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ii.3

Scheme 6 The use of a glucuronic acid derivative to synthesize hyalobiuronic acid.

dene compound II.13. Subsequent bromoacetylation of the 3-OH gave the fully protected glycoside donor II.14 in 55% yield over two steps. Glycosyl acceptor II.15 was prepared by benzoylation of methyl 4,6-O-benzylidene-a-d-glucopyranoside, removal of the benzylidene, and selective bromoacetylation at C6 of the resulting diol II.16. Glycosylation of II.15 with II.14 was carried out in the presence of V-iodo-succinamide (NIS) and a catalytic amount of silver triflate (AgOTf), to give the ยก(1,4)-linked disaccharide II.16 in 68% yield (Scheme 8).

The conversion of II.16 into the glycosyl acceptor II.17 was achieved by treatment with thiourea in methanol [48], followed by reinstallation of a bromoacetyl moiety at C6. Alternatively, conversion of II.16 into glycosyl donor II.18 was ef-

11.16 11.15

Scheme 7 Preparation of monomers used in the Warren synthesis of HA.

11.16 11.15

Scheme 7 Preparation of monomers used in the Warren synthesis of HA.

0(0)CCH2Br 11.19

Scheme 8 Warren synthesis of the fully protected HA tetrasaccharide.

fected by treatment with dichloromethylmethyl ether and freshly fused zinc chloride [49]. Donor II.18 proved to be fairly unstable, so after filtration of the insoluble salts, the crude syrup was dried azeotropically with toluene and used immediately in the next step. The target tetrasaccharide II.19 was obtained in 41% yield with silver triflate mediated coupling of II.17 and II.18 in collidine. The anomeric configuration of II.19 was determined by !H NMR coupling constants, which indicated the presence of a single a and three /3 linkages.

Ogawa and coworkers have synthesized a series of hyaluronan fragments ranging from the di- to the tetrasaccharide with both V-acetylglucosamine and glucuronic acid at the reducing ends. The first HA target described was the tetrasaccharide II.20 with V-acetylglucosamine at the reducing end [19]. The strategy employed the use of two glycosyl donors II.21 and II.22, and a glycosyl acceptor II.23 (Scheme 9). Compound II.23 was prepared by glycosylation of donor II.24 with II.25 using trimethylsilyl triflate (TMSOTf) as a promoter to afford 87% of the corresponding disaccharide II.26. De-isopropylidenation followed by acetylation and removal of allyloxycarbonyl (Aloc) group afforded acceptor II.23 in 82% yield over three steps. Condensation of II.23 with donor II.22 in the presence of boron trifluoride etherate (BF3-Et2O) gave the corresponding trisaccharide II.24 in 88% yield (Scheme 10). Deprotection of the allyloxycarbonyl afforded the trisaccharide acceptor II.25. Tri-

11.24 11.25 11.26

Scheme 9 The Ogawa synthesis of the HA tetrasaccharide with N-acetylglucosamine at the reducing end.

CO y

0 0

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