Org Biomol Chem. 2026 Jul 20. doi: 10.1039/d6ob00784h. Online ahead of print.

ABSTRACT

Cannabis sativa is a major source of phytocannabinoids, with cannabidiol (Δ⁹-CBD) serving as a key precursor to THC-type cannabinoids through acid-catalyzed intramolecular cyclization. However, the origin of regioselectivity under different conditions remains unclear. Herein, combined experimental and theoretical approaches were employed to elucidate the pathways leading to Δ⁹-THC, Δ⁸-THC, and iso-Δ⁸-THC under Brønsted (p-TsOH) and Lewis (BF₃) acid catalysis in batch and continuous-flow systems, respectively. Experimentally, product distribution is strongly temperature-dependent. Under both catalytic conditions, lower temperatures favor Δ⁹-THC formation. Under p-TsOH, harsher conditions promote Δ⁹-THC/Δ⁸-THC interconversion and enrichment of Δ⁸-THC, whereas BF₃ favored formation of iso-Δ⁸-THC at higher temperatures and longer reaction times. Computational simulations reveal that BF₃ promotes parallel cyclization pathways leading to Δ⁹-THC and iso-Δ⁸-THC, whereas p-TsOH follows a sequential mechanism involving cyclization followed by double-bond isomerization. The calculations further indicate that Δ⁹-THC is the kinetic product, formed through lower activation barriers (ΔG^‡), whereas Δ⁸-THC and iso-Δ⁸-THC are thermodynamically favored under Brønsted and Lewis conditions, respectively, displaying lower final free energies (ΔG). Overall, regioselectivity emerges from the interplay between temperature and catalyst type, with dual Lewis-Brønsted activation by BF₃ driving rapid cyclization and suppressing isomerization pathways, as supported by DFT calculations.

PMID:42475118 | DOI:10.1039/d6ob00784h