Syntheses of Minutuminolate and Related Coumarin Natural Products and Evaluation of Their TNF-α Inhibitory Activities

The concise syntheses of the coumarin natural product, minutuminolate (1), and its related natural products, 7-methoxy-8-(2-acetoxy-3-methyl-1-oxobut-2-enyl) coumarin (2) and muralatin I (3), were accomplished for the first time in 4-5 steps from the commercially available umbelliferone. The key step involves a palladium-catalyzed oxidative rearrangement reaction to assemble the alpha-acyloxyenone moiety in 1 and 2. The incorporation of this functionality enables the successful synthesis of coumarin 3 through an acidic hydrolysis reaction. The anti-inflammatory activities of the compounds were also evaluated against tumor necrosis factor-alpha production in lipopolysaccharides-stimulated RAW264.7 cells. Our developed synthetic route will facilitate the development of analogues and derivatives of 1-3 with potent anti-inflammatory activities.