One-Pot Regio- and Stereoselective Synthesis of α′-Methoxy-γ-pyrones: Biological Evaluation as Mitochondrial Respiratory Complex Inhibitors

The one-pot construction of functionalized α′-methoxy-γ-pyrones is detailed. Starting from α,α′-dimethoxy-γ-pyrone, molecular diversity is attained by a regio- and stereoselective desymmetrization using allyllithium followed by vinylogous aldol reaction. Mechanistic considerations including density functional theory calculations and insightful experiments have been gathered to shed light on this complex multistep process. To illustrate the versatility of this methodology, some of the molecules prepared were evaluated for their ability to inhibit NADH-oxidase and NADH-ubiquinone oxidoreductase. In the process, a potent new inihibitor of NADH-oxidase activity (IC50 44 nM) was identified.