Figure 1 Polymeric HA, its degradation product, and methyl hyalobiuronic acid.
useful antitumor drug . HA is found in bacteria and can be produced in larger quantities than can be achieved by extraction methods .
Historically, the chemical preparation of small HA fragments aided in the structure elucidation of HA degradation products as well as providing units that can be used to probe the biological pathways and activities of HA. A step toward this goal was the synthesis of an HA disaccharide fragment, hyalobiuronic acid, which was repeatedly isolated as a degradation product of acid hydrolysis . Identified as 2-deoxy-2-amino-3-O-(^-d-glucopyranosyluronic acid)-a-d-glucose (II.2), the compound most likely existed as a mixture of a and /3 anomers. The chemical preparation of II.2, reported simultaneously by Flowers and Jeanloz  and Takanashi et al.  in 1962, employed mercury-mediated Koenigs-Knorr glycosylation methodology.
Subsequently, Jeanloz and Flowers reported the synthesis of methyl hyalobi-uronic acid (II.3) by condensation of 1-bromo-2,3,4,6-tetra-O-acetyl-a-d-glucopy-ranoside (II.4) with II.5 in the presence of mercuric cyanide [Hg(CN)2], followed by deacetylation to produce II.6 (Scheme 5). Removal of the 4,6-O-benzylidene with acid afforded II.7, methyl 2-acetamido-2-deoxy-3-O- (¡-d-glucopyranosyl)-a-d-glu-copyranoside, in 35% yield. Attempts to selectively oxidize C6 of the d-glucose moiety in II.7 to the corresponding carboxylic acid with platinum oxide proved unsuccessful.
The inability to effect selective oxidation of C6 on the d-glucose moiety led to the use of II.8, methyl(2,3,4-tri-O-acetyl-a-d-glucopyranosyl uronate) bromide, as an alternate glycosyl donor (Scheme 6). Glycosylation with II.5 in the presence of Hg(CN)2 afforded disaccharide II.9 in 54% yield, and subsequent removal of the benzylidene followed by acetylation gave the hexa-acetyl derivative II.10. Treatment of II.10 with lithium borohydride afforded 54% of a product identical to II.3.
Warren and coworkers reported the synthesis of the protected tetrasaccharide of HA with a a-d-glucose derivative at the reducing end . Their strategy utilized the glycosylation of two disaccharides, which were both derived from a common disaccharide precursor. Starting from the known glycosyl bromide II.11 , silver triflate-collidine mediated coupling of 4-penten-1-ol in CH2Cl2 afforded the acety-lated pentenyl glycoside II.12 (Scheme 7). Deacetylation under Zemplen conditions followed by treatment with 2,2-dimethoxypropane furnished the 4,6-O-isopropyli-
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