Chondroitin disaccharides III.56-III.59 were prepared by conversion of the azide in building block III.39 to the acetamide, which was achieved with thioacetic acid. Complete deprotection then afforded the nonsulfated disaccharide III.56. An exchange of the levulinoyl group in III.39 for the pivaloyl group to produce III.60 was utilized for the preparation of the sulfated variants (Scheme 31). Conversion of the azide to the acetamide (III.61) followed by regioselective benzylidene ring opening gave III.62. Subsequent sulfation (71%), saponification, and hydrogenolysis (88% in two steps) gave the target chondroitin 4-sulfate disaccharide (III.57).
The corresponding 6-O-sulfated derivative (III.58) was prepared as follows. Starting from disaccharide III.62, acetylation followed by hydrogenolysis unmasked the 6-OH to give the corresponding alcohol with no acetate migration observed. Subsequent sulfation and saponification afforded III.58 in 87% yield over three steps. Quantitative preparation of the 4,6-di-O-sulfated disaccharide III.59 was achieved by treatment of the diol III.63 with the sulfur trioxide-trimethylamine complex. Alternatively, sulfation of III.62 followed by hydrogenolysis unmasked the 6-OH and subsequent sulfation provided III.59 in 71% yield.
Chondroitin trisaccharides III.64-III.67 were obtained by coupling the disaccharide acceptor III.45 with methyl glucuronate trichloroacetimidate III.68  in the presence of BF3OEt to give the corresponding trisaccharide III.69. The azide was transformed into the corresponding acetamide III.70 by Lindlar reduction followed by acetylation (Scheme 32). Hydrogenation was favored over the use of thioacetic acid as it generally gave higher yields for oligomers larger than the disac-charide. Acid hydrolysis of the benzylidene acetal followed by saponification gave the nonsulfated trisaccharide (III.64). The 4-O-sulfated derivative (III.65) was prepared by reductive ring opening of III.70 to provide the 6-O-benzyl derivative III.71 in 69% yield with formation of 12% of the 4-O-benzylated product. Sulfation of the free 4-OH, saponification, and hydrogenolysis furnished the 4-O-sulfated trisaccharide III.65. The same synthetic strategy used to prepare the 6-O-sulfated disaccharide was applied to the corresponding trisaccharide. Acetylation of III.71 followed by hydrogenolysis afforded the primary alcohol III.72. Subsequent sulfation and saponification gave the target 6-O-sulfated trisaccharide III.66. The 4,6-di-O-disulfate (III.67) could not be obtained directly from the 4,6-diol. Consequently, hydrogenolysis of the 4-O-sulfated derivative III.73 unmasked the 6-OH, which was then sulfated to give target III.67 after saponification. The prolonged reaction time required for O-sulfation of the 6-OH (6 days, 71% yield) was attributed to the electronegativity of the neighboring sulfate.
Tetrasaccharide derivatives (III.74-III.77 ) incorporate an internal and a terminal d-galactosamine residue with varying degrees of sulfation. The strategy for selective sulfation was identical to that used for the di- and trisaccharides. The tetra-saccharides were derived from the fully protected derivatives III.46 (Scheme 33). Reduction of the azides to the corresponding acetamides with thioacetic acid gave III.78 in 43% yield. As with the trisaccharides, higher yields were obtained when the azide was reduced in two steps: hydrogenation with Lindlar catalyst followed by acetylation (60% yield). Saponification of III.78 (88%), followed by hydrogenolysis (68%), gave the target nonsulfated tetrasaccharide III.74. The 4-O-sulfated derivative III.75 was obtained by first converting the levulinoyl ester into the corresponding privaloate, followed by regioselective opening of the benzylidene to give the desired secondary diol (III.79) in 65% yield, as well as a small amount of the 4-O-benzylated
Scheme 31 The disaccharide synthesis.
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