Efficient Synthesis of the Disialylated Tetrasaccharide Motif in N-Glycans through an Amide-Protection Strategy

A disialylated tetrasaccharide, Neu5Ac(alpha 2,3)Gal(beta 1,3)[Neu5Ac(alpha 2,6)] GlcNAc (1), which is found at the termini of some N-glycans, has been synthesized. Compound 1 was obtained through an alpha-sialylation reaction between a sialic acid donor and a trisaccharide that was synthesized from the glycosylation of a sialylated disaccharide with a glucosaminyl donor. This synthetic route enabled the synthesis of the as-described disialylated structure. A more-convergent route based on the glycosylation of two sialylated disaccharides was also established to scale up the synthesis. Protection of the amide groups in the sialic acid residues significantly increased the yield of the glycosylation reaction between the two sialylated disaccharides, thus suggesting that the presence of hydrogen bonds on the sialic acid residues diminished their reactivity.