The goal of modern oligosaccharide synthesis is the efficient production of natural and unnatural oligosaccharides, and their mimetics, capable of interfering constructively in disease states. This interference may be brought about by the blocking of oligosaccharide processing enzymes, by disruption of bacterial cell wall biosynthesis, by modulating cell-cell recognition, by enhancing binding and selectivity of drugs to DNA, and by the provision of antigenic oligosaccharides in synthetic vaccines. All of these very desirable processes require the highly efficient synthesis of oligosaccharides. Ultimately it is to be hoped that oligosaccharide synthesis can be developed to a point at which programmable, automated solid phase synthesis is a real possibility. Although oligosaccharide synthesis has developed in leaps and bounds in the last decade or so, this goal is still a long way off. The reasons for this are multiple and reside in the complexity of the chemistry of formation of glycosidic. An absolutely overwhelming number of methods toward this end however, the vast majority have been developed empirically and they are therefore underpinned by very little detailed understanding of mechanism. The main thesis of this proposal is that the ultimate goal of automated oligosaccharide synthesis demands a simplification of the area and that this simplification can best be brought about by a detailed investigation of the mechanisms of a few of the more successful glycosylation reactions. It is hoped that such careful investigations will shed new light on the true nature of glycosylating species and so help standardize methods and conditions. Toward this end a series of investigations are proposed into the mechanism of three important classes of glycosylation reaction, namely the sulfoxide method, the thioglycoside method, and the trichloroacetimidate method. These studies will involve characterization of the actual intermediates following activation, and determination of the molecularity of the actual coupling processes by a determination of secondary alpha- deuterium kinetic isotope effects and, wherever possible, kinetics. Neighboring group participation is of critical importance for controlling stereochemistry in many types of glycosylation, but its understanding lags far behind its level of application. For this reason a similar study of the mechanism of neighboring group participation will also be conducted. Problems of a more methodological nature, while keeping in mind the same overall goal, include a study of the reasons underlying the poor reactivity of N-acetylglucosamine and N-acetylneuraminic acid in glycosylation reactions. It is hoped that an enhanced understanding of the poor reactivity of these species will enable the development of protecting groups and conditions to circumvent it.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Special Emphasis Panel (ZRG1-SSS-B (01))
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Schwab, John M
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University of Illinois at Chicago
Schools of Arts and Sciences
United States
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Liao, Xiaoxiao; Vetvicka, Vaclav; Crich, David (2018) Synthesis and Evaluation of 1,5-Dithia-D-laminaribiose, Triose and Tetraose as Truncated ?-(1?3)-Glucan Mimetics. J Org Chem :
Wen, Peng; Crich, David (2018) Allylic Strain as a Stereocontrol Element in the Hydrogenation of 3-Hydroxymethyl-cyclohex-3-en-1,2,5-triol Derivatives. Synthesis of the Carbasugar Pseudo-2-deoxy-?-D-glucopyranose. Tetrahedron 74:5183-5191
Adero, Philip Ouma; Amarasekara, Harsha; Wen, Peng et al. (2018) The Experimental Evidence in Support of Glycosylation Mechanisms at the SN1-SN2 Interface. Chem Rev 118:8242-8284
Dhakal, Bibek; Crich, David (2018) Synthesis and Stereocontrolled Equatorially Selective Glycosylation Reactions of a Pseudaminic Acid Donor: Importance of the Side-Chain Conformation and Regioselective Reduction of Azide Protecting Groups. J Am Chem Soc 140:15008-15015
Amarasekara, Harsha; Dharuman, Suresh; Kato, Takayuki et al. (2018) Synthesis of Conformationally-Locked cis- and trans-Bicyclo[4.4.0] Mono-, Di-, and Trioxadecane Modifications of Galacto- and Glucopyranose; Experimental Limiting 3JH,H Coupling Constants for the Estimation of Carbohydrate Side Chain Populations and Beyon J Org Chem 83:881-897
Adero, Philip O; Jarois, Dean R; Crich, David (2017) Hydrogenolytic cleavage of naphthylmethyl ethers in the presence of sulfides. Carbohydr Res 449:11-16
Wen, Peng; Crich, David (2017) Blue Light Photocatalytic Glycosylation without Electrophilic Additives. Org Lett 19:2402-2405
Dhakal, Bibek; Bohé, Luis; Crich, David (2017) Trifluoromethanesulfonate Anion as Nucleophile in Organic Chemistry. J Org Chem 82:9263-9269
Popik, Oskar; Dhakal, Bibek; Crich, David (2017) Stereoselective Synthesis of the Equatorial Glycosides of Legionaminic Acid. J Org Chem 82:6142-6152
Dharuman, Suresh; Crich, David (2016) Determination of the Influence of Side-Chain Conformation on Glycosylation Selectivity using Conformationally Restricted Donors. Chemistry 22:4535-42

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