Recent Advances in Late‐Stage Construction of Stapled Peptides via C−H Activation

Abstract

Stapled peptides have been widely applied in many fields, including pharmaceutical chemistry, diagnostic reagents, and materials science. However, most traditional stapled peptide preparation methods rely on prefunctionalizations, which limit the diversity of stapled peptides. Recently, the emergence of late‐stage transition metal‐catalyzed C−H activation in amino acids and peptides has attracted wide interest due to its robustness and applicability for peptide stapling. In this review, we summarize the methods for late‐stage construction of stapled peptides via transition metal‐catalyzed C−H activation.

Research progress on chemical modifications of tyrosine residues in peptides and proteins

“…Cyclic peptides have attracted significant attention in drug development due to their excellent stability against degradation and cell permeability (Chow et al, 2019; Jwad et al, 2020). Over the past 20 years, various methods for the chemical synthesis of cyclic peptides have been developed, including amide condensation, Click chemistry (Bock et al, 2007; Ingale & Dawson, 2011), C–H activation (Liu et al, 2021), and other strategies. In addition to the formation of disulfide bonds and head‐to‐tail cyclization of peptide termini, natural cyclic peptides from plants are often formed through cyclization of Tyr and Trp side chains (Chooi, 2022).…”

Pd-catalyzed site-selective C(sp2)–H chalcogenation of amino acids and peptides using a picolinamide auxiliary

“…[1][2][3][4][5] Unnatural amino acids are considered as building blocks for the synthesis of non-proteogenic engineered peptide derivatives. [6][7][8][9][10][11] The synthesis of these amino acids have been achieved using traditional cross-coupling reactions. [12][13][14][15][16][17][18][19][20] Recently, metal-catalyzed C-H activation has emerged as a powerful synthetic methodology for various types of challenging chemical transformations including the structural modification of amino acids/peptides.…”

Modular synthesis of clickable peptides via late-stage maleimidation on C(7)-H tryptophan

“…Transition metal-catalyzed late-stage functionalization of complex molecules has a good site-specificity, high tolerance of functional groups, and therefore, providing a straightforward method for an efficient C-H functionalization/macrocyclization of peptides. This strategy provides distinct peptide scaffolds that are not easily achievable with traditional methods, which have been explored by Lavilla 11 , Albericio 12 , Shi 13 , 14 , Ackermann 15 – 17 , Wang 18 – 20 , Yu 21 , Chen 22 , 23 and others 24 – 27 . In this regard, the amino acid tryptophan (Trp) is an ideal modification residue due to its relatively low abundance in peptide/protein sequences and unique impact on biological events, which include a series of important natural products containing C(7)-substituted tryptophan (Fig.…”