Stereoselective Synthesis of Baloxavir Marboxil Using Diastereoselective Cyclization and Photoredox Decarboxylation of l-Serine

J Org Chem. 2024 Jul 19;89(14):9937-9948. doi: 10.1021/acs.joc.4c00799. Epub 2024 Jul 10.

Abstract

Baloxavir marboxil (1; BXM) is a potent drug used for treating influenza infections. The current synthetic route to BXM (1) is based on optical resolution; however, this method results in the loss of nearly 50% of the material. This study aimed to describe an efficient and simpler method for the synthesis of BXM. We achieved a stereoselective synthesis of BXM (1). The tricyclic triazinanone core possessing a chiral center was prepared via diastereoselective cyclization utilizing the readily available amino acid l-serine. The carboxyl moiety derived from l-serine was removed via photoredox decarboxylation under mild conditions to furnish the chiral tricyclic triazinanone core ((R)-14). The synthetic route demonstrated herein provides an efficient and atomically economical method for preparing this potent anti-influenza agent.

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Cyclization
  • Decarboxylation
  • Dibenzothiepins* / chemical synthesis
  • Dibenzothiepins* / chemistry
  • Molecular Structure
  • Morpholines / chemical synthesis
  • Morpholines / chemistry
  • Oxidation-Reduction
  • Photochemical Processes
  • Pyridones / chemical synthesis
  • Pyridones / chemistry
  • Serine* / chemistry
  • Stereoisomerism
  • Triazines / chemical synthesis
  • Triazines / chemistry

Substances

  • Serine
  • baloxavir
  • Dibenzothiepins
  • Triazines
  • Morpholines
  • Pyridones
  • Antiviral Agents