Carbon dioxide radical anion mediated regioselective carboxy-cyclization of alkenes

Cyclopropyl fatty acid linkers and their derivatives serve as high-value pharmacophores in pharmaceutical and biotechnological research. Despite significant advancements in the hydrocarboxylation and carboxy-alkylation of alkenes, controlling regioselectivity in the carboxy-cyclization of alkenes using the CO 2 radical anion remains a problem. Herein, we present the first retrosynthetic analysis-driven carboxy-cyclization strategy for alkenes and introduce a highly cost-efficient radical-polar crossover cyclization protocol that leverages carbon dioxide radical anion (CO 2 • - ) to achieve distinctive regioselectivity. This method enables the economical synthesis of a diverse range of functionalized cyclopropyl fatty acid linkers and seven-membered lactones from readily available starting materials, demonstrating high functional group compatibility. The practicality and versatility of this approach are further validated through gram-scale synthesis, late-stage transformations, and the direct formal total synthesis of three drug molecules, highlighting its broad potential in pharmaceutical development. A regioselective carboxy-cyclization of alkenes for the modular synthesis of cyclopropyl fatty acid linkers and seven-membered lactones via retrosynthesis analytical radical-polar crossover cyclization protocol involving carbon dioxide radical anion (CO 2 •− ) under visible light photoredox catalysis has been developed.