有机合成中的保护基ppt课件

1、Protecting Groups in Organic Synthesis选择维护基的原那么：l (1) 维护基的供应来源，包括经济程度。l (2) 维护基团必需能容易进展维护，且维护效率高。l (3) 维护基的引入对化合物的构造论证不致添加过量的复杂性，如维护中忌讳产生新的手性中心。l (4) 维护以后的化合物必需接受的起以后进展的反响和后处置过程。l (5) 维护基以后的化合物对分别、纯化、各种层析技术要稳定。l (6) 维护基团在高度专注的条件下能选择性、高效率地被除去。l (7) 去维护过程的副产物和产物能容易被分别。l 呼之即来，挥之即去。l l 切莫请神容易，送神难。羟基的维护基

2、羟基的维护基l 1). 酯类维护基l t-BuCO (Pivalyl新戊酰基; Piv); PhCO; MeCO; ClCH2CO et al.l 90% l l Nicolaou, K. C.; Webber, S. E. Synthesis, 1986, 453OHOHHOPivCl (1eq)Py-CH2Cl20-25 oCOHHOOOl 酯类维护基的除去(cleavage)l l 碱性条件下水解， 水解才干： l t-BuCO(Piv) PhCO MeCO ClCH2CO l l 常用的碱：K2CO3, NH3, NH2NH2, Et3N, i-Pr2NEt et al l 去除Piv

3、普通用较强的强碱体系，如 KOH/H2O, LiAlH4, DIBAL, KBH(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)HO

4、Ac-HOMert, 12 h74%Cook, A. F.; Maichuk, D. T. J. Org. Chem., 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). 硅醚维护基硅醚维护基主要有： Me3Si (trimethylsilyl, TMS); Et3

5、Si (triethylsilyl, TES); t-BuMe2Si (tert-butyldimethylsilyl, TBDMS or TBS) i-Pr3Si (triisopropylsilyl, 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) 硅醚维护基的除去： F-Si 142

6、 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-Pr2NEt, 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：T

7、ESCl/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. D.; Hagen, J. P.; Pilli, R.; Badertscher, U. J. Org. Chem., 1985, 50, 2095TBDMS ether：TBDMSCl / imid. / DMF; TBDMSOTf / 2,6-lutidineOBMPOOHikota, M.; To

8、ne, 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: CH2Cl2BnOOHOHOHBnOOTBDPSOHOHTBDPSCl(1.2eq)imidazole(1.2eq)DMF, rt,80%Nicolaou, K. C.; Pavia, M. R.; Seitz, S.

9、 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%Cleavage OHOTBDPSOMeOHOTBSOHOTBDPSOMeOHOHHOAc-THF-H2O3 : 1 : 1Marshell, J. A.; S

10、edrani, 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%CleavageCO2MeOTBDMSOON3OOTBDMSOTBAFCO2MeOTBDMSOON3OOHONakata, T.; Fukui, M.; Oishi,

11、 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.; Ragan, J. A.

12、; 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)/

13、NH3l PMB (对甲氧基苄基醚); DMB or DMPB (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;

14、CF3CO2H; HBr-HOAc, FeCl3; TiCl4; TMSIl allyl (烯丙基醚) l reagent: 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) trimethylsilyletho

15、xymethyl etherl reagents: RCl or RBr/NaH/THFl cleavage: MOM HCl/THF/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 a

16、cid;l THP(四氢吡喃) tetrahydropyrane ether l reagents: DHP(3,4-dihydro-2H-pyran)l 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1,3-二醇的维护：二醇的维护：醛酮的维护：醛酮的维护：O,O-acetals:1,3-dioxalane (5-number ring) and 1,3-dioxane (6-number ring

17、)Catalyst: p-TsOH, CSA, PPTsOOHHHHO(CH2)3OHOOOHHp-TsOH91%Okawara, H.; Nakai, H.; Ohno, M. Tetrahedron 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,

18、 1607.HOOHHO(CH2)2OHp-TsOH81%HOHOOCarboxylic acid： ：l 1) Methyl esterl Reagent: MeOH/HCl; MeOH/TMSCl; MeOH/SOCl2; MeI/KHCO3l Cleavage: LiOH, KOH, NaOH/MeOH, THFHOOHOHOHOHNH2OHOOMeOHOHOHNH2OTMSCl (2 eq.)MeOH, rt, 20 h76%Gerspacher, M.; Rapoport, H. J. Org. Chem., 1991, 56, 3700HOCO2MeCO2MeHOCO2HCO2Me

19、KOH (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 Reagent: isobutene/H2SO4l Cleavage: acetic acid/isopropanol; TFA/CH2Cl2BnO2CNH2OHOBnO2CNH2OO, H2SO4dioxane82%Valerio, R. M.; Alewood, P.

20、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 acid 3： ：l 3) MOM (methoxymethyl), l MEM (2-methoxyethoxymethyl), l BOM (benzyloxymethyl), l MTM (methyl

21、thiomethyl), 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) esterl Amino group 1： ：1) Boc (tert-butoxycarbonyl)Reagent: (Boc)2O; BocON (2-(tert-butoxycarbonyloxyimino)phenylacetonitrile)Cleavage: TFA; T

22、FA/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, 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 hydroge