Enantioselective Access to γ‑All-Carbon Quaternary Center-Containing Cyclohexanones by Palladium-Catalyzed Desymmetrization

An efficient desymmetrization of γ-quaternary carbon-containing
cyclohexanones using readily available Pd/(S)-tBuPhox and benzylamine as dual catalysts
is reported. We describe herein the development of the reaction, exploration
of the substrate scope, and studies on the reaction mechanism. The
intramolecular coupling reaction leads to the formation of bicyclo[3.3.1]­nonanones
with a quaternary carbon bridgehead in synthetically useful yields
(up to 98%) with high enantioselectivities (up to 98:2 er) and good
functional group tolerance (>30 examples). Significantly, aryl
and
alkenyl bromides as well as less reactive triflates are all compatible
substrates for this process. The synthetic versatility of this strategy
is demonstrated by scale-up synthesis and diverse transformations
of the products into valuable building blocks, including quaternary
center-containing dihydronaphthalenes, ring-fused indoles and
lactones, tetralones, and 6,6,5-tricycles. Mechanistic studies by
computational calculations provide insights into the role of benzylamine
in accelerating the reaction rate and enhancing the enantioselectivities.