Stapled Peptides by Late‐Stage C(sp3)−H Activation

Despite the importance of stapled peptides for drug discovery, only few practical processes to prepare cross‐linked peptides have been described; thus the structural diversity of available staple motifs is currently limited. At the same time, C?H activation has emerged as an efficient approach to functionalize complex molecules. Although there are many reports on the C?H functionalization of amino acids, examples of post‐synthetic peptide C?H modification are rare and comprise almost only C(sp²)?H activation. Herein, we report the development of a palladium‐catalyzed late‐stage C(sp³)?H activation method for peptide stapling, affording an unprecedented hydrocarbon cross‐link. This method was first employed to prepare a library of stapled peptides in solution. The compatibility with various amino acids as well as the influence of the size (i ,i +3 and i ,i +4) and length of the staple were investigated. Finally, a simple solid‐phase procedure was also established.