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(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.