鄰苯二甲酰基（Pht）保護氨基

同一般的酰基氨基酸比較，Pht-氨基酸在接肽時不易消旋，但它對堿不穩定，在堿皂化的條件下發生鄰苯二甲酰亞胺環的開環生成鄰羧基苯甲酰基衍生物。因此，當選用Pht作氨基保護基時，肽鏈的羧基末端則不能用甲酯（或乙酯）保護，而只能用芐酯或叔丁酯保護，以避免將來用皂化去酯的步驟。Pht對催化氫解、HBr/HOAc處理以及Na/NH3（液）還原（后處理的堿性條件需要避免）等均穩定，但很容易用肼處理脫去。

鄰苯二甲酰基的引入

最先導入Pht基的方法是將鄰苯二甲酸酐同氨基酸在145-150℃進行熔融反應，但這個方法對有的氨基酸會引起部分消旋作用，因而后來又進行了一些改進，如鄰苯二甲酸酐/CHCl3/70℃下反應。然而最成功的是Nefkens提出的用N-乙氧羰基鄰苯二甲酰亞胺為試劑的方法（見下式），即N-乙氧羰基鄰苯二甲酰亞胺與氨基酸在Na2CO3水溶液中于25℃反應10-15分鐘，就可以得到85-95%的Pht-氨基衍生物。這個試劑可在仲胺的存在的情況下選擇性地保護伯胺。

一、鄰苯二甲酸酐引入鄰苯二甲酰基示例

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、鄰苯二甲酸單乙酯引入鄰苯二甲酰基示例

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-乙氧羰基鄰苯二甲酰胺引入鄰苯二甲酰基示例:

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%).

脫保護

Pht-氨基衍生物很容易用肼處理脫去。一般用水合肼的醇溶液回流2 小時或用肼的水或醇溶液室溫放置1-2 天都可完全脫去Pht保護基。在此條件下Cbz、Boc、甲酰基、Trt、Tos等均可不受影響。在肼效果差的情況下，NaBH4/i-PrOH-H2O(6:1)和AcOH在80℃反應5-8小時，這個方法是很有效的(見下式)。另外，濃HCl回流也容易脫去Pht保護基。

一、 NH2NH2/MeOH脫除鄰苯二甲酰胺示例

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脫除鄰苯二甲酰胺示例

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脫除鄰苯二甲酰胺示例

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脫除示例

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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相關反應

鄰苯二甲酰亞胺鉀鹽是一種-NH2合成子，它可通過和烷基鹵代烴反應制備伯胺。烷基化后，鄰苯二甲酰亞胺沒有親核性，不能繼續反應，產物通過堿或者肼裂解得到伯胺產物和環狀副產物。鄰苯二甲酰亞胺作為酸和醇進行Mitsunobu反應在有機合成中有很好的應用。