ASYMMETRIC REDUCTION OF A 1,5-BENZOTHIAZEPINE DERIVATIVE WITH SODIUM BOROHYDRIDE-(S)-ALPHA-AMINO ACIDS - AN EFFICIENT SYNTHESIS OF A KEY INTERMEDIATE OF DILTIAZEM

A key intermediate of diltiazem synthesis, y-2-(4-methoxyphenyl)-1,5-b enzothiazepin-4(5H)-one [(2S,3S)-1], has been efficiently synthesized by an asymmetric reduction of the prochiral ketone, ethoxyphenyl)-1,5- benzothiazepine-3,4(2H,5H)-dione (3), with NaBH4 and chiral alpha-amin o acids. As the chiral sources, beta-branched-chain amino acids, such as (S)-valine, (S)-isoleucine, and (S)-tert-leucine, were found to be effective. In particular, using (S)-tert-leucine as a ligand resulted in the formation of (2S,3S)-1 with excellent enantioselectivity. (95% ee for cis-isomers). The addition of AcOH to the reaction permitted fu rther improvement of both conversion and stereoselectivity. As a resul t, optically pure (2S,3S)-1 could be isolated in 86% yield. This asymm etric reduction proceeded via dynamic kinetic resolution and made it p ossible to control the two adjacent asymmetric carbons through keto-en ol tautomerism.