A HIGHLY EFFICIENT TOTAL SYNTHETIC ROUTE TO α-SERIES GANGLIOSIDES: GM1α, GD1α, AND GT1α1-2

Abstract

A highly efficient total synthetic route to α-series gangliosides GM1α, GD1α and GT1α is described. The suitably protected gangliotriose (GgOse3) derivatives, i.e., 2-(trimethylsilyl)ethyl (2-acetamido-2-deoxy-3-O-p-methoxybenzyl-β-D-galactopyranosyl)-(1→4)-(2,3,6-tri-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranoside (8) and the corresponding III[3]-levulinoyl derivative (9), were regioselectively glycosylated with the phenyl 2-thioglycoside of N-acetylneuraminic acid (Neu5Ac) promoted by N-iodosuccinimide (NIS)-trimethylsilyl trifluoromethanesulfonate (TMSOTf) or trifluoromethanesulfonic acid (TfOH) in acetonitrile, to give the desired α-Neu5Ac-(2→6)-gangliotriose (III[6]Neu5AcGgOse3) derivatives as the major products (11 and 12). The p-methoxybenzyl (MPM) group in 11 or the levulinoyl group in 12 was selectively removed, and the resulting 2-(trimethylsilyl)ethyl (methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranosylonate)-(2→6)-(2-acetamido-2-deoxy-β-D-galactopyranosyl)-(1→4)-(2,3,6-tri-O-benzyl-β-Dgalactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranoside (13), a key glycosyl acceptor, was systematically glycosylated with the galactose donor (14), α-Neu5Ac-(2→3)-galactose donor (15) and α-Neu5Ac-(2→8)-α-Neu5Ac-(2→3)-galactose donor (20) to give the protected GM1α (16, 70%), GD1α (17, 80%) and GT1α (21, 87%) oligosaccharides, respectively, which can be converted to the target gangliosides by the introduction of ceramide and then complete deprotection.