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 a significant and enduring challenge, owing to steric hindrance and electronic effects. Here we report a Pd/Sadphos-catalyzed dynamic kinetic asymmetric cascade dearomative Heck/Tsuji–Trost reaction of racemic phenolic biaryls with 1,3-dienes, enabled by transient axial-to-point chirality induction and transfer via a dynamic kinetic asymmetric transformation (DyKAT) manifold. Over 40 valuable polycyclic spiro enones bearing three contiguous tertiary/quaternary stereocenters are afforded in moderate to high yields, with excellent regio-, diastereo- and enantioselectivity (up to 99% ee). This work provides a modular synthetic strategy for complex chiral spirocycles and expands the scope of transient chirality transfer chemistry. Chiral polycyclic spirocycles are privileged molecular scaffolds for drug discovery and asymmetric synthesis, yet their efficient stereoselective construction remains challenging. Here, the authors report a Pd/Sadphos-catalyzed asymmetric dearomative cascade that delivers polycyclic spiro enones with three contiguous stereocenters and exceptional stereoselectivity.