Photoredox-Catalyzed Activation of C(sp3)–H Acids and Total Synthesis of Hyperolactone C

We present a detailed study on photoredox catalysis platforms that directly engage 1,3-dicarbonyl C(sp3)–H acids towards radical reactions. This platform enables redox-neutral hydroalkylation and cross-coupling, as well as oxidative transformations that demonstrably improve on the prior state of the art. Interrogations of the underlying catalytic cycle and mechanism for this platform through kinetic, thermodynamic, and computational studies enabled the 4-step synthesis of the spirocyclic natural product hyperolactone C and unnatural analogues. The present investigations also demonstrate the key role of lithium trifluoroacetate under complementary Ce-containing and Ce-free photoredox conditions to enable ligand to metal charge transfer (LMCT) or multi-site proton coupled electron transfer (MS-PCET) activations, respectively.