Palladium-Catalyzed Divergent Enantioselective Functionalization of Cyclobutenes

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....

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Bibliographic Details
Published inJournal of the American Chemical Society Vol. 146; no. 18; pp. 12691 - 12701
Main Authors Wang, Zhonggui, Zhu, Jie, Wang, Minyan, Lu, Ping
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 08.05.2024
Amer Chemical Soc
Subjects
Chemistry
Chemistry, Multidisciplinary
drugs
enantioselectivity
palladium
pharmacokinetics
Physical Sciences
Science & Technology
ALKENES
DIARYLATION
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ISSN0002-7863
1520-5126
1520-5126
DOI10.1021/jacs.4c02215

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Summary: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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ISSN:0002-7863
1520-5126
1520-5126
DOI:10.1021/jacs.4c02215