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

O-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.