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Our programs in this area include the development of novel substrates and the exploitation of native and modified enzymes for organic synthesis. Our synthetic strategy emphasizes a combination of chemical and enzymatic methods, with particular focus on the use of enzymes for stereocontrolled processes.
Major efforts in synthetic carbohydrate chemistry include asymmetric aldol condensations for the synthesis of novel monosaccharides based on aldolases, and stereocontrolled synthesis of oligosaccharides and glycopeptides based on glycosyl transferases. Cloning and overexpression of these enzymes and alteration of their substrate specificity are under way as part of our goals to develop new chemical-enzymatic strategies for practical synthesis of sugar-related substances. Site-directed mutagenesis of proteases, intein-mediated transpeptidation and sugar-assisted ligation for condensation of glycopeptide segments and sugar -assisted glycopeptide ligation have been developed and used in the synthesis of homogeneous glycoproteins.
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Figure 1A. Glycoprotein synthesis. We have developed several chemoenzymatic strategies for the synthesis of glycoproteins in order to study the role carbohydrates play in glycoprotein structure and function. Glycosyltransferases, engineered subtilisins, and self-splicing inteins are the key mediators in the synthesis. (Science (2001) 291, 2344)
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Figure 1B. Sugar-assisted glycopeptide ligation
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Figure 1C. Regeneration of sugar neucleotides for glycosyltranferase-catalyzed synthesis of oligosaccharides on large scales.
Figure 1D. Retrosynthesis of epothilone A and C. A DERA-catalyzed sequential asymmetric aldol addition reaction is employed to make the epothilone precursors. DERA accepts a broad range of acceptor and donor aldehydes in addition to the natural substrates. This transformation of three achiral aldehydes yields pyranoses with two new stereogenic centers. In this sequential reaction, the first aldol product acts as a substrate for the second aldol reaction to give an enantiomerically pure 3,5-dihydroxyaldehyde which then cyclizes to form the stable pyranose, thus driving the reaction toward condensation. Since these 1,3-polyol systems are useful synthons, we have further examined the scope of this enzymatic methodology. Our strategy is to exploit -hydroxyaldehydes as acceptors to generate the products which would cyclize to form stable hemiacetals, thus driving the reaction toward condensation. The hemiacetal could be further oxidized to give a lactone which can be further transformed to other useful synthons. (Angew. Chem. Int. Ed. (2002) 41, 1404)
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