Ketoreductase-catalyzed dynamic reductive kinetic resolution of sterically hindered 2-aryl-1,5-benzothiazepin-3,4(2H,5H)-diones: asymmetric synthesis of a key diltiazem precursor and its analogues

Abstract

Owing to its associated advantages such as the generation of two stereocenters in 100% maximum theoretical yield, mild reaction conditions and environmentally friendliness, ketoreductase (KRED)-catalyzed dynamic reductive kinetic resolution (DYRKR) is a versatile and appealing synthetic approach to access valuable chiral alcohols containing two or more stereocenters. Despite the considerable progress that has been made in this research field, previous studies mostly focused on ketone substrates with relatively simple structures. In the present study, ketoreductases YDR368w and YGL039w were identified through enzyme screening and applied to the KRED-catalyzed DYRKR of sterically hindered 2-aryl-1,5-benzothiazepin-3,4(2H,5H)-diones (1). Eleven structurally diverse chiral cis-(2S,3S)-2,3-dihydro-3-hydroxy-2-aryl-1,5-benzothiazepin-4(5H)-ones (cis-(2S,3S)-2), including the critical synthetic intermediates to the calcium channel blockers diltiazem and clentiazem, were prepared in 50–90% isolated yields with excellent stereoselectivities (all >20 : 1 dr and ≥99% ee). Finally, the successful execution of a gram scale synthesis and the demonstrated excellent recyclability of the immobilized ketoreductase (up to 20 cycles) both underscored the good application potential of the currently established DYRKR method.