Transformative Methods for the Solid Phase Synthesis of Oligosaccharides

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Transformative Methods for the Solid Phase Synthesis of Oligosaccharides Principal Investigator: Matthew Brichacek, Department of Chemistry, University of Maine ABSTRACT When compared to genomics or proteomics, the systematic study of all glycan structures in a cell (glycomics) has received considerably less attention. However, this is not due to a lack of biological significance; where carbohydrates play an integral role in cell signaling, immune response, microbial pathogenesis, tumor metastasis, and modulation of protein activity. Instead, the knowledge gap is due to the immense complexity of the glycome, consisting of a large number of monosaccharide building blocks that are assembled in numerous regio- and stereochemical combinations. Consequently, natural samples are complex mixtures that prevent isolation of substantial quantities of pure glycans. Moreover, current synthetic methodology to obtain oligosaccharides is substantially less developed than those for oligonucleotides (DNA & RNA) and peptides, for which automated solid-phase protocols exist. Typically, oligosaccharides are constructed in solution one glycosidic linkage at a time by combination of the appropriate, prefunctionalized glycosyl donors and acceptors. These glycosylation reactions are extremely sensitive to the steric and electronic attributes of the substituents and protecting groups on the carbohydrates. Therefore, the chemical synthesis of oligosaccharides is tedious and generally performed only by specialized synthetic carbohydrate chemists. One approach that could circumvent the challenges associated with an intermolecular glycosylation is to pair an efficient intermolecular coupling of the glycosyl donor and acceptor with a subsequent intramolecular rearrangement to produce the desired natural glycosidic linkage. The first step will address the shortcomings in efficiency by utilizing rapid, robust condensation reactions. When the donor and acceptor are linked, an intramolecular rearrangement to form the glycosidic bond will be less sensitive to the nature of the protecting groups of the carbohydrates and will have the potential to be highly stereoselective. By applying this approach to carbohydrate synthesis on a solid phase, glycans with complete sequence and stereochemical control will be readily accessible. The development of a solid-phase synthesis of glycans based on an efficient intermolecular coupling and a stereoselective intramolecular rearrangement could provide ample quantities of well-defined oligosaccharides. The carbohydrates produced would enable investigations of numerous glycan-binding proteins that will provide a molecular level of understanding of glycan-associated disorders, such as inflammation, pathogen infection, and cancer. In addition, this technology would enable scientists from a wide variety of disciplines interested in carbohydrates to acquire the desired molecules without highly specialized synthetic training, as is currently possible for oligonucleotides and peptides.