Copper-Catalyzed Radical Enantioselective Synthesis of γ-Butyrolactones with Two Non-vicinal Carbon Stereocenters

Chiral heterocycles with two or more carbon stereocenters are quite important skeletons in many fields. However, powerful strategies for the construction of such synthetically valuable heterocycles, especially with two or more remote carbon stereocenters, have largely lagged behind. We report here a powerful method for the synthesis of chiral gamma-butyrolactones with two non-vicinal carbon stereocenters from readily available chemical feedstocks under mild conditions. Both of the two diastereoisomers can be obtained with good to excellent enantioselectivities. The well-designed copper/PyBox catalytic system overrides the intrinsic stereoinduction of the close chirality center generated by the previous innocent radical addition step. Nevertheless, this work has the power to selectively provide one single diastereoisomer by taking advantage of the epimerization effect but also to synthesize all four diastereoisomers with the pair of chiral ligands L2 and L2 ' having opposite chirality. The obtained useful chiral gamma-butyrolactones can be synthetically transformed into acyclic or cyclic molecules with two non-vicinal carbon stereocenters. Mechanistic studies reveal that this radical reaction follows a linear relationship and can be well performed with a less loading amount of ligand compared to that of the copper catalyst.

Automated summary

Chiral gamma-butyrolactones with two non-vicinal carbon stereocenters were efficiently synthesized using a well-designed copper/PyBox catalytic system. This method overcame the intrinsic stereoinduction of the close chirality center and achieved good to excellent enantioselectivities for both diastereoisomers. Additionally, the method selectively provided a single diastereoisomer through epimerization effect and synthesized all four diastereoisomers using opposite chiral ligands L2 and L2'. The obtained chiral gamma-butyrolactones can be further transformed into acyclic or cyclic molecules with two non-vicinal carbon stereocenters. Mechanistic studies revealed a linear relationship in this radical reaction, requiring less loading of ligand compared to the copper catalyst.