Enantioselective Total Synthesis of (-)-Finerenone Using Asymmetric Transfer Hydrogenation

被引：12

作者：

Lerchen, Andreas ^{[1
]}

Gandhamsetty, Narasimhulu ^{[1
]}

Farrar, Elliot H. E. ^{[2
]}

Winter, Nils ^{[1
]}

Platzek, Johannes ^{[3
]}

Grayson, Matthew N. ^{[2
]}

Aggarwal, Varinder K. ^{[1
]}

机构：

[1] Univ Bristol, Sch Chem, Bristol BS8 1TS, Avon, England

[2] Univ Bath, Dept Chem, Bath BA2 7AY, Avon, England

[3] Bayer AG, Chem Dev, D-42096 Wuppertal, Germany

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2020年 / 59卷 / 51期

基金：

英国工程与自然科学研究理事会;

关键词：

enantioselective synthesis; MR antagonists; partial transfer hydrogenation; pharmaceutical molecule; CASCADE REACTION; ACID; REDUCTION; TETRAHYDROQUINOLINES; ANTAGONIST; QUINOLINES; DISCOVERY; CATALYST; RECEPTOR;

D O I：

10.1002/anie.202011256

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

(-)-Finerenone is a nonsteroidal mineralocorticoid receptor antagonist currently in phase III clinical trials for the treatment of chronic kidney disease in type 2 diabetes. It contains an unusual dihydronaphthyridine core. We report a 6-step synthesis of (-)-finerenone, which features an enantioselective partial transfer hydrogenation of a naphthyridine using a chiral phosphoric acid catalyst with a Hantzsch ester. The process is complicated by the fact that the naphthyridine exists as a mixture of two atropisomers that react at different rates and with different selectivities. The intrinsic kinetic resolution was converted into a kinetic dynamic resolution at elevated temperature, which enabled us to obtain (-)-finerenone in both high yield and high enantioselectivity. DFT calculations have revealed the origin of selectivity.

引用

页码：23107 / 23111

页数：5

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