Within the realm of synthetic carbohydrate chemistry, the stereoselective formation of glycosidic bonds is of paramount importance. Efficient manipulation of bond connectivity at the anomeric center opens up new approaches for the synthesis of complex carbohydrates, including the 1,2-cis-2-amino glycosides. These aminosugars make up one of the most important classes of naturally occurring oligosaccharides and glyco-conjugates, which play a crucial role as cell-surface receptor ligands for lectins, antibodies, and enzymes. However, progress toward understanding the specific functions of 1,2-cis-2-aminosugars has been hampered, due to the formidable challenge of obtaining an adequate supply of well-defined glycosides from natural sources. In many cases, high purity 1,2-cis-2-aminosugars can only be obtained by chemical synthesis, which also provides access to structural variants. Although there have been remarkable advances in the synthesis of 1,2-cis-2-amino glycosides, the disadvantages of current methodologies include the use of excess activating agents and unpredictable/poor anomeric selectivity. In this grant application, our goal is to develop a new and innovative strategy for the effective synthesis of 1,2-cis-2-amino glycosides via transition metal-catalyzed a-selective glycosylation (Specific Aim 1). The method that is currently being developed in our group will be broadly applicable and provide products in high yield and with excellent a-selectivity. The successful completion of the proposed method would have broad impact in the carbohydrate field, where catalytic methods for stereoselective glycosylation are still lacking. This transition-metal catalyzed 1,2-cis-2-amino glycosylation methodology will be applied to the synthesis of bioactive carbohydrate targets, including Campylobcter jejuni N-linked glycan (Specific Aim 2) which can be used to block Campylobacter jejuni adherence to human gastric epithelial cells and biding to mammalian lectins, and heparin oligosaccharides which have potent anticoagulant activity and minimal side effect (Specific Aim 3). 1
The goal of this proposal involves the development of a series of new carbohydrate methodologies allowing for the efficient assembly of complex molecules which will be used as new tools in studies of Campylobacter jejuni which has been identified as the most common cause of bacterial diarrhea worldwide and of heparin-induced thrombocytopenia which is associated with heart attack, strokes and cardiovascular- associated death. Results from the proposed research described here provide the information necessary to advance the development of novel therapeutics to prevent human gastrointestinal illness and blood clotting with minimal side effect. 1
