Solution and fluorous synthesis of bioactive carbohydrates: phosphorylated sugars, hyaluronic acid, and isobutyl-C-galactoside

Abstract

<p>Carbohydrates play important roles in biology; however, studies of the bioactivities of carbohydrates clearly fall behind studies regarding nucleic acids and peptides. In this thesis, through the development of new methods, including multi-gram scale approaches to building blocks, amenable to automation for the solution and fluorous-assisted synthesis of complex carbohydrates, we discuss the progress toward solving the obstacles in the synthesis of carbohydrates.</p> <p>A fluorous phosphate protecting group based on halo ethyl protecting groups which can be used as a facile tag for purification and be removed under mild reducing conditions was designed and synthesized. Synthesis of a disaccharide from Leishmania using this fluorous protecting group demonstrated the group's stability to the acidic conditions necessary for glycosylation as well as its orthogonality to several other common protecting groups.</p> <p>Different synthetic strategies for the synthesis of a series of maltotriose phosphate as probes to be used in the study of glycogen storage diseases are presented depending on the position of the phosphate to find a general and efficient synthetic route of the maltose phosphates. The fluorous phosphate protecting group is evaluated in the synthesis of maltotriose phosphates to probe the feasibility and limitations of using this particular new fluorous protecting group.</p> <p>A new synthesis of isobutyl-β-C-galactoside was achieved in 5 steps from galactose in 81% overall yield without any chromatographic separation steps in multigram scale. An optimized microwave-assisted reaction at high concentration was crucial to making the C-glycosidic linkage. The protecting groups have a profound influence of the reactivity of the substrate for the Wittig reaction.</p> <p>Several different synthetic strategies to hyaluronic acid fragments were studied and compared. A new method to install benzyl groups at the 4- and 6-positions on the trichloroacetyl protected glucosamine and at the 2- and 3-positions on glucuronic acid allowed the synthesis of the more electron rich hyaluronic disaccharide building blocks. Using fluorous assisted synthesis, a tetrasaccharide of hyaluronic acid was synthesized. The conditions developed should be readily applicable for future automated syntheses of this class of glycosaminoglycans.</p>