Iron-catalyzed 1,3-dipolar cycloaddition of alkynes and aryl nitrones for the synthesis of chiral Δ4-isoxazolines

Abstract

The synthesis of chiral Δ⁴-isoxazolines is a crucial area of research due to their biological activity and versatility in synthetic chemistry. Driven by the abundant reserves, low cost and high biocompatibility of iron catalysts, we herein investigated the catalytic potential of iron complexes in asymmetric 1,3-dipolar cycloaddition reactions between N-Bn,α-aryl nitrones and 3-propioloyloxazolidin-2-ones. By utilizing Fe(OTf)₂ and (S,S)-DBFOX-Ph, a series of (R)-Δ⁴-isoxazolines were obtained in high yields (up to 99%) with good to excellent enantioselectivities (up to 98 : 2 er). Additionally, using Fe(OTf)₃ and (±)-BINOL as the catalyst, good to excellent yields (up to 99%) and diastereoselectivities (up to >20 : 1 dr) were achieved for the (S,S)-Δ⁴-isoxazoline derivatives from 3-propioloyloxazolidin-2-ones bearing a chiral Evans auxiliary. Gram-scale synthesis and synthetic utility were also demonstrated.