Stereoselective lactone synthesis via chiral Brønsted acid catalysis

Abstract

Molecular chirality plays a key role in chemical and biological reactivity of molecules. The handedness of a particular molecule, for example, can have drastic effects on its biological or pharmaceutical properties. Synthesis of stereoenriched chiral molecules is challenging, especially molecules containing all-carbon quaternary centers. Desymmetrizations are a method that takes advantage of a prochiral moiety to generate stereoenriched compounds without the drawbacks of other classical asymmetric methods. Lactones are synthetically important target moieties, as they are replete throughout natural products and biological chemistry spaces. Indeed, chiral lactones are key to the functioning of several bioactive molecules, including molecules with anti-cancer activity. Methods for the synthesis of chiral lactones, then, present an important challenge for synthetic chemists. This work builds on previous methods for the synthesis of chiral lactones via desymmetrizations. It introduces new stereoselective uses for known reactions, and builds on methodology to develop a cascade reaction that streamlines our synthetic pathway. Finally, this work delineates a new co-catalytic cascade desymmetrization enhances the rescues the reactivity of chiral phosphoric acid catalysts. These methods add new tools in the synthetic chemist’s toolbox for synthesis of chiral molecules, and particularly chiral lactones