Highly enantioselective mukaiyama aldol reaction of alpha,alpha-dichloro ketene silyl acetal: an efficient synthesis of a key intermediate for diltiazem

Abstract

An efficient synthesis of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2, a key intermediate for diltiazem (1), has been developed on the basis of the highly enantioselective Mukaiyama aldol reaction of p-anisaldehyde (4a) with alpha,alpha-dichloro ketene silyl acetal 5. Thus, the reaction using a stoichiometric amount of chiral oxazaborolidinone catalyst 12a proceeded to excellent yield (83%) and high enantioselectivity (96% ee), together with the chiral ligand 13a in nearly quantitative recovery. The reaction using a substoichiometric amount of 12e (20 mol %) also proceeded to excellent yield (88%), with somewhat lower enantioselectivity (77% ee). The aldol product 3a thus obtained was easily converted to (-)-2 in excellent yield (80%) and high optical purity (>99% ee). The highly enantioselective Mukaiyama aldol reaction with 5 catalyzed by 12a proved to be applicable to various aldehydes. An efficient preparation of 5 from inexpensive starting materials was also described.