We then wondered if the peptide-EBX reagents could be used to develop a new method for macrocyclization. Cyclic peptides are privileged scaffolds in drug discovery. Compared with their linear counterparts, they exhibit greater metabolic stability and enhanced pharmacokinetic properties. Based on our group's previous work and good results from the decarboxylative cross-coupling with peptide-EBXs, we envisioned that the C-terminal radical generated from decarboxylation under photoredox condition could be trapped by EBXs in an intramolecular fashion, which would lead to macrocycles with a unique rigid and lipophilic phenylacetylenyl backbone (Fig ). Visible light photocatalysis is very attractive for biomolecule functionalization, and it has also been applied to peptide macrocyclization. Concerning decarboxylative approaches, only a Giese type addition of radical formed from the C-terminus has been reported by MacMillan and co-workers. The flexible linkers obtained using this method are very different from the rigid and linear aryl alkynes accessible through the macrocyclization of peptide-EBXs. After optimization of the reaction conditions (see Fig for details), we obtained macrocycle 13a, resulting from cyclization of the EBX on the Lys side chain with the C-terminus, in 45% isolated yield (60% calibrated yield) using the organic dye 4CzIPN as the photocatalyst (Fig ). Simple commercially available blue LEDs could be used as light source and the reaction was finished in 30 min at room temperature. Only minor side product formation resulting from intermolecular reactions was observed. We then first tested the feasibility of the head-to-side chain cyclization with different C-terminal amino acids.