復(fù)雜分子全合成

1、會計學(xué)1復(fù)雜分子全合成復(fù)雜分子全合成第1頁/共29頁第2頁/共29頁OH2NOOHOHOHOHOO(+)-discodermolide (Smith,1999)OOPMPIOTBS(+)-AOCHOOTBSOIOPMB(+)-B(-)-CPMBOOHONOMe(-)-CPPMB：對甲氧基芐基，p-methoxybenzylTBS:叔丁基二甲硅醚 以往，在實驗室中獲得較大量的復(fù)雜結(jié)構(gòu)糖類化合物是一個較為艱難的目標(biāo)。高碳糖物質(zhì)神經(jīng)氨酸Neu5Ac克量級以上的合成，以價廉的葡萄糖酸第3頁/共29頁OHOAcHNHOOHCOOHHOOHOOOONHAcTBSOOOOOOOONHAcHOOOHOHOHO

2、HO唾液酸甲脂(Neu5Ac methyl ester) 葡萄糖酸內(nèi)酯第4頁/共29頁OOOONHAcHOOOCHOOONHAcOOOONHAcHOabcOOOONHAcTBSOdOOOOAcHNBreOOOOAcHNOTBSOTBSOH3COOfOHOAcHNHOOHCOOMeHOOHgOAcOAcHNAcOOAcCOOMeAcOOAc第5頁/共29頁第6頁/共29頁MeHOOOOMeMeOOHMeOBnMeOBnOOMeMeOBnOBnmesoClCl+MeMeOOObenzophenoneacetone,hv,rtClClOMeMeOOZn,TMSClAc2O,850CLiAlH4,TH

3、F,rt,47%,3stepsOHOHMeMeBnBr,NaH,99%OsO4,NMO,94%OHOHMeMeHOHOSwernOOHOHMeMeOOCH2=CH-CH2-MgBr-780C,78%OHOHMeMeOHOHRCMOHOHMeMeOBnOBnPd(OAc)4OOMeMeOBnOBn內(nèi)消旋雙酮的獲得內(nèi)消旋雙酮的獲得OOMeMeOBnOBnLiHMDS,THF,-1000CHOHMeMeOBnOBnO75%MCPBA,rt,81%HOHMeMeOBnOBnOO第7頁/共29頁OHMeMeOBnOBnOOBrCH2Br(OEt)62%OMeMeOBnOBnOOOEtBrBu3SnH,E

4、t3B,73%CSA,EtOH,86%OMeMeOBnOBnOOEtOTMSOTf,DIEAEschenmoser saltMCPBA,70%OMeMeOBnOBnOOEtO(1)H3O+(2)MsCl77%OMeMeOBnOBnOOL-selectrideTf2NR,99%Pd(OAc)2,TPPHCOOH,89%OMeMeOBnOBnOMeDIBAL-H,88%Na,NH3,100%OMeMeOHOHMeOHDowexTHF-H2OOMeMeOHOHMeOHHOAg2CO364%OMeMeMeOHDMDO,rt96%OMeMeMeOHOOOOOOOp-TsOH81%OMeMeMeOOHOO

5、Omerrilactone A第8頁/共29頁OHOHOOCOOHOOOHOOHOOCOOHOOOOphomoidride Aphomoidride B第9頁/共29頁MeOOMeOOTBSOOOOTBSOOOC8H15PMBOOOC8H15PMBOOOTBDPSMe2AlCl,90%OOPMBOC8H15OTBDPS1.TBAF;2.Dess-martin;3.SSLi4.NaH,TESOTf,67%OOOMeOOCPMBOC8H15MeOOMeC5H9TESOOOPMBOC8H15TESOO1.KHMDS,PhNTf22.Pd(OAc)2,CO,TPP,MeOH3.PhI(O2CCF3)2

6、,MeOH62%1.DIBAL-H2.VO(acac)2,TBHP3.Et2AlCN55%第10頁/共29頁OOPMBOC8H15MeOOMeC5H9TESONCHOOH1.MsCl,TEA2.K2CO3,MeOH3.10%H2C2O4,air56%OOPMBOC8H15OMeC5H9TESOOOOMeO1.AcOH2.DMOP,CSA3.TBSOTf4.DDQ44%OOHOC8H15C5H9TESOOOO1.PDC2.AcOH3.TESOTf4.Dess-Martin67%C8H15C5H9TESOOOOOTESOHOHOOO1.NaClO22.MsCl,TEA3.CH2Cl24.Ag2O3

7、2%1.TFA,MeSO3H2.Dess-Martin3.TBSOTf63%CHOC8H15C5H9OOOOOTBSOOC8H15C5H9OOOOOTBSOOCOOH第11頁/共29頁1.EDC,amine2.TFA3.Dess-Martin65%C8H15C5H9OOOOOOONO1.parachloroaniline2.LiOH50%C8H15C5H9OOOOHOOOOHOHOMeSO3H90%C8H15C5H9OOOOOOOOHOTBDPS:：叔丁基二苯基硅基；PMB：對甲氧基芐基；TBAF：四丁基氟化銨；DDQ：2，3-二氯-5，6-二氰基-1，4-二醌TFA：三氟乙酸；PDC：吡啶二

8、鉻酸鹽；TES:三乙基硅基合成路線phomoidride B(Fukuyama):第12頁/共29頁HSCOOHEtSCOOHC8H151.LHMDS,ClCOOMe2.cat.Cs2CO3ONOOONOOEtSC8H15MeOOCCOOMeBnBn1.Bu2BOTfO OC5H9OHC2.SO3-Py,DMSOi-Pr2NEt60%ONOOBnOOOC8H15EtSMeOOCCOOMeSOOH1.ZnCl2,Py2.LHNDS,3.DBUSHCH2COOCH2CH=CH2COOAllylHMeOOCCOOMeEtSHC8H15OC5H9O1.Pd(OAc)2,TPP2.Ac2O,Py3.TB

9、SCl,DBU4.NIS5.AgNO351%SOMeOOCCOOMeEtSHC8H15OC5H9OO1.LiOH,Ba(OH)22.(COCl)2,CH2N23.PhCOOAg,ButOH54%SOCOOMeEtSHC8H15OC5H9OOButOOC第13頁/共29頁SOHC8H15OCOOButOOOC5H9OHH1.m-CPBA2.TFAA3.80%AcOH1.JonesO2.HCOOH96%phomoidride B第14頁/共29頁BrOHMeOOOCH3HOONOOOOOOHONphorboxzaole ABrOHMeOOOCH3HOONOOOOOONHOphorboxzaole

10、BPhorboxazoles 合成路線：OOH1.TBSCl,NEt(Pri)22.BuLi,HMPA3.BuLi,Bu3SnCl4.I2,then+KF5.MsCl,Et3NOOHISiButMe21.KCN,thenDibal-H2.LDA,O3.TBSOTfOOISiButMe2TBSOH第15頁/共29頁1.Pd(OAc)2,PPh32.Dibal-H3.TBSOTfHHOTBSOMe2ButSiTBSO1.SeO2,thenTPAP,NMO2.I2,NHHOTBSOMe2ButSiTBSOIO1.(CH2)6OBn3BPd(dppf)Cl22.HF,Py3.TiCl4,SiMeMeM

11、eOHHOBnOSiButMe2OTBSHO1.LAH2.SwenO3.MsCl,DMAP4.DBU,tolueneHOBnOSiButMe2OTBSO1.Cp2TiMe22.Zn,CCl3COClsupersonic wave3.Zn,thenTBAFOOHOBnHOSiButMe21.PhSSPh,NaH-KH2.Dess-Martin3.H2O2,MeOH4.OsO4,NMOOBnHOSiButMe2HO OOHOOSOPh第16頁/共29頁1.NaOMe2.SwernOOBnHOSiButMe2OOCHOMeOOCO1.(E)-MeCH=CHCH2CH2MgBr2.Dess-Marti

12、n3.DDQ4.Dess-Martin5.CrCl2,CH3CHI2HOSiButMe2OOMeOOCOO1.hv,O2,Rose-Bengal2.TPAP3.LiOH,thenMeSO3HHOOOHOOCOOOO1.TMSCHN22.(TMSOCH2)2TMSOTf3.LiOH,TMSCHN24.Dess-MartinHCOOMeMeOOCMeOOCCOOMeOOOOHHOOCOOOHOHOOHOO1.LiAl(OBut)32.LiOH,thenTFAHMPA：六甲基磷酰胺；NMO：N-氧化甲基嗎啉；DMAP：4-二氨基吡啶；TBAF：四丁基氟化銨TMS：三甲基硅基;第17頁/共29頁BrC

13、lMg,CH3CHOClOHCH3PBr3,PhHClBrCH3PPh3then+EtOLilastCHO97%86%71%ClCH3UV(254nm)92%ClCH3NBS,then+KCN93%ClCH2CN1.KOH-H2O2.SOCl23.AlCl3,DCM51%ClOClCl,TiCl485%ClClCl*11000C0.01mmTM第18頁/共29頁第19頁/共29頁第20頁/共29頁第21頁/共29頁謝謝大家，再見！第22頁/共29頁OOOONHAcHOOOCHOOONHAcOOOONHAcHOabcOOOONHAcTBSOdOOOOAcHNBreOOOOAcHNOTBSOTBS

14、OH3COOfOHOAcHNHOOHCOOMeHOOHgOAcOAcHNAcOOAcCOOMeAcOOAc第23頁/共29頁OHMeMeOBnOBnOOBrCH2Br(OEt)62%OMeMeOBnOBnOOOEtBrBu3SnH,Et3B,73%CSA,EtOH,86%OMeMeOBnOBnOOEtOTMSOTf,DIEAEschenmoser saltMCPBA,70%OMeMeOBnOBnOOEtO(1)H3O+(2)MsCl77%OMeMeOBnOBnOOL-selectrideTf2NR,99%Pd(OAc)2,TPPHCOOH,89%OMeMeOBnOBnOMeDIBAL-H,88

15、%Na,NH3,100%OMeMeOHOHMeOHDowexTHF-H2OOMeMeOHOHMeOHHOAg2CO364%OMeMeMeOHDMDO,rt96%OMeMeMeOHOOOOOOOp-TsOH81%OMeMeMeOOHOOOmerrilactone A第24頁/共29頁MeOOMeOOTBSOOOOTBSOOOC8H15PMBOOOC8H15PMBOOOTBDPSMe2AlCl,90%OOPMBOC8H15OTBDPS1.TBAF;2.Dess-martin;3.SSLi4.NaH,TESOTf,67%OOOMeOOCPMBOC8H15MeOOMeC5H9TESOOOPMBOC8H

16、15TESOO1.KHMDS,PhNTf22.Pd(OAc)2,CO,TPP,MeOH3.PhI(O2CCF3)2,MeOH62%1.DIBAL-H2.VO(acac)2,TBHP3.Et2AlCN55%第25頁/共29頁1.EDC,amine2.TFA3.Dess-Martin65%C8H15C5H9OOOOOOONO1.parachloroaniline2.LiOH50%C8H15C5H9OOOOHOOOOHOHOMeSO3H90%C8H15C5H9OOOOOOOOHOTBDPS:：叔丁基二苯基硅基；PMB：對甲氧基芐基；TBAF：四丁基氟化銨；DDQ：2，3-二氯-5，6-二氰基-1，4-二醌TFA：三氟乙酸；PDC：吡啶二鉻酸鹽；TES:三乙基硅基合成路線phomoidride B(Fukuyama):第26頁/共29頁BrOHMeOOOCH3HOONOOOOOOHONphorboxzaole ABrOHMeOOOCH3HOONOOOOOONHOphorboxzaole BPhorboxazoles 合成路線：OOH1.TBSCl,NEt(Pri)22.BuLi,HMPA3.BuLi,Bu3SnCl4.I2,then+KF5