Photoredox catalysis has emerged as a transformative tool in C–H functionalization, enabling new mechanistic platforms for generating C–C bonds via carbon-centered radicals. The application of radical photoredox catalysis not only offers a novel approach to constructing lactones, but also offers improved scope and atom-economy in comparison to previous lactonization techniques. The presence of lactone rings in many biologically and medicinally active compounds, including Simvastatin, Wortmannin, and (R)-(-)-Mevalactone, makes the synthesis of these molecules highly desirable. Herein, we report an approach for achieving 1,6-difunctionalization and intramolecular C–C bond formation at inert C–H bond sites via hydrogen atom transfer (HAT) with readily available photocatalysts and esters. Photocatalysts excited by visible blue light initiate a HAT event with the C(sp³)–H coupling partner to form a highly reactive radical. This approach can be applied to a vast pool of substrates, with both activated and unactivated C(sp³)–H coupling partners, to yield β-, γ-, and δ-lactones. Leveraging the radical stabilization and steric interactions on the ester substrates, further enhances site-selectivity of functionalization and cyclization while maintaining advantages of atom-economy and mild conditions. Molecular characterization, including ¹H/COSY/NOESY NMR, and High-Resolution Mass Spectroscopy confirms the formation of the cyclized products. This new synthetic method holds a promising outlook for advancing our understanding of HAT mechanisms involving unactivated C–H bonds and selective difunctionalization of esters. Selective functionalization of C(sp³)–H bonds and intramolecular cyclization chemistry opens up new avenues for efficient and simple syntheses for natural products, pharmaceuticals, and polymers.

Makeda Tekle-Smith

Columbia University

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