Development of New Method for Construction of Chiral, Non-Racemic Quaternary Carbon Center by Enzymatic Acylation of Alcohols and Application Thereof

醇酶酰化构建手性非外消旋季碳中心新方法的开发及其应用

基本信息

批准号：
13672214
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：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

Construction of chiral, non-racemic quaternary carbon center via enzymatic acylation of alcohols is believed to be an effective environmentally benign process because of its high enantioselectiviry and safe and easy operation; however, the successful examples have been limited. This is mainly due to the problems of the currently-best method using vinyl esters, which involve inactivation of the enzymes and easy racemication via intramolecular acyl group migration. Recently, we have disclosed their resolution by using 1-ethoxyvinyl esters (EVEs), leading to the discovery of the first effective enzymatic desymmetrization of symmetric diols and the first domino asymmetric reactions. This project has aimed at the expansion of these methods for the construction of chiral, non-racemic quaternary carbon centers and also their application for asymmetric synthesis of leading compounds for new drug discovery. The followings are summary of the results:1. The enzymatic desymmetrization method was e … More ffective for wide range of 1,2- and 1,3-diols, and a new general method for the construcntion of chiral, non-racemic quaternary carbon centers has been established. This protocol was successfully applied for asymmetric synthesis of either enantiomer of the ABCDE-analog of antitumor antibiotic fredericamycin A and also for asymmetric preparation of the various oxindoles (86- 98% ee) with a chiral, non-racemic quaternary carbon center at the C-3 position and a variety of N-1 protective group.2. The lipase-catalyzed domino asymmetric synthesis was applied to various furfuryl alcohol to provide a one-pot synthesis of 7-oxabicycloheptenes (91- 99% ee) with a chiral quaternary carbon center. Especially, useful chiral synthons bearing a vinyl bromide moiety were prepared from the 3-bromofurfuryl alcohols. The first domino process involving dynamic kinetic resolution was achieved by the similar reaction of α-hydroxynitrones to give aza-polycyclic products in good yields. The asymmetric total synthesis of a natural pyrrolizidine alkaloid, rosmarinecine, was attained in 3 steps from a readily available racemic hydroxynitrone and a maleic acid. Less

通过醇的酶促酰化构建手性非外消旋季碳中心被认为是一种有效的环境友好方法，因为它具有高对映选择性和安全且易于操作，然而，成功的例子是有限的。目前使用乙烯基酯的最佳方法存在的问题，包括酶的失活和通过分子内酰基迁移容易外消旋，最近，我们公开了通过使用乙烯基酯来解决这些问题。 1-乙氧基乙烯基酯（EVE），导致对称二醇的第一个有效酶促去对称化和第一个多米诺骨牌不对称反应的发现，该项目旨在扩展这些方法用于构建手性非外消旋季碳中心。以及它们在新药发现的主要化合物的不对称合成中的应用，结果总结如下： 1．广泛的1,2-和1,3-二醇，并且建立了一种构建手性非外消旋季碳中心的新通用方法，该方案已成功应用于ABCDE-任一对映体的不对称合成。抗肿瘤抗生素 Fredericamycin A 的类似物，也可用于具有手性非外消旋季碳的各种羟吲哚 (86-98% ee) 的不对称制备C-3位中心和多种N-1保护基。2.将脂肪酶催化的多米诺不对称合成应用于多种糠醇，一锅法合成7-氧杂二环庚烯(91-99%ee)。特别是，有用的带有溴化乙烯部分的手性合成子是由 3-溴糠醇制备的。通过α-羟基硝酮的类似反应实现了动力学拆分，以良好的产率得到氮杂多环产物。天然吡咯里西啶生物碱迷迭香碱的不对称全合成是由容易获得的外消旋羟基硝酮和马来酸通过三个步骤实现的。较少的