The Stetter reaction: modern methodologies and useful applications in total synthesis of natural products and drugs

The Stetter reaction, a powerful umpolung strategy catalyzed by nucleophilic carbenes, enables the formation of 1,4-dicarbonyl compounds through the conjugate addition of aldehydes to Michael acceptors. Since its discovery in the 1970s, this reaction has evolved through thiazolium, triazolium, and many more catalysts, and more recently, with chiral N-heterocyclic carbenes for asymmetric applications. This review explores modern advances in the Stetter reaction under green conditions, enzyme catalysis, photochemical activation, and ball-milling techniques. It integrates recent advances in green chemistry, solvent-free systems, and biocatalytic processes while correlating them with applications in the total synthesis of natural products and pharmaceuticals. Particular focus is placed on the evolution of chiral NHCs, artificial Stetterases, and photoinduced pathways, which expand the reaction′s utility in asymmetric and sustainable synthesis. These methodologies highlight the reaction′s versatility in constructing complex compounds, its environmental compatibility via aqueous or solvent-free conditions, and its expanding role in medicinal chemistry The bibliography includes 140 references.