A synthetic approach to polysialogangliosides containing α-sialyl-(2 → 8)-sialic acid: total synthesis of ganglioside GD 3

Abstract

A stereocontrolled, facile total synthesis of ganglioside GD 3 is described as an example of a proposed systematic approach to the preparation of gangliosides containing an α-sialyl-(2 → 8)-sialic acid unit α-glycosidically linked to O-3 of a d-galactose reesidue in their oligosaccharide chains. Glycosylation of 2-(trimethylsilyl)ethyl 6- O-benzoyl-, 3- O-benzoyl-, or 3- O-benzyl-β- d-galactopyranosides, or 2-(trimethylsilyl)ethyl 2,3,6,2′,6′-penta- O-benzyl-β-lactoside ( 7), with methyl [phenyl 5-acetamido-8- O-(5-acetamido-4,7,8,9- tetra- O-acetyl-3,5-dideoxy- d- glycero-α- d- galacto-2-nonulopyranosyl-ono-1′,9-lactone)-4,7-di- O-acetyl-3,5-dideoxy-2-thio- d- glycero- d- galacto-2-nonulopyranosid]onate ( 3), using N-iodosuccinimide-trifluoromethanesulfonic acid as a promoter, gave the corresponding α glycosides 8 (32%), 13 (33%), 14 (48%), and 17 (31%), respectively. The glycyl donor 3 was prepared from O-(5-acetamido-3,5-dideoxy- d- glycero-α- 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 β-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 α-trichloroacetimidate, which was coupled with (2S,3R,4E)-2-azido-3 O-benzoyl-4-octadecene-1,3-diol to give the β-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 GD 3.