Abstract
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.