三氟乙酰基（Tfa） 

      三氟乙酰基（Tfa）是 Weygand 先引入到多肽合成中的。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和测定天然肽的排列顺序，而且由于含 有 F，也可用 19F NMR 来检测合成肽的纯度、消旋程度以及类似物的鉴定等。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 、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，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。一般而言，CF3COOEt/Et3N/MeOH 是较好的方法，可在仲胺存在下，选择性地保护伯胺。并且 该方法地聚合物方法也已得到发展。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。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。

TFAA 引入三氟乙酰基示例

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.

三氟乙酸乙酯引入三氟乙酰基示例

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

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]24 D = +4.8 (c =0.48, CHCl3).

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，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。也可在 NH3/MeOH，HCl/MeOH或通 过相转移水解(KOH/Et3Bn+Br-/H2O/CH2Cl2或乙醚)脱去。

KOH 脱去三氟乙酰基示例

A solution of compound 1 (1.7 g, 5.4 mmol) in MeOH (250 mL) was cooled to 0°C, and then 5 N KOH solution (30 mL) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred overnight, and then the MeOH was removed by rotary evaporation. The residue was diluted with H2O (25 mL) and extracted with Et2O (4 x 100 mL), dried (Na2SO4), filtered, and evaporated to afford clear oil. This oil was dissolved in Et2O (100 mL), filtered through a plug of glass wool, and neutralized by the slow addition of oxalic acid (54 mL, 0.1 M in MeOH). The solvents were removed, and the resulting white residue was recrystallized from MeOH to afford compound 2 (0.9 g, 59%) as the hemioxalate salt, m.p 243 °C.

K2CO3脱去三氟乙酰基示例

Compound 1 (45 mg, 0.18 mmol) was dissolved in 5% K2CO3 in MeOH/H2O (15 mL), and the soln. was stirred at 23°C for 4 h. H2O (3 mL) was added, the soln. was saturated with NaCl, and then extracted with CH2Cl2 (5×15 mL). The combined org. extracts were dried (Na2SO4) and concentrated under reduced pressure to afford compound 2 (23.5 mg, 85%).