Abstract
In contrast to ynamides, whose chemistry has been extensively explored, ynimines remain underutilized in organic synthesis despite their rich functionalities. Here we report a general strategy to access 2-imido-1,3-dienes, synthetically challenging building blocks, through the reaction of ynimines with carboxylic acids. Leveraging this transformation, we develop a three-component reaction of ynimines, carboxylic acids and electron-deficient alkenes that enables the efficient synthesis of 1-imido-3,4-trans-disubstituted cyclohex-1-enes. The sequence proceeds via regioselective hydroacyloxylation and Mumm rearrangement to generate 2-imido-1,3-dienes, which undergo Diels–Alder cycloadditions. An intramolecular variant furnishes trans-fused tricyclic architectures reminiscent of trans-Δ⁹-tetrahydrocannabinol. Chemoselective hydrolysis further converts 2-imido-1,3-dienes into 2-amido-1,3-dienes, enabling chiral squaramide-catalysed enantioselective Diels–Alder reactions to afford 1-amido-3,4-cis-disubstituted cyclohex-1-enes with high stereocontrol. Distinct concerted and stepwise cycloaddition pathways rationalize the observed stereodivergence.
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Data availability
Crystallographic data for the structure reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2260903 (7k), CCDC 2324899 (8a), CCDC 2324850 (9 h) and CCDC 2324851 (16b). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. The data supporting the findings of this study are available within the article and its Supplementary Information files. All data is available from the corresponding author upon request.
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Acknowledgements
We thank EPFL (Switzerland) and Swiss National Science Foundation (SNSF 20021-219764) for financial supports. RW thanks China Scholarship Council for fellowship (201908430132) and Scientific Research Fund of Hunan Provincial Education Department (N° 21A0245). XQZ thanks Yunan Normal University and Xiamen University for postdoctoral fellowships. We thank Dr. F. Fadaei-Tirani and Dr. R. Scopelliti for the X-ray structural analysis of compounds 7k, 8a, 9h, and 16b.
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R.W., X.Q.Z.,Q.W., J.Z. conceived and designed the experiments. R.W., X.Q.Z., M.D., R. L. carried out the experiments. R.W., Q.W., J.Z. interpreted the results and co-wrote the manuscript.
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Wang, R., Zhu, XQ., Djaïd, M. et al. Ynimines as versatile precursors to 2-imido- and 2-amido-1,3-dienes for stereodivergent diels–alder reactions. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70363-w
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DOI: https://doi.org/10.1038/s41467-026-70363-w
