Elucidating the Mechanism and Selectivity of [3+2] Cycloaddition: A DFT and Molecular Docking Investigation of the Reaction of 6-Butoxy-5,6- Dihydro-4H-1,2-Oxazine 2-Oxide with Dimethyl Maleate

Abstract

Abstract The [3 + 2] cycloaddition (32CA) reactions involving 6-butoxy-5,6-dihydro-4H-1,2-oxazine 2-oxide and dimethyl maleate are examined in this study. Molecular electron density theory (MEDT) is applied at the M06-2X/6-311G(d,p) level, coupled with the D3 dispersion correction. The nitrone species are identified as zwitterionic entities through an analysis of the electron localization function (ELF). Conceptual DFT indices are utilized to classify dimethyl maleate as the electrophilic component and the nitrone as the nucleophilic counterpart. The [3 + 2] cycloaddition processes are predominantly governed by kinetic control, as indicated by activation free energies of -23.64 and − 11.42 kcal.mol − 1 for the exo and endo pathways, respectively, aligning with experimental findings. The formation of a pseudoradical center initiates at carbon atoms C3 and C4. A subsequent docking analysis is conducted on cycloadducts 3 and 4 in relation to the main protease of SARS-CoV2 (6LU7), alongside the co-crystal ligand. The results of this analysis reveal that cycloadducts 3 exhibit higher binding energy, while cycloadducts 4 display lower binding energy compared to the co-crystal ligand.