ORGANIC
LETTERS
2000
Vol. 2, No. 21
3301-3303
Synthesis of a Primary Metabolite of
Cannabidiol
Susanna Tchilibon and Raphael Mechoulam*
Department of Medicinal Chemistry and Natural Products, School of Pharmacy,
Hebrew UniVersity Medical Faculty, Jerusalem 91120, Israel
Received July 23, 2000
ABSTRACT
Cannabidiol 1 is the major nonpsychotropic, neutral constituent in most cannabis preparations. It is devoid of the psychoactive properties
typical of cannabis; however, it produces numerous, potentially therapeutic pharmacological effects, some of which may be due to its metabolites.
We report now the first total synthesis of 7-hydroxycannabidiol 2, a primary metabolite of cannabidiol, in an eight-step procedure.
Cannabidiol (CBD, 1) is the major nonpsychotropic can-
nabinoid in most cannabis preparations, such as hashish and
marihuana. It was isolated from marihuana by Adams1a and
from hashish by Todd1b in the early 1940s. Its structure and
absolute stereochemistry were elucidated only about two
decades later.2 The racemate of CBD was synthesized in
1965,3a the natural enantiomer was prepared in 1967,3b and
the unnatural one was reported in 1982.3c
CBD does not cause any of the psychotropic effects typical
of ∆9-tetrahydrocannabinol (∆9-THC), the psychoactive
constituent of cannabis. It does not bind to the known
cannabinoid receptors CB1 or CB2 and therefore does not
cause the central or peripheral effects mediated by these
receptors. However, it has been shown in in vitro assays, in
animal tests, and in human preliminary trials to produce
numerous pharmacological effects. Thus, recent reports
describe in vitro effects of CBD on immune cells4a and as a
neuroprotective antioxidant.4b These in vitro studies lend
support to earlier reports on analgesic and antiinflammatory
effects in animals.4c Recently it was shown that CBD, through
its combined immunosuppressive and antiinflammatory ac-
tions, has a potent antiarthritic effect in collagen-induced
4d
arthritis in mice. CBD also has anxiolytic activity in rats
4e and mice. 4f
CBD has been found to produce several, potentially
therapeutic, effects in patients with neurological diseases,5a
in particular with epilepsy5b and possibly with psychosis.5c
CBD also reduces experimentally evoked anxiety in
volunteers.5d
(4) (a) Klein, T. W.; Newton, C.; Friedman, H. Immunol. Today 1998,
19, 373. (b) Hampson, A. J.; Grimaldi, M.; Axelrod, J.; Wink, D. Proc.
Natl. Acad. Sci. U.S.A. 1998, 95, 8268. (c) Formukong, E. A.; Evans, A.
T.; Evans, F. J. Inflammation 1988, 12, 361. (d) Malfait, A. M.; Gallily,
R.; Sumariwalla, P. F.; Malik, A. S.; Andreakos, E.; Mechoulam, R.;
Feldmann, M. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 9561. (e) Guimares,
F. S.; de-Aguilar, J. C.; Mechoulam, R.; Breuer, A. Gen. Pharmacol. 1994,
25, 161. (f) Onaivi, E. S.; Green, M. R.; Martin, B. R. J. Pharmacol. Exp.
Ther. 1990, 253, 1002.
(1) (a) Adams, R. Bull. N.Y. Acad. Med. 1942, 18, 705. (b) Todd, A. R.
Experientia 1946, 2, 55.
(2) (a) Mechoulam, R.; Shvo, Y. Tetrahedron 1963, 19, 2073. (b)
Mechoulam, R.; Gaoni, Y. Tetrahedron Lett. 1967, 1109.
(3) (a) Mechoulam, R.; Gaoni, Y. J. Am. Chem. Soc. 1965, 87, 3273.
(b) Petrzilka, T.; Haefliger, W.; Sikemeier, C.; Ohloff, G.; Eschenmoser,
A. HelV. Chim. Acta 1967, 50, 719. (c) Leite, J. R.; Carlini, E. A.; Lander,
N.; Mechoulam, R. Pharmacol. 1982, 124, 141.
(5) (a) Consroe, P. Neurobiol. Disease 1998, 5, 534. (b) Cunha, J. M.;
Carlini, E. A.; Pereira, A. E.; Ramos, O. L.; Pimentel, C.; Gagliardi, E. L.;
Sanvito, E. L.; Lander, N.; Mechoulam, R. Pharmacol. 1980, 21, 175. (c)
Zuardi, A. W.; Morais, S. L.; Guimaraes, F. S.; Mechoulam, R. J. Clin.
Psychiatry 1995, 56, 485. (d) Zuardi, A. W.; Shirakawa, I.; Finkelfarb, E.;
Karniol, I. G. Psychopharmacology- Ber. 1982, 76, 245.
10.1021/ol006369a CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/19/2000