Thumbnail Image
dissertation.pdf(7.37 MB)
No. of downloads: 861
Publication or External Link
Damkaci, Fehmi
DeShong, Philip
Glycoproteins play an important role in biological processes including intercellular communication, cell-cell recognition, and cell growth regulation. The study of cellular processes is often limited by the availability of glycopeptides or glycoproteins from natural sources. The advances in carbohydrate and peptide chemistry in the last decade have created generally applicable methodologies for the synthesis of glycopeptides. The crucial step of any synthesis of a glycopeptide is the introduction of the carbohydrate residue to the amino acid or peptide in a stereoselective manner under conditions which are compatible with glycosidic linkages and common protecting groups for peptide synthesis. A novel synthesis of glycopyranosyl isoxazolines has been developed employing readily available 2-acetoxy-glycosyl azides and triphenylphosphine. The synthesis of the isoxazolines proceeded via epimerization of a beta-phosphorimine to the alpha-phosphorimine followed by cyclization to provide the isoxazoline. This methodology has been employed to synthesize glucopyranosyl, galactopyranosyl, and mannopyranosyl isoxazoline derivatives. The methodology has also been extended with di- and trisaccharide azides. The stereoselective synthesis of the glycosylamide linkage has been developed utilizing in situ generated glycosyl isoxazolines. Results of the coupling studies demonstrated that the optimum conditions for the synthesis of glycosylamides involved the coupling of the isoxazoline with a 2-pyridyl thioester in the presence of copper(II) chloride. The stereoselective syntheses of alpha-glucosylamide and beta-mannosylamide have been accomplished in high yields. Isoxazoline couplings were applied to the synthesis of alpha-glucosyl amino acids derivatives also; particularly noteworthy was the coupling with differentially protected aspartic acid analogs. It was shown that the coupling conditions are compatible with different protection strategies used in peptide couplings. Treatment of 2-NAc- or 2-NPhth-2-deoxyglucopyranosyl azides gave phosphorimine intermediates that failed to cyclize to imidazoline in analogy with the isoxazoline. The phosphorimines, however, coupled efficiently with thiopyridyl esters to provide the glycosyl-beta-amide linkage. The yields in these couplings were superior to the yields from the traditional Staudinger reactions utilizing carboxylic acids. Coupling of these phosphorimines with the thiopyridyl ester of asparagine derivatives has proven to be a superior method for the synthesis of N-linked glycopeptide derivatives.