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1,4- and 1,5-Disubstituted triazole amino acid monomers have gained increasing interest among peptidic foldamers, as they are easily prepared via Cu- and Ru-catalyzed click reactions, with the potential for side chain variation. While the latter is key to their applicability, the synthesis and structural properties of the chiral mono- or disubstituted triazole amino acids have only been partially addressed. We here present the synthesis of all eight possible chiral derivatives of a triazole monomer prepared via a ruthenium-catalyzed azide alkyne cycloaddition (RuAAC). To evaluate the conformational properties of the individual building units, a systematic quantum chemical study was performed on all monomers, indicating their capacity to form several low energy conformers. This feature may be used to effect structural diversity when the monomers are inserted into various peptide sequences. We envisage that these results will facilitate new applications for these artificial oligomeric compounds in diverse areas, ranging from pharmaceutics to biotechnology.

Peptidic foldamers have recently emerged as a novel class of artificial oligomers with properties and structural diversity similar to that of natural peptides, but possessing additional interesting features granting them great potential for applications in fields from nanotechnology to pharmaceuticals. Among these, foldamers containing 1,4- and 1,5-substitued triazole amino acids are easily prepared via the Cu- and Ru-catalyzed click reactions and may offer increased side chain variation, but their structural capabilities have not yet been widely explored. We here describe a systematic analysis of the conformational space of the two most important basic units, the 1,4-substitued (4Tzl) and the 1,5-substitued (5Tzl) 1,2,3-triazole amino acids, using quantum chemical calculations and NMR spectroscopy. Possible conformations of the two triazoles were scanned and their potential minima were located using several theoretical approaches (B3LYP/6-311++G(2d,2p), ωB97X-D/6-311++G(2d,2p), M06-2X/6-311++G(2d,2p) and MP2/6-311++G(2d,2p)) in different solvents. BOC-protected versions of 4Tzl and 5Tzl were also prepared via one step transformations and analyzed by 2D NOESY NMR. Theoretical results show 9 conformers for 5Tzl derivatives with relative energies lying close to each other, which may lead to a great structural diversity. NMR analysis also indicates that conformers preferring turn, helix and zig-zag secondary structures may coexist in solution. In contrast, 4Tzl has a much lower number of conformers, only 4, and these lack strong intraresidual interactions. This is again supported by NMR suggesting the presence of both extended and bent conformers. The structural information provided on these building units could be employed in future design of triazole foldamers.

A library of novel and diverse P-chirogenic phosphine ligands containing a triazole moiety (ChiraClick ligands) were prepared in high yield in a modular fashion that allows for variation of both the phosphine and the triazole structure, as well as giving access to the two enantiomers of the ligand.

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. [ABSTRACT FROM AUTHOR]

The ruthenium-catalyzed azide alkyne cycloaddition (RuAAC) affords 1,5-disubstituted 1,2,3-triazoles in one step and complements the more established copper-catalyzed reaction providing the 1,4-isomer. The RuAAC reaction has quickly found its way into the organic chemistry toolbox and found applications in many different areas, such as medicinal chemistry, polymer synthesis, organocatalysis, supramolecular chemistry, and the construction of electronic devices. This Review discusses the mechanism, scope, and applications of the RuAAC reaction, covering the literature from the last 10 years. [ABSTRACT FROM AUTHOR]

A one-pot method for the functionalization of polyvinylbenzyl chloride with a tris-(benzyltriazolylmethyl)amine (TBTA) ligand via the copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC) is reported, where the ligand is constructed simultaneously with its attachment to the polymer backbone. A hydrophobic TBTA polymer as well as co-polymers containing TBTA ligands were also prepared to demonstrate the possibility of tailoring the properties of the polymers. The polymers were characterized with FT-IR and NMR spectroscopy, elemental analysis, contact angle measurement, differential scanning calorimetry and thermal gravimetric analysis. The metal coordinating properties of films prepared from the polymers was also demonstrated using X-ray photoelectron spectroscopy and their structures inspected by scanning electron microscopy. [ABSTRACT FROM AUTHOR]

An experimentally simple sequential one-pot RuAAC reaction, affording 1,5-disubstituted 1H-1,2,3-triazoles in good to excellent yields starting from an alkyl halide, sodium azide, and an alkyne, is reported. The organic azide is formed in situ by treating the primary alkyl halide with sodium azide in DMA under microwave heating. Subsequent addition of [RuClCp*(PPh3)2] and the alkyne yielded the desired cycloaddition product after further microwave irradiation. [ABSTRACT FROM AUTHOR]