ORGANIC
LETTERS
2007
Vol. 9, No. 5
861-863
Synthesis of
(-)-
9-trans-Tetrahydrocannabinol:
Stereocontrol via Mo-Catalyzed
∆
Asymmetric Allylic Alkylation Reaction
Barry M. Trost* and Kalindi Dogra
Department of Chemistry, Stanford UniVersity, Stanford, California 94305
Received December 14, 2006
ABSTRACT
∆
9-THC is synthesized in enantiomericaly pure form, where all of the stereochemistry is derived from the molybdenum-catalyzed asymmetric
alkylation reaction of the extremely sterically congested bis-ortho-substituted cinnamyl carbonate in high regio- and enantioselectivity.
(-)-∆9-trans-Tetrahydrocannabinol (∆9-THC, 1) isolated1
from female Cannabis satiVa L. in 1964 has been identified
as the primary psychomimetic component of marijuana. It
is also known to show antiemetic, antiglaucoma, and
analgesic properties. Currently it is administered as an
antinauseant to patients undergoing chemotherapy. Discovery
of the cannabinoid receptors CB1 and CB2 and ∆9-THC
analogues2 that bind selectively to them has led to a need
for the development of a flexible synthetic route that would
yield target compounds easily in high yields and in stereo-
chemically pure form.
product enantioselectively from achiral starting materials. The
problems associated with the synthesis of THC involve the
control of cis-trans stereochemistry at the cyclohexene ring
and the position of the double bond, i.e., ∆9 vs ∆8, the latter
being thermodynamically more stable.
Our reterosynthetic analysis of the molecule envisioned
all of the stereochemistry resulting from a single Mo-
catalyzed asymmetric allylic alkylation (AAA) reaction (see
the abstract). Alkylation of malonate adduct 4 with 3 should
(3) Selected examples: (a) Mechoulam, R.; Gaoni, Y. J. Am. Chem. Soc.
1965, 87, 3273. Mechoulam, R.; Braun, P.; Gaoni, Y. J. Am. Chem. Soc.
1967, 89, 4552. Mechoulam, R.; Braun, P.; Gaoni, Y. J. Am. Chem. Soc.
1972, 94, 6159. (b) Fahrenholtz, K. E.; Lurk, M.; Kierstead, R. W. J. Am.
Chem. Soc. 1966, 88, 2079. Fahrenholtz, K. E.; Lurk, M.; Kierstead, R. W.
J. Am. Chem. Soc. 1967, 89, 5934. (c) Chan, T. H.; Chaly, T. Tetrahedron
Lett. 1982, 23, 2935. (d) Rickards, R. W.; Ronneberg, H. J. Org. Chem.
1984, 49, 572. (e) Childers, W. E., Jr.; Pinnick, H. W. J. Org. Chem. 1984,
49, 5276. (f) Malkov, A. V.; Koovsky, P. Collect. Czech. Chem. Commun.
2001, 66 (8), 1257. (g) William, A. D.; Kobayashi, Y. J. Org. Chem. 2002,
67, 8771. William, A. D.; Kobayashi, Y. Org. Lett. 2001, 3, 2017.
(4) (a) Evans, D. A.; Shaughnessy, E. A.; Barnes, D. M. Tetrahedron
Lett. 1997, 38, 3193. (b) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka,
T.; Matt, P. V.; Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy,
E. A.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 7582.
THC itself has been prepared numerous times, though most
routes are either racemic or derive their chirality from chiral
building blocks.3 Only Evan’s4 route targets the natural
(1) Mechoulam, R.; Gaoni, Y. J. Am. Chem. Soc. 1964, 86, 1646.
(2) (a) Mahadevan, A.; Siegel, C.; Martin, B. R.; Abood, M. E.;
Belestskaya, I.; Razdan, R. K. J. Med. Chem. 2000, 43, 3778. (b) Drake,
D. J.; Jensen, R. S.; Busch-Petersen, J.; Kawakami, J. K.; Fernandez-Garcia,
M. C.; Fan, P.; Makriyannis, A.; Tius, M. A. J. Med. Chem. 1998, 41,
3596. (c) Harrington, P. E.; Stergiades, I. A.; Erickson, J.; Makriyannis,
A.; Tius, M. A. J. Org. Chem. 2000, 65, 6576. (d) Tius, M. A.; Makriyannis,
A.; Zou, X. L.; Abadji, V. Tetrahedron 1994, 50, 2671.
10.1021/ol063022k CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/01/2007