The trans-THC family along with their non-natural
analogues have been attractive and popular targets for
synthetic and medicinal chemists.6,7 However, much less
attention has been devoted to the synthesis of THC with a
cis relative stereochemistry at the ring junction,6f,8 partially
because the naturally occurring cis-THC is not psychoactive.9
Most of the reported syntheses of cis-THC suffer from
drawbacks such as low selectivity in the preparation of the
key intermediates or final products because of its decreased
thermodynamic stability compared to its trans isomer.
Herein, we report the first total synthesis of bibenzyl cis-
tetrahydrocannabinol, (-)-perrottetinene (3), in a stereose-
lective manner. The key features of our synthesis are the
creation of stereogenic centers through an Ireland-Claisen
rearrangement and the use of a ring-closing metathesis
(RCM) reaction to construct the cyclohexene ring as pre-
sented in the retrosynthetic Scheme 1.10
5. This transformation would establish the desired relative
stereochemistry of two contiguous stereocenters provided that
the enolate geometry could be effectively controlled. Further
analysis indicated that the readily available starting materials
6 and 8, together with 7 as the source of chirality, should be
suitable synthetic precursors for the Ireland-Claisen rear-
rangement substrate 5.
Our synthesis began with the preparation of naturally
occurring catechol 6 from commercially available 3,5-di-
methoxybenzaldehyde through a conventional three-step
sequence, as previously reported.11 Regioselective iodination
on the activated aromatic ring of 6 could be achieved using
the combination of I2 and NaHCO3 in aqueous THF to
produce the desired iodide 9 in 85% yield (Scheme 2). The
Scheme 2. Preparation of Ireland-Claisen Rearrangement
Substrate 12
Scheme 1. Retrosynthetic Analysis of Perrottetinene
two phenolic hydroxyl groups of 9 were protected as benzoyl
esters to afford 10 in nearly quantitative yield.
With multigram quantities of 10 in hand, we next
investigated the Stille coupling of aryl iodide 10 with the
chiral building block (S)-7 (>99%ee) developed in this
laboratory.12 Different palladium sources, ligands, and sol-
vents were examined for this coupling reaction. Of these,
the Pd2(dba)3/P(t-Bu)3/toluene system13 was found to be
superior to other combinations. With this system, the reaction
occurred at 80 °C to produce the desired (+)-(E)-allylic
alcohol 11 in 78% yield. It is worthwhile to mention that in
the presence of other phenolic hydroxyl protecting groups
such as Bn, PMB, and TBDMS ethers, instead of the
We envisioned that the pyran ring of perrottetinene could
be accessed from the ester functionality and phenolic
hydroxyl group of 4 and that the cyclohexene ring could be
assembled from a diene of 4 via RCM. The presence of the
γ,δ-unsaturated carbonyl unit in compound 4 suggested the
use of an Ireland-Claisen rearrangement of the allylic ester
(5) For isolation of perrottetinene, see: (a) Toyota, M.; Shimamura, T.;
Ishii, H.; Renner, M.; Braggins, J.; Asakawa, Y. Chem. Pharm. Bull. 2002,
50, 1390-1392. (b) Cullmann, F.; Becker, H. Z. Naturforsch. 1999, 54c,
147-150. See also ref 4.
(6) For selected publications on syntheses of natural trans-THC, see:
(a) Trost, B. M.; Dogra, K. Org. Lett. 2007, 9, 861-863. (b) William, A.
D.; Kobayashi, Y. J. Org. Chem. 2002, 67, 8771-8782. (c) 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, 7582-7594. (d) Evans, D. A.; Shaughnessy, E. A.; Barnes,
D. M. Tetrahedron Lett. 1997, 38, 3193-3194. (e) Childers, W. E., Jr.;
Pinnick, H. W. J. Org. Chem. 1984, 49, 5276-5277. For a review, see: (f)
Tius, M. A. In Studies in Natural Products Chemistry; Atta-ur-Rahman,
Ed.; Elsevier: Amsterdam, 1997; Vol. 19, p 185.
(7) For selected publications on recent syntheses of nonnatural trans-
THC, see: (a) Qi, L.; Yamamoto, N.; Meijler, M. M.; Altobell, L. J.; Koob,
G. F.; Wirsching, P.; Janda, K. D. J. Med. Chem. 2005, 48, 7389-7399.
(b) Krishnamurthy, M.; Ferreira, A. M.; Moore, B. M. Bioorg. Med. Chem.
Lett. 2003, 13, 3487-3490. (c) Mahadevan, A.; Siegel, C.; Martin, B. R.;
Abood, M. E.; Belestskaya, I.; Razdan, R. K. J. Med. Chem. 2000, 43,
3778-3785. (d) Harrington, P. E.; Stergiades, I. A.; Erickson, J.; Makriy-
annis, A.; Tius, M. A. J. Org. Chem. 2000, 65, 6576-6582.
(8) For previous syntheses of cis-THC, see: (a) Goujon, J.-Y.; Zammattio,
F.; Kirschleger, B. J. Chem. Soc., Perkin Trans. 1 2002, 1564-1567. (b)
Inoue, S.; Kosugi, C.; Lu, Z. G.; Sato, K. Nippon Kagaku Kaishi 1992, 1,
45-52. (c) Moore, M.; Rickards, R. W.; Rønneberg, H. Aust. J. Chem.
1984, 37, 2339-2348. (d) Uliss, D. B.; Handrick, G. R.; Dalzell, H. C.;
Razdan, R. K. Tetrahedron 1978, 34, 1885-1888. (e) Uliss, D. B.; Razdan,
R. K.; Dalzell, H. C.; Handrick, G. R. Tetrahedron 1977, 33, 2055-2059.
(9) Smith, R. M.; Kempfert, K. D. Phytochemistry 1977, 16, 1088-1089.
(10) We have previously employed this Ireland-Claisen rearrangement/
RCM strategy in the total syntheses of alkaloids, see: (a) Lee, M.; Lee, T.;
Kim, E.-Y.; Ko, H.; Kim, D.; Kim, S. Org. Lett. 2006, 8, 745-748. (b)
Kim, S.; Ko, H.; Lee, T.; Kim, D. J. Org. Chem. 2005, 70, 5756-5759. (c)
Ko, H.; Kim, E.; Park, J. E.; Kim, D.; Kim, S. J. Org. Chem. 2004, 69,
112-121.
(11) Ali, M. A.; Kondo, K.; Tsuda, Y. Chem. Pharm. Bull. 1992, 40,
1130-1136.
(12) Lee, T.; Kim, S. Tetrahedron: Asymmetry 2003, 14, 1951-1954.
270
Org. Lett., Vol. 10, No. 2, 2008