Keratan Sulfate

Keratan sulfate occurs in two principal forms, keratan sulfate I and keratan sulfate II, which are distinguished by their linkages to the core protein. Keratan sulfate I, found exclusively in the cornea and the oligosaccharide, is linked to protein by an N-glycosylic linkage between N-acetyl-d-glucosamine and l-asparagine [106]. Found in skin, cartilage, and bone, keratan sulfate II differs from the first variant by an O-glycosidic linkage between N-acetyl-d-galactosamine and l-serine or l-threonine [107].

Generally, the length of keratan sulfate chains range from short (5-10 disac-charides), to medium (20-30 disaccharides). Structurally, keratan sulfate differs from the other glycosaminoglycans in that it contains a nonacidic residue. The uronic acid moiety is replaced by a neutral d-galactose residue, thereby simplifying its synthesis by obviating the need for elaboration at C6. Additionally, sulfation can occur at the 6-OH on either the d-galactose or the N-acetylglucosamine residue. In cases of low sulfation, keratan sulfates can have a very low anionic character, attributable to the

IV.55 IV.56

Scheme 47 Synthesis of the galactosamine derivatives.


IV.55 IV.56

Scheme 47 Synthesis of the galactosamine derivatives.

lack of a carboxylate group. The copolymer subunit is internally ß(1,4)-linked between d-galactose and V-acetylglucosamine residues with ß(1,3)-linkages between subunits (Fig. 7).

Ogawa and coworkers have synthesized a tetrasaccharide fragment of keratan sulfate I, V.1 [108]. The target V.1 was derived from the fully protected tetrasaccharide V.2, which was in turn assembled by glycosylations involving key components V.3, V.4, and V.5 (Scheme 49). Starting from the known monomers V.6 [109] and V.7 [110], silver triflate promoted condensation afforded 92% of the allyl disaccharide V.8 (Scheme 50). Deactylation of V.8 was carried out with lithium hydroxide and hydrogen peroxide [111] in tetrahydrofuran to give 91% of the corresponding diol. Subsequent treatment with benzyl bromide in the presence of potassium iodide and silver(I) oxide afforded V.9 in 90% yield. Deallylation of V.9 was achieved with a rhodium catalyst and 1,4-diazbicyclo[2.2.2]octane followed by mercury(II) oxide and mercury(II) chloride in 10% aqueous acetone [112] to give the crude hemiacetal. Acetylation afforded V.10 as a mixture of ß and a anomers (11:1) in 71% overall yield. Chemoselective deacetylation was achieved with hydrazine acetate [113] to afford 73% of the hemiacetal, which was then converted to the ß-imidate V.4 (87%) as described earlier. Glycosylation of V.4 with the known compound V.5 [114] in the presence of BF3OEt2 gave the desired trisaccharide V.11 in 83% yield. Deacetylation of V.11 to the diol followed by treatment with ferf-butylchlorodiphenylsilane [115] and imidazole gave the monosilyl ether V.12 in 78% yield. The final glycosylation step was carried out with imidate V.3 in the presence of BF3OEt2 to afford 48% of the desired tetrasaccharide V.13. De-phthaloylation followed by acetylation gave 63% of V.2. Conversion of the target V.1 from V.2 was achieved as follows: removal of the ^-methoxyphenyl protecting group was carried out with cerium(IV) ammonium nitrate to give the diol. Subsequent desilylation with tetrabutylammonium fluoride afforded triol V.14 in 78% yield. Sulfation of V.14 with sulfur trioxide-triethylamine complex produced 93% of the tri-O-sulfated derivative V.15. Finally, hydrogenolysis (Pd/C) of V.15 provided the tetrasaccharide fragment of keratan sulfate I (V.1) in 92% yield.

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