SYNTHETIC STUDIES ON SIALOGLYCOCONJUGATES .66. FIRST TOTAL SYNTHESIS OF A CHOLINERGIC NEURON-SPECIFIC GANGLIOSIDE GQ1B-ALPHA

A first total synthesis of a cholinergic neuron-specific ganglioside, GQ1b alpha (IV(3)Neu5Ac alpha, III(6)Neu5Ac alpha, II(3)Neu5Ac alpha(2)-Gg(4)Cer) is described. Regio- and stereoselective monosialylation of the hydroxyl group at C-6 of the GalNAc residue in 2-(trimethylsilyl)ethyl O-(2-acetamido-2-deoxy-3,4-O-isopropylidene-beta-D-galactopyranosyl)-(1-->4)-O-(2,6-di-O-benzyl-beta-D-galactopyranosyl)-(1--4)-O-2,3,6-tri-O-benzyl-beta-D-glucopyranoside (4) with methyl (phenyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-thio-D-glycero-D-galacto-2-nonulopyranosid)onate (5), and subsequent dimericsialylation of the hydroxyl group at C-3 of the Gal residue with methyl [phenyl 5-acetamido-8-O-(5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-alpha-D-galacto-2-nonulopyranosylono-1',9-lactone)-4,7-di-O-acetyl-3,5-dideoxy-2-thio-D -glycero-D-galacto-2-nonulopyranosid]onate (7), using N-iodosuccinimide (NIS)-trifluoromethanesulfonic acid (TfOH) as a promoter, gave the desired hexasaccharide 8 containing alpha-glycosidically-linked mono- and dimeric sialic acids. This was transformed into the acceptor 9 by removal of the isopropylidene group. Condensation of methyl O-(methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-alpha-D-galacto-2-nonulopyranosylonate)-(2-->3)-2,4,6-tri-O-benzoyl-1-thio-beta-D-galactopyranoside (10) with 9, using dimethyl(methylthio)sulfonium triflate (DMTST) as a promoter, gave the desired octasaccharide derivative 11 in high yield. Compound 11 was converted into alpha-trichloroacetimidate 14, via reductive removal of the benzyl groups, O-acetylation, removal of the 2-(trimethylsilyl)ethyl group, and treatment with trichloroacetonitrile, which, on coupling with (2S,3R,4E)-2-azidp-3-O-benzoyl-4-octadecene-1,3-diol (15), gave the beta-glycoside 16. Finally, 16 was transformed, via selective reduction of the azido group, coupling with octadecanoic acid, O-deacylation, and hydrolysis of the methyl ester group, into the title ganglioside 18 in good yield.