An Yb(OTf)3 and visible light relay catalyzed [3 + 2] cycloaddition/[3,3]-rearrangement/[4 + 2] cycloaddition in one pot to prepare oxazonine-fused endoperoxides

Abstract

We report a relay catalysis for the highly stereoselective synthesis of densely substituted oxazonine-fused endoperoxides in good yields. This domino reaction is based on an Yb(OTf)₃ and visible light promoted [3 + 2] cycloaddition/[3,3]-rearrangement, and in situ [4 + 2] cycloaddition with air in one pot under mild reaction conditions from N-vinyl-α,β-unsaturated nitrones and methylenecyclopropanes, leading to a practical assembly of densely substituted oxazonine-fused endoperoxides containing five stereocenters with a wide substrate scope and excellent diastereoselectivity. Mechanistic studies reveal that the O–O bond of the endoperoxide ring is derived from singlet oxygen (¹O₂) generated by air under a white LED. Moreover, such an asymmetric relay catalyst has also been realized to afford chiral endoperoxides in good enantioselectivity. Biological tests show that the designed oxazonine-fused endoperoxides significantly inhibited nitric oxide (NO) generation in LPS-stimulated RAW264.7 cells and exhibited their bioactivity as good anti-inflammatory agents.