Scheme 20 Preparation of the tetra-, hexa-, and octasaccharides.

sponding acetamides II.88-II.90 in 88, 91, and 92% yield, respectively. Treatment of II.88-II.90 with aqueous acetic acid followed by saponification with aqueous sodium hydroxide afforded the target oligosaccharides II.72-II.74 , as their sodium salts in 80-83% overall yields.

Pursuing our interest in probing the intramolecular hydrogen bonding network and the bond mobilities of the glycosidic linkages in hyaluronan, our group synthesized two complementary HA trisaccharides, II.91 and II.92 (Fig. 3) [61]. These trisaccharides represent the smallest fragments that contain all the structural features of polymeric hyaluronan.

The synthesis of II.91, having V-acetylglucosamine at the reducing end, required the use of monomers II.93, II.94, and II.95 (Scheme 21). Condensation of sulfoxide II.93 and II.94 in the presence of Tf2O produced the corresponding 0(1,3)-disaccharide II.96. Selective ring opening of the 4-methoxybenzylidene with sodium cyanoborohydride and TFA [62] revealed the 4-OH; however, all attempts to gly-cosylate the resulting alcohol with imidate II.95 were unsuccessful. Presumably the steric bulk of the pivaloyl ester at C3 in addition to the low reactivity of the 4-OH precluded the formation of the glycosidic bond. Alternatively, disaccharide acceptor II.97 could be readily obtained from II.96 by conversion of the pivaloyl esters to benzyl ethers followed by regioselective ring opening to reveal the 4-OH. Subsequent glycosylation of II.97 with imidate II.95, using TMSOTf as a catalyst, provided the fully protected trisaccharide II.98 in 86% yield. Reduction of both the trichloro-ethoxycarbonyl (troc) carbamate and the azide and subsequent conversion to the corresponding acetamido groups was carried out in one pot by treatment with cadmium dust in acetic acid/DMF [63], followed by reduction of the azide with thiol acetic acid (Scheme 22). Subsequent treatment with acetic anhydride provided the diacetamido derivative II.99 in 60% yield over three steps. Removal of the ^-meth-oxybenzyl ether followed by oxidation of C6, using a catalytic amount of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) in the presence of sodium hypochlorite [64] (NaOCl), provided the fully functionalized trisaccharide (II.100) in 51% yield over two steps. Finally, hydrogenolysis using Pearlman's catalyst followed by saponification with lithium hydroxide provided the target trisaccharide II.91 in 13 steps and 16% overall yield.

The complementary trisaccharide, II.92, having glucuronic acid at the reducing end, was prepared from monomers II.95, II.101, and II.102 (Scheme 23). Condensation of methyl glycoside II.99 with imidate II.95, using TMSOTf as a catalyst, afforded the corresponding disaccharide II.103 in 93% yield. Saponification of II.103 followed by benzylidenation provided disaccharide acceptor II.104. However, saponification under Zemplen conditions (methanolic sodium methoxide) resulted in the conversion of the troc group to the corresponding methyl carbamate. Consequently, a milder deacetylation method that used a guanidine/guanidinium nitrate solution [65] was adopted, and near-quantitative deacetylation was achieved in 20 min. Condensation of II.104 with the glycosyl donor II.102 with TMSOTf provided the fully protected trisaccharide II.105 in 87% yield.

Reduction of the troc carbamate to the free amine was accomplished with cadmium in AcOH/DMF followed by acetylation to provide II.106. Removal of the ^-methoxybenzyl ether and subsequent saponification yielded the pentaol, II.107 (Scheme 24).

Scheme 21 Preparation of the HA trimer with N-acetylglucosamine at the reducing end.

0 0

Post a comment