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

Angew Chem Int Ed Engl. 2020 Dec 14;59(51):23107-23111. doi: 10.1002/anie.202011256. Epub 2020 Nov 23.

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.

Keywords: MR antagonists; enantioselective synthesis; partial transfer hydrogenation; pharmaceutical molecule.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Density Functional Theory
  • Hydrogenation
  • Mineralocorticoid Receptor Antagonists / chemical synthesis*
  • Mineralocorticoid Receptor Antagonists / chemistry
  • Molecular Structure
  • Naphthyridines / chemical synthesis*
  • Naphthyridines / chemistry
  • Stereoisomerism

Substances

  • Mineralocorticoid Receptor Antagonists
  • Naphthyridines
  • finerenone