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 bonds. An absolutely overwhelming number of methods toward this end have been devised, however, the vast majority of these have been developed empirically and they are therefore underpinned by very little detailed understanding of mechanism. The thesis of this proposal is that the rationalization and improvement of oligosaccharide is best be brought about by a two pronged approach. One prong is the detailed investigation of the mechanisms of a few of glycosylation reactions with the aim of providing a sound basis for further development. The second prong, which can not be entirely separated from the first, is the careful development of improved methodology, with a focus on the more challenging problems. In the mechanistic prong we will investigate the underlying basis for possible neighboring group participation by esters at positions other than the familiar 2-position. The emphasis will be on the detection of bridging intermediates by chemical and spectroscopic methods. In the synthetic prong we will build on our extensive preliminary results to develop a method for the stereoselective synthesis of sialic acid glycosides, with an emphasis on the 1-glycosides of N-glycolyl neuraminic acid and KDO. We will also develop methods for the synthesis of glycopeptides linked based on the labile glycosyl ester motif.

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 to provide methods for the synthesis of the more challenging classes of glycosidic bond and to display these methods through the synthesis of biologically relevant oligosaccharides and glycopeptides.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM062160-11S1
Application #
8496922
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2000-12-01
Project End
2013-03-31
Budget Start
2011-09-01
Budget End
2013-03-31
Support Year
11
Fiscal Year
2012
Total Cost
$101,678
Indirect Cost
$33,071
Name
Wayne State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
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
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
Dharuman, Suresh; Crich, David (2016) Determination of the Influence of Side-Chain Conformation on Glycosylation Selectivity using Conformationally Restricted Donors. Chemistry 22:4535-42
Dhakal, Bibek; Buda, Szymon; Crich, David (2016) Stereoselective Synthesis of 5-epi-α-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 Aci J Org Chem 81:10617-10630
Buda, Szymon; Crich, David (2016) Oxidative Deamination of N-Acetyl Neuraminic Acid: Substituent Effects and Mechanism. J Am Chem Soc 138:1084-92
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
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
Wen, Peng; Crich, David (2015) Absence of Stereodirecting Participation by 2-O-Alkoxycarbonylmethyl Ethers in 4,6-O-Benzylidene-Directed Mannosylation. J Org Chem 80:12300-10
Adero, Philip O; Furukawa, Takayuki; Huang, Min et al. (2015) Cation Clock Reactions for the Determination of Relative Reaction Kinetics in Glycosylation Reactions: Applications to Gluco- and Mannopyranosyl Sulfoxide and Trichloroacetimidate Type Donors. J Am Chem Soc 137:10336-45

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