邻苯二甲酰基（Pht）保护氨基

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

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。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），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。这个试剂可在仲胺的存在的情况下选择性地保护伯胺。

一、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 placedL-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 magneticallystirred and heated under reflux for 4.5 hr at which point approximately 4.5 mLof water has separated. The reaction mixture is allowed to cool to roomtemperature and the precipitated triethylaminehydrochloride (34 g) is collected by suction filtration. Thefiltrate is washed with four 300-mL portions of 1 Naqueous hydrochloric acidfollowed by three 300-mL portions of water. The organiclayer is dried over magnesium sulfate, filtered, and the filtrate is concentrated underreduced pressure using a rotary evaporator. Theresidual oil is placed under reduced pressure for 12 hr at 0.1-0.5 mm, followed by trituration with 200 mL of pentaneto give 59 g (80%) ofproduct as a white solid after collection and drying at room temperature underreduced pressure (mp 37-40°C). mp 37-40°C,; [α]20D−41.6° (CHCl3, c 1.49).

二、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 (10mL) 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 stirredfor 30-40 min at rt. Afterwards, this solution was added to a suspension of 7(0.898 g) inTHF (10 mL) at 0 °C, and themixture was stirred at rt for 3 h. The solvent was eliminated in vacuo, and theresidue was heated at 85 °Covernight. The reaction mixture was then dissolved in 250 mL of dichloromethaneand washed with saturated NaHCO3solution (2 x100 mL) and with brine (100 mL). The organic layer was dried (Na2SO4) andevaporated to give a crude product which was purified by column chromatography toyield 1.28 g of (2S,3S)-4-phenyl-3-phthalimidobutane-1,2-diol (8) (83%) as a white solid: mp 91-93 °C.

三、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 etal., J. Org. Chem., 1980, 45(1), 174-175

Ethyl chloroformate (115 mL, 1.29mol) was added dropwise over a period of 90 min to a stirred solution of phthalimide(149.9 g, 1.02 mol) andtriethylamine (160 mL, 1.15 mol) in dimethylformamide (500 mL)at 0-5°Cunder argon. The reaction mixture was allowed to warm to room temperature andstand for 4 h. It then was slowly added to an agitated mixture of ice and water(3 L). The solid product wascollected and extracted with two portions of chloroform (450 mL and then 50mL). The extract was dried (Na2SO4), cooled overnight inthe refrigerator, and filtered to remove phthalimide (mp 238°C).The chloroform solution was concentrated to about 350 mL, diluted withpetroleum 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 of212 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 wasextracted with EtOAc (4 x 5 mL). The combined organic extracts were washed withsaturated aqueous NH4Cl (3x 3 mL) and brine (3 mL), dried (Na2SO4),and concentrated in vacuo. Chromatography (hexane/EtOAc = 5/1) provided 9as an oil (215 mg, 75%).

脱保护

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。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。

一、 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 compound1 (313 mg, 1.04 mmol) in MeOH (6 mL) was added hydrazinemonohydrate (0.1 mL, 1.67 mmol) at 0 °C.After being stirred at same temperature for 3h, the solvents were removed invacuo and the residue was re-dissolved into water (10 mL). The pH ofsolution 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 filtratewas treated with solid Na2CO3untilthe pH reached 9-10. The mixture was extracted with CH2Cl2(10 mL x 4). Thecombined extracts were dried (Na2SO4), concentrated and dried in vacuo toprovide compound 2 (209mg, quantitatively) as a yellowish oil.

二、NH2NH2/EtOH脱除邻苯二甲酰胺示例

Lee, Chang-Hee;Lee, Jin-Suk et al., J. Org. Chem., 2005, 6, 2067-2074

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. Theresulting mixture was heated at reflux for 24 h and then cooled to roomtemperature. The mixture then was combined with aqueous NaOH (50 mL) andextracted with CH2Cl2. The solvent was removed in vacuoto afford compound 2 (0.79 g,76%), which was used directly in the next step without further purification.

三、HCl脱除邻苯二甲酰胺示例

Lee, Chang-Hee;Lee, Jin-Suk et al., J. Org. Chem., 2005, 6, 2067-2074

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) wasadded. The solid precipitate that formed was removed by filtration anddiscarded, and the aqueous layer was washed with diethyl ether twice, withthese washings also being discarded. The water was removed in vacuo, and the remainingsolid was dried to give compound 2 (0.61 g,95%), which was then used to the next step without further purification due toits instability.

四、 NaBH4/i-PrOH-H2O(6:1)和AcOH脱除示例

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

To a stirred solution ofcompound 1 (0.36 g, 1mmol) in 2-propanol (7.7 ml) and H2O (1.3 ml) was added NaBH4(0.19 g, 5 mmol). After stirring24 h, TLC indicated complete consumption of starting material. AcOH (1 ml) wasadded carefully and when the foaming subsided, the flask was stoppered andheated to 80°C for2 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 werecollected and pooled for freeze drying, and thus afforded compound 2 (0.2 g, 89%) as an ammonium salt.

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相关反应

邻苯二甲酰亚胺钾盐是一种-NH2合成子，它可通过和烷基卤代烃反应制备伯胺。烷基化后，邻苯二甲酰亚胺没有亲核性，不能继续反应，产物通过碱或者肼裂解得到伯胺产物和环状副产物。邻苯二甲酰亚胺作为酸和醇进行Mitsunobu反应在有机合成中有很好的应用。