Lactonization of Acyloxy Radicals

Carboxylic acids have been used extensively as weak nucleophiles in lactonization and esterification processes involving activated electrophiles. Conversion of these building blocks into carboxyl radicals furnishes reactive species that are electrophilic in character but susceptible to decarboxylation. This high propensity for fragmentation, assessed to proceed at rates of 10 9-11 s -1 in the case of acyloxy radicals, has facilitated access to carbon radicals but impeded exploration of umpolung C–O bond forming reactions through non-decarboxylative pathways. Herein, we report an anti -Markovnikov lactonization of acyloxy radicals with unactivated alkene coupling partners initiated through proton-coupled electron transfer (PCET) catalysis. The associative nature of PCET facilitates carboxyl radical stabilization through hydrogen bonding, suppressing typical decarboxylation pathways to enable competitive cyclization. This reactivity provides a mechanistically orthogonal entry to γ- and δ-lactone products complementary to existing nucleophilic functionalization strategies. Notably, a number of secondary and tertiary acids, which possess greater thermodynamic drivers for fragmentation, preferentially undergo radical lactonization under the reported conditions. Luminescence and NMR titration studies were performed to support the intermediacy of acyloxy radicals generated through PCET.