-3.4,-4.7;IR(film)2940,1797cm-1;[R]20D-22.7°(c)1.1,CHCl3);FABHRMSm/ecalcdfor(M+H)C36F3H52O9S1-Si1672.2584,found672.2583.

Diene91.Asolutionof90(234mg,0.314mmol),K2CO3(130mg,0.942mmol),and4Åsievesin16mLofCH3CNat90°CwastreatedwithPd(PPh3)4(400mg,0.345mmol)inportionsoveraperiodof16.5hsoastomaintainanamber-coloredsolution.Theresultingblackslurrywasallowedtocooltoroomtemperature,dilutedwithether(40mL),andfilteredthroughCeliteusingetheraseluent.Theorangefiltratewasconcentratedunderreducedpressure,andtheresiduewaspurifiedbyflashchromatography(SiO2,17:3to4:1petroleumether:ether),affording85.4mg(46%)of91asawhitefoam:1HNMR(400MHz,CDCl3)δ7.38-7.23(m,5H),5.19(s,1H),5.04-4.96(m,2H),4.84(s,2H),4.73-4.61(m,3H),3.57(dd,J)7.2,9.7Hz,1H),2.81(d,J)16.7Hz,1H),2.62-2.33(m,3H),2.22(d,J)4.7Hz,1H),2.14(d,J)16.4Hz,1H),1.97-1.90(m,1H),1.82-1.74(m,1H),1.69(s,3H),1.69-1.57(m,1H),1.32(s,3H),1.30(s,3H),1.17(s,3H),0.94(s,9H),0.07(s,3H),0.07(s,3H);13CNMR(100MHz,CDCl3)δ154.1,143.2,139.4,138.1,134.8,128.4,127.6,127.5,117.8,93.7,82.4,80.3,79.7,74.5,72.0,.8,44.9,44.7,44.5,40.0,38.0,29.4,26.0,25.5,23.2,22.6,22.4,20.6,18.1,16.4,-3.0,-4.5;IR(film)2954,2738,1803,1472,1455,1207,1008cm-1;[R]20D6.6°(c)1,CHCl3);FABHRMSm/ecalcdfor(M+H)C35H51O6Si1595.3463,found595.3455.

Alcohol95.Asolutionof91(255.6mg,0.430mmol)in8.5mLofTHFatroomtemperaturewastreatedwithtetrabutylammoniumfluoride(1.0MsolutioninTHF,1.29mL,1.29mmol).After6h,themixturewasdilutedwithEtOAc(3mL)andconcentratedunderreducedpressure.TheresiduewasdissolvedinCH2Cl2and4:1hexane:EtOAcandpurifiedbyflashchromatography(SiO2,7:3to3:2hexane:EtOAc),affording1.1mg(92%)of95asaclearoil:1HNMR(400MHz,CDCl3)δ7.36-7.22(m,5H),5.23(s,1H),5.09(dd,J)7.1,2.2Hz,1H),4.98(d,J)9.6Hz,1H),4.83(d,J)11.4Hz,1H),4.80(d,J)11.4Hz,1H),4.71(d,J)4.9Hz,1H),4.68(s,1H),4.58(d,J)9.6Hz,1H),3.58-3.52(m,1H),2.66(d,J)16.3Hz,1H),2.58-2.43(m,2H),2.37-2.32(m,1H),2.22-2.16(m,2H),2.02-1.92(m,2H),1.81-1.73(m,1H),1.68(s,3H),1.65-1.58(m,1H),1.33(s,3H),1.30(s,3H),1.16(s,3H);13CNMR(100MHz,CDCl3)δ154.1,142.6,138.8,137.9,135.6,128.5,127.7,127.5,118.4,93.8,82.9,80.1,79.6,77.2,74.4,72.1,.9,45.9,45.0,43.9,40.2,36.2,29.5,25.7,23.2,22.8,21.0,16.4;IR(film)3472,2926,1799,1455,1021,1009cm-1;[R]20D51.4°(c)1,CHCl3);FABHRMSm/ecalcdfor(M+K)C29H36K1O6519.2149,found519.2166.

Diene96.Asolutionof95(1.1mg,0.394mmol)andtriethyl-amine(0.270mL,1.97mmol)in16.0mLofCH2Cl2at-78°Cwastreatedwithtriethylsilyltrifluoromethanesulfonate(0.098mL,0.433mmol).After0.5h,themixturewastreatedwithsaturatedNaHCO3(4mL)anddilutedwithether(30mL),andthemixturewaspouredintoether(20mL)andsaturatedNaHCO3(20mL).Theaqueouslayerwaswashedwithether(20mL),andthecombinedextractswerewashedwithsaturatedNaHCO3(40mL)andsaturatedNaCl(40mL),dried(Na2SO4),andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,9:1to4:1hexane:EtOAc),affording216.2mg(92%)of96asawhitefoam:1HNMR(400MHz,CDCl3)δ7.36-7.24(m,5H),5.16(s,1H),4.99(dd,J)9.2,2.7Hz,1H),4.93(d,J)9.6Hz,1H),4.82(s,2H),4.69(d,J)4.9Hz,1H),4.-4.60(m,2H),3.56(dd,J)10.2,7.0Hz,1H),2.77(d,J)16.6Hz,1H),2.52-2.34(m,3H),2.18(d,J)4.9Hz,1H),2.12(d,J)16.5Hz,1H),1.93-1.90(m,1H),1.84-1.72(m,1H),1.67(s,3H),1.67-1.59(m,1H),1.28(s,6H),1.15(s,3H),0.98-0.93(t,J)7.9Hz,9H),0.59(q,J)8.0Hz,6H);13CNMR(100MHz,CDCl3)δ

2858J.Am.Chem.Soc.,Vol.118,No.12,1996

154.1,143.2,139.4,138.1,134.9,128.4,127.6,127.5,127.4,117.7,93.7,82.4,80.3,79.8,74.6,72.1,.8,44.8,44.4,40.0,37.8,29.4,25.5,23.2,22.4,20.7,16.2,7.0,5.5;IR(film)2954,2876,1805,1455,1008cm-1;FABHRMSm/ecalcdfor(M+H)C35H51O6Si1595.3455,found595.3473.

Epoxide97.Asolutionof96(171.5mg,0.2mmol)andNaHCO3(343mg)in9.7mLofCH2Cl2atroomtemperaturewastreatedwithmCPBA(95%,.7mg,0.520mmol).After10.25h,themixturewastreatedwithMe2S(30µL)andH2O(10mL).Themixturewasthendilutedwithether(50mL)andpouredintosaturatedNaHCO3(30mL).Theaqueouslayerwaswashedwithether(20mL),andthecombinedextractswerewashedwithsaturatedNaHCO3(2×40mL)andsaturatedNaCl(40mL),dried(Na2SO4),andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,17:3to4:1to3:1petroleumether:ether),affording79.6mg(45%)of97asawhitefoam:1HNMR(400MHz,CDCl3)δ7.36-7.24(m,5H),5.13(m,2H),5.01(m,2H),4.90-4.81(m,3H),4.68(d,J)9.7Hz,1H),3.67(dd,J)10.0,7.6Hz,1H),3.04(d,J)16.9Hz,1H),2.59-2.50(m,1H),2.44-2.40(m,1H),2.28(d,J)16.8Hz,1H),2.15(d,J)4.4Hz,1H),1.98-1.92(m,2H),1.60-1.54(m,1H),1.37(s,3H),1.36(s,3H),1.16(s,3H),0.92(s,3H),0.98-0.92(m,9H),0.56(m,6H);13CNMR(100MHz,CDCl3)δ153.9,140.0,137.5,128.5,127.9,127.8,119.5,91.5,82.4,80.0,79.3,77.2,74.1,70.5,69.4,65.0,62.6,43.9,43.5,43.4,40.2,37.6,25.1,24.5,23.0,22.9,20.5,15.8,7.0,5.6;IR(film)2955,1807,1456,1076,1010,733cm-1;FABHRMSm/ecalcdfor(M+H)C35H51O7Si1611.3404,found611.3416.

Alcohol98.Asolutionof97(79.6mg,0.130mmol)andPd(OAc)2(24.9mg,0.111mmol)in4.7mLofEtOHwasplacedunderanatmosphereofhydrogen.After10.0h,themixturewasdilutedwithEtOAc(25mL),filteredthroughCelite,andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,7:3hexane:EtOAc),affording55.6mg(82%)of98asaclearoil:1HNMR(400MHz,CDCl3)δ5.15(s,1H),5.05(s,1H),4.86(d,J)4.7Hz,1H),4.78-4.69(m,2H),4.34(d,J)9.0Hz,1H),3.69(dd,J)9.7,7.7Hz,1H),3.02(d,J)16.9Hz,1H),2.84-2.77(m,1H),2.70(s,1H),2.44-2.38(m,1H),2.38(d,J)16.7Hz,1H),2.29-2.14(m,2H),2.10(d,J)4.7Hz,1H),2.02-1.87(m,2H),1.69-1.58(m,1H),1.40(s,3H),1.30(s,3H),1.22(s,3H),1.20(s,3H),0.93(t,J)7.9Hz,9H),0.54(q,J)8.0Hz,6H);13CNMR(100MHz,CDCl3)δ153.9,140.0,119.5,91.6,88.3,81.0,80.1,77.2,74.3,70.5,69.4,62.6,43.8,43.5,43.0,40.2,37.6,25.4,24.6,23.4,23.0,20.5,15.7,7.0,5.6;IR(film)3507,2955,2876,1792,1458,1235,1011cm-1;[R]20D-24.5°(c)1.0,CHCl3);FABHRMSm/ecalcdfor(M+K)C28H44K1O7Si1559.2493,found559.2502.

Acetate99.Asolutionof98(55.6mg,0.107mmol)andDMAP(14.4mg,0.118mmol)in0.43mLofpyridineatroomtemperaturewastreatedwithaceticanhydride(100µL,1.07mmol).After16h,themixturewastreatedwithsaturatedNaHCO3(5mL)andthendilutedwithEtOAc(15mL).TheaqueouslayerwaswashedwithEtOAc(10mL),andthecombinedextractswerewashedwithsaturatedNaHCO3(2×10mL),dried(Na2SO4),andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,4:1hexane:EtOAc),affording40.1mg(66%)of99asawhitefoamand4.9mg(9%)ofrecovered98:1HNMR(400MHz,CDCl3)δ5.15(s,1H),5.01(s,1H),4.98(d,J)8.8Hz,1H),4.88(d,J)5.2Hz,1H),4.63(d,J)8.8Hz,1H),4.55(d,J)8.8Hz,1H),3.90(t,J)8.0Hz,1H),3.10(d,J)17.1Hz,1H),2.60-2.52(m,1H),2.46(d,J)5.2Hz,1H),2.30(d,J)18.5Hz,1H),2.30-2.08(m,2H),2.14(s,3H),1.87-1.60(m,4H),1.42(s,3H),1.39(s,3H),1.25(s,3H),1.04(s,3H),0.94(t,J)8.0Hz,9H),0.57(m,6H);13CNMR(100MHz,CDCl3)δ170.1,153.3,139.8,119.2,108.7,90.9,84.1,80.7,79.6,77.2,76.3,70.9,69.0,62.2,44.9,43.7,41.0,40.2,38.0,29.7,25.0,24.7,23.8,21.8,21.3,20.4,16.3,7.0,5.6;IR(film)2950,1800,1730,1243,1013,969cm-1;[R]20D-17.3°(c)0.95,CHCl3);FABHRMSm/ecalcdfor(M+K)C30H46K1O8Si1601.2599,found601.2623.

Benzoate100a.Asolutionof99(40.1mg,0.071mmol)in6mLofTHFat-78°CwastreatedwithPhLi(0.5Msolutionin4:1THF:Et2O,0.57mL,0.285mmol).After2min,themixturewastreatedwithsaturatedNH4Cl(10mL)andthendilutedwithether(15mL).Theaqueouslayerwaswashedwithether(20mL),andthecombined

Danishefskyetal.

extractswerewashedwithsaturatedNH4Cl(10mL)andsaturatedNaCl(10mL),dried(Na2SO4),andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2,4:1to3:1to7:3petroleumether:ether),affording42.4mg(93%)of100aasawhitefoam:1HNMR(400MHz,CDCl3)δ8.08(appd,J)7.9Hz,2H),7.59-7.56(m,1H),7.50-7.43(m,2H),5.88(d,J)5.4Hz,1H),5.15(s,1H),5.05-5.02(m,2H),4.34(d,J)8.2Hz,1H),4.23(d,J)8.3Hz,1H),3.91(t,J)8.4Hz,1H),2.99(d,J)16.4Hz,1H),2.59-2.51(m,3H),2.27(s,3H),2.25-2.08(m,2H),1.84(dd,J)9.2,14.9Hz,1H),1.73-1.69(m,1H),1.58(s,1H),1.53(s,3H),1.46(s,3H),1.38(s,3H),1.31(s,3H),0.99(s,3H),0.95(t,J)8.0Hz,9H),0.60-0.50(m,6H);13CNMR(100MHz,CDCl3)δ169.6,140.7,133.5,130.0,129.4,128.6,117.8,108.8,84.1,82.3,78.4,77.2,73.2,71.5,69.8,62.7,44.2,44.1,43.4,42.3,37.6,26.0,25.7,25.6,22.0,21.4,21.3,16.1,7.0,5.7;IR(film)3521,2954,2876,1733,1277,1247,1098cm-1;[R]20D15.1°(c)1.0,CHCl3);FABHRMSm/ecalcdfor(M+)C36H52O8Si10.3431,found0.3410.

Ketone102.Asolutionof100(42.4mg,0.066mmol)in2.4mLofpyridinewastreatedwithOsO4(319.7mg,1.258mmol)andheatedto105°C.After24h,themixturewascooled,dilutedwithEtOAc(10mL),andtreatedwithsaturatedNaHSO3(10mL).TheaqueouslayerwaswashedwithEtOAc(4×10mL),andthecombinedextractswerewashedwithsaturatedNaHSO3(2×10mL),H2O(10mL),andsaturatedNaCl(10mL),dried(Na2SO4),filteredthroughSiO2(1mL),andconcentratedunderreducedpressure.Theresiduewasdissolvedin1:1C6H6:MeOH(8mL),cooledto0°C,andtreatedwithlead(IV)acetate(47.4mg,0.265mmol).After5min,themixturewasdilutedwithether(20mL)andtheresultingyellowslurrywasfilteredthroughSiO2(2mL)usingetheraseluent.Thefiltratewasconcentratedunderreducedpressure,andtheresiduewaspurifiedbyflashchromatography(SiO2,4:1to7:3hexane:EtOAc),affording26.1mg(61%)of102asawhitesolid:1HNMR(400MHz,CDCl3)δ8.11-8.09(appd,2H),7.62-7.59(appt,1H),7.50-7.46(appt,2H),6.07(d,J)5.5Hz,1H),5.00(d,J)8.6Hz,1H),4.38(d,J)8.5Hz,1H),4.26(d,J)8.4Hz,1H),3.76(t,J)8.4Hz,1H),3.35(d,J)15.5Hz,1H),2.85(d,J)15.4Hz,1H),2.70(d,J)5.4Hz,1H),2.51-2.49(m,1H),2.30(s,3H),2.30-2.18(m,2H),1.84-1.70(m,2H),1.50(s,3H),1.45(s,3H),1.32(s,3H),1.04(s,3H),0.95(t,J)8.0Hz,9H),0.63-0.57(m,6H);13CNMR(100MHz,CDCl3)δ202.7,169.8,166.9,133.8,130.1,129.1,128.7,84.0,82.0,77.9,77.2,76.5,73.1,72.1,65.8,62.3,50.9,44.8,44.4,40.1,37.7,26.3,25.8,25.6,23.0,22.0,21.2,16.0,15.3,14.2,6.9,5.8,5.3;IR(film)3515,2955,2876,1731,1695,1272,1247,1098,712cm-1;FABHRMSm/ecalcdfor(M+H)C35H51O9Si13.3303,found3.3301.

Enone103.Asolutionof102(26.1mg,0.041mmol)andaceticanhydride(38µL,0.41mmol)in2.0mLofTHFat-78°CwastreatedwithSmI2(0.1MsolutioninTHF,165µL,0.0165mmol)untilagreensolutionpersisted.After10min,themixturewastreatedwithsaturatedNH4Cl(5mL),allowedtowarm,anddilutedwithEtOAc(10mL)andH2O(2mL).ThemixturewaspouredintoEtOAc(10mL)andsaturatedNH4Cl(5mL),andthelayerswereseparated.TheaqueouslayerwaswashedwithEtOAc(10mL),andthecombinedextractswerewashedwithsaturatedNaHCO3(10mL)andsaturatedNaCl(10mL),dried(Na2SO4),andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2[2mL],7:3hexane:EtOAc),affording23.4mg(92%)of103asawhitesolid:1HNMR(400MHz,CDCl3)δ8.11-8.09(appd,2H),7.61-7.57(appt,1H),7.50-7.45(appt,2H),5.87(d,J)5.8Hz,1H),4.(d,J)8.3Hz,1H),4.34(d,J)8.3Hz,1H),4.16(d,J)8.3Hz,1H),3.72(t,J)9.1Hz,1H),3.14(d,J)15.6Hz,1H),3.08(d,J)5.8Hz,1H),2.65-2.58(m,2H),2.57(d,J)15.6Hz,1H),2.28(s,3H),2.28-2.24(m,1H),1.97-1.86(m,1H),1.82-1.74(m,1H),1.75(s,3H),1.41(s,3H),1.35(s,3H),1.13(s,3H),0.97(q,J)8.0Hz,9H),0.62(t,J)8.0Hz,6H);13CNMR(100MHz,CDCl3)δ202.2,170.0,167.0,144.6,138.2,133.6,130.1,129.3,128.6,84.5,82.4,80.2,77.2,76.5,73.4,72.7,50.4,44.6,44.2,39.6,38.0,30.2,26.7,26.0,22.8,22.3,20.0,16.1,7.0,5.3;IR(film)3502,2956,1731,1677,1456,1273,1244,1098,730,711cm-1;FABHRMSm/ecalcdfor(M+H)C35H51O8Si1627.3353,found627.3376.

r-HydroxyKetone104.Asolutionof103(23.4mg,0.037mmol)in2.5mLofTHFat-78°CwastreatedwithtBuOK(0.24Msolution

TotalSynthesisofBaccatinIIIandTaxol

inTHF,0.62mL,0.149mmol),andthemixturewasplacedina-20°Cbath.After0.75h,themixturewasbrieflywarmedto0°Candthentransferredviacannulatoa0°Csolutionof(PhSeO)2O(107.5mg,0.298mmol)in2.5mLofTHF.After0.75h,themixturewasdilutedwithEtOAc(20mL)andpouredintosaturatedNaHCO3(20mL).TheorganiclayerwaswashedwithsaturatedNa2S2O3(15mL)andsaturatedNaHCO3(15mL),dried(Na2SO4),andconcentratedunderreducedpressure.Theresiduewasdissolvedin2.5mLofTHF,cooledto-78°C,andtreatedwithtBuOK(0.24MsolutioninTHF,0.92mL,0.149mmol).After0.5h,themixturewastreatedAcOH(0.8MsolutioninTHF,0.47mL,0.373mmol)andallowedtostirfor10minat-78°Candthenallowedtowarmfor10min.ThemixturewasdilutedwithEtOAc(40mL)andpouredintosaturatedNaHCO3(20mL).Theorganiclayerwasdried(Na2SO4)andconcentratedunderreducedpressure,andtheresiduewaspurifiedbyflashchromatography(SiO2[2mL],9:1to4:1to7:3hexane:EtOAc),affording19.3mg(81%)of104asawhitesolid:1HNMR(400MHz,CDCl3)δ8.05(appd,2H),7.58(appt,1H),7.43(appt,2H),5.56(d,J)6.Hz,1H),5.18(d,J)2.5Hz,1H),4.95(d,J)8.2Hz,1H),4.37(dd,J)6.8,8.0Hz,1H),4.30(d,J)8.4Hz,1H),4.20(d,J)2.3Hz,1H),4.15(d,J)8.5Hz,1H),3.83(d,J)6.6Hz,1H),2.70-2.65(m,1H),2.49-2.45(m,1H),2.30(s,3H),2.28-2.20(m,1H),1.96(s,3H),1.92-1.77(m,2H),1.70(s,3H),1.53(s,1H),1.50(s,1H),1.30-1.23(m,1H),1.09(s,3H),1.08(s,3H),0.91(t,J)7.9Hz),0.60-0.48(m,6H);IR(film)3455,2956,1727,1452,1370,1271,1248,1107,984,821,718cm-1;FABHRMSm/ecalcdfor(M+H)C35H51O9Si13.3303,found3.3316.

13-Deoxy-7-O-TES-baccatinIII(105).46Asolutionof104(19.3mg,0.03mmol)andDMAP(1.8mg,0.015mmol)in0.2mLofpyridineatroomtemperaturewastreatedwithaceticanhydride(28.3mL,0.3mmol).After16h,themixturewasdilutedwithEtOAc(20mL)andpouredintosaturatedNaHCO3(15mL).TheorganiclayerwaswashedwithsaturatedNaCl(15mL),dried(Na2SO4),andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2[2mL],4:1hexane:EtOAc),affording15.9mg(76%)of105asawhitesolid.

13-Oxo-7-O-TES-baccatinIII(106).46Asolutionof105(15.9mg,0.0232mmol)in3.5mLofPhHwastreatedwithNaOAc(57.1mg,0.696mmol),celite(150mg),andPCC(150mg,0.696mmol).Theresultingmixturewasheatedtorefluxfor1h.Aftercoolingtoroomtemperatureanddilutingwith4mLof9:1PhH:ether,thecrudereaction

J.Am.Chem.Soc.,Vol.118,No.12,19962859

mixturewasflushedthroughaplugofsilicagel.Flashchromatography(SiO2[2mL],9:1PhH:ether)afforded10.3mg(%)of106asawhitesolid.

7-O-TES-baccatinIII(107).46Asolutionof106(10.3g,0.0147mmol)in2.0mLofMeOHwastreatedwithNaBH4(10.3mg,0.272mmol)every30minfor2h.ThereactionwasquenchedwithNH4Cl(4mL)andstirredvigorouslyfor15min.ThemixturewasdilutedwithEtOAc(20mL),washedwithsaturatedNaCl(10mL),driedoverNa2SO4,filtered,andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2[2mL],7:3hex:EtOAc)toprovide8.1mg(79%)of107alongwith1.1mg(11%)ofrecovered106.

BaccatinIII(1).Asolutionof107(8.1mg,0.012mmol)in0.8mLofTHFwastreatedwith0.1mLofHF‚pyrinaTeflonflask.After2h,thereactionwasdilutedwithether(20mL)andextractedwithsaturatedNaHCO3(2×10mL),saturatedCuSO4(10mL),andsaturatedNaCl(10mL).TheorganiclayerwasdriedoverNa2SO4,filtered,andconcentratedunderreducedpressure.Theresiduewaspurifiedbyflashchromatography(SiO2[2mL],7:3hex:EtOAc)toafford5.7mg(85%)of1asawhitesolid.ThismaterialwasidenticaltoanauthenticsampleofbaccatinIIIbyTLC,1HNMR,13CNMR,IR,andopticalrotation.

Acknowledgments.WededicatethisworktoDr.MonroeWalloftheResearchTriangleInstituteforhisdiscoveryoftaxolandmanyotherfascinatingNaturalProducts.ThisresearchwassupportedbytheNationalInstitutesofHealth(NIH,GrantNo.AI16943).ADamonRunyon-WalterWinchellCancerFundPostdoctoralFellowshiptoJ.J.M.,anAmericanCancerSocietyPostdoctoralFellowshiptoW.B.Y.,andaNationalScienceFoundationPostdoctoralFellowshiptoC.A.C.aregratefullyacknowledged.WethankDr.G.Sukenick(MemorialSloan-KetteringCancerCenter)andBarbaraSporerandVinkaParmakovich(ColumbiaUniversity)formassspectralanalyses.WealsothankSusandeGalaofYaleUniversityforcrystal-lographicanalysis.

JA952692A

(46)CompoundreportedbyNicolaou;see:Nicolaou,K.C.;etal.J.Am.Chem.Soc.1995,117,653-659.

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