Tetrahydrocannabinol, isomers

Hollister LE Tetrahydrocannabinol isomers and homologues controlled effects of smoking. Nature 1970 227 968-969. 

Mechoulam, Chemistry and Biochemistry of Cannabis," 76 75 L.E. Hollister, Tetrahydrocannabinol Isomers and Homologues Contrasted Effects of Smoking, Nature 111 (1970) 968 G.W. Kinzer et al., The Fate of the Cannabinoid Components of Marijuana During Smoking, Bulletin on Narcotics 26 (1974) 41 A.R. Patel and G.B. Gori, Preparation and Monitoring of Marijuana Smoke Condensate Samples, Bulletin on Narcotics 27 (1975) 47. 

Alternatively, A9-tetrahydrocannbinol or simply tetrahydrocannabinol is frequently used in the scientific community. When using the short name tetrahydrocannabinol or just THC it always imphes the stereochemistry of the A 9-isomer. 

This compound and its related acidic form, A8-tetrahydrocannabinolic acid (A8-THCA, 2.13) are structural isomers of A9-THC. Although it is the thermodynamically stable form of THC, A8-THC (2.14) contributes approximately only 1% to the total content of THC in C. sativa. In the synthetic production process, A8-THC is formed in significantly higher quantities than in plants. 

The advances in isolation methods made possible a clarification of the chemistry of cannabis. In 1963, our group reisolated CBD and reported its correct structure and stereochemistry. A year later we finally succeeded in isolating pure A -tetrahydrocannabinol (A -THC), elucidated its structure, obtained a crystalline derivative and achieved a partial synthesis from CBD. Several years later, a minor psychotomimetically active constituent, A -THC, was isolated from marijuana. Whether this THC isomer is a natural compound, or an artifact formed during the drying of the plant, remains an open problem. 

The main active ingredients of cannabis are cannabinol, cannabidiol and several isomers of tetrahydrocannabinol, of which delta-9-tetrahydro-cannabinol (THC) is probably responsible for most of the psychoactive effects of the various preparations. It is of interest to note that THC does not contain nitrogen in its three-membered ring system. The structure of THC is shown in Figure 15.8. 

In order to identify cannabis products, one of the most frequently used methods is gas chromatography-mass spectrometry (GC-MS). The identification relies on the presence of A -THC, CBD and CBN in the sample, and to a lesser extent, the presence of A -THC (the isomer of the active principle of cannabis) and A -tetrahydrocannabinolic acid. The following presents a method that has been found to work, although there are a number of similar methods reported in the literature [9], The sample is prepared for GC-MS analysis as follows ... 

Jones, G. Paton, W.D.M. Nilsson, I.M. and Agurell, S. Relative pharmacological potency in mice of optical isomers of delta-1-tetrahydrocannabinol. Biochem Pharmacol 23 439-446,1974. 

Cannabinoids are a specific class of psychoactive compounds present in Indian cannabis (Cannabis sativa), including about 60 different molecules, the most representative being cannabinol, canna-bidiol and several isomers of tetrahydrocannabinol. Knowledge of the therapeutic activity of cannabis dates back to the ancient dynasties in China, where, already 5,000 years ago, cannabis was used for the treatment of asthma, migraine and some gynaecologic disorders. Said use later became so established that about in 1850 cannabis extracts were included in the US Pharmacopaeia and remained therein until 1947. 

Some of the substances that have been separated by this method are given in papers referred to by Morris and Morris (1964) amino acids, peptides (particularly those having molecular weights ranging from 500 to 5000), polypeptide antibiotics, proteins (including enzymes), carbohydrates (although for most compounds in this chemical class other fractionation methods are much more frequently applied), purines, pyrimidines, nucleic acid derivatives, tRNA s that are specific for various amino acids, organic acids, steroids, lipids, antibiotics that are not peptides, porphyrins, pterins, vitamin B,2 and other vitamins, lipoic acid, and alkaloids. The countercurrent-distribution procedure of Holley et al. (1965) is widely used, sometimes with modifications. Korte et al. (1965) have separated three isomers of tetrahydrocannabinol. 

Other examples of buffer gas selectivity include the resolution of arginine from phenylalanine in carbon dioxide but not in nitrogen the separation of lorazepam from diazepam in both helium and carbon dioxide but not in argon and nitrogen " the resolution of carbohydrate isomers such as methyl-P-D-mannopyranoside from methyl-a-D-mannopyranoside in carbon dioxide but not nitrogen and the resolution of heroin from THC (tetrahydrocannabinol) using nitrous oxide as the buffer gas in a commercial IMS instrument. ... 

One approach to ent-4 -tetrahydrocannabinol, which is independent ofthe chiral pool, was developed by David Evans (reaction scheme see next page). [143] Via enantioselective Diels-Alder reaction on a copper-bis-(oxazoline) complex, there is obtained a cyclohexenecarboxamide, which after conversion into its benzyl ester and an exhaustive Grignard reaction gives ent-menth-l-ene-3,8-diol. Also this isomer can be converted in an analogous matmer stepwise into tetrahydrocannabinol. A -Tetrahydrocannabinol would be correspondingly accessible by use ofthe antipode ofthe catalyst. 

Figure 6-6a). Tetrahydrocannabinol (THC), the active constituent of marijuana, also has the molecular formula CjiHjqOj (Figure 6-6b). Progesterone and THC are isomers they have the same chemical formula but veiy different structures. Does this mean that they have similar effects on the human body No The different structures result in different effects-structure is everything. Nature can take exactly the same atoms in exactly the same numbers and make two different molecules with drastically different properties and functions. One of them, progesterone, makes pregnancy possible the other, THC, alters the way the brain processes stimuli. 

Marijuana contains nearly 500 different chemicals. The most important one as far as psychoactive properties are concerned is A-9-tetrahydrocannabinol, also known as delta-9-THC (A -THC). Nature, being a brilliant synthetic chemist, just makes the single isomer (-)-A -THC. It is possible to make the other isomer in the laboratory, but (+)-A -THC has no psychoactive properties. 

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