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