1、第八章 合成设计原理Principle of Synthesis Design Section 1 Basic TermsAim Aimed Target / Compound Molecule目标分子，目标化合物，靶分子目标分子，目标化合物，靶分子切断切断-合成子合成子 Disconnection-Synthon切断切断：将分子中的一个键断开：将分子中的一个键断开。符号符号：条件条件：1）是一个成熟反应的逆过程。）是一个成熟反应的逆过程。 2）原料易得。）原料易得。切断点选择切断点选择：官能团官能团，如杂原子、羰基、羟基、，如杂原子、羰基、羟基、 双键、苯环双键、苯环ClExample:Cl
2、+Cl2AlCl3Cl+ HCl合成子（合成子（synthon）：）：切断时得到的概念性碎片切断时得到的概念性碎片合成等价物合成等价物(equivalent reagent)：能起合成子作用的试剂。能起合成子作用的试剂。合成砌块合成砌块(building block)、分子片段（、分子片段（piece)FGI:Functional Group Interconversion 官能团互换官能团互换 FGI：把一个官能团转换成另一种官能团。：把一个官能团转换成另一种官能团。目的目的：使一种切断成为可能。：使一种切断成为可能。符号符号：FGIExample:CH2CH2CH2CH3CH2CH2CH2
3、CH3ClCH2CH2CH2CH3+CHCH3CH2CH3Example:CH2CH2CH2CH3FGICCH2CH2CH3OCCH2CH2CH3OAlCl3CCH2CH2CH3OClCCH2CH2CH3OZn(Hg)H+CH2CH2CH2CH3切断的选择切断的选择CH2CHCO2EtCO2EtabCH2CHCO2EtCO2EtaCH2CHCO2EtCO2EtbCH2CHCO2EtCO2EtCH2BrCH2CO2EtCO2Et+BaseOOOOOOOCHOOCHOOOOOOOOOOOXXSection 2 Disconnection of mono Functional Group1. Sim
4、ple AlcoholCOHMeMeCNabCOHMeCNMeCOMeCNMeMgIaCOHMeMeCNCOMeMeNaCNbCOHMeMeCNCOMeMeNaCNH+选择最稳定的负离子处切断选择最稳定的负离子处切断CMeOHC CHCMeOHC CHCMeOCMeOCMeOCl+AlCl3CMeONaCCHCMeOHC CHCCH3OHCH2CH3负离子等价物负离子等价物CCH3OHCH2CH3Li(MgX) CCH3OCH2CH3COHCH2CH3CH3COCH2CH3CH3MgI , CH3LiCCH3OHCH2CH3CCH3OBrMgCH2CH3 LiCH2CH3OHMgBrO+OCH
5、3MgI有了两个好的切断标准：1）合理 。2）简单OHMgBrOOBrMgCO2Et2 BrMg带有两个相同取代基的叔醇带有两个相同取代基的叔醇=酯酯+2GrignardOHCO2EtMgBr2MgBrOCO2EtCO2EtHHOHNaBH4OHOOEtLiAlH4CHOCHOCH2OHNaBH4CO2EtCO2EtCH2OHLiAlH4NaBH4 只能还原醛，酮。不能还原酯只能还原醛，酮。不能还原酯LiAlH4 能还原所有羰基化合物能还原所有羰基化合物2 Derivatives of alcohol涉及涉及H-还原时，实际是还原时，实际是FGIROHRXPX3HXRO2CRRCOCl(RCO
6、)2O(O)COCOOH(O)RORH+- H2O遇到上述结构，遇到上述结构，FGI到醇是一种好的思路到醇是一种好的思路OAcFGIOHMgBrHCO2Et2Br1. Mg, Ether2. HCO2EtOHAc2OPy.OAcBrFGIOHMgBrO3 Disconnection of simple alkeneAddition of H2OFGIHOOMgBrFGIHOUselessFGIOHFGIOH1. Mg,Et2O2. Me2COH3PO3BrOHPPh3OWittig ReactionPPh3OHCPh3PCHOCHOCHOBrPPh3BasePPh3切断：切断：1）合理。）合理
7、。2）简单。）简单。3）原料易得）原料易得4 Disconnection of Aromatic Ketone将将醇醇切断成切断成羰基羰基化合物和化合物和Grignard试剂试剂-第一种主要切割第一种主要切割将将烯键烯键切断成切断成羰基羰基化合物和化合物和Wittig试剂试剂-第二种主要切断第二种主要切断将将芳香环芳香环上上脂肪侧链脂肪侧链切断切断-第三种主要切断第三种主要切断OMeOMeOOClOOOabOOOClOMeMeNO2OabOMeMeNO2OCl5 Controlling OHOOEtOOMgBrOEtOOMgBrOEtOHOOEtOOOMgBrOHOOH3O+Protectio
8、n !OOBrOBrOOOLess selectivityOOEtOBrOEtOOOdilu.OH- or H+CO2HBrCO2HCO2EtCO2EtCH2OHLiAlH4CH2BrCO2EtCO2EtCH2BrCO2EtCO2EtEtONaCO2Hdilu. H+OOBrBrBrOOEtOBrOOEtOOHHOOEtOOONaNH2MeIOEtOOOH2Pd/CBaSO4OEtOOOHClH2OO真麻烦！真麻烦！6 Disconnection of Simple ketone and AcidOFGIOHMgBrONONHOHOBrMgBrMgFGIHOOBrMgBr1 Mg, Et2O2
9、.EtCHOHO1 PBr32 Mg, Et2O3 CO2OHOOHO1 SO2Cl22 NHNO7 Long Chain AlkaneHydrogenation is one of may method FGIPPh3O交叉点交叉点OHMgBrOWorkHNOMeOMeMeOMeOOCO2HSection 3 : Disconnection of Bifunctional Groups1). 1,3-oxidized skeletonA) 3-hydroxycarbonylsHOCHOOCHOOHCHOCHOCH2OOOHOOOOOOOOOOCHOO2NCHOO2NH3CCHOCO2HCHO
10、CH3COOHOOOB) 2,3-Unsaturated carbonyl compoundOHOOOOC) 1,3-Dicarbonyl compoundOOOClOEtOOOOClOEtOOCO2EtOOEtOOEtCO2HBrCO2HCO2EtCO2EtBrCO2EtEtO2CH3O+CO2EtCO2EtCHCO2HOHCO2EtOO-HOOHCNOOCHORBrOCHOROCHORNOOCHORHO-, H2OOROOBrOBrOOmajorminorOCHOBrOCHOHO-,H2OOOCHO-OHOt_BuO2C CO2Bu_tStable aniont_BuO2C CO2Bu_t
11、Ot_BuO2C CO2Bu_tHOOONMe2扩瞳剂work2) 1,5-Dicarbonyl compoundOCHOEtO-OOMichael AdditionRROOROROROROOOCO2EtOCO2EtO1. stable anion2. obtainableOCO2EtOOOEtCNOOOEtCNOOOEtCNOCHOOEtCNOOCHOMichael addition is very important in some long synthetic processes.OOEtOOOEtOOOOOEtOOOHCOOOEtOOOEtORobinsonOMeOOOMeOOOMeC
12、HOOOOEtOOOOOOOCO2EtBrMannich reaction & 2,3-ketenoneRO CH2OR2NHRONR2MeIRONR2Me+ROH+B:OOOOOOOCO2EtBrWorkCO2EtOOCO2EtOSection 4: Disconnection of Special Bifunctional Group1) 1,2-oxidized skeletonA) 2-hydroxy carbonylOHOHOOOHOCN-OCN-H+OHCNNaOHH2OOHOHOOHHOOFGICNHOOCNCO2HCO2HOHCO2HOCN-CO2HHCO2EtBrCO2HOH
13、OHOHOHOHOEtOOOHOBenzoin reaction 苯偶姻反应苯偶姻反应CHOCN-OOHOOOOOHBrHCO2EtRHg+2, H2OROOOHFGIOHOOOOOHOHFGIOHOHOOOOOHOOHOCHOOB) 1,2-Diol KMnO4OH OHWittigOHOHOMGBrOOCO2MeHHHOHOCO2MeHHOCO2MeCO2MeCO2MeOMg-HgROHOHROH+OOHOHOPinacol RearrangementRMCPBAROMeO-ROHOMeROMeOHOOHOHOOWork !OOCO2HOO2) 1,4-Oxidized SkeletonA
14、) 1,4-Dicarbonyl CompoundOOOOOCO2MeOCO2MeBrOCO2MeBrMeO-MeOOCO2MeBrOR2NHNR2CO2MeClNR2CO2MeH3O+OCO2MeOOOOOClONHN1. OBr2. H3O+OOB:OOEtO2COEtO2COThe anion is stable enoughB) 4-Hydroxy Carbonyl CompoundOOHOOOR2NHNR2OOOHOOHCOCOXOHOOEtOHOOOEtOOOOEtOOOEtO-OOOBrOFGIOHOOOOEtOOOEtO-OOOBrO1.H3O+2. Heat3. HBrOOH
15、OFGICONOC NWorkOOHOHHO3) 1,6-Dicarbonyl CompoundROROOORRRROOHOOOHOOMgBrOHHOO OOHHOOOOOOHHOOOOHHOOOOOOOOOOOHHOOO1. OH-2.H3OOHHOO OOHHOOOMeNaNH3MeBirch ReacitonOHMeOOFGIOMeOOOMeOMeNaNH3OMeO3OOMeONaBH4OHMeOOCHOCHOORCO3HOH2OOHOHNaIO4OOCHOWorkOOOHOOOOOOMeO Comprehensive excisesOOOCO2MeOOOMeOEtOCO2EtOOEtO
16、2CMeEtO2C CO2EtSection 5 Concerted CyclizationDiels-Alder reaction产品特征：环己烯对面一侧带有吸电子基团Z(Z)Z(Z)Z=COR, CO2Et, CN, NO2OOMeOMeOOOMeOMeOOOOOMeOMeOOOMeOMeOOOOOMeOMeOOOMeOOHMeOOCO2MeCO2MeOCO2MeCO2MeOCO2MeCO2MeOOCO2MeCO2MeOHOHFGIOEtOEtOOOEtEtOOOOMeOOOOOMeOOOOOMeOOOOCHOOMeBrSection 6 Compounds Containing Hete
17、roatom1) Ether and amineOC OO-BrOHFGICO2RFGICO2RBrNHNHHBrNHHBrNHNNHHOClNHONHLiAlH4LiAlH4Na/EtOH(Sol)orNOHNH2RCNLiAlH4or H2/PdRCH2NH2RNO2LiAlH4or H2/PdorNa/EtOH(Sol)RNH2NHFGINHOOClNHHFGINHONHOHHOOMeOMeONH2MeOMeONO2FGIFGIMeOMeONO2MeOMeOCHOCH3NO2MeOMeONFGIMeOMeOBrCNNH2FGINO2FGINO2WorkMeOMeONOMeOMeHO2N2
18、) HeterocycyleNOMeNOMeOEtHOOEtBrCH3NH2FGIOOEtOHOOEtONOOCO2EtNOOCO2EtOOCO2EtOEtOEtOCO2EtOEtOOEtCHOOOEtHNOH2NOFGINOONOBrNHNOFGINHNOOOOOONHNOOONHORRNRRNMeNMeCHOOOCHOOOOOCO2EtOBrNNOHOEtOONH2NH2HNNOOHH2NNHOHOEtONHNHOHFGINOOCNOOOHOCH3MgIOOBrClOOOEtOOOAlCl3OOOHHOOH1. SOCl22. AlCl3OOH1. MeLi2. H+OOO3OKOHEtO
19、HH2OHCNAlCl3OCNCNOOOHOHOONH2LiAlH4HClO4NHWorkO2NSOMeOSCO2MeOMeOHOOHNHHSection 7 Small Ring 1) Three member ringOOBrFGIOOHOOOEtOOOEtO-OOOHBrOBrEtO-OOOOXX=C,N,OOHOOH, RCOOOHHHOOMeHHOMeRCO3HPh3PCOMeOHOOOOOOOOOOH+OOOEtO H3O+1.2. EtO-OOH2O2, B:OROC:ROROOROClDarzen reactionOOBu-tOOBu-tOClOOSCSCOOOMeHOMeHO
20、MeHOMeOOMeOOHCH2I2, Cu-Znor CH2N2OHHHHHHHHHBrBrOPBr5BrBrMeLiHHOCN2OOHO1.SO2Cl22. C2N2CN2OhvO2) Four Member RinghvOOOOOOOOOOOOOOOOOOBr2OOOBrBrB:OOOOOOhvWorkOCO2EtCOCO2MeCOCO2EtOOSection 8 Strategy in Synthesis1）串联与并联合成路线比较A90%B90%C90%D90%E90%TM （35%）A90%B90%CD90%E90%FTM （73%）90%NOHMgXNOONHCH2OONOMgXO
21、NXMgONOOHOBrBrOOOBrOBrHOOBr1简化简化2利用分支点利用分支点2）Strategic Designa) Carbon-Heteroatom BondOHBrOheatOHOHMeOOMeOOHMeOOHHOOOOCarroll RearrangementOOOHOOOHOOONaCCHOHPd/C/BaSO4H2OHOOEtOOOOOheatNRRRXNRRRNRRBrH2OONRRBrNRRNRRH2OO多记有特点的反应多记有特点的反应B) Fused CycleShared atomO1234O2-41234O1-31234O3-41234OHH1234OHH124
22、3OHH1234FGIOHHX13FGIOHHO124FGIOHHX1C) All Possible DisconnectionD) Functional Group interconversion(Cost)ClCO2HH2NFGIClCO2HH2NOCClCO2HNClCO2HO2NClCO2HNClCHOCO2HCO2HClO2NCO2HCO2HClCHOO2NClCO2HO2NClCHOCO2HCO2HHOOHOOHOOHOOE) Addition of Functional GroupFGIOHOOOOOOOOOOOHOOHOOO1.H2/Pd2.H3OOHOMeSO2ClOMeSO
23、2OB:OZn-HgHClOEtOMeMgIOEtOOPPh3OPh3P=CH2OBrOExamples of Drug Synthesis1、Vitamin E2、Vitamin A3、Cefradine1、Synthesis of Vitamin ELewis Acid, ZnCl2(1)2,3,5-三甲基氢醌（三甲基氢醌（TMHQ)的的 合成合成 CH3CH3CH3H2SO4CH3CH3CH3HO3SKNO3, H2SO4CH3CH3CH3NO2HO3SO2NSn, HClCH3CH3CH3NH2 .HClHCl.H2NNa2Cr2O7, H2SO4CH3CH3CH3OO C6H6TM(
24、2)异植物醇（异植物醇（IPL）的合成）的合成(Roche,BASF,西南化工研究院）西南化工研究院）O+HCCHOHLindlar catalystOHAl(i-PrO)3CH3COCH2COOEtOHCCHNa， NH3OH(2)异植物醇（异植物醇（IPL）的合成）的合成(Roche,BASF,西南化工研究院）西南化工研究院）Lindlar catalystOHOHFOLH2Al(i-OPr)3MAAO GAClTHF,MgCOLOHAl(i-OPr)3MAA(2)异植物醇（异植物醇（IPL）的合成）的合成(Roche,BASF,西南化工研究院）西南化工研究院）COLOHAl(i-OPr)3MAAFAOTHF, MgClPd-C, H2PAOOHSummary: 15 steps (5+10) 1 Sulfonation 1 Nitration 5 Reduction( 3 catalytic hydrogenation) 1 Oxidation 2 Nucleophilic addition of carbonyl group 3 Carroll rearrangement 2 Grignard reaction
