Although glycochemistry has developed in leaps and bounds in the last two decades, the synthesis of a complex oligosaccharide or of a glycoconjugate remains a very challenging albeit critically important task. The difficulties inherent in such syntheses arise because of numerous reasons that center on the complexity of the chemistry when compared to that of oligonucleotide and peptide synthesis. The most important reactions in any oligosaccharide synthesis are the formation of the glycosidic bonds and there exists an absolutely overwhelming number of methods toward this end. Unfortunately, the vast majority of these methods have been developed empirically, are therefore underpinned by very little detailed understanding of mechanism, and have very little generality. The underlying theme of this proposal is that the challenge of the simplification of complex oligosaccharide synthesis is best met by an improved understanding of the mechanisms of glycosidic bond formation, coupled with the development of more efficient, straightforward and general mechanism-based methods. A necessary step toward this goal is the detailed investigation of the mechanisms of glycosylation mechanisms, and accordingly this proposal addresses several issues considered critical to the resolution of this problem. The issues to be addressed include i) the development of cation clock methods for the determination of reaction kinetics in sialic acid and furanoside glycosidic bond formation. ii) The determination of the interplay of the side chain conformation and of protecting groups and their combined influence on glycosylation stereoselectivity. iii) The development of methods for the efficient synthesis of the microbial sialic acids, legionaminic acid and pseudaminic acid, and of their glycosides. iv) The development of novel methods for the synthesis of C5 modified sialic acids by stereocontrolled substitutive deamination.
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. The goal of this project is to provide, through a deeper understanding of reaction mechanism, new and improved methods for the synthesis of glycosidic bonds that will be displayed through the synthesis of biologically relevant oligosaccharides.
|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|
|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|
|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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