American Chemical Society
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Synthesis of Structurally Defined Scaffolds for Bivalent Ligand Display Based on Glucuronic Acid Anilides. The Degree of Tertiary Amide Isomerism and Folding Depends on the Configuration of a Glycosyl Azide

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journal contribution
posted on 2005-05-13, 00:00 authored by Manuela Tosin, Paul V. Murphy
Syntheses and structural analyses of bivalent carbohydrates based on anilides of glucuronic acid are described. Secondary anilides predominantly adopted the Z-anti structure; there is also evidence for population of the Z-syn isomer. Bivalent tertiary anilides displayed two signal sets in their NMR spectra, consistent with the presence of (i) a major isomer where both amides have E configurations (EE) and (ii) a minor isomer where one amide is E and the other Z (EZ). Qualitative NOE/ROE spectroscopic studies in solution support the proposal that the anti conformation is preferred for E amides. The crystal structure of one bivalent tertiary anilide showed E-anti and E-syn structural isomers; intramolecular carbohydrate−carbohydrate stacking was observed and mediated by carbonyl−pyranose, azide−azide, and pyranose−aromatic interactions. The EE to EZ isomer ratio, or the degree of folding, for tertiary amides, was greatest for a bivalent compound containing two α-glycosyl azide groups; this was enhanced in water, suggesting that hydrophobic interactions are partially but not wholly responsible. Computational methods predicted azide−aromatic (N···H−C interaction) and azide−azide interactions for folded isomers. The close contact of the azide and aromatic protons (N···H−C interaction) was observed upon examination of the close packing in the crystal structure of a related monomer. It is proposed that the α-azide group is more optimally aligned, compared to the β-azide, to facilitate interaction and minimize the surface area of the hydrophobic groups exposed to water, and this leads to the increased folding. The alkylation of bivalent secondary anilides induces a switch from Z to E amide that alters the scaffold orientation. The synthesis of a bivalent mannoside, based on a secondary anilide scaffold, for investigation of mannose-binding receptor cross-linking and lattice formation is described.