氨基酸合成060226.docVIP

经典化学合成反应标准操作 Stereoselective Synthesis of Amino acid and its derivant 编者：张治柳 药明康德新药开发有限公司化学合成部 目 录 前言…………………………………………………………………2 2． rennin inhibitor Aliskiren 2.3 Efficient syntheses of biologically important amino acid Synthesis of α-amino acid and its derivant from aziridine 3． synthesis of the amino acids from 2-isopropyl-3,6-dimethoxy (or: diethoxy)-2,5-dihydro-pyrazine 4． Synthesis of α-amino acid from Evans Reagent 1．前言 不对称合成a-氨基酸的工作自1970年代后期系统地开展起来，在其后的十余年中，发现了几十种不对称合成方法。已经报道的a-氨基酸不对称合成方法可以分为五类，即酶合成法、αβ-脱氢氨基酸氢化或环加成法、Strecker型反应、亲电或亲核氨基化法以及亲电或亲核烷基化法，上述反应都涉及α-碳的手性控制.就立体选择性的控制方法而言，手性辅基(chiral auxiliary)方法仍占多数。 用于 不 对 称合成a-氨基酸的手性辅基种类较多，常见的环系模板(cyclic templates)(也叫环系手性辅基)和非环系模板(acyclic templates)（也叫非环系手性辅基）应用 手 性 辅基的a-氨基酸不对称合成方法 甘氨酸或丙氨酸衍生烯醇盐(enolates)的亲电烷基化是最早发展的a-氨基酸合成方法，该法变化形式丰富，研究和应用广泛，其中有几种已成为当前制备手性氨基酸的常规方法. U.Schollkopf法—从氨基酸模块开始的合成, D.Seebach法手性中心自我再生”原理的成功应用, Y. N. Belokon法—含甘氨酸席夫碱的金属配位化合物, W.Oppolzer法方便回收的天然手性源辅基, D.A .E vans法一种广泛应用的手性辅基, M.J .O Donnell法基于金鸡纳碱的手性相转移催化。 2.制备手性氨基酸的常用方法 2．1 U.Schollkopf法从氨基酸模块开始的合成 U.Schollkopf用L-Val和Gly缩合制得环二肽7,7与Meerwein盐(Me30+BF4-)作用得甲基醚1，经丁基锂脱质子得甘氨酸负离子8，烷基化生成9，酸水解，得手性a-氨基酸10. 此法所得氨基酸的ee值可达95%以上. 制备反应如Scheme 1所示。 Scheme1 Example: 2.1.1 U.Schollkopf法从氨基酸模块开始的合成示例 References: Tetrahedran Asymmetry, 10 (1999), 4151~4156. To a stirred suspension of D-valine 1 (117.15 g, 1.0 mol) in THF (1200 mL) was added phosgene (148.5 g, 0.5 mol), the temperature was maintained at 40 ℃ with a heating mantle. After the solid in solution disappeared, the solution which resulted was purged with N2 for 2 h, the solvent was removed in vacuo and the residue was flashed with THF twice, the N-carboxyanhydride which formed was dried in the vacuum to provide a rude product 2 (206.37 g, 100%), due to the unstable nature of this anhydride it was used immediately in the next step without further purification. A solution of the N-carboxyanhydride 2 (206.37 g, 1.44 mol) in THF (1600 mL) was added dropwise to a vigorously stirred mixture of glycin