Enantioselective Total Synthesis of Verrucosamide

The enantioselective total synthesis of the C₂-symmetric cyclic polypeptide verrucosamide has been completed. The synthesis features a nucleophilic substitution-based dipeptide thioether formation with high regioselectivity, enabling straightforward access to the rare N-methylated 1,4-thiazepane scaffold. Starting from natural amino acids, this work culminates in a 27-step total synthesis of verrucosamide, establishing its absolute configuration and addressing a void in the total synthesis of the nonribosomal peptide bis-intercalators.