Understanding the domino retro [3+2] cycloaddition/cyclization reaction of bicyclic isoxazolidines in the synthesis of spirocyclic alkaloids. A DFT study.

The domino retro [3+2] cycloaddition/cyclization reaction of bicyclic isoxazolidines 4 yielding [6.6.5]-tricyclic isoxazolidines 7 and [6.5.5]-tricyclic isoxazolidines 8, experimentally reported by Holmes et al., has been studied in toluene using DFT methods at the MPWB1K/6-311G** level. This domino reaction begins by a reto [3+2] cycloaddition reaction of the bicyclic isoxazolidines 4 forming the cyclic nitrones 5, which undergo a subsequent cyclization reaction yielding [6.6.5]-tricyclic isoxazolidines 7 or [6.5.5]-tricyclic isoxazolidines 8. The [3+2] cycloaddition reactions of cyclic nitrone 12 with ethylene 13, and with (Z)-but-2-enenitrile 15 were also studied in order to explain the role of the tether in the cyclization step. The present study shows that, unlike the [3+2] cycloaddition reaction of cyanoalkene 15, the cyano group in the cyclization step does not have any effect on the selectivity. The present study suggests that the presence of the BF3 catalyst in the domino reaction can change the formation of the [6.5.5]-tricyclic isoxazolidine 7 to the [6.6.5]-tricyclic isoxazolidine 8.