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

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

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-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. Herein, 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 which react at different rates and 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
Volume(2020) 59
Issue number51
DOIs
Publication statusPublished - 23 Nov 2020

Keywords

  • enantioselective synthesis
  • partial transfer hydrogenation
  • pharmaceutical molecule
  • MR antagonists

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