Neo-glycoconjugates: Stereoselective synthesis of a-glycosyl amides and a-glycosyl ureas

alfa -Glycosyl amides can be synthesised from the corresponding O-benzyl-alfa-glycosyl azides using a traceless Staudinger ligation with diphenylphosphanyl-phenyl esters 4. All the phosphines employed and their phenol precursors are stable to air at 4 °C for months. Fast intramolecular trapping of the reduction intermediates results in the direct formation of the amide link which, in turn, prevents epimerisation and allows retention of configuration at the anomeric carbon. Yields and alfa -selectivity are high when the reaction is performed in polar aprotic solvents. Removal of the benzyl ether protecting groups is achieved by catalytic hydrogenation. alfa -Glycosyl amides represent a class of virtually unexplored non-hydrolysable monosaccharide derivatives that may find useful application as sugar mimics. Conformational studies by NMR spectroscopy confirm that deprotected alfa-glycosyl amides in the gluco-, galacto- and fuco- series retain the normal pyranose conformation of the monosaccharide. The reaction of phosphines 4 with tetra-O-acetyl-glycosyl azides is non-stereoconservative and beta-glycosyl amides are obtained in good yields and complete stereoselectivity starting from both alfa and beta-azides. A stereoselective procedure for the synthesis of alfa-glycosyl ureas was also developed. Compared to the most recent literature reports this method allows to directly transform alfa-glycosyl azides into the corresponding ureas in a one-pot facile reaction, avoiding the four steps and one chromatographic separation involved in the previous best procedure. Treatment of perbenzylated -azides with trimethylphosphine followed by addition of the isocyanate and subsequent acid catalysed hydrolysis of the intermediate diimide, led to the corresponding urea with complete alfa-selectivity and in good yield. Removal of the protecting benzyl groups was achieved by catalytic hydrogenolysis.