New peptide architectures through C–H activation stapling between tryptophan–phenylalanine/tyrosine residues

Abstract

Natural peptides show high degrees of specificity in their biological action. However, their therapeutical profile is severely limited by their conformational freedom and metabolic instability. Stapled peptides constitute a solution to these problems and access to these structures lies on a limited number of reactions involving the use of non-natural amino acids. Here, we describe a synthetic strategy for the preparation of unique constrained peptides featuring a covalent bond between tryptophan and phenylalanine or tyrosine residues. The preparation of such peptides is achieved in solution and on solid phase directly from the corresponding sequences having an iodo-aryl amino acid through an intramolecular palladium-catalysed C–H activation process. Moreover, complex topologies arise from the internal stapling of cyclopeptides and double intramolecular arylations within a linear peptide. Finally, as a proof of principle, we report the application to this new stapling method to relevant biologically active compounds.

Iminoboronate-Based Peptide Cyclization That Responds to pH, Oxidation, and Small Molecule Modulators

“…1,2 Recently much attention has been paid to synthetic cyclic peptides designed to resemble the structure and function of their natural counterparts. 3,4 A number of strategies have been introduced for the synthesis of cyclic and bicyclic peptides, including thioether formation, 5,6 azide-alkyne click chemistry, 7,8 olefin metathesis, 9,10 KAHA ligation, 11 C-H activation stapling, 12 as well as formation of disulfide bonds and macrolactams. 13 These strategies have enabled the preparation of cyclic and bicyclic peptide libraries, screening of which has yielded an impressive array of biological probes and potential therapeutics.…”

Backbone‐Enabled Directional Peptide Macrocyclization through Late‐Stage Palladium‐Catalyzed δ‐C(sp2)−H Olefination

“…[12] Recently,several elegant examples of late-stage site-selective C À Hf unctionalization of peptides using Pd catalyst have been achieved, including b-C(sp 3 )ÀHa rylation and alkynylation at the N-terminal amino acid by Yu, [13] g-C(sp 3 )ÀHc arbonylation of peptides by Carretero, [14] b-C-(sp 3 ) À Ha rylation, and BODIPY labeling of peptides using internal 1,2,3-triazole moieties as the directing group by Ackermann. [17] Noisier/Albericio and our group independently developed an intramolecular b-C(sp 3 ) À Harylation method to construct peptide macrocycles containing bC-Ar crosslinks. [16] To achieve peptide macrocyclization, Albericio/Lavilla utilized Pd-catalyzed C-2 arylation of the indole side chain of tryptophans (Trp) by iodo-aryl amino acids to synthesize stapled peptides with aryl-aryl crosslinks.…”

Bicyclic Peptides as Next‐Generation Therapeutics

“…[16] Lavilla and colleagues later expanded on this stapling approach via application of a palladium catalyzed C-C bond formation between tryptophan and iodinated tyrosine or phenylalanine (Figure 3c). [17] Very recently, Waldmann and Grossman [18] employed orthogonal ring-closing olefin and alkyne metathesis schemes to form either manacle or butterfly shaped bicyclic peptides (Figure 3d). In an alternative approach, Grandas et al prepared metabolically stable bicyclic peptides via successive Michael addition reactions between thiols and maleimides.…”