浙江三基鋼管有限公司

三氟乙?；═fa）是Weygand最先引入到多肽合成中的。三氟乙酰基（Tfa）可用三氟醋酐導(dǎo)入，在稀堿液中很容易脫去。Tfa保護的氨基酸或多肽在高真空下易于氣化，因而能用于氣相層析以檢測消旋的程度和測定天然肽的排列順序，而且由于含有F，也可用19F NMR來檢測合成肽的純度、消旋程度以及類似物的鑒定等。由于N-Tfa-氨基酸在接肽時易于消旋，也是采用此保護基時應(yīng)該注意的地方。

三氟乙?；囊?/p>

由于三氟醋酐同氨基酸反應(yīng)時易生成惡唑烷酮而發(fā)生消旋，因此，同甲?；囊胍粯?，在低溫下于三氟醋酸溶液中用三氟醋酐酰化為好。一般而言，CF3COOEt/Et3N/MeOH是較好的方法，可在仲胺存在下，選擇性地保護伯胺。并且該方法地聚合物方法也已得到發(fā)展。在TFAA/18-crown-6/Et3N中，伯胺與18-crown-6形成絡(luò)合物，可選擇性地?；侔?。而在仲胺存在下，CF3COO-鄰苯二甲酰亞胺也可選擇性地將TFA基團引入到伯胺。

一、TFAA引入三氟乙?；纠?/p>

Chambers, JamesJ; Parrish, Jeasen C et al., J. Med.Chem., 2003, 46(16),3526-3535

To a stirred suspension of thehydrobromide salt of compound1 (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 themixture was cooled to 0 °C.Trifluoroacetic anhydride (2.5 mL, 17 mmol) was then added to the reaction dropwise. Themixture was allowed to warm to room temperature and stirred for 8 h. The mixturewas then diluted with CH2Cl2(50 mL) andwashed with 2 N HCl (50 mL), saturated NaHCO3(50 mL), and brine (50 mL). The organic phase was thendried (MgSO4), filtered, and evaporated to leave compound2as a white solid that was recrystallized fromEt2O (1.2 g, 92%):mp 197-198 °C.

二、 三氟乙酸乙酯引入三氟乙?；纠?/p>

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 °Cfor 10 minutes. Compound1 (8.8mmol) was added and the reaction mixture was stirred at the same temperaturefor one hour. After removal of the solvent, the residues were purified by fastcolumn chromatography (SiO2; CHCl3) to give compound 2(yield98 %) as a yellow crystalline m.p.: 68-69 °C(CH2Cl2/hexanes).

三、三氟乙酸乙酯選擇性保護伯胺示例

Whitlock, GavinA; 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) wasadded. The mixture was stirred at 0°Cfor 1 h and then at 23°Cfor 1 h. The solvent was then evaporated under reduced pressure to give a paleyellow 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).

三氟乙?；拿撊?/p>

三氟乙酰胺也是較易去保護地酰胺之一。Tfa基可以在水或乙醇水溶液中用0.1-0.2 N NaOH處理或者用1 M哌啶溶液處理很容易地脫去。由于脫去地條件溫和，也適用于一些長鏈肽中的Tfa基的脫去，例如，Anfisen用上述條件于8 M尿素中5℃處理8小時脫去42肽中的Lys側(cè)鏈的Tfa基，不過考慮到溶解度以及斷鏈副反應(yīng)等不利因素，長鏈肽的堿水解脫除保護基時要綜合考慮各種因素。在K2CO3或Na2CO3/MeOH/H2O條件下，Tfa可在甲基酯存在下于室溫去保護。也可在NH3/MeOH，HCl/MeOH或通過相轉(zhuǎn)移水解(KOH/Et3Bn+Br-/H2O/CH2Cl2或乙醚)脫去。

一、KOH脫去三氟乙?；纠?/p>

Chambers, James J; Parrish, Jason C etal., J. Med. Chem., 2003, 46(16), 3526-3535

A solution of compound 1 (1.7 g, 5.4 mmol) in MeOH (250 mL) was cooledto 0°C, and then 5 N KOH solution(30 mL) was added slowly. The reaction mixture was allowed to warm to roomtemperature and stirred overnight, and then the MeOH was removed by rotaryevaporation. 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 inEt2O (100 mL), filtered through a plug of glass wool, and neutralized by theslow addition of oxalic acid (54 mL, 0.1 Min MeOH). The solvents were removed, and the resulting white residue wasrecrystallized from MeOH to afford compound 2(0.9 g, 59%) asthe hemioxalate salt, m.p 243 °C.

二、 K2CO3脫去三氟乙?；纠?/p>

Whitlock, GavinA; Carreira, Erick M et al., Helv. Chim.Acta., 2000, 83(8), 2007-2022

Compound 1(45 mg, 0.18 mmol) wasdissolved in 5% K2CO3 in MeOH/H2O (15 mL), and the soln. was stirred at 23°C for 4 h. H2O (3 mL) wasadded, 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 toafford compound 2 (23.5 mg, 85%).

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