We report the total synthesis and configurational assignment of pargamicin A, a highly oxidized nonribosomal peptide that potently inhibits the growth of drug-resistant bacteria. Our synthetic approach relies on late-stage piperazine ring formation and careful selection of condensation reagents to assemble the densely substituted hexapeptide backbone. This work enables the synthesis of pargamicin congeners for the development of structure−activity relationships and informs strategies for accessing other sterically congested piperazic acid-containing natural products.

We report the total synthesis and configurational assignment of pargamicin A, a highly oxidized non-ribosomal peptide that potently inhibits the growth of drug-resistant bacteria. Our synthetic approach relies on late-stage piperazine ring formation and careful selection of condensation reagents to assemble the densely substituted hexapeptide backbone. This work enables the synthesis of pargamicin congeners for the development of structure-activity relationships and informs strategies to access other sterically congested piperazic acid-containing natural products.