Glucose-2,3,4,6-tetraacetate

Submitted by Chester M. McCloskey and George H. Coleman. Checked by C. S. Hamilton, Robert Angler, and Ivan Baumgart. 

A solution of 82.2 g. (0.2 mole) of acetobromoglucose1 (Note 1) in 125 ml. of dry acetone (Note 2) in a 250-ml. flask is cooled to 0° in an ice bath. To the cold solution is added 2.3 ml. of water and then 46.5 g. (0.17 mole) of silver carbonate (Note 3) in small portions in the course of 15 minutes. The mixture is shaken well during the addition and for 30 minutes longer (Note 4). The mixture is then warmed to 50-60° and filtered. The mass of silver salts is washed with 65 ml. of dry acetone (Note 5), removed from the funnel, warmed in a flask with 65 ml. more of acetone, filtered, and washed again on the funnel. 

The combined filtrates are concentrated under reduced pressure in a 500-ml. filter flask (Note 6) until most of the solution is filled with crystals. The mixture is warmed to dissolve the crystals, the solution is poured into a 600-ml. beaker, and an equal volume of absolute ether and a similar volume of ligroin are added. The resulting solution is cooled in a freezing mixture with gentle stirring. The crystals of the tetraacetate form quickly and after 

The silver carbonate should be freshly prepared and finely ground. Silver carbonate can be prepared by the addition of a solution of sodium carbonate (53 g. in 600 ml. of water) to one of silver nitrate (172 g. in 2 1. of water). This is a very slight excess of the silver nitrate. The sodium carbonate solution is added slowly (10 minutes), and the reaction mixture is stirred vigorously with a mechanical stirrer. The silver carbonate is filtered, washed with a little acetone to facilitate drying, and then air-dried. All operations are carried out in dim light. 

At the end of this time, evolution of carbon dioxide should no longer be appreciable. The time required for the reaction depends largely on the agitation of the silver carbonate. In large runs mechanical stirring is required. 

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A critical study of the preparation of the two anomeric 6-desoxy-D-glucose tetraacetates (LXXXIV) from D-glucose has been made by Hardegger and Montavon.70 The final step, namely, the reduction of the two 6-iodo-6-desoxy-D-glucose tetraacetates (LXXXII) in high yield, proved to be particularly difficult and a variety of methods were studied. Highest yields were obtained when LXXXII was allowed to react with thiourea to form the S-substituted isothiuronium iodide (LXXXIII) which was then desulfurized with Raney nickel. In actual practice the 6-iodo derivative was refluxed briefly in amyl alcohol with thiourea and... 

When acetobromoglucose was treated with moist silver oxide, a mixture of bromine-free acetates was formed from which was obtained, besides glucose tetraacetate, a small proportion of a crystalline disaccharide octa-... 

Hoschele62 has recently treated 6-0-trityl-/3-D-glucose tetraacetate with zinc chloride to form tri-0-acetyl-l,6-anhydro-/3-D-glucopyranose. The course of reaction undoubtedly was analogous to that described above for the formation of the latter substance from 1,2,3,4-tetra-0-acety 1-/3-d-glucose.33... 

Later a number of other oligosaccharides of trehalose type were prepared.49 A trehalose, assigned the a, -configuration on the basis of Hudson s rules of isorotation,47 was prepared in 15% yield by treating a toluene solution of D-glucose tetraacetate first with zinc chloride and then with phosphorus pentoxide. 

Ohle s formula essentially expressed the same features as are embodied in the orthoester formulas proposed six years later for this type of sugar derivative. Unlike Helferich and Klein s glucose tetraacetate, this new benzoyl-derivative may very well possess an orthoacid structure, since the slightest alkalinity of the medium causes a rapid rearrangement of the compound into the normal 6-derivative. - On the other hand, the new glucose tetraacetate of Helferich and Klein probably possesses a normal structure, since it is comparatively stable in alkaline medium, in fact, it is obtained from the 1,2,3,4-tetraacetate by the action of dilute alkali. 

Additional monosaccharide derivatives have been involved in biological studies that do not fall into the previously listed chemical categories. Of these, the acetylated monosaccharide derivatives have attracted the highest consideration. In particular, the insulinotropic action of L-glucose pentaacetate has been evaluated in animal and clinical studies [243]. Similarly, the tetraacetate derivative of 2-deoxy-D-glucose has been evaluated because of its cytotoxic effects upon lymphocytes, fibroblasts, and melanoma cells [244]. 2-Deoxy-D-glucose tetraacetate has been shown to display cytostatic and cytotoxic activity in various lines of tumoral cells. It was found to inhibit cell growth and confer chemosensitivity to cisplatin in two lines of human melanoma cells, poorly responsive to cisplatin [245]. 

The attachment and use of enzymes on hydrophilic supports covered with a dense layer of highly hydrophobic groups has been shown by Vita-Invest in recent years [78]. Various lipases were immobilized on Octyl-Sepharose CL-4B, and in certain cases an increase of activity of more than 100 times could be observed. The usefulness of these supported enzymes was demonstrated in first experiments by the regioselective hydrolysis of glucose pentaacetate (57) to glucose tetraacetate with Candida rugosa lipase (Scheme 18). The regioselectivity was found to be pH dependent, and the 2-0-deacylated derivative 58 could be obtained at pH 5, whereas the 6-0-deacylated product 59 was formed at pH 7. 

Scheme 11.22. A representation of a Koenigs-Knorr process. The incoming nucleophile will orient itself p on the glucose tetraacetate because of neighboring group participation by the acetate at C-2. See Koenigs, W. Knorr, E. Chem. Ber., 1901,34, 957 and Stazi, E Pahnisano, G. Turconi, M. Clini, S. Santagostino, M. J. Org. Chem., 1994, 69,1097.

Deoxy-3-fluoro-D-glucose (see Section 11,2), a weak substrate for yeast hexokinase, is phosphorylated enzymically - to give the 6-phosphate 588, which is transformed into 2-deoxy-2-fluoro-D-arabinose 5-phos-phate (589) by lead tetraacetate oxidation. 

Neither has oxidation, with lead tetraacetate, of the sirup obtained by dehydration of the D-galactose condensate VIII so far resulted in isolation of the expected dialdehyde. On the other hand, when the anhydride from the D-glucose condensate (XXXIV) was oxidized with lead tetraacetate, an appreciable amount of dialdehyde (XXXVI) was isolated. This discrepancy in behavior is probably attributable to the trans position of the hydroxyl groups of the anhydride derived from D-galactose as compared with the cis configuration for the anhydride from D-glucose. 

Thioglucobioses (69a) and (70a) were easily prepared from 2-0-triflyl-man-nose tetraacetate (68) and 1-thio-glucoses (8a) or (10b). However, Zemplen 0-deacetylation led to an intractable mixture of compounds. Thus, prior to methoxide treatment, the readily cleavable allyl group was introduced at the anomeric position (Scheme 22) [20] of the acetylated disaccharides (69a) and (70a). Benzyl -thiokojibioside (70c) was also prepared by condensation of (68) and (16a) [29bj. 

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