有机合成中的保护基课件.ppt

1、Protecting Groups in Organic Synthesis选择保护基的原则：l(1)保护基的供应来源，包括经济程度。l(2)保护基团必须能容易进行保护，且保护效率高。l(3)保护基的引入对化合物的结构论证不致增加过量的复杂性，如保护中忌讳产生新的手性中心。l(4)保护以后的化合物必须承受的起以后进行的反应和后处理过程。l(5)保护基以后的化合物对分离、纯化、各种层析技术要稳定。l(6)保护基团在高度专一的条件下能选择性、高效率地被除去。l(7)去保护过程的副产物和产物能容易被分离。l 呼之即来，挥之即去。呼之即来，挥之即去。l l 切莫请神容易，送神难。切莫请神容易，送神难。

2、羟基的保护基羟基的保护基l 1).酯类保护基l t-BuCO(Pivalyl新戊酰基;Piv);PhCO;MeCO;ClCH2CO et al.90%Nicolaou,K.C.;Webber,S.E.Synthesis,1986,453OHOHHOPivCl(1eq)Py-CH2Cl20-25 oCOHHOOOl 酯类保护基的除去(cleavage)碱性条件下水解，水解能力：t-BuCO(Piv)PhCO MeCO ClCH2CO 常用的碱：K2CO3,NH3,NH2NH2,Et3N,i-Pr2NEt et al 去除Piv一般用较强的强碱体系，如 KOH/H2O,LiAlH4,DIBAL,K

3、BH(OEt)3 OTBDMSTBDMSOOOOTBDMSTBDMSOOHDIBAL(2.5eq)CH2Cl2,-78 oC95%Nicolaou,K.C.;Webber,S.E.Synthesis,1986,453ClCH2CO的去除可以用硫脲，氨/甲醇，苯，吡啶水溶液，NH2CH2CH2SH,NH2CH2CH2NH2,PhNHCH2CH2NH2 等除去。OOOBnOAcHNOBnOBnOBnOClAcOOBnOOOOBnOAcHNOBnOBnOBnHOAcOOBnNH2NH2(15eq)HOAc-HOMert,12 h74%Cook,A.F.;Maichuk,D.T.J.Org.Chem.

4、,1970,35,1940.OAcOOORAcOROOROOOOOOPhH2NHNSHSOAcOOOHAcOHOOHOOOOOOPhDioxane,i-Pr2NEtSmith,A.B.;Hale,K.J.;Vaccaro,H.A.;Rivero,R.A.J.Am.Chem.Soc,1991,113,2112.R=ClCH2CO40%2).硅醚保护基硅醚保护基主要有：Me3Si (trimethylsilyl,TMS);Et3Si (triethylsilyl,TES);t-BuMe2Si(tert-butyldimethylsilyl,TBDMS or TBS)i-Pr3Si (triisop

5、ropylsilyl,TIPS)t-BuPh2Si (tert-butyldiphenylsilyl,TBDPS)酸水解相对稳定性:TMS(1)TES(64)TBDMS(20,000)TIPS(700,000)TBDPS(5,000,000)碱水解相对稳定性:TMS(1)TES(50)TBDMS=TBDPS(20,000)TIPS(100,000)硅醚保护基的除去：（F-Si 142 kcal/mol;O-Si 112 kcal/mol）通常用 HF/CH3CN;TBAF/THF;HF.Py/CH3CNTMS ether：TMSCl or TMSOTf in pyridine,NEt3,i-P

6、r2NEt,imidazole,DBUOOOOTBSCOOBu-tCO2MeOHOHMe3SiCl-ImOOOOTBSCOOBu-tCO2MeOTMSOH100 oC,90 min.100%Kerwin,S.M.;Paul,A.G.;Heathcock,C.H.J.Org.Chem.,1987,52,1686TES ether：TESCl/Imid.DMAP;TESOTf/Py.or 2,6-dimethylpyridine(2,6-lutidine)OHOHOTES OHTESOTf(1.1eq)Py,MeCN,-50 oC,10 min.79%Heathcook,C.H.;Young,S.

7、D.;Hagen,J.P.;Pilli,R.;Badertscher,U.J.Org.Chem.,1985,50,2095TBDMS ether：TBDMSCl/imid./DMF;TBDMSOTf /2,6-lutidineOBMPOOHikota,M.;Tone,H.,Horita,K.;Yonemitsu,O.J.Org.Chem.,1990,55,7.OHOBzOBMPOOOTBSOBzTBDMSOTf2,6-di-tert-buylpyridineCH2Cl2,rt,24 hTBDPS ether：TBDPSCl/imidazole/DMF,catalyst:DMAP,solvent

8、:CH2Cl2BnOOHOHOHBnOOTBDPSOHOHTBDPSCl(1.2eq)imidazole(1.2eq)DMF,rt,80%Nicolaou,K.C.;Pavia,M.R.;Seitz,S.P.J.Am.Chem.Soc.,1981,103,1224.TIPS ether：TIPSCl/DMF/imidazole.OHCO2MeOTIPSCO2MeTIPSCl(1 eq)imidazole(2.5 eq)DMF,rt,48 hBennett,F.;Knight,D.W.;Fenton,G.J.Chem.Soc.Perkin.Trans.I,1991,1543.87%Cleavag

9、e OHOTBDPSOMeOHOTBSOHOTBDPSOMeOHOHHOAc-THF-H2O3:1:1Marshell,J.A.;Sedrani,R.J.Org.Chem.,1991,56,5496.87%CleavageOOTBSOOOOTBSHOPivHF-CH3CNOOTBSOOOOHHOPivDanishefsky,S.J.;Armistead,D.M.;Wincott,F.E.;Selnick,H.G;Hungate,R.J.Am.Chem.Soc.,1989,111,2967.-25 oC85%CleavageCO2MeOTBDMSOON3OOTBDMSOTBAFCO2MeOTBD

10、MSOON3OOHONakata,T.;Fukui,M.;Oishi,T.Tetrahedron Lett.,1988,29,2219.90%THF,rtCleavageTBSOOHTBSOOTBSHOOTBSCollington,E.W.;Finch,H.Smith,I.J.Tetrahedron Lett.,1985,26,681.TBAF(1 eq)THF,0 oCHF(2 eq)MeCN,50 oC92%83%cleavageNOOOOTIPSOHOOTIPSOOTBSOOOOHNOOOOHOHOOHOHOHOOOOHHF/MeCNFK-506,73%Nakatsuka,M.;Raga

11、n,J.A.;Sammakia,T.;Smith,D.B.;Uehling,D.E.;Schreiber,S.L.J.Am.Chem.Soc.,1990,112,5583.烷基醚类：烷基醚类：l Me(甲基醚)l reagent:MeI;(MeO)2SO2;MeOTf l cleavage:TMSI/CH3Cl(CH2Cl2 or MeCN)or BBr3/CH2Cl2l Bn(苄基醚)l reagent:PhCH2Br or PhCH2Cll cleavage:H2/10%Pd/C,Raney-Ni,Rh-Al2O3;Li(Na)/NH3l PMB(对甲氧基苄基醚);DMB or DMPB(

12、3,4-二甲氧基苄基醚)l reagent:PMBCl;p-MeOC6H4CH2O-C(=NH)CCl3l cleavage:DDQ,CANl Tr(三苯甲基醚)l reagent:TrCl/Py/DMAP;TrOTf/2,6-lutidinel claevage:HCO2H-H2O;HCO2H-t-BuOH;HCl/MeCN;Na/NH3l tert-butyl(叔丁基醚)l reagent:isobutene/CH2Cl2;t-BuO-C(=NH)CCl3l cleavage:HCO2H;CF3CO2H;HBr-HOAc,FeCl3;TiCl4;TMSIl allyl(烯丙基醚)l rea

13、gent:Allyl bromidel cleavage:t-BuOK/DMSO/NaOH烷氧基烷基醚：烷氧基烷基醚：l MOM(甲氧基甲基醚)methoxymethyl etherl MTM(甲硫基甲基醚)methylthiomethyl etherl MEM(甲氧基乙氧基甲基醚)methoxyethoxymethyl etherl BOM(苄氧基甲基醚)benzyloxymethyl etherl SEM(三甲硅基乙氧基甲基醚)trimethylsilylethoxymethyl etherl reagents:RCl or RBr/NaH/THFl cleavage:MOM HCl/TH

14、F/H2O(1:2:1);Lewis acid:Me3SiBr/CH2Cl2;Me2BBr/CH2Cl2l MTM AgNO3/2,6-lutidine;HgCl2/CaCO3l MEM ZnBr2/CH2Cl2;HBr/THF;TiCl4/CH2Cl2;Me2BBr/CH2Cl2 l BOM Na/NH3/EtOH,H2/Pd(OH)2/C;Raney-Ni/EtOH;l BF3/PhSH/CH2Cl2l SEM HCl/MeOH;Lewis acid;l THP(四氢吡喃)tetrahydropyrane ether l reagents:DHP(3,4-dihydro-2H-pyran)

15、cleavage:HOAc/THF/H2O(4:2:1)O,O-Acetals(缩醛和缩酮）Reagents:Acetone;benzaldehyde,cyclo-ketoneCleavage:Acid;Lewis acid1,2或或1,3-二醇的保护：二醇的保护：醛酮的保护：醛酮的保护：O,O-acetals:1,3-dioxalane(5-number ring)and 1,3-dioxane(6-number ring)Catalyst:p-TsOH,CSA,PPTsOOHHHHO(CH2)3OHOOOHHp-TsOH91%Okawara,H.;Nakai,H.;Ohno,M.Tetra

16、hedron lett.,1982,23,1087.OCO2MeOOHOCH2CH2OHTMSCl,rt,16 hCO2MeOOOO+(TMS)2OChan,T.H.;Schwerdtfeger,A.E.J.Org.Chem.,1991,56,3294.Crimmins,M.T.;Deloach,J.A.J.Am.Chem.Soc.,1990,112,1607.HOOHHO(CH2)2OHp-TsOH81%HOHOOCarboxylic acid：l 1)Methyl esterl Reagent:MeOH/HCl;MeOH/TMSCl;MeOH/SOCl2;MeI/KHCO3l Cleava

17、ge:LiOH,KOH,NaOH/MeOH,THFHOOHOHOHOHNH2OHOOMeOHOHOHNH2OTMSCl(2 eq.)MeOH,rt,20 h76%Gerspacher,M.;Rapoport,H.J.Org.Chem.,1991,56,3700HOCO2MeCO2MeHOCO2HCO2MeKOH(0.95 eq.)MeOH/H2O95%Honda,M.;Hirata,K.;Sueoka,H.;Katsuki,T.;Yamaguchi,M.Tetrahedron Lett.,1991,22,2679.Carboxylic acid 2l 2)tert-butyl esterl R

18、eagent:isobutene/H2SO4l Cleavage:acetic acid/isopropanol;TFA/CH2Cl2BnO2CNH2OHOBnO2CNH2OO,H2SO4dioxane82%Valerio,R.M.;Alewood,P.F.;Johns,R.B.Synthesis,1988,786.NHNOOCO2MeHOAc-i-PrOH-H2ONHNOOHCO2Me100%Gmeiner,P.;Feldman,P.L.;Chu-Moyer,M.Y.;Rapoport,H.J.Org.Chem.,1990,55,3068.4:4:1100 oC,15 hCarboxylic

19、 acid 3：l 3)MOM(methoxymethyl),l MEM(2-methoxyethoxymethyl),l BOM (benzyloxymethyl),l MTM(methylthiomethyl),l SEM (2-trimethylsilyl ethoxymethyl)l TCE(2,2,2-trichloroethyl)l TMSE(2-trimethylsilylethyl)l TsE (2-tosylethyl)l Bn (benzyl)l allyl(allyl)ester Amino group 1：1)Boc(tert-butoxycarbonyl)l Reag

20、ent:(Boc)2O;l BocON(2-(tert-butoxycarbonyloxyimino)phenylacetonitrile)l Cleavage:TFA;TFA/CH2Cl2NH2CO2HBoc2O,NaOHHNCO2HOO78-87%Pope,B.M.;Yamamoto,Y.;Tarbell,D.S.Org.Synthesis,1988,Coll.Vol.VI,418.H2O/t-BuOH20-40 oC,12 hNH2CO2HBocONPhCNHNCO2HOO80-83%Itoh,M.;Hagiwara,D.;Kamiya,T.Bull.Chem.Soc.Jpn.,1977

21、,50,718.rt,3 hEt3N,H2O,dioxaneOOO(Boc)2O(tert-butoxycarbonyl anhydride)OOONHBocNOONNHOOMeTFA1,3-dimethoxybenzeneONH2 TFANOONNHOOMe100%Yamashiro,D.;Blake,J.;Li,C.H.J.Am.Chem.Soc.,1972,94,2855.rt,30 minAmino group 22)Cbz(benzyloxycarbonyl)Bergman(1932)reagent:CbzCl/base cleavage:catalytic hydrogenatio

22、nNBrTBSOAcOHNCOOMeCOOMeHCbzNHBrTBSOAcOHNCOOMeCOOMeH100%Sakaitani,M.,Ohfune,Y.J.Org.Chem.,1990,55,870.Et3N,rt,30 minEt3SiH,PdCl2NHCOOHNCOOHCbz92%Bergman,M.;Zervas,L.Ber.Deutsch.Chem.Ges.,1932,65,1192.5-10 oC,1 hBnOCOCl2 mol/L NaOHOClOCbzCl(benzyloxycarbonyl chloride)Amino group 3：l 3)Fmoc(9-fluorenyl

23、methoxycarbonyl)l reagent:Fmoc-Cl/NaHCO3l Cleavage:NH3,Et2NH,piperidine,marpholineOClOFmoc(9-fluorenylmethoxycarbonyl chloride)91%Hoogerhout,P.;Guis,C.P.;Erkelens,C.;van Boom,J.H.Recl.Trav.Chim.Pays-Bas,1985,104,54.dioxane-H2O,0 oC,4 h,rt.8 hFmocCl/NaHCO3NHNH2COOHNHHNCOOHOOOBzOBzOOBzOOBzNHCOOBnOONHOOBzOBzOOBzOOBzNH2COOBn97%Schultheiss-Reimann,P.;Kunz,H.Angew.Chem.Int.Ed.Engl.,1983,22,62.