A modular and enantioselective synthesis of the pleuromutilin antibiotics

• DOI: 10.1126/science.aan0003
• Publication Date: 2017-06-29T17:28:20Z
• Authors: Stephen K. Murphy; Mingshuo Zeng; Seth B. Herzon
• Keywords: Semisynthesis

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 human use, and derivatization C12 led to 12-epi-pleuromutilins with extended-spectrum antibacterial activity, including activity against Gram-negative pathogens. Given inherent limitations semisynthesis, however, accessing derivatives full control over their structure presents an opportunity develop improved activities. Here we disclose modular synthesis pleuromutilins by convergent union enimide bifunctional iodoether. We illustrate our approach through (+)-12-epi-mutilin, (+)-11,12-di-epi-mutilin, (+)-12-epi-pleuromutilin, (+)-11,12-di-epi-pleuromutilin, itself in 17 20 steps.