Syntheses of disaccharides with (1→4)-β glycosidic linkages related to the 4- and 6-sulfates and the 4,6-disulfates of chondroitin

Abstract

The sodium salts of the 6′-sulfate 12, the 4′-sulfate 15 and the 4′,6′-disulfate 17 of benzyl 4- O-(β- d-galactopyranosyl)-β- d-glucopyranosiduronate 10 have been synthesized. Methyl [benzyl 2,3-di- O-benzoyl-4- O-(2,3-di- O-benzoyl-β- d-galactopyranosyl)-β- d-glucopyranosid]uronate ( 9) has been prepared as a key intermediate from benzyl 4′,6′- O-benzylidene-β- d-lactopyranoside ( 2). Protection of 2 at C-6 with the tert-butyldimethylsilyl group, followed by O-perbenzoylation and disilylation, gave benzyl 2,3-di- O-benzoyl-4- O-(2,3-di- O-benzoyl-4,6- O-benzylideneβ- d-galactopyranosyl)-β- d-glucopyranoside ( 7). Oxidation of the 6-position of 7 protocol to be difficult. However, 7 could be converted into the tert-butyl glucuronate 8 using chromium trioxide-pyridine and tert-butanol. Simultaneous hydrolysis of the benzylidene acetal and the tert-butyl ester groups, followed by esterification of the resulting free acid with diazomethane, yielded 9. Compound 9 was directly sulfated with sulfur trioxide-trimethylamine within 12 h to give the 6′-sulfate 11. The 4′,6′-disulfate 16 was accessible by running the reaction under the same conditions for 14 days. The 4′-sulfate 14 was obtained after protecting the 6′-OH group of 9 with benzoyl cyanide to give the 6′-benzoate 13 followed by sulfation under more vigorous reaction conditions. Deesterification of 9, 11, 14, and 16 was achieved by treatment with aqueous sodium hydroxide in tetrahydrofuran to give 10, 12, 15, and 17, respectively.