Mechanism and stereoselectivity of a [3 + 2] cycloaddition involving a glucosyl nitrone: a MEDT study

In this study, Molecular Electron Density Theory (MEDT) is employed to investigate the reaction mechanism and the experimentally observed stereoselectivity of the [3 + 2] cycloaddition (32CA) between C-(D-glucoso)-N-methyl nitrone 1 and 1H-pyrrole-2,5-dione 2. Within the Conceptual DFT (CDFT) framework, 2 behaves as an electrophile, while 1 acts as the nucleophile. Bonding Evolution Theory (BET) analysis reveals that this 32CA reaction proceeds through a one-step asynchronous mechanism, where the formation of the C3-C4 bond occurs before that of the O1-C5 bond along both the endo and exo pathways. This asynchronous nature is further supported by analyses based on the Electron Localization Function (ELF) and the Quantum Theory of Atoms in Molecules (QTAIM), which confirm the absence of new disynaptic basins (V(C3,C4) and V(O1,C5)) and of new covalent bonds, respectively. Overall, the endo pathway is found to be both thermodynamically and kinetically more favorable than the exo pathway. Finally, using the distortion/interaction-activation strain model, we demonstrate that the observed endo/exo selectivity is primarily governed by differences in interaction energies. Moreover, molecular docking analyses revealed that the endo product has considerable binding affinity to the 1CIN protease, indicating its potential as a therapeutic inhibitor. Moreover, drug-likeness evaluations verified that the compounds adhere to Lipinski's rule of five, signifying advantageous pharmacokinetic characteristics.