Synthesis of Azasugars Using Enzyme-catalyzed Reaction

 Azasugar is defined as the monosaccharide in which the ring-oxygen is replaced with an imino-group. However, recently, further derivatives of iminocyclitols have also come to be included in this category, e.g., five-membered iminocyclitols. Nojirimycin, mannojirimycin, galactostatin, and their deoxy-derivatives are well-known representatives of azasugars. They are, respectively, potent inhibitors of glucosidases, mannosidases, and galactosidases, and the ionic bond formation between the imino group of azasugars and the carboxylate of glutamine or asparagines in the active sites of these enzymes are attributed to the mechanism of the inhibitory activity.

Since azasugars affect the biosynthetic process of oligosaccharides, a number of synthetic studies have been conducted not only for developing novel researching reagents in biological studies but also for finding promising leading compounds of medicines. The synthesis using enzymatic reaction does not require a protection-deprotection procedure and can be achieved in an aqueous medium at room temperature. Therefore, it is practical even for industrial applications.

The first azasugar synthesis using enzyme reaction was reported by Kinast and Schadel in 1981. They prepared deoxynojirimycin (DNJ) in four steps from D-glucose using dehydrogenase from Gluconobacter oxydans in a key step to oxidize one of four hydroxyl groups selectively .1)

In the 1990’s, Wong et al. established a facile synthetic scheme using aldolase-catalyzed reactions. The aldolases are classified by the enolate substrates used in the catalyzed aldol reaction, and dihydroxyacetone phosphate (DHAP)-dependent aldolases have most often been used in azasugar synthesis.
Fructose-1,6-diphosphate (FDP)-aldolase, a well-known aldolase glycolysis enzyme, is DHAP-dependent and the enzyme-catalyzed reaction was utilized for the synthesis of DNJ and deoxymannojirimycin (DMJ) 2). Wong’s procedure prepared DNJ and DMJ in three steps from the starting material, 3-azido-2-hydroxy-propanal and DHAP. The same synthetic strategy was also applied in the preparation of aza-N-acetylglucosamine. 3) Moreover, usage of fuculose-1-phosphate aldolase instead of FDP-aldolase in the synthetic scheme of DNJ provided deoxygalactostatin. 4)

Recently, Miura et al. reported the synthesis of azasugars with inhibitory activity toward glucuronidase by taking advantage of the L-threonine aldolase-catalyzed reaction, the enolate substrate of which is glycine. 5) This result expanded the utility of this enzymatic aldol reaction in the synthesis of azasugars.

These enzymatic and chemo-enzymatic syntheses of azasugars will become more useful and necessary in the near future, especially in the 21st century with the demand for more effective environmental protection.
Tetsuya Kajimoto (Department of Biotechnology, Tokyo University of Agriculture and Technology)
References (1) G, Kinast M, Schedel Angew. Chem. Int. Ed. Engl. 20, 805, 1981
(2) Nishimura, S-I, Lee, YC: Synthetic Glycopolymers: New Tools for Glycobiology, Structural Diversity and Functional Versatility of Polysaccharides. edited by Dumitryu, Marcel Dekker, Inc. 15, 523-537, 1998
(3) T, Kajimoto KK-C, Liu RL, Pederson Z, Zhong Y, Ichikawa JA, Porco Jr, C-H, Wong J. Am. Chem. Soc. 113, 6187, 1991
(4) T,Kajimoto L,Chen KK-C,Liu C-H,Wong J.Am.Chem.Soc. 113, 678, 1991
(5) M, Fujii T, Miura T, Kajimoto Y, Ida Synlett. in press (2000).
Sep. 15, 2000

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