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Organocatalytic stereoselective [8+2] and [6+4] cycloadditions

Nature Chemistry volume 9, pages 487–492 (2017)Cite this article

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Abstract

Cycloadditions that involve more than six π electrons are termed higher-order cycloadditions and are an excellent tool for solving complex synthetic challenges, as they provide direct access to polycyclic scaffolds that contain medium-sized rings. They have interesting synthetic potential for the discovery of new bioactive molecules and in natural product synthesis. It is peculiar that stereocontrolled [8+2] and [6+4] cycloadditions have been largely neglected for the past 50 years. Here we demonstrate a cross-dienamine activation of 2-cyclopentenone and the unprecedented endocyclic linear-dienamine activation of 2-cyclohexenones and 2-cycloheptenones. These dienamine intermediates undergo aminocatalytic stereoselective [8+2], [6+4] and formal [4+2] cycloadditions with various heptafulvenes. The periselectivities of the cycloadditions are controlled based on the ring size of the 2-cycloalkenones and the substitution patterns of the heptafulvenes. The chiral products obtained undergo various chemical and photochemical single-step transformations that give access to other classes of all-carbon polycyclic scaffolds.

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Figure 1: Aminocatalytic dienamine activation of 2-cycloalkenones and their applications in higher-order cycloadditions.
Figure 2: Elucidating the reaction pathway.
Figure 3: Control of formal [4+2] and [8+2] periselectivity of the cycloadditions of 2-cyclohexenones 7 by reactions with heptafulvenes.
Figure 4: Rationalization of peri- and stereoselectivities.
Figure 5: Selected transformations.

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Acknowledgements

This work was made possible by grants from Aarhus University and Carlsberg Foundation's ‘Semper Ardens’ programme. This research was supported by European Social Fund's Doctoral Studies and Internationalisation Programme DoRa, which is carried out by Foundation Archimedes. Our thanks are expressed to L. Næsborg, V. H. Lauritsen and M. E. Jensen for X-ray analysis.

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Authors and Affiliations

  1. Department of Chemistry, Aarhus University, Aarhus C, DK-8000, Denmark

    Rasmus Mose, Gert Preegel, Jesper Larsen, Sofie Jakobsen, Eva Høgh Iversen & Karl Anker Jørgensen

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  1. Rasmus Mose
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Contributions

R.M. and G.P. optimized the reactions. R.M., G.P., J.L. and E.H.I. performed the experiments. S.J. performed the calculations. R.M. and K.A.J. wrote the manuscript.

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Correspondence to Karl Anker Jørgensen.

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Crystallographic data for compound 4aA (CIF 182 kb)

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Crystallographic data for compound 11 (CIF 30 kb)

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Structure factors file for compound 11 (HKL 767 kb)

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Crystallographic data for compound 15 (CIF 1534 kb)

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Crystallographic data for compound 16 (CIF 15 kb)

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Structure factors file for compound 16 (HKL 717 kb)

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Mose, R., Preegel, G., Larsen, J. et al. Organocatalytic stereoselective [8+2] and [6+4] cycloadditions. Nature Chem 9, 487–492 (2017). https://doi.org/10.1038/nchem.2682

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