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

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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