A Combined Experimental and Theoretical Study of Chroman‐6‐ol α‐ and β‐ O ‐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.