Enantioselective N-Heterocyclic Carbene-Catalyzed Hauser-Kraus Annulations for the Construction of C–N Axially Chiral Phthalimde Derivatives

The Hauser-Kraus annulation is one of the most powerful methods to construct polycyclic hydroquinone from 3-cyano phthalides and Michael acceptors. Although these methods have been developed for more than 46 years, the asymmetric catalytic version has remained underdeveloped. Inspired by the N-heterocyclic carbene (NHC)-catalyzed asymmetric Stetter reaction via the Breslow intermediate, herein, we developed an NHC-catalyzed enantioselective Hauser-Kraus annulation via a phthalide-type Breslow intermediate. With the help of the NHC catalyst and ynamide coupling reagent, the reaction proceeds under mild conditions at room temperature, giving the corresponding chiral polycyclic hydroquinone in moderate to good yields, with high enantioselectivities. The key phthalide-type Breslow intermediate was successfully isolated and confirmed. The kinetic and thermal dynamic features of the cascade reaction were also explored with a density functional theory (DFT) calculation. Learning from the wide application of Hauser-Kraus annulation, this asymmetric catalytic method is hopeful to bring shortcuts for the facile synthesis of sophisticated chiral polycyclic compounds. Besides, the discovery and application of the phthalide-type Breslow intermediate expand the synthetic potentials of NHC organocatalysis.