Total Synthesis of the Posttranslationally Modified Polyazole Peptide Antibiotic Plantazolicin A

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).