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Effective Enzymatic Kinetic Resolution of Alcohols using Reactive Ketene-acetal Acylating Reagents

使用反应性乙烯酮缩醛酰化试剂对醇进行有效的酶动力学拆分

基本信息

批准号：
09557180
负责人：
KITA Yasuyuki
金额：
$ 4.16万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

In recent years, enzyme-catalyzed kinetic resolution of racemic alcohols using vinyl esters (VEs) has become one of the most commonly employed tools for asymmetric syntheses. However, in this method there remain some problems such as deactivation of enzymes by the by-product, viz., acetaldehyde and difficulties in the preparation of VEs having various acyl moieties. We have recently established a convenient method for preparation of ketene acetal acylating reagents [H2C=C(OEt)OCOR] (1) from the corresponding carboxylic acids [JCS 1, 1993]. We applied 1 to the enzymatic reactions for the first time and have disclosed an effective kinetic resolution method featuring similar to higher reactivity and selectivity than the previous methods as well as generation of a by-product, viz., ethyl acetate, which does not deactivate the enzymes [TL, 1996]. By the use of 1, this project aims at establishing practical kinetic resolution protocols and developing novel asymmetric synthetic method that co … More uld not be attained by the previous methods using VEs. The followings are summary of the results :1. We have disclosed versatile applicability of our new method to variety of secondaryalcohols. We have also developed one-pot performing method involving in situ preparation of I followed by the kinetic resolution, which enabled us to use 1 having labile acyl moiety that was difficult to isolate.2. Lipase-catalyzed asymmetrization of prochiral 2, 2-disubstituted 1, 3-propanediols was developed using the benzoate (1 ; R = Ph), giving high chemical and optical yields of the products bearing quaternary carbon centers. This protocol enabled us to accomplish an asymmetric synthesis of the quaternary carbon center of antitumor antibiotic, fredericamycin A, and thereby, great progress was made in our another project towards the asymmetric total synthesis of this natural product.3. A novel lipase-catalyzed tandem asymmetric synthesis has been developed, which involves in situ preparation of 1-ethoxyvinyl methyl fumarate (1 ; R=CH=CHCO_2Me), lipase-catalyzed kinetic resolution of (2-furyl) carbinols, and intramolecular Diels-Alder reaction of thus introduced acyl moiety, providing the tricyclic adducts with up to 99% ee. We also have discovered for the first time that this lipase can affect the Diels-Alder reaction to improve enantio-and diastereo-selectivities. Less

近年来，使用乙烯基酯（VE）进行外消旋醇的酶催化动力学拆分已成为不对称合成最常用的工具之一。然而，该方法仍然存在一些问题，例如副产物乙醛使酶失活以及难以制备具有各种酰基部分的VE。我们最近建立了一种从相应的羧酸制备乙烯酮缩醛酰化试剂 [H2C=C(OEt)OCOR] (1) 的简便方法 [JCS 1, 1993]。我们首次将1应用于酶促反应，并公开了一种有效的动力学拆分方法，其特征是比以前的方法具有更高的反应性和选择性，并且会产生副产物，即乙酸乙酯，而该副产物不会使酶失活[TL, 1996]。通过使用 1，该项目旨在建立实用的动力学拆分方案并开发新颖的不对称合成方法，这是以前使用 VE 的方法无法实现的。结果总结如下： 1．我们已经公开了我们的新方法对各种仲醇的通用性。我们还开发了一锅法，包括原位制备I，然后进行动力学拆分，这使我们能够使用具有难以分离的不稳定酰基部分的1。2．使用苯甲酸酯（1；R = Ph）开发了前手性 2, 2-二取代 1, 3-丙二醇的脂肪酶催化不对称化，从而使带有季碳中心的产物具有高化学和光学产率。该方案使我们能够完成抗肿瘤抗生素 Fredericamycin A 季碳中心的不对称合成，从而使我们在该天然产物的不对称全合成的另一个项目中取得了重大进展。 3．开发了一种新型脂肪酶催化串联不对称合成方法，包括原位制备富马酸 1-乙氧基乙烯基甲酯 (1；R=CH=CHCO_2Me)、脂肪酶催化 (2-呋喃基) 甲醇的动力学拆分以及由此引入的酰基部分的分子内 Diels-Alder 反应，提供三环 ee 高达 99% 的加合物。我们还首次发现这种脂肪酶可以影响第尔斯-阿尔德反应以提高对映体和非对映体选择性。较少的