Bioinspired Three-bond Disconnection Approach for the Synthesis of (±)-Cannabicitran and its Derivatives

Cannabicitran [(±)-CBT-C, 1] is a minor phytocannabinoid found in very low concentrations (0.2-0.9%) in the flowers of female Cannabis sativa plants¹ and has been the subject of a limited number of pharmacological studies.² (±)-CBT-C (1) is biosynthesized from the phytocannabinoid cannabigerol (CBG, 3), via 
cannabichromene [(±)-CBC, 2], and has been synthesized using inefficient approaches.³ Herein, we accomplished the bioinspired synthesis of (±)-CBT-C (1) and its derivatives (4 and 5) via a DDQ-promoted double cyclization of CBG (3) and corresponding derivatives,⁴ in yields ranging from 18% to 62%. The double cyclization is presumed to involve a hydride abstraction⁵ followed by an oxidation-reduction sequence, both mediated by DDQ, which can be affected by strongly electron-withdrawing substituents. Consequently, (±)-CBC derivatives (6 and 7) were obtained in some cases, with yields of 55% and 56%. Currently, efforts toward the reoptimization of the reaction conditions for compounds 4 and 5 are underway.