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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一种环境友好的有机合成方法受到越来越多的关注。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，其中脂肪酶催化的动力学拆分外消旋醇与乙氧基乙烯基酯（EVES）带有反应性功能部分，随后通过分子内Diels-Alder反应，得到的光学活性酯直接得到多环化合物。该项目旨在实际推广这种多米诺骨牌式综合方法。主要研究结果如下：1.一些钌配合物在室温下能有效地催化光学活性醇的外消旋化反应，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 ...更多信息 xes和脂肪酶，我们已经实现了第一个多米诺骨牌型的合成伴随着动态动力学决议。因此，在该方法中，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和分子内Diels-Alder反应同时发生，以直接提供多取代的十氢萘（90- 95%ee，69.83%产率）。应用脂肪酶催化的多米诺式合成法，对外消旋的无环和环状α-羟基硝酮进行了动力学拆分和分子内偶极环加成反应，得到了单一非对映体的异恶唑烷衍生物（ee>90%）。该方案首次用于从市售外消旋3-羟基吡咯烷催化不对称全合成（-）-迷迭香碱（一种天然吡咯里西啶生物碱）。系统研究了钌催化光学活性醇的外消旋反应，发现钌配合物中苯配体的取代基对其催化活性有显著影响。少