Construction of Peptide Macrocycles via Radical-Mediated Intramolecular C-H Alkylations

Enzyme-catalyzed radical-mediated C-H functionalization reactions allow nature to create natural products of unusual three-dimensional structures from simple linear peptide precursors. In comparison, chemist's ability to harness radical C-H functionalization reactions for synthesis of complex peptides remains limited. In this work, new methods have been developed to construct peptide macrocycles via radical-mediated intramolecular C-H alkylation reactions under photoredox catalysis. Linear peptide precursors equipped with a C-terminal N-(acyloxy)phthalimide ester can cyclize with the alpha C-H bond of N-terminal glycine or aryl C-H bond of N-heteroarene capping units in high yield and selectivity under mild conditions. The strategy uses the C-H cyclization step to incorporate lysine, homolysine, and various heteroarene-derived amino acid linchpins into peptide macrocycles, enabling convergent and flexible synthesis of complex peptide macrocycles from simple building blocks.

Automated summary

New methods have been developed in this study to construct peptide macrocycles via radical-mediated intramolecular C-H alkylation reactions under photoredox catalysis, providing a new strategy for the synthesis of complex peptide macrocycles.