Asymmetric Reduction of a 1,5-Benzothiazepine Derivative with Sodium Borohydride−(S)-α-Amino Acids: An Efficient Synthesis of a Key Intermediate of Diltiazem

A key intermediate of diltiazem synthesis, (2 S,3 S )-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5 H )-one [(2 S,3 S )- 1 ], has been efficiently synthesized by an asymmetric reduction of the prochiral ketone, 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2 H,5 H )-dione ( 3 ), with NaBH 4 and chiral α-amino acids. As the chiral sources, β-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 (2 S,3 S )- 1 with excellent enantioselectivity. (95% ee for cis -isomers). The addition of AcOH to the reaction permitted further improvement of both conversion and stereoselectivity. As a result, optically pure (2 S,3 S )- 1 could be isolated in 86% yield. This asymmetric reduction proceeded via dynamic kinetic resolution and made it possible to control the two adjacent asymmetric carbons through keto−enol tautomerism.