Total Synthesis of the Posttranslationally Modified Polyazole Peptide Antibiotic Plantazolicin A

Abstract

The power of rhodium-carbene methodology in chemistry is demonstrated by the synthesis of a structurally complex polyazole antibiotic. Plantazolicin A, a novel soil-bacterium metabolite, comprises a linear array of 10 five-membered rings in two pentacyclic regions that derive from ribosomal peptide synthesis followed by extensive posttranslational modification. The compound possesses potent antimicrobial activity, and is selectively active against the anthrax-causing organism. A conceptually different synthesis of plantazolicin A is reported in which the key steps are the use of rhodium(II)-catalyzed reactions of diazocarbonyl compounds to generate up to six of the seven oxazole rings of the antibiotic. NMR spectroscopic studies and molecular modeling reveal a likely dynamic hairpin conformation with a hinge region around the two isoleucine residues. The compound has modest activity against methicillin-resistant Staphylococcus aureus (MRSA).

Keywords: antibiotics; carbenes; diazo compounds; heterocycles; total synthesis.