Total Synthesis of Feglymycin Using Umpolung Amide Synthesis

The preparation of peptidic molecules is a mainstay of synthesis, creating new tools that advance chemical biology, catalysis, and drug discovery. Despite the wide adoption of methods for amide synthesis based on electrophilic acyl transfer reactions, significant limitations remain that restrict access to chemical space and plague accessible peptides with imperfect conservation of stereochemical information. These problems persist in key applications (i.e., solid phase peptide synthesis) where reagent excess can be used to drive maximal yield. As a general tactic, however, use of excess coupling agents that are often hazardous is unsustainable. Here we report the synthesis of the antiviral tridecapeptide feglymycin where half of the amides are formed using umpolung amide synthesis (UmAS) to replace conventional amide synthesis. Reliance on UmAS further allowed the enantioselective synthesis of each noncanonical residue from an inexpensive aldehyde. As a result, the most process-intensive components were simplified to a chiral Brønsted acid organocatalyst and potassium iodide/urea·hydrogen peroxide (KI/UHP). This solution-phase total synthesis illustrates the harmonious, strategic application of complementary amide synthesis methods, and it serves as a touchstone for the green synthesis of peptides composed of noncanonical amino amides.