Synthesis of cannabidiols via alkenylation of cyclohexenyl monoacetate

Article abstract of DOI:10.1021/ol060692h

Because of the lack of potency binding to the receptors responsible for psychoactivity, cannabidiol has received much attention as a lead compound to develop a nonpsychotropic drug. Herein, we establish a method to access not only cannabidiol but also its analogues. The key reaction is nickel-catalyzed allylation of 2-cyclohexene-1,4-diol monoacetate with a new reagent, (alkenyl)ZnCl/TMEDA, which gives a S_N2-type product with 94% regioselectivity in good yield.

Full text of DOI:10.1021/ol060692h

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2699-2702
Synthesis of Cannabidiols via
Alkenylation of Cyclohexenyl
Monoacetate
Yuichi Kobayashi,* Akira Takeuchi, and Yong-Gang Wang
Department of Biomolecular Engineering, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan
ykobayas@bio.titech.ac.jp
Received March 21, 2006
ABSTRACT
Because of the lack of potency binding to the receptors responsible for psychoactivity, cannabidiol has received much attention as a lead
compound to develop a nonpsychotropic drug. Herein, we establish a method to access not only cannabidiol but also its analogues. The key
reaction is nickel-catalyzed allylation of 2-cyclohexene-1,4-diol monoacetate with a new reagent, (alkenyl)ZnCl/TMEDA, which gives a SN2-type
product with 94% regioselectivity in good yield.
After the finding of receptors (CB1)1 binding ∆9-tetrahydro-
cannabinol (∆9-THC, 1) (Figure 1),2 biological study using
cannabinoid analogues has led to the discovery of another
subtype defined as CB2.3 Both receptors are now believed
to be responsible for the psychoactivity triggered by cannabis
preparations such as hashish and marijuana.4 In contrast to
1, cannabidiol (CBD, 2), another constituent of the cannabis
preparations, does not bind to the receptors,5 and in
consequence, 2 has received much attention as a lead
compound to develop a nonpsychotropic drug. Moreover,
recent studies have revealed other pharmacological properties
such as antiinflammatory effects and activation of PPAR-
γ.6 These aspects have created urgent demand for analogues
as well as metabolites for further study.7
So far, 2 has been synthesized by several methods,8,9
among which the BF3‚OEt2/Al2O3-promoted reaction9h of the
(1) (a) Devane, W. A.; Dysarz, F. A., III; Hohnson, M. R.; Melvin, L.
S.; Howlett, A. C. Mol. Pharmacol. 1988, 34, 605-613. (b) Matsuda, L.
A.; Lolait, S. J.; Brownstein, M. J.; Young, A. C.; Bonner, T. I. Nature
1990, 346, 561-564. (c) Devane, W. A.; Hanus, L.; Breuer, A.; Pertwee,
R. G.; Stevenson, L. A.; Griffin, G.; Gibson, D.; Mandelbaum, A.; Etinger,
A.; Mechoulam, R. Science 1992, 258, 1946-1949.
(2) In this paper, two different numbering systems are adopted to indicate
a specific site in the tricyclic and bicyclic cannabinoids to use the well-
known abbreviations with the familiar numbers, for example, ∆9-THC (based
on the dibenzopyran ring system) and 7-OH-CBD (based on the monoter-
penoid system), etc.
(3) Munro, S.; Thomas, K. L.; Abu-Shaar, M. Nature 1993, 365, 61-
65.
(4) (a) Tullo, A. Chem. Eng. News 2005, 83(25), 84. (b) Di Marzo, V.;
Bifulco, M.; Petrocellis, L. D. Nat. ReV. Drug DiscoVery 2004, 3, 771-
784. (c) Palmer, S. L.; Thakur, G. A.; Makriyannis, A. Chem. Phys. Lipids
2002, 121, 3-19. (d) Kunos, G.; Ba´tkai, S.; Offerta´ler, L.; Mo, F.; Liu, J.;
Karcher, J.; Harvey-White, J. Chem. Phys. Lipids 2002, 121, 45-56.
Figure 1. Representative examples of cannabinoids.
10.1021/ol060692h CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/25/2006

Table 1. Reaction of Isopropenyl Anions with Monoacetate 4a
entry
reagent
reagent source (equiv)
additive(s) (equiv)
catalystb
ratioc of 5a/11
yield, %d
1
2
3
4
5
6
7
8
7
8
8
9
9
9
9
10
6 (1.8), n-BuLi (2)
8 (4)
8 (4)
8 (4), ZnCl2 (10)
8 (4), ZnCl2 (10)
8 (6), ZnCl2 (10)
8 (3.5), ZnCl2 (4)
8 (6), ZnCl2 (2.5)
NaI (1), t-BuCN (5)
s
NiCl2(tpp)2
CuCN
CuCN
67:33
60:40
86:14
-
67:33
92:8
46e
81
90
0
31
MgCl2 (15)
s
CuCN
s
NiCl2(tpp)2
NiCl2(tpp)2
NiCl2(tpp)2
NiCl2(tpp)2
TMEDA (10)
TMEDA (4.2)
TMEDA (2.5)
95
94:6
86:14
85 (80)f
88
a Reactions were carried out in THF at room temperature overnight (entries 1 and 4-8) or for 3 h (entries 2 and 3). b NiCl2(tpp)2 (20 mol %), CuCN (40
1
1
mol %). c Determined by H NMR spectroscopy. d Combined yields determined by H NMR spectroscopy with pyridine as a standard. e 2-Cyclohexenone
was also coproduced in 15% yield. f Isolated yield.
monoterpene with olivetol furnished 2 in a satisfactory
manner. However, the methods would hardly be applicable
to synthesis of structurally related analogues, especially those
possessing a longer alkenyl side chain in place of the
isopropenyl group.4,10 A recent seven-step oxidation11 of the
C(7) methyl group of 2 producing 7-hydroxy-CBD (3), a
metabolite of 2, also implies the unavailability of a synthetic
route to the CBD family.
Herein, we report a new reagent system for this purpose and
a synthesis of 2 and CBD analogues.
Scheme 1. Synthetic Strategy Furnishing Bicyclic
Cannabidiols
Recently, we reported an indirect method for installation
of a bulky aromatic ring onto the γ-substituted cyclohex-
enone and subsequent generation of a reactive enolate.12 By
using this method, we synthesized 1 and its analogues
successfully. However, the substituent we could place at the
γ position of the cyclohexanone is limited to that derived
by aldol reaction with an aldehyde. To gain wider flexibility
in this method, we envisaged reaction of 2-cyclohexene-1,4-
diol monoacetate 413 with alkenyl reagents furnishing
compounds of type 5, which would be transformed into the
CBD family and related analogues by the method mentioned
above (Scheme 1). A synthetic advantage of this strategy is
availability of optically active 4 by the established method.13
The present investigation was started with an application
of the reagent systems originally developed for cyclopentene
monoacetate.14 Thus, reaction of 4 with lithium isopropenyl
borate 7,15 prepared in situ from the boronate ester 6 and
n-BuLi, proceeded at room temperature but afforded a
mixture of products, among which the desired product 5a
(R ) Me) and the regioisomer 11 were detected in moderate
yield with a 67:33 ratio by 1H NMR spectroscopy (Table 1,
entry 1). Next we studied the CuCN-catalyzed reaction with
(5) Mechoulam, R.; Hanus, L. Chem. Phys. Lipids 2002, 121, 35-43.
(6) Sumariwalla, P. F.; Gallily, R.; Tchilibon, S.; Fride, E.; Mechoulam,
R.; Feldmann, M. Arthritis Rheum. 2004, 50, 985-998.
(7) Mechoulam, R.; Parker, L. A.; Gallily, R. J. Clin. Pharmacol. 2002,
42, 11S-19S.
(8) Tius, M. A. Stud. Nat. Prod. Chem. 1997, 19, 185-244.
(9) (a) Mechoulam, R.; Gaoni, Y. J. Am. Chem. Soc. 1965, 87, 3273-
3275. (b) Mechoulam, R.; Braun, P.; Gaoni, Y. J. Am. Chem. Soc. 1972,
94, 6159-6165. (c) Vaillancourt, V.; Albizati, K. F. J. Org. Chem. 1992,
57, 3627-3631. (d) Childers, W. E., Jr.; Pinnick, H. W. J. Org. Chem.
1984, 49, 5276-5277. (e) Evans, D. A.; Barnes, D. M.; Johnson, J. S.;
Lectka, T.; von Matt, P.; Miller, S. J.; Murry, J. A.; Norcross, R. D.;
Shaughnessy, E. A.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 7582-
7594. (f) Petrzilka, T.; Haefliger, W.; Sikemeier, G.; Ohloff, G.; Eschen-
moser, A. HelV. Chim. Acta 1967, 719-723. (g) Razdan, R. K.; Dalzell,
H. C.; Handrick, G. R. J. Am. Chem. Soc. 1974, 96, 5860-5865. (h) Baek,
S.-H.; Srebnik, M.; Mechoulam, R. Tetrahedron Lett. 1985, 26, 1083-
1086. (i) Hanus, L. O.; Tchilibon, S.; Ponde, D. E.; Breuer, A.; Fride, E.;
Mechoulam, R. Org. Biomol. Chem. 2005, 3, 1116-1123.
(10) (a) Tius, M. A.; Busch-Petersen, J.; Marris, A. R. Chem. Commun.
1997, 1867-1868. (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, 3596-3608. (c) Harrington, P. E.;
Stergiades, I. A.; Erickson, J.; Makriyannis, A.; Tius, M. A. J. Org. Chem.
2000, 65, 6576-6582. (d) Chu, C.; Ramamurthy, A.; Makriyannis, A.; Tius,
M. A. J. Org. Chem. 2003, 68, 55-61 and references therein.
(11) Tchilibon, S.; Mechoulam, R. Org. Lett. 2000, 2, 3301-3303.
(12) (a) William, A. D.; Kobayashi, Y. Org. Lett. 2001, 3, 2017-2020;
J. Org. Chem. 2002, 67, 8771-8782.
alkenyl Grignard reagents. According to the earlier result
with 2-cyclopentene-1,4-diol monoacetate, isopropenylmag-
nesium chloride would be a suitable reagent for the present
reaction with 4.14c However, preparation of the chloride
reagent was unsuccessful as stated.14c Instead, the bromide
reagent 8, prepared easily, resulted in lower regioselectivity
2700
Org. Lett., Vol. 8, No. 13, 2006

(entry 2). The incompatibility between the reagent prepara-
tion and the regioselectivity was overcome by addition of
excess MgCl2, which afforded an improved ratio of 86:14
and a good combined yield (entry 3). In addition, separation
of the regioisomers 5a and 11 by silica gel column chro-
matography was an easy task.
Scheme 2. Synthesis of Cannabidiol (2)
Although the result of entry 3 might be practical, we next
explored reaction with zinc reagents to attain a better
selectivity. Thus, zinc reagent 9 (4 equiv), prepared from 8
and excess ZnCl2, was subjected to reaction with 4 in the
presence of CuCN or NiCl2(tpp)2 (tpp/PPh3) as a catalyst
(entries 4 and 5). Among the catalysts, NiCl2(tpp)2 afforded
products 5a and 11 but in lower regioselectivity and in lower
yield. Fortunately, addition of TMEDA improved the regio-
selectivity and reactivity to afford 5a in good yield (entry
6). Use of smaller quantities of the reagents and TMEDA
also provided good results with 80% isolated yield (entry
7). In contrast, the reagent prepared from 8 and ZnCl2 in a
2:1 ratio, probably 10, was inferior in regioselectivity (entry
8).
Product 5a was transformed successfully into the dimethyl
ether of CBD (Scheme 2). Oxidation of 5a afforded an enone,
which underwent iodination at the R position by I2 in the
presence of 2,5-di-tert-butylhydroquinone (DBHQ) as a
radical scavenger to produce R-iodo enone 14 in 63% yield
(two steps). Addition of the 2,6-dimethoxy-4-pentylphenyl
group (abbreviated as Ar in the scheme) to enone 14 was
performed with the higher-order cyanocuprate 13 derived
from the lithium anion 12 and CuCN according to our
previous procedure12 with modification.16 Compound 15,
obtained as a 1:1 stereoisomeric mixture at the R position,
underwent reaction with EtMgBr17 to produce the reactive
magnesium enolate, which was quenched with ClP(dO)-
(OEt)2 to furnish enol phosphate 16 in 51% yield from 14.
Nickel-catalyzed coupling of 16 with MeMgCl afforded
Synthesis of the dimethyl ether 19, the known precursor
of 7-hydroxy-CBD (3),9i,11 was achieved commencing with
enol phosphate 16 as summarized in Scheme 3. Thus, nickel-
Scheme 3. Synthesis of 7-Hydroxycannabidiol (3)
1
dimethyl ether 17 in good yield. The H and 13C NMR
spectra of synthetic 17 were identical with the data
published.9c,i Demethylation of 17 using MeMgI to CBD (2)
and demethylation/cyclization to ∆9-THC (1) have been
reported in the literature.9a,d
(13) (a) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J. Org. Chem. 1991, 56, 2656-2665. (b) Harris, K. J.; Gu, Q.-M.;
Shih, Y.-E.; Girdaukas, G.; Sih, C. J. Tetrahedron Lett. 1991, 32, 3941-
3944. (c) Ba¨ckvall, J.-E.; Gatti, R.; Schink, H. E. Synthesis 1993, 343-
348. (d) Lo´pez-Pelegr´ın, J. A.; Janda, K. D. Chem.-Eur. J. 2000, 6, 1917-
1922. (e) Suzuki, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 2001,
66, 1494-1496. (f) Hua, Z.; Yu, W.; Su, M.; Jin, Z. Org. Lett. 2005, 7,
1939-1942.
(14) (a) Review: Kobayashi, Y. Curr. Org. Chem. 2003, 7, 133-147.
(b) Nakata, K.; Kobayashi, Y. Org. Lett. 2005, 7, 1319-1322. (c)
Kobayashi, Y.; Nakata, K.; Ainai, T. Org. Lett. 2005, 7, 183-186. (d)
Kobayashi, Y.; Murugesh, M. G.; Nakano, M.; Takahisa, E.; Usmani, S.
B.; Ainai, T. J. Org. Chem. 2002, 67, 7110-7123.
(15) The highly volatile nature of the isopropenyl boronate ester with
the original 2,3-butanediol ligand prevented its isolation, whereas compound
6, studied herein, was less volatile.
catalyzed reaction with ClMgCH2Si(Me)2(OPr-i) afforded the
coupling product 18 in 80% yield, which upon Tamao
oxidation18 produced alcohol 199i,11 in good yield.
We then turned our attention to the synthesis of analogues
possessing a longer alkenyl chain in place of the isopropenyl
group because the isopropenyl moiety is an important
pharmacophore to control the biological property.4,10 The
CH2dC(C5H11) group was chosen as a typical example. Thus,
Org. Lett., Vol. 8, No. 13, 2006
2701

4 in the presence of NiCl2(tpp)2 as a catalyst to afford 5b in
86% yield with a 94:6 regioisomeric ratio19 (Scheme 4).
Alcohol 5b was converted to enol phosphate 23 in the same
manner as 5a was transformed to 16. Finally, coupling of
23 with MeMgCl afforded 24, and coupling with ClMgCH2-
Si(Me)2(OPr-i) followed by Tamao oxidation18 of the result-
ing 25 furnished 26 in 60% yield over two steps.
Scheme 4. Synthesis of Cannabidiol Analogues 23 and 25
In summary, we have developed a new way to prepare
cannabinoids starting with monoacetate 4, in which regiose-
lective installation of an alkenyl group to the cyclohexenyl
ring of 4 is accomplished with a new reagent system
consisting of (alkenyl)ZnCl, TMEDA, and NiCl2(tpp)2 (cat.).
Application of this reagent to other allylic substrates is under
investigation.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Science, Sports, and Culture, Japan.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds described herein.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL060692H
(16) Because we had occasionally experienced insufficient lithiation of
the dimethyl ether of olivetol (Ar-H in Scheme 2) with n-BuLi in Et2O,
thus producing a mixture of 15 and the Bu group incorporated product i,
we reinvestigated this step with or without any additive. We now recommend
a procedure of stirring the olivetol ether (Ar-H) in Et2O with n-BuLi (1.2
equiv) and DME (2.4 equiv) at room temperature for 2 h. Other conditions
attempted are presented in the Supporting Information.
(17) Aoki, Y.; Oshima, K.; Utimoto, K. Chem. Lett. 1995, 463-464.
(18) Tamao, K.; Ishida, N. Tetrahedron Lett. 1984, 25, 4245-4248.
(19) The reagent system with CH2dCH(C5H11)MgBr (3.5 equiv), CuCN
(30 mol %), and MgCl2 (10 equiv) in THF afforded a 77:23 mixture of 5b
and its regioisomer quantitatively.
CH2dC(C5H11)ZnCl (20) was prepared from CH2dC(C5H11)-
MgBr and ZnCl2 and subjected to reaction with monoacetate
2702
Org. Lett., Vol. 8, No. 13, 2006