Insights into the mechanism, selectivity, solvent, and temperature effect in the Diels-Alder reactions of 2,5-bis(hydroxymethyl)furan and maleimides derivatives leading to anticancer norcantharimide derivatives: an MEDT study.

contextThe [4 + 2] cycloaddition involving 2,5-bis(hydroxymethyl)furan (BHMF) and N-substituted maleimides constitutes an efficient synthetic strategy for accessing norcantharimide derivatives, which are of considerable interest due to their diverse pharmacological properties. Understanding the electronic and mechanistic determinants governing this transformation is essential for controlling the competition between en- and ex-stereoselective approaches and reactivity. In this study, the cycloaddition process was investigated from a molecular perspective to elucidate the nature of the interactions driving the reaction. The results indicate that the transformation proceeds via a polar, yet electronically asynchronous mechanism, characterized by a donor-acceptor interaction between the electron-rich BHMF and electron-deficient maleimides. The computed energy profiles reveal a preference between en- and ex-stereoselective approaches, while electron density analyses confirm a forward charge transfer from the diene to the dienophile. Furthermore, noncovalent interactions contribute significantly to transition-state stabilization, providing a rational basis for the observed selectivity and energetic trends.

methodsAll calculations were performed within the framework of density functional theory (DFT). The geometries of all stationary points, including reactants, transition states, and cycloadducts, were fully optimized at the ωB97XD/6-311++G(d,p) level of theory. Frequency calculations were carried out at the same level to confirm the nature of the stationary points and to obtain thermochemical corrections. Conceptual DFT descriptors were derived to evaluate global reactivity indices and to characterize the electrophilic and nucleophilic behavior of the reacting species. Topological analysis of the electron density was conducted to gain insight into bonding patterns and charge distribution. The global electron density transfer (GEDT) was calculated at the transition states to quantify the polar character of the reaction. In addition, noncovalent interactions were analyzed using the independent gradient model (IGM), allowing visualization and quantification of weak intermolecular interactions governing transition-state stabilization. All computational analyses were carried out using standard quantum chemical software packages.