Cannabinoids synthesis

Exposure of the diastereomeric mixture of alcohols 497 to TFA leads to the construction two nonaromatic rings via a cation-alkene cyclization process. The chroman 498 is isolated as a 1 1 mixture of epimeric alcohols and is a key intermediate during cannabinoid synthesis (Equation 203) <2000JOC6576>. 

Lee CM, Michaels RJ, Zaugg HE, Dren AT, Plotnikoff NP, Young PR (1977) Cannabinoids. Synthesis and central nervous system activity of 8-substituted 10-hydroxy-5,5-dimethyl-5H-[ l]benzopyrano[4,3-c]pyridine and derivatives. J Med Chem 20 1508-1511... 

Tius MA, Kannangara GSK, Kerr MA, Grace KJS (1993) Halogenated cannabinoid synthesis. Tetrahedron 49 3291-3304... 

Razdan and coworkers (10) have reported a modification of the Petrzilka (9) cannabinoid synthesis. Thus, condensation of olivetol with (-h)-cjs- or trans-p-mentha-2,8-dien-l-ol in the presence of boron trifluoride-etherate and anhydrous magnesium sulfate at 0°C yielded (-)-A -THC, and practically no A -iso-mer was formed (Scheme 2). This modification represents a useful direct route to (-)-A -THCs, (-)-A -tetrahydrocaimabivarins, and their regiospecifically deuterated analogs (22-24). It was recently reported that the synthesis of a (-)-A -THC derivative was accomplished without the presence of a drying agent by keeping the reaction temperature at 0°C (25). 

Chapter 9 Synthetic Cannabinoids Synthesis and Biological Activities... 

Sanofi-Synthelabo researchers discovered pyrazole 53 and analogs to have potent Cannabinoid receptor-1 (CB-1) antagonist/inverse agonist activity and have progressed 53 into development for treatment of obesity and alcohol dependence. The synthesis of 53 was accomplished by heating the diketone sodium salt 51 with the aryl hydrazine hydrochloride in acetic acid to provide the intermediate 52, which was further derivatized... 

It is quickly deacylated in vivo and may qualify as a prodrug. The published synthesis is rather long and bears conceptual similarities to the synthesis of cannabinoids. It has some five asymmetric centers. Dane salt formation between 3,5-di-methoxyani1ine and ethyl acetoacetate followed by borohydride reduction gives synthon The amino group is protected by... 

Dronabinol (tetrahydrocannabinol), the active principle from cannabis and synthetic cannabinoids, nabilone and levonantradol are effective in treating nausea and vomiting in cancer chemotherapy. The mode of action is unclear but appears to involve cannabinoid CBi receptors. Cannabinoids have been shown to reduce acetylcholine release in the cortex and hippocampus, and have been suggested to inhibit medullary activity by a cortical action. Inhibition of prostaglandin synthesis and release of endorphins may also be involved in the antiemetic effect. A review of trials of dronabinol, nabilone or levonantradol concluded that while the cannabinoids were superior to placebo or dopamine receptor antagonists in controlling emesis... 

Gaoni Y, Mechoulam R Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc 86 1646—1647, 1964 Gardner EL Addictive potential of cannabinoids the underlying neurobiology. Chem Phys Lipids 121 267-290, 2002... 

The lUPAC name of cannabidiol is 2-[(lS, 6iI)-3-methyl-6-prop-l-en-2-yl-l-cyclohex-2-enyl]-5-pentyl-benzene-1,3-diol. Cannabidiol (CBD, 2.9) in its acidic form cannabidiolic acid (CBDA, 2.10) is the second major cannabinoid in C. sativa besides A9-THC. As already mentioned for A9-THC, variations in the length of the side chain are also possible for CBD. Important in this context are the propyl side chain-substituted CBD, named cannabidivarin (CBDV, 2.11), and CBD-C4 (2.12), the homologous compound with a butyl side chain. Related to the synthesis starting from CBD to A9-THC as described in Sect. 3.1, it was accepted that CBDA serves as a precursor for THCA in the biosynthesis. Recent publications indicate that CBDA and THCA are formed from the same precursor, cannabigerolic acid (CBGA), and that it is unlikely that the biosynthesis of THCA from CBDA takes place in C. sativa. 

After identification of A9-THC as the major active compound in Cannabis and its structural elucidation by Mechoulam and Gaoni in 1964 [66], a lot of work was invested in chemical synthesis of this substance. Analogous to the biosynthesis of cannabinoids, the central step in most of the A9-THC syntheses routes is the reaction of a terpene with a resorcin derivate (e.g., olivetol). Many different compounds were employed as terpenoid compounds, for example citral [67], verbenol [68], or chrysanthenol [69]. The employment of optically pure precursors is inevitable to get the desired (-)-trans-A9-THC. 

So, the 20th century actually led to an almost total disappearance of C. sativa for medicinal purposes. The only source for THC, which became the focus of scientific research, was fhe rafher fedious exfracfion and purification from confiscated hashish or marihuana. In 1972 the first commercially viable total synthesis of A9-THC was established and it became the first cannabinoid available as a modern medicine in the form of soft gel capsules (the active ingredient being called dronabinol from tetrahydrocannabinol) under the trade name Marinol for the prevention of nausea and vomiting during cancer chemotherapy. 

Deutsch D, Chin SA. Enzymatic synthesis and degradation of ananadmide, a cannabinoid receptor agonist. Biochem Pharmacol 1993 46 791-796. 

Devane WA, Axelrod J. Enzymatic synthesis of anandamide, an endogenous ligand for the cannabinoid receptor, by brain membranes. Proc Natl Acad Sci USA 1994 91 6698-6701. 

Huffman JW, Yu S, Showalter Y, Abood ME, Wiley JL, Compton DR, Martin BR, Bramblett RD, Reggio PH. Synthesis and pharmacology of a very potent cannabinoid lacking a phenolic hydroxyl with high affinity for the CB2 receptor. J Med Chem 1996 39 3875-3877. 

Mathews WB, Ravert HR, Musachio JL, Frank RA, Rinaldi-Carmona M, Barth F, Dannals RF. Synthesis of [1SF] SR144385 a selective radioligand for positron emission tomographic studies of brain cannabinoid receptors. J Labelled Compd Radiopharm 1994 42 589-596. 

Mechoulam R, Ben-Zvi Z, Carboxylation of resorcinols with methyl magnesium carbonate. Synthesis of cannabinoid acids, Chem Commun 343—344, 1969. 

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