Organophotocatalytic radical relay for distal C(sp)–H lactonization of unactivated alkenes

Abstract

We report a green and atom-economical strategy for distal lactonization, enabling the efficient construction of structurally diverse lactone frameworks under mild conditions. This protocol employs a low loading of a metal-free photocatalyst to enable distal Csp³-H activation at the C6 and C11 sites via the 1,5-HAT process, thereby avoiding the use of stoichiometric reagents and minimizing hazardous waste generation. Notably, the reaction proceeds with high regioselectivity at distal C6 and C11 positions, offering a valuable platform for site-selective molecular editing.γ-Lactones are versatile synthetic intermediates and privileged structural motifs widely found in bioactive natural products and pharmaceuticals. 1 For example, γ-decalactone contributes to the aromas of numerous foods, the antibacterial peptidoglycan biosynthesis inhibitor Avenaciolide, the neurotrophic sesquiterpene Jiadifenolide, etc. (Figure 1a). The classical methods for the synthesis of saturated γ-lactones commonly rely on strategies such as halo-lactonization or intramolecular substitution, which require prefunctionalized γpositions bearing electrophilic or nucleophilic functionalities. 2 Recently, the straightforward and attractive alternative is direct access to γ-lactones from the corresponding carboxylic acids, which often requires a transition-metal-based catalyst or a directing group (Figure 1b) . 3a-3g Baeyer-Villiger oxidation, although reliable, often displays limited regioselectivity and requires stoichiometric oxidants that generate substantial waste. 3h-3i Transition-metal-catalyzed methods, while powerful, often rely on expensive or toxic metals, directing groups, or stoichiometric oxidants, and may operate under harsh conditions with limited site. In addition, substrate scope and functional-group tolerance are frequently constrained. Moreover, conventional radical-based lactonization reactions often demand elevated temperatures or strong oxidants, leading to poor selectivity and competing side reactions. Accordingly, the development of a simple, mild, and efficient method to address these challenges remains highly desirable. Radical-mediated C(sp³)-H functionalization provides a complementary strategy for selectively activating γ-methylene C-H bonds in aliphatic amides via a 1,5-hydrogen atom transfer (1,5-HAT) pathway. The advent of photoredox catalysis has further expanded the synthetic toolbox by activating inert and inaccessible C(sp3)–H bonds under mild, redox-neutral conditions. Because bond dissociation