Synthesis of hyaluronic acid related di- and tetra-saccharides having a glucuronic acid at the reducing end

The synthesis is reported of 4-methoxyphenyl O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-(1→4)-β-D-glucopyranosyluronic acid (1) and 4-methoxyphenyl O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-(1→4)-O-(β-D-glucopyranosyluronic acid)-(1→3)-O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-(1→4)-β-D-glucopyranosyluronic acid (5), which represent structural elements of hyaluronic acid. 3,4,6-Tri-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopylanosyl trichloroacetimidate (3) was condensed with 4-methoxyphenyl 6-O-levulinoyl-2,3-di-O-p-toluoyl-β-D-glucopyranoside (4) in dichloromethane, using boron trifluoride etherate as a promoter, yielding 4-methoxyphenyl O-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranosyl)-(1→4)-6-O-levulinoyl-2,3-di-O-p-toluo-yl-β-D-glucopyranoside (2). Subsequent delevulinoylation, oxidation, complete deprotection, and N-acetylation gave 1. Coupling of 3-O-allyloxycarbonyl-2-deoxy-4,6-O-isopropylidene-2-phthalimido-β-D-glucopyranosyl trichloroacetimidate (9) with 4, followed by de-allyloxycarbonylation of the obtained disaccharide derivative gave 4-methoxyphenyl O-(2-deoxy-4,6-O-isopropylidene-2-phthalimido-β-D-glucopyranosyl)-(1→4)-6-O-levulinoyl-2,3-di-O-p-toluoyl-β-D-glucopyranoside (8). Demethoxyphenylation and subsequent imidation of 2 afforded O-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranosyl)-(1→4)-6-O-levulinoyl-2,3-di-O-p-toluoyl-α/β-D-glucopyranosyl trichloroacetimidate (7). Condensation of 7 with 8 in dichloromethane, with trimethylsilyl trifluoromethane-sulfonate as a promoter, gave tetrasaccharide derivative 15. Subsequent de-isopropylidenation, O-acetylation, delevulinoylation, oxidation, complete deprotection, and N-acetylation yielded 5.