Enantioselective\nN‑Heterocyclic Carbene-Catalyzed\nHauser-Kraus Annulations for the Construction of C–N Axially\nChiral Phthalimde Derivatives

The Hauser-Kraus annulation is one of the most powerful\nmethods\nto construct polycyclic hydroquinone from 3-cyano phthalides and Michael\nacceptors. Although these methods have been developed for more than\n46 years, the asymmetric catalytic version has remained underdeveloped.\nInspired by the N-heterocyclic carbene (NHC)-catalyzed asymmetric\nStetter reaction via the Breslow intermediate, herein, we developed\nan NHC-catalyzed enantioselective Hauser-Kraus annulation via a phthalide-type\nBreslow intermediate. With the help of the NHC catalyst and ynamide\ncoupling reagent, the reaction proceeds under mild conditions at room\ntemperature, giving the corresponding chiral polycyclic hydroquinone\nin moderate to good yields, with high enantioselectivities. The key\nphthalide-type Breslow intermediate was successfully isolated and\nconfirmed. The kinetic and thermal dynamic features of the cascade\nreaction were also explored with a density functional theory (DFT)\ncalculation. Learning from the wide application of Hauser-Kraus annulation,\nthis asymmetric catalytic method is hopeful to bring shortcuts for\nthe facile synthesis of sophisticated chiral polycyclic compounds.\nBesides, the discovery and application of the phthalide-type Breslow\nintermediate expand the synthetic potentials of NHC organocatalysis.