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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"<jats:p>Strained, multicyclic hydrocarbons are increasingly important structural motifs for drug discovery. In particular, substituted bicyclo[1.1.1]pentanes (BCPs) have risen to prominence as bioisosteres for the ubiquitous benzene ring. Despite their favorable pharmacokinetic properties, synthetic strategies toward BCPs suffer from significant drawbacks\u2014namely an overreliance on [1.1.1]propellane, an operationally challenging to utilize starting material which complicates scale-up and hampers widespread adoption of these motifs. In this work, the synthesis of 2,2-dibromo BCPs is described, presenting a class of versatile substituted BCPs and circumventing the need for [1.1.1]propellane-based precursors. Scalable access to these compounds is demonstrated in a simple and inexpensive process, and their applicability for medicinal chemistry campaigns is highlighted through the synthesis of a diverse range of valuable building blocks\u2014including highly sought-after bridge heteroarylated BCP derivatives which are prepared via an electrocatalytic cross-coupling procedure.<\/jats:p>","DOI":"10.1073\/pnas.2524130122","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T17:38:17Z","timestamp":1761759497000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":12,"title":["Dibromocarbene addition to bicyclo[1.1.0]butanes: A facile route to substituted bicyclo[1.1.1]pentanes"],"prefix":"10.1073","volume":"122","author":[{"given":"Flynn C.","family":"Attard","sequence":"first","affiliation":[{"name":"Research School of Chemistry, Australian National University","place":["Canberra, Australia"]},{"name":"Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Australian National University","place":["Canberra, Australia"]},{"name":"Department of Chemistry, Scripps Research","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrii","family":"Slobodianyk","sequence":"additional","affiliation":[{"name":"Enamine Ltd.","place":["Kyiv, Ukraine"]},{"name":"Taras Shevchenko National University of Kyiv","place":["Kyiv, Ukraine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Bychek","sequence":"additional","affiliation":[{"name":"Enamine Ltd.","place":["Kyiv, Ukraine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaroslav","family":"Panasiuk","sequence":"additional","affiliation":[{"name":"Enamine Ltd.","place":["Kyiv, Ukraine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Neigenfind","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Scripps Research","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Massaro","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Scripps Research","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Gardiner","sequence":"additional","affiliation":[{"name":"Research School of Chemistry, Australian National University","place":["Canberra, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vadym V.","family":"Levterov","sequence":"additional","affiliation":[{"name":"Enamine Ltd.","place":["Kyiv, Ukraine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9193-9053","authenticated-orcid":false,"given":"Phil S.","family":"Baran","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Scripps Research","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel K.","family":"Mykhailiuk","sequence":"additional","affiliation":[{"name":"Enamine Ltd.","place":["Kyiv, Ukraine"]},{"name":"Taras Shevchenko National University of Kyiv","place":["Kyiv, Ukraine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara R.","family":"Malins","sequence":"additional","affiliation":[{"name":"Research School of Chemistry, Australian National University","place":["Canberra, Australia"]},{"name":"Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Australian National University","place":["Canberra, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,10,29]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00473"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1039\/c2md20347b"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm901241e"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1039\/C8OB02812E"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41570-024-00623-0"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.6b00281"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm300094u"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c00746"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2008.11.015"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm960254o"},{"key":"e_1_3_4_11_2","volume-title":"Solid Forms of a Compound for Modulating Cot","author":"Carra E. 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Distinct differences between the spectral data of confirmed 2 2-dibromobicyclo[1.1.1]pentane derivatives reported in the present work relative to the previously reported data (IR and NMR) by Hall et al. in 1971 corroborate misassignment of the original structure. 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