Scheme 11 The Ogawa synthesis of the HA tetrasaccharide with glucuronic acid at the reducing end.

phenyl group into the trichloroacetimidate gave the glycosyl donor II.33 in 88% yield over two steps. Similarly, glycosylation of II.30 with II.31 under the same conditions produced the corresponding ^(1,4) dimer II.34 in 81% yield. Following this, treatment with tetrakis(triphenylphosphine)palladium ((Ph3P)4Pd) [53] and morpholine unblocked the 3'-OH and produced the disaccharide acceptor II.35 in 88% yield.

Trimethylsilyl triflate promoted coupling of II.33 with II.35 gave, after acid hydrolysis of the isopropylidene, tetrasaccharide II.36 in 77% yield (Scheme 12). Compound II.36 was acetylated, and removal of the levulinoyl groups with hydrazine acetate unmasked the 6-OH on each of the glucuronic acid precursors. A Swern oxidation of the two primary hydroxyl groups was achieved in two steps to give the diacid II.37 in 76% overall yield. Finally, following deacylation of II.37 with methylamine in methanol, selective N-acetylation afforded the target tetrasaccharide II.38.

Using the strategy developed and described by Ogawa and coworkers in the preparation of tetrasaccharides II.20 and II.38, the methodology was expanded to an additional set of HA-related di-, tri-, and tetrasaccharides having N-acetylglucos-amine at the reducing end [54]. For the synthesis of II.39, II.40, and II.41, synthons II.42-II.46 were employed. Imidates II.42 and II.45 are precursors for the d-glu-curonic acid moiety at the nonreducing terminal and internal position, respectively. Similarly, II.43, II.44, and II.46 [52] are precursors for the N-acetyl-d-glucosamine residue (Fig. 2). The preparation of each of the synthons is detailed and fully described by Ogawa and coworkers.

The preparation of disaccharide II.39 is outlined in Scheme 13. Condensation of II.42 with II.43 using TMSOTf as a promoter afforded disaccharide II.47 in 81% yield. Treatment with aqueous TFA followed by acetylation replaced the isopropyl-idene moiety with two acetate groups, and subsequent de-levulinoylation with hy-drazine acetate gave the primary alcohol II.48. A Swern oxidation of the primary

Scheme 12 Deprotection of the HA tetrasaccharide with glucuronic acid at the reducing end.

11.45 11.46

Figure 2 Other HA fragments prepared by Ogawa and coworkers.

11.45 11.46

Figure 2 Other HA fragments prepared by Ogawa and coworkers.

hydroxyl group was carried out in two steps with oxalyl chloride and dimethyl sulfoxide [55], followed by treatment with sodium chlorite [56] to give II.49 in 70% yield. Subsequent treatment with methylamine followed by selective N-acetylation afforded a disaccharide with an O-acetyl group present, indicating that acetylation

Scheme 13 The Ogawa synthesis of the HA disaccharide.

TolO PhthN

0 0

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