Synthesis of side chain specifically deuterated (-)-Δ9-tetrahydrocannabinols

Article abstract of DOI:10.1002/jlcr.626

(-)-Δ⁹-Tetrahydrocannabinols specifically deuterated at the n-pentyl side chain were prepared using the corresponding resorcinols as key intermediates. To obtain the deuterated resorcinols we developed conditions under which no deuterium scramb

Full text of DOI:10.1002/jlcr.626

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2002; 45: 1065–1076.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.626
Research Article
Synthesis of side chain specifically deuterated
(ꢀ)-D9-tetrahydrocannabinols
Spyros P. Nikas1,2, Ganesh A. Thakur1,2 and Alexandros
Makriyannis1,2,
*
1 Department of Pharmaceutical Sciences, Center for Drug Discovery, University
of Connecticut, Storrs, Connecticut CT 06269, USA
2 Department of Molecular and Cell Biology and Institute of Materials Science,
Center for Drug Discovery, University of Connecticut, Storrs, Connecticut CT
06269, USA
Summary
(ꢀ)-D9-Tetrahydrocannabinols specifically deuterated at the n-pentyl side chain
were prepared using the corresponding resorcinols as key intermediates. To
obtain the deuterated resorcinols we developed conditions under which no
deuterium scrambling or loss was observed. The methodology allows for the
preparative scale synthesis of deuterated resorcinols and corresponding (ꢀ)-D9-
tetrahydrocannabinols. Copyright # 2002 John Wiley & Sons, Ltd.
Key Words: (ꢀ)-D9-tetrahydrocannabinols; deuterated 5-pentylresorcinols;
cerium(III) chloride; deoxygenation
Introduction
For centuries marijuana has been a popular recreational drug of abuse
because of its psychoactive properties. (ꢀ)-D9-Tetrahydrocannabinol
*Correspondence to: A. Makriyannis, Center for Drug Discovery, Department of Pharmaceutical
Sciences, University of Connecticut, Storrs, Connecticut, CT 06269, USA.
E-mail: markriyan@uconnvm.uconn.edu.
Contract/grant sponsor: National Institute of Drug Abuse; contract/grant numbers: DA03801,
DA07215, DA09158
Copyright # 2002 John Wiley & Sons, Ltd.
Received 28 March 2002
Revised 23 May 2002
Accepted 4 June 2002

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S. P. NIKAS ET AL.
(D9-THC), the major ingredient of marijuana, quickly metabolizes to
several cannabinoids}mainly 11-hydroxy-D9-THC, 11-nor-9-carboxy-
D9-THC, and 8b, 11-dihydroxy-D9THC and their glucuronide con-
jugates. Deuteration and tritiation of these cannabinoids in the alkyl
side chain1–3 and various other positions4 makes them eligible as mass
spectral internal standards4 for studying their biochemical properties
and for confirming illicit use of marijuana. Moreover, deuterated
cannabinoids serve as important probes for solid-state NMR experi-
ments aimed at studying the interactions of cannabinoids with
membranes5 and other sites of action. Such information can be used
for the development of novel cannabinergic medications.
Our interest in the synthesis of various deuterated cannabinoids for
all the above-mentioned purposes required the availability of specifically
deuterated pentylresorcinols of high isotopic purity with no significant
deuterium scrambling or loss. The present work describes the
methodology we developed for the efficient preparative scale synthesis
of such specifically deuterated resorcinols and their corresponding
D9-tetrahydrocannabinols.
Results and discussion
Although the existing literature reports a number of methods6–12 for the
preparation of unlabeled alkylresorcinols, only a relatively small
number of these can be adapted for the synthesis of their deuterium
labeled analogs,2c,3,13 since most of the methods are expected to be
accompanied by deuterium loss or isotopic scrambling. Our choice of
synthetic approaches was also restricted by the availability of suitable
deuterated starting materials. The available procedures for the synthesis
of (ꢀ)-tetrahydrocannabinol analogs generally involve the condensation
of a suitable chiral terpene with a 5-alkyl resorcinol. Synthesis of the
2
specifically H-labeled D9-THC to be used in our biochemical and
biophysical experiments would require 5-pentylresorcinols specifically
deuterated at either the terminal ethyl group of the side chain 5a or the
terminal methyl group 5b. Of these, no synthetic procedure for the
pentadeuterated product 5a had been carried out while synthesis of the
trideuterated compound 5b has been reported using two different
procedures. In the first of these, reported by Pitt and co-workers,14
compound 5b was obtained from 3,5-dimethoxybenzaldehyde through a
six-step sequence involving first a Wittig reaction to give methyl 5-(30,50-
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SYNTHESIS OF SIDE CHAIN
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dimethoxyphenyl)penta-2,4-dien-1-oate and then introduction of two
deuterium atoms at the terminal carbon of the chain using LiAl2H4
reduction. This was followed by bromination and subsequent substitu-
tion of the bromo functionality, again using LiAl2H4. The second
approach, by Girard et al.,13 involved conversion of 3-5-dimethox-
ybenzoic acid to 4-(3,5-dimethoxyphenyl)-1-bromobutane in five steps
followed by its coupling with C2H3MgI under Li2CuCl4 conditions.
Our interest in developing a convergent and efficient approach for the
synthesis of pentylresorcinols led us to a versatile starting material,
3-(3,5-dimethoxyphenyl)-propanal 1, previously utilized for synthesis of
various functionalized cannabinoids.15 This intermediate was synthe-
sized on a large scale using an efficient route developed in our
laboratory.16
The reaction sequence carried out for the synthesis of 5a and 5b is
outlined in Scheme 1.
The first step involves a Grignard reaction between 1 and
ethylmagnesium bromide. In our hands this coupling gave nearly 25%
of the corresponding alcohol with several by-products under both
normal and reverse addition of the Grignard reagent. To improve these
low yields we utilized the CeCl3-based Grignard reaction reported by
Imamoto and co-workers.17 Indeed, reaction of 1 with ethylmagnesium
bromide in the presence of anhydrous CeCl3 at ꢀ788C gave the hitherto
unknown alcohol 2c in 87% isolated yield. This alcohol was
Scheme 1. Synthesis of deuterated 5-pentylresorcinols
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S. P. NIKAS ET AL.
Scheme 2. Synthesis of (ꢀ)-D9-tetrahydrocannabinols
subsequently deoxygenated following standard methodology,18 invol-
ving mesylate formation and lithium triethylborohydride (super-
hydride) reduction. These two reactions were carried out without
purification of the unstable mesylate intermediate 3c leading to 4c in an
overall 95% yield. The same reaction sequence was used for the
preparation of the penta- and tri-deuterated products 2a, 2b, 3a, 3b, 4a
and 4b by using C22H5Br and C2H3CH2Br, respectively. The H-NMR
1
(500 MHz) spectrum showed no deuterium loss or scrambling. The
percentage of deuterium incorporation was also determined by mass
spectrometry using field ionization techniques and was found to be 2H5:
2
2
2
2
98.4%, H4: 1.4%, H3: 0.1% and H2: 0.1% for 4a and H3: 98.8%,
2H2: 1.0%, H1: 0.1% and H0: 0.1% for 4b. Indeed, the deuterium
content in all the above resorcinols was almost identical to that of the
deuterated ethyl bromides used as starting materials. Demethylation of
4a and 4b under boron tribromide conditions gave 5a and 5b,
respectively, in nearly quantitative yields. These two labeled resorcinols
were condensed19 with (+)-trans-p-mentha-2,8-dien-1-ol to afford the
corresponding (ꢀ)-D9-tetrahydrocannabinols 6a and 6b (Scheme 2).
2
2
Experimental
All reagents and solvents were purchased from Aldrich Chemical
Company unless specified otherwise and used without further purifica-
tion. C2H3CH2Br and C2H3C2H2Br were obtained in 99% isotopic
purity from Aldrich. Melting points were determined on a micro-
melting point apparatus and are uncorrected. NMR spectra were
recorded in CDCl3, unless otherwise stated, on a Bruker DMX-500
instrument (1H at 500.13 MHz, 13C at 125.77 MHz), and chemical shifts
are in d (ppm) relative to internal TMS. GC/MS data were recorded on
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SYNTHESIS OF SIDE CHAIN
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a HP6890 GC/MS instrument operating at 70 eV. Low-, high-resolution
mass spectra and isotopic ratio analyses were performed on a
Micromass 70-VSE instrument at the School of Chemical Sciences,
University of Illinois at Urbana-Champaign. Flash column chromato-
graphy employed silica gel 60 (230–400 mesh).
1,3-Dimethoxy-5-[30-(hydroxy)-40-(2H2)-50-(2H3)-pentyl]benzene (2a)
(A) Preparation of 1-(2H2)-2-(2H3)-ethyl magnesium bromide. To a
stirred mixture of magnesium turnings (11.0 g, 454.0 mmol) and
anhydrous Et2O (40 ml), under an argon atmosphere was added a
solution of C2H3C2H2Br (52.0 g, 454.0 mmol) in anhydrous Et2O
(400 ml) over a period of 1 h. Subsequently, the reaction mixture was
refluxed for an additional 10 min and then cooled to 08C.
(B) Reaction of 3-(3,5-dimethoxyphenyl)propanal with organomagne-
sium reagent. To a solution of aldehyde 1 (42.0 g, 216.5 mmol) in
anhydrous THF (720 ml) under an argon atmosphere was added
anhydrous CeCl3 (112.0 g, 454.4 mmol). The resulting suspension was
stirred at r.t. for 1 h, cooled to ꢀ788C and the Grignard reagent was
added gradually over a period of 30 min. Subsequently, the reaction
mixture was warmed to r.t. and stirring was continued for additional
1 h. The reaction was quenched by dropwise addition of 3% aq AcOH
solution at 08C, the crude suspension warmed to r.t., diluted with
EtOAc and brine, and stirred vigorously. The organic layer was
separated, and the aqueous phase was extracted with EtOAc. The
combined organic layer was washed with brine, dried (MgSO4) and the
solvent evaporated under reduced pressure. The residue obtained was
purified by flash column chromatography (EtOAc/petroleum ether
30:70) on silica gel to afford 2a (43.1 g) as a white crystalline solid in
87% yield; mp=50–518C.
1H NMR: d=6.37 (d, 2H, J=2.1, H-4, H-6), 6.30 (t, 1 H, J=2.1,
H-2), 3.78 (s, 6 H, OMe), 3.56 (dd, 1 H, J=8.0, J=3.7, H-30), 2.74
(m, 1 H, H-10), 2.61 (m, 1 H, H-10), 1.82–1.76 (m, 1 H, H-20), 1.75–1.67
(m, 1 H, H-20), 1.62 (brs, 1 H, OH). 13C NMR: d=160.8 (C-1, C-3),
144.7 (C-5), 106.5 (C-4, C-6), 97.8 (C-2), 72.5 (C-30), 55.3 (OMe), 38.3
(C-10), 32.4 (C-20), 29.3 (qt, J=19.5, C-40), 8.8 (septet, J=19.5, C-50).
MS: m/e (relative intensity)=229 (M+, 7), 165 (4), 152 (100), 139 (10),
121 (4), 77 (5). HRMS calculated for C13H15D5O3: 229.1726; found:
229.1725.
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1,3-Dimethoxy-5-[30-hydroxy)-50-(2H3)-pentyl]benzene (2b)
The synthesis was carried out as with 2a using 1 (14.0 g, 72.2 mmol),
anhydrous CeCl3 (37.2 g, 150.9 mmol), C2H3CH2Br (16.9 g, 150.9 mmol),
Mg (3.6g, 150.0mmol), in anhydrous Et2O (151 ml), and anhydrous THF
(240ml); yield: 88% (14.4 g); white solid; mp=50–518C.
1H NMR: d=6.37 (d, 2 H, J=2.1, H-4, H-6), 6.30 (t, 1 H, J=2.1,
H-2), 3.78 (s, 6 H, OMe), 3.56 (tt, 1 H, J=7.8, J=4.3, H-30), 2.74
(m, 1 H, H-10), 2.61 (m, 1 H, H-10), 1.82–1.75 (m, 1 H, H-20), 1.74–1.67
(m, 1 H, H-20), 1.53 (dd, 1 H, J=13.6, J=4.2, H-40), 1.50 (brs, 1 H, OH),
1.45 (dd, 1 H, J=13.6, J=7.1, H-40). 13C NMR: d=160.9 (C-1, C-3),
144.9 (C-5), 106.6 (C-4, C-6), 97.9 (C-2), 72.7 (C-30), 55.4 (OMe), 38.5
(C-10), 32.6 (C-20), 30.2 (C-40), 9.1 (septet, J=19.1, C-50). MS: m/e
(relative intensity)=227 (M+, 8), 165 (4), 152 (100), 139 (12), 121 (5), 77
(4). HRMS calculated for C13H17D3O3: 227.1601; found: 227.1602.
1,3-Dimethoxy-5-(30-hydroxy-pentyl)benzene (2c)
The synthesis was carried out analogous to the preparation of 2a using 1
(2.00 g, 10.3 mmol), anhydrous CeCl3 (5.30 g, 21.5 mmol), CH3CH2Br
(2.35 g, 21.6 mmol), Mg (0.52 g, 21.6 mmol), in anhydrous Et2O (22 ml),
and anhydrous THF (35 ml); yield: 88% (2.03 g); white solid; mp=
50–518C.
1H NMR: d=6.37 (d, 2 H, J=2.1, H-4, H-6), 6.30 (t, 1 H, J=2.1,
H-2), 3.78 (s, 6 H, OMe), 3.57 (m, 1 H, H-30), 2.68 (m, 2 H, H-10), 1.83–
1.66 (m, 2 H, H-20), 1.61 (brs, 1 H, OH), 1.58–1.45 (m, 2 H, H-40), 0.95 (t,
3 H, J=7.5, H-50). 13C NMR: d=160.8 (C-1, C-3), 144.7 (C-5), 106.5
(C-4, C-6), 97.8 (C-2), 72.7 (C-30), 55.3 (OMe), 38.4 (C-10), 32.4 (C-20),
30.3 (C-40), 9.8 (C-50). MS: m/e (relative intensity)=224 (M+, 9), 165
(5), 152 (100), 139 (12), 121 (5), 77 (8). HRMS calculated for C13H20O3:
224.1412; found: 224.1411.
1,3-Dimethoxy-5-[30-(methanesulfonyloxy)-40-(2H2)-50-(2H3)-
pentyl]benzene (3a)
To a solution of alcohol 2a (42.0 g, 183.0 mmol) and Et3N (32 ml,
238.0 mmol) in anhydrous THF (1.3 L) at 08C under an argon
atmosphere was added methanesulfonyl chloride (17 ml, 220 mmol)
dropwise over a period of 10 min. After stirring for 10 min the reaction
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SYNTHESIS OF SIDE CHAIN
1071
was treated with water and diluted with Et2O. The organic layer was
separated, washed with water and brine, dried over MgSO4, and the
solvent was removed under reduced pressure. The pale yellow residue 3a
was sufficiently pure (1H-NMR) and used for the next reaction without
further purification.
1H NMR: d=6.37 (d, 2 H, J=2.1, H-4, H-6), 6.32 (t, 1 H, J=2.1,
H-2), 4.71 (t, 1 H, J=5.9, H-30), 3.79 (s, 6 H, OMe), 3.02 (s, 3 H,
OSO2Me), 2.79–2.55 (m, 2 H, H-10), 2.11–1.90 (m, 2 H, H-20). MS: m/e
(relative intensity)=307 (M+, 23), 228 (63), 211 (27), 193 (18), 177 (27),
165 (17), 151 (100), 121 (11). HRMS calculated for C14H17D5O5S:
307.1502; found: 307.1507.
1,3-Dimethoxy-5-[30-(methanesulfonyloxy)-50-(2H3)-pentyl]
benzene (3b)
The synthesis was carried out as with 3a starting from 2b (13.5 g,
59.5 mmol), and Et3N (10.8 ml, 77.3 mmol), CH3SO2Cl (5.5 ml,
71.4 mmol) in anhydrous THF (400 ml). The corresponding mesylate
3b was used for the next step without further purification.
1H NMR: d=6.37 (d, 2 H, J=2.1, H-4, H-6), 6.32 (t, 1 H, J=2.1,
H-2), 4.71 (qt, 1 H, J=6.0, H-30), 3.79 (s, 6 H, OMe), 3.02 (s, 3 H,
OSO2Me), 2.80–2.55 (m, 2 H, H-10), 2.11–1.72 (m, 4 H, H-20, H-40). MS:
m/e (relative intensity)=305 (M+, 20), 226 (55), 209 (23), 193 (15), 177
(25), 165 (15), 151 (100), 121 (10). HRMS calculated for C14H19D3O5S:
305.1373; found: 305.1379.
1,3-Dimethoxy-5-[30-(methanesulfonyloxy)-pentyl]benzene (3c)
The synthesis was carried out anologous to the preparation of 3a
starting from 2c (1.5 g, 6.7 mmol), and Et3N (1.21 ml, 8.71 mmol),
CH3SO2Cl (0.62 ml, 8.04 mmol) in anhydrous THF (45 ml). The
corresponding mesylate 3c was used for the next step.
1H NMR: d=6.37 (d, 2 H, J=2.1, H-4, H-6), 6.32 (t, 1 H, J=2.1,
H-2), 4.71 (qt, 1 H, J=6.0, H-30), 3.79 (s, 6 H, OMe), 3.02 (s, 3 H,
OSO2Me), 2.80–2.56 (m, 2 H, H-10), 2.10–1.92 (m, 2 H, H-20), 1.79 (qt,
2 H, J=6.8, H-40), 0.99 (t, 3 H, J=7.4, H-50). MS: m/e (relative
intensity)=302 (M+, 18), 223 (50), 206 (21), 191 (13), 177 (23), 165 (15),
151 (1 0 0), 121 (9). HRMS calculated for C14H22O5S: 302.1188; found:
302.1180.
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1,3-Dimethoxy-5-[40-(2H2)-50-(2H3)-pentyl]benzene (4a)
To a stirred solution of mesylate 3a (56.3 g, 183.4 mmol) in anhydrous
THF (1.4 L) at 08C under an argon atmosphere was added lithium
triethylborohydride (790 ml, 1 M solution in THF) over a period of
30 min. Following the addition, the mixture was warmed to r.t. and
stirring was continued until the reaction was complete (2 h). Excess
hydride was decomposed by drop wise addition of water at 08C,
subsequently the pH was adjusted to approximately 8 using 10% aq
NaOH solution. The mixture was diluted with Et2O, warmed to r.t. and
stirred vigorously for 30 min. Insoluble materials were filtered off
through celite, the organic phase was separated and the aqueous phase
was extracted with Et2O. The combined organic layer was washed with
water, brine, dried over MgSO4 and solvent evaporated under reduced
pressure to give an oil. The crude product was purified by flash column
chromatography (Et2O/petroleum ether 6:94) on silica gel to give 4a as a
colorless liquid (36.7 g) in 94% yield (2 steps).
1H NMR: d=6.34 (d, 2 H, J=2.1, H-4, H-6), 6.29 (t, 1 H, J=2.1,
H-2), 3.78 (s, 6 H, OMe), 2.54 (t, 2 H, J=7.8, H-10), 1.60 (qt, 2 H,
J=7.7, H-20), 1.30 (t, 2 H, J=7.6, H-30), 13C NMR: d=160.9 (C-1, C-3),
145.6 (C-5), 106.7 (C-4, C-6), 97.7 (C-2), 55.4 (OMe), 36.5 (C-10), 31.5,
31.1, 21.7 (qt, J=19.0, C-40), 13.1 (septet, J=19.0, C-50). MS: m/e
(relative intensity)=213 (M+, 21), 166 (8), 152 (100), 137 (6), 121 (10),
91 (20), 77 (24). HRMS calculated for C13H15D5O2: 213.1777; found:
213.1777. The deuterium incorporation on the molecular ion cluster was
2
2
2
2H5: 98.4%, H4: 1.4%, H3: 0.1% and H2: 0.1%.
1,3-Dimethoxy-5-[50-(2H3)-pentyl]benzene (4b)
The synthesis was carried out analogous to the preparation of 4a
starting from 3b (18.13 g, 59.44 mmol), LiEt3BH (256 ml, 1 M solution
in THF) in anhydrous THF (457 ml) to give 4b as a colorless liquid13,14
1
in overall 95% yield from 2b (11.92 g). H NMR: d=6.34 (d, 2 H,
J=2.1, H-4, H-6), 6.29 (t, 1 H, J=2.1, H-2), 3.78 (s, 6 H, OMe), 2.54
(t, 2 H, J=7.7, H-10), 1.60 (qt, 2 H, J=7.5, H-20), 1.30 (m, 4 H, H-30,
H-40), 13C NMR: d=160.7 (C-1, C-3), 145.4 (C-5), 106.5 (C-4, C-6),
97.5 (C-2), 55.2 (OMe), 36.3 (C-10), 31.5, 31.0, 22.3 (C-40), 13.1 (septet,
J=19.0, C-50). MS: m/e (relative intensity)=211 (M+, 15), 152 (100),
137 (6), 121 (8), 91 (17), 77 (19). HRMS calculated for C13H17D3O2:
211.1652; found: 211.1654. The deuterium incorporation on the
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SYNTHESIS OF SIDE CHAIN
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2
2
2
molecular ion cluster was H3: 98.8%, H2: 1.0%, H1: 0.1%, and
2H0: 0.1%.
1,3-Dihydroxy-5-[40-(2H2)-50-(2H3)-pentyl]benzene (5a)
To a solution of olivetol dimethyl ether (4a) (33.5 g, 157.3 mmol) in
anhydrous CH2Cl2 (1.57 L) at ꢀ788C under an argon atmosphere was
added BBr3 (393 ml, 1.0 M solution in CH2Cl2) over a period of 15 min.
Following the addition the reaction was warmed to r.t. over a period of
30 min and stirring continued at r.t. for 4 h. The reaction was quenched
by the addition of MeOH and crushed ice at 08C, the resulting mixture
was warmed to r.t., stirred for 40 min and the solvent removed under
reduced pressure. The residual oil was diluted with EtOAc and the
solution was washed with sat. NaHCO3, water and brine. The organic
layer was dried over MgSO4, filtered and concentrated under reduced
pressure. Purification by flash column chromatography on silica gel
using Et2O/petroleum ether 50:50 as eluent afforded 5a (27.9 g) in 96%
yield as a white solid; mp=50–518C.
1HNMR: d=6.25 (d, 2 H, J=1.9, H-4, H-6), 6.17 (t, 1 H, J=1.9,
H-2), 4.89 (brs, 2 H, OH), 2.48 (t, 2 H, J=7.7, H-10), 1.57 (qt, 2 H,
J=7.7, H-20), 1.27 (t, 2 H, J=7.5, H-30). 13C NMR: d=156.4 (C-1, C-3),
146.6 (C-5), 108.5 (C-4, C-6), 100.5 (C-2), 36.0 (C-10), 31.4, 30.9, 21.6
(qt, J=19.3, C-40), 13.1 (septet, J=19.0, C-50). MS: m/e (relative
intensity)=185 (M+, 29), 138 (7), 124 (100), 77 (4), 69 (8). HRMS
calculated for C11H11D5O2: 185.1464; found: 185.1472.
1,3-Dihydroxy-5-[50-(2H3)-pentyl]benzene (5b)
The synthesis was carried out analogous to the preparation of 5a
starting from 4b (11.0 g, 52.1 mmol) and BBr3 (130 ml, 1.0 M solution in
CH2Cl2) in anhydrous CH2Cl2 (521 ml); yield: 97% (9.3 g); white solid;
mp=50–518C (lit., 13mp=38–398C, lit., 14mp=39–408C).
1HNMR: d=6.25 (d, 2 H, J=1.9, H-4, H-6), 6.17 (t, 1 H, J=1.9, H-
2), 5.18 (brs, 2 H, OH), 2.48 (t, 2 H, J=7.7, H-10), 1.57 (qt, 2 H, J=7.5,
H-20), 1.29 (m, 4 H, H-30, H-40). 13C NMR: d=156.2 (C-1, C-3), 146.7
(C-5), 108.6 (C-4, C-6), 100.6 (C-2), 36.0 (C-10), 31.6, 30.9, 22.4 (C-40),
13.3 (septet, J=19.0, C-50). MS: m/e (relative intensity)=183 (M+, 22),
137 (7), 124 (100), 77 (4), 69 (7). HRMS calculated for C11H13D3O2:
183.1339; found: 183.1332.
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40-(2H2)-50-(2H3)-D9-Tetrahydrocannabinol (6a)
To a stirred suspension of olivetol (5a) (13.0 g, 70.3 mmol), (+)-trans-p-
mentha-2,8-dienl-ol (11.7 g, 77.3 mmol) and MgSO4 (8.8 g) in anhydrous
CH2Cl2 (440 ml) at ꢀ38C, under an argon atmosphere was added
BF3.Et2O (4.4 ml). Stirring was continued for 2.5 h at 08C and
anhydrous sodium bicarbonate (23 g) was added. The mixture was
warmed to r.t. stirred vigorously for 30 min and filtered through florisil.
The filtrate was evaporated under reduced pressure to give pale yellow
gum. Purification by repeated flash column chromatography (three
times) on silica gel using 10% Et2O: Hexane as eluent afforded 6.5 g
(29% yield) of the title compound in 98–99% purity, as confirmed by 1H
NMR.
1H NMR: d=6.30 (m, 1 H, H-10), 6.27 (d, 1 H, J=1.2, H-4), 6.14
(d, 1 H, J=1.2, H-2), 4.76 (s, 1 H, OH), 3.20 (brd, 1 H, J=11.0, H-10a),
2.43 (td, 2 H, J=7.5, J=2.4, H-10) 2.17–2.15 (m, 2 H, H-8), 1.93–1.89
(m, 1 H, H-7), 1.72-1.67 (m, 4 H, H-6a, H-11, especially 1.68, brs, H-11),
1.55 (qt, 2 H, J=7.7, H-20), 1.44–1.36 (m, 4 H, H-7, 6b-Me, especially
1.40, s, 6b-Me), 1.27 (t, 2 H, J=7.4, H-30), 1.09 (s, 3 H, 6a-Me). GC/MS:
m/e (relative intensity)=319 (M+, 22), 304 (41), 276 (32), 252 (13), 236
(90), 219 (19), 187 (25), 174 (32), 128 (41), 115 (60), 91 (100), 77 (94).
HRMS calculated for C21H25D5O2: 319.2560; found: 319.2557. The
2
deuterium incorporation on the molecular ion cluster was H5: 98.3%,
2
2
2H4: 1.5%, H3: 0.1% and H2: 0.1%.
50-(2H3)-D9-Tetrahydrocannabinol (6b)
The synthesis was carried out analogous to the preparation of 6a
starting from 5b (2.0 g, 10.9 mmol), (+)-trans-p-mentha-2,8-dien-l-ol
(1.8 g, 12.0 mmol) and MgSO4 (1.5 g) in anhydrous CH2Cl2 (70 ml);
yield: 30% (1.0 g); pale yellow gum.14
1H NMR: d=6.30 (m, 1 H, H-10), 6.27 (d, 1 H, J=1.2, H-4), 6.14
(d, 1 H, J=1.2, H-2), 4.80 (s, 1 H, OH), 3.19 (brd, 1 H, J=11.0, H-10a),
2.43 (td, 2 H, J=7.5, J=2.4, H-10) 2.17–2.15 (m, 2 H, H-8), 1.93–1.88
(m, 1 H, H-7), 1.72–1.67 (m, 4 H, H-6a, H-11, especially 1.68, brs, H-11),
1.55 (qt, 2 H, J=7.7, H-20), 1.44–1.36 (m, 4 H, H-7, 6b-Me, especially
1.40, s, 6b-Me), 1.28 (t, 2 H, J=7.4, H-30), 1.09 (s, 3 H, 6a-Me). GC/MS:
m/e (relative intensity)=317 (M+, 29), 302 (23), 274 (19), 252 (46), 234
(82), 219 (58), 187 (19), 174 (26), 128 (37), 115 (42), 91 (81), 77 (100).
HRMS calculated for C21H27D3O2: 317.2434; found: 317.2440. The
Copyright # 2002 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2002; 45: 1065–1076

SYNTHESIS OF SIDE CHAIN
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2
deuterium incorporation on the molecular ion cluster was H3: 98.7%,
2
2
2H2: 1.1%, H1: 0.1% and H0: 0.1%.
Acknowledgement
This work was supported by grants from the National Institute of Drug
Abuse (DA03801, DA07215, and DA09158). We are thankful to Dr.
Steven Mullen from School of Chemical Sciences, University of Illinois
at Urbana-Champaign for recording HRMS and isotopic ratio analysis.
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