Synthesis of Spiro Carbocycles via Methyl β-C(sp 3 )–H Functionalization of Cyclic Aliphatic Acids

Despite the superior innate reactivity of methyl C–H bonds over methylene C–H bonds in acyclic substrates, selective activation of methyl C–H bonds in carbocycles remains a significant challenge. Recent effective bifunctional pyridone ligands have consistently demonstrated selectivity toward methylene C–H bonds on various cyclic carboxylic acids. Selective functionalization of β-methyl C–H bonds of cyclic carboxylic acids could further expand the diversity of carbocycles, especially as this reactivity could open a new route for the synthesis of spirocyclic scaffolds desirable in medicinal chemistry. Herein, we report a ligand-controlled β-C(sp 3 )–H methyl olefination and arylation that enables efficient syntheses of spirocyclic lactones, spiro-3,4-dihydrocoumarins, and spirocyclic ketones. Computational and deuterium incorporation studies suggest that MPAA (mono- N -protected amino acid) and MPAThio (mono- N -protected amino aryl thioether) ligands reverse the preference for methylene C–H activation observed with bidentate pyridone ligands by favoring the activation of primary C–H bonds. Furthermore, sequential functionalization of both methyl and methylene C–H bonds in cyclic acids was realized to significantly expand the structural diversity of carbocycles.