The Π-bonds in unsaturated organic molecules are typically associated with having well-defined geometries. However, these geometries can be distorted when constrained into a rigid system, leading to heightened reactivity of the Π-bond, which enables otherwise challenging transformations to proceed. While unsaturated compounds with bent geometries have been well utilized (e.g., benzyne, cyclooctyne), the corresponding study of transient strained intermediates that display other types of geometric distortion remains underdeveloped.1
Toward this end, we recently disclosed practical synthetic chemistry of cubene,2 which displays both bending and significant pyramidalization associated with the alkene. While the intermediacy of cubene has been validated in seminal contributions by Eaton,3,4 this remarkable compound remains relatively understudied, with unconventional properties associated with the strained olefin. This presentation will focus on our studies, which demonstrate the in situ generation of cubene and its trapping in cycloaddition reactions. These transformations provide intricate structures that bear four highly substituted, contiguous carbon centers embedded in complex, three-dimensional frameworks. In addition, the geometric distortion parameters that lead to the unusual properties of cubene will be discussed. Overall, this study advances the field of strained intermediate chemistry, while also providing a means to access cubane derivatives, which are valuable in medicinal chemistry.5,6
1. L. McDermott, Z. G. Walters, A. M. Clark, N. K. Garg. Nat. Synth. 2025, 4, 421-431.
2. J. Ding,† S. A. French,† C. A. Rivera,‡ A. T. Meza,‡ D. C. Witkowski,‡ K. N. Houk, N. K. Garg. Nat. Chem. 2026, https://doi.org/10.1038/s41557-025-02055-9.
3. P. E. Eaton, M. Maggini. J. Am. Chem. Soc. 1988, 110, 7230–7232.
4. K. Lukin, P. E. Eaton. J. Am. Chem. Soc. 1995, 117, 7652–7656.
5. Chalmers, B. A. et al. Angew. Chem. Int. Ed. 2016, 55, 3580–3585.
6. M. P. Wiesenfeldt et al. Nature 2023, 618, 513–518.