Palladium‐Catalyzed Enantioselective Arylative Dearomatization of Naphthols and Phenols for Constructing Quinazoline‐Containing Spirocycles

Abstract We report a palladium‐catalyzed enantioselective arylative dearomatization of phenols and naphthols, demonstrating a broad substrate scope and excellent functional group tolerance. This approach enables the efficient construction of a diverse library of quinazoline‐containing spirocyclic compounds, featuring enantioenriched, three‐dimensional molecular architectures through the strategic integration of quinazolinone and spirocyclic frameworks. The successful transformation of planar aromatic precursors into complex three‐dimensional molecular architectures using our developed methodology was further validated by principal moment of inertia (PMI) calculations. Additionally, we systematically evaluated the antiproliferative potential of the synthesized compounds against two representative cancer cell lines: Mino (human mantle cell lymphoma) and MV4‐11 (human acute myeloid leukemia), revealing that compound ( S )‐4ac, characterized by well‐defined stereochemistry and structural novelty, exhibited significantly enhanced antiproliferative efficacy against both cancer cell lines, with IC 50 values 0.9 µM and 0.5 µM, respectively. In addition, flow cytometry quantification and western blot analysis showed that these compounds induced apoptosis through caspase activation and mitochondrial dysfunction. These results demonstrated ( S )‐4ac as a highly promising lead compound for further anticancer drug development.