Deacylative Homolysis of Ketone C(sp3)–C(sp2) Bonds: Streamlining Natural Product Transformations

The homolytic cleavage of C–C bonds adjacent to specific functional groups has lately emerged as a versatile approach for molecular diversification. Despite the ubiquity and synthetic utility of ketones, radical fragmentation of their α-C–C bonds has proven to be a formidable challenge. Here, we present a broadly applicable deacylative strategy designed to homolytically cleave aliphatic ketones of various complexities, including transformations of cycloalkanones into carboxylic acids tethered to C-centered free radicals that can be engaged in diverse radical-based processes. The method involves ketone activation through treatment with hydrogen peroxide, yielding gem-dihydroperoxides. Subsequent single-electron-transfer reduction mediated by a low-valent metal complex generates alkyl radicals that can be captured selectively with a radicophile of choice, including through catalytic cross-coupling. The logic of our deacylative functionalization is exemplified by the total synthesis of 14 natural products, one analogue, and two drugs starting from readily available natural products, showcasing its transformative power in complex settings. This approach obviates the need for complex reagents and allows the controlled conversion of ketones to reconstructed products, making the process highly applicable across a spectrum of domains.