Issue 64, 2022

Biocatalytic dynamic reductive kinetic resolution of aryl α-chloro β-keto esters: divergent, stereocontrolled synthesis of diltiazem, clentiazem, and siratiazem

Abstract

The first systematic study of ketoreductase (KRED)-catalyzed dynamic reductive kinetic resolution (DYRKR) on aryl α-chloro β-keto esters was performed, and 15 structurally diverse chiral anti-aryl α-chloro β-hydroxy esters were synthesized in 74–98% isolated yields, along with moderate-to-excellent diastereoselectivity (up to >99 : 1 dr) and good-to-excellent enantioselectivity (mostly >99% ee). LfSDR1-catalyzed complete reduction of 100 g L−1 of substrate 6b at a ten-gram scale was achieved with a continuous fed-batch strategy, affording anti-(2S,3S)-1b, the key intermediate of diltiazem, in a record-breaking space-time yield of 96 g L−1 d−1. An eight-step synthesis of diltiazem, clentiazem, and siratiazem was accomplished in 32–45% overall yields, featuring this versatile biocatalytic reduction reaction as well as an efficient, green chlorination reaction in flow.

Graphical abstract: Biocatalytic dynamic reductive kinetic resolution of aryl α-chloro β-keto esters: divergent, stereocontrolled synthesis of diltiazem, clentiazem, and siratiazem

Supplementary files

Article information

Article type
Communication
Submitted
01 lip 2022
Accepted
14 srp 2022
First published
15 srp 2022

Chem. Commun., 2022,58, 9010-9013

Biocatalytic dynamic reductive kinetic resolution of aryl α-chloro β-keto esters: divergent, stereocontrolled synthesis of diltiazem, clentiazem, and siratiazem

X. Yue, Y. Li, M. Liu, D. Sang, Z. Huang and F. Chen, Chem. Commun., 2022, 58, 9010 DOI: 10.1039/D2CC03102G

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