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中最常用的工具之一，然而，该方法仍然存在一些问题，例如副产物使酶失活。，即乙醛和制备具有各种酰基部分的VE的困难，我们最近建立了一种制备乙烯酮缩醛酰化试剂的简便方法。 [H2C=C(OEt)OCOR] (1) 从相应的羧酸 [JCS 1, 1993] 我们首次将 1 应用到酶促反应中，并公开了一种有效的动力学拆分方法，具有类似的更高的反应活性和选择性。与以前的方法相比，并且产生了副产物，即乙酸乙酯，它不会使酶失活[TL，1996]。 1，该项目旨在建立实用的动力学拆分方案并开发以前使用VE的方法无法实现的新型不对称合成方法，结果总结如下：1。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，这使得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。抗肿瘤抗生素 Fredericamycin A 季碳中心的不对称合成，从而使我们的另一个不对称全合成项目取得了重大进展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)、脂肪酶催化动力学拆分(2-呋喃基)我们还发现，甲醇和由此引入的酰基部分的分子内狄尔斯-阿尔德反应，提供了高达 99% ee 的三环加合物。首次发现该脂肪酶可以影响 Diels-Alder 反应以提高对映体和非对映体选择性。