Synthesis of Chiral Spiro-2-pyrrolidinones with Anti-Inflammatory Properties

High Resolution Image Download MS PowerPoint Slide Spiro motifs are privileged three-dimensional scaffolds that offer a balance of rigidity and flexibility. Herein, we report the synthesis of spiro-2-pyrrolidinones via a Michael addition reaction promoted by bifunctional organocatalysts, involving cyclic 1,3-ketoesters and nitroalkenes to generate products bearing two stereocenters. Through a sequence involving ketone reduction, nitro-group reduction followed by lactamization in a one-pot procedure, and finally oxidation, requiring a single chromatographic purification, we obtained 18 chiral spiro-2-pyrrolidinones with different substituents in the lactam ring and different rings spiro-fused to the 2-pyrrolidinone moiety. The resulting compounds were evaluated for in vivo anti-inflammatory activity using a mouse ear edema model induced by 12- O -tetradecanoylphorbol-13-acetate (TPA), showing similar or slightly improved activity compared with celecoxib. Additionally, myeloperoxidase activity was measured to evaluate leukocyte infiltration, and in vitro inhibition assays of COX-1 and COX-2 were performed for three selected compounds, which showed selective inhibition of COX-2.