trans-八氢吲哚酸的合成及其在不对称串联反应中的应用  

The Synthesis of trans-Perhydroindolic Acids and Their Application in Asymmetric Organocatalyzed Cascade Reactions

作　　者：刘德龙[1] 张万斌[1,2] 

机构地区：[1]上海交通大学药学院,上海200240 [2]上海交通大学化学化工学院,上海200240

出　　处：《中国医药工业杂志》2017年第10期1395-1408,共14页Chinese Journal of Pharmaceuticals

基　　金：国家自然科学基金(21372152;21232004)

摘　　要：(2S,3aR,7aS)-八氢-1H-吲哚-2-甲酸(trans-八氢吲哚酸1a),是合成抗高血压药群多普利的关键中间体。由于其分子结构中存在3个手性中心(其中有2个为呈反式构型的桥头氢),1a的高效合成始终是群多普利能否廉价易得的一个挑战。我们在综合文献和大量实验探索的基础上,选择从关键的反式桥头氢构建入手,设计了1a的全新合成路线并进行了合成工艺优化。从另一方面看,1a连同其合成过程中同时生成的另外3个副产物(1b^1d,共4个trans-八氢吲哚酸)具有非常独特的结构特征:在脯氨酸的结构基础上,增加了1个刚性六元骈环以及2个反式桥头氢。这使得trans-八氢吲哚酸被作为脯氨酸类手性小分子催化剂在多个不对称催化反应中均取得了高效的不对称催化效果。本文简要综述了本课题组对1a及其副产物1b^1d的合成探索,及其所催化的不对称串联反应合成多手性中心脂肪碳环、氧杂环特别是氮杂环化合物的进展。（2S,3aR,7aS）-Perhydroindolic acid （also known as trans-perhydroindolic acid, 1a）, is a key intermediate for the synthesis of trandolapril. The efficient synthesis of la is challenging because of the special nature of the fused ring system, in which there are three chiral centers and two hydrogen atoms trans to each other at the bridgehead carbon atoms. Therefore, the industrial-scale synthesis of trandolapril is dependent upon a feasible synthesis of la. Based on literature reviews and our own research, la has been synthesized in a relative high yield. The synthesis of la also yields three other trans-perhydroindolic acids （1b-1d）. Similar to la, these proline-like molecules are unique in that they contain a rigid bicyclic structure, with two hydrogen atoms trans to each other at the bridgehead carbon atoms. These trans-perhydroindolic acids have been proven to be suitable organocatalysts for model asymmetric Michael addition reactions of aldehydes to nitroolefins （up to 99 % yield, 99 ：1 dr and 98 % ee）. They have also been applied to several asymmetric cascades for the convenient construction of complex heterocyclic compounds bearing multiple stereocenters. This review provides a brief summary on our synthesis of la and its proline-type by-products 1b-1d. The application of these compounds as organocatalysts for the asymmetric construction of cyclic products bearing multiple stereocenters, especially those containing oxygen or nitrogen heterocyclic skeletons, is also discussed.

关 键 词：群多普利 关键中间体 有机小分子催化剂 不对称串联反应 手性 

分 类 号：R97[医药卫生—药品]