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Towards the Automated Synthesis of Carbohydrates
2022, Kapito, Gaffney, 0000-0002-5699-0045
The research described in this thesis deals with the use of MIDA-boronate type purification tags in the synthesis of monosaccharide building blocks. The MIDA boronate tag was successfully installed onto a carbohydrate scaffold utilizing a visible light mediated photocatalytic thiol-ene click methodology using glycosyl thiols, an alkene bearing the MIDA moiety, and 9-mesityl-10-methylacridinium tetrafluoroborate as catalyst (1 mol%). This allowed access to MIDA-tagged monosaccharides in good to excellent yields. The MIDA tag was able to influence the behaviour of the monosaccharides on silica as desired and the MIDA-tagged monosaccharides were purified using a “catch-and-release” procedure. Following attempts at deprotections (O-deacetylation, O-debenzylation), it was found that the MIDA tag was unstable under these conditions. However, further stability studies determined that the MIDA tag was stable to a range of protecting group conditions (Fmoc protection/deprotection, benzoyl protection, and Lev protection). The MIDA-tagged donors were also successfully used in glycosylation under standard activation conditions. A tetramethylated variant of the MIDA tag (TIDA) was also synthesised on gram-scale. This facilitated access to a TIDA-bearing thiol tag which was successfully installed onto a range of monosaccharides using the thioglycosylation reaction under BF3·OEt2 activation. This new tag was found to be compatible with a range of protecting group manipulation conditions: acetyl deprotection, benzoyl protection, Fmoc protection, Lev protection, silyl protection, and benzylidene protection/regioselective ring-opening. This enabled the synthesis of monosaccharide building blocks bearing the TIDA tag. The TIDA tag was able to influence the behaviour of the monosaccharides on silica as desired and the TIDA-tagged monosaccharide intermediates were purified using a “catch-and-release” procedure. The reactivity of TIDA-tagged thioglycoside donors was tested and found to be comparable to S-ethyl donors, giving similar yields and stereochemical outcome. The TIDA-tagged monosaccharides were also utilised in the construction of a trisaccharide. The TIDA-thiol tag was successfully recovered following glycosylation.