Palladium-catalyzed [4+4] cycloadditions for highly diastereo- and enantioselective synthesis of functionalized benzo[b]oxocines

Asymmetric cycloaddition reactions represent a powerful strategy for building up complex molecular architectures, especially those with medium-sized rings. Herein, we disclose a highly diastereo- and enantioselective cycloaddition strategy that involves the palladium-catalyzed [4 + 4] cycloaddition between ortho-quinone methides and gamma-methylene-delta-valerolactones. This method provided a straightforward and applicable approach to access various functionalized benzo[b]oxocines bearing adjacent all-carbon quaternary and tertiary stereocenters (38 examples, up to 95% yield, 20 : 1 dr, 98% ee). The process was efficient and scalable, and the products could be further transformed to various chiral eight-membered molecules. In addition, DFT calculations were performed to shed light on the mechanism of good stereoselectivities.

Automated summary

This study discloses a palladium-catalyzed cycloaddition strategy that achieves high selectivity and yield. The method is capable of constructing complex molecules with specific stereostructures, and the products can be further transformed into other chiral compounds.