The synthesis of mono- and difluorinated 2,3-dideoxy-d-glucopyranoses

The synthesis of 2,3-dideoxy-2,3-difluoro-d-glucose and 2,3-dideoxy-3-fluoro-d-glucose is reported in, respectively, 5 and 6 steps from d-glucal, using a fluorination strategy

The synthesis of fluorinated carbohydrates and fluorinated cyclohexanols

Carbohydrates are central to many fundamental processes. However, their interactions to proteins are characterized by low binding affinity. An attractive strategy to improve this affinity is polyfluorination of carbohydrates. This thesis describes the synthesis and extensive NMR characterisation of monoand difluorinated 2,3-dideoxysugars in which a sugar (CHOH)(CHOH) section was replaced with the more hydrophobic CH2CHF, CH2CF2 and CHFCHF groups. An important consequence of sugar fluorination is that the hydrogen bond properties of the adjacent alcohol group(s) are modified. Part of this thesis describes the synthesis of a number of fluorinated cyclohexanol and benzyl alcohol derivatives as probes to investigate the influence of fluorination on the alcohol hydrogen bond donating capacity

Influence of fluorination on the conformational properties and hydrogen-bond acidity of benzyl alcohol derivatives

The effect of fluorination on the conformational and hydrogen-bond (HB)-donating properties of a series of benzyl alcohols has been investigated experimentally by IR spectroscopy and theoretically with quantum chemical methods (ab initio (MP2) and DFT (MPWB1K)). It was found that o-fluorination generally resulted in an increase in the HB acidity of the hydroxyl group, whereas a decrease was observed upon o,o?-difluorination. Computational analysis showed that the conformational landscapes of the title compounds are strongly influenced by the presence of o-fluorine atoms. Intramolecular interaction descriptors based on AIM, NCI and NBO analyses reveal that, in addition to an intramolecular OH???F interaction, secondary CH???F and/or CH???O interactions also occur, contributing to the stabilisation of the various conformations, and influencing the overall HB properties of the alcohol group. The benzyl alcohol HB-donating capacity trends are properly described by an electrostatic potential based descriptor calculated at the MPWB1K/6-31+G(d,p) level of theory, provided solvation effects are taken into account for these flexible HB donors

Observation on how intramolecular hydrogen bonding of alcohol with fluorine affects its intermolecular hydrogen bonding with acceptors

248th National Meeting of the American-Chemical-Society (ACS), San Francisco, CA, AUG 10-14, 2014International audienc

Effect of fluorine introduction on hydrogen bond donating capacity of alcohols

248th National Meeting of the American-Chemical-Society (ACS), San Francisco, CA, AUG 10-14, 2014International audienc

Influence of alcohol beta-fluorination on hydrogen-bond acidity of conformationally flexible substrates

Rational modulations of molecular interactions are of significant importance in compound properties optimization. We have previously shown that fluorination of conformationally rigid cyclohexanols leads to attenuation of their hydrogen-bond (H-bond) donating capacity (designated by pKAHY) when OH⋅⋅⋅F intramolecular hydrogen-bond (IMHB) interactions occur, as opposed to an increase in pKAHY due to the fluorine electronegativity. This work has now been extended to a wider range of aliphatic β-fluorohydrins with increasing degrees of conformational flexibility. We show that the observed differences in pKAHY between closely related diastereomers can be fully rationalized by subtle variations in populations of conformers able to engage in OH⋅⋅⋅F IMHB, as well as by the strength of these IMHBs. We also show that the Kenny theoretical Vα(r) descriptor of H-bond acidity accurately reflects the observed variations and a calibration equation extended to fluorohydrins is proposed. This work clearly underlines the importance of the weak OH⋅⋅⋅F IMHB in the modulation of alcohol H-bond donating capacity

Effects of sugar functional groups, hydrophobicity, and fluorination on carbohydrate–DNA stacking interactions in water

Carbohydrate–aromatic interactions are highly relevant for many biological processes. Nevertheless, experimental data in aqueous solution relating structure and energetics for sugar–arene stacking interactions are very scarce. Here, we evaluate how structural variations in a monosaccharide including carboxyl, N-acetyl, fluorine, and methyl groups affect stacking interactions with aromatic DNA bases. We find small differences on stacking interaction among the natural carbohydrates examined. The presence of fluorine atoms within the pyranose ring slightly increases the interaction with the C–G DNA base pair. Carbohydrate hydrophobicity is the most determinant factor. However, gradual increase in hydrophobicity of the carbohydrate does not translate directly into a steady growth in stacking interaction. The energetics correlates better with the amount of apolar surface buried upon sugar stacking on top of the aromatic DNA base pai