A Total Synthesis of Sialyl Dimeric Le^x Ganglioside¹

Abstract

The first total synthesis of tumor-associated glycolipid antigen, sialyl dimeric Le^x, is described. Regioselective glycosylation of the suitably protected Lewis X (Le^x) pentasaccharide derivative 6 with phenyl 4-O-acetyl-6-O-benzyl-2-deoxy-3-O-(4-methoxy-benzyl)-2-phthalimido-1-thio-β-d-glucopyranoside (5) gave the hexasaccharide 7, which was converted, via removal of the phthaloyl groups and selective N-acetylation, into the hexasaccharide acceptor 9. Dimethyl(methylthio)sulfonium triflate (DMTST) promoted glycosylation of 9 with methyl O-(methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-d-glycero-α-d-galacto-2-nonulopyranosylonate)-(2→3)-2,4,6-tri-O-benzoyl-1-thio-β-d-galactopyranoside (10) afforded regioselectively the expected octasaccharide 11, which was converted into 13 via O-acetylation and removal of the methoxybenzyl group. Fucosylation of 13 with the methyl thioglycoside 14 was performed by use of N-iodosuccinimide (NIS)-trifluoromethanesulfonic acid(TfOH) as a promoter to give the desired nonasaccharide 15. After replacing the benzyl groups of 15 by the acetyl groups, the 2-(trimethylsilyl)ethyl group at the reducing end was selectively transformed into the α-trichloroacetimidate 18. Coupling of 18 with (2S, 3R, 4E)-2-azido-3-O-tert-butyldiphenylsilyl-4-octadecene-1,3-diol (19) gave the corresponding β-glycoside 20, which was transformed, via selective reduction of the azide group, coupling with octadecanoic acid, O-desilylation, O-deacylation, and hydrolysis of the methyl ester group, into the title ganglioside 1 in good yield.