Preparation of Racemic, (-)- And (+)-11-Nor-δ9-Tetrahydrocannabinol-9-carboxylic Acid

Journal of Organic Chemistry

Volumn 62, Issue 20, 1997, Pages 7065-7068

  Kachensky, David F ^a,b   Hui, Raymond A H F ^a  

^a HOFFMANN LA ROCHE INC   (United States)

^b Molecular Biosciences   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0000924220     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo970969e     Document Type: Article

References (29)

1. Please note Agurell, S.; Halldin, M.; Lindgren, J. E.; Ohlsson, A.; Widman, M. Pharmacol. Rev. 1986, 38, 21-43 and references therein.
2. Williams, P. L.; Moffat, A. C. J. Pharm. Pharmacol. 1980, 32, 445-448.
3. Halldin, M. M.; widman, M. Arzneim. Forsch. Drug Res. 1983, 33, 177-178.
4. The extent of carboxylic glucuronidation has been observed to vary from individual to individual and is dependent upon at least a few parameters which include the origin of the urine, the pH of the urine, and the length of time for which it has been stored.
5. 9tetrahydrocannabinol-9-carboxylic acid phenolic glucuronide, but its structure has never been authenticated. Please note Wall, M. E.; Perez-Reyes, M. J. Clin. Pharmacol. 1981, 21, 1785-1795; Kanter, S. L.; Hollister, L. G.; Williams, M. J. Chromatogr., 1982, 234, 255-260 and reference 2.
6. 9tetrahydrocannabinol-9-carboxylic acid phenolic glucuronide, but its structure has never been authenticated. Please note Wall, M. E.; Perez-Reyes, M. J. Clin. Pharmacol. 1981, 21, 1785-1795; Kanter, S. L.; Hollister, L. G.; Williams, M. J. Chromatogr., 1982, 234, 255-260 and reference 2.
7. (a) Fahrenholtz, K. E.; Lurie, M.; Kierstead, R. W. J. Am. Chem. Soc., 1966, 88, 2079; 1967, 89, 5934.
8. (a) Fahrenholtz, K. E.; Lurie, M.; Kierstead, R. W. J. Am. Chem. Soc., 1966, 88, 2079; 1967, 89, 5934.
9. (b) For optically pure (-)-11-nor-9-ketohexahydrocannabinol derivatives, please note Archer, R. A.; Blanchard, W. B.; Day, W. A.; Johnson, D. W., Lavaghino, E. R.; Baldwin, J. E. J. Org. Chem. 1977 42, 2277-2284.
10. Schwartz, A.; Madan, P. J. Org. Chem., 1986, 51, 5463-5465.
11. Shapiro, R. H.; Heath, M. J. J. Am. Chem. Soc., 1967, 89, 5734-5735
12. Chamberlin, R. A.; Stemke, J. G.; Bond, F. T. J. Org. Chem., 1978, 43, 147-154.
13. R = 5,84 min.
14. We thank the synthesis research department of Hoffmann-La Roche for a supply of this material.
15. 9tetrahydrocannabinol-9-carboxylic acid.
16. We thank Professor George Whitesides for suggesting the use of this material for the resolution of this ketone.
17. Resolution of 3a is also achievable by Chromatographic separation of the (2R,4R)-pentanediol ketals, but not of the (2R,3R)-butanediol ketals.
18. 1H NMR spectra.
19. For a review, see: Pirkle, W. H.; Hoover, D. J. Topics in Stereochemistry; Allinger, N. L., Eliel, E. L., Wilen, S. H., Eds.; Wiley-Interscience: New York, 1982; Vol. 13, pp 316-319.
20. Details will be reported elsewhere.
21. Obtained from (a) Research Triangle Institute; (b) Aldrich Chemical Co., (c) Fluka AG.
22. 9-THC: Pitt, C. G.; Fowler, M. S.; Sathe, S.; Srivastava, S. C.; Williams, D. L. J. Am. Chem. Soc. 1975, 97, 3798. No optical rotations were reported by the authors; it is not clear if the materials obtained were racemic or not.
23. Racemic 2c has also been previously synthesized; Mago', E.; Szirmai, M.; Ohlsson, A.; Agurell, S. Marihuana, 1984 Proceedings of the Oxford Symposium on Cannabis; Harvey, D. J., Ed.; IRL Press: Oxford, 1985; pp 191-195.
24. D = -278 (EtOH).
25. The quality of the n-butyllithium is crucial to the success of the synthesis. The use of "aged" reagent, even allowing for titrated strength of reagent, gave considerably lower yields (typically 25-40%) of eventual 2c.
26. See also: Schacht, E.; Desmarets, G.; Bogaert, Y. Makromol. Chem. 1978, 179, 837 for syntheses of tartrate acetals of an aromatic aldehyde.
27. For leading references, see: Greene, T. W. Protective Groups in Organic Synthesis; Wiley: New York, 1981; pp 124-128.
28. 21
29. The IR spectra of (+)-2c and (-)-2c are identical to each other but nonsuperimposable on that of (±)-2c.