Synthesis of sialyl Le x ganglioside analogues modified at C-6 of the galactose residue to elucidate the mechanism of selection recognition

Abstract

Sialyl Lewis X ganglioside analogues modified at C-6 of the galactose residue, having 6- O-methoxy, 6-acetamido and 6-amino functional groups, have been synthesized. Treatment of 2-(trimethylsilyl)ethyl (methyl 5-acetamido-4,7,8,9-tetra- O-acetyl-3,5-dideoxy- D-glycero- α- D-galacto-2-nonulopyranosylonate)-(2→3)-2- O-benzoyl- β- D-galactopyranoside with trimethyloxonium tetrafluoroborate or Tf 2O, followed by NaN 3, gave the 6- O-methyl and 6-azido derivatives, respectively, which were converted into their respective methyl 1-thioglycoside derivatives. The glycosyl donors obtained were coupled with 2-(trimethylsilyl)ethyl 2-acetamido-6- O-benzyl-2-deoxy-3- O-(4-methoxybenzyl)- β- D-glucopyranosyl-(1→3)-2,4,6-tri- O-benzyl- β- D-galactopyranosyl-(1→4)-2,3,6-tri-O-benzyl- β- D-galactopyranoside in the presence of dimethyl(methylthio)sulfonium triflate (DMTST) to give their respective pentasaccharides. The glycosylation of the pentasaccharide acceptors derived from their precursors by removal of the 4-methoxybenzyl group, with phenyl 1-thioglycoside derivative of L-fucose using N-iodosuccinimide–TfOH afforded the corresponding hexasaccharides, which were transformed in good yield, via reductive removal of the benzyl group, the simultaneous transformation of azide to amine and acetamide, O-deacylation and saponification of the methyl ester into the target compounds without the ceramide groups. On the other hand, the proper manipulation of the protecting group of the hexasaccharides, including a transformation of azide into acetamide and trifluoroacetamide, gave the hexasaccharide imidates, which were coupled with (2 S,3 R,4 E)-2-azido-3- O- tert-butyldiphenylsilyl-4-octadecene-1,3-diol. Selective reduction of the azido group, N-acylation with octadecanoic acid, and the complete removal of the protecting groups gave the desired sialyl Le X ganglioside analogues.