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The synthesis of several fluorinated disaccharides and the elucidation of their conformation using ¹H and¹⁹F NMR

University of British Columbia

The goal of this project was to synthesize a fluorinated disaccharide as a substrate or inhibitor for a glycosidase enzyme. A substrate analogue with only one strategically positioned fluorine atom could be used to probe such a complex interaction by using ¹⁹F NMR to monitor any changes in chemical shift, line width, and p coupling constants which arise when the analogue binds to the enzyme. Such changes would be more easily observed by using ¹⁹F NMR to monitor the perturbations around the single F nucleus than by monitoring the ¹H NMR because the spectrum in the latter case is much more complex due to the number of protons inherent in both the natural substrate and the enzyme. The compounds 3,4,6-tri-0-acetyl-2-deoxy-2-fluoro-α-D-glucopyranosyl bromide [5] and 2,3-di-0-acetyl-l,6-anhydro-β-D-glucose [2] were synthesized as appropriate starting materials and then coupled in diethyl ether in the presence of Ag₂CO₃, using AgSO₃CF₃ as a catalyst; these are the simple conditions of the well-known Koenigs-Knorr reaction. The coupling of a halosugar bearing a non-participating group at C-2 with an alcohol in low concentration has been shown by many other workers to result in a mixture of a- and 3-linked products, with the former being predominant. In this study, only the a-linked disaccharide 2,3-di-0-acetyl-l,6-anhydro-4-0-(3,4,6-tri-0-acetyl-2-deoxy-2-fluoro-α-D-glycopyranosyl)-B-D-glucopyranose [12] was obtained, the corresponding β-linked disaccharide was not observed in the reaction mixture. This fact suggests that some factor in either the reaction conditions employed or in the nature of the two sugars involved in the coupling was responsible for the exclusive production of only one type of linkage. The α-linked disaccharide [12] was deprotected to give the free sugar 2'-deoxy-2'-fluoro-maltose (4-0-(2-deoxy-2-fluoro-α-D-glucopyranosyl)-D-glucopyranose [14]) which is the C-2' fluorinated analogue of maltose. This compound should be a suitable probe for enzyme systems such as Maltase or α-glycosidase. The proton decoupled ¹⁹F NMR of [14] displayed two distinct resonances separated by 0.1 ppm which could be due to the α and β anomeric forms of that compound. The optical rotations values and the α/β anomeric ratios deduced from the ¹H NMR spectra for maltose and [14] were comparable, suggesting that this may indeed be the case. The synthesis of 4-0-(2-deoxy-2-fluoro-α-D-galacto-pyranosyl)-D-glucopyranose [17] was initiated with the view of using such a compound to study an α-galactosidase system; the partial synthesis of this molecule is also included herein. The conformational aspects of all the sugars synthesized in this work were deduced from ¹H NMR and then confirmed by ¹⁹F NMR and optical rotation. The ¹⁹F NMR spectra of the disaccharides were simple and were shown to provide sufficient information for the deduction of the conformational and configurational aspects of these sugars in the region of interest. This indicated that changes in the region about the fluorine could be monitored using ¹⁹F NMR and that these sugars could thus prove to be valuable probes for the elucidation of enzyme mechanisms.

Text

2010-03-03

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http://hdl.handle.net/2429/21458

Chemistry

University of British Columbia

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