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

A versatile and economical reaction from diketene 1, aryl amine 2, cyclic 1,3-diketone 3, primary amine 4, and aryl aldehyde 5 was explored to synthesize 3,4-dihydropyran-3-carboxamide derivatives under mild conditions. Three stereogenic centers were generated in products and the structure for the major diastereomer of 6{1,1,3,1} was identified by XRD as well as 2D NMR. 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.