Scaleable catalytic asymmetric Strecker syntheses of unnatural alpha-amino acids.
Scaleable catalytic asymmetric Strecker syntheses of unnatural alpha-amino acids.
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α-氨基酸是蛋白质合成的基本组成部分，也是广泛使用的药用活性分子和手性催化剂的组成部分。高效的化学-酶合成对映体富集α-氨基酸的方法已经被设计出来，但是这些方法用于合成非天然氨基酸的范围是有限的。烯烃加氢反应广泛用于对映选择性催化合成许多种类的氨基酸，但这种方法不适用于合成含有芳基或季烷基α-取代基的α-氨基酸。Strecker合成——亚胺或亚胺等效物与氰化氢反应，然后是腈水解——是合成外消旋α-氨基酸的一种特别通用的化学方法（图1）。利用化学计量手性试剂进行的不对称Strecker合成已成功地在克到数千克的尺度上用于制备对映体富集的α-氨基酸。原则上，使用亚化学计量量的手性试剂的Strecker合成为这些方法提供了一种实用的替代方法，但报道的催化不对称方法仅在制备规模（例如，bbb10 - 1克）上使用有限。现有催化方法的有限使用可归因于几个重要的实际缺陷，包括催化剂相对复杂和珍贵的性质，以及必须使用有害的氰化物来源。本文报道了一种新的催化不对称方法，用于合成高度对映体富集的非蛋白氨基酸，该方法使用简单的手性氨基硫脲催化剂来控制关键的氢化步骤。由于这种催化剂是坚固的，缺乏敏感的官能团，它与安全处理的氰化物水盐兼容，因此适用于大规模合成。这种新的方法可以应用于氨基酸的有效合成，不容易通过酶的方法或化学氢化制备。
α-Amino acids are essential building blocks for protein synthesis, and are also widely useful as components of medicinally active molecules and chiral catalysts. Efficient chemo-enzymatic methods for the synthesis of enantioenriched α-amino acids have been devised, but the scope of these methods for the synthesis of unnatural amino acids is limited. Alkene hydrogenation is broadly useful for enantioselective catalytic synthesis of many classes of amino acids, but this approach is not applicable to the synthesis of α-amino acids bearing aryl or quaternary alkyl α-substituents. The Strecker synthesis—the reaction of an imine or imine equivalent with hydrogen cyanide, followed by nitrile hydrolysis—is an especially versatile chemical method for the synthesis of racemic α-amino acids (Fig. 1). Asymmetric Strecker syntheses using stoichiometric chiral reagents have been applied successfully on gram-to-multi-kilogram scales to the preparation of enantiomerically enriched α-amino acids. In principle, Strecker syntheses employing sub-stoichiometric quantities of a chiral reagent provide a practical alternative to these approaches, but the reported catalytic asymmetric methods have seen only limited use on preparative scales (e.g., > 1 gram). The limited use of existing catalytic methodologies may be ascribed to several important practical drawbacks, including the relatively complex and precious nature of the catalysts, and the requisite use of hazardous cyanide sources. Herein we report a new catalytic asymmetric method for the syntheses of highly enantiomerically enriched non-proteinogenic amino acids using a simple chiral amido-thiourea catalyst to control the key hydrocyanation step. Because this catalyst is robust and lacks sensitive functional groups, it is compatible with safely handled aqueous cyanide salts, and is thus adaptable to large-scale synthesis. This new methodology can be applied to the efficient syntheses of amino acids that are not readily prepared by enzymatic methods or by chemical hydrogenation.
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影响因子：
15
作者：
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