Enantioselective synthesis of 11-hydroxy-(1′S,2′R)-dimethylheptyl-Δ8-THC, a very potent CB1 agonist

Article abstract of DOI:10.1016/S0040-4020(01)00729-3

An enantioselective synthesis of the (1S,2R)-dimethylheptyl cannabinoid side chain has been developed and employed in the synthesis of 11-hydroxy-(1′S,2′R)-dimethylheptyl-Δ⁸-THC, one of the most potent traditional cannabinoids known. The synthesis involves a highly stereoselective addition of dimethylcopperlithium to an enoyl sultam which incorporates Opplozer's auxiliary.

Full text of DOI:10.1016/S0040-4020(01)00729-3

TETRAHEDRON
Pergamon
Tetrahedron 57 2001) 7607±7612
Enantioselective synthesis of 11-hydroxy-ꢀ10S,20R)-
dimethylheptyl-D8-THC, a very potent CB1 agonist
John Liddle and John W. Huffmanp
233 Howard L. Hunter Chem Laboratory, Department of Chemistry, Clemson University, P.O. Box341905, Clemson, SC 29634-1905, USA
Received 15 May 2001; accepted 11 July 2001
AbstractÐAn enantioselective synthesis of the 1S,2R)-dimethylheptyl cannabinoid side chain has been developed and employed in the
synthesis of 11-hydroxy- 10S,20R)-dimethylheptyl-D8-THC, one of the most potent traditional cannabinoids known. The synthesis involves a
highly stereoselective addition of dimethylcopperlithium to an enoyl sultam which incorporates Opplozer's auxiliary. q 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
In the thirty years since Gaoni and Mechoulam described
the isolation and elucidation of the structure of D9-THC
D9-tetrahydrocannabinol),1a comprehensive set of struc-
ture±activity relationships SAR) for cannabinoids has
been developed.2 For traditional cannabinoids structurally
related to D9-THC, these SAR have demonstrated that the
cannabinoid side chain is an important pharmacophore.
While the 1,2-dimethylheptyl DMH) side chain is known
to dramatically increase potency,3 the 1,1-dimethylheptyl
side chain is used almost exclusively in contemporary
investigations. Not only are those cannabinoids which
incorporate the 1,1-dimethylheptyl side chain very potent,
but their precursor 1,3-dimethoxy-5- 1,1-dimethylheptyl)-
benzene is readily available and this side chain substitution
pattern does not introduce additional chiral centers.4 Recent
work has focused on the preparation of all four homochiral
isomers of 1,2-DMH-D8-THC via resolution methodology
and 10S,20R)-DMH-D8-THC 1) was shown to be signi®-
cantly more potent than 1,1-DMH-D8-THC 2) at the CB1
receptor.5 In view of the potency of 1, an enantioselective
synthesis of the 10S,20R)-dimethylheptyl cannabinoid side
2. Results and discussion
chain has been developed and employed in the synthesis of
11-hydroxy- 10S,20R)-dimethylheptyl-D8-THC 3). We
recently reported that 3 is one of the most potent traditional
cannabinoids, both in vitro and in vivo at the CB1 receptor,6
and herein we report the asymmetric synthesis in detail.
The synthetic approach was based on a strategy reported by
Mechoulam et al.7 which employs 4-hydroxy-myrtenyl
pivalate 4) as a source of the non-aromatic portion of an
11-hydroxy-cannabinoid. The cannabinoid skeleton is
constructed via the Lewis acid catalyzed condensation of
4-hydroxy-myrtenyl pivalate with the corresponding homo-
chiral resorcinol as shown in Scheme 1.
We reasoned that the two stereogenic centers of the
resorcinol 5 could be developed via an asymmetric conju-
gate addition of dimethylcopperlithium to a cinnamic acid
derivative which incorporated Opplozer's chiral auxiliary.
Keywords: cannabinoid; THC; cannabinoid receptor; Oppolzer's auxiliary.
Corresponding author. Tel.: 11-864-656-3133; fax: 11-864-656-6613;
e-mail: huffman@clemson.edu
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020 01)00729-3

7608
J. Liddle, J. W. Huffman / Tetrahedron 57 12001) 7607±7612
Scheme 1.
The synthesis of resorcinol 5 employed 3,5-dimethoxy-
benzaldehyde as starting material, which was subjected to
a Horner±Emmons reaction with triethyl phosphonopropio-
nate in the ®rst step Scheme 2).8 The cinnamate ester
underwent essentially complete hydrolysis during work up
and was not isolated. The resulting cinnamic acid 7) was
converted to the acid chloride using standard conditions and
coupled to Oppolzer's auxiliary in 88% yield. Oppolzer's
auxiliary was prepared from 1)- 1S)-camphor-10-sulfonic
acid in four steps following the literature procedure.9,10 The
key step in the synthesis was the asymmetric addition of
dimethylcopperlithium to enoyl sultam 8 and subsequent
asymmetric protonation which established the stereo-
chemistry at both chiral centers in a single step. Asymmetric
conjugate addition of organocopper reagents to N-enoyl
sultams and subsequent enolate protonation is well docu-
mented.10 Oppolzer has reported that the addition of
dimethylcopperlithium to N-[ E)-2-methyl-3-phenyl-2-
propenoyl]-bornane-10,2-sultam, the phenyl derivative of
8, gave the desired S,S)-diastereoisomer in 80% diastereo-
meric excess and 60% yield.10 In our hands the addition of
dimethylcopperlithium to 8 proceeded well at 2408C to
give a 94:2:2:2 mixture of diastereoisomers. The diastereo-
selectivity was determined by capillary GC±MS analysis of
the crude reaction mixture and the major isomer 9) was
isolated in 85% yield and .98% de following recrystalli-
zation. The acyl sultam 9) was homogeneous to capillary
1
GC, H- and 13C NMR. Mild saponi®cation using LiOH in
THF/H2O gave the corresponding butanoic acid in quanti-
tative yield with no signs of epimerization and also served to
recover the chiral auxiliary. Reduction of the acid with
LiAlH4 gave primary alcohol 10. Comparison of the
spectroscopic data and optical rotation of 10 to that of
material prepared previously in these laboratories con®rmed
the absolute and relative stereochemistry.5 Conversion of 10
to the resorcinol dimethyl ether 11) was effected by ®rst
formation of the tosylate, followed by a copper catalyzed
reaction with butylmagnesium bromide using a modi®cation
of the procedure developed by Kochi.8,11 Ether cleavage
with boron tribromide gave resorcinol 5 and completed
Scheme 2. a) Ref. 8; b) COCl)2 then sodium salt of Oppolzer's auxiliary, Toluene, 3 h, 0±208C, 90%; c) Me2CuLi, Toluene, 24 h then NH4Cl, 2408C,
85%; d) LiOH, H2O, THF, 4 days, 608C, 100%; e) LiAlH4, THF, 16 h, 0±208C, 90%; f) p-Toluenesulfonyl chloride, CHCl3, Pyridine, 3 h, 08C, 75%;
g) n-BuMgBr, Li2CuCl4, THF, 48 h, 278±08C, 64%; h) BBr3, CH2Cl2, 16 h, 0±208C, 94%.

J. Liddle, J. W. Huffman / Tetrahedron 57 12001) 7607±7612
7609
Scheme 3. a) CH3)3COCl, CH2Cl2, Pyridine, 4 h, 08C, 84%; b) CrO3, 3,5-dimethylpyrazole, CH2Cl2, 4 h, 2208C, 53%; c) LiAlH O±Bu)3, THF, 4 h,
0±208C, 89%.
Scheme 4. a) BF3´OEt2, CH2Cl2, 1 h, 220±208C, 43%; b) LiAlH4, THF, 2 h, 0±208C, 81%.
the synthesis of the aromatic portion of the target cannabi-
noid.
3. Experimental
3.1. General
4-Hydroxy-myrtenyl pivalate 4) was employed to intro-
duce the correct absolute stereochemistry in the synthesis
of the carbocyclic portion of the cannabinoid ring structure.
Pivalate 4 was prepared in three steps from 1R,5S)-
myrtenol by a modi®cation of the procedure reported by
Mechoulam.7 The hydroxyl group of 12 was ®rst protected
by esteri®cation with trimethylacetyl chloride Scheme 3),
and allylic oxidation of the pivalate with the 3,5-di-
methylpyrazole-chromium trioxide complex12 gave 4-oxo-
myrtenyl pivalate 13) in 53% yield. This method compares
favorably to the 30% yield reported for the procedure using
sodium chromate in acetic anhydride and acetic acid.7
Finally, reduction of the ketone 13 with lithium tri-tert-
butoxyaluminium hydride in THF led to 4-hydroxy-
myrtenyl pivalate 4) as a single diastereoisomer.
1H and 13C NMR spectra were recorded on a Bruker 300AC
spectrometer. Mass spectral analyses were performed on a
Hewlett±Packard 5890A gas chromatograph with a mass
sensitive detector and HRMS data were obtained in the
Mass Spectrometry Laboratory, School of Chemical
Sciences, University of Illinois. THF was distilled from
Na-benzophenone ketyl; toluene from sodium; dichloro-
methane from calcium hydride; other solvents were puri®ed
using standard procedures. Column chromatography was
carried out on Universal silica gel 32±63 m). All new
compounds were homogeneous to TLC and NMR.
3.1.1. N-[ꢀE)-2-Methyl-3-{3,5-dimethoxyphenyl}-2-pro-
penoyl]-bornane-10,2-sultam ꢀ8). To a slurry of sodium
hydride 600 mg, 80% dispersion in mineral oil, 20.0
mmol) in dry toluene 20 ml) at 08C was added a solution
of 2R)-bornane-10,2-sultam9 2.80 g, 13.0 mmol) in tolu-
ene 30 ml) and the mixture was allowed to warm to
ambient temperature over 1 h. To a slurry of cinnamic
acid 78 3.50 g, 15.77 mmol) in dry dichloromethane
10 ml) under argon was added a drop of DMF followed
by the dropwise addition of oxalyl chloride 7.0 ml,
80 mmol). The mixture was stirred at ambient temperature
for 1 h, evaporated to dryness, the residue was dissolved in
dry toluene 30 ml) and added dropwise with stirring to the
sultam solution at 08C. The mixture was allowed to warm to
ambient temperature over 3 h and poured into saturated
aqueous ammonium chloride. The product was extracted
with ethyl acetate, the combined extracts were washed
with brine, dried MgSO4) and the solvent evaporated in
vacuo. The crude product was puri®ed by ¯ash chroma-
tography petroleum ether/ethyl acetate 3:1) to give 4.9 g
Alcohol 4 was condensed with homochiral resorcinol 5 in
dry dichloromethane at 2208C to give the resulting canna-
binoid ester in 43% yield Scheme 4). The ester was reduced
with LiAlH4 to afford cannabinoid 3 in 81% yield. Alcohol
10 and the 1R,5S)-myrtenol 12) employed in the synthesis
of cannabinoid 3 are both of .98% ee and consequently the
®nal cannabinoid 3 is of comparable optical purity.
In summary, we have developed a facile, and highly stereo-
selective synthesis of the 10S,20R)-dimethylheptyl side
chain making it a viable alternative to the more commonly
used 10,10-dimethylheptyl side chain. This methodology has
been applied to the synthesis of 11-hydroxy- 10S,20R)-
dimethylheptyl-D8-THC 3), one of the most potent
traditional cannabinoids known Ki 0.49 nM). Cannabinoid
3) is approximately eighty times more potent than D9-THC
Ki 41 nM) at the CB1 receptor. Second, an improved syn-
thesis of the key intermediate, 4-hydroxy-myrtenyl pivalate,
has been described.
1
90%) of enoyl sultam 8 as a pale yellow oil: H NMR
300 MHz, CDCl3) d 0.99 3H, s), 1.26 3H, s), 1.32±1.46

7610
J. Liddle, J. W. Huffman / Tetrahedron 57 12001) 7607±7612
2H, m), 1.89±2.05 5H, m), 2.08 3H, d, Jˆ1.4 Hz), 3.40
1H, d, Jˆ13.6 Hz), 3.50 1H, d, Jˆ13.6 Hz), 3.77 6H, s),
4.06 1H, dd, Jˆ5.1, 7.2 Hz), 6.40 1H, t, Jˆ2.2 Hz), 6.51
2H, d, Jˆ2.2 Hz), 7.07 1H, d, Jˆ1.4 Hz); 13C NMR
75.5 MHz, CDCl3) d 14.5, 19.5, 21.0, 26.2, 32.8, 37.9,
44.9, 47.4, 53.1, 55.0, 65.1, 100.0, 107.0, 131.6, 136.9,
138.1, 160.6, 172.1; IR neat) 1653, 1463 cm21; MS EI)
m/z 419 30), 420 20); HRMS calcd for C22H29NO5S:
419.1734, found 419.1733.
with water, the THF was removed in vacuo and the residue
was acidi®ed with 10% aqueous hydrochloric acid and
extracted with ether. The ethereal extracts were washed
with brine, dried MgSO4) and the ether removed in vacuo
to give alcohol 10 as a pale yellow oil 0.51 g, 90%) which
was used without further puri®cation. The spectroscopic
1
data were consistent with previously reported data5b: H
NMR 300 MHz, CDCl3) d 0.97 3H, d, Jˆ6.7 Hz), 1.21
3H, d, Jˆ7.1 Hz), 1.80 2H, m), 2.60 1H, quintet, Jˆ
7.1 Hz), 3.28 1H, dd, Jˆ6.7, 10.6 Hz), 3.45 1H, dd, Jˆ
5.0, 10.6 Hz), 3.77 6H, s), 6.31 1H, t, Jˆ2.2 Hz), 6.36 2H,
d, Jˆ2.2 Hz); 13C NMR 75.5 MHz, CDCl3) d 14.0, 17.9,
41.9, 55.1, 66.5, 97.5, 105.5, 149.0, 160.6; IR neat) 3329,
3.1.2.
30S-ꢀ3,5-Dimethoxyphenyl)-20S-methylbutanoic
acid. To a stirred slurry of copper I) iodide 5.60 g,
29.50 mmol) in anhydrous toluene 90 ml) at 2408C
under argon was added dropwise methyllithium 42.0 ml,
1.4 M in ether, 58.8 mmol) and the mixture was stirred for
1 h at 2408C. The resulting complex was cooled to 2788C
and a solution of enoyl sultam 8 4.1 g, 9.97 mmol) in
anhydrous toluene 50 ml) was added dropwise and the
mixture was allowed to warm to 2408C and stirred over-
night. The reaction mixture was quenched at 2408C with
saturated aqueous ammonium chloride/THF and extracted
with dichloromethane. The combined extracts were washed
with brine, dried MgSO4), and the solvent evaporated to
yield a crystalline solid. The crude product was puri®ed by
two recrystallizations from ethyl acetate/petroleum ether to
1496, 1454 cm21; [a]D ˆ126.58 cˆ1.0, CHCl3) lit.5b
25
25
[a]D ˆ120.58 cˆ0.5, CHCl3)); HRMS calcd for
C13H20O3: 224.1412, found 224.1416.
3.1.4. 20S-ꢀ3,5-Dimethoxyphenyl)-30R-methyloctane ꢀ11).
To a stirred solution of the alcohol 10 0.40 g, 1.78 mmol) in
dry CHCl3 5 ml) at 08C was added 0.3 ml of dry pyridine,
followed by p-toluenesulfonyl chloride 0.34 g, 1.78 mmol).
The reaction was stirred for 3 h at 08C, diluted with water
and extracted with ether. The ethereal extracts were washed
successively with 10% aqueous hydrochloric acid, saturated
aqueous sodium bicarbonate solution, brine, dried MgSO4)
and the solvent removed in vacuo to give the crude tosylate
as a yellow oil which was chromatographed petroleum
ether/ethyl acetate 4:1) to provide 0.51 g 75%) of pure
1
give 9 3.6 g, 85%) as a white solid, mp 212±2158C: H
NMR 300 MHz, CDCl3) d 0.59 3H, s), 0.85 3H, s),
1.19±1.39 9H, m), 1.59±1.86 4H, m), 2.95 1H, m), 3.22
1H, m), 3.33 1H, d, Jˆ14.0 Hz), 3.39 1H, d, Jˆ14.0 Hz),
3.71 1H, m), 3.75 6H, s), 6.23 1H, t, Jˆ2.2 Hz), 6.40 2H,
d, Jˆ2.2 Hz); 13C NMR 75.5 MHz, CDCl3) d 15.1, 18.6,
19.8, 20.5, 26.4, 32.9, 38.3, 44.4, 44.6, 46.6, 47.8, 53.2,
55.2, 65.1, 99.4, 105.6, 146.8, 160.4, 175.1; IR neat)
1671, 1620, 1593 cm21; MS EI) m/z 435 40); HRMS
calcd for C23H33NO5S: 435.2076, found 435.2079; Anal.
calcd for C23H33NO5S: C, 63.42; H, 7.64; N, 3.22, found:
C, 63.41, H, 7.80, N, 3.25.
1
material: H NMR 300 MHz, CDCl3) d 0.93 3H, d, Jˆ
6.7 Hz), 1.13 3H, d, Jˆ7.1 Hz), 1.92 1H, m), 2.40 3H, s),
2.55 1H, d, Jˆ7.6 Hz), 3.64 1H, dd, Jˆ6.3, 9.4 Hz), 3.73
6H, s), 3.80 1H, dd, Jˆ4.6, 9.4 Hz), 6.21 2H, d, Jˆ
2.2 Hz), 6.26 1H, t, Jˆ2.2 Hz), 7.26 2H, d, Jˆ8.2 Hz),
7.67 2H, d, Jˆ8.2 Hz); 13C NMR 75.5 MHz, CDCl3) d
14.0, 17.9, 21.5, 39.0, 41.4, 55.1, 73.8, 97.9, 105.3, 127.7,
129.6, 132.8, 144.5, 147.6, 160.6.
A solution of LiCl 0.084 g, 2.0 mmol) and CuCl2
0.1345 g, 1.0 mmol) in 10 ml of dry THF was stirred for
15 min under N2 to produce the Li2CuCl4 complex. This
Li2CuCl4 complex 1.2 ml 0.12 mmol) was added dropwise
to a solution of the tosylate 0.45 g, 1.19 mmol) and butyl-
magnesium bromide 12 ml, 2 M in ether, 24 mmol) in dry
THF 15 ml) at 2788C. The reaction mixture was allowed to
warm to ambient temperature and was stirred for 48 h. The
mixture was poured into saturated aqueous ammonium
chloride and extracted with ether. The ethereal extracts
were ®ltered through celitew to remove any copper salts,
washed well with 10% aqueous hydrochloric acid, brine,
dried MgSO4) and the solvent removed in vacuo to give
0.20 g 64%) of 11 as a colorless oil after chromatography
petroleum ether/ethyl acetate 19:1). The spectroscopic data
were consistent with previously reported data:5b 1H NMR
300 MHz, CDCl3) d 0.85±1.03 7H, m), 1.12±1.38 10H,
m), 1.66 1H, m), 2.52 1H, quintet, Jˆ7.0 Hz), 3.80 6H, s),
6.31 1H, t, Jˆ2.2 Hz), 6.35 2H, d, Jˆ2.2 Hz); 13C NMR
75.5 MHz, CDCl3) d 14.1, 16.1, 17.3, 22.7, 26.9, 32.1,
34.9, 30.9, 45.1, 55.2, 97.2, 105.9, 150.0, 160.5; IR 2957,
A mixture of sulphonamide 9 2.3 g, 5.29 mmol) in THF
20 ml) and aqueous lithium hydroxide solution 7 M,
20 ml) was heated at 608C for 4 days. The reaction mixture
was evaporated to dryness and the residue was triturated
with dichloromethane. The precipitate was ®ltered off and
the ®ltrate was dried MgSO4) and the solvent was removed
to give the recovered auxiliary 0.90 g, 79%) as a cream
colored solid. The dichloromethane-insoluble residue was
acidi®ed with 2 M hydrochloric acid, extracted with
dichloromethane, dried MgSO4) and the solvent evaporated
to give the butanoic acid 1.26 g, 100%) as a colorless solid.
The spectroscopic data were consistent with previously
13
reported data:5b mp 108±1118C lit.
mp 101±1058C);
1H NMR 300 MHz, CDCl3) d 1.14 3H, d, Jˆ7.0 Hz),
1.23 3H, d, Jˆ7.1 Hz), 2.68 1H, quintet, Jˆ7.0 Hz),
3.08 1H, quintet, Jˆ7.1 Hz), 3.74 6H, s), 6.31 1H, t, Jˆ
2.2 Hz), 6.53 2H, d, Jˆ2.2 Hz); 13C NMR 75.5 MHz, CDCl3)
d 13.2, 16.6, 41.7, 46.0, 55.1, 98.2, 105.5, 147.1, 160.5, 181.9.
3.1.3. 30S-ꢀ3,5-Dimethoxyphenyl)-20S-methyl-1-butanol
ꢀ10). A solution of the butanoic acid 0.60 g, 2.52 mmol)
in dry THF 5 ml) was added dropwise to a suspension of
LiAlH4 0.20 g, 5.26 mmol) in THF 20 ml) at 08C under
argon. The reaction mixture was stirred for 16 h and allowed
to warm to room temperature. The reaction was quenched
2872, 2836, 1596, 1457 cm21; [a]D ˆ131.98 cˆ1.0,
25
CHCl3) Lit.13 [a]D ˆ136.98); HRMS calcd for
25
C17H28O2: 264.2089, found 264.2087.
3.1.5. 4-Oxomyrtenyl pivalate ꢀ13). To a solution of

J. Liddle, J. W. Huffman / Tetrahedron 57 12001) 7607±7612
7611
1R,5S)-myrtenol 12 5.0 g, 32.8 mmol) in anhydrous
dichloromethane 30 ml) and pyridine 30 ml) at 08C
under argon was added dropwise trimethylacetyl chloride
5 ml, 41.0 mmol). The reaction was stirred for 4 h at 08C,
ether 100 ml) was added and the mixture was washed well
with 10% aqueous hydrochloric acid, saturated aqueous
bicarbonate solution, brine, dried MgSO4) and evaporated
to yield myrtenyl pivalate 6.5 g, 84%) as a colorless oil
which was used without further puri®cation: 1H NMR
300 MHz, CDCl3) d 0.75 3H, s), 1.20 9H, s), 1.29 3H,
s), 2.10 2H, d, Jˆ5.5 Hz), 2.21±2.43 4H, m), 4.44 2H, dd,
Jˆ12.4, 17.1 Hz), 5.55 1H, brs).
To a solution of resorcinol 5 0.070 g, 0.30 mmol) and
pivalate ester 4 0.075 g, 0.30 mmol) in anhydrous dichloro-
methane 100 ml) at 2208C under argon was added boron
tri¯uoride etherate 0.20 ml, 1.6 mmol). The mixture was
allowed to warm up to room temperature and then stirred
for a further 1 h. The mixture was carefully washed with
brine, dried MgSO4) and the solvent removed in vacuo. The
product was puri®ed by chromatography petroleum ether/
ethyl acetate 9:1) to give the cannabinoid ester 0.060 g,
43%) as a colorless oil: Rf 0.38 petroleum ether/ethyl
1
acetate 9:1); H NMR 300 MHz, CDCl3) d 0.80 6H, m),
0.86±1.31 20H, m), 1.37 3H, s), 1.55 2H, m), 1.88 4H,
m), 2.20 1H, m), 2.42 1H, quintet, Jˆ6.8 Hz), 2.69 1H, dt,
Jˆ6.3, 10.7 Hz), 3.35 1H, dd, Jˆ16.8, 4.1 Hz), 4.49, 2H s),
5.21 1H, m), 5.73 1H, d, Jˆ4.6 Hz), 6.10 1H, d,
Jˆ1.2 Hz), 6.24 1H, d, Jˆ1.2 Hz); 13C NMR 75.5 MHz,
CDCl3) d 14.1, 15.8, 16.2, 18.4, 22.6, 27.0, 27.2, 27.5, 31.1,
31.7, 32.0, 34.9, 39.0, 43.9, 44.8, 68.1, 76.4, 107.0, 109.3,
109.9, 123.2, 133.9, 147.3, 154.5, 154.7, 178.7; MS EI) m/z
To a suspension of chromium trioxide 15.3 g, 153.0 mmol)
in dry dichloromethane 120 ml) at 2208C under argon was
added 3,5-dimethylpyrazole 14.6 g, 152.0 mmol) in small
portions. After stirring for 15 min a solution of myrtenyl
pivalate 3.0 g, 12.7 mmol) in dichloromethane 30 ml)
was added and the mixture was stirred at 2208C for 4 h.
Aqueous sodium hydroxide solution 5 M, 10 ml) was
added and the mixture stirred at 08C for 1 h. The organic
phase was separated, washed with 10% aqueous hydro-
chloric acid, brine, dried MgSO4) and evaporated to give
ketone 13 1.7 g, 53%) as a yellow oil after chromatography
petroleum ether/ethyl acetate 7:3). The spectroscopic data
25
470 20); [a]D ˆ22358 cˆ1.1, CHCl3).
A solution of the cannabinoid ester 0.030 g, 0.064 mmol) in
dry THF 1 ml) was added dropwise to a suspension of
LiAlH4 0.010 g, 0.26 mmol) in THF 1 ml) at 08C under
argon. The reaction mixture was stirred for 2 h and allowed
to warm to room temperature. The reaction was quenched
with water and extracted with ether. The ethereal extracts
were washed with brine, dried MgSO4) and the ether
removed in vacuo. The product was puri®ed by chroma-
tography petroleum ether/ethyl acetate 7:3) to give the
cannabinoid 0.020 g, 81%) as a colorless oil which crystal-
lizes slowly on standing: Rf 0.22 petroleum ether/ethyl
acetate 7:3), Rf 0.15 CHCl3); 1H NMR 300 MHz,
CDCl3) d 0.77 3H, d, Jˆ6.7 Hz), 0.83 3H, t, Jˆ6.5 Hz),
0.96±1.35 8H, m), 1.04 3H, s), 1.07 3H, d, Jˆ7.1 Hz),
1.35 3H, s), 1.55 1H, m), 1.82 3H, m), 2.21 2H, m), 2.38
1H, quintet, Jˆ6.7 Hz), 2.67 1H, dt, Jˆ4.4, 11.1 Hz), 3.48
1H, dd, Jˆ3.7, 15.7 Hz), 4.02 1H, d, Jˆ12.5 Hz), 4.08
1H, d, Jˆ12.5 Hz), 5.71 1H, d, Jˆ4.1 Hz), 6.10 1H, d,
Jˆ1.1 Hz), 6.14 1H, br s), 6.22 1H, d, Jˆ1.1 Hz); 13C
NMR 75.5 MHz, CDCl3) d 14.1, 15.8, 16.3, 18.4, 22.7,
27.0, 27.5, 27.7, 31.4, 32.0, 34.9, 38.9, 43.9, 45.0, 67.1,
76.4, 107.1, 109.3, 110.1, 121.8, 138.2, 147.3, 154.4,
1
were consistent with previously reported data7: H NMR
300 MHz, CDCl3) d 0.92 3H, s), 1.22 9H, s), 1.50 3H,
s), 2.12 1H, d, Jˆ9.3 Hz), 2.42 1H, t, Jˆ5.3 Hz), 2.68 1H,
dt, Jˆ1.6, 5.9 Hz), 2.85 1H, m), 4.65 1H, d, Jˆ16.8 Hz),
4.73 1H, d, Jˆ16.8 Hz), 5.84 1H, m); 13C NMR 75.5
MHz, CDCl3) d 22.0, 26.4, 27.1, 38.3, 40.7, 45.3, 54.0,
58.0, 63.9, 119.1, 165.9, 177.5, 202.8; MS EI) m/z 252 10).
3.1.6. 4-Hydroxy-myrtenyl pivalate ꢀ4). To a solution of
ketone 13 0.50 g, 2.0 mmol) in dry THF 2 ml) at 08C under
argon was added dropwise a solution of lithium tri-tert-
butoxyaluminium hydride 2.0 ml, 1 M in ether, 2.0
mmol). The mixture was allowed to warm to room tempera-
ture and stirred for a further 4 h. The reaction was quenched
with saturated aqueous ammonium chloride solution and
extracted with ether. The combined ethereal extracts were
dried MgSO4) and evaporated in vacuo to yield alcohol 4
0.45 g, 89%) as a colorless oil. 1H NMR 300 MHz, CDCl3)
d 0.91 3H, s), 1.21 9H, s), 1.43 3H, s), 1.78 1H, m), 2.10
1H, t, Jˆ5.3 Hz), 2.33 1H, m), 2.51 1H, m), 4.50 3H, m),
5.65 1H, m); 13C NMR 75.5 MHz, CDCl3) d 22.8, 26.6,
27.1, 35.6, 38.7, 38.8, 44.0, 48.3, 65.7, 72.8, 122.1, 145.2,
178.1.
25
154.8; MS EI) m/z 386 60), 387 40); [a]D ˆ22068
cˆ0.9, CHCl3); HRMS calcd for C25H38O3: 386.2821,
found 386.2827.
Acknowledgements
3.1.7. 11-Hydroxy-ꢀ10S,20R)-dimethylheptyl-D8-THC ꢀ3).
A solution of the dimethyl ether 11 0.18 g, 0.68 mmol) in
1.5 ml of boron tribromide 1.0 M in CH2Cl2) was stirred at
08C under argon for 1 h. The reaction mixture was allowed
to warm to ambient temperature, stirred for 16 h and care-
fully quenched with water. The mixture was extracted with
ether, the combined ethereal extracts were washed with
brine, dried MgSO4) and the solvent removed in vacuo to
give 0.15 g 94%) of resorcinol 5 as a brown oil which was
The authors thank the National Institute on Drug Abuse for
support of this work grant under DA03590. We also thank
Drs Billy R. Martin and Jenny L. Wiley, Department
of Pharmacology and Toxicology, Medical College of
Virginia, Virginia Commonwealth University, for carrying
out the pharmacological evaluation of cannabinoid 3. The
work at the Medical College of Virginia, Virginia Common-
wealth University was supported by grant DA03672, also
from the National Institute on Drug Abuse. High resolution
mass spectral data were determined by the Mass Spec-
trometry Laboratory, School of Chemical Sciences, Uni-
versity of Illinois. We also thank Dr Simon M. Bushell for
his assistance with the preparation of the manuscript.
1
used without puri®cation: H NMR 300 MHz, CDCl3) d
0.74±1.37 17H, m), 1.77 1H, m), 2.45 1H, quintet,
Jˆ6.8 Hz), 5.93 2H br s), 6.22 1H, s), 6.30 2H, s); 13C
NMR 75.5 MHz, CDCl3) d 14.1, 15.8, 16.8, 22.7, 26.9,
32.0, 39.0, 44.5, 100.3, 107.6, 151.0, 156.0.

7612
J. Liddle, J. W. Huffman / Tetrahedron 57 12001) 7607±7612
6. Liddle, J.; Huffman, J. W.; Wiley, J. L.; Martin, B. R. Bioorg.
Med. Chem. Lett. 1998, 8, 2223.
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