The chalcone class of natural products displays a wide variety of biological activities and is a convenient starting point to access numerous natural-product like molecules, such as flavonoids. A route was developed utilizing microwave–assisted organic synthesis to access 3-amino-2,3-dihydrobenzofurans from chalcones to rapidly prepare analogues with increased stereochemical complexity and diverse substituents to explore the effect of these alterations on biological activity. The four step synthesis to access 3-amino-2,3-dihydrobenzofurans begins with utilizing commercially available acetophenones and benzaldehydes to synthesize chalcones through a microwave-assisted, acid-catalyzed aldol condensation. The chalcones then undergo a stereoselective Corey-Bakshi-Shibata reduction followed by a Sharpless asymmetric epoxidation to access the stereoisomeric epoxyalcohols. The final step is a one-pot, microwave-assisted, regioselective, europium-mediated epoxide opening with various amines followed by an intramolecular nucleophillic aromatic substitution reaction to afford the 3-amino-2,3-dihydrobenzofurans. Modifications to this route are currently being explored to access benzopyran flavonoid derivatives. A pilot library of chalcones and benzofurans was synthesized and evaluated in two human carcinoma cell lines to assess the biological activity diversity of the two compound classes, revealing that the benzofurans had a much more diverse biological response than the chalcones.

Microwave-assisted, asymmetric synthesis of flavonoid derivatives from chalcones

256th National Meeting (2018)

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