Studies in anomerisation of glycosyl thiols and glycosides

Abstract

The stereoselective generation of 1,2-cis linkages continues to be a substantial challenge in carbohydrate chemistry today. Lewis acid-promoted anomerisation of 1,2-trans linkages offers a facile method to generate 1,2-cis linkages. The primary aim of this thesis was on the development of the anomerisation reaction, focusing on approaches that would improve the rate of reaction and increase selectivity for the desired anomer. The first chapter outlines the importance of carbohydrate chemistry and advances that have been made in anomerisation. The second chapter of this thesis describes the anomerisation of a series of D-xylopyranosides, L-arabinopyranosides and L-fucopyranosides. Elements that led to higher rates of epimerisation were established by a kinetic study using 1H NMR spectroscopy to monitor the anomerisation of the various glycosides under SnCl4-conditions. Crossover experiments were used to confirm that xylopyranosides underwent epimerisation primarily through exocyclic cleavage, as opposed to endocyclic cleavage. The third and fourth chapters of this thesis detail the stereoselective epimerisation of glycosyl thiols. Glycosyl thiols are widely used in stereoselective synthesis of S-glycosides due to their configurational stability. Few methods exist for the stereoselective synthesis of 1,2-cis glycosyl thiols. Their epimerization from 1,2-trans to 1,2-cis thiols was attained using TiCl4, while SnCl4 promoted their axial-to-equatorial epimerization. The formation of a SnCl4-glycosyl thiol complex accounted for the unusual equatorial selectivity obtained. The generation of a 2- phenyl-1,3-oxathiolan-2-ylium cation is thought to somewhat explain the selectivity obtained under TiCl4 conditions. The final chapter outlines the efforts undertook in developing a synthetic route towards a constrained sialylated galactose compound, which has potential as a hemagglutinin inhibitor for influenza. The outbreak of a lethal strain of influenza remains a continual threat and the development of novel inhibitors is vital, as there is widespread resistance in the influenza virus against neuraminidase and M2 ion channel inhibitors. Research focusing on the development of hemagglutinin binding agents is currently limited. This chapter summarises the development of a synthetic pathway towards a novel hemagglutinin inhibitor based on work carried out previously by the Murphy group.