Cyclic peptides exhibit improved biostability, strong receptor affinity, and better selectivity, contrary to their linear analogs. Disulfide cyclic peptides are the most popular cyclic peptides. However, the reversibility between thiol and disulfide limited their applications, especially on the periphery of branched peptides. Several surrogates of disulfide analogous were developed, and lactam is one potential surrogate.[1] Despite the potential of lactams, conventional liquid-phase macrocyclization suffers from low yield, slow reaction, and poor purity. Several on-bead macrocyclizations have been reported to address the difficulty. However, most require special residue, which leads to extra considerations in solid-phase synthesis.[2] We used 1,2-diamino-4-nitrobenzene (Dnb) as a protecting group for the β- and γ-carboxylate of both aspartic and glutamic acids. The resulting Fmoc-Asp/Glu(Dnb)-OH could be directly applied to solid-phase peptide synthesis with a typical Fmoc approach. After synthesizing the peptide, we activated Dnb in the presence of alkyl nitrite, which created nitrobenzotriazole. This nitrobenzotriazole acted as a leaving group for the macrocyclization to give lactams. To implant lactams on the branched peptide, Fmoc-Asp/Glu(Dnb)-OH was used as a site for on-resin ligation. This method provides a convenient and diverse approach for producing the desired cyclic peptide-decorated branched peptides. 

Acknowledgments: The authors appreciated the financial support from the National Science and Technology Council and Kaohsiung Medical University. 

References:
 [1] C. Bechtler, C. Lamers, RSC Med. Chem., 2021, 12, 1325-1351
[2] Y.-K. Qi, Q. Qu, D. Bierer, L. Liu, Chem. Asian J. 2020, 15, 2793.