Photocatalytic Transannular Migration to Stereodefined Cyclobutanes and Bicyclo[2.1.1]hexanes as Benzenoid Bioisosteres

often correlates with clinical success, driving the replacement of flat arenes with saturated carbocycles. Stereodefined 1,1,3-trisubstituted cyclobutane and 1,2,4-trisubstituted bicyclo[2.1.1]hexane (BCH) serve as bioisosteres for para- and 1,2,4-trisubstituted 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-trisubstituted cyclobutanes from alkylidene cyclobutanes and diverse radical precursors at room temperature. The reaction proceeds through a rigid BCH-type transition state, delivering exclusive cis-selectivity. 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-trisubstituted BCHs via a base-promoted 5-exo-tet cyclization and cross-coupling sequence. The resulting BCH scaffolds are effective bioisosteres of 1,2,4-trisubstituted benzenes, demonstrated by BCH-Olaparib and BCH-Fluzoparib-analogues 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-Olaparib surpasses Olaparib in PARP1 inhibition, validating 1,2,4-trisubstituted BCHs as faithful benzenoid bioisosteres for drug innovation.