Diastereoselective and Scalable Synthesis of 6-(S)-Hydroxycannabidivarin

Abstract

The synthesis of 6-(S)-hydroxycannabidivarin was required to assess its biological activity in the treatment of neurological disorders. A novel and scalable synthesis has been developed where the key step involves a Friedel-Crafts alkylation of phloroglucinol with (1S,2R,5R)-2-hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclohex-3-en-1-ylbenzoate. Careful optimization of the reaction conditions identified trifluoromethanesulfonic acid in isopropyl acetate as the best catalyst/solvent combination, providing optimum regioselectivity, diastereoselectivity, and yield for this step. This enabled the multigram synthesis of 6-(S)-hydroxycannabidivarin in 10 steps from S-(+)-carvone.