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

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Nivedita Acharjee
Haydar A. Mohammad-Salim
Mrinmoy Chakraborty


The regioselective synthesis of a potent antiviral sugar nucleoside iso­xazole analogue in the [3+2] cycloaddition (32CA) reaction of aceto­nitrile-N-oxide (ANO) and acetyl-protected 5-ethynyl-2’-deoxyuridine (EDU) has been studied at the MPWB1K/6-311G(d,p) level within perspective of the molecular electron density theory (MEDT). From an electron localization func­tion (ELF) analysis, ANO is classified as a zwitterionic species devoid of any pseudoradical or carbenoid centre. 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 the 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 an 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 a bonding evolution theory (BET) study.


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N. Acharjee, H. A. . Mohammad-Salim, and M. . Chakraborty, “Unveiling the regioselective synthesis of antiviral 5-isoxazol-5-yl-2’-deoxyuridines from the perspective of a molecular electron density theory: Scientific paper”, J. Serb. Chem. Soc., vol. 87, no. 6, pp. 707–721, Feb. 2022.
Theoretical Chemistry


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