Atom Transfer Radical Coupling Enables Highly Enantioselective Carbo-Oxygenation of Alkenes with Hydrocarbons

Abstract

The selective functionalization of C­(sp3)–H bonds has emerged as a transformative approach for streamlining synthetic routes, offering remarkable efficiency in the preparation and modification of complex organic molecules. However, the direct enantioselective transformation of hydrocarbons to medicinally valuable chiral molecules remains a significant challenge that has yet to be addressed. In this study, we adopt an atom transfer radical coupling (ATRC) strategy to achieve the asymmetric functionalization of C­(sp3)–H bonds in hydrocarbons. This approach involves intermolecular H atom transfer (HAT) between a hydrocarbon and an alkoxy radical, leading to the formation of a carbon-centered radical. The resulting radical adds to alkenes, generating a new radical species that is intercepted by a chiral copper-mediated C–O bond coupling. By employing this method, we can directly access valuable chiral lactones bearing a quaternary stereocenter with high efficiency and excellent enantioselectivity. Importantly, ATRC exhibits great potential as a versatile platform for achieving stereoselective transformations of hydrocarbons.

Asymmetric Three-Component Radical Alkene Carboazidation by Direct Activation of Aliphatic C–H Bonds

“…Herein, we demonstrate such an asymmetric three-component carboazidation of α,β-enones with inexpensive hydrocarbon chemical feedstocks through the direct and selective activation of aliphatic C–H bonds by merging HAT and chiral iron catalysis. In this protocol, the peroxide [e.g., tert -butyl peroxybenzoate (TBPB)] is reduced by iron complexes to generate an alkoxyl radical, which can readily abstract a hydrogen atom from unactivated hydrocarbons, thereby providing a carbon-centered radical. − Then, radical addition to the α,β-enone would afford a trisubstituted α-keto radical species, followed by a chiral iron­(III)-catalyzed intramolecular enantioselective azido radical ligand transfer to deliver the desired carboazidation product (Scheme C). This strategy shows good compatibility with various primary, secondary, and tertiary alkyl radicals, producing the corresponding enantioenriched chiral alkylazides bearing a quaternary stereocenter in good to excellent enantioselectivity.…”