Unveiling the regioselective synthesis of antiviral 5-isoxazol-5-yl-2´-deoxyuridines from the perspective of a molecular electron density theory

Abstract

The regioselective synthesis of a potent antiviral sugar nucleoside isoxazole analogue from the [3+2] cycloaddition (32CA) reaction of aceto-nitrile-N-oxide (ANO) and acetyl-protected 5-ethynyl-2?-deoxyuridine (EDU) has been studied at MPWB1K/6-311G(d,p) level within the molecular electron density theory (MEDT) perspective. ANO is classified as a zwitterionic species devoid of any pseudoradical or carbenoid center from the electron localization function (ELF) analysis. The ortho regioisomer is energetically preferred over the meta one by the activation enthalpy of 21.7-24.3 kJ mol-1, suggesting complete regioselectivity in agreement with the experiment. The activation enthalpy increases from 53.9 kJ mol-1 in gas phase to 71.5 kJ mol-1 in water suggesting more facile reaction in low polar solvents. The minimal global electron density transfer (GEDT) at the TSs suggests non-polar character and the formation of new covalent bonds has not been started at the located TSs showing non-covalent intermolecular interactions from Atoms-in-Molecules (AIM) study and in the Independent Gradient Model (IGM) isosurfaces. The AIM analysis shows more accumulation of electron density at the C-C interacting region relative to the C-O one, and earlier C-C bond formation is predicted from the bonding evolution theory (BET) study.

Unveiling [3 + 2] Cycloaddition Reactions of N-Methyl-C-3-Bromophenyl-Nitrone to Dimethyl Maleate: Molecular Electron Density Theory Perspective

“…The Berny analytical gradient optimisation approach was used at the MPWB95/6-311++G (d,p) level for the optimization of the stationary points along the potential energy surface of the 32CA reactions [28,29]. The use of MPWB95 functional in the analysis of 32CA reaction has been shown to be a reliable and accurate approach [20,21,[30][31][32][33][34]. The optimized TSs' frequency computations revealed the existence of a single imaginary frequency, while the disappearance of imaginary frequencies was shown to be the local minimum.…”

Unveiling the Stereoselectivity and Regioselectivity of the [3+2] Cycloaddition Reaction between N-methyl-C-4-methylphenyl-nitrone and 2-Propynamide from a MEDT Perspective

“…Nitrones are important three-atom components (TACs) commonly utilized in [3+2] cycloaddition (32CA) reactions, which have significant synthetic potential for the production of pharmacologically active isoxazolidines and isoxazolines that are stereochemically and regioselectively defined [1]. Over the last decade, numerous conceptual DFT (density functional theory) studies have been published on nitrone cycloadditions to demonstrate the productive interaction between experimental discoveries and DFT-based selectivity predictions [2][3][4][5][6][7][8][9][10]. From this perspective, communications published after 2003 have indicated the changes in electron density during the cycloaddition process and categorized TACs and ethyne derivatives according to the absolute electrophilicity scale [11].…”