Atroposelective construction of axially chiral alkenylindole-fused nine-membered rings via catalytic asymmetric formal (4 + 5) cycloaddition

Si-Jia Liu, Xue Wang, Ji-Xiang Yang, Xian-Song Ao, Shao-Fei Ni (), Yu-Chen Zhang () and Feng Shi ()
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Si-Jia Liu: Jiangsu Normal University
Xue Wang: Jiangsu Normal University
Ji-Xiang Yang: Shantou University
Xian-Song Ao: Jiangsu Normal University
Shao-Fei Ni: Shantou University
Yu-Chen Zhang: Jiangsu Normal University
Feng Shi: Jiangsu Normal University

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Catalytic atroposelective construction of axially chiral aryl-fused medium-sized rings, particularly nine-membered rings, is of great importance but with enormous challenges. To overcome these challenges, in this work, the catalytic atroposelective construction of axially chiral arylalkene-fused nine-membered rings has been established, which makes use of organocatalytic asymmetric formal (4 + 5) cycloaddition of 3-alkynyl-2-indolylmethanols with 2-indolylethanols. By this strategy, various axially chiral alkenylindole-fused nine-membered rings were constructed in high enantioselectivities with moderate to good yields (up to 74% yield, 98% ee). Theoretical calculations provide an in-depth understanding on the reaction pathway and activation mode of the organocatalytic asymmetric formal (4 + 5) cycloaddition, and application explorations demonstrate the great potential of these axially chiral arylalkene-fused nine-membered rings in asymmetric catalysis and medicinal chemistry. Besides, this strategy could be extended to organocatalytic formal (4 + 4) cycloaddition of 3-alkynyl-2-indolylmethanols with 2-indolylmethanols. This work has not only realized the organocatalytic asymmetric formal (4 + 5) cycloaddition, but also provided an efficient strategy for the synthesis of axially chiral aryl-fused nine-membered rings, which will greatly advance the chemistry of cycloadditions and atropisomers.

Date: 2025
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DOI: 10.1038/s41467-025-62035-y

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