STEREOSELECTIVE SYNTHESIS OF GLYCOSYL AMIDES BY TRACELESS STAUDINGER LIGATION OF GLYCOSYL AZIDES

alpha-Glycosyl amides represent a little known class of non-hydrolysable monosaccharide derivatives that may find useful application as sugar mimics and neo-glycoconjugates. Their stereoselective synthesis has proven difficult because glycosyl amines are not configurationally stable and undergo easy alpha to betaanomerization. Various methods have been proposed to get around this problem by reducing alpha glycosyl azides in the presence of acylating agents, but only a few have been reported to afford alpha-glycosyl amides, most of which require two steps and/or have been described for a limited number of substrates. Much work has been devoted to the Staudinger reduction/acylation process, which consists in the reduction of glycosyl azides with phosphines in the presence of carboxylic acids or derivatives. In this PhD thesis we have developed a stereoconservative Staudinger ligation of unprotected fluorophenyl esters to afford α- and β-N-glycosyl amino acids. The ligation method works reliably well for unprotected β-azides of the gluco, galacto and fuco series. Lower yields (ca. 50%) were obtained with a β-glucosyl-Nacetyl azide. The reaction of an α-glucosyl azide also led to major improvements compared with the use of non-fluorinated phosphines. All the N-glycosyl amino acid products can be isolated and by-products removed from the crude reaction mixtures by simple water extraction. alpha- or beta-glycofuranosyl amides can be synthesized with high stereoselectivity by traceless Staudinger ligation using a non-fluorinated phosphines, starting from unprotected beta-glycofuranosyl azide or tetra-O-acetyl-beta-glycofuranosyl azide, respectively. In particular, the resulting galactofuranosyl amides are hitherto unknown molecules, with interesting potential as inhibitors of mycobacterial growth especially for the alpha compounds.