Complex carbohydrates play critical roles in a number of biological processes including, protein folding, cellular adhesion, signaling, and modulating the biological activity of natural products. Despite their importance, very little is understood about the molecular basis of their activity. Research in the Bennett lab is directed at developing new and efficient methods for carbohydrate synthesis, and the application of these methods to developing carbohydrate based therapeutics with novel modes of action. Representative projects include:
1. Reagent Controlled Methods for Stereoselective Carbohydrate Synthesis.
One of the biggest hurdles to carbohydrate synthesis lies in controlling the stereochemical outcome of glycosylation reactions. To address this issue, we are developing new chemical methodologies for the stereoselective (or stereospecific) construction of glycosidic linkages. Traditional approaches to controlling the selectivity of these reactions rely on substrate control, in which the intrinsic diastereochemical information present in the two coupling partners dictates the stereochemical outcome of the reaction. A drawback of this approach is that for new linkages extensive optimization of both the coupling partners and reaction conditions is necessary to obtain productive reactions. To address these issues we are developing reagent controlled approaches to carbohydrate synthesis. In this latter approach it is possible to obtain either anomer (diastereomer) of a glycosidic linkage starting from the same coupling partners, simply by changing the glycosylation promoter. We have demonstrated that this approach is effective in the construction of 2-deoxy-sugars and 1,2-cis-a-linked glycosides, two of the most difficult glycosidic linkages to synthesize using conventional approaches. Ongoing projects include:
- examining the scope and mechanism or our approach
- developing next-generation glycosylation chemistries that can be used by investgators with minimal synthetic training
- the synthesis of complex oligosaccharides and small molecule glycoconjugates.
2. Total Synthesis of Antimicrobial Complex Carbohydrates.
Increasing drug resistance in bacteria coupled with a paucity of new antibiotics is setting the stage for what might well be the greatest public health crisis of the 21st century. As a result, new therapies are necessary to combat drug resistant pathogens. One such compound is saccharomicin B. Isolated by Kong and coworkers, this molecule displayed potent activity against both gram positive and gram-negative pathogens. We are examining the application of our methodologies to the total synthesis of Saccharomicin B, with the long-term goal of establishing a route that is capable of supplying analogs of this potent natural product.