3．酰基类

3.1 邻苯二甲酰基（Pht）

同一般的酰基氨基酸比较，Pht-氨基酸在接肽时不易消旋，但它对碱不稳定，在碱皂化的条件下发生邻苯二甲酰亚胺环的开环生成邻羧基苯甲酰基衍生物[1]。因此，当选用Pht作氨基保护基时，肽链的羧基末端则不能用甲酯（或乙酯）保护，而只能用苄酯或叔丁酯保护，以避免将来用皂化去酯的步骤。Pht对催化氢解、HBr/HOAc处理以及Na/NH3（液）还原（后处理的碱性条件需要避免）等均稳定，但很容易用肼处理脱去。

3.1.1 邻苯二甲酰基的引入

最先导入Pht基的方法是将邻苯二甲酸酐同氨基酸在145-150℃进行熔融反应，但这个方法对有的氨基酸会引起部分消旋作用，因而后来又进行了一些改进，如邻苯二甲酸酐/CHCl3/70℃下反应[2]。然而最成功的是Nefkens提出的用N-乙氧羰基邻苯二甲酰亚胺为试剂的方法（见下式）[3]，即N-乙氧羰基邻苯二甲酰亚胺与氨基酸在Na2CO3水溶液中于25℃反应10-15分钟，就可以得到85-95%的Pht-氨基衍生物[4]。这个试剂可在仲胺的存在的情况下选择性地保护伯胺[5]。

1. S. J. Leach, H. Lindley., Australian, J. Chem., 1954, 7, 173 2. T. Sasaki, K. Minamoto et al., J. Org. Chem., 1978, 43, 2320

3. G. H. I. Nefkens, G. I. Tesser et al., Rec. Trav. Chim., 1960, 79, 688; Soai,

Kenso; Ookawa, Atsuhiro et al., Bull. Chem. Soc. Jpn., 1982, 55(5), 1671-1672; N. Aguilar; A. Moyano et al., J. Org. Chem., 1998, 11, 3560; Santaniello, Enzo; Ponti, Fedegco et al., Synth. Commun., 1980, 10(8), 611-614; Siedlecka, Renata; Skarzewski, Jacek et al., Synth. Commun., 1997, 27(12), 281-2086

4. C. R. McArthur, P. M. Worster et al., Synth. Commun., 1983, 13, 311 5. G. Sosnovsky, J. Lukszo., Z. Naturforsch. B., 1986, 41B, 122

3.1.1.1 邻苯二甲酸酐引入邻苯二甲酰基示例

P. Meffre, P. Durand., Org. Syn., 76, 123

Into a 2-L, round-bottomed flask fitted with a Dean-Stark apparatus, reflux condenser, and drying tube containing calcium chloride are placed L-methionine methyl ester hydrochloride (50.0 g, 0.25 mol), phthalic anhydride (37.1 g, 0.25

mol), triethylamine (100 mL, 0.72 mol), and toluene (1 L). The mixture is magnetically stirred and heated under reflux for 4.5 hr at which point approximately 4.5 mL of water has separated. The reaction mixture is allowed to cool to room temperature and the precipitated triethylamine hydrochloride (34 g) is collected by suction filtration. The filtrate is washed with four 300-mL portions of 1 N aqueous hydrochloric acid followed by three 300-mL portions of water. The organic layer is dried over magnesium sulfate , filtered, and the filtrate is concentrated under reduced pressure using a rotary evaporator. The residual oil is placed under reduced pressure for 12 hr at 0.1-0.5 mm, followed by trituration with 200 mL of pentane to give 59 g (80%) of product as a white solid after collection and drying at room temperature under reduced pressure (mp 37-40°C). mp 37-40°C,; [α]20 D 41.6° (CHCl3, c 1.49).

3.1.1.2 邻苯二甲酸单乙酯引入邻苯二甲酰基示例

N. Aguilar; A. Moyano et al., J. Org. Chem., 1998, 11, 3560

To a suspension of PyBOP (2.84 g, 5.46 mmol, 1.1 equiv) in dry THF (10 mL) was added a solution of 2-ethoxycarbonylbenzoic acid (1.08 g, 5.46 mmol, 1.1 equiv) in THF (10 mL) and i-Pr2NEt (1.27 mL, 7.44 mmol, 1.5 equiv), and the resulting mixture was stirred for 30-40 min at rt. Afterwards, this solution was added to a suspension of 7 (0.898 g) in THF (10 mL) at 0 °C, and the mixture was stirred at rt for 3 h. The solvent was eliminated in vacuo, and the residue was heated at 85 °C overnight. The reaction mixture was then dissolved in 250 mL of dichloromethane and washed with saturated NaHCO3 solution (2 x 100 mL) and with brine (100 mL). The organic layer was dried (Na2SO4) and evaporated to give a crude product which was purified by column chromatography to yield 1.28 g of (2S,3S)-4-phenyl-3-phthalimidobutane-1,2- diol (8) (83%) as a white solid: mp 91-93 °C.

3.1.1.3 N-乙氧羰基邻苯二甲酰胺引入邻苯二甲酰基示例:

Worster, Paul M; Leznoff, Clifford C et al., J. Org. Chem., 1980, 45(1), 174-175 Ethyl chloroformate (115 mL, 1.29 mol) was added dropwise over a period of 90

min to a stirred solution of phthalimide (149.9 g, 1.02 mol) and triethylamine (160 mL, 1.15 mol) in dimethylformamide (500 mL) at 0-5°C under argon. The reaction mixture was allowed to warm to room temperature and stand for 4 h. It then was slowly added to an agitated mixture of ice and water (3 L). The solid product was collected and extracted with two portions of chloroform (450 mL and then 50 mL). The extract was dried (Na2SO4), cooled overnight in the refrigerator, and filtered to remove phthalimide (mp 238°C). The chloroform solution was concentrated to about 350 mL, diluted with petroleum ether (bp 60-80 °C; 350 mL) and allowed to stand at room temperature to give N-(ethoxycarbony1)phthalimide (179 g, followed by two additional crops for a total of 212 g, 95% yield): mp 83°C.

W. Shijun; Y. Zhujun et al., Org. Lett., 2004, 16, 2721

The solution of compound 1 (150.2 mg, 1.05 mmol) in THF (4 mL) was treated with

N-(ethoxycarbonyl)-phthalimide (230 mg, 1.05 mmol), and NaHCO3 (88 mg, 1.05 mmol) at 0°C. The reaction was stirred for 7 h at rt, and separated. The aqueous layer was extracted with EtOAc (4 x 5 mL). The combined organic extracts were washed with saturated aqueous NH4Cl (3 x 3 mL) and brine (3 mL), dried (Na2SO4), and concentrated in vacuo. Chromatography (hexane/EtOAc = 5/1) provided 9 as an oil (215 mg, 75%). 3.1.2 邻苯二甲酰基的脱去

Pht-氨基衍生物很容易用肼处理脱去。一般用水合肼的醇溶液回流2 小时[1, 4]或用肼的水或醇溶液室温放置1-2 天都可完全脱去Pht保护基[2]。在此条件下Cbz、Boc、甲酰基、Trt、Tos等均可不受影响。在肼效果差的情况下，NaBH4/i-PrOH-H2O(6:1)和AcOH在80℃反应5-8小时，这个方法是很有效的(见下式)。另外，浓HCl回流也容易脱去Pht保护基[4]。

1. J. C. Sheehan, D. W. Chapman et al., J. Am. Chem. Soc., 1952, 74, 3822; F. E. King et al., J. Chem. Soc., 1951, 243, 2976

2. F. Dasgupta, P. J. Garegg., J. Carbohydr. Chem., 1988, 7, 701

3. J. O. Osby; M. G. Martin et al., Tetrahedron Lett., 1984, 25, 2093-2096

[3]

4. Lee, Chang-Hee; Lee, Jin-Suk et al., J. Org. Chem., 2005, 6, 2067-2074 3.1.2.1 NH2NH2/MeOH脱除邻苯二甲酰胺示例

W. Shijun; Y. Zhujun et al., Org. Lett., 2004, 16, 2721

To a solution of compound 1 (313 mg, 1.04 mmol) in MeOH (6 mL) was added hydrazine monohydrate (0.1 mL, 1.67 mmol) at 0 °C. After being stirred at same temperature for 3h, the solvents were removed in vacuo and the residue was re-dissolved into water (10 mL). The pH of solution was then adjusted to 1-2 by adding 1N HCl at 0 °C. The whole mixture was stirred for 1 h at rt, and then filtered. The filtrate was treated with solid Na2CO3 until the pH reached 9-10. The mixture was extracted with CH2Cl2 (10 mL x 4). The combined extracts were dried (Na2SO4), concentrated and dried in vacuo to provide compound 2 (209 mg, quantitatively) as a yellowish oil.