Anion-Binding Properties of a Cyclic Pseudohexapeptide Containing 1,5-Disubstituted 1,2,3-Triazole Subunits

Abstract

A C(3) symmetric cyclic pseudohexapeptide containing 2-aminopicoline-derived subunits and 1,5-disubstituted 1,2,3-triazole rings is introduced as a potent anion receptor. This macrocycle was designed to mimic both the conformation and the receptor properties of a previously described cyclic hexapeptide containing alternating L-proline and 6-aminopicolinic acid subunits. Conformational analyses demonstrate that the cyclic peptide and the cyclic pseudopeptide are structurally closely related. Most importantly, both exhibit a converging arrangement of the NH groups, hence a good preorganization for anion binding. As a consequence, the pseudopeptide also very efficiently interacts with halide and sulfate ions, and this is the case even in competitive aqueous solvent mixtures. However, there are clear differences in the structures of both compounds, which translate into characteristic differences in receptor properties. Specifically, (i) the pseudopeptide possesses an anion affinity intrinsically higher than that of the cyclopeptide, (ii) the pseudopeptide is well preorganized for anion binding in a wider range of solvents from aprotic to protic, (iii) anion affinity in aprotic solvents is very high and associated with complexation equilibria that are slow on the NMR time-scale, (iv) the propensity of the pseudopeptide to form sandwich-type 2:1 complexes with two receptor molecules surrounding one anion is significantly lower than that of the cyclopeptide. A solvent-dependent calorimetric characterization of the binding equilibria of both compounds provided clear evidence for the stabilizing effect of hydrophobic interactions between the receptor subunits in such 2:1 complexes. The pseudopeptide thus represents the first member of a new family of anion receptors whose properties may be fine-tuned by varying the side chains in the periphery of the cavity.

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

“…167 The in-vitro generation of disulfides bridges is usually achieved post-synthetically and is not always straightforward, especially for controlled regiospecific formation of such linkages. 169 Fang et al used RuAAC for macrocyclization to obtain 11-and 12-membered macrocycles, 171 using previously reported unoptimized conditions 156 but with a slightly higher temperature (Scheme 42). Macrocycles 96 and 97 were obtained in moderate to good yield, but it remains uncertain to what degree the yield was reduced by any dimer formation.…”

Anion recognition by cyclic peptides

“…Detailed conformational studies and anion binding analysis were also reported. 58 Conformational analysis confirmed that 32 is structurally similar to cyclic hexapeptide 18 where retention of converging NH groups pointing inside the macrocyclic cavity indicated a favourable preorganisation for anion binding. However, subtle differences in the structures of both receptors (Fig.…”

Non‐covalent Interactions for the Preparation of Pseudopeptidic Synthetic Compounds and Materials

“…For instance, the cyclic pseudopeptides developed by Kubik and coworkers [10][11][12] represent a very good example of how the molecular design has evolved for the optimization of the properties in the molecular recognition of different guests (Scheme 22.4) even in a very competitive medium, like aqueous solution. Starting from a conformationally based design of alternating 3-aminobenzoic acid and natural N-methylated amino acids (10), the better performance of proline as the amino acid was identified [10].…”

“…Later on, the isosteric substitution of the tertiary amide bonds by triazole rings has been developed [12]. The corresponding pseudopeptide also interacts very efficiently with anions in competitive solvent mixtures, with a somehow higher efficiency.…”