Synthesis of novel glycolipids and investigation into the anomerisation of selenium glycosides
McDonagh, Anthony W.
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The first section of this thesis describes the synthesis of novel glycosphingolipids with an α-triazole at the anomeric carbon. Glycosphingolipids are amphiphilic molecules containing a carbohydrate head glycosidically linked to a sphingoid base. The α-linked derivatives KRN7000 (α-GalCer) and PBS-59 are of particular interest, due to their ability to stimulate iNKT cells and produce cytokines that can assist against various infections or alleviating the effects of autoimmune diseases. The Murphy group has previously reported the synthesis of α-O, α-SO2 and α-S PBS-59 analogues. Key to the success of each synthesis was a stereoselective anomerisation reaction in forming the α-anomer. These anomerisation reactions are promoted by either TiCl4 or SnCl4 and are successful in generating α-O and α-S-glycosides from the corresponding β-anomer. A more recent development in the Murphy group has illustrated the anomerisation for glycosyl azides. Therefore, chapter two is focused on applying these α-glycosyl azides as intermediates to synthesise new PBS-59 analogues with either a 1,5- or 1,4-triazole linkage. Chapter 3 describes an investigation into the anomerisation of selenium glycosides. There are various procedures in the literature for the synthesis of β-Se-glycosides and a lesser number reported for α-Se-glycosides. It was therefore envisioned that Lewis acid promoted anomerisation could give α-Se-glycosides from the corresponding β-anomer. The anomerisation was successful for galacturonic acid derivatives with TiCl4 as the reaction promoter. To investigate the substrate scope, various alkyl, alkenyl, alkynyl, saccharide and steroid groups were attached to the anomeric selenium atom. The anomerisation was found only to be unsuccessful for 1→4 linked disaccharides. Yields were higher when the reactions were carried out at higher dilution. Increasing the complexity of the aglycon led to the requirement to increase the amount of Lewis acid and/or temperature to ensure reaction completion. The selenium anomerisation was then applied to the first synthesis of selenoglycoside analogues of the potent immunostimulant α-GalCer. Chapter four presents the synthesis of α-Se-GalCer and analogues thereof. Synthetic challenges deemed the initial route involving an azide intermediate to be unsuccessful. However, revising the retrosynthesis to omit the azido gave a successful route to the target glycolipids.
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