Chondroitin Sulfate

Chondroitin sulfates occur in tissues attached to proteoglycans and form a family of polysaccharides that differ in the degree and position of sulfation. Cartilage and the intervertebral disc contain the highest concentration: as much as 10% of the wet weight can be due to chondroitin sulfate [66]. Chondroitin sulfate is a repeating copolymer of d-glucuronic acid (GlcUA) and 4-O- or 6-O-sulfated 2-acetamido-2-deoxy-d-galactose (GalNAc). Three different sulfated variants of chondroitin are known: the 4-O-sulfated, the 6-O-sulfated, and the 4,6-di-O-sulfated variants (Fig. 4). Several strategies have been developed and implemented to synthesize various oligomers of chondroitin sulfate. Jacquinet reported the synthesis of the methyl glycosides of chondroitin disaccharides (III.1, III.2, III.7, and III.8), which represent the four possible repeating units of chondroitin 4-O- and 6-O-sulfate [20].

The 4-O-sulfate (III.1) and 6-O-sulfate (III.2) of methyl 2-acetamido-2-deoxy-3-O-(^-d-glucopyranosyluronic acid)-(1,3)-^-d-galactopyranoside were obtained by condensation of glycosyl acceptors III.3 and III.4 with donors III.5 and III.6 (Scheme 25). The corresponding ^(1,4)-linked disaccharides III.7 and III.8 were obtained by condensation of glycosyl donors III.9 or III.10 and III.11 or III.12 with acceptors III.13 and III.14 (Scheme 26). The design of monomer building blocks for sulfated GAGs requires that the 4-OH and 6-OH of the galactosamine unit be orthogonally protected to facilitate regiospecific monosulfation. This resulted in the need for an increased number of protecting group transformations.

Glycosyl acceptors III.3 and III.4, used in the preparation of the ^(1,3)-disac-charides, were obtained from methyl 2-azido-2-deoxy-^-d-galactopyranoside [67]. Selective 3,6-di-O-silylation followed by treatment with benzyl bromide led to the installation of the benzyl ether at C4. Desilylation occurred in situ under the ben-zylation reaction conditions to produce III.15 and subsequent 6-O-acetylation of III.15 with 1-acetylimidazole produced III.3 in 78% yield (Scheme 25). The preparation of III.4, carried out as reported earlier by Jacquinet and Sinay [67], was obtained from III.16 by regioselective ring opening of the isopropylidene to unmask

Glycosyl donors III.5 and III.6 were derived from the corresponding acetylated derivative III.17. Treatment of III.17 with dibutyltin oxide [68] afforded the hemi-

Scheme 23 Preparation of the HA trimer with glucuronic acid at the reducing end.

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