Modular synthesis of planar-chiral cycloalkenes via trans-retentive trapping of π-allyl-Pd dipoles

Planar-chiral cycloalkenes are challenging synthetic targets due to the medium-sized ring and the trans-configured olefin. Asymmetric resolution of racemic E-cycloalkenes, UV-induced asymmetric isomerization of Z-cycloalkenes, and asymmetric intramolecular cyclization of olefinic substrates are known as the limited approaches to these scaffolds. However, these methods usually suffer from tedious synthesis, harsh conditions, and insufficient structural diversity. Here, we present a novel palladium-catalyzed asymmetric [7+2] cycloaddition to facilitate the modular synthesis of planar-chiral 9-membered cycloalkenes from readily available chemicals. Excellent selectivity for planar chirality was achieved by retaining the trans-2H configuration of the π-allyl-Pd species throughout the whole process. Mechanistic studies were performed to elucidate the pivotal role of hydrogen bonding from the chiral ligand in enhancing both reaction efficiency and stereocontrol. In addition, synthetic transformations of planar chiral cycloalkene products and their applications in the identification of anticancer agents and selective bioimaging of cancer cells demonstrated the synthetic value of this new methodology. This research provides a promising way to access synthetically valued planar-chiral cycloalkenes.