Toward a Better Understanding of Factors Controlling Selectivity in Deoxy Sugar Oligosaccharide Synthesis

With the support of the Chemical Synthesis Program in the Division of Chemistry, Professor Clay S. Bennett of Tufts University is developing methods for controlling the synthesis of deoxy sugars. Deoxy sugars are an important component of many biologically active natural products but are only available through their chemical synthesis. Professor Bennett is developing new chemistry to synthesize deoxy sugars with control over their three-dimensional structure. His lab is studying the mechanisms of the transformations being developed, so that the reactions can be more generally applied to the synthesis of other classes of compounds including naturally occurring deoxy sugars. This research has the potential to impact a number of academic and industrial laboratories including those in the agricultural, chemical, and pharmaceutical industries. The project will provide excellent training in synthetic and carbohydrate chemistry for undergraduate and graduate students, and will also be used to introduce high school chemistry students to organic chemistry through outreach and by having high school students visit and run experiments at Tufts. Under this award, the Bennett group will expand upon an approach to the synthesis of deoxysugars that involves activating sugar hemiacetals as either glycosyl sulfonates or tert-butyldimethylsilyl glycosides (TBS glycosides). The glycosyl sulfonates react directly with oxygen nucleophiles to generate new glycosidic linkages with high levels of stereoselectivity. Similarly, the TBS glycosides can be activated with Lewis Acids to react with nucleophiles to afford products also with high levels of selectivity. Importantly, these two methods are complementary to one another: the glycosyl sulfonate approach is being used to create one diastereomer of a particular glycosidic linkage, while the TBS glycoside chemistry is being used to create the other. The Bennett research team will apply these reactions to the synthesis of a number of oligosaccharides to investigate the generality of the method, and they plan to explore the mechanism of the reactions using primary kinetic isotope experiments with eye toward establishing the SN1 vs. SN2 nature of these reaction manifolds. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.