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

Abstract

A key intermediate of diltiazem synthesis, (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one [(2S,3S)-1], has been efficiently synthesized by an asymmetric reduction of the prochiral ketone, 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione (3), with NaBH4 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 (2S,3S)-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 (2S,3S)-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.

Microwave assisted synthesis and biological evaluation of a series of 1,5-benzothiazepines as potential cytotoxic and antimicrobial agents

“…Some of the 1,5-benzothiazepine derivatives were also used clinically for CNS disorders, which includes thiazesim, clothiapine and quetiapine [3]. Therefore, the 1,5-benzothiazepines are useful compounds in the drug research that has stimulated the invention of a wide range of synthetic methods for their preparation and chemical transformations [4]. The common strategy for the construction of the 1,5-benzothiazepine moiety is the reaction of 1,3-diaryl prop-2-enones with o-aminothiophenol [5].…”

Diltiazem Synthesis, Microbial Asymmetric Reduction

“…Substrate (RS)-10 is easily obtained from (±)-MPGM through three steps of chemical ring closure with aminothiophenol, chemical oxidation, and chemical hydrolysis ( Fig. 1) (20). Table 2 shows microorganisms that have the ability for the asymmetric reduction of (RS)-10 (19).…”

Second‐Generation cycloSal‐d4TMP Pronucleotides Bearing Esterase‐Cleavable Sites — The “Trapping” Concept

“…[16] The pivaloyl ester (9f) of 12 was synthesised from an activated pivaloyl donor by the "twisted amide" method reported previously (80 % yield). [17] Phenols 9a-f were then transformed into the salicyl alcohols 8a-f by treatment with paraformaldehyde and phenylboronic acid in the presence of 0.5 equiv. of propionic acid (50-85 % yield).…”