Although glycochemistry has developed in leaps and bounds in the last decade or so, 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 the development of methods for the spectroscopic identification and study of glycosyl oxocarbenium ions, the development of NMR-based kinetic isotope effect methods for the study of glycosylation kinetics, the development of mass spectrometry-based methods for the study of the influence of protecting groups on oxocarbenium ion stability, and the development of improved glycosylation systems based these studies of mechanism.

Public Health Relevance

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 t 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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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Wayne State University
Schools of Arts and Sciences
United States
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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
Dharuman, Suresh; Wang, Yichen; Crich, David (2016) Alternative synthesis and antibacterial evaluation of 1,5-dideoxy-1,5-imino-L-rhamnitol. Carbohydr Res 419:29-32
Dhakal, Bibek; Buda, Szymon; Crich, David (2016) Stereoselective Synthesis of 5-epi-?-Sialosides Related to the Pseudaminic Acid Glycosides. Reassessment of the Stereoselectivity of the 5-Azido-5-deacetamidosialyl Thioglycosides and Use of Triflate as Nucleophile in the Zbiral Deamination of Sialic Acid J Org Chem 81:10617-10630
Amarasekara, Harsha; Crich, David (2016) Synthesis and intramolecular glycosylation of sialyl mono-esters of o-xylylene glycol. The importance of donor configuration and nitrogen protecting groups on cyclization yield and selectivity; isolation and characterization of a N-sialyl acetamide indica Carbohydr Res 435:113-120
Huang, Min; Furukawa, Takayuki; Retailleau, Pascal et al. (2016) Further studies on cation clock reactions in glycosylation: observation of a configuration specific intramolecular sulfenyl transfer and isolation and characterization of a tricyclic acetal. Carbohydr Res 427:21-8
Buda, Szymon; Crich, David (2016) Oxidative Deamination of N-Acetyl Neuraminic Acid: Substituent Effects and Mechanism. J Am Chem Soc 138:1084-92

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