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。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。

  邻苯二甲酰基的引入 

       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。然而成功的是 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），即 N-乙氧羰基邻苯二甲酰亚胺与氨基酸在 Na2CO3水溶 液仲于 25℃反应 10-15 分钟，就可以得到 85-95%的 Pht-氨基衍生物。这个试剂可在仲 胺的存在的情况下选择性地保护伯胺。 

邻苯二甲酸酐引入邻苯二甲酰基示例 

     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). 

邻苯二甲酸单乙酯引入邻苯二甲酰基示例 

    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

 N-乙氧羰基邻苯二甲酰胺引入邻苯二甲酰基示例:  

      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. 

    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%). 

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)[3]。另外，浓 HCl 回流也容易脱去 Pht 保护基。

 NH2NH2/MeOH 脱除邻苯二甲酰胺示例 

     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. 

NH2NH2/EtOH 脱除邻苯二甲酰胺示例 

     Compound 1 (1.66 g, 4.77 mmol) was dissolved in ethanol (50 mL), and then hydrazine monohydrate (0.93 mL, 19 mmol) was added. The resulting mixture was heated at reflux for 24 h and then cooled to room temperature. The mixture then was combined with aqueous NaOH (50 mL) and extracted with CH2Cl2. The solvent was removed in vacuo to afford compound 2 (0.79 g, 76%), which was used directly in the next step without further purification. 

 HCl 脱除邻苯二甲酰胺示例 

   Compound 1 (1.0 g, 3.86 mmol) and concentrated HCl (3 mL) was heated for 60 h at 100 °C. After the mixture was allowed to cool to room temperature, water (20 mL) was added. The solid precipitate that formed was removed by filtration and discarded, and the aqueous layer was washed with diethyl ether twice, with these washings also being discarded. The water was removed in vacuo, and the remaining solid was dried to give compound 2 (0.61 g, 95%), which was then used to the next step without further purification due to its instability.  

NaBH4/i-PrOH-H2O(6:1)和 AcOH 脱除示例 

   To a stirred solution of compound 1 (0.36 g, 1 mmol) in 2-propanol (7.7 ml) and H2O (1.3 ml) was added NaBH4 (0.19 g, 5 mmol). After stirring 24 h, TLC indicated complete consumption of starting material. AcOH (1 ml) was added carefully and when the foaming subsided, the flask was stoppered and heated to 80°C for 2 h. The crude reaction mixture was then eluted onto a Dowex 50 (H+) column (2.7 x 10 cm), washed with H2O (150 ml), then eluted with 1 M NH4OH (200 ml). Ninhydrin-active fractions were collected and pooled for freeze drying, and thus afforded compound 2 (0.2 g, 89%) as an ammonium salt.