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.
Authors
- Mikk Kaasik (ORCID: https://orcid.org/0000-0003-1141-3604)
- Philipp Waser
- Karl Anker Jørgensen (ORCID: https://orcid.org/0000-0002-3482-6236)
- Erlaitz Basabe Obregón (ORCID: https://orcid.org/0000-0002-3723-6776)
- Chi Zhang (ORCID: https://orcid.org/0000-0002-1827-8137)
- Ida R. Kocemba (ORCID: https://orcid.org/0000-0001-8326-3882)
- Metin Cakiroglu
- Pan-Pan Chen
- K. N. Houk
Institutions
- University of California, Los Angeles (US)
- Aarhus University (DK)
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
Funders
- National Science Foundation
- Aarhus Universitet
- Villum Fonden
- Novo Nordisk
- Novo Nordisk Fonden
- Division of Chemistry