Transition metal-catalyzed C-H activation/annulation for the construction of unnatural amino acids and peptides

Peptides play important roles in chemistry, medicinal chemistry and life science, due to their high efficiency and specificity, unusual biological and therapeutic properties. As naturally occurring peptides often face with their intrinsic limitations including metabolic instability and low membrane permeability, the strategies for synthesizing unnatural amino acids and peptides are explored. Among the methods for modifying amino acids and peptides, chemo- and site-selective approaches are preferred because of the ability to fine-tuning structural features. Recently, transition metal-catalyzed C-H activation has been employed for the functionalization of amino acids and peptides. Through domino C-H activation/annulation, a series of structurally complex and diverse amino acids and peptides is constructed. This review highlights recent advances in the synthesis of unnatural amino acids and peptides via transition metal-catalyzed C-H activation/annulation. © 2025