Expanding the family of pleuromutilin antibiotics by chemical synthesis

Abstract

The threat of bacterial drug-resistance has emerged as a significant threat against human health, and the discovery of new effective antibiotics is becoming a resurgent challenge for mankind's battle with pathogenic bacteria. Most currently known antibiotics are isolated directly from living organisms or derived from natural products; the unique molecular frameworks of natural products inspire the discovery and design of novel classes of antibiotics.

Pleuromutilin is a diterpene originally isolated from fungi. This naturally occurring compound and its derivatives have been shown to suppress bacterial growth by selectively binding to bacterial ribosomes. Encouraged by the clinical utility of other antibiotics developed from the pleuromutilin family, we proposed a further expansion of the pleuromutilin antibiotic family by de novo chemical synthesis of pleuromutilin scaffolds with novel topologies.

We studied several strategies toward the synthesis of cis-hydrindanone, a common bicyclic motif in natural products, including pleuromutilin. We accomplished two concise strategies to pleuromutilin-like scaffolds featuring ring closing olefin metathesis and chromium-mediated carbonyl addition reactions.