The phytocannabinoids from cannabis have been shown to possess a myriad of therapeutically important biological activities. The isolated compounds themselves may also be viewed as reactive species that can serve as starting materials for other structural derivatives through the use of different chemical transformations. These analog compounds maintain much of the molecular features of the phytocannabinoid starting materials while introducing minor structural modifications which can enhance their biological activity while maintaining their inherent safety of in humans and animals. This presentation will focus on the chemical transformation of phytocannabinoids into both known and new compounds of interest as therapeutic agents. One such chemical transformation being applied to phytocannabinoids today is the acid-catalyzed ring closure of CBD (ACRCC) reaction to produce both Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and Δ⁸-tetrahydrocannabinol (Δ⁸-THC) which also produces non-natural THC isomers such as iso-Δ⁸-tetrahydrocannabinol (iso Δ⁸-THC) and iso-Δ⁴⁽⁸⁾-tetrahydrocannabinol (iso Δ⁸-THC). We have previously reported iso Δ⁸-THC‘s impact on neuronal cell signaling. The conversion to a single THC isomer is of great importance today as so-called “hemp-derived” THC are being produced and formulated into consumable products such as edibles, beverages and vape pens. More recently, hydrogenation of THC derived from ACRCC reaction is being used to produce hexahydrocannabinol (HHC), a non-natural synthetic derivative that has recently received a lot of attention. Applying hydrogenation broadly to phytocannabinoid starting materials provides access to library of hydrogenated derivatives that includes hexahydrocannabinolic acid (HHCA). Another chemical transformation that we have recently explored is the hydrofluorination reaction of the double bonds present in phytocannabinoids. This reaction adds hydrogen fluoride across the double bonds generating mono-fluorinated derivatives of hydrogenated cannabinoids such produce 9-fluoro-hexahydrocannabinolic acid (9F-HHCA) and produce 9-fluoro-hexahydrocannabinol acid (9F-HHC). A series of novel fluorinated derivatives will be presented as potential leads for new drug discovery.

Mark Scialdone

Appearances