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

in Angewandte Chemie (International ed. in English) by Chiyue Zhang, Gaoya Xu, Wenlu Zhao, Xutong Li, Mingyue Zheng, Yubo Zhou, Jia Li, Qi Li

TLDR

  • A palladium-catalyzed enantioselective arylative dearomatization reaction is developed for the efficient synthesis of quinazoline-containing spirocyclic compounds, which exhibit potent antiproliferative activity against cancer cell lines.

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 ICvalues 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.

Overview

  • This study reports a palladium-catalyzed enantioselective arylative dearomatization of phenols and naphthols.
  • The method allows for the efficient construction of a diverse library of quinazoline-containing spirocyclic compounds.
  • The study aims to demonstrate the potential of this approach in the discovery of new anticancer agents.

Comparative Analysis & Findings

  • The study presents a broad substrate scope and excellent functional group tolerance for the palladium-catalyzed enantioselective arylative dearomatization reaction.
  • The reaction produces enantioenriched, three-dimensional molecular architectures featuring quinazolinone and spirocyclic frameworks.
  • Compound (S)-4ac exhibits significantly enhanced antiproliferative efficacy against human mantle cell lymphoma and human acute myeloid leukemia cell lines, with IC50 values of 0.9 μM and 0.5 μM, respectively.

Implications and Future Directions

  • The study demonstrates a new approach to the discovery of anticancer agents with improved efficacy and selectivity.
  • Future studies should focus on optimizing the reaction conditions and scaling up the synthesis procedure.
  • Further in vitro and in vivo studies are necessary to evaluate the full potential of compound (S)-4ac as an anticancer lead compound.
Read Full Article