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

近年来，酶催化乙烯酯动力学拆分外消旋醇已成为不对称合成中最常用的手段之一。然而，这种方法存在一些问题，如副产物乙醛使酶失活，以及制备具有各种酰基片段的ve困难。我们最近建立了一种由相应的羧酸制备酮烯缩醛酰化试剂[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分解方法，该方法具有与以前的方法相似的更高的反应性和选择性，并且产生了一种副产物，即乙酸乙酯，它不会使酶失活[TL， 1996]。本项目旨在利用1建立实用的动力学解析协议，并开发新的不对称合成方法，这是以往的方法使用VEs无法获得的。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适用性。我们还开发了一锅执行方法，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。采用苯甲酸酯（1;R = Ph）催化脂肪酶催化前手性2,2 -二取代1,3 -丙二醇的不对称反应，得到了含季碳中心的高化学收率和光学收率。该方案使我们完成了抗肿瘤抗生素fredericamycin A的季碳中心的不对称合成，从而使我们的另一个项目在该天然产物的不对称全合成方面取得了很大进展。建立了一种新的脂肪酶催化串联不对称合成方法，包括原位制备1-乙氧基富马酸甲酯（1；R=CH=CHCO_2Me），脂肪酶催化（2-呋喃基）甲醇的动力学分解，以及由此引入的酰基部分的分子内diols - alder反应，使三环加合物的ee含量高达99%。我们还首次发现这种脂肪酶可以影响Diels-Alder反应，从而提高对映体和非对映体选择性。少

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