Synthesis and Applications of Biologically Active Carbohydrate Derivatives and Related Compounds

The broad aims of the Grindley research program are to develop tools and methods to use carbohydrates and other oxygen-containing organic compounds in useful ways. This proposal consists of four parts.

The first part involves studying a reaction that is widely used to differentiate among the many hydroxyl groups of carbohydrates, the stannylene reaction. This reaction is widely used because it gives predictable products that can be obtained reliably by both experienced and beginning researchers. A disadvantage of the organotin reagents is their toxicity. Catalytic versions of the reaction are being introduced but there is no general agreement about the mechanism of the reaction and the reasons for the observed regioselectivity. Key questions are: Are the most populated species in solution, the dimers, the reaction intermediates, or are monomers?; How do added nucleophiles influence the reaction mechanism and regioselectivity? Experiments are proposed to answer these questions, to expand the set of reactions that are possible catalytically, and to improve regioselectivity.

The second part proposes studying trichloroethylidene acetals as a way to access furanose sugars. Reaction of sugars with chloral and acid always yield 1,2-O-trichloroethylidene-furanoses, a potential route to furanose derivatives. We propose to make the synthesis of these derivatives greener, by using stoichiometric chloral rather than using chloral as the solvent, and to investigate improved methods for the removal of these acid-stable acetals.

Thirdly, we propose to investigate glycolipid immunology, an emerging area, through investigation of the antigenic glycolipids, BbGL1 and 2, of Borrelia burgdorferi, the bacteria that cause Lyme disease. We would attempt to find more antigenic derivatives by extensive modification of the BbGL1 structure and by modelling studies of the CD1-glycolipid complexes and of the terniary CD1-glycolipid-T-cell receptor complexes. We would establish which of the CD1 subtypes are involved in recognition of BbGL1 by binding and modelling studies.

Multivalency are been shown to be critical for obtaining protein-carbohydrate binding in a way that influences biological events. In the fourth section, we propose to investigate two new ways to obtain multivalency, both of which are designed to produce dilute concentrations of binding ligands that are highly concentrated in small areas, consistent with achieving strong binding to the widely spaced carbohydrate receptors on bacteria and viruses. It is proposed to do this by synthesizing dendronized polysaccharides and dendronized polymers, where the dendrons would provide the high local concentrations of carbohydrate ligands. These polymers should have good water solubility.