A modular and enantioselective synthesis of the pleuromutilin antibiotics

Science. 2017 Jun 2;356(6341):956-959. doi: 10.1126/science.aan0003.

Abstract

The tricyclic diterpene fungal metabolite (+)-pleuromutilin has served as a starting point for antibiotic development. Semisynthetic modification of its glycolic acid subunit at C14 provided the first analogs fit for human use, and derivatization at C12 led to 12-epi-pleuromutilins with extended-spectrum antibacterial activity, including activity against Gram-negative pathogens. Given the inherent limitations of semisynthesis, however, accessing derivatives of (+)-pleuromutilin with full control over their structure presents an opportunity to develop derivatives with improved antibacterial activities. Here we disclose a modular synthesis of pleuromutilins by the convergent union of an enimide with a bifunctional iodoether. We illustrate our approach through synthesis of (+)-12-epi-mutilin, (+)-11,12-di-epi-mutilin, (+)-12-epi-pleuromutilin, (+)-11,12-di-epi-pleuromutilin, and (+)-pleuromutilin itself in 17 to 20 steps.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Diterpenes / chemical synthesis
  • Diterpenes / chemistry
  • Drug Design*
  • Molecular Structure
  • Pleuromutilins
  • Polycyclic Compounds
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Diterpenes
  • Polycyclic Compounds