Asymmetric Dearomatization of Nonfunctionalized 1-Naphthols via Copper-Catalyzed Enantioselective [4 + 1] Spiroannulation

Abstract

Catalytic asymmetric dearomatization (CADA) is a powerful tool for the rapid construction of complex chiral three-dimensional cyclic molecules featuring quaternary carbon centers from readily available arenes. However, the asymmetric dearomatization of ubiquitous nonfunctionalized 1-naphthols to afford chiral quaternary centers remains challenging and undeveloped. This study reports the asymmetric dearomative [4 + 1] spiroannulation of nonfunctionalized 1-naphthols via copper catalysis. This reaction features a highly chemo-, regio-, and stereoselective nucleophilic addition and intramolecular annulation cascade of a reactive π-extended copper-allenylidene, thus enabling the practical synthesis of a range of valuable spirocyclic enones bearing a chiral quaternary stereocenter with high efficiency. Furthermore, this protocol is applicable to phenols. Control experiments supported the substitution-annulation cascade mechanism by excluding a process involving a 1,3-sigmatropic shift. Preliminary biological activity studies indicated that the synthesized spirocyclic enones hold significant promise as anticancer agents by inducing tumor cell apoptosis.

Copper-Catalyzed Dual Remote Asymmetric Vinylogous Alkynylallylic Substitution of Yne-Allylic Esters with Coumarins

“…The copper allenylidene complex as the key reactive intermediate was applied in this reaction mode. Recently, a new copper–vinylvinylidene complex was reported by Fang et al, He et al, Xu et al, our group, and other groups, which formed from the substrate that when an extended CC bond or aryl group assembly into propargylic alcohol derivatives (Scheme a). In particular, the He group described an elegant copper-catalyzed enantioselective propargylic amination of yne-allylic esters with amines at the γ position of the copper–vinylvinylidene complex to yield chiral 1,4-enyne products. , Xu et al and our group independently reported the copper-catalyzed remote asymmetric alkynylallylic substitution of yne-allylic esters with 1,3-dicarbonyl compounds or sodium sulfinates at the ε position of the copper–vinylvinylidene complex.…”

Copper-Catalyzed Remote Asymmetric Yne-Allylic Substitution of Yne-Allylic Esters with Anthrones

“…It has been well-established that a copper allenylidene complex is formed in situ as the key reactive intermediate, which can be trapped by various nucleophilic reagents at the γ position to furnish chiral terminal alkynes. − Copper-catalyzed asymmetric propargyl substitution of anthrones with propargylic esters was proven to be feasible . Recently, a new copper–vinylvinylidene complex was reported by Fang, He, Xu, our group, and other groups, which is formed in the presence of an extended CC bond or aryl group assembled on propargylic alcohol derivatives (Scheme c). A series of enantioenriched 1,3-enyne or 1,4-enyne products can be obtained with the regio- and enantioselective addition of the nucleophile to the ε or γ position of the copper-vinylvinylidene complex.…”