Bicyclo1.1.1pentane (BCP) scaffolds are increasingly recognized as sp3-rich bioisosteres of benzene rings in drug discovery. Herein, we disclose a copper-catalyzed carbonylative transformation of 1.1.1propellane that enables efficient access to BCP-containing carboxylic acid derivatives. By leveraging a (carbamoyl)copper intermediate to intercept BCP radicals, this strategy circumvents the inherent challenges of direct carbonylation at sterically congested tertiary carbon radicals. The reaction displays a broad substrate scope, wide functional-group tolerance, and good chemoselectivity. Notably, this methodology enables the concise two-step synthesis of a BCP bioisostere of Tamibarotene, highlighting its practical utility in medicinal chemistry.
Yang et al. (Wed,) studied this question.