Organocatalytic desymmetrization of triols to access terminal epoxides bearing quaternary stereocenters

Chiral epoxides are widely used as versatile synthetic intermediates, thanks to the regioselective ringopening, which allows to obtain functionalized molecules, with a well-defined stereochemistry of the centers. Although there are several methods for obtaining epoxides, there is a lack of general methodologies that allow the preparation of chiral 1,1-disubstituted terminal epoxides which are the most synthetically useful, since ring-opening reactions occurs in a highly regioselective manner. In this work, we focused on the development of the first enantioselective and catalytic methodology for the synthesis of protected terminal 1,1-disubstituted epoxides via a desymmetrization process of triols. We envisioned a desymmetrization process to access to an enantioenriched product starting from an achiral or meso compound, through the loss of an improper symmetry element. After protection of the two primary alcohols into good leaving groups, the free tertiary alcohol could be selectively engaged in a SN2 reaction with one of the two leaving groups, in the presence of a bifunctional organocatalyst, to afford enantioenriched chiral epoxides. After optimization of the reaction conditions, the protocol will be employed for the synthesis of a library of functionalized enantioenriched terminal epoxides with various substitutions at the stereogenic center. These products can be exploited as key intermediates for accessing biologically active molecules through ring-opening reactions.