Unravelling the regio- and stereoselective synthesis of bicyclic N,O-nucleoside analogues within the molecular electron
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ORIGINAL RESEARCH
Unravelling the regio- and stereoselective synthesis of bicyclic N,O-nucleoside analogues within the molecular electron density theory perspective Nivedita Acharjee 1 Received: 19 May 2020 / Accepted: 18 June 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The [3 + 2] cycloaddition (32CA) reactions of 1-pyrroline-1-oxide with N-vinyl nucleobases leading to bicyclic N,O nucleoside analogues have been studied within the molecular electron density theory (MEDT) at the MPWB1K/6-311G(d,p) computational level. These non-polar zwitterionic type 32CA reactions take place through a one-step mechanism with minimal global electron density transfer (GEDT) at the TSs and the exo/ortho approach mode as the energetically favoured reaction path. The 32CA reactions of N-vinyl nucleobases with thymine and cytosine substituents respectively show the activation enthalpies of 15.2 and 12.5 kcal mol−1 in toluene. The reactions are irreversible due to strong exothermic character of − 35.4–− 26.4 kcal mol−1 in toluene. The bonding evolution theory (BET) study suggests that these 32CA reactions take place through the coupling of pseudoradical centres with earlier C–C bond formation and the formation of new C–C and C–O covalent bonds has not been started in the TSs. Non-covalent interactions (NCI) are predicted at the TSs from the visualization of NCI gradient isosurfaces. Keywords Molecular electron density theory . [3 + 2] Cycloaddition reactions . Nucleosides . Electron localization function
Introduction Nucleoside analogues [1] constitute an important class of compounds in medicinal chemistry due to their unique therapeutic potential to mimic physiological nucleosides. The sphere of antiviral research experienced a major breakthrough with the evolution of nucleoside analogues [1, 2] that have been identified to exhibit broad spectrum activity for the treatment of chronic hepatitis B in 2011 [3] and for coronaviruses in 2019 [4]. Recently, Thomson and Lamont have also identified the use of modified nucleoside analogues as antibacterial agents [5]. The mechanism of drug resistance by nucleoside analogues is also well documented to establish them as important antimetabolites in the treatment of malignancies and tumours [6]. Owing to the important involvement of naturally Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11224-020-01569-x) contains supplementary material, which is available to authorized users. * Nivedita Acharjee [email protected] 1
Department of Chemistry, Durgapur Government College, Paschim Bardhaman, Durgapur, West Bengal 713214, India
occurring nucleosides in DNA and RNA synthesis, modified nucleoside analogues have been designed by chemists to act on the DNA/RNA chain terminators to achieve interesting biological results [7]. One of these modification strategies is to replace the carbohydrate moiety of the natural nucleoside with an isoxazolidine nucleus [8–10]. As model strategy of synthesis, the [3 + 2] cycloaddit
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