Conformational Behavior of D-Lyxose in Gas and Solution Phases by Rotational and NMR Spectroscopies

Understanding the conformational preferences of carbohydrates is crucial to explain the interactions with their biological targets and to improve their use as therapeutic agents. We present experimental data resolving the conformational landscape of the monosaccharide D-lyxose, for which quantum mechanical (QM) calculations offer model-dependent results. This study compares the structural preferences in the gas phase, determined by rotational spectroscopy, with those in solution, resolved by nuclear magnetic resonance (NMR) and molecular dynamics (MD) simulations. In contrast to QM calculations, D-lyxose adopts only pyranose forms in the gas phase, with the alpha-anomer exhibiting both the C-4(1) and C-1(4) chairs (60:40). The predominantly populated beta-anomer shows the C-4(1) form exclusively, as determined experimentally by isotopic substitution. In aqueous solution, the pyranose forms are also dominant. However, in contrast to the gas phase, the alpha-anomer as C-1(4) chair is the most populated, and its solvation is more effective than for the beta derivative. Markedly, the main conformers found in the gas phase and solution are characterized by the lack of the stabilizing anomeric effect. From a mechanistic perspective, both rotational spectroscopy and solid-state nuclear magnetic resonance (NMR) corroborate that alpha <->beta or furanose <-> pyranose interconversions are prevented in the gas phase. Combining microwave (MW) and NMR results provides a powerful method for unraveling the water role in the conformational preferences of challenging molecules, such as flexible monosaccharides.