Diastereoselective Synthesis of 3,4-Dihydropyran-3-carboxamides with in Vitro Anti-inflammatory Activity

A versatile and economical reaction of diketene (1), aryl amines 2, cyclic 1,3-diketones 3, primary amines 4, and aryl aldehydes 5 was explored to synthesize 3,4-dihydropyran-3-carboxamide derivatives under mild conditions. Three stereogenic centers are generated in the products, and the structure of the major diastereomer of 6{1,1,3,1} was identified by X-ray diffraction and 2D NMR spectroscopy. The scope and limitation investigation provided two series of (2S,3R,4S)-chromene-3-carboxamides in good to excellent yields with high diastereoselectivity. Two products, 6{5,3,1,1} and 6{7,3,1,1}, exhibited in vitro anti-inflammatory activity with significant inhibition of pro-inflammatory cytokine IL-6 and TNF-α expression in lipopolysaccharide (LPS)-treated Raw 264.7 cells.