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A modular and enantioselective synthesis of the pleuromutilin antibiotics

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Science  02 Jun 2017:
Vol. 356, Issue 6341, pp. 956-959
DOI: 10.1126/science.aan0003

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A versatile synthesis of pleuromutilin

Synthetic flexibility is crucial for antibiotic development, because numerous subtle structural variations can contribute to combating resistant strains. A derivative of the fungal natural product pleuromutilin was approved a decade ago for treatment of Gram-positive bacterial skin infections; recent efforts to tune the structure for activity against Gram-negative bacteria have focused on the stereochemistry at a particular carbon center. Murphy et al. present a synthetic route to pleuromutilin that allows the configurations in that segment of the molecule to be varied, offering a distinct path for structural optimization.

Science, this issue p. 956

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.

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