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

近年来，使用乙烯基酯(VES)的酶催化动力学拆分外消旋醇已成为不对称合成中最常用的工具之一。但是，该方法还存在一些问题，如副产物乙醛对酶的失活，以及制备各种酰基VE的困难。我们最近建立了一种从相应的羧酸制备酮缩醛酰化试剂[H_2C=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，并揭示了一种有效的动力学拆分方法，该方法具有比以往方法更高的反应活性和选择性，并产生副产物乙酸乙酯，它不会使酶失活[TL，1996]。通过使用1，本项目的目的是建立实用的动力学拆分方案，开发新的不对称合成方法，并与…以前使用VES的方法不能得到更多的结果。研究结果总结如下：1.我们揭示了我们的新方法对各种仲醇具有广泛的适用性。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，这使得我们能够使用1具有难以分离的不稳定的酰基部分。用苯甲酸酯(1；R=Ph)催化前手性2，2-二取代1，3-丙二醇的不对称反应，得到了高的化学和光学产率的含季碳中心的产物。这一方案使得我们能够完成抗肿瘤抗生素弗雷德霉素A的四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的进展。开发了一种新的脂肪酶催化的串联不对称合成方法，包括原位合成富马酸乙氧基甲酯(1；R=CH=CHCO_2Me)，脂肪酶催化动力学拆分(2-呋喃)醇，以及由此引入的酰基部分的分子内Diels-Alder反应，提供了高达99%ee的三环加合物。我们还首次发现，这种脂肪酶可以影响Diels-Alder反应，以提高对映体和非对映体的选择性。较少

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