Stereoselective Synthesis of Cannabidiol and its Unnatural Enantiomer to Evaluate Anxiolytic‐Like Properties and Memory Interactions

Both (−)- and (+)-cannabidiol (CBD and ent-CBD, respectively) are synthesized via a highly diastereoselective CSA-catalyzed Friedel–Crafts reaction. ent-CBD exhibits anxiolytic-like effects in aged male mice without impairing long-term memory formation.

(−)-Cannabidiol (CBD) is a nonpsychotropic phytocannabinoid found in Cannabis strains with well-established pharmacological applications. Conversely, (+)-cannabidiol (ent-CBD), the non-natural enantiomer of CBD, has been involved in a limited number of pharmacological studies. Therefore, CBD and ent-CBD are synthesized using (R)-(−)- and (S)-(+)-carvone as starting materials, respectively, via a highly diastereoselective 10-camphorsulfonic acid (CSA) catalyzed Friedel–Crafts reaction as the key step. Pharmacological studies are conducted using the plus-maze discriminative avoidance task (PM-DAT) to evaluate the interaction between memory and anxiety-like behavior as well as spontaneous motor activity in both young adult and aged male mice. The results show that ent-CBD at a dose of 20 mg kg⁻¹ has an anxiolytic-like effect in aged male mice. In addition, ent-CBD did not impair discriminative avoidance memory formation at all doses evaluated.

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