Enantioselective total synthesis of (-)-Δ8-THC and (-)-Δ9-THC via catalytic asymmetric hydrogenation and S NAr cyclization

Article abstract of DOI:10.1021/ol303351y

The highly efficient asymmetric total syntheses of (-)-Δ⁸- tetrahydrocannabinol ((-)-Δ⁸-THC) (13 steps, 35%) and (-)-Δ⁹-tetrahydrocannabinol ((-)-Δ⁹-THC) (14 steps, 30%) have been developed by using ruthenium-ca

Full text of DOI:10.1021/ol303351y

ORGANIC
LETTERS
2013
Vol. 15, No. 4
764–767
Enantioselective Total Synthesis
of (ꢀ)‑Δ8‑THC and (ꢀ)‑Δ9‑THC via
Catalytic Asymmetric Hydrogenation and
SNAr Cyclization
Li-Jie Cheng, Jian-Hua Xie,* Yong Chen, Li-Xin Wang, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University,
Tianjin 300071, China
jhxie@nankai.edu.cn; qlzhou@nankai.edu.cn
Received December 7, 2012
ABSTRACT
The highly efficient asymmetric total syntheses of (ꢀ)-Δ8-tetrahydrocannabinol ((ꢀ)-Δ8-THC) (13 steps, 35%) and (ꢀ)-Δ9-tetrahydrocannabinol
((ꢀ)-Δ9-THC) (14 steps, 30%) have been developed by using ruthenium-catalyzed asymmetric hydrogenation of racemic R-aryl cyclic ketones via
dynamic kinetic resolution and intramolecular SNAr cyclization.
Many biologically active natural products and pharma-
ceutical agents contain chiral hexahydro-6,6-dimethyl-6H-
benzo[c]chromene motifs (Figure 1). (ꢀ)-Δ9-Tetrahydro-
cannabinol ((ꢀ)-Δ9-THC), isolated from Cannabis sativa
L. in 1964,1 is one of the most well-known examples of this
class of tricyclic compounds and has been used as a medicine
under the trademarks of Marinol and Sativex for the treat-
ment of cancer, nausea, and vomiting during chemotherapy
and spasticity in patients with multiple sclerosis.2 (ꢀ)-Δ8-
Tetrahydrocannabinol ((ꢀ)-Δ8-THC), also isolated from
Cannabis sativa L.,3 is a double bond isomer of (ꢀ)-Δ9-THC
and functions similarly to (ꢀ)-Δ9-THC pharmacologically.
(þ)-Conicol4 and its epimer (þ)-epiconicol,5 isolated from
ascidians Aplidium conicum and Synoicum castellatum, are
also tetrahydrocanabinol derivatives, and the latter exhibits
mild cytotoxic activities against P388 (murine leukemia),
A549 (human lung cacinoma), etc. Moreover, the natural
bibenzyl tetrahydrocannabinol (ꢀ)-perrottetinene,6 iso-
lated from the liverwort plant Radula marginata, and
synthetic pharmaceutical agents such as 1-deoxyl-Δ8-tetra-
hydrocannabinols JWH-051 and JWH-0577 also contain a
chiral hexahydro-6,6-dimethyl-6H-benzo[c]chromene struc-
ture. Thus, the enantioselective construction of the chiral
hexahydro-6,6-dimethyl-6H-benzo[c]chromene motif con-
stitutes a basic requisite for the stereoselective synthesis of
tetrahydrocanabinol derivatives (and/or analogues).
(1) Gaoni, Y.; Mechoulam, R. J. Am. Chem. Soc. 1964, 86, 1646.
(2) (a) Sarfaraz, S.; Adhami, V. M.; Syed, D. N.; Afaq, F.; Mukhtar,
H. Cancer Res. 2008, 68, 339. (b) Ware, M. A.; Daeninck, P.; Maida, V.
Ther. Clin. Risk Manage. 2008, 4, 99. (c) Pertwee, R. G. Mol. Neurobiol.
2007, 36, 45. (d) Mackie, K. Annu. Rev. Pharmacol. Toxicol. 2006, 46,
101. (e) Romero, J.; Lastres-Becker, L.; deMiguel, R.; Berrendero, F.;
Ramos, J. A.; Fernandez-Ruiz J. Pharmacol. Ther. 2002, 95, 137.
(3) (a) Taylor, E. C.; Lenard, K.; Shvo, Y. J. Am. Chem. Soc. 1966,
88, 367. (b) Fahrenholtz, K. E.; Lurie, M.; Kierstead, R. W. J. Am.
Chem. Soc. 1967, 89, 5934. (c) Binder, M.; Franke, I.; Schmidt, B.;
Dietrich, W. Helv. Chim. Acta 1982, 65, 807.
Although considerable efforts have been devoted to the
development of the methodology for the synthesis of chiral
hexahydro-6,6-dimethyl-6H-benzo[c]chromenes, most of
the methods reported in the literature produced these
(6) (a) Cullmann, F.; Becker, H. Z. Naturforsch. 1999, 54c, 147. (b)
Toyota, M.; Shimamura, T.; Ishii, H.; Renner, M.; Braggins, J.;
Asakawa, Y. Chem. Pharm. Bull. 2002, 50, 1390.
(7) Huffman, J. W.; Yu, S.; Showalter, V.; Abood, M. E.; Wiley, J. L.;
Compton, D. R.; Martin, B. R.; Bramblett, R. D.; Reggio, P. H. J. Med.
Chem. 1996, 39, 3875.
ꢀ
(4) Garrido, L.; Zubıa, E.; Ortega, M. J.; Salva, J. J. Nat. Prod. 2002,
65, 1328.
(5) Carroll, A. R.; Bowden, B. F.; Coll, J. C. Aust. J. Chem. 1993, 46,
1079.
r
10.1021/ol303351y
Published on Web 01/24/2013
2013 American Chemical Society

and pharmaceutical agents such as (ꢀ)-CP-55940.15 Here-
in, we reported a highly efficient asymmetric total synthesis
of (ꢀ)-Δ9-THC and (ꢀ)-Δ8-THC by using catalytic asym-
metric hydrogenation of ketones via DKR and intramole-
cular SNAr cyclization as key steps.
Scheme 1. Retrosynthetic Analysis of (ꢀ)-Δ8-THC and
(ꢀ)-Δ9-THC
Figure 1. Natural products and pharmaceutical agents contained
chiral hexahydro-6,6-dimethyl-6H-benzo[c]chromene motifs.
tricyclic compounds either in racemic form or from chiral
building blocks.8 Very few examples used asymmetric
catalysis to construct the chiral hexahydro-6,6-dimethyl-
6H-benzo[c]chromene structure. Evans et al.9 reported an
asymmetric synthesis of (þ)-Δ9-THC via an enantioselec-
tive DielsꢀAlder reaction catalyzed by copper(II) com-
plexes of chiral bis(oxazoline) ligands. Trost and Dogra10
applied a molybdenum-catalyzed asymmetric allylic alky-
lation reaction in the synthesis of (ꢀ)-Δ9-THC. Recently,
Hong et al.11 reported a total synthesis of (þ)-conicol by
using an asymmetric organocatalytic cascade reaction.
The catalytic asymmetric hydrogenation is one of the
most versatile and powerful tools for the preparation of
optical compounds and has been successfully applied to
the total synthesis of biologically active natural products
and pharmaceutics.12 Recently, we developed highly effi-
cient ruthenium-catalyzed asymmetric hydrogenations of
racemic R-substituted ketones and aldehydes via dynamic
kinetic resolution (DKR)13 for the preparation of chiral
alcohols with one or two continuous stereocenters, which
have been successfully applied to the enantioselective total
synthesis of natural products such as (ꢀ)-galanthamine14
The retrosynthetic analysis suggested that the target
molecules (ꢀ)-Δ8-THC and (ꢀ)-Δ9-THC could be synthe-
sized from the precursor 1 using an intramolecular SNAr
cyclization to construct the benzopyran ring and a regio-
selective elimination of H2O to form the double bond
(Scheme 1). The diol 1 was expected to be obtained from
optically active R-arylcycloketone (S)-2 via several steps
including olefination and the addition of a methyl metal
reagent such as MeMgBr to the carbonyl groups of both
the ketone and ester group. According to our previous
procedure for the synthesis of potent cannabinoid receptor
agonist (ꢀ)-CP-55940,15 the chiral R-aryl-1,4-cyclohexa-
nedione monoethylene acetal (S)-2 could be easily ob-
tained from the Suzuki cross-coupling of 2-iodo-1,4-
cyclohexanedione monoethylene acetal (4) with fluorine-
substituted phenylboronic acid 5 followed by a palladium-
catalyzed hydrogenation, ruthenium-catalyzed asymmetric
hydrogenation via DKR, and Swern oxidation.
Initially, we attempted to construct the benzopyran ring
by using ZnBr2-promoted intramolecular cyclization ac-
cording tothe literaturemethod.16 Asamodel reaction, the
asymmetric hydrogenation of racemic 2-(2,6-dimethoxy-
phenyl)cyclohexanone catalyzed by RuCl2((S)-SDP)((R,R)-
DPEN) ((Sa,R,R)-6)17 was carried out. This hydrogenation
reaction was found to be very difficult and impractical
presumably due to the steric hindrance caused by two
ortho-methoxy groups in the substrate.18 In contrast, the
R-arylcyclohexanones with one ortho-methoxy group were
hydrogenated smoothly with the same catalyst to produce
(8) For selected recent papers on synthesis of cannabinoids, see: (d)
William, A. D.; Kobayashi, Y. Org. Lett. 2001, 3, 2017. (e) William,
A. D.; Kobayashi, Y. J. Org. Chem. 2002, 67, 8771. (f) Pearson, L. E.;
Kanizaj, N.; Willis, A. C.; Paddon-Row, M. N.; Sherburn, M. S.
Chem.;Eur. J. 2010, 16, 8280. (g) Ballerini, E.; Minuti, L.; Piermatti,
O. J. Org. Chem. 2010, 75, 4251. (h) Huang, Q.; Ma, B.; Li, X.; Pan, X.;
She, X. Synthesis 2010, 1766. (i) Minuti, L.; Ballerini, E. J. Org. Chem.
2011, 76, 5392.
(9) (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.
(10) Trost, B. M.; Dogra, K. Org. Lett. 2007, 9, 861.
(11) Hong, B.-C.; Kotame, P.; Tsai, C.-W.; Liao, J.-H. Org. Lett.
2010, 12, 776.
(12) For reviews, see: (a) Ohkuma, T.; Kitamura, M.; Noyori, R. In
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;Wiley-Interscience:
New York, 2000; pp 1ꢀ110. (b) de Vries, J. G.; Elsevier, C. J. The
Handbook of Homogeneous Hydrogenation; Wiley-VCH: Weinheim,
2007. (c) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029. (d) Xie,
J.-H.; Zhou, Q.-L. Acta Chim. Sinica 2012, 70, 1427.
(15) Cheng, L.-J.; Xie, J.-H.; Wang, L.-X.; Zhou, Q.-L. Adv. Synth.
Catal. 2012, 354, 1105.
(16) Stoss, P.; Merrath, P. Synlett 1991, 553.
(17) Xie, J.-H.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Fan, B.-M.; Duan,
(13) (a) Xie, J.-H.; Zhou, Z.-T.; Kong, W.-L.; Zhou, Q.-L. J. Am.
Chem. Soc. 2007, 129, 1868. (b) Xie, J.-H.; Liu, S.; Kong, W.-L.; Wang,
X.-C.; Wang, L.-X.; Zhou, Q.-L. J. Am. Chem. Soc. 2009, 131, 4222.
(14) Chen, J.-Q.; Xie, J.-H.; Bao, D.-H.; Liu, S.; Zhou, Q.-L. Org.
Lett. 2012, 14, 2714.
H.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2003, 125, 4404.
Org. Lett., Vol. 15, No. 4, 2013
765

the corresponding chiral alcohols with excellent enantio-
selectivity and cis-selectivity in our previous study.15 Thus,
we introduced a fluorine atom, which has a similar size as
hydrogen, to replace one of the methoxy groups of the
2-(2,6-dimethoxyphenyl)cyclohexanone and designed an
intramolecular SNAr cyclization for the construction of a
benzopyran ring (Scheme 2).
K2CO3 as a base, and isomerization with NaOMe (1 M)
in MeOH at room temperature to afford ester 10 in 76%
yield (4 steps) with 31:1 trans/cis-selectivity and 93% ee. A
slight loss of ee value possibly occurred in the olefination
step of (S)-2 with the Wittig reagent, which involved the
use of a strong base. Ester 10 reacted with MeMgBr in
refluxing THF for 3 h to provide chiral diol 1 in 91% yield.
Scheme 2. Synthesis of Racemic R-Arylcyclohexanone 2
Scheme 3. Synthesis of Chiral Diol 1
The fluorinated R-arylcyclohexanone rac-2 was synthe-
sized from commercially available 1,4-cyclohexenedione
monoethylene acetal7accordingtothe methodwerecently
developed (Scheme 2).15 The cyclic enone 7 was iodinated
with iodine at room temperature to afford cyclic R-iodoe-
none 4 in 84% yield. The Suzuki cross-coupling of 4 with
arylboronic acid 5, which was prepared from 3-flouro-5-
bromoanisole in two steps including boronation with
triisopropyl borate (see Supporting Information), in the
presence of 5.0 mol % of Pd(PPh3)4 as a catalyst and
aqueous Na2CO3 (2.8 equiv) as a base in dimethoxyethane19
yielded the R-arylated cyclic enone 8 in 93% yield. The
enone 8 was hydrogenated on Pd/C (10 mol %) to produce
ketone rac-2 in 90% yield.
When the cyclic ketone rac-2 was subjected to the
hydrogenation (conditions: S/C = 1000, 50 atm of H2,
0.05 M [KOtBu], in iPrOH at room temperature) with the
catalyst (Sa,R,R)-6, we were delighted to find that the
hydrogenation completed in 12 h and the desired product,
chiral alcohol (S,S)-3, was obtainedin 98% yield with96%
ee and >99:1 cis/trans-selectivity (Scheme 3). The chiral
alcohol (S,S)-3 was oxidized to ketone (S)-2 in 96% yield
by Swern oxidation (conditions: 2.4 equiv of dimethyl
sulfoxide, 1.2 equiv of oxalyl chloride, and 2.4 equiv of
Et3N). The olefination of (S)-2 with the Wittig reagent,
which was generated in situ from MeOCH2PPh3Cl
(2.0 equiv) and BuLi (2.0 equiv), yielded the olefin (R)-9
in 90% yield (E-isomer/Z-isomer = 4:1). The olefin (R)-9was
treated with an aqueous AcOH solution at 100 °C for 2 h,20
followed by an oxidation with the Jones reagent (1.2 equiv)
in acetone, esterification with MeI in the presence of
With enantiomer-enriched diol 1 in hand, we then
attempted to construct the benzopyran ring via a base-
promoted intramolecular SNAr cyclization and to com-
plete the enantioselective synthesis of (ꢀ)-Δ8-THC and
(ꢀ)-Δ9-THC. The mixture of cis- and trans-diol 1 was
treated with NaH (5.0 equiv) in refluxing DMF for 1 h to
yield the tricyclic compound 11 in 94% yield (Scheme 4).
Demethylation of 11 by NaS(CH2)2NEt2 generated in situ
from NaH (10.0 equiv) and HS(CH2)2NEt2 (10.0 equiv)
afforded the compound 12 in 95% yield. Since the intra-
molecular SNAr cyclization and the demethylation reac-
tion proceeded under similar reaction conditions, we
attempted to perform these two reactions in one pot. In
the presence of 10.0 equiv of NaH and 5.0 equiv of
HS(CH2)2NEt2 in refluxing DMF, we delightedly ob-
tained the desired compound 12 in high yield (90%). An
acid-promoted dehydration of compound 12 in refluxing
benzene in the presence of 20 mol % TsOH according to
the literature method3b produced the target molecule (ꢀ)-
Δ8-THC in 96% yield21 ([R]D25 ꢀ163 (c 1.0, CHCl3); lit.10
[R]2D5 ꢀ152 (c 0.46, CHCl3)). When compound 12 was
converted to a chlorinated intermediate with the Lucas
reagent (ZnCl2/HCl) in acetic acid at room temperature,
followed by treatment with potassium tert-pentoxide in
benzene at 65 °C for 15 min using the same procedure by
Petrzilka et al.,22 the target compound (ꢀ)-Δ9-THC was
(18) The asymmetric hydrogenation of racemic 2-(2,6-dimethoxyphenyl-
)cyclohexanone catalyzed by RuCl2((S)-SDP)((R,R)-DPEN) (conditions:
S/C = 500, 50 atm H2, room temperature) afforded the desired product in
less than 10% yield.
(19) Wustrow, D. J.; Wise, L. D. Synthesis 1991, 993.
(20) Petrzilka, M.; Germann, A. Mol. Cryst. Liq. Cryst. 1985, 131,
327.
(21) (ꢀ)-Δ8-THC/(ꢀ)-Δ9-THC > 99:1.
(22) Petrzika, T.; Haefliger, W.; Sikemeier, C. Helv. Chim. Acta 1969,
52, 1102.
(23) (ꢀ)-Δ9-THC/(ꢀ)-Δ8-THC = 97:3. The same results were ob-
tained by using isolated cis-1 or trans-1 as starting material; see
Supporting Information.
766
Org. Lett., Vol. 15, No. 4, 2013

obtained in 80% yield ([R]2D5 ꢀ232 (c 0.96, CHCl3); lit.8g
[R]2D5 ꢀ245 (c 0.78, CHCl3)).23 The NMR spectroscopic
data and the optical rotations of our synthetic (ꢀ)-Δ8-
THC and (ꢀ)-Δ9-THC are identical to those reported in
previous syntheses.
(ꢀ)-Δ9-THC. With commercially available 1,4-cyclohex-
enedione monoethylene acetal 7 as starting material and
the ruthenium-catalyzed asymmetric hydrogenation of
ketone via DKR and intramolecular SNAr cyclization as
key steps, the optical (ꢀ)-Δ8-THC and (ꢀ)-Δ9-THC were
synthesized in 35% and 30% overall yields via 13 and 14
steps, respectively. This synthetic strategy has a high poten-
tial for wide application in the synthesis of other biologically
active natural products and pharmaceutical agents contain-
ing chiral hexahydro-6,6-dimethyl-6H-benzo[c]chromene
motifs.
Scheme 4. Synthesis of (ꢀ)-Δ8-THC and (ꢀ)-Δ9-THC
Acknowledgment. We thank the National Natural
Science Foundation of China, the National Basic Research
Program of China (973 Program, No.2012CB821600), and
“111” Project of the Ministry of Education of China
(Grant No. B06005) for financial support.
Supporting Information Available. Experimental pro-
cedures and the characterizations of substrates and prod-
ucts. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, we have developed a new efficient metho-
dology for the enantioselective syntheses of (ꢀ)-Δ8- and
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
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