Decarboxylative Peptide Macrocyclization via Photoredox Catalysis

A method for the decarboxylative macrocyclization of peptides bearing N-terminal Michael acceptors has been developed. This synthetic protocol enables the efficient synthesis of γ-amino acid-containing cyclic peptides and is tolerant of functionality present in both natural and non-proteinogenic amino acids. Linear precursors ranging from 3 to 15 amino acids cyclize effectively under this photoredox protocol. To demonstrate the preparative utility of this method in the context of bioactive molecules, we have generated COR-005, a somatostatin analog currently in clinical trials. A method for the decarboxylative macrocyclization of peptides bearing N -terminal Michael acceptors has been developed. This synthetic protocol enables the efficient synthesis of γ-amino acid-containing cyclic peptides and is tolerant of functionality present in natural amino acids. Linear precursors ranging from 3 to 15 amino acids cyclize effectively under this photoredox protocol.