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Stereodefined 1,1,3\u2010trisubstituted cyclobutane and 1,2,4\u2010trisubstituted bicyclo[2.1.1]hexane (BCH) serve as bioisosteres for\n                    <jats:italic>para<\/jats:italic>\n                    \u2010 and 1,2,4\u2010trisubstituted benzenes, respectively. Yet, general stereoselective routes to these frameworks remain underdeveloped. In this study, we report a photocatalytic transannular functional group migration (TFGM) strategy that enables highly diastereoselective synthesis of 1,1,3\u2010trisubstituted cyclobutanes from alkylidene cyclobutanes and diverse radical precursors at room temperature. The reaction proceeds through a rigid BCH\u2010type transition state, delivering exclusive\n                    <jats:italic>cis<\/jats:italic>\n                    \u2010selectivity. The mild conditions accommodate broad functional group tolerance and support the migration of various groups, including heteroarenes, nitrile, aldehyde, oxime, and alkene derivatives. This platform further provides general and modular entry to 1,2,4\u2010trisubstituted BCHs via a base\u2010promoted 5\u2010exo\u2010tet cyclization and cross\u2010coupling sequence. The resulting BCH scaffolds are effective bioisosteres of 1,2,4\u2010trisubstituted benzenes, demonstrated by BCH\u2010Olaparib and BCH\u2010Fluzoparib\u2014analogues of the anticancer drugs Olaparib and Fluzoparib. These analogues retain potent activity comparable to Olaparib in a panel of cancer cell lines (enhanced in breast and liver cells), and the preferred enantiomer of BCH\u2010Olaparib surpasses Olaparib in PARP1 inhibition, validating 1,2,4\u2010trisubstituted BCHs as faithful benzenoid bioisosteres for drug innovation.\n                  <\/jats:p>","DOI":"10.1002\/anie.7845758","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:11:02Z","timestamp":1790655062000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Photocatalytic Transannular Migration to Stereodefined Cyclobutanes and Bicyclo[2.1.1]hexanes as Benzenoid Bioisosteres"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1730-2415","authenticated-orcid":false,"given":"Hao\u2010Song","family":"Ren","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy East China University of Science and Technology  Shanghai P. 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