Catalytic Asymmetric Spiroannulation to Access Polycyclic Spiro Enones via Transient Axial-to-Point Chirality Induction and Transfer

Abstract Chiral spirocycles exhibit tremendous potential in drug discovery and asymmetric synthesis, owing to their unique three-dimensional rigid framework and superior stability. However, stereoselective construction of polycyclic spiro compounds through a single catalytic transformation remains significant and enduring challenge, owing to steric hindrance and electronic effects. Here we report a Pd/Sadphos-catalyzed dynamic kinetic asymmetric cascade Heck/Tsuji–Trost dearomative spiroannulation of racemic phenolic biaryls with 1,3-cyclohexadienes via transient axial-to-point chirality induction and transfer. A variety of valuable polycyclic spiro enones bearing three contiguous tertiary/quaternary stereocenters were afforded with excellent regio-, diastereo- and enantioselectivity. Moreover, in vitro experiments suggested that these multifunctional spiro enones have the potential to be lead compounds for anti-inflammatory drugs.