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

Abstract

A stereoselective route to access substituted pyrrolidine cores via Lewis acid catalyzed (3 + 2)-annulation of donor–acceptor cyclopropanes (DACs) and isoxazolines has been developed. Exclusive cis-2,5-stereoselectivity was governed by kinetically controlled conditions using Sn(OTf)₂ as the catalyst, while excellent trans-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.