Rhodium-Catalyzed [3 + 2] Annulation of Cyclic N-Acyl Ketimines with Activated Olefins: Anticancer Activity of Spiroisoindolinones.

Abstract

The rhodium(III)-catalyzed redox-neutral coupling reaction of N-acyl ketimines generated in situ from 3-hydroxyisoindolinones with various activated olefins is described. This approach leads to the synthesis of bioactive spiroisoindolinone derivatives in moderate to high yields. In the case of internal olefins such as maleimides, maleates, fumarates, and cinnamates, spiroindanes were obtained by the [3 + 2] annulations reaction. In sharp contrast, acrylates and quinones displayed the β-H elimination followed by Prins-type cyclization furnishing spiroindenes. The synthetic compounds were evaluated for in vitro anticancer activity against androgen-sensitive human prostate adenocarcinoma cells (LNCaP), human prostate adenocarcinoma cells (DU145), human endometrial adenocarcinoma cells (Ishikawa), human breast cancer cell (MCF-7), and triple negative human breast cancer cells (MDA-MB-231). Notably, quinone-containing spiroindenes displayed potent anticancer activity about 2- to 3-fold stronger than that of anticancer agent doxorubicin.