Syntheses of the tumor associated carbohydrate antigen Lewis a Lewis x fragments and one step deprotections in Birch reduction conditions

Chemical syntheses of two Lex trisaccharide derivatives, a tetrasaccharide and a linear trisaccharide are described. All the oligosaccharides synthesized belong to the LeaLex fragments family.;After 14 steps starting from D-glucosamine hydrochloride, tetrasaccharide methyl 2-acetamido-2-deoxy-3-O-alpha-L-fucopyranosy1-4- O-[3-O- (2-deoxy-2-acetamido-beta-D-glucopyranosyl)-beta- D-galactopyranosyl]-beta- D - glu- copyranoside has been successfully synthesized in 2% yield. The glycosylation method employing a trichloroacetimidate donor and BF3·Et 2O has proved useful for the glycosylation at OH-4 of the N -acetylglucosamine acceptor. Using mild basic conditions, a selective dechloroacetylation between two different chloroacetyl groups was achieved to afford the desired disaccharide acceptor. Glucosaminylation (catalyzed by TMSOTf) of this acceptor with a trichloroacetamido glycosyl trichloroacetimidate donor delivered the corresponding trisaccharide. The chloroacetyl group of this trisaccharide was selectively removed to deliver the corresponding trisaccharide acceptor. Fucosylation (catalyzed by copper (II) bromide and tetrabutylammonium bromide) of this acceptor was achieved by using a thioethyl fucosyl donor. Finally, the desired tetrasaccharide was obtained after deprotection in Birch reduction conditions.;The synthesis of the linear trisaccharide methyl 3-O-[2-deoxy-2-acet- amido-3-O-(beta-D-galactopyranosyl)-beta- D-glucopyranosyl]-beta-D-galactopyrano- side was explored via two routes. In the first route, when a trichloroacetimidate donor was used, galactosylation at OH-3 of the phthalimido glucosamine acceptor delivered an orthoester compound in 91% yield when TMSOTf was used in small amount. Increasing the amount of TMSOTf delivered the desired disaccharide but the yield was just moderate (around 60%). Therefore the first route was abandoned. In the second route, the protected trisaccharide was successfully achieved by two glycosylations: glucosaminylation (catalyzed by TMSOTf) at OH-3 of the tribenzoate galactose acceptor with a trichloroacetamido glycosyl trichloroacetimidate donor delivered the corresponding disaccharide. This disaccharide was converted to the corresponding acceptor which was then glycosylated (catalyzed by BF3·Et2O) with a galactosyl trichloroacetimidate donor. Finally, the desired free sugar was obtained (4%, 14 steps) after deprotection in Birch reduction conditions.;Starting from D-glucosamine hydrochloride, the 6-aminohexyl Le x trisaccharide has been successfully synthesized (4%, 12 steps) as well as the n-hexyl Lex derivative (6%, 11 steps). Birch reduction conditions have been successfully adopted as a simple one step deprotection method. Many protecting groups (e.g. benzyl, benzylidene, benzoyl, azido, acetyl, chloroacetyl and trichloroacetamido groups) can be removed or reduced in the Birch reduction conditions in one pot. It was also found that Birch reduction conditions would lead to desulfurization of thioacetate compounds.