Construction of enantioenriched eight-membered lactones via Pd-catalyzed asymmetric (6+2) dipolar annulation

Concise synthesis of eight-membered lactones, a kind of medium-sized heterocycles widespread in many bioactive natural products, is highly significant. However, it still remains a challenge due to unfavorable entropic factor and transannular interaction. Herein, we disclose an enantioselective synthesis of eight-membered lactones through a Pd-catalyzed asymmetric (6+2) dipolar annulation of vinyl oxetanes and alpha-diazo ketones (20 examples, up to 93% yield and 95:5 er). This reaction features simple operation, mild conditions and good enantiocontrol, especially the challenging chiral all-carbon quaternary stereocenter. A newly developed chiral hybrid P,S ligand and the in-situ photo-generation of ketene dipolarophiles are crucial to this success.

Automated summary

The concise synthesis of eight-membered lactones, which are widely found in many bioactive natural products, has been a challenging task. In this study, an enantioselective synthesis of eight-membered lactones through a Pd-catalyzed asymmetric (6+2) dipolar annulation was successfully achieved. The reaction exhibits simple operation, mild conditions, and good enantioselectivity.