Stereoselective synthesis of functionalized perhydropyrrolo[1,2- <i>b</i> ]isoxazoles based on (3 + 2)-annulation of donor–acceptor cyclopropanes and isoxazolines

A stereoselective route to access substituted pyrrolidine cores <i>via</i> Lewis acid catalyzed (3 + 2)-annulation of donor-acceptor cyclopropanes (DACs) and isoxazolines has been developed. Exclusive <i>cis</i>-2,5-stereoselectivity was governed by kinetically controlled conditions using Sn(OTf)₂ as the catalyst, while excellent <i>trans</i>-2,5-stereoselectivity was achieved by thermodynamically controlled conditions using Sc(OTf)₃ as the catalyst. For DACs bearing electron-poor substituents, Yb(NTf₂)₃ proved to be the most efficient catalyst due to its higher Lewis acidity compared to triflates. The isoxazoline (3 + 2)-annulation reaction was also extended to bicyclo[1.1.0]butanes (BCBs), providing easy access to the 2-azabicyclo[2.1.1]hexane core, which may be considered as a promising 3D-bioisosteric replacement for pyrrole and pyrrolidine motifs.