trans-八氢吲哚酸的合成及其在不对称串联反应中的应用

发布时间：2018-01-14 01:18

本文关键词：trans-八氢吲哚酸的合成及其在不对称串联反应中的应用　出处：《中国医药工业杂志》2017年10期 　论文类型：期刊论文

【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。
[Abstract]:2S 3a Rn 7a Sf- octahydro-1H -indole-2-formic acid trans-octahydroindole acid 1a). It is a key intermediate in the synthesis of antihypertensive drug group. There are three chiral centers in its molecular structure (2 of which are bridgehead hydrogen with trans configuration). The efficient synthesis of 1a has always been a challenge to the low cost and easy availability of group-dopril. Based on the comprehensive literature and a lot of experimental exploration, we choose to start with the key trans-bridgehead hydrogen construction. A new synthesis route of 1a was designed and the synthesis process was optimized. There are four transoctachloroindole acids) with very unique structural characteristics: based on the structure of proline. A rigid six-member double ring and two trans bridgehead hydrogen are added. This makes transoctachloroindole acid as a proline chiral small molecule catalyst with high efficiency in many asymmetric catalytic reactions. The synthesis of 1a and its by-product 1bC1d was briefly reviewed in this paper. Progress in the synthesis of multi-chiral central aliphatic carbon rings, oxygen heterocycles, especially nitrogen heterocyclic compounds, catalyzed by asymmetric tandem reactions.
【作者单位】：上海交通大学药学院;上海交通大学化学化工学院;
【基金】：国家自然科学基金(21372152、21232004)
【分类号】：R914
【正文快照】： 群多普利(trandolapril,图1),化学名为(2S,3a R,7a S)-1-[[(2S)-[(1S)-(乙氧羰基)苯基丙基]氨基]丙酰基]八氢-1H-吲哚-2-羧酸,最早是由法国Roussel Uclaf公司、Knoll公司和德国Hoechst公司共同开发,并由Roussel Uclaf公司于1993年首次在法国上市、2004年在北美上市的抗高血压

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