Probing deoxysugar conformational preference: A comprehensive computational study investigating the effects of deoxygenation.

Deoxysugars are intrinsic components in a number of antibiotics, antimicrobials, and therapeutic agents that often dictate receptor binding, improve efficacy, and provide a diverse toolbox in modifying glycoconjugate function due to an extensive number of unique isomers and inherent conformational flexibility. Hence, this work provides a comprehensive examination of the conformational effects associated with deoxygenation of the pyranose ring. Both the location and degree of deoxygenation were evaluated by interrogating the energetic landscape for a number of mono- and dideoxyhexopyranose derivatives using DFT methods (M05-2X/cc-pVTZ(-f)). Both anomeric forms and in some cases, the alternate chair form, have been investigated in the gas phase. As was documented in a preceding study, variation of the C-6 oxidation state has been shown to affect the anomeric preference of select glucose stereoisomers. Similar results were also observed for several deoxysugar isomers in this work, wherein the alternate anomer was favored upon reduction to the 6-deoxyhexose derivative or oxidation to the hexonic acid. Additionally, comparison of relative Gibbs free energies revealed C-3 deoxygenation imparts greater instability compared to C-2 or C-4 deoxygenation, as indicated by an increase in free energy for 3-deoxysugars. A polarizable continuum solvation model was also applied to empirically validate theoretical results for several deoxysugars, wherein good agreement with both carbon (σ = 1.6 ppm) and proton (σ = 0.20 ppm) NMR shifts was observed for the majority of isomers. Solvated and gas phase anomeric ratios were also calculated and compared favorably to reported literature values, although some discrepancies are noted.

Effects of varying the 6-position oxidation state of hexopyranoses: a systematic comparative computational analysis of 48 monosaccharide stereoisomers.

Knowledge of multi-dimensional carbohydrate structure is essential when delineating structure-function relationships in the development of analytical techniques such as ion mobility-mass spectrometry and of carbohydrate-based therapeutics, as well as in rationally modifying the chemical and physical properties of drugs and materials based on sugars. Although monosaccharides are conventionally presumed to adopt the canonical 4C1 chair conformation, it is not well known how altering the substituent identity around the pyranose ring affects the favored conformational state. This work provides a comprehensive and systematic computational comparison of all eight aldohexose isomers in the gas phase with reduction and oxidation at the C-6 position using density functional theory (M05-2X/cc-pVTZ(-f)//B3LYP/6-31G**) to determine the conformational and anomeric preference for each sugar in the gas phase. All 6-deoxyhexose and aldohexose isomers favored the 4C1 chair conformation, while oxidation at C-6 showed a shift in equilibrium to favor the 1C4 chair for ß-alluronic acid, ß-guluronic acid, and ß-iduronic acid. The anomeric preference was found to be significantly affected by a remote change in oxidation state, with the alternate anomer favored for several isomers. These findings provide a fundamental platform to empirically test steric and electronic effects of pyranose substituents, with the goal of formulating straightforward rules that govern carbohydrate reactivity and drive quicker, more efficient syntheses. Graphical abstract A systematic comparative conformational analysis of all eight aldohexose isomers using DFT methods (M05-2X/cc-pVTZ(-f)) reveals changes in anomeric and ring conformational preference upon reduction or oxidation at the C-6 position for several sugars.