周其林院士-手性螺环催化剂助推制药工业

手性螺环催化剂助推制药工业Qi-LinZhou（周其林）元素有机化学国家重点实验室(南开大学)StateKeyLabofElemento-orgChem,NankaiUniversity武汉2015-3-19ChiralityWidelyExistsinNatureChiralDrugsPlayACriticalRoleforHumanHealth~50%Marketingdrugsand2/3developingdrugsarechiralChiralResolutionChiralTransformation.........AsymmetricCatalysisChiralAmplification.........StoichoimetricAsy.SynthesisTheMethodsforPreparationofOpticallyActiveCompoundsAsymmetriccatalysis(chemicallyandenzymetically)isthemostefficientmethodforthepreparationofopticallyactivecompoundsVeryFewAsymmetricCatalyticHydrogenationsHaveBeenAppliedinIndustryStatisticsfortheindustrialapplicationofenantioselectivecatalyticreactionsTransformationProductionPilotBenchscale5t/y5t/y50k50kgHydrogenationofenamides11264HydrogenationofC=C-COOR10346andC=C-CH-OHHydrogenationofotherC=C10122Hydrogenationofα-and22364β-functionalizedC=OHydrogenation/reduction00014ofotherC=OHydrogenationofC=N10100DihydroxylationofC=C01004EpoxidationofC=Cand21202oxidationofsulfideIsomerizationetc.20301M.Thommen,H.-U.BlaserinPhosphorusLigandsinAsymmetricCatalysis,ed.A.Börner,Wiley-VCH,2008ProcessesofAsymmetricHydrogenationinIndustryAsymmetriccatalytichydrogenationisthemostpopularchiraltechnology,70%asymmetricprocessesusedinindustryareasymmetrichydrogenationTakasagoProcessfor4AA(intermediateforantibioticcarbapenems)SyngentaProcessof(S)-MetolachlorAgoodasymmetriccatalysis?1)NewcatalystAgoodasymmetrichydrogenation?Highefficiency2)Highyield3)Highchemoselectivity4)Highregioselectivity5)Highenantioselctivity6)Highdiasteroselectivity7)Lowcatalystloading8)Mildreactioncondition9)……Asy.AdditionAsy.AlkylativeCouplingAsy.AllylicOxidationAsy.AllylicSubstitutionAsy.CyclopropanationAsy.HydrovinylationAsy.ReductiveCouplingAsy.RingOpeningAsy.SilylcyclizationAsy.HydrogenationofOlefinsAsy.HydrogenationofAldehydesAsy.HydrogenationofKetonesAsy.HydrogenationofIminesAsy.HydrogenationofEnaminesAsy.N-HInsertionAsy.O-HInsertionAsy.Si-HInsertionAsy.S-HInsertionAsy.B-HInsertionDevelopmentofChiralSpiroLigandsLigandsAreAvailableFromJiuzhouPharma,StremandAldrichCoAsymmetricHydrogenationofAldehydesandKetonesviaDynamicKineticResolutionAsymmetricHydrogenationofUnsaturatedAcidsAsymmetricHydrogenationofKetoneswithHighTurnoverNumbersASYMMETRICHYDROGENATIONOFa-ARYLALDEHYDESVIADYNAMICKINETICRESOLUTIONHydrogenationofKetonesHydrogenationofa-ArylaldehydesNoyoritypecatalystHighlyenantioselectiveEnantioselective?SynthesisofSpirobiindaneDiphosphinesY.Uozumi,A.Tanahashi,S.-Y.Lee,T.Hayashi,J.Org.Chem.1993,58,1945AsymmetricHydrogenationofa-PhenylpropanalUsingRuCl2(SDPs)(Diamine)CatalystsRuCl2[(S)-DMM-SDP)][(R,R)-DACH)],S/B=5,S/C=1000,rt,100%conv.,78%eeSynthesisofChiralPrimaryAlcoholsbyAsymmetricHydrogenationofa-ArylaldehydesviaDKRZ.-T.Zhou,J.-H.Xie,Q.-L.Zhouetal.JACS2007,129,1868DeuterationExperimentShowsThattheHydrogenationTakesPlaceonCarbonylGroupAsymmetricSynthesisofa-AminoCyclicAlcoholsS.Liu,J.-H.Xie,Q.-L.Zhouetal.ACIE2007,46,7506AsymmetricHydrogenationofa-AminoCyclicKetoneswithNoyoriCatalystNoyorietal.JACS2000,122,6510AsymmetricSynthesisofAcyclicChiral1,2-AminoAlcoholsS.Liu,J.-H.Xie,Q.-L.Zhouetal.JACS2009,131,4222石蒜烷(-)-a-Lycorane的不对称合成G.Li,J.-H.Xie,Q.-L.Zhouetal.Adv.Synth.Catal.2013,355,1597Galanthamine的不对称合成ChenJ.Q.;Xie,J.-H.*;Zhou,Q.-L.*;etal.Org.Lett.2012,14,2714加兰他敏是乙酰胆碱酯酶抑制剂，用于治疗阿尔茨海默氏症和重症肌无力等。一次构筑三个手性中心：石蒜烷(+)-g-Lycorane的不对称合成C.Liu,J.-H.Xie,Q.-L.Zhouetal.ACIE2013,52,593Synthesisof(+)-g-LycoraneAsymmetricHydrogenationofAldehydesandKetonesviaDynamicKineticResolutionAsymmetricHydrogenationofUnsaturatedAcidsAsymmetricHydrogenationofKetoneswithHighTurnoverNumbersASYMMETRICHYDROGENATIONOFa,b-UNSATURATEDACIDSNon-steroidalanti-inflammatoryagentsSynthesisofChiralSpiroP-N/IrCatalystsAsymmetricHydrogenationofa-MethylcinnamicAcidwithSpiroIr/SIPHOSCatalysts(WithoutEt3N:58%conv.,99%eeafter24h)HighlyEnantioselectiveSynthesisofChiralCarboxylicAcidsS.Li,S.-F.Zhu,Q.-L.Zhouetal.JACS2008,130,8584AsymmetricHydrogenationofa-SubstitutedAcrylicAcidsUsingIridiumCatalystofChiralSpiroAminophosphineLigandsEnantioselectiveSynthesisofa-SubstitutedPropanoicAcidsY.-B.Yu,S.-F.Zhu,Q.-L.Zhouetal.ACIE2012,51,8872ProposedMechanismAsymmetricHydrogenationofa-Aryloxyanda-Alkyloxya,b-UnsaturatedCarboxylicAcidErtiprotafib,TesaglitazarandAleglitazararepotentialagonistsagainstperoxisomeproliferator-activatedreceptors(PPARs)inthetreatmentoftype2diabetesanddyslipidemia.Fenoxaprop-Pisacropprotectionreagent.AsymmetricHydrogenationofa-PhenoxyCrotonicAcidwithIr-SIPHOSComplexesAsymmetricHydrogenationofa-Aryloxyanda-AlkyloxyCinnamicAcidwithIr-SIPHOSComplexesS.Li,S.-F.Zhu,Q.-L.Zhouetal.JACS2010,132,1172RocheProcessofAleglitazar(NewdrugfortreatmentofT2D,WO2010/108861A1)ApplicationofIr-SIPHOXCatalystsintheSynthesisofChiralDrugAleglitazarAsymmetricHydrogenationofUnsaturatedHeterocyclicAcidsAsymmetricHydrogenationofUnsaturatedN-HeterocyclicAcidsAsymmetricHydrogenationofUnsaturatedO-HeterocyclicAcidsS.Song,S.-F.Zhu,Q.-L.Zhouetal.ACIE2013,52,6072IsotopicLabelingExperimentSynthesisof(R)-tiagabinetiagabineisag-aminobutyrica