Highly enantioselective mukaiyama aldol reaction of alpha,alpha-dichloro ketene silyl acetal: an efficient synthesis of a key intermediate for diltiazem.
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.
Imashiro
Ritsuo
R
CMC Research Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89 Kashima, Yodogawa-ku, Osaka 532-8505, Japan.
Kuroda
Tooru
T
D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D004110:Diltiazem / Q000737:chemistry*; D004852:Epoxy Compounds / Q000032:analysis / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011422:Propionates; D012821:Silanes / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism
D004852:Epoxy Compounds; D011422:Propionates; D012821:Silanes; C055263:3-(-methoxyphenyl)glycidic acid methylester; D004110:Diltiazem