羧酸叔丁酯的保护方法

羧酸叔丁酯的保护方法

1) 质子酸（如H 2SO4）催化羧酸与异丁烯反应得到叔丁酯。

To a solution of compound 8 (21 g, 43.12 mmol) in DCM (420 mL) was added H2SO 4 (2.1 mL) at -780C under N2. Then inlet the isobutene in DCM for 30 min, stirred overnight at RT. The mixture was poured into sat.aq. NaHCO3, filtered an dried the organic layer and purified by flash chromatography to get the compound 9(16.6 g, Yield: 70.9%) as a oily for the next step.

2) 在DMAP-Boc 2O 条件下，催化羧酸形成叔丁酯。

( 示例反应用了1eq 的Boc 2O 是为了保证两个羧基只上一个叔丁酯。实际反应中会有少量上双叔丁酯的副产物生成 )

To a flame dried flask containing t-BuOH (500mL), was added compound 1 (50g,1.0 eq), DMAP (1.97g, 0.1eq), anhydrous pyridine (12.8mL, 1.0eq). Boc2O (34.7g, 1.0eq) was then added slowly, the resulting mixture was stirred for overnight at 30 oC. Reaction was monitored by LC-MS, 100mL H2O was added to the reaction mixture, and some insoluble material was formed, it was filtered. The solid was dried over vacuum, and it was purified by silica gel column with eluent of PE/ EtOAc (5:1) to obtain the desired product as a white powder. (20.5g, 35.2% yelid)

3) DCC-DMAP催化羧酸与t-BuOH 直接缩合形成叔丁酯。DCC - 1-甲基咪唑也是有效的催化体系。

Tetrahedron Lett. 1978, 46, 4475

Typical procedure:

A solution of carboxylic acid (0.010 mol), DCC (0.011 mol), the alcohol (0.011 mol) and DMAP (0.001 mol) in ether of DCM (25-50 mL) was allowed to stand at r.t. until esterification was complete. The N,N-dicyclohexyl urea was filtered and the filtrate washed with water (3 x 50 mL), 5% acetic acid solution (3 x 50 mL) and again with water (3 x 50 mL), dried and the solvent evaporated in vacuuo to

give the ester.

4) 三氯乙酰亚胺叔丁酯试剂。该方法条件温和，副反应较少。

To a stirring suspension of N-Fmoc-L-serine (5, 8.19 g, 25.0 mmol) in EtOAc (125 mL) was added tert-butyl 2,2,2-trichloroacetimidate (8.95 mL, 50.0 mmol) in cyclohexane (50 mL) by an addition funnel over 15 min. The reaction was stirred for 18 h, then washed with saturated aqueous NaHCO3, water, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (SiO2, 3:1 hexane/EtOAc) to yield product (8.90 g, 23.2 mmol, 93%) as a white solid.

5) 羧酸和醇的Mitsunobu 反应。一般醇为伯醇或仲醇，叔丁醇由于位阻大，该方法应用较少。

Journal of Medicinal Chemistry, 56(9), 3620-3635; 2013

To a solution of starting material (324 mg, 1 mmol) in dry THF (10 mL) were added t-BuOH (1.5 mmol) and PPh3 (392 mg, 1.5 mmol). Then DEAD (260 mg, 1.5 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 18 h, then poured into water and taken up into DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated to dryness. The crude residue was purified by flash chromatography.

6) 高氯酸催化

To a solution of (S)-6-amino-2-(((benzyloxy)carbonyl)amino)hexanoic acid (4 g, 14.27 mmol)) in t-Butyl acetate (80 mL) was added perchloric acid (2.0 mL, 14.27 mmol) at r.t. Then, the mixture was stirred at r.t overnight. LCMS showed that the reaction was finished. The solution was added into EA (100 mL) and was basified with aqueous NaHCO3 to pH=7. The mixture was separated and

the water phase extracted with EA (20 mL x 3). The combined organic phase was washed with brine and dried over Na2SO4. The organic phase was concentrated under vacuum to give

(S)-tert-butyl 6-amino-2-(((benzyloxy)carbonyl)amino)hexanoate (4.2 g, 12.48 mmol, 87 % yield) as a colorless oil: 1H NMR (400 MHz, CD3OD) δ 7.39-7.30 (m, 5H), 5.15-5.08 (m, 2H), 4.09-4.04 (m, 1H),

2.93-2.87 (m, 2H), 1.91-1.81 (m, 1H), 1.74-1.63 (m, 3H), 1.52-1.40 (m, 12H); ES-LCMS m/z 337 (M+H).

羧酸叔丁酯保护的方法有多种，各有其优缺点，需要灵活运用。例如方法(3) DCC-DMAP 直接催化羧酸与醇缩合操作方便，方法(4)三氯乙酰亚胺叔丁酯试剂反应条件温和且较干净，容易纯化。方法 (1)质子酸催化羧酸与异丁烯反应，虽然需要用到异丁烯气体，操作起来较麻烦，但是在其他方法生成叔丁酯效果不好时，该方法可以得到较好的收率。