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

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.