发布时间 : 星期六 文章氨基的保护及脱保护策略更新完毕开始阅读
Na/萘脱除对甲苯磺酰基示例
NH2NHTosNH2NH2NaNaphthalenide12
Kaiser, Alexander; Balbi, Miriam et al., Tetrahedron: Asymmetry, 1999, 10(5), 1001-1014 To a solution of compound 1 (0.78 g, 1.83 mmol) in dry THF (20 ml) a solution of sodium naphthalenide [31 ml; prepared by stirring naphthalene (3.96 g, 31.2 mmol) and small pieces of sodium (1.92 g, 83.8 mmol) in dry THF (120 ml) for 3 h at room temperature under nitrogen] was added over 10 min at -78°C. After 6.5 h at -78°C, water (5 ml) was added, and THF was removed under reduced pressure. The mixture was diluted with water (10 ml) and extracted with EtOAc (3 x 30 ml). The combined EtOAc layers were washed with brine (2 x 20 ml), dried and evaporated. Column chromatography (CH2Cl2: MeOH, 9:1) afforded compound 2 (0.17 g, 39%) as a colorless oil.
HBr/苯酚脱除对甲苯磺酰基示例
OHO1HBr/PhOHHBr.H2NHBr.H2N2OH2NTosNHOH
Calvisi, Giuseppina; Dell-Uomo, Natalina et al., Eur. J. Org. Chem., 2003, 23, 4501-4506
A round-bottom flask containing a mixture of compound 1 (600 mg, 1.94 mmol), phenol (547 mg, 5.82 mmol) and HBr (7.5 mL, 48%) was placed in an oil bath previously heated to 130 °C and refluxed for 18 hours. The reaction mixture was then allowed to cool to room temperature, diluted with water and extracted twice with EtOAc. The aqueous layer was evaporated under vacuum, the residue was taken up several times with CH3CN (evaporating under vacuum every time) until a solid residue, insoluble in CH3CN, was obtained. The solid was filtered and dried to give compound 2 (230 mg, 95%) as the dihydrobromide salt.
Page 52 of 77
Mg/MeOH脱除对甲苯磺酰基示例
TosHNS1Mg/MeOHSH2N2
Nenajdenko, Valentine G; Karpov, Alexei S et al., Tetrahedron: Asymmetry, 2001, 12(18), 2517-2528
To a suspension of Mg (0.45 g, 20 mmol) in MeOH (5 mL) was added a solution of compound 1 (0.74 g, 2 mmol) in MeOH (10 mL). The resulting suspension was sonicated for 1 h until consumption of the starting material was complete. The reaction mixture was then diluted with aqueous NH4Cl and extracted with ether (3 x 5 mL). The organic layer was dried over MgSO4 and evaporated. To resulting oil ethanolic solution HCl (2 M, 0.5 mL) was added. Hydrochloride was precipitated, filtered and washed with ether to afford compound 2 HCl salt (0.46 g, 90%) as a white solid.
3.3 三氟乙酰基（Tfa）
三氟乙酰基（Tfa）是Weygand最先引入到多肽合成中的[1]。三氟乙酰基（Tfa）可用三氟醋酐导入，在稀碱液中很容易脱去。Tfa保护的氨基酸或多肽在高真空下易于气化，因而能用于气相层析以检测消旋的程度[2]和测定天然肽的排列顺序[3]，而且由于含有F，也可用
19
F NMR来检测合成肽的纯度、消旋程度以及类似物的鉴定等[4]。由于
N-Tfa-氨基酸在接肽时易于消旋，也是采用此保护基时应该注意的地方。
1. F. Weygand, E. Csendes., Angew. Chem., 1952, 64, 136
2. F. Weygand, D.Hoffmann, A. Prox., Z. Naturforsch., 1968, 23b, 279 3. N. Ikekawa., J. Biochem., 1963, 54, 279 4. E. Bayer et al., J. Am. Chem. Soc., 1972, 94, 265
3.3.1 三氟乙酰基的引入
由于三氟醋酐同氨基酸反应时易生成恶唑烷酮而发生消旋[1]，因此，同甲酰基的引入一样，在低温下于三氟醋酸溶液中用三氟醋酐酰化为好[2]。一般而言，
Page 53 of 77
CF3COOEt/Et3N/MeOH是较好的方法[3]，可在仲胺存在下，选择性地保护伯胺[4]。并且该方法地聚合物方法也已得到发展[5]。在TFAA/18-crown-6/Et3N中，伯胺与18-crown-6形成络合物，可选择性地酰化仲胺[6]。而在仲胺存在下，CF3COO-邻苯二甲酰亚胺也可选择性地将TFA基团引入到伯胺[7]。
1. F. Weygand, E. Leising., Chem. Ber., 1954, 87, 248 2. F. Weygand, R. Geiger., Chem. Ber., 1956, 89, 647 3. T. J. Curphey., J. Org. Chem., 1979, 44, 2805
4. D. Xu, K. Prasad, D. M. Dalrymple et al., Tetrahedron Lett., 1995, 36, 7357; M. C. O’Sullivan, D. M. Dalrymple., Tetrahedron Lett., 1995, 36, 3451
5. P. I. Svirskaya, C. C. Leznoff, M. Steinman., J. Org. Chem., 1987, 52, 1362 6. A. G. M. Barrett, J. C. Lana., J. Chem. Soc. Chem. Commun., 1978, 471 7. R. J. Bergeron, J. J. McManis., J. Org. Chem., 1988, 53, 3108
3.3.1.1 TFAA引入三氟乙酰基示例
OHNH2TFAABrO1HEt3N, DMAPBrO2HOHNHCOCF3
Chambers, James J; Parrish, Jeasen C et al., J. Med. Chem., 2003, 46(16), 3526-3535 To a stirred suspension of the hydrobromide salt of compound 1 (1.3 g, 3.6 mmol) and 4-N,N- (dimethylamino) pyridine (0.04 g, 0.3 mmol) in CH2Cl2 (40 mL) was added Et3N (16.0 mL, 12.0 mmol), and the mixture was cooled to 0 °C. Trifluoroacetic anhydride (2.5 mL, 17 mmol) was then added to the reaction dropwise. The mixture was allowed to warm to room temperature and stirred for 8 h. The mixture was then diluted with CH2Cl2 (50 mL) and washed with 2 N HCl (50 mL), saturated NaHCO3 (50 mL), and brine (50 mL). The organic phase was then dried (MgSO4), filtered, and evaporated to leave compound 2 as a white solid that was recrystallized from Et2O (1.2 g, 92%): mp 197-198 °C.
Page 54 of 77
3.3.1.2 三氟乙酸乙酯引入三氟乙酰基示例
ONH2OMe1CF3COOEtEt2O2NHOMeCF3
Knoops, Niele; Derioover, Geert ret al., Tetrahedron, 1997, 53(37), 12699-12716
Ethyl trifluoroacetate (9.2 mmol) was dissolved in 10 ml dry diethylether and stirred at 0 °C for 10 minutes. Compound 1 (8.8 mmol) was added and the reaction mixture was stirred at the same temperature for one hour. After removal of the solvent, the residues were purified by fast column chromatography (SiO2; CHCl3) to give compound 2(yield 98 %) as a yellow crystalline m.p.: 68-69 °C (CH2Cl2/hexanes).
三氟乙酸乙酯选择性保护伯胺示例
HNH1OBnNH2CF3COOEtHNH2OBnNHCOCF3
Whitlock, Gavin A; Carreira, Erick M et al., Helv. Chim. Acta., 2000, 83(8), 2007-2022 Compound 1 (0.39 mmol) was dissolved in THF (10 mL), cooled to 0°C, and CF3COOEt (0.01 mL, 0.39 mmol) was added. The mixture was stirred at 0°C for 1 h and then at 23°C for 1 h. The solvent was then evaporated under reduced pressure to give a pale yellow oil. Purification by FC (silica gel; MeOH) afforded 2 (119 mg, 85%) as colorless oil. TLC (MeOH): Rf = 0.29. [α]24D = +4.8 (c =0.48, CHCl3).
3.3.2 三氟乙酰基的脱去
三氟乙酰胺也是较易去保护地酰胺之一。Tfa基可以在水或乙醇水溶液中用0.1-0.2 N NaOH处理或者用1 M 哌啶溶液处理很容易地脱去。由于脱去地条件温和，也适用于一些长链肽中的Tfa基的脱去，例如，Anfisen用上述条件于8 M 尿素中5℃处理8小时脱去42肽中的Lys侧链的Tfa基[1]，不过考虑到溶解度以及断链副反应等不利因素，长链肽的碱水解脱除保护基时要综合考虑各种因素。在K2CO3或Na2CO3/MeOH/H2O条件下，Tfa可在甲基酯存在下于室温去保护[2]。也可在NH3/MeOH[3]，HCl/MeOH[4]或通过相转移水解(KOH/Et3Bn+Br-/H2O/CH2Cl2或乙醚)脱去[5]。
Page 55 of 77