Total synthesis of (-)-δ8- trans -Tetrahydrocannabinol

Article abstract of DOI:10.1055/s-0029-1218732

(-)-⁸-trans-Tetrahydrocannabinol was synthesized with high regio- and stereoselectivity through S_N2′ addition of an arylcyanocuprate to the optically pure enol silyl ether of α,β- epoxycyclohexanone. Georg Thieme Verlag Stuttgart - N

Full text of DOI:10.1055/s-0029-1218732

1766
PAPER
Total Synthesis of (–)-D8-trans-Tetrahydrocannabinol
8
(
–)-
D
-
trans-Tetr
a
i
n
nnabinol ggang Huang,a Bin Ma,a Xi’an Li,a Xinfu Pan,a Xuegong She*a,b
a
State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou 730000, P. R. of China
b
Fax +86(931)8912582; E-mail: shexg@lzu.edu.cn
Received 21 January 2010; revised 9 March 2010
this strategy, we attempted a total synthesis of D8-THC as
Abstract: (–)-D8-trans-Tetrahydrocannabinol was synthesized
with high regio- and stereoselectivity through SN2¢ addition of an
arylcyanocuprate to the optically pure enol silyl ether of a,b-epoxy-
cyclohexanone.
an example of an asymmetric synthesis of a cannabinoid.
Our retrosynthetic analysis is shown in Scheme 2. D8-
THC (1) consists of a tricyclic core structure and two ste-
Key words: addition reactions, heterocycles, tetrahydrocanna- reogenic centers. The problems associated with the syn-
binol, deoxygenation, stereoselective synthesis
thesis of 1 involve the control of the trans-stereochemistry
at the cyclohexene ring and the position of the double
bond. According to our analysis, we surmised that the tar-
get molecule 1 might be available from ketone 2 by sever-
(–)-D8-trans-Tetrahydrocannabinol (D8-THC; 1), which
al transformations involving acid-catalyzed cyclization
and Barton radical deoxygenation. In turn, the ketone 2
might be prepared by the SN2¢-hydrolysis reaction of enol
silyl ether 3 with the arylcyanocuprate 4. By this method,
the problems of controlling the relative stereochemistry
and the position of the double bond might be overcome.
was isolated from the female flowering tops of Cannabis
sativa L. for the first time in 1966,1 is an important mem-
ber of the family of cannabinoids that exhibit varying de-
grees of antiemetic, antiglaucoma, and analgesic
activities. Recently, two cannabinoid receptors, CB1 and
CB2 , have been discovered,2 and these have attracted at-
tention as potential therapeutic targets for the develop-
ment of anti-obesity,3 anticancer,4 analgesic,5 and
antiglaucoma agents.6–7 The biological activities of the
cannabinoids have prompted chemists to study their syn-
thesis. Despite many efforts to synthesize compounds of
this type,8 there are few reports of regio- and stereoselec-
tive syntheses of D8-THC,9 and this remains a significant
challenge. We report a general strategy for the total syn-
thesis of D8-THC by using a highly regio- and stereoselec-
tive SN2¢ reaction.10 The SN2¢ addition of aryl- or
alkylcyanocuprates to enol silyl ether epoxides, which oc-
curs with high regio- and stereoselectivities, is an impor-
tant method for the formation of carbon–carbon bonds
(Scheme 1).11
OMOM
O
OH
acid-catalyzed
cyclization
O
MOMO
Barton
deoxygenation
Δ8-THC (1)
2
OTMS
OMOM
SN2'
reaction
+
O
Cu(CN)MgBr
hydrolysis
OMOM
4
3
Scheme 2 Retrosynthetic analysis of D8-THC
O
OH
R1
R2
OTMS
acid
hydrolysis
OTMS
R3
R1
R2
O
R1
R2
AlkylCuCNLi
ArCuCNMgBr
We began our synthesis by preparing the enol silyl ether 3
in an optically pure form from commercially available (–)-
(R)-carvone through a conventional four-step sequence
that has been previously reported.12a We then prepared the
bromide 7, another precursor for the SN2¢ addition reac-
tion (Scheme 3). The hydroxy bromide 5 was converted
into the corresponding methyl sulfonate 6 in almost quan-
titative yield, and the desired precursor 7 was obtained in
70% yield from sulfonate 6 by means of an SN2 reaction
with butyl cyanocuprate.13 The reaction between the
freshly prepared arylmagnesium bromide of 7 and copper
cyanide gave the arylcyanocuprate reagent 4. Having the
necessary components in hand, we conducted the anti
SN2¢ addition according to our previously reported proce-
dure.12 The unstable silyl enol ether 8 was obtained as a
single diastereoisomer and immediately subjected to acid-
R3
( )n
( )n
( )n
R1, R2 = H or alkyl; R3 = alkyl or aryl
n = 0, 1
Scheme 1 Regio- and stereoselective SN2¢ reactions
In our recent work on the total synthesis of (+)-machaeriol
D,12 we successfully used an SN2¢-hydrolysis reaction in
the stereoselective construction of the hexahydrodiben-
zopyran nucleus. To explore the scope and generality of
SYNTHESIS 2010, No. 11, pp 1766–1770
x
x.
x
x
.
2
0
1
0
Advanced online publication: 12.04.2010
DOI: 10.1055/s-0029-1218732; Art ID: F01510SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
(–)-D8-trans-Tetrahydrocannabinol
1767
C5H11
OMOM
OMOM
Br
OMOM
Br
MsO
HO
n-BuLi, CuCN, THF
70%
MsCl, Et3N
Br
CH2Cl2, 0 °C
OMOM
OMOM
OMOM
5
7
6
OMOM
C5H11
OTMS
C5H11
OMOM
3
Mg, THF, reflux
Cu(CN)MgBr
OMOM
THF, –78 °C, 60%
MOMO
then CuCN, THF,
–40 °C to 0 °C
OH
4
8
S
OMOM
C5H11
Me
OMOM
O
C5H11
O
S
1) DIBAL-H, CH2Cl2, –30 °C
HCl (1 M), THF
85%
2) NaH, CS2, MeI, 50 °C
64% for two steps
MOMO
MOMO
2
9
Scheme 3 Preparation of intermediate xanthate 9
S
C5H11
OMOM
C5H11
OH
Me
O
S
AIBN (cat.), n-Bu3SnH
toluene, 90 °C, 89%
AIBN (cat.), n-Bu3SnH
p-TsOH, MeOH
reflux, 77%
1
9
toluene, 90 °C, 89%
MOMO
O
10
11
Scheme 4 Completion of the total synthesis of D8-THC (1)
ic hydrolysis to afford the ketone 2 in 51% yield for the achieved. The application of this methodology to the syn-
two steps. Further elaboration of the enone 2 by reduction thesis of other cannabinoids is ongoing in our laboratory.
with diisobutylaluminum hydride and subsequent xan-
thation gave the key intermediate 9 in 63% yield for the
All chemicals were used as received. THF and toluene were re-
fluxed with Na, whereas CH2Cl2 was refluxed with CaH2 and fresh-
two steps.14
ly distilled prior before use. Other solvents were purified and dried
by standard methods. All reactions under standard conditions were
monitored by TLC on gel F254 plates. Silica gel (200–300 mesh)
We then subjected the xanthate 9 to Barton radical de-
oxygenation to give the compound 10 (Scheme 4).14 We
had hoped that compound 10 would cyclize under the
acidic reaction conditions to give 1, but unfortunately, a
complex mixture of products was formed. Attempts to use
was used for column chromatography, and the distillation range of
the PE was 60–90 °C. 1H and 13C NMR spectra were recorded on a
Bruker AM 400-MHz instrument; the spectral data are reported in
other acidic reagents for remove the methoxymethyl pro- ppm relative to TMS as internal standard. Chemical shifts are re-
ported as d values relative to CDCl3 (d = 7.27 for 1H NMR and 77.0
for 13C NMR). IR spectra were recorded on a Nicolet FT-170SX
spectrometer. HRMS data were determined on a Bruker Daltonics
APEXII 47e FTIR spectrometer. Oxygen- and moisture-sensitive
reactions were carried out under an argon atmosphere. All commer-
cially available reagents were used without further purification un-
less otherwise noted. Optical rotations were measured on a
precision automated polarimeter.
tecting group gave similar results.8m
Given the failure of the direct synthesis from 9, we at-
tempted a two-step approach instead. The acidic cycliza-
tion was first performed in the presence of 4-
toluenesulfonic acid for one hour in refluxing methanol
and, to our delight, the desired tricyclic product 11 was
isolated in 75% yield. Subsequent Barton radical deoxy-
genation of 11 gave the required (–)-D8-THC (1) smoothly
in 90% yield; the spectral properties of this product were
identical with those of the natural product.1
4-Bromo-3,5-bis(methoxymethoxy)benzyl Methanesulfonate
(6)
MsCl (2.65 mL, 34.2 mmol) was added to a soln of the bromo com-
pound 5 (7.0 g, 22.8 mmol) and Et3N (6.31 mL, 45.6 mmol) in
CH2Cl2 (20 mL) at 0 °C, and the mixture was stirred for 15 min. The
reaction was then quenched with H2O, and the mixture was extract-
ed with CH2Cl2 (3 × 100 mL). The combined organic layers were
washed with brine, dried (Na2SO4), filtered, and evaporate to dry-
ness. The residue was purified by column chromatography [silica
To summarize, we have completed an asymmetric synthe-
sis D8-THC through the highly regio- and stereoselective
SN2¢ addition of an arylcyanocuprate to the enol silyl ether
of an a,b-epoxycyclohexanone; this reaction gave trans-
stereocontrol at the cyclohexene ring, and regioselective
installation of the trisubstituted double bond was readily
Synthesis 2010, No. 11, 1766–1770 © Thieme Stuttgart · New York

1768
Q. Huang et al.
PAPER
gel, PE–EtOAc (3:1)] to give a white amorphous solid; yield: 8.5 g
(97%).
ing slurry was filtered and the residue was washed with EtOAc
(8 × 5 mL). The combined organic phase was dried (Na2SO4), and
concentrated in vacuo. The residue was purified by column chroma-
tography [silica gel, petroleum–EtOAc (10:1)] to give the interme-
diate alcohol as a colorless oil; yield: 0.35 g (70%); [a]D25 +38.0 (c
1.0, CHCl3).
IR (KBr): 3379, 2921, 2852, 1761, 1586, 1436, 1350, 1242, 1152,
1100, 1043, 920, 852, 804, 669 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.87 (s, 2 H), 5.25 (s, 4 H), 5.14
(s, 2 H), 3.50 (s, 6 H), 2.96 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 155.1, 133.9, 109.4, 104.7, 95.0,
70.8, 56.4, 38.3.
HRMS (ESI): m/z [M + H]+ calcd for C12H18BrO7S: 384.9956;
found: 384.9956.
IR (KBr): 3400, 2955, 2926, 2856, 1710, 1643, 1610, 1579, 1437,
1398, 1376, 1153, 1108, 1038, 923, 896 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.70 (s, 1 H), 6.65 (s, 1 H), 5.60
(s, 1 H), 5.07–5.21 (m, 4 H), 4.61 (s, 1 H), 4.54 (s, 1 H), 3.94 (s, 1
H), 3.70 (td, J = 12.8, 4.0 Hz, 1 H), 3.49 (s, 3 H), 3.47 (s, 3 H),
3.30–3.35 (m, 1 H), 2.52 (t, J = 8.0 Hz, 2 H), 2.11–2.18 (m, 2 H),
1.85 (s, 3 H), 1.58–1.61 (m, 2 H), 1.46 (s, 3 H), 1.26–1.32 (m, 4 H),
0.88–0.90 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 157.6, 155.6, 146.4, 143.6, 136.3,
123.1, 115.4, 111.1, 108.7, 108.4, 95.6, 94.7, 72.3, 56.2, 56.1, 40.7,
39.5, 36.2, 33.3, 31.7, 30.9, 22.5, 21.2, 18.1, 14.1.
2-Bromo-1,3-bis(methoxymethoxy)-5-pentylbenzene (7)
BuLi (18.5 mL, 45 mmol) was added to a soln of CuCN (4.21 g,
46.8 mmol) in anhyd THF (60 mL) under argon at –50 °C. The het-
erogeneous mixture was allowed to warm gradually until complete
dissolution occurred, and then cooled again to –78 °C. The mesylate
6 (6.91 g, 18 mmol) was added and then allowed to warm gradually
to r.t. for 4 h. The resulting mixture was quenched with sat. aq
NH4Cl soln, stirred at r.t. for 30 min, and then extracted with EtOAc
(3 × 50 mL). The combined organic layers were washed with brine,
dried (Na2SO4), filtered, and evaporate to dryness. Purification of
the residue by column chromatography [silica gel, PE–EtOAc
(30:1)] gave a colorless oil; 4.36 g (70%).
HRMS (ESI): m/z [M + NH4]+ calcd C25H42NO5: 436.3105; found:
436.3110.
To a soln of the alcohol intermediate (0.33 g, 0.80 mmol) in anhyd
THF (2 mL) at r.t. was added NaH (60% suspension in mineral oil,
64 mg, 1.6 mmol) under argon. The mixture was stirred for 30 min
then CS2 (0.5 mL) was added and the mixture was heated to 50 °C
for 2 h. MeI (0.54 mL, 8.7 mmol) was added and the mixture was
stirred for another 5 h at 50 °C, then cooled to r.t. The cooled mix-
ture was filtered and concentrated to give a residue that was purified
by column chromatography [silica gel, PE–EtOAc (10:1)] to give
IR (KBr): 3402, 2955, 2928, 2856, 1587, 1461, 1435, 1393, 1154,
1111, 1090, 1045, 922, 849, 726 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.68 (s, 2 H), 5.23 (s, 4 H), 3.51
(s, 6 H), 2.54 (td, J = 9.6, 2.4 Hz, 2 H), 1.57–1.61 (m, 2 H), 1.27–
1.34 (m, 4 H), 0.90 (t, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 154.6, 143.7, 109.7, 100.6, 95.0,
56.2, 36.0, 31.3, 30.8, 22.3, 13.9.
25
the xanthate ester 9 as a yellow oil; yield: 0.37 g (91%); [a]D
–128.2 (c 1.0, CHCl3).
IR (KBr): 3393, 2955, 2926, 2854, 1710, 1642, 1609, 1582, 1436,
1397, 1378, 1238, 1152, 1110, 1082, 1046, 972, 924, 867 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C15H24BrO4: 347.0858; found:
347.0858.
1H NMR (300 MHz, CDCl3): d = 6.57 (s, 2 H), 5.45 (s, 1 H), 5.09–
5.18 (m, 4 H), 4.53 (s, 1 H), 4.47 (s, 1 H), 4.39 (s, 1 H), 3.99 (dd,
J = 10.5, 1.8 Hz, 1 H), 3.52 (s, 6 H), 3.09 (t, J = 10.8 Hz, 1 H), 2.51
(t, J = 7.8 Hz, 2 H), 2.44 (s, 3 H), 2.18–2.28 (m, 1 H), 1.97–2.05 (m,
1 H), 1.75 (s, 3 H), 1.62 (s, 3 H), 1.56–1.58 (m, 2 H), 1.23–1.32 (m,
4 H), 0.87–0.91 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 190.3, 156.3, 147.3, 142.8, 132.1,
128.0, 117.9, 111.1, 107.9, 95.2, 77.0, 55.9, 47.1, 40.8, 36.4, 36.2,
31.6, 30.9, 22.5, 21.3, 19.5, 14.0, 12.9.
(5R,6R)-6-[2,6-Bis(methoxymethoxy)-4-pentylphenyl]-5-iso-
propenyl-2-methylcyclohex-2-en-1-one (2)
1 M HCl (1 mL) was added to a soln of bromide 8 (0.70 g, 1.38
mmol) in THF (2 mL), and the mixture was stirred for 1 h. The re-
action quenched with H2O, and the mixture was extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed
with brine, dried (Na2SO4), filtered, and evaporate to dryness. Puri-
fication of the residue by column chromatography [silica gel, PE–
EtOAc (5:1)] gave a colorless oil; yield: 0.49 g (85%); [a]D25 +52.6
(c 1.0, CHCl3).
HRMS (ESI): m/z [M + H]+ calcd for C27H41O5S2: 509.2395; found:
509.2388.
IR (KBr): 3331, 2954, 2927, 2856, 1675, 1611, 1585, 1435, 1397,
1238, 1153, 1109, 1083, 1043, 968, 925, 893 cm–1.
2-[(1R,6R)-6-Isopropenyl-3-methylcyclohex-3-en-1-yl]-1,3-
bis(methoxymethoxy)-5-pentylbenzene (10)
AIBN (cat.) and Bu3SnH (neat, 0.23 mL, 1.34 mmol) were added
sequentially to a soln of the xanthate 9 (0.02 g, 0.039 mmol) in an-
hyd toluene (0.5 mL) at r.t. under argon. The mixture was carefully
deoxygenated by bubbling argon through it for 10 min. The flask
was then immersed in a preheated oil bath (110 °C), and the mixture
was stirred at this temperature for 1 h then cooled to r.t. The solvent
was evaporated and the residue was purified by column chromatog-
raphy [silica gel, PE–EtOAc (30:1)] to give a colorless oil; yield:
0.014 mg (89%); [a]D25 –68.0 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 6.77 (d, J = 6.0 Hz, 1 H), 6.59 (s,
2 H), 5.06 (s, 4 H), 4.56 (s, 1 H), 4.53 (s, 1 H), 4.14 (d, J = 12.4 Hz,
1 H), 3.47 (td, J = 12.4, 4.4 Hz, 1 H), 3.43 (s, 6 H), 2.50–2.59 (m, 3
H), 2.32 (dt, J = 18.0, 4.8 Hz, 1 H), 1.82 (s, 3 H), 1.64 (s, 3 H), 1.59
(t, J = 7.2 Hz, 2 H), 1.29–1.33 (m, 4 H), 0.90 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 199.0, 146.1, 143.3, 142.9, 135.2,
114.9, 112.0, 108.2, 94.5, 56.0, 48.6, 47.2, 36.3, 31.6, 31.5, 30.8,
22.5, 18.9, 16.2, 14.0.
HRMS (ESI): m/z [M + NH4]+ calcd for C25H40NO5: 434.2949;
found: 434.2948.
IR (KBr): 3428, 2956, 2927, 2856, 1643, 1609, 1581, 1435, 1397,
1237, 1153, 1110, 1044, 971, 925, 886 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.55 (s, 2 H), 5.24 (s, 1 H), 5.07–
5.13 (m, 4 H), 4.47 (s, 1 H), 4.45 (s, 1 H), 4.00 (dd, J = 10.5, 1.8 Hz,
1 H), 3.42–3.48 (m, 6 H), 2.91 (td, J = 10.5, 4.8 Hz, 1 H), 2.50 (t,
J = 8.0 Hz, 2 H), 2.14–2.16 (m, 1 H), 1.96–2.02 (m, 1 H), 1.70–1.79
(m, 2 H), 1.52–1.66 (m, 8 H), 1.31–1.32 (m, 4 H), 0.89 (t, J = 6.3
Hz, 3 H).
O-{(1R,5R,6R)-6-[2,6-Bis(methoxymethoxy)-4-pentylphenyl]-5-
isopropenyl-2-methylcyclohex-2-en-1-yl} S-Methyl Dithiocar-
bonate (9)
DIBAL-H (1.42 mL, 1.42 mmol) was added to a soln of ketone 2
(0.49 g, 1.18 mmol) in CH2Cl2 (5 mL) at –78 °C under argon, and
the mixture was stirred for 3 h. The reaction was quenched with sat.
aq NH4Cl and the mixture was stirred at r.t. for 30 min. The result-
Synthesis 2010, No. 11, 1766–1770 © Thieme Stuttgart · New York

PAPER
(–)-D8-trans-Tetrahydrocannabinol
1769
13C NMR (75 MHz, CDCl3): d = 149.1, 142.3, 131.3, 125.9, 120.1,
110.0, 108.4, 95.1, 55.9, 45.1, 36.6, 36.2, 31.7, 31.0, 30.7, 29.5,
23.4, 22.5, 19.3, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C25H39O4: 403.2848; found:
403.2850.
References
(1) (a) Taylor, E. C.; Lenard, K.; Shvo, Y. J. Am. Chem. Soc.
1966, 88, 367. (b) Fahrenholtz, K. E.; Lurie, M.; Kierstead,
R. W. J. Am. Chem. Soc. 1967, 89, 5934. (c) Binder, M.;
Franke, I.; Schmidt, B.; Dietrich, W. Helv. Chim. Acta 1982,
65, 807.
(2) (a) Gernard, C. M.; Mollereau, C.; Vassart, G.; Parmentier,
M. Biochem. J. 1991, 279, 129. (b) Skaper, S. D.; Buriani,
A.; Dal Toso, R.; Petrelli, L.; Romamello, S.; Faca, L.; Leon,
A. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 3984.
O-[(6aR,10aR)-1-Hydroxy-6,6,9-trimethyl-3-pentyl-
6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-10-yl] S-Methyl
Dithiocarbonate (11)
TsOH (0.20 g, 1.16 mmol) was added to a soln of the xanthate 9
(0.30 g, 0.59 mmol) in MeOH (3 mL), and the mixture was refluxed
for 1 h. The MeOH was removed in vacuo, H2O (2 mL) was added,
and the resulting mixture was extracted with EtOAc (3 × 10 mL).
The combined organic layers were washed with brine, dried
(Na2SO4), filtered, and evaporate to dryness. The residue was puri-
fied by column chromatography [silica gel, PE–EtOAc (10:1)] to
give a yellow oil; yield: 0.19 g (77%); [a]D25 –96.0 (c 1.0, CHCl3).
(c) Matsuda, L. A.; Lolait, S. J.; Brownstein, M. J.; Young,
A. C.; Bonner, T. I. Nature (London, U.K.) 1990, 346, 61.
(d) Munro, S.; Thomas, K. L.; Abu-shaar, M. Nature
(London, U.K.) 1993, 365, 61.
(3) Di Marzo, V.; Goparaju, S. K.; Wang, L.; Liu, J.; Batkai, S.;
Jarai, Z.; Fezza, F.; Miura, G. I.; Palmiter, R. D.; Sugiuram,
T.; Kunos, G. Nature (London, U.K.) 2001, 410, 822.
(4) Parolaro, D.; Massi, P.; Rubino, T.; Monti, E.
Prostaglandins, Leukotrienes Essent. Fatty Acids 2002, 66,
319.
(5) Palmer, S. L.; Thakur, G. A.; Makriyannis, A. Chem. Phys.
Lipids 2002, 121, 3.
(6) Porcella, A.; Maxia, C.; Gessa, G. L.; Pani, L. Eur. J.
Neurosci. 2001, 13, 409.
IR (KBr): 3428, 2956, 2928, 2856, 1706, 1642, 1623, 1578, 1427,
1380, 1362, 1262, 1182, 1131, 1114, 1046, 973, 869, 785 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.77 (s, 1 H), 6.28 (s, 1 H), 6.11
(d, J = 0.8 Hz, 1 H), 4.84 (s, 1 H), 4.42 (d, J = 3.2 Hz, 1 H), 3.27
(dd, J = 11.2, 1.6 Hz, 1 H), 2.44 (s, 3 H), 2.43 (t, J = 7.2 Hz, 2 H),
1.93 (td, J = 12.6, 4.8 Hz, 1 H), 1.81–1.85 (m, 1 H), 1.79 (s, 3 H),
1.56 (t, J = 7.2 Hz, 2 H), 1.41 (s, 3 H), 1.22–1.37 (m, 4 H), 1.10 (s,
3 H), 0.89 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 190.2, 154.9, 154.1, 143.2, 130.6,
129.9, 110.3, 107.6, 77.0, 76.6, 47.9, 42.0, 35.4, 34.3, 31.5, 30.6,
27.4, 22.5, 21.8, 19.8, 14.0, 13.1.
(7) Chien, F. Y.; Wang, R. F.; Mittag, T. W.; Podos, S. M. Arch.
Ophthalmol. 2003, 121, 87.
(8) For selected examples, see: (a) Mechoulam, R.; Gaoni, Y.
J. Am. Chem. Soc. 1965, 87, 3273. (b) Mechoulam, R.;
Braun, P.; Gaoni, Y. J. Am. Chem. Soc. 1967, 89, 4552.
(c) Mechoulam, R.; Braun, P.; Gaoni, Y. J. Am. Chem. Soc.
1972, 94, 6159. (d) Fahrenholtz, K. E.; Lurk, M.; Kierstead,
R. W. J. Am. Chem. Soc. 1966, 88, 2079. (e) Fahrenholtz,
K. E.; Lurk, M.; Kierstead, R. W. J. Am. Chem. Soc. 1967,
89, 5934. (f) Chan, T. H.; Chaly, T. Tetrahedron 1982, 23,
2935. (g) Rickards, R. W.; Ronneberg, H. J. Org. Chem.
1984, 49, 572. (h) Childers, W. E. Jr.; Pinnick, H. W. J. Org.
Chem. 1984, 49, 5276. (i) Malkov, A. V.; Koovsky, P.
Collect. Czech. Chem. Commun. 2001, 66, 1257.
(j) William, A. D.; Kobayashi, Y. J. Org. Chem. 2002, 67,
8771. (k) William, A. D.; Kobayashi, Y. Org. Lett. 2001, 3,
2017. (l) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka,
T.; Matt, P. V.; Millier, S. J.; Murry, J. A.; Norcross, R. D.;
Shaughnessy, E. A.; Campos, K. R. J. Am. Chem. Soc. 1999,
121, 7582. (m) Trost, B. M.; Dogra, K. Org. Lett. 2007, 9,
861. (n) Song, Y.; Hwang, S.; Gong, P.; Kim, D.; Kim, S.
Org. Lett. 2008, 10, 269. (o) Ballerini, E.; Minuti, L.;
Piermatti, O.; Pizzo, F. J. Org. Chem. 2009, 74, 4311.
(9) (a) Taylor, E. C.; Lenard, K.; Shvo, Y. J. Am. Chem. Soc.
1966, 88; 367. (b) Petrzika, T.; Sikemeier, C. Helv. Chim.
Acta. 1967, 50, 1416. (c) Handrick, G. R.; Razdan, R. K.;
Uliss, D. B.; Dalzell, H. C.; Boger, E. J. Org. Chem. 1997,
42, 2563. (d) Kowalski, C. J.; Lal, G. S. J. Am. Chem. Soc.
1988, 110, 3693. (e) Qi, L.; Yamamoto, N.; Meijler, M. M.;
Altobell, L. J. III; Koob, G. F.; Wirsching, P.; Janda, K. D.
J. Med. Chem. 2005, 48, 7389.
(10) For a review of the SN2¢ reaction, see: (a) Marshall, J. A.
Chem. Rev. 1989, 89, 1503. For recent references on the
SN2¢ reaction, see: (b) Li, L.; Rayabarapu, D. K.; Nandi, M.;
Cheng, C. Org. Lett. 2003, 5, 1621. (c) Smith, A. B. III;
Pitram, S. M.; Gaunt, M. J.; Kozmin, S. A. J. Am. Chem. Soc.
2002, ; 124, 14516. (d) Spino, C.; Beaulieu, C.; Lafreniére,
J. J. Org. Chem. 2000, 65, 7091. (e) Wang, X.; Wu, Y.;
Jiang, S.; Singh, G. J. Org. Chem. 2000, 65, 8146. (f) Xie,
C.; Nowak, P.; Kishi, Y. Org. Lett. 2002, 4, 4427. (g) Iura,
Y.; Sugahara, T.; Ogasawara, K. Org. Lett. 2001, 3, 291.
(h) Harrington-Frost, N.; Leuser, H.; Calaza, M. I.; Kneisel,
F. F.; Knochel, P. Org. Lett. 2003, 5, 2111. (i) Soorukram,
HRMS (ESI): m/z [M + H]+ calcd for C23H33O3S2: 421.1871; found:
421.1879.
D8-THC (1)
AIBN (cat.) and Bu3SnH (neat, 1 mL, 5.96 mmol) were added se-
quentially to a soln of the xanthate ester 11 (0.042 g, 0.10 mmol) in
anhyd toluene (2 mL) at r.t. under argon. The mixture was carefully
deoxygenated by bubbling argon through it for 10 min. The flask
was then immersed into a preheated oil bath (110 °C), and the mix-
ture was stirred at this temperature for 1 h then cooled to r.t. The sol-
vent was evaporated, and the residue was purified by column
chromatography [silica gel, PE–EtOAc (10:1)] to give a yellow oil;
yield: 0.028 g (89%); [a]D25 –185 (c 0.6, CHCl3).
IR (KBr): 3410, 2957, 2928, 2856, 1625, 1580, 1428, 1376, 1259,
1184, 1130, 1083, 1031, 833 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.29 (d, J = 1.2 Hz, 1 H), 6.12 (d,
J = 1.2 Hz, 1 H), 5.44 (d, J = 4.4 Hz, 1 H), 4.68 (s, 1 H), 3.20 (dd,
J = 16.0, 4.0 Hz, 1 H), 2.71 (td, J = 10.8, 4.8 Hz, 1 H), 2.43–2.47
(m, 2 H), 2.14–2.19 (m, 1 H), 1.80–1.84 (m, 3 H), 1.67 (s, 3 H),
1.55–1.58 (m, 2 H), 1.39 (s, 3 H), 1.27–1.33 (m, 4 H), 1.12 (s, 3 H),
0.87–0.91 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 154.8, 154.7, 142.7, 134.7, 119.3,
110.8, 110.1, 107.6, 76.6, 44.9, 36.0, 35.4, 31.6, 30.6, 27.9, 27.6,
23.5, 22.5, 18.5, 14.0.
HRMS (ESI): m/z [M – H]+ calcd for C21H29O2: 313.2168; found:
313.2169.
Acknowledgment
We are grateful for the generous financial support by the MOST
(No. 2010CB833200) and the NSFC (QT program, 20872054,
20732002).
Synthesis 2010, No. 11, 1766–1770 © Thieme Stuttgart · New York

1770
Q. Huang et al.
PAPER
D.; Knochel, P. Org. Lett. 2004, 6, 2409. (j) Calaza, M. I.;
Yang, X.; Soorukram, D.; Knochel, P. Org. Lett. 2004, 6,
529.
(12) (a) Wang, Q. L.; Huang, Q. G.; Chen, B.; Lu, J. P.; Wang,
H.; She, X. G.; Pan, X. F. Angew. Chem. Int. Ed. 2006, 22,
3651. (b) Huang, Q. G.; Wang, Q. L.; Zheng, J. Y.; Zhang,
J. Y.; Pan, X. F.; She, X. G. Tetrahedron 2007, 63, 1014.
(13) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A.; Parker, D.
J. J. Org. Chem. 1984, 49, 3928.
(14) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 16, 1574. (b) Barton, D. H. R.; Lobberding,
D. C. A.; Zard, S. Z. Tetrahedron 1986, 42, 2329. (c) For a
review see: Crich, D.; Quintero, L. Chem. Rev. 1989, 89,
1413.
(11) (a) Marino, J. P.; Hatanaka, N. J. Org. Chem. 1979, 44,
4467. (b) Wender, P. A.; Erhardt, J. M.; Letendre, L. J.
J. Am. Chem. Soc. 1981, 103, 2114. (c) Marino, J. P.; Jaén,
J. C. J. Am. Chem. Soc. 1982, 104, 3165. (d) Marino, J. P.;
Kelly, M. G. J. Org. Chem. 1981, 46, 4389. (e) Marino, J.
P.; Pradilla, F.; Laborde, E. J. Org. Chem. 1987, 52, 4898.
(f) Clive, D. L. J.; Wickens, P. L.; Silva, G. V. J. J. Org.
Chem. 1995, ; 60, 5532.
Synthesis 2010, No. 11, 1766–1770 © Thieme Stuttgart · New York