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Palladium-Catalyzed Divergent Enantioselective Functionalization of Cyclobutenes
Zhonggui Wang1, Jie Zhu2, Minyan Wang2
1Research Center for Molecular Recognition and Synthesis, Department of Chemistry, Fudan University, 220 Handan Lu, Shanghai 200433, China.
Abstract:
Aliphatic strained rings have been increasingly applied in medicinal chemistry due to their beneficial physicochemical and pharmacokinetic properties. However, the divergent synthesis of enantioenriched cyclobutane derivatives with various structural patterns continues to be a significant challenge. Here, we disclose a palladium-catalyzed enantioselective desymmetrization of cyclobutenes, resulting in a series of hydroarylation and 1,2- and 1,3-diarylation products via the interceptions of a common Heck intermediate. Mechanistic investigations provide valuable insights into understanding the catalytic mode of the palladium catalysts and the observed variations in the deuterium-responsive behavior during reactions. Furthermore, the synthetic utility is demonstrated in the syntheses of deuterated drug candidate belaperidone skeletons and pseudosymmetrical truxinic acid-type derivatives.
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