title: 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.
abstract: [structures: see text] 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 alpha-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 alpha-azide group is more optimally aligned, compared to the beta-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.
authors.affiliation: Centre for Synthesis and Chemical Biology, Department of Chemistry, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Manuela
authors.initials: M
authors.lastname: Tosin
authors.forename: Paul V
authors.initials: PV
authors.lastname: Murphy
mesh_terms: D000577:Amides / Q000737:chemistry; D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001386:Azides / Q000737:chemistry*; D002236:Carbohydrate Conformation; D020723:Glucuronic Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006031:Glycosylation; D007536:Isomerism; D008024:Ligands; D008956:Models, Chemical
chemical_list: D000577:Amides; D000813:Anilides; D001386:Azides; D008024:Ligands; D020723:Glucuronic Acid