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More recently, however, cubanes have emerged as attractive bioisosteres for aromatic rings. Although substituted derivatives are relatively common, ring-fused cubanes (a.k.a. \u201cfused cubes\u201d) are rare and can be difficult to access. Here, we report a strategy for the synthesis of fused cubes leveraging cubenes, unusual fleeting intermediates possessing hyperpyramidalized alkenes, in strain-promoted trapping reactions. Further, experimental and computational studies for the generation and reactivity of unsubstituted cubene and new substituted cubenes are disclosed. These studies not only push the limits of strained intermediate chemistry but also provide an entryway to highly functionalized fused cubes, including new three-dimensional hybrid structures and other unprecedented chemical space.<\/jats:p>","DOI":"10.1021\/jacs.6c15216","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T21:01:40Z","timestamp":1791838900000},"page":"44963-44972","source":"Crossref","is-referenced-by-count":0,"title":["Leveraging Cubenes\nto Access Highly Functionalized\nFused Cubes"],"prefix":"10.1021","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2089-3857","authenticated-orcid":true,"given":"Sarah A.","family":"French","sequence":"first","affiliation":[{"name":"University of California , , , ,","place":["Los Angeles, California, United States, 90095"]},{"name":"The University of Melbourne , , , ,","place":["Parkville, Victoria, Australia, 3010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1588-7017","authenticated-orcid":true,"given":"Christina A.","family":"Rivera","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasey K.","family":"Chung","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8387-5261","authenticated-orcid":true,"given":"K. N.","family":"Houk","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7793-2629","authenticated-orcid":true,"given":"Neil K.","family":"Garg","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"key":"2026102111095832600_cit1","first-page":"346","article-title":"A new series of ring compounds","volume":"29","author":"Beesley","year":"1913","journal-title":"Proc. Chem. Soc., London"},{"key":"2026102111095832600_cit2","doi-asserted-by":"publisher","first-page":"4224","DOI":"10.1021\/ja01113a026","article-title":"\u201cAcetylenic\u201d\nstrained hydrocarbons","volume":"75","author":"Weltner","year":"1953","journal-title":"J. Am. Chem. Soc."},{"key":"2026102111095832600_cit3","doi-asserted-by":"publisher","first-page":"6719","DOI":"10.1021\/cr500523x","article-title":"Cubane: 50 years later","volume":"115","author":"Biegasiewicz","year":"2015","journal-title":"Chem.\nRev."},{"key":"2026102111095832600_cit4","doi-asserted-by":"publisher","first-page":"2998","DOI":"10.1021\/jp511756v","article-title":"The thermochemistry of cubane 50 years after its synthesis:\nA high-level theoretical study of cubane and its derivatives","volume":"119","author":"Agapito","year":"2015","journal-title":"J. Phys. Chem. A"},{"key":"2026102111095832600_cit5","doi-asserted-by":"publisher","first-page":"962","DOI":"10.1021\/ja01059a072","article-title":"The cubane system","volume":"86","author":"Eaton","year":"1964","journal-title":"J. Am. Chem.\nSoc."},{"key":"2026102111095832600_cit6","doi-asserted-by":"publisher","first-page":"3157","DOI":"10.1021\/ja01069a041","article-title":"Cubane","volume":"86","author":"Eaton","year":"1964","journal-title":"J. Am. Chem. Soc."},{"key":"2026102111095832600_cit7","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1021\/acsenergylett.6b00075","article-title":"Energy storage in cubane derivatives and their real-time\ndecomposition: Computational molecular dynamics and thermodynamics","volume":"1","author":"Chaban","year":"2016","journal-title":"ACS Energy Lett."},{"key":"2026102111095832600_cit8","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1021\/ma9511715","article-title":"Synthesis and properties of a new\npolymer with a cubane-containing\nbackbone. Synthesis and metathesis polymerization and copolymerization\nof 1,4-bis(homoallyl)cubane","volume":"29","author":"Chauvin","year":"1996","journal-title":"Macromolecules"},{"key":"2026102111095832600_cit9","doi-asserted-by":"publisher","first-page":"4094","DOI":"10.1021\/ol501750k","article-title":"Cubanes in\nmedicinal chemistry; Synthesis\nof functionalized building blocks","volume":"16","author":"Wlochal","year":"2014","journal-title":"Org. Lett."},{"key":"2026102111095832600_cit10","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1002\/anie.199214211","article-title":"Cubanes:\nStarting materials for the chemistry of the 1990s and the new century","volume":"31","author":"Eaton","year":"1992","journal-title":"Angew. Chem., Int. 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Chem."},{"key":"2026102111095832600_cit13","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1038\/s41586-023-06021-8","article-title":"General access to cubanes as benzene\nbioisosteres","volume":"618","author":"Wiesenfeldt","year":"2023","journal-title":"Nature"},{"key":"2026102111095832600_cit15","doi-asserted-by":"publisher","first-page":"6752","DOI":"10.1021\/jm901241e","article-title":"Escape from flatland: Increasing\nsaturation as an approach to improving clinical success","volume":"52","author":"Lovering","year":"2009","journal-title":"J. Med. Chem."},{"key":"2026102111095832600_cit16","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1039\/c2md20347b","article-title":"Escape from\nflatland 2: Complexity and promiscuity","volume":"4","author":"Lovering","year":"2013","journal-title":"MedChemComm"},{"key":"2026102111095832600_cit17","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1038\/s41570-024-00623-0","article-title":"Three-dimensional saturated C(sp3)-rich bioisosteres for\nbenzene","volume":"8","author":"Tsien","year":"2024","journal-title":"Nat.\nRev. Chem."},{"key":"2026102111095832600_cit18","doi-asserted-by":"publisher","first-page":"3147","DOI":"10.1021\/cr950066q","article-title":"Bioisosterism: A rational approach in drug design","volume":"96","author":"Patani","year":"1996","journal-title":"Chem. 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Ed."},{"key":"2026102111095832600_cit22","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1002\/ijch.202100013","article-title":"Unmasking\ninherent chirality within the cubane skeleton","volume":"61","author":"Yoshino","year":"2021","journal-title":"Isr. J. Chem."},{"key":"2026102111095832600_cit23","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1021\/acs.orglett.2c03659","article-title":"Chiral auxiliary-directed\nsite-selective deprotonation of the cubane skeleton","volume":"25","author":"Takebe","year":"2023","journal-title":"Org. Lett."},{"key":"2026102111095832600_cit24","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1055\/a-2124-3823","article-title":"Decoration on cubane with an awareness\nof chirality:\nDevelopment of substituted cubane syntheses","volume":"56","author":"Takebe","year":"2024","journal-title":"Synthesis"},{"key":"2026102111095832600_cit25","doi-asserted-by":"publisher","first-page":"7971","DOI":"10.1039\/D3CC02164E","article-title":"A practical synthesis\nof 1,3-disubstituted cubane derivatives","volume":"59","author":"Kazi","year":"2023","journal-title":"Chem.\nCommun."},{"key":"2026102111095832600_cit26","doi-asserted-by":"publisher","DOI":"10.1002\/hlca.202300200","article-title":"Functionalization of cubane formation\nof C\u2013C and C\u2013heteroatom bonds","volume":"107","author":"Yasukawa","year":"2024","journal-title":"Helv. Chim. Acta"},{"key":"2026102111095832600_cit27","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.202401055","article-title":"Strategy for C\u2013H functionalization\nof cubanes: From stoichiometric reaction to catalytic methodology","volume":"27","author":"Hosaka","year":"2024","journal-title":"Eur. J. Org. Chem."},{"key":"2026102111095832600_cit29","doi-asserted-by":"publisher","first-page":"4590","DOI":"10.1002\/chem.201804225","article-title":"Nonconjugated hydrocarbons as rigid-linear\nmotifs: Isosteres for material sciences and bioorganic and medicinal\nchemistry","volume":"25","author":"Locke","year":"2019","journal-title":"Chem. - Eur. J."},{"key":"2026102111095832600_cit30","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1021\/op400181g","article-title":"Pilot-scale\nproduction of dimethyl 1,4-cubanedicarboxylate","volume":"17","author":"Falkiner","year":"2013","journal-title":"Org. Process Res. Dev."},{"key":"2026102111095832600_cit31","unstructured":"Parra, J. C. M.; Patarroyo, K. Y.; Sharma, A.; Alobo, D. O.; Cronin, L.\n          Elucidating the Size of Chemical\nSpace with Assembly Theory. 2026, arXiv:2606.11486.\narXiv.org e-Print archive. https:\/\/arxiv.org\/abs\/2606.11486."},{"key":"2026102111095832600_cit32","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1111\/cbdd.12260","article-title":"Two- and three-dimensional\nrings in drugs","volume":"83","author":"Aldeghi","year":"2014","journal-title":"Chem. Biol. Drug Des."},{"key":"2026102111095832600_cit33","doi-asserted-by":"publisher","first-page":"13389","DOI":"10.1021\/acs.jmedchem.0c00915","article-title":"Analysis of benzenoid\nsubstitution patterns in small molecule active pharmaceutical ingredients","volume":"63","author":"Nilova","year":"2020","journal-title":"J. Med. Chem."},{"key":"2026102111095832600_cit35","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1038\/s41557-025-02055-9","article-title":"Hyperpyramidalized\nalkenes with bond orders near 1.5 as synthetic building blocks","volume":"18","author":"Ding","year":"2026","journal-title":"Nat. Chem."},{"key":"2026102111095832600_cit37","doi-asserted-by":"publisher","first-page":"5746","DOI":"10.1021\/jo00309a018","article-title":"Cubanourea: A cubane-propellane","volume":"55","author":"Eaton","year":"1990","journal-title":"J. Org. Chem."},{"key":"2026102111095832600_cit38","doi-asserted-by":"publisher","first-page":"4281","DOI":"10.1021\/acs.orglett.5c00967","article-title":"Monobromination of cubane 1,4-diester: A synthetic\nhandle for fluorosulfonylation and Giese-type reactions","volume":"27","author":"Donnier-Valentin","year":"2025","journal-title":"Org. Lett."},{"key":"2026102111095832600_cit39","doi-asserted-by":"publisher","first-page":"4059","DOI":"10.1039\/D5CC07169K","article-title":"Photochemical\nHAT-mediated site-selective C(sp3)\u2013H aminoalkylation\nof cubanes catalyzed by TBADT","volume":"62","author":"Tang","year":"2026","journal-title":"Chem. Commun."},{"key":"2026102111095832600_cit40","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1021\/acs.orglett.3c04019","article-title":"C\u2013H\nalkylation of cubanes\nvia catalytic generation of cubyl radicals","volume":"26","author":"Hosaka","year":"2024","journal-title":"Org. Lett."},{"key":"2026102111095832600_cit41","doi-asserted-by":"publisher","first-page":"8717","DOI":"10.1021\/acs.orglett.1c03144","article-title":"ortho-C\u2013H\nacetoxylation of cubane enabling access to cubane analogues of pharmaceutically\nrelevant scaffolds","volume":"23","author":"Nagasawa","year":"2021","journal-title":"Org. Lett."},{"key":"2026102111095832600_cit42","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1039\/C8OB02959H","article-title":"Enantioselective\nsynthesis of (R)-2-cubylglycine including unprecedented\nrhodium mediated C\u2013H insertion of cubane","volume":"17","author":"Houston","year":"2019","journal-title":"Org. Biomol. Chem."},{"key":"2026102111095832600_cit43","doi-asserted-by":"publisher","first-page":"7230","DOI":"10.1021\/ja00229a057","article-title":"Cubene (1,2-dehydrocubane)","volume":"110","author":"Eaton","year":"1988","journal-title":"J.\nAm. Chem. Soc."},{"key":"2026102111095832600_cit44","doi-asserted-by":"publisher","first-page":"7652","DOI":"10.1021\/ja00134a009","article-title":"Dimerization of cubene. 1-Iodoadamantane as a probe\nfor radical intermediates","volume":"117","author":"Lukin","year":"1995","journal-title":"J. Am. Chem. Soc."},{"key":"2026102111095832600_cit46","doi-asserted-by":"publisher","DOI":"10.1126\/science.adq3519","article-title":"A solution to the\nanti-Bredt olefin synthesis problem","volume":"386","author":"McDermott","year":"2024","journal-title":"Science"},{"key":"2026102111095832600_cit47","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/s44160-025-00776-w","article-title":"Geometric\ndistortion\nas an enabling tool for organic synthesis","volume":"4","author":"McDermott","year":"2025","journal-title":"Nat.\nSynth."},{"key":"2026102111095832600_cit48","doi-asserted-by":"publisher","first-page":"3892","DOI":"10.1021\/acs.chemrev.0c01011","article-title":"o-Silylaryl triflates: A journey of\nKobayashi aryne precursors","volume":"121","author":"Shi","year":"2021","journal-title":"Chem. Rev."},{"key":"2026102111095832600_cit49","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1021\/jacsau.1c00214","article-title":"Leveraging fleeting\nstrained intermediates to access complex scaffolds","volume":"1","author":"Anthony","year":"2021","journal-title":"JACS Au"},{"key":"2026102111095832600_cit50","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1080\/17460441.2024.2322990","article-title":"Molecular hybridization: A powerful tool for multitarget\ndrug discovery","volume":"19","author":"De Sena Murteira Pinheiro","year":"2024","journal-title":"Expert Opin. Drug Discovery"},{"key":"2026102111095832600_cit51","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2020.127514","article-title":"Structural\nhybridization as a facile\napproach to new drug candidates","volume":"30","author":"Kumar","year":"2020","journal-title":"Bioorg. Med.\nChem. Lett."},{"key":"2026102111095832600_cit52","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1021\/ar7000843","article-title":"Hybrid molecules\nwith a dual mode of action: Dream or reality?","volume":"41","author":"Meunier","year":"2008","journal-title":"Acc. Chem. Res."},{"key":"2026102111095832600_cit53","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1016\/j.ejmech.2016.08.039","article-title":"Hybrid molecules:\nThe privileged scaffolds for various pharmaceuticals","volume":"124","author":"Shaveta","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"2026102111095832600_cit54","doi-asserted-by":"publisher","first-page":"4710","DOI":"10.1021\/ja00222a032","article-title":"Ab initio calculations of the olefin\nstrain energies\nof some pyramidalized alkenes","volume":"110","author":"Hrovat","year":"1988","journal-title":"J. Am. Chem.\nSoc."},{"key":"2026102111095832600_cit55","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1021\/ja00158a062","article-title":"Ab initio calculations of the relative energies of\n1,2-, 1,3-, and 1,4-dehydrocubane: Prediction of dominant through-bond\ninteraction in 1,4-dehydrocubane","volume":"112","author":"Hrovat","year":"1990","journal-title":"J. Am. Chem.\nSoc."},{"key":"2026102111095832600_cit56","doi-asserted-by":"publisher","first-page":"4164","DOI":"10.1021\/jp010023f","article-title":"Comment\non the relationship of the pyramidalization angle at a conjugated\ncarbon atom to the \u03c3 bond angles","volume":"105","author":"Haddon","year":"2001","journal-title":"J. Phys.\nChem. A"},{"key":"2026102111095832600_cit57","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1021\/cr00095a008","article-title":"Pyramidalized\nalkenes","volume":"89","author":"Borden","year":"1989","journal-title":"Chem. 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Sci."},{"key":"2026102111095832600_cit61","doi-asserted-by":"publisher","first-page":"205","DOI":"10.3390\/org5030010","article-title":"Spontaneous\nformation of stained anti-Bredt bridgehead\nalkenes upon computational geometry optimization of bicyclic \u03b2-halo\ncarbanions","volume":"5","author":"Breton","year":"2024","journal-title":"Organics"},{"key":"2026102111095832600_cit62","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/S0166-1280(96)04672-6","article-title":"Density\nfunctional study of N-methylpyrrole transformation\ninto N-methylisoindole through cycloaddition-elimination\nreactions","volume":"370","author":"Jursic","year":"1996","journal-title":"J. Mol. Struct.: THEOCHEM"},{"key":"2026102111095832600_cit63","doi-asserted-by":"publisher","first-page":"10070","DOI":"10.1002\/anie.201701486","article-title":"Analyzing reaction\nrates with the distortion\/Interaction\u2013activation\nstrain model","volume":"56","author":"Bickelhaupt","year":"2017","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026102111095832600_cit65","doi-asserted-by":"publisher","first-page":"6790","DOI":"10.1039\/C9OB01238A","article-title":"The cubane paradigm\nin bioactive molecule discovery: Further scope, limitations and the\ncyclooctatetraene complement","volume":"17","author":"Houston","year":"2019","journal-title":"Org. Biomol. Chem."},{"key":"2026102111095832600_cit66","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1002\/anie.199306121","article-title":"Photochemical\ncarboxylation of cubanes","volume":"32","author":"Bashir-Hashemi","year":"1993","journal-title":"Angew. 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