A Combined Experimental and Theoretical Study of Chroman‐6‐ol α‐ and β‐ <i>O</i> ‐Glucosides: Dynamic Solution NMR, Solid‐State NMR, Single‐Crystal X‐Ray Diffraction, and Density Functional Theory Calculations

Naturally occurring chromanols, such as α-tocopherol (vitamin E), exhibit diverse biological activities. Their structural complexity, arising from the conformationally labile dihydropyran ring, has prompted extensive research into their conformational behavior. α-Tocopherol O-glycosides are promising vitamin E prodrug candidates, driving research on their synthesis and molecular dynamics (MD). In this work, four chromanyl glucosides were studied. Using crystallography, dynamic nuclear magnetic resonance (DNMR), solid-state NMR (ssNMR), and computational modeling (MD simulations, CASTEP), the conformational effects induced by sugar residues at the C6 position of a vitamin E model compound (2,2,5,7,8-pentamethylchroman-6-ol) in α- and β-orientations were investigated. Despite structural similarities, significant solid-state differences were observed, particularly between the anomers of peracetylated derivative 4, where the α-anomer displayed molecular disorder absent in the β-isomer - suggesting the presence of multiple conformational states in the crystal lattice. Density functional theory calculations confirmed insignificant energy differences (<0.5 kcal/mol) among the four optimized structures of chromanyl 2,3,4,6-tetra-O-acetyl-α-D-glucopyranoside (4α), implying that the coexisting configurations are stabilized by entropy. Gauge-including projector-augmented wave NMR calculations enabled precise ssNMR peak assignments, while MD simulations indicated static crystalline disorder in 4α. This integrated approach provided a detailed structural insight into chromanyl glucosides, advancing understanding of their conformational behavior.