Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, P. R. China.
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, 220 Handan Road, Shanghai, 200433, P. R. China.
Chem Commun (Camb). 2022 Aug 9;58(64):9010-9013. doi: 10.1039/d2cc03102g.
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 -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 of substrate 6b at a ten-gram scale was achieved with a continuous fed-batch strategy, affording -(2,3)-1b, the key intermediate of diltiazem, in a record-breaking space-time yield of 96 g L d. 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.
首次对酮还原酶（KRED）催化的动态还原动力学拆分（DYRKR）进行了系统研究，合成了 15 种结构多样的手性 -芳基 α-氯代 β-羟基酯，产率为 74-98%，非对映选择性适中至优秀（高达>99∶1 dr），对映选择性好至优秀（大多数>99%ee）。采用连续补料分批策略，在 10 克规模下实现了 LfSDR1 催化 100 克 L 底物 6b 的完全还原，以创纪录的时空产率 96 g L d 获得地尔硫卓的关键中间体 -(2,3)-1b。以这种多功能的生物催化还原反应以及在流动相中高效、绿色的氯化反应为特色，完成了地尔硫卓、氯噻嗪和西拉嗪的八步合成，总收率为 32-45%。
