Late-Stage Native Peptide Modification Approach to the Total Synthesis of Koshidacin B

Herein, total synthesis of the antimalarial natural product, koshidacin 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 (LPPS). The key advances involve head-to-tail macrocyclization to provide the carrier-supported cyclic tetrapeptide and photo-induced deaminative alkylation to edit the native peptide functional group that enabled to construct the requisite alkyl chain in this unique natural product family.