Construction of Carbon Skeleton via Lipase-Catalyzed Domino-Type Syntheses with Dynamic Kinetic Resolution

近年来，脂肪酶催化有机合成作为一种环境友好的合成工艺越来越受到人们的关注。然而，它们的应用主要局限于通过外消旋醇的动力学分解制备旋光性化合物，在构建碳骨架方面的应用很少。最近，我们披露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功能化乙氧基乙烯酯的动力学分解，随后产生旋光性酯的分子内环加成反应，直接得到多环化合物。我们还开发了一些钌配合物，可以在室温下有效地催化旋光性醇的外消旋化。钌配合物与脂肪酶的结合首次实现了多米诺骨牌型合成，并伴有动态动力学分辨率（DKR）。本项目旨在实际扩展这种多米诺骨牌-…More型综合方法。结果总结如下：1。利用氧化钒化合物VO(OSiPh_3)_3与脂肪酶相结合，以69 ~ 99%的收率合成了具有光学活性的烯丙基酯（88 ~ 99% ee）。该方法通过钒催化烯丙醇的1,3-转位，具有独特的外消旋过程。发达的外消旋作用使叔烯丙醇的DKR发生了前所未有的迁移，得到了光学纯度更高的相同产物；也就是说，99%的ee，在大多数情况下。这些结果表明，两种烯丙醇的结构异构体均可用于该DKR，为不对称合成光纯醋酸烯丙酯提供了一种新的方便策略。本实验室正在研究将这些方法应用于含二烯部分的烯丙醇，期望通过多米诺骨牌法构建碳骨架。为了开发更有效的金属催化剂来加速上述外消旋过程，已经进行了研究，并发现了一些钼化合物作为潜在的候选物。少

The lipase-catalyzed organic syntheses have been gaining increased attention as environmentally benign processes recently. However, their use has been limited mainly for the preparation of optically active compounds via the kinetic resolution of racemic alcohols, and their application to the construction of carbon skeleton are few. Recently, we disclosed the first domino-type asymmetric synthesis, in which the lipase-catalyzed kinetic resolution of racemic alcohols with functionalized ethoxyvinyl esters was followed by the intramolecular cycloaddition reaction of the resulting optically active esters to directly give polycyclic compounds. We also developed some ruthenium complexes that effectively catalyze the racemization of optically active alcohols at room temperature. The combination of the ruthenium complexes and lipases have achieved the first domino-type synthesis accompanied by a dynamic kinetic resolution (DKR). This project has aimed at the practical expansion of this domino- … More type synthetic methodology. The followings are summary of the results:1. A novel DKR of secondary allyl alcohols has been developed by the combined use of the oxovanadium compound, VO(OSiPh_3)_3, and the lipases to give optically active allyl esters (88-99% ee) in 69-99% isolated yields. This method features the unique racemization process through the vanadium-catalyzed 1,3-transposition of the allyl alcohols.2. The developed racemization enabled an unprecedented DKR of the tertiary allyl alcohols with the migration to give the same products with better optical purity; viz., 99% ee, in most cases. These results have shown that the structural isomers of two kinds of allyl alcohols can be equally employed for this DKR and offer a new convenient strategy for the asymmetric synthesis of optically pure allyl acetates. The application of these methods to the allyl alcohols having a diene moiety is now under study in our laboratory, which is expected to construct the carbon skeleton via the domino-type process.3. Studies for the development of more potent metal catalysts to accelerate the above-mentioned racemization process have been carried out, and some molybdenum compounds were discovered as potential candidates. Less