Unravelling the regio- and stereoselective synthesis of bicyclic N,O-nucleoside analogues within the molecular electron density theory perspective

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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11224-020-01569-x) contains supplementary material, which is available to authorized users.