Unveiling the Origin of Regioselectivity in Iron(III)-Promoted Friedel-Crafts Synthesis of Cannabinoids: Theoretical Studies and Synthetic Applications.

Phytocannabinoids, particularly cannabidiol (CBD), are important targets in pharmaceutical and industrial development due to their promising biological properties. However, access to CBD and related cannabinoids remains limited by their low abundance and variable composition in plant sources, whereas chemical synthesis of CBD is often hampered by the poor regioselectivity and modest yields associated with conventional Friedel-Crafts approaches. We recently disclosed an FeCl3·6H2O-catalyzed reaction that enables diastereoselective and highly regioselective preparation of (-)-CBD under mild and scalable conditions. Here, we report experimental and computational mechanistic studies that provide insight into the origin of this regioselectivity and support the involvement of a catalytically relevant iron(III)-olivetol complex, which reacts regioselectively with the carbocation generated from the terpenic unit. We also define the scope and limitations of the method and demonstrate its synthetic utility through the efficient formal synthesis of bioactive cannabinoid derivatives, including HU-210 and ajulemic acid.