SYNTHETIC STUDIES ON SIALOGLYCOCONJUGATES .47. A SYNTHETIC APPROACH TO POLYSIALOGANGLIOSIDES CONTAINING ALPHA-SIALYL-(2-]8)-SIALIC ACID - TOTAL SYNTHESIS OF GANGLIOSIDE GD3

A stereocontrolled, facile total synthesis of ganglioside GD3 is described as an example of a proposed systematic approach to the preparation of gangliosides containing an alpha-sialyl-(2 --> 8)-sialic acid unit alpha-glycosidically linked to O-3 of a D-galactose residue in their oligosaccharide chains. Glycosylation of 2-(trimethylsilyl)ethyl 6-O-benzoyl-, 3-O-benzoyl-, or 3-O-benzyl-beta-D-galactopyranosides, or 2-(trimethylsilyl)ethyl 2,3,6,2',6'-penta-O-benzyl-beta-lactoside (7), 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-nonulopyrano sid]onate (3), using N-iodosuccinimide-trifluoromethanesulfonic acid as a promoter, gave the corresponding alpha glycosides 8 (32%), 13 (33%), 14 (48%), and 17 (31%), respectively. The glycosyl donor 3 was prepared from O-(5-acetamido-3,5-dideoxy-D-glycero-alpha-D-galacto-2-nonulopyranosylonic acid)-(2 --> 8)-5-acetamido-3,5-dideoxy-D-glycero-D-galacto-2-nonulopyranosonic acid by treatment with Amberlite IR-120 (H+) in methanol, O-acetylation, and subsequent replacement of the anomeric acetoxy group with phenylthio. Compound 8 was converted into the methyl beta-thioglycoside via O-benzoylation, replacement of the 2-(trimethylsilyl)ethyl group by acetyl, and introduction of the methylthio group by reaction with methylthiotrimethylsilane. Compound 17 was converted, via O-acetylation, selective removal of the 2-(trimethylsilyl)ethyl group, and reaction with trichloroacetonitrile, into the alpha-trichloroacetimidate, which was coupled with (2S,3R,4E)-2-azido-3-O-benzoyl-4-octadecene-1,3-diol to give the beta-glycoside. This glycoside was easily transformed, via selective reduction of the azido group, condensation with octadecanoic acid, O-deacylation, and hydrolysis of the methyl ester and lactone functions, into ganglioside GD3.