(S)-Selective Dynamic Kinetic Resolution of Allylic Alcohols by Enzyme-Metal Bicatalysis

Abstract

Dynamic kinetic resolution (DKR) provides a useful methodology for the conversion of racemic substrates to single enantiomeric products. In the last decade, a new approach for DKR has been intensively explored, in which an enzyme as the resolution catalyst is combined with a metal or metal complex as the racemization catalyst. Several enzyme-metal combinations have been developed for the DKR of alcohols. Among them, lipase-ruthenium combinations are particularly useful for the (R)-selective DKR of secondary alcohols. A wide range of simple and functionalized secondary alcohols have been transformed to enantiomerically-enriched forms with them. In many cases, high yields and enantiomeric excesses approaching 100% were realized. The (S)-selective DKR of secondary alcohols, however, has been much less intensively explored compared to its counterpart. We reported for the first time the use of a subtilisin-ruthenium combination for such DKR, which was applied to a limited number of simple secondary alcohols. As our continuous efforts in this area, we now wish to report an application of subtilisin-ruthenium combination in the DKR of functionalized alcohols such as allylic alcohols. Chiral allylic alcohols in optically pure forms are synthetically important synthons which can be transformed to a wide range of more complex molecules. Previously we reported a procedure based on a lipase-ruthenium combination for the (R)-selective DKR of allylic alcohols. Accordingly, we became interested in developing a complementary procedure for the synthesis of opposite enantiomers, which would be realized by using subtilisin as the resolution catalyst in the presence of a ruthenium-based racemization catalyst (Scheme 1). For the (S)-selective DKRs of allylic alcohols, 10 different compounds 2a-j were examined as substrates with a commercial enzyme (subtilisin CLEC) and a ruthenium complex 1 as the catalysts (Scheme 2). In a typical procedure, the reaction was performed for 3 days at room temperature with a mixture of substrate (0.3 mmol), subtilisin CLEC (15 mg/mmol of substrate), 1 (4 mol%, preactivated with potassium t-butoxide), and trifluoroethyl butyrate (5.1 mmol) as an acyl donor in THF. The acylated products were isolated by silica gel chromatography and their optical purities were analyzed by chiral HPLC. The data from Table 1 indicate that satisfactory resolution has been accomplished in all the cases. The isolated yields ranged from 73 to 92% and the enantiomeric excesses reached 96% or greater. It was observed that the yields were lowered by side reactions such as oxidation and isomerization, leading to the formation of ketones such as 4 and 5 (Scheme 3). The yields of byproducts ranged from 5 to 9%. The S-configuration of the acylated products was confirmed by comparing the optical rotation (−23.1 for c = 1, CHCl3, >99% ee) of allylic alcohol (S)-2d obtained from the hydrolytic deacylation of 3d with the literature value (−25.4 for c = 1, CHCl3, >99% ee). 7