有机化合物的合成与分析-药明康德培训资料

WuXiAppTecTrainingCommitteeAlkene/AlkyneMetathesisJianguangLeiOverviewoftopicstobediscussed:CarboncarbondoublebondformationviaAlkeneoralkynemetathesisreactionsGeneralmechanismBackground-MilestonesW(CO)5PhR(Katz,1974)R=Ph;OMeTiClAlCpCp1978TebbereagentMoPhN(F3C)2HCOCiPriPr(F3C)2HCOC1990SchrockRuPhPhClPcy3ClPcy3RuPhClPcy3ClPcy3RuPhClClNNNNCyCyCyCyRuPhClPcy3ClNNMesMesRuClClPcy3ORuClClNNMesMesO199219951998HermannGrubbs'2ndgenerationcatalystGrubbs'1stgenerationcatalystHoveyda-GrubbsCatalyst2ndGenerationHoveyda-GrubbsCatalyst1stGenerationCatalystsRR1R2R3[M]R'RR1[M]R'R1R'R[M]RR3[M]R2RR3[M]R2R'R1[M]R2R1R212534ACBDEFWuXiAppTecTrainingCommitteeAlkene/AlkyneMetathesisJianguangLeiSchrock’sCatalystMoPhN(F3C)2HCOCiPriPr(F3C)2HCOC‹ElectrondeficientMo(VI),4-especies‹NArligand,ORligands,andinitialalkylidene,needtobebulkytoallowforisolation‹ElectronwithdrawingalkoxidesincreasereactivityGrubbs'MetathesisCatalyst1.Commerciallyavailable2.ReasonablystabletowardH2O,O2,andminorimpuritieseaseofhandling3.Lowerreactivityvs.Molybdenumimidoalkylidenecatalyst4.Highfunctionalgrouptolerance1.Commerciallyavailable2.Airandwatersensitive3.Intolerantofprotonsonheteroatoms(RCO2H,RSH,ROH,etc.)andsomefunctionalities(eg.RCHO)RingClosingMetathesis(RCM)Finkel'shsteinetal.J.Mol.Cat.1992,76,133.Forbesetal.J.Am.Chem.Soc.1992,114,10978.RCMofSmallRings:OlefinSubstitution1.Intramolecularmetathesisofadienetoformacyclicolefin2.Reactionpathwayofdienedependsoncatalyst,dilution,ringsize,andsubstrate3.Dilution:IntermolecularADMETcangenerallybepreventedbyapplyingdilutionprinciple1.Synthesisof5-7memberedringsisfairlyfacile2.Typicallyrutheniumcatalystsarepreferredovermolybdenumcatalysts‹LigandEffectonCatalystActivity:Halides:IBrCl‹Phosphines:CatalystactivityincreasesasconeangleandEletrondonatingabilityincreaseRuPhClPcy3ClPcy3RuPhClPcy3ClNNMesMesSiOSiSiSiOADMETRe2O7/Al2O3-SnBu4diluteSchrock'scatalystconcentrated14%86%95%5%WuXiAppTecTrainingCommitteeAlkene/AlkyneMetathesisJianguangLeiGrubbs,R.Hetal.Org.Lett1999,1,953.RCMofSmallRings:AlcoholsHighlycompatiblewithRubasedcatalysts;MocatalystshavelowtoleranceforROHY.Matsuya,etal,Org.Lett.,ArticlesASAP,PublicationDate(Web):August4,2009RCMofSmallRings:EthersRichardP.Hsungetal,Org.Lett.,2008,2525-2528.RCMofSmallRings:AminesK.Yoshidaetal,Org.Lett.,2008,515-518PrimaryandsecondaryaminesareincompatibleRCMofSmallRings:CarbonylsY.Georges,etal,J.Org.Chem.2009,74,2008–2012MoPhN(F3C)2HCOCPriiPr(F3C)2HCOCRuPhClPcy3ClPcy3RuPhClPcy3ClNNMesMes123EEEEEEEEEEEEEEEEproducttimeyield(%)usingsubstrate10min10min90min24h100100529310020N.P.N.P.1001009031123OR2OHHHHOR1HHOR1=OTBS,HR2=Me,HOOHHHHOR1HHOR2Toluene,80oCRuPrOClClNNArArAr=o-tolylcatalyst10%OOPMBOOMeOPivOTBSHOOPMBOOMeOPivOTBSH30%Grubbs'G-IItoluene[0.01M],rt2%Grubbs'G-IIcatalystDCM[0.01M]OAcOAcOAcOAcOOOAcOAcOAcOAcOOSpicigerolide(1)NOBn7.5%catalysttoluene,80oCNOBn1.1.2eq.DDQdioxane,rtNNH22.Pd/C,H2MeOH,rt,76%MOMO71%MOMONNOHBnMOMONH2OH.HClPyridine,rt,66%MOMORuPhClNNMesMesCy3PClWuXiAppTecTrainingCommitteeAlkene/AlkyneMetathesisJianguangLeiRCMofSmallRings:VinylethersOOOTBDPSOOOTBDPSOCp2TiAlMe2Cl1.THF,pyr,(-50to20oC),61%2.p-cymene,130oC,76%OTBDPSO[3,3]OBernardelli,Petal,J.Am.Chem.Soc.2001,123,9021-9032RCMofSmallRings:PhosphorusHetherington,L.;Greedy,B.;Gouverneur,V.Tetrahedron2000,56,2053.RCMofSmallRings:SulfurWhitehead,A.etal,TetrahedronLett.2003,44,4275.RCMofSmallRings:EnyneMetathesis“ene-then-yne”mechanismYRYRRuArYRRuArRuYRYRRuRuArArYRRuRYYRRuYRYRuRTIPSOOOOORuOClClNMesMesN20%AO(10eq)DCM(0.005M)45oC,83%A(+)-8-epi-XanthatinDavidA.Kummer,etal,Org.Lett.,2005,7(21),4621–4623H2NHNNHPPhOHNNHPPhOPhPOCl2Et3N,DMAP/DCM41%Grubbs'IDCM,40oC,3d36%RuPhClPcy3ClPcy3WuXiAppTecTrainingCommitteeAlkene/AlkyneMetathesisJianguangLeiRCMofMediumRings(8-12memberedrings)Cooketal.Org.Lett.1999,1,6151.Becauseofenthalpicandentropicinfluences,mediumsizedringsaredifficulttoprepare;hencesubstratesaremorepronetointermolecularacyclicdienemetathesisreactions(ADMET)2.Desiredcyclizationcanbefacilitatedbyprovidingsomesortofconformationalconstraint.CyclicConformationalControlMatthewJ.Campbelletal,J.Am.Chem.Soc.2009,131,10370–10371AcyclicConformationalControlUseofgaucheeffectof1,2-dioxygensubstituentstofacilitateringclosureLisaMitchell,etal，J.Org.Chem.2008,73,2389-2395RCM:Macrocyclizations1.DienesdevoidofanyconformationalpredispositiontowardsringclosurecanbegoodRCMsubstrates2.Formationofcisandtransisomersintheformationoflargerings3.ExperimentalConsiderations:a.Rateofoligimerizationcanbeslowedbydilutingthereactionoraddingthedieneslowlyb.Highertemperaturesgenerallyrequiredc.HighercatalystloadingsNNOArZHHNNOArZHHNHNOHZHHArOBalanolGrubbscatalystOOOTMSRHOOOTMSRHOHHOAcORHOOTMSRu-cata.(10mol%),0.0011M,(CH2Cl)2,80oC,N2sparge(+)-PolyanthellinAR=CO2MeRuClClNNMesMesOORFFOORFFO5%330%Ti(O-iPr)4DCM,refluxyield:R=BzBnHWuXiAppTecTrainingCommitteeAlkene/AlkyneMetathesisJianguangLeiSubstrateconsiderations1.Presenceofapolarfunctionalgroup(ester,amide,ketone,ether,sulfonamide,urethane)RCM:Macrocyclizations(continued)2.SiteofringcloseisakeyissueOOOO4mo