Asymmetric Synthesis of the <i>cis</i>-1,2-Diaryltetralin Vepdegestrant Core via an Enantioselective Intramolecular Corey-Chaykovsky Epoxidation

Abstract

An asymmetric synthesis of cis-1,2-diaryltetralin ( 2 ), a key chiral intermediate in the synthesis of Vepdegestrant ( 1 ), an orally available PROTAC being evaluated for the treatment of ER+/HER2- breast cancer, is reported. Chirality is initially introduced via a catalytic enantioselective intramolecular Corey-Chaykovsky epoxidation utilizing isothiocineole, a chiral sulfide. Although several asymmetric intermolecular epoxidations using chiral sulfides have been reported, our approach represents a unique intramolecular variant. The subsequent introduction of the cis-1,2-diaryl motif is achieved via diastereoselective hydrogenation.