A series of C-glycosides with bulky aromatic fragments: Synthesis, characterization and computational studies

Abstract
In this work, a multistep synthesis of closely related compounds, namely (2R,3R,6S)-2-(((tert‑butyldimethylsilyl)oxy)methyl)-6-(4-phenoxyphenyl)-3,6-dihydro-2H-pyran-3-ol (8), ((2R,3R,6S)-3‑hydroxy-6-(4-phenoxyphenyl)-3,6-dihydro-2H-pyran-2-yl)methyl pivalate (9) and ((2R,3R,6S)-3‑hydroxy-6-(4-phenoxyphenyl)-3,6-dihydro-2H-pyran-2-yl)methyl benzoate (10), is reported. The obtained compounds 8–10 were characterized by the HRMS data, and by the 1H and 13C{1H} NMR spectroscopy. The crystal structure of compound 10 was elucidated by single-crystal X-ray diffraction and its crystal packing was additionally studied in detail using the Hirshfeld surface analysis. Structural and electronic properties of compounds 8–10 were studied using the DFT-based calculations, which showed similar structures, dipole moments and HOMO energies for all three. Compounds 8 and 9 share similar LUMO energies and band gaps, while compound 10 exhibits a slightly lower LUMO. All compounds are predicted to be strong electrophilic electron acceptors with low electron exchange susceptibility, with compound 10 predicted as the strongest. The HOMO is similarly localized on the 4-phenoxyphenyl fragment, while the LUMO resides on this fragment in compounds 8 and 9 but shifts to the benzoate in compound 10. MEP identifies the carbonyl oxygen as a potential key nucleophile and the hydroxyl hydrogen as a potential key electrophile. Predicted as Toxicity Class 4, all compounds show favorable bioavailability, including high GI absorption and BBB penetration. They are predicted highly active against kinases, prompting in silico evaluation as CDK2 inhibitors – a cancer-critical kinase. Compounds 8–10 are predicted to bind CDK2 with parameters meeting Hit criteria, exhibiting calculated ligand efficiency scores comparable or superior to the known inhibitor Roscovitine.

Author
Rebaz Anwar Omer

DOI
https://doi.org/10.1016/j.molstruc.2026.146126

ISSN
1872-8014

Publish Date: 3-Apr-2026