A practical synthesis of (S)-oxybutynin

(S)-Oxybutynin, an important drug acting as muscarinic receptor antagonist, was practically synthesized using catalytic enantioselective cyanosilylation of cyclohexyl phenyl ketone (6a) as a key step. Cyanohydrin 7a with 94% ee was obtained with 1 mol% of Gd-5 catalyst. The key α-hydroxy carboxylic acid 8 was synthesized from 7a in an enantiomerically pure form without column chromatography. Other cycloalkyl phenyl ketones, except cyclopentyl phenyl ketone (6e-H) gave products with high enantioselectivity. The enantioselectivity of the reaction of 6e was dramatically improved using α-deuterium substituted 6e-D. The dramatic deuterium effect provides an important insight into the competitive reaction pathway.