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

A modular and enantioselective synthesis of the pleuromutilin antibiotics.

Author information

1
Department of Chemistry, Yale University, New Haven, CT 06520, USA.
2
Department of Chemistry, Yale University, New Haven, CT 06520, USA. seth.herzon@yale.edu.
3
Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA.

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.

PMID:
28572392
DOI:
10.1126/science.aan0003
[Indexed for MEDLINE]

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