Synthesis of Spiro Carbocycles via Methyl β-C(sp3)-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(sp3)-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.