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Development of Lipase-Catalyzed Domino-Type Asymmetric Syntheses

脂肪酶催化多米诺骨牌型不对称合成的发展

基本信息

批准号：
15590005
负责人：
AKAI Shuji
金额：
$ 2.3万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

The lipase catalyzed organic syntheses have been gaining increased attention as environmentally benign processes. However, their application has been limited mainly to the preparation of optically active compounds via the kinetic resolution of racemic carboxylic acid derivatives or the alcohols. Recently, we disclosed the first domino type asymmetric synthesis, in which the lipase catalyzed kinetic resolution of racemic alcohols with ethoxyvinyl esters (EVEs) bearing reactive functional moieties was followed by the intramolecular Diels-Alder reaction of the resulting optically active esters to directly give polycyclic compounds. This project has aimed at the practical expansion of this domino type synthesis methodology. The followings are summary of the results :1. Some ruthenium complexes were discovered to effectively catalyze the racemization of optically active alcohols at room temperature and have no inhibition of the lipase-catalyzed reactions. By the combined use of these comple … More xes and lipases, we have achieved the first domino-type synthesis accompanied by a dynamic kinetic resolution. Thus, in this process, the kinetic resolution of 3-vinylcyclohexen-1-ols, the racemization of the remaining optically active alcohols, and the intramolecular Diels-Alder reaction concurrently took place to directly afford multi-substituted decalines (90-95% ee, 69.83% yields).2. The lipase catalyzed domino type synthesis was applied to racemic acyclic and cyclicα-hydroxynitrones, and the kinetic resolution and the intramolecular dipolar cycloaddition reactions continuously proceeded to give isoxazolidine derivatives (>90% ee) as a single diastereomer in each case. This protocol was used for the first catalytic asymmetric total synthesis of (-)-rosmarinecine, a natural pyrrolizidine alkaloid, from commercially available racemic 3-hydroxypyrrolidine.3. Systematic investigation on the ruthenium-catalyzed racemization of optically active alcohols has found that the substituents of the benzene-ligands of the ruthenium complexes had significant affect on their catalytic reactivity. Less

脂肪酶催化的有机合成作为环境友好的过程越来越受到关注。然而，它们的应用主要限于通过外消旋羧酸衍生物或醇的动力学拆分来制备光学活性化合物。最近，我们公开了第一个多米诺骨牌型不对称合成，其中脂肪酶催化外消旋醇与带有反应性功能部分的乙氧基乙烯基酯（EVE）的动力学拆分，然后所得光学活性酯进行分子内Diels-Alder反应，直接得到多环化合物。该项目旨在实际扩展这种多米诺骨牌合成方法。结果总结如下： 1．一些钌配合物被发现可以在室温下有效催化光学活性醇的外消旋化，并且对脂肪酶催化的反应没有抑制作用。通过结合使用这些复杂的 xes 和脂肪酶，我们实现了第一个伴随动态动力学解析的多米诺骨牌型合成。因此，在此过程中，3-乙烯基环己烯-1-醇的动力学拆分、剩余光学活性醇的外消旋化以及分子内Diels-Alder反应同时发生，直接得到多取代十氢化萘（90-95% ee，产率69.83%）。2．将脂肪酶催化的多米诺骨牌型合成应用于外消旋无环和环状α-羟基硝酮，并且连续进行动力学拆分和分子内偶极环加成反应，在每种情况下均得到作为单一非对映异构体的异恶唑烷衍生物（> 90% ee）。该方案用于首次催化不对称全合成 (-)-迷迭香碱（一种天然吡咯里西啶生物碱），从市售外消旋 3-羟基吡咯烷中提取。3。对钌催化光学活性醇外消旋化的系统研究发现，钌配合物苯配体的取代基对其催化反应活性有显着影响。较少的