δ‐Peptides from RuAAC‐Derived 1,5‐Disubstituted Triazole Units

Abstract

Non‐natural peptides with structures and functions similar to natural peptides have emerged lately in biomedical as well as nanotechnological contexts. They are interesting for pharmaceutical applications since they can adopt structures with new targeting potentials and because they are generally not prone to degradation by proteases. We report here a new set of peptidomimetics derived from δ‐peptides, consisting of n units of a 1,5‐disubstituted 1,2,3‐triazole amino acid (5Tzl). The monomer was prepared using ruthenium‐catalyzed azide–alkyne cycloaddition (RuAAC) chemistry using [RuCl2Cp*]x as the catalyst, allowing for simpler purification and resulting in excellent yields. This achiral monomer was used to prepare peptide oligomers that are water soluble independent of peptide chain length. Conformational analysis and structural investigations of the oligomers were performed by 2D NOESY NMR experiments, and by quantum chemical calculations using the ωB97X‐D functional. These data indicate that several conformations may co‐exist with slight energetic differences. Together with their increased hydrophilicity, this feature of homo‐5Tzl may prove essential for mimicking natural peptides composed of α‐amino acids, where the various secondary structures are achieved by side chain effects and not by the rigidity of the peptide backbone. The improved synthetic method allows for facile variation of the 5Tzl amino acid side chains, further increasing the versatility of these compounds.

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

“…147 phase. 119 The relatively rich set of stable conformers for the 1,5-disubstituted triazole amino acids, the on-purpose extended nature of their 1,4-regioisomers, 149 and their applicability in both standard peptide synthesis and expressed protein ligation, 120 has already provided some initial studies toward the "foldamer direction". 119,[150][151] The latter examples together also foreshadow a rapid increase in the number of new promising triazole foldamer constructs in the near future.…”

Metal-catalyzed azide-alkyne “click” reactions: Mechanistic overview and recent trends

“…These complexes catalyzed the regioselective RuAAC reaction of terminal alkynes forming, unlike CuAAC catalysts, 1,5-disubstituted 1,2,3-triazoles, and also unlike the CuAAC catalysts, they reacted with internal alkynes providing trisubstituted 1,2,3-triazoles [28,39,40,82]. The Cp*RuCl based catalysts provided multiple application that were recently developed (vide infra) [81,[83][84][85][86][87]. M a n u s c r i p t The first mechanistic investigation was proposed by Lin, Jia, Fokin and coworkers based on DFT calculations [39].…”

“…Recent applications of Cp*RuCl-based catalysts included the synthesis of 4-haloisoxazoles and 5-halotriazoles [81], thiolactoside glycoclusters [83], one-step synthesis of triazoles [84], palladium-based metallocene complexes [85], 1,2,3-triazole peptides [86], 5-TTF-1,2,3-triazoles [87], 1,5-substitued 1,2,3-triazole amino acids [182], 5-amino-1,2,3-triazole-4-carboxylic acid [183a], and fluorinated 1,4,5-substituted 1,2,3-triazoles [183b]. RuAAC reactions catalyzed by Ru(II) complexes and RuNPs were also reported.…”

“…The RuNP catalyst exhibited good results in terms of reactivity in the RuAAC reactions, but the size effect strongly influenced the catalytic activity of these RuNP catalysts, because the size of the catalyst was sensitive to parameters such as the pH of the medium and the type and concentration of the surfactant [186]. MW-assistance promoted RuAAC reactions [82,84,87], as recently exemplified by Johansson et al who reported one-pot RuAAC reactions to synthesize 1,5-disubstituted 1H-1,2,3-triazoles involving two steps under microwave heating (Fig. 34).…”

1,5‐Disubstituted 1,2,3‐Triazole‐Containing Peptidotriazolamers: Design Principles for a Class of Versatile Peptidomimetics

“…In 2014, Johansson et al. published the synthesis of achiral peptidomimetic foldamers containing 1,5‐disubstituted 1,2,3‐triazoles and amide bonds in an alternating fashion (Scheme ) . As the triazole is considered a peptide bond surrogate, we suggest to adapt the peptidomimetics nomenclature accordingly: If the amide bond ‐(C=O)−NH‐ in the dipeptide ‐Gly‐Gly‐ is replaced by a 1,5‐disubstituted triazole it is represented by ‐Gly [5Tz] Gly‐.…”