Investigation of Synthesis and Application of Thioglycosides

Carbohydrates are one of the essential biomolecules for all life, having roles in every facet of biology from metabolism to structure to immunity and infection. In chemistry, the construction of oligo-and polysaccharides from their monomers is a persistent challenge due to the inherent complexity of carbohydrates. Continuous effort has been put toward regio- and stereoselective synthesis of glycosidic linkages over the last century, with contemporary work focused on increasing the efficiency with which oligosaccharides can be assembled. One key building block which has arisen is the thioglycoside: installation of an anomeric thioether imparts stability, but in the presence of thiophilic reagents the sugar can become activated to act as a glycosyl donor. Synthesis of thioglycosides can be realised from electrophilic donor moieties or by conjugation of an aglycon to a glycosyl thiol. Chapter one of this thesis provides an introduction to carbohydrate chemistry with a focus on the state of the art in oligosaccharide synthesis. The chapter focuses particularly on the synthesis, activation and applications of thioglycosides both as glycosyl donors and as glycomimetics. Chapter two presents work toward the synthesis of 1,2-cis glycosyl thiols and thioglycosides. Firstly, a copper-mediated epimerisation of the readily available 1,2-trans isomers is developed. The reaction proceeds catalytically and mildly however the conversion to the desired anomer is not high. Further, attempted synthesis of 1,2-cis glycosyl thiols via 1-thioacetates is investigated through thioacetolysis of acylated 1,6-anhydrosugars. Under the conditions studied, the products were either the 1,2-cis O-glycoside or the 1,2-trans S-glycoside, but the desired product was not obtained. Finally, the synthesis of ethyl α-thioglycosides is realised from ring-opening of benzylated 1,6-anhydrosugars of glucose and galactose or through the ethylation of α-glycosyl thiols generated through a metho already developed by the Zhu group. Chapter three explores the synthesis of aryl thioglycosides from glycosyl thiols in a nickel catalysed cross-coupling reaction. Building on work from the Lipshutz group, the reactions are carried out in aqueous micellar media in order to minimise the use of organic solvent, and to accelerate the reaction in what is known as micelle-assisted catalysis. The reaction affords aryl thioglycosides in good yields and tolerates a wide variety of aryl and heteroaryl groups without the need for protection of reactive substituents such as amines or alcohols. Importantly, the reaction does not affect anomeric stereochemistry, allowing the facile synthesis of 1,2-cis aryl thioglycosides from the parent glycosyl thiol. Chapter four explores a new route to the synthesis of superarmed thioglycoside donors which can be used in one-pot, chemoselective glycosylation reactions. Direct thioglycosidation of the parent orthoester provides convenient access to the superarming protecting group pattern and 1,2-trans stereochemistry. Use of tris-(pentafluorophenyl) borane as the acid promoter provided an expedient reaction and minimised side product formation. It was attempted to demonstrate the utility of the superarmed donors in the one-pot synthesis of the trisaccharide portion of Saikosaponin C, however only a disaccharide has been realised to date.