Chemoselective C-Terminal Activation Platform for Direct Conversion of Native Linear Peptides into Thiazoline/Thiazole Macrocycles

We report a sequence-independent, chemoselective C-terminal activation platform to synthesize thiazoline/thiazole macrocycles from native linear peptides. Selective C-terminal primary amide-to-nitrile conversion proceeds in solution on fully unprotected peptides with broad functional-group compatibility. This approach eliminates the need for presynthesized α-amino nitrile building blocks and minimizes epimerization risk. Our method enables rapid macrocyclization, supporting the direct total syntheses of Mollamide F, Sanguinamide A, and Haligramide A from linear precursors.