Electrolytic macrocyclizations: scalable synthesis of a diazonamide-based drug development candidate

Angew Chem Int Ed Engl. 2015 Apr 13;54(16):4818-22. doi: 10.1002/anie.201411663. Epub 2015 Feb 26.

Abstract

An electrochemical method to synthesize the core macrolactam of diazonamides is described. Large ring-forming dehydrogenation is initiated by anodic oxidation at a graphite surface. The reaction requires no tailoring of the substrate and occurs at ambient temperature in aqueous DMF in an undivided cell open to air. This unique chemistry has enabled a concise, scalable preparation of DZ-2384; a refined analog of diazonamide A slated for clinical development as a cancer therapeutic.

Keywords: anodic oxidation; electrosynthesis; macrocycles; natural products; oxazoles.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Azo Compounds / chemistry
  • Crystallography, X-Ray
  • Cyclization
  • Graphite / chemistry
  • Lactams, Macrocyclic / chemical synthesis
  • Lactams, Macrocyclic / chemistry*
  • Molecular Conformation
  • Oxazoles / chemical synthesis
  • Oxazoles / chemistry*
  • Oxidation-Reduction
  • Pharmaceutical Preparations / chemistry*
  • Surface Properties

Substances

  • Amides
  • Azo Compounds
  • DZ-2384
  • Lactams, Macrocyclic
  • Oxazoles
  • Pharmaceutical Preparations
  • Graphite