Late-Stage Native Peptide Modification Approach to the Total Synthesis of Koshidacins A and B

Herein, the total synthesis of the antimalarial natural products, koshidacins A and B, is disclosed. We developed an inverse peptide elongation sequence to elaborate the linear tetrapeptide by leveraging a soluble hydrophobic tag (TCbz group) for liquid-phase peptide synthesis. The key advances involve head-to-tail macrocyclization to provide the carrier-supported cyclic tetrapeptide and photoinduced deaminative alkylation to edit the native peptide residue that enabled us to construct the requisite alkyl chain in this unique natural product family.