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Scheme 25 The Jacquinet synthesis of the 4- and 6-O-sulfated chondroitin disaccharides.

Benzyl Penicillin

111.37 111.38

Scheme 26 Azidonitration for the preparation of chondroitin sulfate disaccharides.

111.37 111.38

Scheme 26 Azidonitration for the preparation of chondroitin sulfate disaccharides.

Simultaneous reduction of the benzyl ethers and the azide proved unsatisfactory in the presence of methyl esters. An alternate procedure utilized thioacetic acid to reductively N-acetylate the azide. Thus, treatment of III.18 and III.19 with thioacetic acid afforded the corresponding 2-deoxy-2-acetamido derivatives III.20 and III.21, respectively. Hydrogenolysis followed by sulfation with the sulfur trioxide-tri-methylamine complex gave the corresponding 4- and 6-O-sulfated disaccharides III.22 and III.23. Final saponification of III.22 and III.23 with aqueous sodium hydroxide in methanol gave the target disaccharides III.1 and III.2 in 83 and 86 yield, respectively.

Four different galactosamine imidate donors were designed and used in the preparation of the target 0(1,4)-linked disaccharides. These glycosyl donors, III.9-III.12, were all prepared by azidonitration of d-galactal (Scheme 26). Selective 3,6-di-O-ferf-butyldimethylsilylation of d-galactal followed by treatment with methoxy-ethoxymethyl chloride (MEMCl) and benzyl bromide gave III.24. Azidonitration of III.24 proceeded cleanly, and the product was subsequently converted to the corresponding hemiacetal III.25 with sodium nitrite [69]. The 4-(2-methoxyethoxymethyl) group in III.25 was replaced by an acetate group by treatment with aqueous TFA followed by acetylation. Subsequent l-O-deacetylation with benzylamine [70] gave III.26. Conversion of III.25 and III.26 to the corresponding imidates III.9 and III.10 was achieved in the usual manner.

Similarly, preparation of the 6-O-sulfated galactosamine donors III.11 and

111.12 utilized the selective 6-O-silylation of d-galactal followed by benzylation to afford alcohol III.27. Subsequent treatment with either MEMCl or benzoyl chloride provided the corresponding galactal derivative, III.28 or III.29. Azidonitration followed by hydrolysis to the hemiacetal and conversion into the corresponding tri-chloroacetimidate afforded donors III.11 and III.12.

Glycosyl acceptors III.13 and III.14 were obtained by 6-O-selective chloro-acetylation and ferf-butyldimethylsilylation of methyl 2,3-di-O-benzyl-0-d-glucopy-ranoside, respectively. Glycosylations involving acceptors III.9-nI.12 and donors

111.13 and III.14 were carried out by using BF3Et2O as a promoter and are summarized in Table 2. Most coupling products could be isolated only after deprotection of the 6-OH on the glucose unit. The reported yields for the glycosylations and the stereoselectivity of the (1,4)-linkages are moderate, at best. Lower selectivities observed may be due to the lack of a participating group at C2 on the glycosyl donors. Of the four different disaccharides prepared, only the deprotection/oxidation sequence of disaccharides III.32 and III.34 led to targets III.7 and III.8, respectively. All attempts at removing the methyl ether protecting groups in disaccharides III.31 and III.33 were unsuccessful.

Preparation of the target disaccharide III.7 is described as follows. Transformation of azide III.32 to the ^-acetate III.35 was achieved in 81% yield by sodium

Table 2 Glycosylation Conditions for the Chondroitin Disaccharides

Donor

Acceptor

Solvent

Product

Yield (%)

a/ß Ratio

0 0

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