α-氨基酸的合成

1.4. 甘氨酸片断引入法.

引入甘氨酸片断是一种常见的合成氨基酸的策略。这里我们介绍下面五种比较常用常见的甘氨酸片段：

目前，就这类化学本身而言比较直观，大多数的研究方向相当热门关注与如何以手性诱导的方式引入甘氨酸片断。

1.4.1 Wittig reaction结合氢化还原反应制备氨基酸

反应示例：

WO 2011087740

TMG (6.3 mL, 50 mmol) was added to a stirred solution of cpd1 (17.2 g, 52 mmol) in THF (200 mL) at -78 ^oC under N₂ atmosphere for 1 hour, then dihydro-2H-pyran-4(3H)-one (5.0 g, 50 mmol) was added. The resulting solution was stirred at room temperature for 12 hours, evaporated the solvent, washed with 1N HCl (80 mL). Then extracted with EtOAc (80 mL * 2), the organic layer was dried over Na₂SO₄, filtered, concentrated, purified by column (PE/EA: 4 /1) to afford the desired product (12.3 g, yield: 80 %).

Knowles-Monsanto 反应

值得一提的是William S. Knowles 因为其在不对称催化氢化合成手性氨基酸方面的卓越贡献，于2001 被授予诺贝尔化学奖。一同得奖的还有大名鼎鼎的Noyori 和 Sharpless。

在此基础上发展的不对称催化氢化合成手性氨基酸还有还多，比如下图所示。

1.4.2 甘氨酸席夫碱类似物饱和碳原子上的取代/加成反应制备氨基酸

1.4.2.1取代反应

通过对甘氨酸席夫碱衍生物饱和碳原子的不对称亲电取代反应，我们可以非常方便的得到大量非天然氨基酸，如下例所示。

不对称催化剂作用下，甘氨酸席夫碱衍生物饱和碳原子的不对称亲电取代反应近年来发展较快，备受人们关注。如Cu(salen)络合物能有效催化甘氨酸席夫碱类似物饱和碳原子上的不对称亲电取代反应，该类反应对映选择性较高。

反应实例1

Tetrahedron, 2004, 1849-1861

Imine 3a (0.24 g, 1.0 mmol) was dissolved in dry toluene (2.5 ml) and copper(salen) complex 1 (7.7 mg, 0.02 mmol) was added. Powdered sodium hydroxide (0.14 g, 3.5 mmol) and allyl bromide (14.5 mg, 1.2 mmol) were added to the mixture. The resulting solution was stirred overnight under an argon atmosphere at room temperature. Then, methanol (2 ml) followed by acetyl chloride (0.5 ml) were added drop wise to the mixture. The mixture was stirred for four more hours and the solvents were removed in vacuum. The residue was purified by column chromatography using first ethyl acetate and then a mixture of ethyl acetate and ethanol (4:1) as eluent to give compound 4a (72.2 mg, 46%) as a colourless oil.

反应实例 2

反应实例3

反应实例4

The reaction was carried out with BnBr (1.2-2.4 equiv), 2a (0.1-10 mol %), and 1.0 M aqueous KOH (5 equiv) in the presence of several surfactants (0.4 equiv) at room temperature. b Isolated yield. c Enantiomeric excess of 3 was determined by HPLC analysis of the alkylated imine using a chiral column (DAICEL Chiralcel OD) with hexane/2-propanol as solvent. d The reaction was performed with 50% KOH. e Me3CCH2C(Me)2C6H4-(OCH2CH2)nOH (n ) 10). f Sodium dodecyl sulfate. g Cetyltrimethylammonium bromide.

上述内容主要是甘氨酸席夫碱类似物在手性催化剂诱导下进行亲电取代反应, 下面我们介绍两种含有手性辅基甘氨酸席夫碱类似物在手性辅基诱导下进行亲电取代反应,反应后脱去手性辅基得到光活性氨基酸，手性辅基种类繁多, 但是不外乎两大类型，一是在N-端引入手性辅基，另一种是在C-端引入手性辅基。在这里我们分别各挑了一种试剂作了简单介绍。

N-端手性辅基反应实例：

下面我们介绍一种C-端手性辅基，采用手性咪唑琳酮作手性助剂, 碱性条件下亲电试剂对甘氨酸席夫碱类似物进行亲电取代反应制备氨基酸的方法，如下图所示。

从含手性辅基的中间体上切割

1.4.2.2 加成反应

上面部分我们就甘氨酸席夫碱类似物亲电取代反应进行了简单介绍，亲电试剂多为卤代烷。甘氨酸席夫碱类似物饱和碳原子由于收到羰基和亚胺基的去电子效应，有较强的酸性，在碱的作用下可以与醛，酮或α，β-不饱和羰基化合物加成制备氨基酸。如果在手性催化剂的作用下，亦可以选择性生成光学纯的氨基酸， 如下例所示：

反应实例2：

A highly efficient direct asymmetric aldol reaction of a glycinate Schiff base with aldehydes has been achieved under mild biphasic conditions with excellent stereochemical control, using a chiral quaternary ammonium salt as a phase-transfer catalyst.
T. Ooi, M. Kameda, M. Taniguchi, K. Maruoka, J. Am. Chem. Soc., 2004, 126, 9685-9694.

1.4.3. N-酰基甘氨酸的应用

1.4.3.1  1,3-δ重排合成氨基酸

Chem,. A Eur. J., 2002, 1850-1855

Alumin um chloride (65 mg, 0.49 mmol) was suspended in THF (2 mL) at 0^oC. The suspension was cooled to -20 oC before a solution of LHMDS (8 mL, 3.55 mmol) was added. The cooling bath was removed and the mixture was stirred for 10 min. After cooling to -20^oC, a solution of quinine (216 mg, 0.67 mmol) in THF (3 mL) was added slowly. The mixture was stirred for 2 h at RT. The resulting clear yellow solution was added via syringe to a solution of ester 1a (100 mg, 0.44 mmol) in THF (2 mL) at -78 ^oC. The mixture was allowed to warm to room temperature overnight, and the workup was carried out as described in the general procedure for Claisen rearrangements. Ester ent-2a was obtained as a colorless oil (74% yield, 71% ee, 85%ds).

1.4.3.2 与羰基加成反应合成氨基酸

Synth. Commun., 2000, 3167-3170 Indian J. Chem., 2003, 2878-2881

A mixture of aldehyde 1 (1.18 g, 11.0 mmol), hippuric acid(2.00 g,11.1 mmol), acetic anhydride(3.37 g, 33.0 mmol) and bismuth(III) acetate (0.42 g, 1.1 mmol) was heated at reflux 1 h. Ethanol (10 ml) was added to the reaction mixture and it was stirred for 10 min at which a yellow solid precipitated. The mixture was cooled in ice, suction filtered, and the solid collected was washed thoroughly with hot water(20 ml) to yield 2.41 g (88%) of pure azlactone.

1.4.4 手性咪唑啉啶-4-酮法

 利用卤代烃、醛、酮等在强碱作用下与（2S,5S）-1-N-Boc-2-tBu-3,5-二甲基咪唑啉啶-4-酮进行亲电反应在合成氨基酸的策略得到了广泛的应用。如下例所示：

α-二取代氨基酸是一类很重要的非蛋白氨基酸。Seebach等以手性的丙氨酸为起始物，同甲胺反应形成酰胺，然后与新戊醛发生环合反应，用Boc保护a氨基后得到咪唑啉酮型底物7，通过简单的提纯方法即可将其与少量顺式异构体分离

Karady 等合成出一种结构类似的恶唑啉酮型底物10，10在氨基酸不对称合成方面同7一样优异.。Seebach等还报道恶唑啉11在LDA作用下与亲电试剂反应以高非对映选择性得到烷基化产物12，继而以6mol／L 的盐酸水解得到苏氨酸衍生物13.

Alonso等人在此基础上，以二茂铁甲醛替代苯甲醛，以新戊酰基作为氨基的保护基，合成了中间体14．由于在环系中引入了2个体积更大的基团，因而在形成14以及用14进行反应时，立体选择性均大幅度提高(>96 e.e.)．Achatz等以手性5-甲氧基-1，4-恶嗪-2-酮15作为一种新的手性甘氨酸类似物，和卤代烷在正丁基锂、DME存在下发生不对称烷基化反应．产物再水解即可得到双取代的氨基酸．具有很好的立体选择性，e.e.值可达89。Williams等[3]用手性恶嗪酮16和卤代烷在金属有机物等条件下发生不对称烷基化反应，生成单取代的恶嗪酮17．再还原得光学活性的a-单取代氨基酸，具有极高的立体选择性，光学收率达95 ee以上．

1.4.5  Schollkopf 手性辅基法

天然氨基酸是一类非常易得的手性化合物。Schoellkopf等缬氨酸为手性源，与甘氨酸形成二肽，然后与Meerwein甲基/已基化试剂作用得到化合物1. 在碱作用下，化合物1的甘氨酸部分的α-位脱去质子，形成烯醇氧负离子型中间体2，然后与亲电试剂作用，引入反应物基团。由于异丙基屏蔽了环的一个侧面，亲电试剂选择性地进攻2的另一面，水解取代产物后得到手性α-氨基酸。

反应示例：

Helvetica Chimica Acta 2003 2848~2870.

To a soln. of (R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine (51.3 g, 0.279 mol) in THF (0.5 l) at 75 ^oC was added dropwise 1.6 M BuLi in hexane (174 ml, 0.279 mol) during 45 min. After additional stirring for 30 min at 75 ^oC a solution of (R)-4-(2-(bromomethyl)-3- methylbutyl)-1-methoxy-2-(3-methoxypropoxy)benzene (66.8g, 0.186 mol) in THF (0.3 l) was added drop wise over 30 min. The mixture was stirred for 2 h at 75 ^oC and then for 18h at 25 ^oC. After evaporation, the residue was partitioned between AcOEt (3 X 1 L) and H₂O (3 X 1 L). The org. layers were washed with brine (1 L), combined, dried (MgSO₄), and evaporated. The residue was purified by column to afford cpd 2 (78.0 g, 91%)

To a stirred soln. of cpd 2 (77.5 g, 0.167 mol) in MeCN (0.67 l) at r.t. was added 1 HCl (0.67 l, 0.670 mol), and stirring was continued for 1.5 h. The mixture was poured into ice-cooled sat. aq. NaHCO₃ solution and extracted with H2Cl2. Evaporation of the org. phase gave 82 g of a pale yellow oil, which was purified by column to get cpd 3 (55.5 g, 90%).