Work

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

Year: 2026

Type: article

Abstract: 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.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.6c01021

Authors: Tao Sheng, Zhihan Zhao, Yilin Lu, Nikita Chekshin, Jin-Quan Yu

Institution: Scripps Research Institute

Language: English

Topic: Catalytic C–H Functionalization Methods

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: green

Funders: National Institutes of Health, National Institute of General Medical Sciences

Award: Enantioselective and site-selective C-H activation reactions with Bifunctional ligands