Enantiomeric cannabidiol derivatives: Synthesis and binding to cannabinoid receptors

Article abstract of DOI:10.1039/b416943c

(-)-Cannabidiol (CBD) is a major, non psychotropic constituent of cannabis. It has been shown to cause numerous physiological effects of therapeutic importance. We have reported that CBD derivatives in both enantiomeric series are of pharmaceutical interest. Here we describe the syntheses of the major CBD metabolites, (-)-7-hydroxy-CBD and (-)-CBD-7-oic acid and their dimethylheptyl (DMH) homologs, as well as of the corresponding compounds in the enantiomeric (+)-CBD series. The starting materials were the respective CBD enantiomers and their DMH homologs. The binding of these compounds to the CB₁ and CB₂ cannabinoid receptors are compared. Surprisingly, contrary to the compounds in the (-) series, which do not bind to the receptors, most of the derivatives in the (+) series bind to the CB₁ receptor in the low nanomole range. Some of these compounds also bind weakly to the CB₂ receptor. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b416943c

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A R T I C L E
Enantiomeric cannabidiol derivatives: synthesis and binding to
cannabinoid receptors†
Lum´ır O. Hanusˇ,*a Susanna Tchilibon,a Datta E. Ponde,a Aviva Breuer,a Ester Frideb and
Raphael Mechoulama
a Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Medical
Faculty, The Hebrew University of Jerusalem, Ein Kerem, 91120, Jerusalem, Israel.
E-mail: lumir@cc.huji.ac.il; Fax: +972-2-6757076; Tel: +972-2-6758042
b Department of Behavioural Sciences, College of Judea and Samaria, Ariel, 44837, Israel
Received 8th November 2004, Accepted 25th January 2005
First published as an Advance Article on the web 16th February 2005
(−)-Cannabidiol (CBD) is a major, non psychotropic constituent of cannabis. It has been shown to cause numerous
physiological effects of therapeutic importance. We have reported that CBD derivatives in both enantiomeric series
are of pharmaceutical interest. Here we describe the syntheses of the major CBD metabolites, (−)-7-hydroxy-CBD
and (−)-CBD-7-oic acid and their dimethylheptyl (DMH) homologs, as well as of the corresponding compounds in
the enantiomeric (+)-CBD series. The starting materials were the respective CBD enantiomers and their DMH
homologs. The binding of these compounds to the CB1 and CB2 cannabinoid receptors are compared. Surprisingly,
contrary to the compounds in the (−) series, which do not bind to the receptors, most of the derivatives in the
(+) series bind to the CB1 receptor in the low nanomole range. Some of these compounds also bind weakly to the
CB2 receptor.
compounds in the (−) series do not bind to the cannabinoid CB1
receptor but, surprisingly, derivatives in the (+) series bind to this
receptor.19 We also showed that some of the (+) CBD derivatives,
which show significant binding to the CB1 receptor, do not
exhibit any effects in the tetrad group of assays (ambulation,
sedation, analgesia, temperature lowering), which are typical
for cannabinoid CB1 agonists.20 This observation indicates that
these (+)-CBD derivatives apparently do not activate the CB1
receptor in the brain. Although the reason for this discrepancy
is not known, such compounds may be of significant thera-
peutic interest as non-psychotropic cannabinoid agonists to the
peripheral CB1 receptors, with possible activity in reduction
of peripheral pain and inflammation. Peripherally restricted
agonists to the CB1 receptor have not been described so far.
In the present publication we describe the syntheses of (−)-
CBD metabolites and derivatives, as well as (+)-CBD deriva-
tives, whose binding to the CB1 receptor we have previously
described,19 and some new additional, related compounds. The
binding of all new compounds are presented in Table 1, together
with those of the corresponding enantiomers. The binding of
all previously reported compounds and those reported here,
is summarized in two Tables as Electronic Supplementary
Information.† The synthetic procedures described include those
of the major CBD metabolites, (−)-7-hydroxy-CBD (12a) and
(−)-CBD-7-oic acid (18a) and their dimethylheptyl (DMH)
homologs (12b and 18b) as well as the corresponding compounds
in the enantiomeric (+)-CBD series (12c,18c,12d and 18d).
We have published a short communication on the synthesis
of (−)-7-hydroxy-CBD (12a),21 and a low yield synthesis of
(+)-7-hydroxy-CBD diacetate.22 The starting materials for the
syntheses of the CBD derivatives were (−)-CBD (4a) and (−)-
CBD-DMH (4b) and their enantiomers (4c) and (4d).
Introduction
Cannabidiol (CBD) (4a) is the major non psychotropic, neutral
cannabinoid in most cannabis preparations, such as marijuana
and hashish. It was isolated in the early 1940s,1 but its structure
and absolute configuration were fully elucidated only in the mid
1960s.2 Several syntheses of CBD and of its (+)-enantiomer
have been reported; however most of them were low yielding.3
An improved synthesis of (−)-CBD and of its dimethylheptyl
homolog (CBD-DMH) was reported by Baek et al.4 For a review
of the chemistry of CBD see reference 5.
The precursor of CBD, namely cannabidiolic acid, is usually
the major cannabinoid present in the cannabis plant and CBD is
actually a product formed on decarboxylation of cannabidiolic
acid.6 In cannabis preparations, such as hashish and marijuana,
CBD is found in higher concentrations than in the plant,
presumably due to decarboxylation during the collection and
drying of the material.7 Cannabidiolic acid was isolated and its
structure was elucidated by Santavy´’s group and our group.
2b,8
ˇ
CBD has been shown to cause a wide range of biological
effects. These observations may be of clinical importance as
CBD has low toxicity and causes no psychotropic effects in
either humans or animals. Thus, CBD has been found to be
anti-epileptic9 and anxiolytic10 in man. Recently we showed
that CBD and the related 7-nor-7-carboxy-CBD-DMH (18b)
are potent anti-arthritic therapeutics in models of arthritis in
mice.11a–d Other physiological effects reported are prolongation
of barbiturate sleeping time, apparently caused by inhibition
of barbiturate metabolism,12 reduction of serotonin uptake,13
prevention of vomiting and nausea,14 extinction of memories
15
in animal models and inhibition of neurodegeneration in an
animal model of Parkinson’s disease.16 Cannabidiol is a potent
anti-oxidant.17 For a review of the biological effects of CBD see
reference 18.
Results and discussion
In view of the therapeutically promising effects of CBD
we assayed several derivatives both in the natural (−) series
as well as in the unnatural (+) series. We reported that the
Syntheses
The syntheses of (+)-CBD (4c) and of (+)-CBD-DMH (4d)
are depicted in Scheme 1. Our synthetic route follows that
generally employed in most cannabinoid total syntheses, namely
the condensation of a monoterpenoid allylic alcohol with a
resorcinol derivative.
† Electronic supplementary information (ESI) available: Tables S1 and
S2. Binding of (−)- and (+)-CBD, (−)- and (+)-CBD-DMH, and
their derivatives to the central (CB1) and peripheral (CB2) cannabinoid
receptors. See http://www.rsc.org/suppdata/ob/b4/b416943c/
1 1 1 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 1 1 6 – 1 1 2 3
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Table 1 Binding of (−)- and (+)-cannabidiol derivatives to the central (CB1) and peripheral (CB2) cannabinoid receptors
Compound
R1
R2
R3
CB1 (Ki/nM)
CB2 (Ki/nM)
n-Pentyl chain:
5a
5c
12a
12c
18a
18c
CH3
CH3
CH2OH
CH2OH
COOH
COOH
CH3
CH3
H
H
H
CH3
CH3
H
H
H
>10000
>10000
>10000
5.3 0.5
>10000
13.2 0.4
>10000
>10000
>10000
101.0 5.1
>10000
H
H
321.8 15.8
1,1-Dimethylheptyl chain:
5b
CH3
CH3
COOH
COOH
CH3
CH3
H
CH3
CH3
H
>10000
>10000
>1000
>10000
<10000
<10000
155.5 5.3
5d
18b
18d
H
H
5.8 0.7
butyldimethylsilyl bromide (TMSBr) into the allylic bromide
9a. Reaction with tetrabutylammonium acetate led to 10a, which
gave 11a on hydrolysis. The ether blocking groups were removed
by heating with methylmagnesium iodide at 200 ◦C,23 producing
(−)-7-hydroxy-cannabidiol (12a), a primary CBD metabolite.
The same sequence of reactions starting with (−)-CBD-DMH
(4b) led to (−)-7-hydroxy-CBD-DMH (12b).
The second major metabolite, CBD-7-oic acid (18a), was
prepared as described in Scheme 3. Here the same reaction
sequence was followed up to the allyl alcohol (7a), as in
Scheme 2. Then the ether protecting groups were removed
with methylmagnesium iodide at 200 ◦C, leading to the triol
(13a), which was then acetylated to the triacetate (14a). On
bromination, as described above, the bromide 15a was obtained.
The bromide 15a was oxidized with potassium chromate in
hexamethylphosphoric triamide to the aldehyde 16a, which on
further oxidation with sodium chlorite led to (−)-CBD-DMH-
7-oic acid diacetate (17a). The deacetylation was carried out by
sodium borohydride in ethanol to give desired acid metabolite
(18a). The same pathway was followed in the synthesis of the
dimethylheptyl homolog 18b.
Scheme 1
The synthetic pathways described above represent the first
preparation of the major natural and unnatural CBD metabo-
lites, 12a and 18a, and their dimethylheptyl homologs 12b and
18b and make them available for biological evaluation.
The same sequence of reactions starting from the enan-
tiomeric (−)-p-mentha-1,8-diene-3-one led to the (+) enan-
tiomeric alcohols 12c,18c and carboxylic acids 12d and 18d.
Condensation of (−)-p-mentha-1,8-diene-3-ol3c with olivetol
in the presence of boron trifluoride in diethyl ether led predomi-
nantly to the formation of the cyclised (+)-D9-THC (3). However
when the modified procedure reported by Baek et al.4 was
employed, namely condensation with boron trifluoride etherate
absorbed on basic alumina, we obtained the desired 4c in 44%
and 4d in 55% yields. The syntheses of 12a and 12b are depicted
in Scheme 2. CBD (4a) was converted into its dimethyl ether
(5a) by dimethyl sulfate–potassium carbonate in acetone, which,
on reaction with one mole of meta-chloroperbenzoic acid gave
the epoxide (6a). Epoxidation, being an electrophilic reaction,
selectively attacked the ring double bond without a reaction on
the terminal olefinic group, as the electron density on the latter
is lower than in the former. The epoxide presumably is trans
to the aromatic ring, on the basis of related previous NMR
studies.2a Methylmagnesium-N-cyclohexylisopropylamide (pre-
pared in situ) opened the epoxide ring, to give 7a exclusively.
The use of methyl ether as a protecting group was found to
be necessary. Every attempt to change it to a different group
that is easier to remove, such as methoxyethoxymethyl (MEM),
methoxymethyl (MOM) or silyl ethers, was unsuccessful as
the epoxidation reaction did not proceed or the protecting
group was removed during the reaction. Acetylation of 7a with
acetic anhydride–pyridine gave 8a, which was converted by t-
Binding to the cannabinoid receptors CB1 and CB2
In a previous publication describing the biological properties of
cannabidiol derivatives, we presented binding data for some of
the compounds whose synthesis is described here, namely 4a–
d,12a,b,d,18a,b. We were surprised to note that while compounds
in the natural, levorotatory, 3R,4R series did not bind, or bound
very weakly, to the CB1 and the CB2 cannabinoid receptors,
compounds in the dextrorotatory, 3S,4S series showed potent
binding to CB1 and somewhat lower binding to CB2. Thus (−)-
CBD-DMH (4b) binds to the CB1 receptor with a Ki above
10 lM and to the CB2 receptor with a Ki of 1800 nM, while the
(+) enantiomer (4d) does so with a Ki of 17.4 nM and 211 nM
respectively. In the 7-hydroxy series (+)-7-OH-CBD-DMH (12d)
binds with a Ki of 2.5 nM to CB1 and 44.0 nM to CB2, while the
numbers for the (−) enantiomer (12b) were 4400 nM and 671 nM
respectively. When all the cannabidiol metabolites not assayed
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Scheme 2 Reagents and conditions: (a) CH3I, K2CO3 in DMF; (b) 3-chloroperbenzoic acid in CH2Cl2; (c) methylmagnesium-N-cyclo-
hexylisopropylamide in toluene; (d) Ac2O in pyridine; (e) TMSBr in CH2Cl2; (f) (nBu)4NH4OAc in acetone; (g) NaOH aq; (h) CH3MgI at 200 ◦C.
Scheme 3 Reagents and conditions: (a) CH3MgI at 210 ◦C; (b) Ac2O in pyridine; (c) TMSBr in CH2Cl2; (d) K2CrO4 in HMPA; (e) NaClO2;
(f) NaBH4 reflux in ethanol.
1 1 1 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 1 1 6 – 1 1 2 3

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previously were investigated we observed the same phenomenon.
We compared five sets of enantiomers (see Table 1). The
phenolic ethers, 5a and 5c, as well as 5b and 5d, did not bind
to either CB1 or CB2. In the three remaining sets in which
the phenolic groups are not substituted, the (−) enantiomers
(12a,18a,b) were essentially inactive on binding, while potent
activity was noted with the (+) enantiomers (12c,18c,d). These
stereochemical differences may be useful in future investigations
on the structural features of the receptors which are required
for binding. We would like to stress that not all cannabinoid
activities are CB1/CB2-mediated. Several additional, putative
receptors have been proposed but so far none of these have been
cloned or well-identified.24 Indeed (−)-CBD (4a) and the acid
18b, which do not bind significantly to either receptor, are
potent anti-inflammatory compounds in models of rheumatoid
arthritis. The molecular mechanism of this activity is unknown.
In summary, we report a synthetic pathway to the unnatural
enantiomer of CBD, namely (+)-CBD (4c) and to its DMH
homologue, (+)-CBD-DMH (4d), as well as the first syntheses
of the major (−)-CBD metabolites (−)-7-hydroxy-CBD
(12a) and (−)-CBD-7-oic acid (18a) and the corresponding
compounds in the (+) series, and report their binding to the
CB1 and CB2 receptors.
was extracted with ether. The organic phase was washed with
brine until neutral, dried on MgSO4 and filtered. Removal
of the solvent under reduced pressure afforded 3.2 g of the
1
product 5a. Yield 98%; H-NMR: d 6.344 (2H, s, Ar), 5.220
(1H, s, olefin), 4.460–4.436 (2H, d, J = 7.2 Hz), 4.023–3.971
(1H, m, benzyl), 3.741 (6H, s, OCH3), 2.960–2.869 (1H, td, J =
11.5, 4.5 Hz, allyl), 2.717–2.569 (2H, t, J = 7.5 Hz, benzyl),
2.259–2.144 (1H, m), 2.018–1.960 (1H, m), 1.789–1.722 (1H,
m), 1.678 (3H, s, allyl CH3), 1.568 (6H, br s), 1.352 (4H, m),
0.936–0.890 (3H, t, J = 6.8 Hz, terminal CH3); IR mmax/cm−1:
2875, 1600, 1570, 1440, 1410, 1220, 1100, 880; [a]2D0 −96.8 (c
12.19 mg ml−1 in CHCl3); MS m/z: 342 (M+, 14%), 274 (100),
243 (27), 235 (10), 221 (40), 173 (16); HR-MS m/z calculated
for C23H35O2: 342.2559, found 342.2551.
Dimethoxy-CBD-DMH (5b)
Prepared by the same procedure reported for 5a, with CBD-
DMH as starting material. Yield 96%; 1H-NMR: d 6.449 (2H, s,
Ar), 5.238 (1H, s, olefin), 4.422–4.382 (2H, d, J = 12.0 Hz),
4.120–3.901 (1H, m, benzyl), 3.784 (6H, s, OCH3), 2.933–2.801
(1H, m, benzyl), 2.270–2.086 (1H, m, allyl), 2.048–1.924 (1H,
m), 1.781–1.501 (10H, m), 1.253–1.185 (10H, m), 1.105–0.962
(2H, m), 0.849–0.8816 (3H, t, J = 6.8 Hz, terminal CH3); IR
mmax/cm−1: 2900, 1600, 15780, 1440, 1400, 1100; [a]2D0 −98.1 (c
2.04 mg ml−1 in CHCl3); MS m/z: 398 (M+, 19%), 331 (25),
330 (100), 301(14), 291(15), 277 (57), 245 (35); HR-MS m/z
calculated for C27H42O2: 398.3185, found 398.3186.
Experimental
General remarks
1H-NMR spectra were measured on a Varian VXR-300S
spectrophotometer using CDCl3 as solvent with TMS as the
internal standard. All chemical shifts are reported in ppm.
Specific rotations were determined with a Perkin-Elmer 141
polarimeter. Column chromatography was performed with ICN
1,6-Epoxy-2,6-dimethoxy-dihydrocannabidiol (6a)
-Chloroperbenzoic acid (70% pure 1.2 g, 4.85 mmol) was
dissolved in 50 ml CH2Cl2 and the solution was cooled to
0
◦C. A solution of 5a (1.65 g, 4.82 mmol) in 10 ml CH2Cl2
was slowly injected. The reaction mixture was stirred at 0 ◦C
for 30 min and monitored by TLC (10% ether–petroleum
ether). The reaction was quenched by addition of a saturated
aqueous solution of NaHCO3 and the organic phase was
separated by a separatory funnel, then the aqueous phase
was extracted with ether. The combined organic extracts were
washed with brine, dried over MgSO4 and filtered. Removal of
the solvents under reduced pressure afforded a residue that was
flash chromatographed (7% ether–petroleum ether) to give the
˚
silica gel 60 A. Organic solvents were dried over anhydrous
sodium sulfate.
Preparation of synaptosomal membranes and transfected cells
Synaptosomal membranes, used in this assay for CB1 receptor
binding, were prepared from the brains of Sabra male rats (250–
300 g) after removal of the brain stem by centrifugation and
gradient centrifugation after their homogenization.25 For CB2
receptor binding assays transfected cells were prepared. COS-
7 cells were transfected with plasmids containing CB2 receptor
cDNA, and crude membranes were prepared.26
1
epoxy-derivative 6a. Yield 65%; H-NMR: d 6.348–6.322 (2H,
d, J = 7.7 Hz, Ar), 4.369 (1H, s, olefin), 4.159 (1H, s, olefin),
3.803 (3H, s, OCH3), 3.714 (3H, s, OCH3), 3.612–3.571 (1H,
d, J = 12.2, Hz, H on epoxide ring), 2.574–2.522 (2H, t, J =
7.9 Hz, benzyl), 2.293–2.201 (1H, m), 2.081–1.995 (1H, m),
1.882–1.757 (1H, m), 1.628–1.585 (6H, m), 1.364–1.313 (9H, m),
0.936–0.890 (3H, t, J = 6.5 Hz, terminal CH3); IR mmax/cm−1:
2900, 1610, 1580, 1460, 1420, 1120, 760; MS m/z: 358 (M+,
26%), 341 (5), 287 (7), 274 (16), 250 (29), 221 (100); HR-MS
m/z calculated for C23H34O3: 358.2508, found 358.2531.
Receptor binding assays
The high affinity receptor probe,27 [3H]HU-243 (Tocris Cookson
Ltd., United Kingdom), with a dissociation constant of 45
7 pM for the CB1 receptor, was incubated with synaptosomal
membranes (3–4 lg) for CB1 assays and/or transfected cells for
CB2 assays, for 90 min at 30 ◦C with different concentrations of
the assayed CBD derivatives or with the vehicle alone (fatty-
acid-free bovine serum albumin at a final concentration of
0.5 mg ml−1). Bound and free radioligands were separated by
centrifugation. The data were normalized to 100% of specific
binding, which was determined with 50 nM unlabeled HU-243.
The results presented are the average of triplicate determination
from three independent experiments. The Ki value was deter-
mined with the GraphPad Prism (Version 3.02) program which
follows the Cheng–Prusoff equation. A sigmoid dose-response
(variable slope) built-in equation in this Prism program was used
to fit the curves.
1,6-Epoxy-2,6-dimethoxy-dihydrocannabidiol-DMH (6b)
Prepared by the same procedure as reported above for 6a. Yield
1
70%; H-NMR: d 6.466–6.442 (2H, d, J = 7.2 Hz, Ar), 4.358
(1H, s, olefin), 4.121 (1H, s, olefin), 3.805 (3H, s, OCH3), 3.719
(3H, s, OCH3), 3.591–3.555 (1H, d, J = 10.8, Hz, H on epoxide
ring), 2.235–2.193 (1H, m, benzyl), 2.105–1.995 (1H, m, allyl),
1.907–1.761 (1H, m), 1.745–1.514 (10H, m), 1.369 (3H, s, allyl
CH3), 1.268–1.180 (10H, m), 1.081–0.942 (2H, m.), 0.856–0.812
(3H, t, J = 6.5 Hz, terminal CH3); IR mmax/cm−1: 2900, 1600,
1580, 1460, 1450, 1210, 1110, 750; MS m/:414 (M+, 13%), 346
(26), 331 (13), 290 (80), 277 (100), 261 (20), 221 (21); HR-MS
m/z calculated for C27H42O3: 414.3134, found 414.3098.
Dimethoxy-CBD (5a)
CBD, isolated from hashish, (3 g, 9.95 mmol) was dissolved in
DMF (55 ml). K2CO3 (7.35 g, 53.3 mmol) and CH3I (2.3 ml,
36.9 mmol) were added and the mixture was stirred at room
temperature for 4 hours. The reaction was monitored by TLC
(10% ether–petroleum ether) until the starting material had
disappeared. Then water (200 ml) was added and the solution
(3R,4R)-3-(4-Pentyl-2,6-dimethoxyphenyl)-2-hydroxy-4-
isopropenyl-1-methylenecyclohexane (7a)
Butyllithium in hexane (5.6 ml, 14 mmol) was added to a solution
of N-cyclohexylisopropylamine (1.85 ml, 11.3 mmol) at 0 ◦C in
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anhydrous toluene (10 ml, distilled over sodium) under an N2
atmosphere. After 15 min, methylmagnesium bromide in ether
(3.8 ml, 11.4 mmol) was injected, and the reaction mixture was
stirred for 45 min at room temperature. A solution of 6a (1 g,
2.79 mmol) in dry toluene (3 ml) was added, and the mixture
was heated to 40 ◦C and stirred for two hours. Then the reaction
was cooled to 0 ◦C and quenched by the slow addition of 5 M
HCl. The organic phase was separated by a separatory funnel,
and the aqueous phase was extracted with ether. The combined
organic extracts were washed with brine, dried over MgSO4
and filtered. Removal of the solvents under reduced pressure
afforded a residue that on TLC (20% ether–petroleum ether)
3.802 (3H, s, OCH3), 3.754 (3H, s, OCH3), 3.268–3.181 (1H, m,
benzyl), 2.522–2.459 (1H, m, allyl), 1.781–1.717 (1H, m), 1.695
(3H, s, OAc), 1.540–1.484 (6H, m), 1.239–1.171 (14H, m), 0.980–
0.923 (2H, m), 0.854–0.809 (3H, t, J = 6.7 Hz, terminal CH3);
IR mmax/cm−1: 290, 1750, 1450, 1360, 1240, 1120, 880; MS m/z:
456 (M+, 40%), 396 (11), 370 (100), 290 (28), 277 (41); HR-MS
m/z calculated for C29H44O4: 456.3239, found 456.3222.
7-Bromo-dimethoxy-CBD (9a)
8a (1 g, 2.5 mmol) was dissolved in dry CH2Cl2 (50 ml, distilled
over CaH2) under nitrogen atmosphere and TMSBr (1.6 ml,
12.1 mmol) was added. The reaction was stirred at rt for
4 hours, then it was shaken with a saturated aqueous solution of
NaHCO3 and the organic phase was separated by a separatory
funnel, and the aqueous phase was extracted with ether. The
combined organic extracts were washed with brine, dried over
MgSO4 and filtered. Removal of the solvents afforded a residue
1
showed only one spot, and by H-NMR was identified as 7a.
Yield 97%; 1H-NMR: d 6.332 (2H, s, Ar), 5.083 (1H, s, olefin),
4.821 (1H, s, olefin), 4.662–4.622 (1H, d, J = 11.8 Hz, CHOH),
4.387 (1H, s, olefin), 4.379 (1H, s, olefin), 3.798 (3H, s, OCH3),
3.745 (3H, s, OCH3), 3.200–3.154 (1H, td, J = 11.2, 3.0 Hz,
benzyl), 2.564–2.452 (3H, m), 2.255–1.625 (1H, m), 1.754–1.707
(1H, m), 1.609–1.350 (4H, m), 1.432 (3H, s, allyl CH3), 1.350–
1.313 (4H, m), 0.924–0.878 (3H, t, J = 6.5 Hz, terminal CH3); IR
mmax/cm−1: 3400, 2920, 1590, 1450, 1120, 900, 730; [a]2D0 +62.3 (c
15.36 mg ml−1 in CHCl3); HR-MS m/z calculated for C23H34O3:
358.2508, found 358.2508.
1
that H-NMR and TLC (20% ether–petroleum ether) showed
predominantly a single component, that was used with no
1
purification. Yield 90%; H-NMR: d 6.322 (2H, s, Ar), 5.736
(1H, s, olefin), 4.767 (1H, s, olefin), 4.454), 4.535 (1H, s, olefin),
4.006 (2H, s, CH2Br), 3.736 (6H, s, OCH3), 2.853–2.767 (1H,
td, J = 11.9, 3.2 Hz, benzyl), 2.565–2.512 (1H, t, J = 7.9, Hz,
benzyl), 2.397–2.359 (1H, m), 2.277–2.183 (1H, m), 1.870–1.662
(2H, m), 1.619 (3H, s, allyl CH3), 1.439–1.237 (7H, m), 0.928–
0.882 (3H, t, J = 6.6 Hz, terminal CH3); IR mmax/cm−1: 2900,
1580, 1460, 1230, 1120; [a]2D0 −20.5 (c 1.7 mg ml−1 in ethanol);
MS m/z): 423 (M+, 0.6%), 342 (27), 340 (28), 287 (42), 274 (61),
221 (100); HR-MS m/z calculated for C23H34O2 Br: 423.1722,
found 423.1708.
(3R,4R)-3-[4-(1ꢀ,1ꢀ-Dimethylheptyl)-2,6-dimethoxyphenyl]-2-
hydroxy-4-isopropenyl-1-methylenecyclohexane (7b)
Prepared by the same procedure as reported above for 7a. Yield
97%; 1H-NMR: d 6.440 (2H, s, Ar), 5.080 (1H, s, olefin), 4.821
(1H, s, olefin), 4.655–4.621 (1H, d, J = 9.0 Hz, CHOH), 4.448
(1H, s, olefin), 4.338 (1H, s, olefin), 3.802 (3H, s, OCH3), 3.744
(3H, s, OCH3), 3.215–3.127 (1H, td, J = 11.7, 3.0 Hz, benzyl),
2.505–2.444 (1H, dt, J = 12.6, 3.0 Hz allyl), 2.255–2.182 (1H,
td, J = 9.0, 3.0 Hz), 1.740–1.688 (2H, m), 1.555–1.423 (8H, m),
1.301–1.177 (10H, m), 1.025–0.955 (2H, m), 0.859–0.814 (3H, t,
J = 6.5 Hz, terminal CH3); IR mmax/cm−1: 3400, 2900, 1600, 1560,
1450, 1400, 1110, 750; [a]2D0 +47.6 (c 1.05 mg ml−1 in CHCl3);
MS m/z: 414 (M+, 10%), 370 (45), 290 (22), 278 (20), 277 (100);
HR-MS m/z calculated for C27H42O3: 414.3134, found 414.3134.
7-Bromo-dimethoxy-CBD-DMH (9b)
Prepared by the same procedure as reported above for 9a. Yield
90%; 1H-NMR: d 6.431 (2H, s, Ar), 5.602 (1H, s, olefin), 4.821–
4.337 (4H, m, CH2Br + olefin), 4.042–3.961 (1H, m, olefin),
3.720 (6H, s, OCH3), 3.116–3.010 (1H, m, benzyl), 2.842–2.762
(1H, allyl), 1.782–1.517 (9H, m), 1.247–1.178 (10H, m), 1.010
(2H, br s), 0.831 (3H, br s, terminal CH3); IR mmax/cm−1:
2910, 1580, 1460, 1230, 1120; [a]2D0 −17.5 (c 6.1 mg ml−1 in
ethanol); HR-MS m/z calculated for C27H42O2Br: 477.2368,
found 477.2378.
(3R,4R)-3-[2,6-Dimethoxy-4-pentylphenyl]-2-acetoxy-
4-isopropenyl-1-methylenecyclohexane (8a)
7a (0.9 g, 2.5 mmol) was dissolved in pyridine (2 ml) and acetic
anhydride (2 ml) and the reaction was stirred for 18 hours at
room temperature. Then the solution was poured onto iced
water (20 ml) and extracted with ether. The combined organic
extracts were washed successively with 1 M HCl, aqueous
sodium bicarbonate and brine, dried on MgSO4 and filtered.
Removal of the solvents under reduced pressure afforded an oily
residue that on TLC (20% ether–petroleum ether) showed only
one spot, that by 1H-NMR was proved to be 8a. Yield ∼100%;
1H-NMR: d 6.281–6.267 (2H, d, J = 4.2 Hz, Ar), 5.967–5.931
(1H, d, J = 10.8 Hz, olefin), 4.767–4.721 (2H, d, J = 13.7 Hz,
olefin), 4.535 (1H, s, olefin), 4.419 (1H, s, olefin), 3.793 (3H, s,
OCH3), 3.745 (3H, s, OCH3), 3.491–3.416 (1H, t, J = 11.4 Hz),
3.286–3.197 (1H, td, J = 11.4, 2.7, Hz, benzyl), 2.533–2.469
(2H, t, J = 7.2 Hz), 2.325–2.249 (1H, m), 1.717 (3H, s, OAc),
1.625–1.447 (6H, m), 1.404–1.250 (6H, m), 0.924–0.878 (3H, t,
J = 6.5 Hz, terminal CH3); IR mmax/cm−1: 2910, 1750, 1450,
1360, 1240, 1120, 890; MS m/z: 400 (M +, 16%), 340 (14), 314
(73), 234 (22), 221 (100); HR-MS m/z calculated for C25H36O4:
400.2614, found 400.2603.
7-Acetoxy-dimethoxy-CBD (19a)
9a (570 mg, 1.35 mmol) was dissolved in acetone (15 ml, stored
˚
on 4 A molecular sieves) and tetrabutylammonium acetate
(450 mg, 1.49 mmol) was added. The mixture was stirred,
refluxed and monitored by TLC (20% ether–petroleum ether).
After 2 hours there was no more starting material. The acetone
was removed under reduced pressure, and the residue was diluted
with water (20 ml) and extracted with ether. The combined
organic extracts were washed with aqueous sodium bicarbonate
and brine, dried on MgSO4 and filtered. Removal of the solvents
under reduced pressure afforded 520 mg of an oily residue.
Yield 96%; 1H-NMR: d 6.320 (2H, s, Ar), 5.581 (1H, s, olefin),
4.492–4.386 (4H, m, CH2OAc + olefin), 4.040–3.986 (1H, m,
benzyl), 3.715 (6H, s, OCH3), 2.853–2.801 (1H, m), 2.195–2.071
(2H, m), 2.060 (3H, s, OAc), 1.823–1.695 (2H, m), 1.605 (5H,
br s), 1.323 (4H, br s), 0.921–0.875 (3H, t, J = 6.7 Hz, terminal
CH3); IR mmax/cm−1: 2900, 1720, 1580, 1440, 1110; [a]2D0 −135.2
(c 15.95 mg ml−1, CHCl3); MS m/z: 400 (M+, 3%), 332 (26), 331
(100), 241 (41), 221 (55), 208 (11); HR-MS m/z calculated for
C25H36O4: 400.2614, found 400.2609.
(3R,4R)-3-[4-(1ꢀ,1ꢀ-Dimethylheptyl)-2,6-dimethoxyphenyl]-2-
acetoxy-1-methylenecyclohexane (8b)
7-Acetoxy-dimethoxy-CBD-DMH (10b)
Prepared by the same procedure as reported above for 8a. Yield
Prepared by the same procedure as reported above for 10a, but
the yield was slightly lower. Yield 90%; 1H-NMR: d 6.440 (2H, s,
Ar), 5.609 (1H, s, olefin), 4.498–4.343 (4H, m, CH2OAc + olefin),
4.041–3.965 (1H, m, benzyl), 3.719 (6H, s, OCH3), 2.845–2.763
1
∼ 100%; H-NMR: d 6.409–6.377 (2H, d, J = 8.1 Hz, Ar),
5.980–5.931 (1H, d, J = 14.5 Hz, CHOAc), 4.768–4.717 (2H, d,
J = 15.2 Hz, olefin), 4.521 (1H, s, olefin), 4.405 (1H, s, olefin),
1 1 2 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 1 1 6 – 1 1 2 3

View Article Online
(1H, m, allyl), 2.193–2.099 (2H, m), 2.061 (3H, s, OAc), 1.796–
1.776 (2H, m), 1.594–1.518 (7H, m), 1.254–1.179 (10H, m), 1.015
(2H, br s), 0.856–0.861 (3H, t, J = 6.4 Hz, terminal CH3); IR
mmax/cm−1: 2900, 1720, 1600, 1580, 1450, 1410, 1220; [a]2D0 −90.5
(c 2.53 mg ml−1, CHCl3); MS m/z: 456 (M+, 7%), 396 (8), 388
(71), 383 (25), 303 (13), 277 (68); HR-MS m/z calculated for
C29H44O4: 456.3239, found 456.3239.
(1H, s, olefin), 4.538 (1H, s, olefin), 4.108 (2H, s, CH2OH), 3.920–
3.889 (1H, d, J = 9.3 Hz, benzyl), 2.498–2.433 (1H, m, allyl),
2.228 (2H, br s), 2.064–1.715 (2H, m), 1.648–1.428 (7H, m),
1.312–1.168 (12H, m), 0.853–0.808 (3H, t, J = 6.5 Hz, terminal
CH3); IR mmax/cm−1: 3300, 2900, 1620, 1580, 1420, 1210, 1020,
750; [a]D −61.1 (c 1.8 mg ml−1, CHCl3); MS m/z: 386 (M+, 24%),
369 (30), 368 (30), 355 (100), 300 (43), 287 (510), 283 (34), 249
(38), 233 (22), 187 (10); HR-MS m/z calculated for C25H38O3:
386.28210, found 386.2825.
7-Hydroxy-dimethoxy-CBD (11a)
10a (500 mg, 1.25 mmol) was dissolved in ethanol (20 ml),
1 M NaOH (2 ml) was added and the reaction was refluxed
for 1 hour. The ethanol was removed under reduced pressure,
and the residue was diluted with water (20 ml) and 2 M HCl
was added till acidic. The solution was extracted with ether.
The combined organic extracts were washed with brine, dried
on MgSO4 and filtered. Removal of the solvents under reduced
pressure afforded 430 mg of an oily residue. Yield 96% yield;
1H-NMR: d 6.328 (2H, s, Ar), 5.510 (1H, s, olefin), 4.458–4.414
(2H, d, J = 13.2 Hz, olefin), 4.010 (2H, br s, CH2OH), 3.728
(6H, s, OCH3), 2.858–2.806 (1H, m, benzyl), 2.566–2.508 (2H, t,
J = 7.5 Hz, benzyl), 2.213 (2H, m), 1.817–1.582 (7H, m), 1.451–
1.259 (5H, m), 0.924–0.878 (3H, t, J = 6.5 Hz, terminal CH3);
IR mmax/cm−1: 3300, 2900, 1580, 1440, 1220, 1110; [a]2D0 −80.7
(19 mg/10 ml ethanol); MS m/z: 358 (M+, 7%), 327 (52), 290
(80), 221 (100), 152 (33); HR-MS m/z calculated for C25H38O3:
358.25080, found 358.2511.
(3R,4R)-3-[2,6-Dihydroxy-4-pentylphenyl]-2-hydroxy-4-
isopropenyl-1-methylenecyclohexane (13a)
A Grignard reagent was prepared with magnesium (84 mg,
3.5 mmol) and CH3I (0.2 ml, 3.5 mmol) in dry ether (1 ml,
distilled over sodium) under N2 atmosphere. 7a (360 mg, 1 mmol)
in ether (0.5 ml) was added to the stirred solution and the ether
was distilled. The residue was heated under N2 atmosphere to
210 ◦C for 45 min. The flask was cooled to the room temperature
and the reaction was quenched with ice water. The aqueous
solution was extracted several times with ether. The combined
organic extracts were dried on MgSO4 and filtered. Removal of
the solvents under reduced pressure afforded a residue that was
chromatographed on silica gel (25% ether–petroleum ether) to
give 132 mg of the pure 13a. Yield 45%; 1H-NMR: d 6.156–6.097
(2H, d, J = 17.7 Hz, Ar), 5.612 (1H, s, OH), 5.370 (1H, s, OH),
5.092 (1H, s, olefin), 4.847 (1H, s, olefin), 4.684–4.625 (2H, m,
CHOH + olefin), 4.462 (1H, s, olefin), 3.300–3.205 (1H, td, J =
12.7, 2.7 Hz, benzyl), 3.128–3.058 (1H, t, J = 10.5, Hz, allyl),
2.270–2.141 (1H, m), 2.122–2.049 (1H, br s, OH), 1.767–1.712
(1H, m), 1.534–1.48 (5H, m), 1.290–1.183 (4H, m), 0.895–0.881
(3H, t, J = 6.6 Hz, terminal CH3); IR mmax/cm−1: 3350, 2900,
1620, 1580, 1420, 1160, 1000, 750; MS m/z: 330 (M+, 18%),
312 (23), 286 (14), 244 (16), 207 (27), 193 (100); HR-MS m/z
calculated for C21H30O3: 330.2195, found 330.2206.
7-Hydroxy-dimethoxy-CBD-DMH (11b)
Prepared by the same procedure as reported above for 11a. Yield
94%; 1H-NMR: d 6.446 (2H, s, Ar), 5.528 (1H, s, olefin), 4.434–
4.367 (2H, d, J = 20.1 Hz, olefin), 4.010 (3H, br s, CH2OH +
OH), 3.729 (6H, s, OCH3), 2.905–2.785 (1H, m, benzyl), 2.248–
2.105 (2H, m), 1.759–1.704 (2H, m), 1.535 (3H, s, allyl CH3),
1.495–1.460 (4H, m), 1.360–1.120 (10H, m), 0.980–0.9875 (2H,
m), 0.797–0.752 (3H, t, J = 6.5 Hz, terminal CH3); IR mmax/cm−1:
3300, 2900, 1600, 1570, 1420, 1400, 1230, 1110, 750; [a]D −135.2
(c 15.95 mg ml−1, CHCl3); MS m/z: 414 (M+, 14%), 396 (8), 383
(100), 346 (43), 277 (50), 119 (7); HR-MS m/z calculated for
C27H42O3: 414.3134.
(3R,4R)-3-[4-(1ꢀ,1ꢀ-Dimethylheptyl)-2,6-dihydroxyphenyl]-2-
hydroxy-4-isopropenyl-1-methylenecyclohexane (13b)
Prepared by the same procedure as reported above for 13a.
1
Yield 58%; H-NMR: d 6.295 (1H, s. Ar), 6.229 (1H, s, Ar),
7-Hydroxy-CBD (12a)
5.786 (1H, s, OH), 5.546 (1H, s, OH), 5.127 (1H, s, olefin),
4.861 (1H, s, olefin), 4.751–4.716 (1H, d, J = 3.3 Hz, CHOH),
5.127 (1H, s, olefin), 4.444 (1H, s, olefin), 3.421–3.276 (1H, m,
benzyl), 3.132–3.062 (1H, t, J = 10.5, Hz, allyl), 2.502–2.459
(1H, d, J = 12.9 Hz), 2.251–2.175 (2H, m), 1.780–1.739 (1H,
m), 1.528 (3H, s, allyl CH3) 1.460–1.433 (4H, m), 1.251–1.170
(10H, m), 0.954 (2H, br s), 0.845 (3H, br s, terminal CH3); IR
mmax/cm−1: 3300, 2900, 1620, 1580, 1410, 1210, 750; [a]2D0 +47.3
(c 1.48 mg ml−1 in CHCl3); MS m/z: 386 (M+, 60%), 368 (58),
302 (47), 283 (72), 263 (37), 262 (70), 249 (100); HR-MS m/z
calculated for C25H38O3: 386.2821, found 386.278.
A Grignard reagent was prepared with magnesium (100 mg,
4.17 mmol) and CH3I (0.26 ml, 4.17 mmol) in dry ether (3 ml,
distilled over sodium) under N2 atmosphere. 11a (420 mg,
1.17 mmol) in ether (1 ml) was slowly added to the stirred
solution and the ether was distilled off. The residue was heated
under N2 atmosphere to 210 ◦C for 45 min. The flask was
cooled to room temperature and the reaction was quenched
with ice water. The aqueous solution was extracted with ether
several times. The combined organic extracts were dried on
MgSO4 and filtered. Removal of the solvents under reduced
pressure afforded a residue that was chromatographed on silica
gel (25% ether–petroleum ether) to give 150 mg of pure 12a.
Yield 40%); 1H-NMR: d 6.200 (2H, s, Ar), 5.822 (1H, s, olefin),
4.629 (1H, s, olefin), 4.518 (1H, s, olefin), 4.075 (2H, s, CH2OH),
3.962–3.923 (1H, m, benzyl), 2.567–2.484 (1H, td, J = 13.3,
2.7 Hz, allyl), 2.435–2.384 (2H, t, J = 7.5 Hz, benzyl), 1.882–
1.734 (2H, m), 1.660 (6H, s. allyl CH3), 1.584–1.487 (2H, m),
1.285–1.248 (6H, m), 0.886–0.843 (3H, t, J = 6.3 Hz, terminal
CH3); IR mmax/cm−1: 3300, 2900, 1620, 1580, 1440, 1240, 1020,
730; [a]D −67.3 (c 19.51 mg ml−1, CHCl3); MS m/z: 330 (M+,
10%), 312 (44), 299 (53), 284 (44), 244 (100), 231(56), 187 (29),
147 (13); HR-MS m/z calculated for C21H30O3: 330.21949, found
330.2231.
(3R,4R)-3-[2,6-Diacetoxy-4-pentylphenyl]-2-acetoxy-4-
isopropenyl-1-methylenecyclohexane (14a)
13a (100 mg, 0.3 mmol) was dissolved in pyridine (0.5 ml)
and acetic anhydride (0.5 ml) and the reaction was stirred
for 18 hours at room temperature. Then the solution was
poured onto iced water (10 ml) and extracted with ether. The
combined organic extracts were washed successively with 1 M
HCl, aqueous sodium bicarbonate and brine, dried on MgSO4
and filtered. Removal of the solvents under reduced pressure
afforded 136 mg of an oily residue that was proved to be 14a
1
by NMR. Yield ∼100%; H-NMR: d 6.861 (1H, s, Ar), 6.696
(1H, s, Ar), 5.725–5.688 (1H, d, J = 11.1 Hz, CHOAc), 4.083
(1H, s, olefin), 4.689 (1H, s, olefin), 4.540–4.515 (2H, d, J =
7.5 Hz, olefin), 3.180–3.105 (1H, t, J = 11.3 Hz, benzyl), 2.893–
2.802 (1H, td, J = 11.3, 3.2 Hz, allyl), 2.563–2.513 (2H, t, J =
7.5, Hz, benzyl), 2.374 (3H, s, OAc), 2.280 (3H, s, OAc), 1.798
7-Hydroxy-CBD-DMH (12b)
Prepared by the same procedure as reported above for 12a. Yield
42%; 1H-NMR: d 6.335 (2H, s, Ar), 5.863 (1H, s, olefin), 4.652
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 1 1 6 – 1 1 2 3
1 1 2 1

View Article Online
(3H, s, OAc), 1.614–1.470 (5H, m), 1.286–1.246 (8H, m), 0.886–
0.844 (3H, t, J = 6.3 Hz, terminal CH3); IR mmax/cm−1: 2910,
1750, 1410, 1350, 1180, 1130, 890; HR-MS m/z calculated for
C27H36O6: 456.2512, found 456.2502.
4.633 (1H, s, olefin), 4.489 (1H, s, olefin), 3.746–3.718 (1H, d,
J = 8.4 Hz, benzyl), 2.686–2.552 (4H, m), 2.304–2.075 (6H, br s),
1.965–1.921 (1H, m), 1.754–1.590 (6H, m), 1.318–1.305 (5H, m),
0.909–0.865 (3H, t, J = 6.2 Hz, terminal CH3); IR mmax/cm−1:
2900, 1750, 1670, 1160, 1020; [a]2D0 −111.5 (c 3.5 mg ml−1 in
CHCl3); MS m/z: 412 (M+, 11%), 383 (15), 341 (30), 328 (20), 302
(37), 284 (11), 260 (100); HR-MS m/z calculated for C25H32O5:
412.2250, found 412.2263.
(3R,4R)-3-[2,6-Diacetoxy-4-(1ꢀ,1ꢀdimethylheptyl)phenyl]-2-
acetoxy-4-isopropenyl-1-methylenecyclohexane (14b)
Prepared by the same procedure as reported above for 14a. Yield
∼100%; 1H-NMR: d 6.947 (1H, s, Ar), 6.795 (1H, s, Ar), 5.732–
5.695 (1H, d, J = 11.0 Hz, CHOAc), 4.798 (1H, s, olefin), 4.691
(1H, s, olefin), 4.540–4.515 (2H, d, J = 7.5 Hz, olefin), 3.167–
3.095 (1H, t, J = 11.3 Hz, benzyl), 2.854–2.816 (1H, m, allyl),
2.561–2.515 (1H, d, J = 13.8, Hz, benzyl), 2.372 (3H, s, OAc),
2.287 (3H, s, OAc), 2.230–2.195 (1H, m), 1.825–1.770 (4H, m),
1.538–1.424 (6H, m), 1.224–1.151 (12H, m), 0.955–0.945 (2H,
m), 0.840–0.799 (3H, t, J = 6.1 Hz, terminal CH3); IR mmax/cm−1:
2900, 1750, 1410, 1360, 1180, 1130, 890; MS m/z: 512 (M+,
26%), 452 (22), 424 (24), 410 (100), 368 (16), 342 (12), 325 (32),
249 (30); HR-MS m/z calculated for C31H44O6: 512.3128, found
512.3188.
7-Nor-7-formyl-diacetate-CBD-DMH (16b)
Prepared by the same procedure reported for 16a. Yield 40%;
1H-NMR: d 9.420 (1H, s CHO), 6.861 (2H, s, Ar), 6.501 (1H, s,
olefin), 4.611 (1H, s, olefin), 4.455 (1H, s, olefin), 3.705–3.671
(1H, m, benzyl), 2.667–2.552 (3H, m), 2.292–2.071 (6H, br s,
OAc), 1.960–1.890 (2H, m), 1.601 (3H, s, allyl CH3), 1.590–1.485
(4H, m), 1.241–1.711 (8H, m) 1.100–0.931 (2H, m) 0.854–0.865
(3H, t, J = 5.7 Hz, terminal CH3); IR mmax/cm−1: 2900, 1750,
1660, 1160, 1020; [a]D20 −85.7 (c 1.4 mg ml−1 in CHCl3); MS m/z:
468 (M+, 72%), 382 (35), 358 (40), 316 (94), 302 (11), 249 (30);
HR-MS m/z calculated for C29H41O5: 468.2876, found 468.2878.
7-Bromo-diacetate-CBD (15a)
7-Nor-7-carboxy-diacetate-CBD (17a)
14a (100 mg, 0.2 mmol) was dissolved in dry CH2Cl2 (10 ml, dis-
tilled over CaH2) under nitrogen atmosphere. TMSBr (0.13 ml,
1 mmol) and ZnI2 (3.4 mg, 0.01 mmol) were added. The
reaction was stirred at rt for 4 hours, then it was shaken with a
saturated aqueous solution of NaHCO3 and the organic phase
was separated by a separatory funnel. Then the aqueous phase
was extracted with ether. The combined organic extracts were
washed with brine, dried over MgSO4 and filtered. Removal of
the solvents afforded a residue that showed only one spot on TLC
(5% ether–petroleum ether) and it was used immediately with
no purification. Yield 90%; 1H-NMR: d 6.764 (2H, s, Ar), 5.456
(1H, s, olefin), 4.901 (1H, s, olefin), 4.752 (1H, s, olefin), 3.930–
3.903 (2H, m, CH2Br), 3.784–3.756 (1H, d, J = 8.2 Hz, benzyl),
2.592–2.643 (2H, m,), 2.306 (6H, s, OAc), 2.198–2.131 (2H, t,
J = 10.2 Hz), 1.708 (3H, s, allyl CH3), 1.698–1.472 (4H, m),
1.439–1.194 (5H, m), 0.090–0.865 (3H, t, J = 5.3 Hz, terminal
CH3); IR mmax/cm−1: 2900, 1750, 1360, 1200, 1020, 900, 720; MS
m/z: 478 (M+, 3%), 397 (57) 355 (96), 354 (61), 313 (100), 245
(77); HR-MS m/z calculated for C25H33O4 81Br: 478.1542, found
478.1560.
NaClO2 (80% pure 82.6 mg, 0.73 mmol) was added in small
quantities to a stirred mixture of 16a (70 mg, 0.17 mmol), 2-
methyl-2-butene (0.45 ml, 4.25 mmol) and a saturated aqueous
solution of KH2PO4 (0.2 ml) in t-butanol (4 ml). The reaction
was stirred at room temperature for 5 hours, and monitored
by TLC (50% ether–petroleum ether). Water was added (20 ml)
and the mixture was extracted several times with ethyl acetate.
The organic phase was washed with brine, dried over MgSO4
and filtered. Removal of the solvent under reduced pressure
afforded a residue that was chromatographed on silica gel (30%
ether–petroleum ether) to give 61.8 mg of the 17a. Yield 85%;
1H-NMR: d 6.939 (1H, s, olefin), 6.770 (2H, s, Ar), 4.611 (1H, s,
olefin), 4.462 (1H, s, olefin), 3.618–3.718 (1H, m, benzyl), 2.589–
2.538 (3H, m, allyl + benzyl), 2.212 (6H, s, OAc), 1.961–1.862
(1H, m), 1.858–1.641 (1H, m), 1.592 (5H, br s), 1.321–1.255 (7H,
m), 0.903–0.858 (3H, t, J = 6.8 Hz, terminal CH3); IR mmax/cm−1:
3300, 2900, 1750, 1270, 1020; MS m/z: 428 (M+, 3%), 410 (8),
368 (43), 326 (24), 298 (14), 276 (100), 258 (24); [a]2D0 −112.2
(c 3.7 mg ml−1, CHCl3); HR-MS m/z calculated for C25H32O6:
428.2199, found 428.2198.
7-Bromo-diacetate-CBD-DMH (15b)
7-Nor-7-carboxy-diacetate-CBD-DMH (17b)
Prepared by the same procedure as reported above for 15a. Yield
90%; 1H-NMR: d 6.816 (2H, s, Ar), 5.645 (1H, s, olefin), 4.557
(1H, s, olefin), 4.448 (1H, s, olefin), 4.016–3.966 (2H, m, CH2Br),
3.483–3.405 (1H, m, benzyl), 2.655–2.459 (1H, m, allyl), 2.220
(6H, s, OAc), 1.883–1.637 (4H, m), 1.510 (3H, s, allyl CH3),
1.485–1.426 (4H, m), 1.410–1.176 (10H, m), 1.010–0.995 (2H,
m) 0.853–0.807 (3H, t, J = 6.5 Hz, terminal CH3); IR mmax/cm−1:
2900, 1750, 1370, 1220, 1020, 900, 750; MS m/z: 534 (M+, 9%),
489 (14), 411 (100), 393 (25), 370 (15), 351 (30), 343 (32), 301
(47), 285 (25), 283 (43), 243(24); HR-MS m/z calculated for
C29H41O4Br: 532.2188, found 532.2201.
Prepared by the same procedure reported for 17a. Yield 86%;
1H-NMR: d 6.946 (1H, s, olefin), 6.854 (2H, s, Ar), 4.592 (1H, s,
olefin), 4.436 (1H, s, olefin), 3.635–3.590 (1H, m, benzyl), 2.605–
2.455 (1H, m, allyl), 2.208 (6H, s, OAc), 1.950–1.803 (2H, m),
1.795–1.610 (2H, m), 1.574 (3H, s, allyl CH3), 1.529–1.475 (4H,
m), 1.267–1.174 (10H, m), 1.022 (2H, br s), 0.845–0.805 (3H,
t, J = 6.6 Hz, terminal CH3); IR mmax/cm−1: 3300, 2900, 1750,
1270, 1020; MS m/z: 484 (M+, 9%), 466 (21), 442 (20), 424 (90),
382 (28), 374 (41), 328 (31), 314 (28), 291 (27), 247 (44); [a]D20
−122.7 (c 2.77 mg ml−1, CHCl3); HR-MS m/z calculated for
C29H40O6: 484.2815, found 484.2792.
7-Nor-7-formyl-diacetate-CBD (16a)
7-Nor-7-carboxy-CBD (18a)
15a (100 mg, 0.21 mmol), 18-Crown-16 (55.4 mg, 0.21 mmol)
17a (50 mg, 0.12 mmol) was dissolved in ethanol (10 ml), NaBH4
(6 mg, 0.16 mmol) was added and the reaction was refluxed
for 1 hour. The ethanol was removed under reduced pressure,
the residue was diluted with water (20 ml) and the solution
was extracted with ether. The combined organic extracts were
washed brine, dried on MgSO4 and filtered. Removal of the
solvents under reduced pressure afforded a residue that was
chromatographed on silica gel (30% ether–petroleum ether) to
and K2CrO4 (50.9 mg, 0.26 mmol) were dissolved in anhydrous
˚
HMPA (2 ml, distilled under vacuum and stored over 4 A
molecular sieves). The mixture was stirred and heated at 110 ◦C
for 2 hours. The reaction was cooled and quenched by addition
of 1 M HCl and the aqueous phase was extracted with ether.
The organic phase was washed with brine, dried over MgSO4 and
filtered. Removal of the solvent under reduced pressure afforded
a residue that was chromatographed on silica gel (20% ether–
petroleum ether) to give 30 mg of pure 16a. Yield 35%; 1H-NMR:
d 9.434 (1H, s, CHO), 6.778 (2H, s, Ar), 6.638 (1H, s, olefin),
1
give 38.2 mg of the 18a. Yield 95%; H-NMR: d 7.085 (1H, s,
olefin), 6.173 (2H, s, Ar), 4.604–4.566 (2H, d, J = 11.4 Hz,
olefin), 4.115–4.033 (1H, m, benzyl), 2.799–2.688 (1H, m, allyl),
1 1 2 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 1 1 6 – 1 1 2 3

View Article Online
2.623–2.541 (1H, m), 2.444–2.391 (2H, t, J = 7.5 Hz), 1.950–
1.869 (1H, m), 1.803–1.669 (5H, m), 1.623–1.453 (4H, m), 1.309–
1.178 (5H, m), 0.902–0.857 (3H, t, J = 6.5 Hz, terminal CH3);
IR mmax/cm−1: 3350, 2950, 1700, 1440, 1400, 1160, 920, 740; [a]2D0
−112.3 (c 1.87 mg ml−1 in MeOH); MS m/z: 344 (M+, 11%),
299 (15), 276 (100), 220 (24), 207 (11); HR-MS m/z calculated
for C21H28O4: 344.1987, found 344.1948.
Acknowledgements
This work was supported by the US National Institute of Drug
Abuse and the Israel Science Foundation.
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d, J = 19.1 Hz, olefin), 4.036–4.033 (1H, d, J = 8.9 Hz, benzyl),
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(+)-CBD (4c). Basic aluminium oxide (15.6 g) was added
to dry dichloromethane (150 ml). To this suspension BF3·OEt2
(2.3 ml) was added under nitrogen. The mixture was stirred
for 15 min at room temperature and then boiled for 1 min.
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1.329 (m, 7H), 1.529–1.603 (m, 2H), 1.660 (s, 3H), 1.794 (s, 3H),
2.00–2.210 (br t, 2H), 2.397–2.458 (m, 3H), 3.900 (br s, 1H),
4.556 (s, 1H), 4.658 (s, 1H), 4.90–5.00 (br, 1H, OH), 5.574 (s,
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(13), 231 (100), 193 (9), 174 (9), 121 (10); HR-MS m/z calculated
for C21H30O2: 314.2246, found 314.2212.
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d 0.832 (t, J = 7.5 Hz, 3H), 0.950–1.050 (br, 2H), 1.208 (br s,
12H), 1.454–1.505 (m, 2H), 1.635 (s, 3H), 1.794 (s, 3H), 2.050–
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8c (∼100%), 8d (∼100%), 9c (90%), 9d (90%), 10c (94%), 10d
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 1 1 6 – 1 1 2 3
1 1 2 3