A novel phytocannabinoid isolated from Cannabis sativa L. with an in vivo cannabimimetic activity higher than Δ9-tetrahydrocannabinol: Δ9-Tetrahydrocannabiphorol
Isolation and characterization of natural CBDP and Δ9-THCP
In order to selectively obtain a cannabinoid-rich fraction of FM2, n-hexane was used to extract the raw material instead of ethanol, which carries other contaminants such as flavonoids and chlorophylls along with cannabinoids26. An additional dewaxing step at −20 °C for 48 h and removal of the precipitated wax was necessary to obtain a pure cannabinoids extract. Semi-preparative liquid chromatography with a C18 stationary phase allowed for the separation of 80 fractions, which were analyzed by LC-HRMS with the previously described method. In this way, the fractions containing predominantly cannabidiphorolic acid (CBDPA) and tetrahydrocannabipgorolic acid (THCPA) were separately subject to heating at 120 °C for 2 h in order to obtain their corresponding neutral counterparts CBDP and Δ9-THCP as clear oils with a >95% purity. The material obtained was sufficient for a full characterization by 1H and 13C NMR, circular dichroism (CD) and UV absorption.
Stereoselective synthesis of CBDP and Δ9-THCP
(-)-trans-Cannabidiphorol ((-)-trans-CBDP) and (-)-trans-Δ9-tetrahydrocannabiphorol ((-)-trans-Δ9-THCP) were stereoselectively synthesized as previously reported for the synthesis of (-)-trans-CBDB and (-)-trans-Δ9-THCB homologs11,12,24. Accordingly, (-)-trans-CBDP was prepared by condensation of 5-heptylbenzene-1,3-diol with (1 S,4 R)-1-methyl-4-(prop-1-en-2-yl)cycloex-2-enol, using pTSA as catalyst, for 90 min.
Longer reaction time did not improve the yield of (-)-trans-CBDP because cyclization of (-)-trans-CBDP to (-)-trans-Δ9-THCP and then to (-)-trans-Δ8-THCP occurred. 5-heptylbenzene-1,3-diol was synthesized first as reported in the Supporting Information (Supplementary Fig. SI-1). The conversion of (-)-trans-CBDP to (-)-trans-Δ9-THCP using diverse Lewis’ acids, as already reported in the literature for the synthesis of the homolog Δ9-THC27,28,29, led to a complex mixture of isomers which resulted in an arduous and low-yield isolation of (-)-trans-Δ9-THCP by standard chromatographic techniques.
Therefore, for the synthesis of (-)-trans-Δ9-THCP, its regioisomer (-)-trans-Δ8-THCP was synthesized first by condensation of 5-heptylbenzene-1,3-diol with (1 S,4 R)-1-methyl-4-(prop-1-en-2-yl)cycloex-2-enol, as described above, but the reaction was left stirring for 48 hours. Alternatively, (-)-trans-CBDP could be also quantitatively converted to (-)-trans-Δ8-THCP in the same conditions. Hydrochlorination of the Δ8 double bond of (-)-trans-Δ8-THCP, using ZnCl2 as catalyst, allowed to obtain (-)-trans-HCl-THCP, which was successively converted to (-)-trans-Δ9-THCP in 87% yield by selective elimination on position 2 of the terpene moiety using potassium t-amylate as base (Fig. 2a).
This article originally appeared here in https://www.weedworldmagazine.org/2020/01/21/a-novel-phytocannabinoid-isolated-from-cannabis-sativa-l-with-an-in-vivo-cannabimimetic-activity-higher-than-%ce%b49-tetrahydrocannabinol-%ce%b49-tetrahydrocannabiphorol/