Mimicking the Vancomycin Carboxylate Binding Site: Synthetic receptors for sulfonates, carboxylates, and N-protected α-amino acids in water

The novel H2O-soluble cyclophanes 1 and 2 incorporating different anion-recognition sites were prepared in short synthetic routes (Schemes 1 and 2) as first-generation mimics of the natural, D-Ala-D-Ala binding antibiotic vancomycin. The X-ray crystal structure of 1, a tris(hydrochloride)salt, revealed an open, preorganized cavity of sufficient size for the incorporation of small aliphatic residues (Fig. 3). In the crystal, molecules of 1 are arranged in parallel stacks, generating two types of channels, an ‘intra-stack’ channel passing through the cyclophane cavities and an ‘inter-stack’ channel located between cyclophane stacks (Fig. 4). The strongest intermolecular interactions between macrocycles in the crystal are CO…HN H-bonds between the carboxamide residues of adjacent cyclophanes in neighboring stacks (Fig. 5). The ‘intra-’ and ‘inter-stack’ channels incorporate the three ordered Cl− counterions and several, partially ordered solvent molecules (4 MeOH, 1 H2O) (Fig. 6). Counterion Cl(2) is located within the ‘intra-stack’ channel and interacts with a protonated piperazinium N-atom and both ‘intra-stack’ MeOH molecules. The two other counterions, Cl(1) and Cl(3), are located within the ‘inter-stack’ channel. They are connected to two MeOH and one H2O molecules and also interact both with the NH group of the protonated spiropiperidinium ring in 1, forming an infinite, chain-like H-bonding network …Cl(1)…HOH…MeOH…Cl(3)…HNH…Cl(1′)…. Both ‘intra-’ and ‘inter-stack’ MeOH molecules undergo weak CH…π interactions with neighboring aromatic rings. Cyclophane 1 complexed aromatic sulfonates in 0.5M KCl/DCl buffer in D2O, whereas the tetrakis(quaternary ammonium) receptor 2 bound the sodium salts of aliphatic and aromatic carboxylates and sulfonates, of N-acylated α-amino acids as well as of N-acetyl-D-alanyl-D-alanine (Ac-D-Ala-D-Ala), a substrate of vancomycin, in pure H2O. In all of these complexes, ion pairing between the cationic recognition site in the periphery of the cyclophane receptor and the anionic substrates represents the major driving force for host-guest association. The 1H-NMR analysis of complexation-induced changes in chemical shift clearly demonstrated that, in solution, this ion pairing exclusively takes place outside the cavity. Nevertheless, the macrocyclic bridges are essential for the efficiency of the anion-recognition sites in the two cyclophane receptors 1 and 2. Control compounds 3 and 4 possess nearly the same anion-recognition sites than 1 and 2, but lack their macrocyclic preorganization; as a consequence, they do not form stable ion-pairing complexes with mono-anionic substrates in the considered concentration ranges ( < 50 mM) in D2O.

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