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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062160-13
Application #
8639575
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2000-12-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
13
Fiscal Year
2014
Total Cost
$301,695
Indirect Cost
$93,695
Name
Wayne State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
McCormick, Susan P; Kato, Takayuki; Maragos, Chris M et al. (2015) Anomericity of T-2 toxin-glucoside: masked mycotoxin in cereal crops. J Agric Food Chem 63:731-8
Mandhapati, Appi Reddy; Rajender, Salla; Shaw, Jonathan et al. (2015) The isothiocyanato moiety: an ideal protecting group for the stereoselective synthesis of sialic acid glycosides and subsequent diversification. Angew Chem Int Ed Engl 54:1275-8
Moume-Pymbock, Myriame; Furukawa, Takayuki; Mondal, Sujit et al. (2013) Probing the influence of a 4,6-O-acetal on the reactivity of galactopyranosyl donors: verification of the disarming influence of the trans-gauche conformation of C5-C6 bonds. J Am Chem Soc 135:14249-55
Kancharla, Pavan K; Crich, David (2013) Influence of side chain conformation and configuration on glycosyl donor reactivity and selectivity as illustrated by sialic acid donors epimeric at the 7-position. J Am Chem Soc 135:18999-9007
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Crich, David; Rahaman, Md Yeajur (2010) Dihydro-3-(triphenylphosphoranylidene)-2,5-thiophendione: A Convenient Synthon for the Preparation of Substituted 1,4-Thiazepin-5-ones and Piperidinones via the Intermediacy of Thioacids. Tetrahedron 66:6383-6390
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Crich, David; Li, Ming; Jayalath, Prasanna (2009) Dimethylthexylsilyl 2-acetamido-3-O-allyl-2-deoxy-6-O-(4-methoxybenzyl)-beta-D-glucopyranoside, dimethylthexylsilyl 3,4,6-tri-O-benzyl-beta-D-mannopyranosyl-(1-->4)-2-acetamido-3-O-allyl-2-deoxy-6-O-(4-methoxybenzyl)-beta-D-glucopyranoside, and dimethylth Carbohydr Res 344:140-4

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