Deciphering the Mechanism and Stereoselectivity of the [3+2] Cycloaddition Between C-(D-Glucoso)-N-Methyl Nitrone and 1H-Pyrrole-2,5-Dione: A MEDT Investigation

Abstract

In this study, a molecular electron density theory (MEDT) is used to describe the reaaction mechanism and the experimental stereoselctivity of the [3+2] cycloaddition (32CA) reactions of C-(D-glucoso)-N-methyl nitrone 1 and 1H-pyrrole-2,5-dione 2. From the analysis of the global reactivity indices, 2 behave as electrophiles while 1 as nucleophile. Then, Bonding Evolution Theory (BET) reveals that this 32CA reaction takes place via a one-step asynchronous process with the formation of the C–C bond before the O–C one along of both endo and exo pathways. Further, topological ELF and QTAIM analyses confirmed the asynchronous character of the bond formations along with the polarity of the reaction evaluated by the computed GEDT at the TSs. Generally, the endo pathway is both thermodynamically and kinetically favored than the exo one. Finally, using the Distortion/Interaction-Activation Strain, it is shown that the endo/exo selectivity is mostly driven by the differences of 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. This extensive work combines theoretical and computational approaches to clarify the intricate processes of 32CA reactions, offering significant insights into their synthetic applications and possible medicinal benefits.