Asymmetric Dearomatization of Nonfunctionalized 1-Naphthols via Copper-Catalyzed Enantioselective [4 + 1] Spiroannulation
Xingguang Li, Jiaxing Guo, Jin Zhang, Qian-Yu Chen, Yu He, Feng Sha, Huijing Xiang, Peiyuan Yu, Pei Nian Liu
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.