Study of silyl protecting groups in anomerisation reactions: Total synthesis of a glycolipid from Plakortis simplex and its mimetics

This thesis deals with anomerisation, which is, in other words, epimerisation at the anomeric centre, usually interpreted as being from the equatorial to the axial anomer. An objective was to enhance the knowledge of this reaction, in particular to gain knowledge about the behaviour of silylated pyranosides towards Lewis acids that promote anomerisation. Gaining a greater understanding of how silyl protection influences reactivity could lead to wider applications of the reaction more generally. The thesis begins with a short introduction to carbohydrate chemistry. This includes a description of two reactions that take place at the anomeric centre, glycosylation and anomerisation. The second chapter focuses on the synthesis of various silylated butyl β-O-D-glucopyranosides. These carbohydrates are then anomerised using a Lewis acid, with the rate of each reactant being determined using NMR spectroscopy. From this NMR study, it is demonstrated that the reactivity depends on structure and how it influences Lewis acid coordination, as well as the inductive effects of the protecting groups and finally on the conformation adopted by the saccharide. The presence of multiple silyl protecting groups, with a focus on TBS and TIPS groups, as well as their precise location is shown to influence conformation and reactivity. Two di-TBS protected glucopyranosides display significant rate enhancements in the presence of SnCl4 which encouraged further exploitation of these protecting group patterns. Based on the reactivity enhancements identified in Chapter 2, a protecting group strategy was thus designed for a disaccharide derived from cellobiose, with a view to investigating its anomerisation (Chapter 3). Synthesis of two silylated cellobiose derivatives is achieved and their behaviour to SnCl4 and TiCl4 investigated. In this latter case the disaccharides were shown to have different conformational preferences to the monosaccharidic butyl glycosides, which may account for different behaviour of these disaccharides to the monosaccharide, where successful anomerisation reactions were not attained. Nevertheless, some interesting products were observed and characterised, including those from a silylated glycosyl azide, which support the endocyclic cleavage mechanism for anomerisation. The fourth and fifth chapter is about simplexide synthesis and includes applications of anomerisation. Simplexides are an important class of glycolipids. It was found recently that they induced expression and release of cytokines and chemokines from human monocytes. It was furtherly proposed that this is CD1d dependent, which could suggest that their mode of action is relatable to the mode of action of α-GalCer to human monocytes, a very important glycolipid. In these two chapters, the synthesis of a natural simplexide and five of its mimetics is achieved. These reaction steps include anomerisation reaction, S-glycosylation, O-glycosylation using the trichloroacetimidate donors, and the Birch reduction for benzyl group cleavage. Their biological activities are described, with some interesting results, which encourage further synthesis of simplexides and their mimetics, including those based on S-glycosides and simpler lipids.

Funder

Science Foundation Ireland

Publisher

NUI Galway

Rights

Attribution-NonCommercial-NoDerivs 3.0 Ireland

cbn

Collections

University of Galway Theses (PhD Theses)