A research group from the University of Leipzig has developed a new method for synthesizing cis-tetrahydrocannabinol (THC) - a natural substance that is part of the cannabis plant, which causes the characteristic psychoactive effect and could be used in the pharmaceutical industry, among other things.
"With our strategy, it is now possible to produce cis-tetrahydrocannabinoids and to study their biological activity," explains researcher Caroline Dorsch, who shared her new findings with Prof. Dr. Christoph Schneider from the Institute of Organic Chemistry published in the journal "Angewandte Chemie".
So far, she emphasizes, there has been no way of synthesizing this structural class in a standardized way. With their synthesis method, which is as simple as it is inexpensive and closely based on nature, the Leipzig researchers have made the substance class of cis-tetrahydrocannabinoids accessible for a wide range of applications for the first time. It is clearly superior to previous methods, which require many steps and large amounts of chemicals and solvents. With the new method, the substance can be synthesized in high overall yield and excellent optical purity.
Tetrahydrocannabinol is one of the phytocannabinoids produced in the cannabis plant. These compounds accumulate primarily in the inflorescences of female plants. It has been known since the 1960s that this also causes the characteristic psychotropic effect in the body. Research on this natural compound led to the elucidation of the underlying mechanism of its effects - the endocannabinoid system. This is the name of the signal transduction pathway in the body that tetrahydrocannabinol influences and which causes the characteristic effect, for example when smoking marijuana.
“Influencing this signaling pathway is of pharmaceutical relevance. Cannabinoids can trigger a variety of effects in the body, for example as pain relievers, antipsychotics or antiepileptics. However, there are currently only a few cannabinoids on the pharmaceutical market. Prescribing natural cannabis products is sometimes considered an exception,” says Dorsch. The possession, cultivation and distribution of narcotic cannabis products is prohibited in Germany under the Narcotics Act. Samples containing trans-configured cannabinoids are classified as narcotic. Recent studies have shown that cis-THC accumulates primarily in parts of the cannabis plant where the related trans compounds are absent. This has so far led to the classification of such samples as textile or non-narcotic hemp. However, cis-THC exhibits mild psychotropic activity.
THC is one of the chiral compounds. Chirality describes a spatial arrangement of atoms in a molecule in which mirroring does not lead to self-image. Image and mirror image of such compounds are called enantiomers and often have different effects in the human organism. Nature can easily direct the directed synthesis of these compounds. Under laboratory conditions, however, this is a major challenge that could be successfully mastered in the present work. The newly developed process also requires very small amounts of the catalyst, which is also very attractive from an ecological point of view in terms of saving energy and resources and minimizing by-products.
Cis-THC has received less research than the more potent trans-THC due to its milder psychotropic activity. Nonetheless, other natural compounds not derived from cannabis also share a backbone with cis-THC. These represent valuable compounds whose promising pharmacological activity profile has not yet been fully explored. With the new strategy now presented, an important cornerstone has been laid for a more detailed investigation of this family of substances. Using this method, a number of other natural and non-natural representatives of this structural class could be produced in addition to cis-THC.
Original title of the publication in “Angewandte Chemie”: “Brønsted Acid Catalyzed Asymmetric Synthesis of cis-Tetrahydrocannabinoids”, doi.org/10.1002/anie.202302475.
Press release from “idw – Informationsdienst Wissenschaft” from May 17.05.2023th, XNUMX