Bioinspired Total Synthesis of Pyritide A2 through Pyridine Ring Synthesis

Pyritides belong to the ribosomally synthesized and post-translationally modified peptide class of natural products that were recently genome-predicted are structurally defined by unique pyridine-containing macrocycles. Inspired their biosynthesis, proceeding through modification cycloaddition form heterocyclic core, we report chemical synthesis pyritide A2 involving pyridine ring from an amino acid precursor via aza Diels–Alder reaction. This strategy permitted preparation decorated core with appended residue in two steps a commercially available arginine derivative secured ten steps. Moreover, synthetic logic enables efficient different subunits associated pyritides, allowing rapid convergent access this new analogs thereof.