Synthesis of a sialyl-α-(2→6)-lactosamine trisaccharide with a 5-amino-3-oxapentyl spacer group at C-1I

As part of a continuing study aimed to achieve improved monoclonal antibodies against carcinoembryonic antigen (CEA) carbohydrate fragments, the synthesis of a sialyl-(2→6)-lactosamine trisaccharide with a 5-amino-3-oxapentyl spacer group at C-1I has been developed. Two different routes to access this target are described. For this purpose 5-azido-3-oxapentyl 6-O-benzyl-2-deoxy-2-phthalimido-β-d-glucopyranoside (4) was selectively β-galactosylated in 81% yield using the crystalline 2,3-di-O-acetyl-4,6-O-benzylidene-α-d-galactopyranosyl trichloroacetimidate as the donor, taking advantage of the bulky phthalimido group at C-2 of 4. On the other hand, galactosylation of the suitable protected acceptor 5-azido-3-oxapentyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-β-d-glucopyranoside with the crystalline 2,3-di-O-acetyl-4,6-O-benzylidene-α-d-galactosyl bromide renders the corresponding disaccharide in a moderate 58% yield. Despite the fact that the first strategy, unlike the second one, requires a hydrazinolysis–acetylation reaction at the disaccharide stage, it was found to be more convenient to access the disaccharide acceptor. Sialylation was performed using a thiophenyl donor under an NIS–TfOH activation procedure in acetonitrile to give a mixture of α and β trisaccharides in 49 and 16% yields, respectively.