A research program devoted to the development of new methods for the synthesis of biologically important complex oligosaccharides and glycoconjugates is proposed. Several new methods for glycosidic bond formation will be developed in this granting period. The first is the establishment of the concept of sulfoxide covalent catalysis in the context of dehydrative glycosylation employing 1-hydroxy glycosyl donors. The second reaction is an oxidative glycosylation reaction employing glycal donors. Through the use of hypervalent l(lll) reagents, we intend to establish C2-acyloxyglycosylation as an efficient glycal assembly process for complex carbohydrate synthesis. Investigations into the scope, mechanism, and stereochemical determinants in these new reactions should lead to a series of powerful glycosylation methods that can be applied to the synthesis of natural and non-natural oligosaccharides that are of importance to biology and human medicine. With the use of our glycosylation methodologies, we are in a unique position to perform the first systematic structure-function studies of QS-21 A, a potent immunostimulatory adjuvant used in more than 80 recent and ongoing vaccine clinical trials. Following our recent chemical synthesis of QS-21A, the design and synthesis of several structurally modified/truncated analogs of QS-21A is proposed to generate more potent adjuvants and to probe its unkown mechanism of immunostimulatory activity through SAR studies. We also propose to develop a new strategy for the site selective covalent conjugation of complex carbohydrates with peptides. The efficient synthesis of this class of glycoconjugates will allow for the preparation of diverse glycosylated mucin fragments not only for fundamental studies on mucin glycopeptide architecture, but also for the design of more hydrolytically stable mucin-associated subunit antigens for vaccine therapy. The full development of this research program will expand the repertoire of available carbohydrate synthesis methods and facilitate access to complex carbohydrate immunostimulants for immunological evaluation, mechanistic investigation, and clinical application.
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