Stapled Peptides by Late‐Stage C(sp 3 )−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(sp 2 )−H activation. Herein, we report the development of a palladium‐catalyzed late‐stage C(sp 3 )−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.