发布时间 : 星期一 文章氨基的保护及脱保护更新完毕开始阅读f72c97b71611cc7931b765ce0508763230127459
concentrated to yield a white-yellow solid. Recrystalization from petroleum ether (40-60 °C) gave the imide as needles (3.21 g, 7.80 mmol, 78%). Rf (hexane/ CH2Cl2 1:9, SiO2): 0.10. Mp: 106-109 °C. 2.2.1.6 酰胺的Boc保护示例
Lars G. J. Hammarstrm, Yanwen Fu et al., Org. Syn., 81, 213
A 2000-mL, three-necked, round-bottomed flask equipped with an argon inlet adapter, glass stopper, and an overhead mechanical stirrer is charged with a suspension of the hydantoin 1 (26.0 g, 154 mmol) in 1000 mL of 1,2-dimethoxyethane. Triethylamine (15.7 g, 154 mmol) is added in one portion, and the resulting white suspension is stirred for 30 min. Di-tert-butyl dicarbonate (168.0 g, 770 mmol) is then added by pipette, followed by 4-dimethylaminopyridine (DMAP) (0.2 g, 1.5 mmol). Six additional 0.2 g-portions of DMAP are added at 12 hr intervals during the course of the reaction. The reaction mixture is stirred vigorously for a total of 72 hr, and the resulting light yellow solid is then collected in a Büchner funnel using suction filtration. The filtrate is concentrated to a volume of 60 mL by rotary evaporation, and the resulting solution is cooled to 15°C. The precipitate which appears is collected using suction filtration, added to the first crop, and the combined solids are dissolved in 500 mL of chloroform. This solution is washed with three 200-mL portions of 1.0N HCl, and the combined aqueous phases are extracted with 100 mL of chloroform. The combined organic layers are washed with 100 mL of saturated aq NaHCO3 solution and 100 mL of brine, dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation. The resulting solid is dried at room temperature at 0.01 mm for 24 hr. The resulting finely ground light yellow solid is suspended in 400 mL of diethyl ether in a 1000-mL, round-bottomed flask equipped with a magnetic stirbar, stirred for 2 hr, and filtered on a Büchner funnel washing with four 50-mL portions of diethyl ether. The product is dried under vacuum (85°C; 0.5 mm) for 24 hr to give 60.0–65.3 g (83-90%) of 2 as a ivory-colored solid.
2.2.1.6 叠氮还原Boc保护示例
Seiki Saito, Kanji Komada, and Toshio Moriwake., Org. Syn., 73, 184 A 500-mL, single-necked, round-bottomed flask, equipped with a Teflon-coated stirring bar, is charged with a suspension of 0.91 g of 10% palladium on carbon catalyst in 100 mL of ethyl acetate. The flask is connected to a normal pressure hydrogenation apparatus and the catalyst is saturated with hydrogen. After removal of the hydrogen, a solution of 18.2 g (0.0785 mol) of 1 and 20.6 g (0.0942 mol) di-tert-butyl dicarbonate in 80 mL of ethyl acetate is added to the suspension of catalyst, a hydrogen atmosphere reestablished, and the suspension is stirred at room temperature under a slight positive pressure of hydrogen for 4–6 hr, The suspension is filtered through a Celite pad, and the pad is rinsed with several portions of ethyl acetate. The combined ethyl acetate solutions are concentrated on a rotary evaporator and finally under high vacuum to give a pale yellow oil that is initially purified by means of a column packed with silica gel (100 g) using hexane-ethyl acetate (6:1) as eluent. Fractions containing the product are combined and concentrated on a rotary evaporator to give 23.3 g of crude 2 as a colorless oil. The oily crude 2 is dissolved in 70 mL of hexane-ether (3:1), and the solution is cooled to 30°C, seeded, and kept overnight at that temperature (freezer) to allow crystallization. The mother liquor is siphoned out while the mixture is kept at 30°C (dry ice-acetone bath). The crystals are washed with several portions of hexane-ether (3:1) at 30°C, then dried under high vacuum to provide 12.2–12.7 g of diastereomerically
and
enantiomerically
pure
diethyl
(2S,3R)-2-(N-tert-butoxycarbonyl)amino-3-hydroxysuccinate (2) as colorless prisms, mp 33–34°C;.The combined mother liquor and the hexane–ether (3:1)
washings are concentrated on a rotary evaporator to give a colorless oil, which upon crystallization as above provides an additional 2.7–3.8 g of product 2. The combined yield of crystalline 2 is 15.9–16.5 g (66–73%). 2.2.1.7 吡咯Boc保护示例
Wha Chen, E. Kyle Stephenson et al., Org. Syn., 70, 151
The solution of 2-bromo-1H-pyrrole (9.8 g, 67.2 mmol) in 40 mL of THF is cooled to 78°C in a dry ice-acetone bath. The flask is equipped with a magnetic
stirring bar and a three-way stopcock attached to a balloon filled with nitrogen. To the stirred dark-green solution is added 2.71 g (26.9 mmol) of triethylamine followed immediately by addition of 20.4 g (93.9 mmol) of di-tert-butyl dicarbonate and a catalytic amount (ca. 0.1 g) of 4-dimethylaminopyridine. The flask is evacuated and purged with nitrogen. The mixture is stirred for 8 hr while it is allowed to warm to room temperature. The solvent is removed under reduced pressure at room temperature and 100 mL of hexane is added to the crude product, which is washed with deionized water (3 × 100 mL), dried over sodium sulfate, and concentrated under reduced pressure at room temperature. The crude product is purified by chromatography on amine-treated neutral silica (270 g) using hexane as the eluent. The fractions containing the product are identified by TLC, combined, and concentrated under reduced pressure at room temperature to yield N-tert-Butoxycarbonyl-2-bromopyrrole as a colorless oil (13.5–14.7 g, 82–89%).
2.2.1.8 吲哚Boc保护示例
G. Tong; P. Ruiyan et al., J. Org. Chem., 1997, 26, 9298
To a solution of 6-methoxy-3-methylindole (5.0 g, 31 mmol) in distilled acetonitrile (150 mL) were added di-tertbutyl dicarbonate (7.44 g, 34.1 mmol) and DMAP (0.195 g, 1.6 mmol). The reaction mixture was stirred at rt for 12 h. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL) and washed with an aqueous solution of 1 N HCl (2 x 50 mL). The aqueous layer was extracted with CH2Cl2 (3 x 30 mL). The combined organic ayers were dried (K2CO3). After removal of solvent under reduced pressure, the residue was solidified to afford the product (8.12 g, 99%) as a yellow solid: mp 45-46 °C.
2.2.2 叔丁氧羰基的脱去
Boc比Cbz对酸敏感，酸解产物为异丁烯和CO2（见下式）。在液相肽的合成中，Boc的脱除一般可用TFA或50%TFA（TFA:CH2Cl2 = 1:1,v/v）。而在固相肽合成中，由于TFA会带来一些副反应（如在得到的胺上上一个三氟乙酰基等），因此多采用1-2M HCl/有
机溶剂。一般而言用HCl/二氧六环，比较多见。
用甲醇作溶剂，HCl/EtOAc的组合使TBDMS和TBDPS酯[1]以及叔丁酯和非酚类酯在Boc脱除时不被断裂，而S-Boc除外[2]。但当同时脱除分子中Boc和叔丁酯, 或分子中有游离羧酸基，千万记住不能用HCl/MeOH,其可将羧酸变为甲酯。同时AcCl/MeOH，则是一个在甲醇中产生无水HCl的便利方法。这些条件也可用来从羧酸制备酯以及形成胺的盐酸盐[3]。
在中性的无水条件下Me3SiI在CHCl3或CH3CN中除了能脱除Boc外，也能断裂氨基甲酸酯、酯、醚和缩酮。通过控制条件可以得到一定的选择性[4]。
当分子中存在一些官能团其可与副产物叔丁基碳正离子在酸性下反应时，需要添加硫酚(如苯硫酚)来清除叔丁基碳正离子，如此举可防止蛋氨酸和色氨酸的脱Boc时的烷基化[5]。也可使用其它的清除剂，如苯甲醚、苯硫基甲醚、甲苯硫酚、甲苯酚及二甲硫醚[6]。在Boc脱去过程中TBDPS[7]和TBDMS[8]基对CF3COOH是稳定的（在TBS存在，用相对稀一些的10－20 ％TFA）。伯胺衍生物存在下，ZnBr2/CH2Cl2可以选择性的脱除仲胺上的Boc[9]。
1. F. Cavelier, C. Enjabal., Tetrahedron Lett., 1996, 37, 5131
2. F. S. Gibson, S. C. Bergmeier, H. Rapoport., J. Org. Chem., 1994, 59, 3216 3. A.Nudelman, Y. Bechor et al., Synth. Commun., 1998, 28, 471
4. R. S. Lott, V. S. Chauhan et al., J. Chem. Soc. Chem. Commun., 1979, 495; G. A. Olah, S. C. Narang., Tetrahedron., 1982, 38, 2225
5. R. A. T. M. van Benthem, H. Hiemstra et al., J. Org. Chem., 1992, 57, 6083 6. M. Bodanszky, A. Bodanszky., Int. J. Pept. Protein Res., 1984, 23, 565; Y. Masui, N. Chino et al., Bull. Chem. Soc. Jpn., 1980, 53, 464 7. P. A. Jacobi, S. Murphree et al., J. Org. Chem., 1996, 61, 2413 8. J. Deng, Y. Hamada et al., J. Am. Chem. Soc., 1995, 117, 7824 9. S. C. Nigam, A. Mann et al., Synth. Commun., 1989, 19, 3139 2.2.2.1.1 TMSOTf中性条件下脱Boc示例
Gilbertson, Scott R; Chang, Cheng-Wei et al., J. Org. Chem., 1998, 63(23),
8424-8431
To a solution containing 2 (1.0 g, 3.9 mmol) in 30 mL of dry CH2Cl2 was slowly