Computational Study on the Conformational Flexibility-Mediated Intramolecular Oxidative Spirocyclization of Procyanidin B4.

Procyanidins, found widely in foods and beverages, are prone to oxidation, yet the chemical structures of their oxidation products and the mechanisms involved remain unclear. Herein, we report that the conformation of procyanidin B4 influences its oxidation products and their stereochemistry. Eight spirocyclized oxidation products were obtained from procyanidin B4 and classified as S - or R -forms based on the configuration of the spiro carbons. The ratios of S - and R -forms derived from the compact and extended rotamers of procyanidin B4, respectively, varied with the solvent. DFT calculations suggested that the four lowest-energy conformers of procyanidin B4 are diverged by interflavan bond rotation and heterocyclic ring inversion. Conformations with an axial-oriented B-ring were estimated as reactive conformations showing proximity between reaction sites on the B- and D-rings. Moreover, the extended rotamer bearing the axially oriented B-ring showed greater stabilization by noncovalent interactions (NCIs), such as OH-π interactions, compared to the counterpart of the compact rotamer. This NCI-based stabilization accounts for a higher production of the R -form despite the predominant presence of the compact rotamer in H 2 O. These findings highlight the conformational effects that bias the stereoselectivity of oxidative spirocyclization in procyanidin B4, advancing our understanding of procyanidin oxidation mechanisms and product stereochemistry.