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 )-H activation. Herein, we report the development of a palladium-catalyzed late-stage C(sp )-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.
The late‐stage functionalization (LSF) of peptides represents a valuable strategy for the design of potent peptide pharmaceuticals by enabling rapid exploration of chemical diversity and offering novel opportunities for peptide conjugation. While the C(sp2)−H activation of tryptophan (Trp) is well documented, the resurgence of radical chemistry is opening new avenues for the C−H functionalization of other aromatic side‐chains. Herein, we report the first example of LSF at C2 of histidine (His) utilizing a broad scope of aliphatic sulfinate salts as radical precursors. In this work, the exquisite selectivity for histidine functionalization was demonstrated through the alkylation of complex unprotected peptides in aqueous media. Finally, this methodology was extended for the installation of a ketone handle, providing an unprecedented anchor for selective oxime/hydrazone conjugation at histidine.
An efficient synthesis of racemic or optically active α-amino acids by modified-Mitsunobu alkylation of a racemic or chiral glycine template from alcohols was developed. Libraries of amino acids were prepared in moderate to good yield with good to high enantioselectivity. This simple method widens the scope for preparation of structurally diverse amino acids.
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