Molecular Electron Density Theory Study of Fused Regioselectivity in the Intramolecular [3+2] Cycloaddition Reaction of Cyclic Nitrones

• Published in: ChemistrySelect (Weinheim) 2018-05, Vol.3 (19), p.5412-5420
• Main Authors: Domingo, Luis R., Ríos‐Gutiérrez, Mar , Adjieufack, Abel I., Ndassa, Ibrahim M., Nouhou, Cyrille N., Mbadcam, Joseph K.
• Format: Article
• Language: English
• Subjects: domino reactions; intramolecular [3+2] cycloaddition reactions; Molecular Electron Density Theory; molecular mechanisms; nitrones
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.201800224

The intramolecular [3+2] cycloaddition (IM32CA) reactions of cyclic nitrones Z‐7 and E‐7 have been studied within the Molecular Electron Density Theory at the MPWB1K/6‐311G(d) computational level. For these IM32CA reactions, which take place through a one–step mechanism, two regioisomeric reaction paths associated with the formation of the 6,6,5‐ring fused and 6,5,5‐ring bridged isoxazolidines have been considered. Analysis of the relative Gibbs free energies indicates that under thermodynamic control, these IM32CA reactions are completely regioselective, stereoselective and stereospecific, cyclic nitrones Z‐7 and E‐7 yielding the fused isoxazolidines 8 and 9, respectively, as the only product, in complete agreement with the experimental outcomes. The low electrophilic character of nitrones Z‐7 and E‐7 together with the strain caused by the chain along these intramolecular processes are responsible for the high activation energies found in these IM32CA reactions. An ELF topological analysis of the asynchronous TSs associated with the IM32CA reaction of cyclic nitrone Z‐7 indicates that along the more favourable fused reaction path, the IM32CA reaction begins with the formation of the C−O single bond involving the most nucleophilic and electrophilic centers of the molecule. The intramolecular [3+2] cycloaddition reactions of cyclic nitrones Z‐7 and E‐7 have been studied within the Molecular Electron Density Theory. The reaction paths associated with the formation of the 6,6,5‐ring fused and 6,5,5‐ring bridged isoxazolidines have been studied. The regioselective, stereoselective and stereospecific formation of tricyclic isoxazolidine 8 and 9 takes place through thermodynamic control.