Enantioselective Synthesis of Cyclobutane‐fused Heterocycles via Lewis Acid‐Catalyzed Dearomative [2+2] Photocycloaddition of Indoles, Benzofurans, and Benzothiophenes with Alkenes

Enantioselective Synthesis of Cyclobutane‐fused Heterocycles via Lewis Acid‐Catalyzed Dearomative [2+2] Photocycloaddition of Indoles, Benzofurans, and Benzothiophenes with Alkenes Full article

Journal

Angewandte Chemie International Edition
ISSN: 1433-7851 , E-ISSN: 1521-3773

Output data

Year: 2025, Volume: 64, Number: 22, Article number : e202513342, Pages count : DOI: 10.1002/anie.202513342

Authors

Li Muzi ¹ , Kobelev Andrey D. ² , Wang Zhiping ¹ , Gao Yuan‐Jun ¹ , Cheng Yuan‐Zheng ¹ , Ananikov Valentine P. ² , You Shu‐Li ¹

Affiliations

1	New Cornerstone Science Laboratory, State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry University of Chinese Academy of Sciences Chinese Academy of Sciences 345 Lingling Lu Shanghai 200032 China
2	Zelinsky Institute of Organic Chemistry Russian Academy of Sciences Leninsky Prospect, 47 Moscow 119991 Russia

Cyclobutane-fused heterocycles are important motifs in biologically active molecules, yet their enantioselective synthesis remains a significant challenge. We report a broadly applicable and modular strategy for constructing these strained architectures through a visible-light-mediated, Lewis acid-catalyzed dearomative [2+2] photocycloaddition of indoles, benzofurans, and benzothiophenes with alkenes. The method employs a simple catalytic system based on commercially available rare-earth Lewis acids and chiral pyridine-2,6-bis(oxazoline) (PyBox) ligands. A wide array of heteroarenes and styrenes bearing diverse functional groups participate efficiently, delivering cyclobutane-fused products in up to 96% yield, >20:1 dr, and >99% ee. The synthetic utility is further demonstrated by gram-scale synthesis and facile removal of the directing group to access functionalized amino acid derivatives. Mechanistic investigations, including ultraviolet-visible (UV–vis) spectroscopy, nonlinear effect studies, kinetic isotope effects, and density functional theory (DFT) calculations, reveal that a triplet-state heteroarene engages in regio- and enantio-selective C─C bond formation under mild photochemical conditions. This study highlights the potential of excited-state Lewis acid catalysis in unlocking enantioselective dearomatization pathways for complex molecular architectures.

Li M. , Kobelev A.D. , Wang Z. , Gao Y. , Cheng Y. , Ananikov V.P. , You S.
Enantioselective Synthesis of Cyclobutane‐fused Heterocycles via Lewis Acid‐Catalyzed Dearomative [2+2] Photocycloaddition of Indoles, Benzofurans, and Benzothiophenes with Alkenes
Angewandte Chemie International Edition. 2025. V.64. N22. e202513342 . DOI: 10.1002/anie.202513342 WOS OpenAlex

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