Divergent concerted and stepwise cycloadditions via enantioselective cross-conjugated iminium-ion catalysis

Cycloadditions are described as either concerted or stepwise processes, where a catalyst can influence both the mechanism and the peri-, regio- and stereoselectivity. We report experimental and DFT-computational investigations that reveal the versatile reactivities of cross-conjugated unsaturated iminium-ion intermediates. These undergo cycloadditions with cyclic and linear dienes via both stepwise and concerted pathways, respectively, providing two distinct classes of enantioenriched cycloadducts. Activation of 2-formyl-1,3-cyclohexadiene with a chiral 1,2-diaminocatalyst generates an acyclic cross-conjugated iminium-ion intermediate, which by utilizing 4π-electrons, undergoes enantioselective inverse-electron-demand [4 + 2] cycloadditions with cyclic dienes via a stepwise mechanism, as well as indene and a styrene, affording cycloadducts in high yields and up to 96% ee. In contrast, only 2π-electrons of the cross-conjugated iminium-ion intermediate are involved in the [4 + 2] cycloaddition with linear dienes, proceeding via an ambimodal asynchronous concerted pathway, yielding decalin derivatives in up to 96% ee. The generality of this catalytic enantioselective concept is expanded to also include acyclic cross-conjugated iminium-ion intermediates, which react with both cyclic and linear dienes following the same two distinct reaction pathways. In contrast, the analogous iminium-ion, generated from 1-formylcyclohexene, does not react under the same conditions. The authors report experimental and DFT-computational investigations that reveal the versatile reactivities of cross-conjugated unsaturated iminium-ion intermediates. These undergo cycloadditions with cyclic and linear dienes via both stepwise and concerted pathways, respectively, providing two distinct classes of enantioenriched cycloadducts.

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Publication Details

Journal
Nature Communications
Published
2026-08-03
DOI
https://doi.org/10.1038/s41467-026-76222-y
Primary Topic
Asymmetric Synthesis and Catalysis
Type
article
Field-Weighted Citation Impact
0.00

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article

Divergent concerted and stepwise cycloadditions via enantioselective cross-conjugated iminium-ion catalysis

Mikk Kaasik, Philipp Waser, Karl Anker Jørgensen, Erlaitz Basabe Obregón et al.
Nature Communications
Asymmetric Synthesis and Catalysis
article

Divergent concerted and stepwise cycloadditions via enantioselective cross-conjugated iminium-ion catalysis

Mikk Kaasik, Philipp Waser, Karl Anker Jørgensen, Erlaitz Basabe Obregón, Chi Zhang, Ida R. Kocemba, Metin Cakiroglu, Pan-Pan Chen, K. N. Houk
article en

Abstract

Cycloadditions are described as either concerted or stepwise processes, where a catalyst can influence both the mechanism and the peri-, regio- and stereoselectivity. We report experimental and DFT-computational investigations that reveal the versatile reactivities of cross-conjugated unsaturated iminium-ion intermediates. These undergo cycloadditions with cyclic and linear dienes via both stepwise and concerted pathways, respectively, providing two distinct classes of enantioenriched cycloadducts. Activation of 2-formyl-1,3-cyclohexadiene with a chiral 1,2-diaminocatalyst generates an acyclic cross-conjugated iminium-ion intermediate, which by utilizing 4π-electrons, undergoes enantioselective inverse-electron-demand [4 + 2] cycloadditions with cyclic dienes via a stepwise mechanism, as well as indene and a styrene, affording cycloadducts in high yields and up to 96% ee. In contrast, only 2π-electrons of the cross-conjugated iminium-ion intermediate are involved in the [4 + 2] cycloaddition with linear dienes, proceeding via an ambimodal asynchronous concerted pathway, yielding decalin derivatives in up to 96% ee. The generality of this catalytic enantioselective concept is expanded to also include acyclic cross-conjugated iminium-ion intermediates, which react with both cyclic and linear dienes following the same two distinct reaction pathways. In contrast, the analogous iminium-ion, generated from 1-formylcyclohexene, does not react under the same conditions. The authors report experimental and DFT-computational investigations that reveal the versatile reactivities of cross-conjugated unsaturated iminium-ion intermediates. These undergo cycloadditions with cyclic and linear dienes via both stepwise and concerted pathways, respectively, providing two distinct classes of enantioenriched cycloadducts.

Nature Communications
University of California, Los Angeles (US), Aarhus University (DK)
National Science Foundation, Aarhus Universitet, Villum Fonden, Novo Nordisk, Novo Nordisk Fonden, Division of Chemistry
Openalex Percentile: Top 18%
Asymmetric Synthesis and Catalysis
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