Enantioselective Total Synthesis of (‐)‐Finerenone using Asymmetric Transfer Hydrogenation

Varinder Kumar Aggarwal, Andreas Lerchen, Narasimhulu Gandhamsetty, Elliot Farrar, Nils Winter, Johannes Platzek, Matthew Grayson

Research output: Contribution to journalArticlepeer-review

Abstract

(−)‐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.

Original languageEnglish
Pages (from-to)23107-23111
Number of pages5
JournalAngewandte Chemie-International Edition
Volume51
Issue number57
Early online date5 Sep 2020
DOIs
Publication statusPublished - 14 Dec 2020

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