The Synthesis of Carbohydrates for the Treatment of Disease

In this thesis I investigated two aspects of glycobiology. In the first, I investigated the potential of α-GalCer analogues to be used in cancer immunotherapy. Two 4-deoxy α-GalCer analogues, with either a sphinganine or a sphingosine base, were synthesised using a convergent strategy. The α-GalCer sphinganine derivative was synthesised in 14 steps from D-arabinose, and in an overall 13% yield. The α-GalCer sphingosine analogue was synthesised in 13 steps also in 13% yield. Biological analysis revealed that both 4-deoxy analogues possessed comparable activity to α-GalCer in mice, however demonstrated significantly reduced hNKT cell activity. The reduced activity was attributed to species-specific differences in iNKT cell glycolipid recognition rather than reduced CD1d presentation. From these results we suggest that glycolipids developed for potent CD1d-iNKT cell activity in humans should contain a ceramide base with the 4-hydroxyl present. The second part of this thesis focused on protecting group free methodology for the synthesis of sugar mimetics that have proven potential as glycosidase inhibitors. In this work I developed an efficient, high yielding and diastereoselective strategy for the synthesis of a number of five and six membered azasugars. This strategy utilises two novel reaction methodologies. The first enabled the stereoselective formation of cyclic carbamates from olefinic amines, the transition states controlling the stereoselectivity during this reaction are discussed. The second reaction facilitated the synthesis of primary amines without the need for protecting groups, the scope of this reductive amination methodology is also investigated. The five membered azasugars 1,4-dideoxy-1,4-imino-Dxylitol, 1,4-dideoxy-1,4-imino-L-lyxitol, 1,4-dideoxy-1,4-imino-L-xylitol and 1,2,4-trideoxy-1,4-imino-L-xylitol were prepared in 5 steps, in good overall yields (57%, 55%, 54% and 48% respectively), and without the need for protecting groups. The six membered azasugar DGJ was prepared over six steps in 33% yield using similar methodology. The synthesised compounds were also tested for anti-tubercular activity using a BCG alamar blue assay