Enantioselective Total Synthesis of Potent 9β-11-Hydroxyhexahydrocannabinol

Article abstract of DOI:10.1021/acs.joc.9b02962

The first total synthesis of potent cannabinoid, 9β-11-hydroxyhexahydrocannabinol, is achieved through a proline-catalyzed inverse-electron-demand Diels-Alder reaction. Using this asymmetric catalysis, the cyclohexane ring is constructed with two chiral centers as a single diastereomer with 97% ee. The creation of the third chiral center and benzopyran ring is demonstrated with the elegant synthetic strategies. This mild and efficient synthetic methodology provides a new route for the asymmetric synthesis of the other potent hexahydrocannabinols.

Full text of DOI:10.1021/acs.joc.9b02962

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Note
Enantioselective Total Synthesis of Potent
9#-11-Hydroxyhexahydrocannabinol
Vidyasagar Maurya, and Chandrakumar Appayee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02962 • Publication Date (Web): 13 Dec 2019
Downloaded from pubs.acs.org on December 13, 2019
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The Journal of Organic Chemistry
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Enantioselective Total Synthesis of Potent 9β-11-
Hydroxyhexahydrocannabinol
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Vidyasagar Maurya and Chandrakumar Appayee*
Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar, Gujarat 382355, India
*E-mail: a.chandra@iitgn.ac.in
Supporting Information Placeholder
O
O
O
CO2H
N
O
H
O
+
(20 mol %)
CH3CN, 0 o
C
C5H11
O
C5H11
O
OTBS
IEDDA
reaction
OTBS
72% yield, 97% ee
single diastereomer
CO2
H
24%
N
H
HO2C
8 steps
overall yield
N
H
OH
MeO
H
H
OH
OMe
OTBS
C5H11
C5H11
O
proposed transition state
for IEDDA reaction
9β-11-hydroxy hexahydrocannabinol
ABSTRACT: The first total synthesis of potent cannabinoid, 9b-11-hydroxyhexahydrocannabinol is achieved through proline catalyzed
inverse-electron-demand Diels–Alder reaction. Using this asymmetric catalysis, the cyclohexane ring is constructed with two chiral centers as
a single diastereomer with 97% ee. The creation of the third chiral center and benzopyran ring is demonstrated with the elegant synthetic
strategies. This mild and efficient synthetic methodology provides a new route for the asymmetric synthesis of the other potent hexahydro-
cannabinols.
More than five hundred compounds have been isolated from
Cannabis sativa L.1 Among them, nearly one hundred compounds
show cannabinoid activity.2 Apart from their psychotropic activi-
ties,3 these cannabinoids are used for the treatment of anorexia,4
inflammation5 neuropathic pain,6 cancer,7 chemotherapy-induced
vomiting and nausea,8 and spasticity in patients with multiple scle-
rosis.9
Δ9-Tetrahydrocannabinol 1 and Δ8-tetrahydrocannabinol 2 are
the most notable cannabinoids isolated from Cannabis sativa L.10
More than eighty secondary metabolites of these cannabinoids (1–
2) have been isolated and tested for their psychotropic activity.11
Among them, 11-hydroxy-Δ9-tetrahydrocannabinol 3, isolated as a
major metabolite of 1, was found nearly four times more active than
Δ9-tetrahydrocannabinol
1.11d
However,
9β-11-
hydroxyhexahydrocannabinol 4 was isolated as one of the minor
metabolites11e and was found to be nearly seventeen times11c more
potent than Δ9-tetrahydrocannabinol 1 (Figure 1).
OH
OH
There are many synthetic methodologies12-16 reported for the to-
tal synthesis of the tetrahydrocannabinols 1 and 2. In most meth-
odologies, direct six-membered cyclohexene or cyclohexenone
derivatives have been used for synthesis of tetrahydrocannabinols 1
and 2 via Lewis acid catalysis,12 and metal catalysis.13 In other ap-
proaches, six-membered cyclohexene ring of tetrahydrocannabinols
1 and 2 have been constructed through [4+2] cycloaddition reac-
tion,14 ene-reaction15, and ring-closing metathesis.16 However, only
semisyntheses of hexahydrocannabinol 4 were described in the
literature. The first semisynthesis of cannabinoid 4 was carried out
from Δ11-tetrahydrocannabinol 5 in three steps with 1:1 dr
(Scheme 1).17 The other semisynthesis of 4 was reported starting
from Δ8-tetrahydrocannabinol in six steps with 3:1 dr.18 To the best
C5H11
O
C5H11
O
2
1
Δ9-tetrahydrocannabinol
Δ8-tetrahydrocannabinol
OH
OH
OH
OH
C5H11
O
C5H11
O
3
4
11-hydroxy-Δ9-tetrahydrocannabinol
9β-11-hydroxyhexahydrocannabinol
Figure 1. Cannabinoid natural products and their metabolites.
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of our knowledge, there is no total synthesis of the potent canna-
binoid 4 so far reported in the literature.
Scheme 1. Synthesis of Potent Hexahydrocannabinol 4
Grignard reaction. The aldehyde 8 was identified as the starting
1
2
3
4
5
6
7
compound for the synthesis of the silyl ether 10 via hydrogenation
followed by NaBH4 reduction. The aldehyde 8 could be achieved
through the IEDDA reaction of dimethyl olivetol acetaldehyde 6
and a,b,g,d-unsaturated aldehyde 721 catalyzed by D-proline. The
dimethyl olivetol acetaldehyde 6 was proposed to access from di-
methyl olivetol 1116a via lithiation, ethylene oxide ring opening and
oxidation.
semisynthetic approach
OH
6 steps
8% overall
yield
3 steps
25% overall
yield
OH
OH
OH
3:1 dr
1:1 dr
8
9
Scheme 3. Synthesis of Dimethyl Olivetol Acetaldehyde 6
C5H11
O
C5H11
O
C5H11
O
2
5
4
COCl2 (2 equiv)
DMSO (3 equiv)
Et3N (10 equiv)
Δ8-tetrahydrocannabinol
Δ
11-tetrahydrocannabinol
n-BuLi (1.5 equiv)
LiCl (10 equiv)
ethylene oxide (4 equiv)
10
11
12
13
14
15
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9β-11-hydroxy
hexahydrocannabinol
HO
O
O
O
O
THF, −78 oC to rt
−78 oC to rt, 3 h
C5H11
O
6.5 h, 78%
O
CH2Cl2
C5H11
C5H11
O
asymmetric catalytic approach (present work)
O
88%
11
12
6
O
OH
CO2H
N
Initially, we attempted to synthesize one of the IEDDA reaction
partner, dimethyl olivetol acetaldehyde 6. Accordingly, dimethyl
olivetol 1116a was treated with n-BuLi in the presence of LiCl and
quenched with ethylene oxide to yield the alcohol 12 in 78% yield.
The alcohol 12 was subjected for Swern oxidation to yield dimethyl
olivetol acetaldehyde 6 in 88% yield (Scheme 3).
H
O
OH
8 steps
IEDDA
reaction
O
+
OTBS
C5H11
O
OTBS
C5H11
O
O
O
7
4
8
9β-11-hydroxy
single diastereomer
hexahydrocannabinol
C5H11
97% ee
6
Although para- or meta-substituted phenyl acetaldehydes were
tested for the asymmetric IEDDA reaction,20 ortho-substituted
phenyl acetaldehyde was not studied. Dimethyl olivetol acetalde-
hyde (di-ortho-substituted phenyl acetaldehyde) 6 was treated with
Inverse-electron-demand Diels–Alder (IEDDA) reaction is one
of the most powerful and atom-economical tool for the synthesis of
stereoselective six-membered ring which is useful for the synthesis
of bioactive natural products.19 Recently, we have reported the first
organocatalytic approach for the asymmetric synthesis of 3,4-
disubstituted cyclohexadiene carbaldehydes through an inverse-
electron-demand Diels–Alder (IEDDA) reaction starting from
a,b,g,d-unsaturated aldehydes and arylacetaldehydes.20 We have
also successfully applied this methodology for the formal total syn-
thesis of cyclobakuchiols A and C.
a,b,g,d-unsaturated aldehydes 721 in the presence of D-proline in
o
CH3CN at 0 C for the IEDDA reaction (Scheme 4). To our de-
light, the 3,4-disubstituted cyclohexadiene carbaldehyde 8 was
observed as a single diastereomer in 72% yield with excellent enan-
tioselectivity (97% ee). The enantiomeric excess of 8 was deter-
mined after converting it into the corresponding alcohol 13.
Scheme 4. Asymmetric Synthesis of 3,4-Disubstituted Cyclo-
hexane Carbinol 10
Herein, we report the first total synthesis of the potent psycho-
tropic cannabinoid, 9b-11-hydroxyhexahydrocannabinol 4 through
O
O
CO2H
(20 mol %)
an inverse-electron-demand Diels–Alder reaction of dimethyl
O
N
O
H
olivetol acetaldehyde 6 and a,b,g,d-unsaturated aldehyde 721.
O
+
CH3CN, 0 o
28 h, 72%
C
Scheme 2. Retrosynthetic Plan for the Synthesis of Hexahydro-
cannabinol 4
C5H11
O
C5H11
O
OTBS
OTBS
6
8
7
single diastereomer
OBn
OH
OH
OH
CO2
97% ee
O
OH
O
H
N
H
HO2C
H
proposed transition
state for IEDDA
reaction
N
C5H11
O
C5H11
O
C5H11
O
OTBS
MeO
H2 (1 atm)
Pd/C (20 mol %)
EtOAc, rt, 6 h
H
H
4
9
10
9β-11-hydroxy
hexahydrocannabinol
OMe
OTBS
C5H11
O
OH
O
O
i) DBU (1 equiv)
MeOH, rt, 24 h
O
O
O
O
ii) NaBH4 (4 equiv)
MeOH, 0 oC, 0.5 h
O
O
C5H11
O
C5H11
O
60% yield
for 2 steps
C5H11
O
OTBS
OTBS
C5H11
O
OTBS
C5H11
O
OTBS
11
6
7
8
10, 5:1 dr
14
The retrosynthetic analysis (Scheme 2) suggested that the can-
nabinoid 4 could be synthesized by the deprotection followed by
the cyclization of tertiary alcohol 9, which in turn could be accessed
from the silyl ether 10 through Jones oxidation, esterification and
Then, 3,4-disubstituted cyclohexadiene carbaldehyde 8 was sub-
jected for the hydrogenation reaction to form the saturated alde-
hyde 14 in 2:1 dr albeit the required isomer to achieve the potent
cannabinoid 4 (containing equatorial carbinol) was found to be the
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The Journal of Organic Chemistry
OBn
OH
minor isomer. To improve the diastereoselectivity at the newly
OH
1
2
3
4
5
6
7
1) SOCl2 (3 equiv)
generated chiral center, the crude saturated aldehyde 14 was sub-
O
pyridine, −10 oC, 0.5 h
jected to epimerization using DBU22 in MeOH. An in situ reduction
OH
2) BBr3 (5 equiv), CH2Cl2
−78 oC, to rt, 24 h
o
of the epimerized product using NaBH4 at 0 C resulted the satu-
C5H11
O
rated alcohol 10 in 60% isolated yield after two steps with 5:1 dr.
The relative stereochemistry of the alcohol 10 was assigned based
on the COSY and NOE experiments (see the Supporting Infor-
mation).
C5H11
O
62% (for 2 steps)
9
4
9β-11-hydroxy
hexahydrocannabinol
In conclusion, we have achieved the first total synthesis of potent
cannabinoid, 9b-11-hydroxyhexahydrocannabinol 4 through pro-
line catalyzed inverse-electron-demand Diels–Alder reaction of
dimethyl olivetol acetaldehyde 6 and a,b,g,d-unsaturated aldehyde
7. Two out of the three chiral centers in cannabinoid 4 are generat-
ed through asymmetric catalysis as a single diastereomer with excel-
lent enantioselectivity (97% ee). The third chiral center in canna-
binoid 4 is constructed via DBU mediated epimerization to achieve
5:1 dr. The benzopyran ring is formed using BBr3 via the deprotec-
tion followed by the cyclization. Using this methodology, hexahy-
drocannabinol 4 is accessed from the 3,4-disubstituted cyclohexa-
diene carbaldehyde 8 in eight steps with 24% overall yield. This
asymmetric synthetic methodology has a potential for the synthesis
of the other potent cannabinoids including synthetic23 hexahydro-
cannabinols, which is currently underway in our laboratory.
8
9
Scheme 5. Conversion of Silyl Ether 10 to Tertiary Alcohol 9
OBn
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
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60
BnBr (1,2 equiv)
NaH (2 equiv)
TBAI (0.2 equiv), THF
O
O
0 oC to rt, 48 h
90%
C5H11
O
OTBS
C5H11
O
OTBS
15
10
1) Jones reagent (2 equiv)
acetone, 0 oC to rt, 2 h
2) TMSCHN2 (2.6 equiv)
C6H6/MeOH, 0 oC to rt
12 h
79% (for 2 steps)
OBn
OH
OBn
O
O
MeLi (3 equiv), THF
-78 oC to 0 o
C
EXPERIMENTAL SECTION
3 h, 91%
COOMe
C5H11
O
C5H11
O
General information. All the reagents and catalysts were
purchased from Aldrich, TCI and used without further purification
unless otherwise mentioned. All the solvents were purchased from
Merck or SD Fine and used for the purification of products. Thin-
layer chromatography (SiO2, TLC) was performed on Merck TLC
silica gel 60 F254 visualized by ultraviolet irradiation, KMnO4
solution. Column chromatography was performed on Merck silica
gel 100-200 using standard flash chromatographic methods. The
NMR spectra were recorded on Bruker Advance III (500 MHz)
spectrometer and were referenced against the residual solvent
peaks [CDCl3: δ 7.26 ppm (1H NMR) and 77.00 ppm (13C
NMR)]. Chemical shifts are reported in parts per million as
follows: chemical shift, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, bs = broad singlet), coupling
constant, and integration. Infrared spectra were recorded on Perkin
Elmer Spectrum Two FT-IR spectrometer. Selected absorption
bands are reported in wave numbers (cm−1). The HR-LCMS data
for all the compounds (except the compounds 9 and 13) was
recorded (in positive ion mode) with Agilent Technologies 6550
iFunnel Q-TOFs Mass instrument. The HRMS data for the com-
pounds 9 and 13 was recorded (in positive ion mode) with Waters
Synapt-G2S ESI-Q-TOF Mass instrument. Chiral HPLC analysis
was performed using an Agilent 1200 series and Daicel Chiralpak
OD-H (Chiral Technologies Eur., 25 cm × 4.6 mm I.D.) column
was used. Specific rotations were measured with a Rudolph
9
16
For the oxidation of silyl protected primary alcohol, an orthogo-
nal benzyl protection of the carbinol in 10 was envisaged. There-
fore, the saturated alcohol 10 was treated with NaH followed by
benzyl bromide in THF to afford the benzyl ether 15 in 90% yield
(Scheme 5). Direct oxidation of the TBS ether to the carboxylic
acid in the presence of the benzyl ether using Jones reagent fol-
lowed by treatment with TMSCHN2 resulted in the ester 16 in
79% yield. Addition of MeLi to the ester 16 gave the tertiary alco-
hol 9 in 91% yield.
During the demethylation of 9 using PhSH or MeMgI at high
temperature, an undesired complex mixture of products was
formed. When the tertiary alcohol 9 was treated with BBr3, we were
pleased to observe the formation of hexahydrocannabinol 4 after
the demethylation, debenzylation and cyclization although in poor
yield along with an unidentified mixture of products. The reason
for the formation of complex mixture of products during the de-
methylation of 9 could possibly be the presence of free tertiary
alcohol group in 9 that could generate multiple dehydrat-
ed/rearranged products during the reaction. To test this hypothe-
sis, the tertiary alcohol in 9 was selectively converted into a termi-
nal alkene using SOCl2 in pyridine and the crude product was treat-
ed with BBr3 in CH2Cl2 that resulted in hexahydrocannabinol 4 in
62% yield for the two steps (Scheme 6). The NMR spectroscopic
t
Polarimeter 341 at 589 nm, and were reported as [α]D (c in g per
22
data and optical rotation {[ɑ]D = –90 (c 0.2, EtOH)} of 9β-11-
100 mL, solvent). Melting points (m.p.) for solid compounds were
recorded using Labindia MR-VIS instrument in open glass
capillaries. Racemic product (racemic-13) was synthesized by using
DL-proline. α,β,γ,δ-unsaturated aldehyde 721 and dimethyl olivetol
1116a were prepared according to the reported procedures.
hydroxyhexahydrocannabinol 4 are in good agreement with that of
reported in the literature { lit.18 [ɑ]D = –87.5 (EtOH)}. The relative
stereochemistry of 4 was further assigned based on the COSY and
NOE experiments (see the Supporting Information).
Scheme 6. Synthesis of Hexahydrocannabinol 4
2-(2,6-dimethoxy-4-pentylphenyl)ethanol (12). To a solution of
dimethyl olivetol 11 (3.00 g, 14.4 mmol, 1 equiv) and LiCl (6.11 g,
144 mmol, 10 equiv) in dry THF (100 mL) at 0 °C was added 1.6
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M solution of n-BuLi (13.5 mL, 21.6 mmol, 1.5 equiv) dropwise.
Page 4 of 7
9.34 (s, 1H), 6.56–6.55 (m, 1H), 6.43 (dd, J = 10.0, 2.0 Hz, 1H),
6.39 (s, 2H), 6.05 (dd, J = 10.0, 1.5 Hz, 1H), 4.31 (dd, J = 15.5, 2.5
Hz, 1H), 3.76 (s, 6H), 3.52–3.44 (m, 2H), 2.97–2.90 (m, 1H), 2.59
(t, J = 8.0 Hz, 2H), 1.67–1.61 (m, 2H), 1.39–1.32 (m, 4H), 0.92 (t,
J = 7.0 Hz, 3H), 0.84 (s, 9H), –0.04 (s, 3H), –0.05 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 191.2, 158.2, 155.1, 143.7,
135.4, 131.7, 117.6, 116.0, 104.2, 65.1, 55.5, 42.0, 36.6, 33.5, 31.6,
31.1, 25.9, 22.6, 18.3, 14.0, –5.5, –5.5; IR (neat) ν 2955, 2930,
2856, 1684, 1609, 1583, 1459, 1419, 1235, 1197, 1161, 1117, 838,
777 cm−1; HRMS (ESI) m/z calculated for C27H43O4Si+ [M + H]+
459.2925, found 459.2955.
1
2
3
4
5
6
7
8
After stirring at room temperature for 0.5 h, the reaction mixture
was cooled to −78 °C. 2.5 M solution of ethylene oxide in THF (23
mL, 57.6 mmol, 4 equiv) covered with dry ice in syringe was
cautiously dropped to the solution. The resulting mixture was
stirred at −78 °C for 0.5 h and thereafter reaction allowed to warm
at room temperature and stirred 6 h. 2 N HCl (50 mL) was added
at 0 °C and the heterogeneous mixture was stirred for 0.5 h. The
aqueous layer was extracted with EtOAc (3 x 150 mL) and the
combined organic layers were dried over Na2SO4, and concentrated
under reduced pressure to afford the crude product which further
purified by flash column chromatography (SiO2, hexane/EtOAc =
8:2), affording white solid alcohol 12 (2.85 g, 78% yield). M. P.:
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
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59
60
((1R,6R)-6-(((tert-butyldimethylsilyl)oxy)
dimethoxy-4'-pentyl-1,6-dihydro-[1,1'-biphenyl]-3-yl)methanol (13).
To a solution of 8 (0.100 g, 0.218 mmol, 0.2 equiv) in methanol (2
methyl)-2',6'-
o
1
73–80 C; H NMR (500 MHz, CDCl3) δ 6.39 (s, 2H), 3.81 (s,
6H), 3.75 (t, J = 6.5 Hz, 2H), 2.94 (t, J = 6.5 Hz, 2H), 2.57 (t, J =
8.0 Hz, 2H), 1.94 (s, 1H), 1.65–1.59 (m, 2H), 1.39–1.31 (m, 4H),
0.91 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
158.3, 142.9, 112.5, 104.1, 63.1, 55.7, 36.6, 31.6, 31.2, 26.4, 22.6,
14.0; IR (neat) ν 3316, 2952, 2869, 1607, 1587, 1452, 1419, 1244,
1190, 1132, 1042, 1016, 815 cm−1; HRMS (ESI) m/z calculated for
o
mL) at 0 C was added NaBH4 (33 mg, 0.872 mmol, 4 equiv) in
small portions and stirred at same temperature for 30 minutes.
Then the reaction mass was quenched with ice-cold water (20 mL)
and extracted with CH2Cl2 (3 x 20 mL), and organic layer was
washed with brine (60 mL), dried over Na2SO4, concentrated
under reduced pressure to afford the crude product which further
purified by flash column chromatography (SiO2, hexane/EtOAc =
8:2), affording liquid 13 as a single diastereomer (0.077 g, 77%
yield). HPLC analysis DAICEL CHIRALPAK OD-H, 4.6 mm ×
250 mm (hex/IPA = 98:2, 0.5 mL/min, 254 nm), tR (major) = 25.2
+
C15H25O3 [M + H]+ 253.1798, found 253.1769.
2-(2,6-dimethoxy-4-pentylphenyl) acetaldehyde (6). To a solution
of oxalyl chloride (1.4 mL, 15.85 mmol, 2 equiv) in dry CH2Cl2 (30
mL) at −78 °C was added DMSO (1.7 mL, 23.79 mmol, 3 equiv)
dropwise. The reaction medium was stirred for 30 min, followed by
the dropwise addition of a solution of alcohol 12 (2.00 g, 7.93
mmol, 1 equiv) in CH2Cl2 (20 mL). After 60 min, Et3N (11 mL,
79.3 mmol, 10 equiv) was added dropwise, and the resulting slurry
was warmed to 0 °C and stirred for 1.5 h. The reaction was then
diluted with Et2O (50 mL) and saturated aqueous solution of
NH4Cl (50 mL). The layers were separated, and the aqueous layer
was extracted with Et2O (3 x 50 mL). The combined organic layers
were washed with H2O (3 x 100 mL) and brine (100 mL), dried
over Na2SO4, and concentrated under reduced pressure to afford
the crude product which further purified by flash column
chromatography (SiO2, hexane/EtOAc = 9:1), affording liquid
aldehyde 6 (1.75 g, 88% yield). 1H NMR (500 MHz, CDCl3) δ 9.58
(t, J = 2.5 Hz, 1H), 6.42 (s, 2H), 3.80 (s, 6H), 3.64 (d, J = 2.0 Hz,
2H), 2.60 (t, J = 8.0 Hz, 2H), 1.67–1.61 (m, 2H), 1.40–1.34 (m,
4H), 0.92 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
201.2, 158.4, 144.2, 106.8, 103.9, 55.7, 38.1, 36.7, 31.6, 31.2, 22.6,
14.0; IR (neat) ν 2930, 2857, 1724, 1609, 1588, 1456, 1419, 1242,
1200, 1125, 1039, 822 cm−1; HRMS (ESI) m/z calculated for
22
min, tR (minor) = 22.2 min, 97% ee; [α]D = –104.6 (c = 0.6,
1
CHCl3); H NMR (500 MHz, CDCl3) δ 6.36 (s, 2H), 6.01 (d, J =
1.0 Hz, 2H), 5.51–5.50 (m, 1H), 4.09–4.05 (m, 3H), 3.75 (s, 6H),
3.44 (s, 1H), 3.42 (d, J = 1.5 Hz, 1H), 3.00–2.92 (m, 1H), 2.57 (t, J
= 8.0 Hz, 2H), 1.66–1.60 (m, 2H), 1.42–1.24 (m, 4H), 0.91 (t, J =
13
7.0 Hz, 3H), 0.83 (s, 9H), –0.06 (s, 3H), –0.07 (s, 3H); C{1H}
NMR (125 MHz, CDCl3) δ 158.4, 142.8, 132.4, 130.7, 128.7,
123.5, 117.6, 104.4, 65.8, 65.5, 55.6, 41.2, 36.5, 32.3, 31.6, 31.1,
25.9, 22.6, 18.3, 14.1, –5.4, –5.5; IR (neat) ν 3371, 2929, 2856,
1608, 1581, 1458, 1419, 1252, 1233, 1116, 1057, 836, 776 cm−1;
HRMS (ESI) m/z calculated for C27H45O4Si+ [M + H]+ 461.3082,
found 461.3097.
((1R,3R,4R)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(2,6-
dimethoxy-4-pentylphenyl)cyclohexyl)methanol (10). To a solution
of 8 (1.00 g, 2.18 mmol, 1 equiv) in ethyl acetate (100 ml), 10%
Pd/C (464 mg, 0.436 mmol, 0.2 equiv) was added. The reaction
mixture was purged with H2 gas for 5 minutes and then H2
atmosphere was maintained with a H2 balloon. The reaction was
stirred at room temperature for 6 h. After completion of the
+
C15H23O3 [M + H]+ 251.1642, found 251.1632.
1
reaction (monitored by H NMR), Pd/C was removed by celite
(1R,6R)-6-(((tert-butyldimethylsilyl)oxy) methyl)-2',6'-dimethoxy-
bed filtration and washed with ethyl acetate (100 mL), the solvent
was evaporated off under reduced pressure to afford the crude
aldehyde product (1:1.8, equatorial /axial) which subjected to next
step for isomerization.
4'-pentyl-1,6-dihydro-[1,1'-biphenyl]-3-carbaldehyde (8). To
a
solution of D-proline (102 mg, 0.884 mmol, 0.2 equiv) in dry
acetonitrile (4.5 mL, 1M), α,β,γ,δ-unsaturated aldehyde 7 (1.00 g,
4.42 mmol, 1 equiv) and dimethyl olivetol acetaldehyde 6 (1.66 g,
To a solution of above the crude product in dry MeOH (50 mL),
DBU (332 mg, 2.18 mmol, 1.0 equiv) was added at room
temperature and stirred under argon atmosphere for 24 h. After
that the reaction was cooled to 0 oC, NaBH4 (330 mg, 8.72 mmol, 4
equiv) was added in small portions and stirred for 0.5 h at same
temperature. After completion of the reaction (monitored by
TLC), reaction mass was quenched with ice-cold water (50 mL)
and extracted with CH2Cl2 (3 x 50 mL), and organic layer was
washed with brine (100 mL), dried over Na2SO4, concentrated
under reduced pressure to afford the crude product which further
purified by flash column chromatography (SiO2, hexane/EtOAc =
8:2), affording liquid 10 (0.610 g, 60% yield for 2 steps, 5:1 dr).
o
6.63 mmol, 1.5 equiv) were added at 0 C and stirred under argon
atmosphere for 28 h. After completion of the reaction (monitored
1
by H NMR), the crude reaction mass was quenched with ice-cold
water (50 mL) and extracted with EtOAc (3 x 50 mL), and organic
layer was washed with brine (100 mL), dried over Na2SO4,
concentrated under reduced pressure to afford the crude product
which further purified by flash column chromatography (SiO2,
hexane/EtOAc = 8:2), affording liquid as a single diastereomer 8
(1.46 g, 72% yield). HPLC analysis enantiomeric excess was
determined after converting to their corresponding alcohol 13;
23
1
[α]D = –97.5 (c = 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ
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26
1
o
[α]D = –25.2 (c = 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ
6.33 (s, 1H), 6.32 (s, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 3.46 (d, J =
6.0 Hz, 2H), 3.31 (dd, J = 10.0, 3.5 Hz, 1H), 3.13 (dd, J = 10.0, 8.5
Hz, 1H), 3.07–3.02 (m, 1H), 2.54 (t, J = 8.0 Hz, 2H), 2.33–2.25
(m, 1H), 2.11–2.07 (m, 1H), 1.87–1.85 (m, 1H), 1.75–1.68 (m,
1H), 1.66–1.57 (m, 3H), 1.37–1.21 (m, 6H), 1.20–1.02 (m, 2H),
0.90 (t, J = 7.0 Hz, 3H), 0.81 (s, 9H), –0.11 (s, 3H), –0.13 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 159.1, 158.0, 141.9, 118.0,
104.6, 104.3, 68.9, 66.9, 56.0, 55.1, 41.5, 41.3, 36.4, 35.7, 33.4, 31.6,
31.0, 30.1, 29.1, 26.0, 22.6, 18.3, 14.0, –5.5, –5.5; IR (neat) ν 3370,
2928, 2855, 1607, 1579, 1457, 1420, 1251, 1235, 1193, 1110, 834,
774, 665 cm−1; HRMS (ESI) m/z calculated for C27H49O4Si+ [M +
H]+ 465.3395, found 465.3415.
0.6 M in hexane) was added at 0 C and allowed to stir at room
1
2
3
4
5
6
7
8
temperature for 12 h. After completion of the reaction (monitored
by TLC), the solvent was removed under reduce pressure to afford
the crude product which further purified by flash column
chromatography (SiO2, hexane/EtOAc = 8:2), affording liquid 16
25
(0.334 g, 79% yield for 2 steps). [α]D = –19.6 (c = 1.0, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.36–7.25 (m, 5H), 6.32 (s, 2H),
4.50 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 3.79 (s, 3H),
3.78 (s, 3H), 3.55–3.50 (m, 1H), 3.36 (s, 3H), 3.30 (d, J = 6.5 Hz,
2H), 3.26 (dd, J = 12.0, 3.5 Hz, 1H), 2.52 (t, J = 8.0 Hz, 2H), 2.04–
1.99 (m, 1H), 1.97–1.94 (m, 1H), 1.92–1.83 (m, 1H), 1.74–1.65
(m, 2H), 1.63–1.57 (m, 2H), 1.38–1.23 (m, 5H), 1.13–1.05 (m,
1H), 0.90 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
176.4, 159.3, 157.8, 142.3, 138.8, 128.3, 127.6, 127.4, 117.3, 105.0,
104.7, 76.0, 73.1, 56.3, 55.5, 50.9, 46.2, 38.3, 36.4, 36.1, 33.2, 31.6,
31.0, 29.8, 29.1, 22.6, 14.1; IR (neat) ν 2928, 2856, 1733, 1608,
1580, 1453, 1420, 1365, 1237, 1196, 1145, 1128, 737, 698 cm−1;
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(((1R,2R,4R)-4-((benzyloxy)methyl)-2-(2,6-dimethoxy-4-
pentylphenyl)cyclohexyl)methoxy)(tert-butyl)dimethylsilane (15). To
a solution of 10 (0.500 g, 1.08 mmol, 1 equiv) in dry THF (30 mL)
at 0 °C was added 60% NaH (86.4 mg, 2.16 mmol, 2 equiv). The
reaction medium was stirred for 30 min at room temperature,
followed by the dropwise addition of benzyl bromide (0.154 mL,
1.30 mmol, 1.2 equiv) and TBAI (80 mg, 0.216 mmol, 0.2 equiv),
and the resulting slurry was stirred for 48 h at room temperature.
After completion of the reaction (monitored by TLC), the reaction
was cooled to 0 °C and quenched with saturated aqueous solution
of NH4Cl (50 mL). The aqueous layer was extracted with EtOAc
(3 × 50 mL). The combined organic layers were washed with H2O
(100 mL), and dried over Na2SO4, and concentrated under
reduced pressure to afford the crude product which further purified
by flash column chromatography (SiO2, hexane/EtOAc = 9:1),
HRMS (ESI) m/z calculated for C29H41O5 [M + H]+ 469.2949,
+
found 469.2983.
2-((1R,2R,4R)-4-((benzyloxy)methyl)-2-(2,6-dimethoxy-4-
pentylphenyl)cyclohexyl)propan-2-ol (9). To a solution of 16 (0.300
g, 0.64 mmol, 1 equiv) in dry THF (30 mL), MeLi (1.2 mL, 1.92
mmol, 3 equiv, 1.6 M in diethyl ether) was added at -78 C and
stirred under argon atmosphere for 1 h and allowed to warm up to
0 C and stirred 2 h. After completion of the reaction (monitored
by TLC), the reaction mass was quenched with saturated NH4Cl
solution (20 mL) and extracted with EtOAc (3 x 30 mL), and
organic layer was washed with brine (100 mL), dried over Na2SO4,
concentrated under reduced pressure to afford the crude product
which further purified by flash column chromatography (SiO2,
hexane/EtOAc = 8:2), affording liquid 9 (0.273 g, 91% yield).
o
o
23
affording liquid 15 (0.537 g, 90% yield). [α]D = –23.2 (c = 0.5,
CHCl3); H NMR (500 MHz, CDCl3) δ 7.36–7.24 (m, 5H), 6.32
1
(s, 1H), 6.31 (s, 1H), 4.50 (d, J = 12.0 Hz, 1H), 4.46 (d, J = 12.0
Hz, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 3.33–3.27 (m, 3H), 3.12 (dd, J
= 10.0, 8.5 Hz, 1H), 3.06–3.01 (m, 1H), 2.54 (t, J = 8.0 Hz, 2H),
2.35–2.23 (m, 1H), 2.09–2.06 (m, 1H), 1.92–1.90 (m, 1H), 1.79–
1.68 (m, 2H), 1.65–1.58 (m, 2H), 1.39–1.23 (m, 6H), 1.15–1.02
(m, 2H), 0.90 (t, J = 7.0 Hz, 3H), 0.81 (s, 9H), –0.11 (s, 3H), –
0.13 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 159.1, 158.0,
141.7, 139.0, 128.3, 127.5, 127.3, 118.2, 104.6, 104.3, 76.5, 73.0,
67.0, 56.0, 55.1, 41.5, 38.9, 36.4, 35.7, 33.9, 31.6, 31.0, 30.2, 29.8,
26.0, 22.6, 18.3, 14.1, –5.5, –5.5; IR (neat) ν 2927, 2855, 1608,
1580, 1455, 1420, 1236, 1145, 1112, 1028, 836, 775, 698 cm−1;
HRMS (ESI) m/z calculated for C34H55O4Si+ [M + H]+ 555.3864,
found 555.3860.
(1R,2R,4R)-methyl 4-((benzyloxy)methyl)-2-(2,6-dimethoxy-4-
pentylphenyl)cyclohexanecarboxylate (16). To a solution of 15
(0.500 g, 0.90 mmol, 1 equiv) in dry acetone (100 mL), Jones
reagent (1.33 mL, 1.8 mmol, 2 equiv, 1.35 M, prepared by
dissolving chromium trioxide (6.68 g, 0.067 mol) in concentrated
sulphuric acid (5.75 mL, 0.108 mol) and the cooled (0 oC) solution
was further diluted with water up to 50 mL) was added at 0 oC and
stirred under argon atmosphere for 1 h and then allowed to stir at
room temperature for 1 h. After completion of the reaction
(monitored by TLC), solvent was removed under reduce pressure
to afford a watery residue. The residue was diluted with water (50
mL) and extracted with ethyl acetate (3 x 50 mL), and the organic
layer was washed with brine (100 mL) and dried over Na2SO4,
concentrated under reduced pressure to afford the crude product
which forwarded next step without further purification.
25
1
[α]D = –8.3 (c = 0.8, CHCl3); H NMR (500 MHz, CDCl3) δ
7.35–7.25 (m, 5H), 6.36 (s, 1H), 6.34 (s, 1H), 4.50 (d, J = 12.0 Hz,
1H), 4.46 (d, J = 12.0 Hz, 1H), 3.80 (s, 6H), 3.30–3.25 (m, 2H),
3.24–3.19 (m, 1H), 2.53 (t, J = 8.0 Hz, 2H), 2.38–2.33 (m, 1H),
1.98–1.95 (m, 1H), 1.93–1.90 (m, 1H), 1.79–1.69 (m, 3H), 1.62–
1.58 (m, 3H), 1.39–1.26 (m, 4H), 1.17–1.07 (m, 2H), 1.04 (s,
3H), 1.03 (s, 3H), 0.90 (t, J = 7.0 Hz, 3H); C{1H} NMR (125
13
MHz, CDCl3) δ 159.4, 156.4, 142.8, 138.9, 128.3, 127.6, 127.4,
119.5, 105.3, 104.6, 76.2, 74.3, 73.1, 55.8, 55.3, 49.0, 38.7, 36.4,
35.2, 35.1, 31.6, 31.0, 30.2, 28.9, 28.9, 25.7, 22.5, 14.0; IR (neat) ν
3561, 2929, 2856, 1607, 1578, 1454, 1421, 1366, 1236, 1196, 1147,
1113, 736, 698 cm−1; HRMS (ESI) m/z calculated for C30H45O4
+
[M + H]+ 469.3312, found 469.3306.
(6aR,9R,10aR)-9-(hydroxymethyl)-6,6-dimethyl-3-pentyl-
6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-ol (4). To
solution of 9 (0.100 g, 0.21 mmol, 1 equiv) in dry pyridine (10
mL), SOCl2 (0.046 mL, 0.63 mmol, 3 equiv) was added at -10 C
and stirred under argon atmosphere for 0.5 h at same temperature.
After completion of the reaction (monitored by TLC), the reaction
mass was quenched with ice-cold water (30 mL) and extracted with
CH2Cl2 (3 × 30 mL), and dried over Na2SO4, and concentrated
under reduced pressure to afford the crude product which
subjected for next step without further purification.
To a solution of above the crude product in dry CH2Cl2 (10
mL), BBr3 (6.4 mL, 3.2 mmol, 5 equiv, 0.5 M in CH2Cl2) was
added at -78 C and stirred under argon atmosphere for 1 h and
a
o
o
allowed to warm up to room temperature and stirred 24 h. After
completion of the reaction (monitored by TLC), the reaction mass
was cooled to 0 °C, and quenched with ice-cold water (30 mL) and
To a solution of above the crude product in dry benzene and
methanol (50 mL, 1:1), TMSCHN2 (3.9 mL, 2.34 mmol, 2.6 equiv,
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(5) Williamson, E. M.; Evans, F. J. Cannabinoids in Clinical Practice.
Drugs 2000, 60, 1303–1314.
stirred at room temperature for 0.5 h. After that the aqueous layer
was extracted with CH2Cl2 (3 x 30 mL), and dried over Na2SO4,
and concentrated under reduced pressure to afford the crude
product which further purified by flash column chromatography
(SiO2, hexane/EtOAc = 5:5), affording pale yellow liquid 4 (0.043
1
2
3
4
5
6
7
8
(6) (a) Xiong, W.; Cui, T.; Cheng, K.; Yang, F.; Chen, S.-R.; Willen-
bring, D.; Guan, Y.; Pan, H.-L.; Ren, K.; Xu, Y.; Zhang, Li. Cannabinoids
Suppress Inflammatory and Neuropathic Pain by Targeting ɑ3 Glycine
Receptors. J. Exp. Med. 2012, 209, 1121–1134. (b) Lynch, M. E.; Camp-
bell, F. Cannabinoids for Treatment of Chronic Non-Cancer Pain; a Sys-
tematic Review of Randomized Trials. Br. J. Clin. Pharmacol. 2011, 72,
735–744.
(7) Sarfaraz, S.; Adhami, V. M.; Syed, D. N.; Afaq, F.; Mukhtar, H. Can-
nabinoids for Cancer Treatment: Progress and Promise. Cancer Res. 2008,
68, 339–342.
(8) (a) Ware, M.A.; Daeninck, P.; Maida, V. A Review of Nabilone in
the Treatment of Chemotherapy-Induced Nausea and Vomiting. Ther.
Clin. Risk Manag. 2008, 4, 99–107. (b) Tramèr, M. R.; Carroll, D.; Camp-
bell, F. A.; Reynolds, D. J. M.; Moore, R. A.; McQuay, H. J. Cannabinoids
for Control of Chemotherapy Induced Nausea and Vomiting: Quantitative
Systematic Review. Br. Med. J. 2001, 323, 16–21.
22
g, 62% yield for 2 steps). [α]D = –90 (c = 0.2, EtOH), lit.18 [α]D –
87.5 (EtOH); 1H NMR (500 MHz, CDCl3) δ 6.25 (s, 1H), 6.07 (s,
1H), 4.81 (s, 1H), 3.55–3.48 (m, 2H), 3.19 (d, J = 13.5 Hz, 1H),
2.50–2.41 (m, 3H), 1.98–1.91 (m, 2H), 1.80–1.67 (m, 1H), 1.65–
1.46 (m, 3H), 1.37 (s, 3H), 1.34–1.26 (m, 4H), 1.19–1.11 (m,
2H), 1.08 (s, 3H), 0.94 (d, J = 6.0 Hz, 1H), 0.88 (t, J = 7.0 Hz, 3H),
0.85–0.77 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 155.0,
154.7, 142.7, 110.1, 109.9, 107.6, 76.8, 68.6, 49.4, 40.5, 35.4, 35.1,
33.2, 31.6, 30.6, 29.8, 27.7, 27.5, 22.5, 19.0, 14.0; IR (neat) ν 3561,
2929, 2856, 1607, 1578, 1454, 1421, 1366, 1236, 1196, 1147, 1113,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
736, 698 cm−1; HRMS (ESI) m/z calculated for C21H33O3 [M +
H]+ 333.2424, found 333.2425.
(9) Pertwee, R. G. Cannabinoids and Multiple Sclerosi Mol. Neurobiol.
2007, 36, 45–59.
(10) (a) Binder, M.; Franke, I.; Schmidt, B.; Dietrich, W. 79. I3C-NMR.
Spectra of Natural and Semi-Synthetic Cannabinoids. Helv. Chim. Acta
1982, 65, 807–811. (b) Fahrenholtz, K. E.; Lurie, M.; Kierstead, R. W.
ASSOCIATED CONTENT
Supporting Information
The Total Synthesis of dl-D9-Tetrahydrocannabinol and Four of Its
Isomers. J. Am. Chem. Soc. 1967, 89, 5934–5941. (c) Taylor, E. C.;
The Supporting Information is available free of charge on the ACS
Publications website.
Lenard, K.; Shvo, Y. Active Constituents of Hashish. Synthesis of dl-D6-
3,4-trans-Tetrahydrocannabinol. J. Am. Chem. Soc. 1966, 88, 367–369.
(d) Gaoni, Y.; Mechoulam, R. Isolation, Structure, and Partial Synthe-
sis of an Active Constituent of Hashish. J. Am. Chem. Soc. 1964, 86,
1646–1647.
Copies of 1H and 13C{1H} NMR spectra for all compounds and HPLC
chromatograms of compound 13 (PDF)
AUTHOR INFORMATION
Corresponding Author
(11) (a) Gonçalves, J.; Rosado, T.; Soares, S.; Simão, A.; Caramelo, D.;
Luís, Â.; Fernández, N.; Barroso, M.; Gallardo, E.; Duarte, A. Cannabis and
Its Secondary Metabolites: Their Use as Therapeutic Drugs, Toxicological
Aspects, and Analytical Determination. Medicines 2019, 6, 1–47. (b) Dinis-
Oliveira, R. J. Metabolomics of Δ9-Tetrahydrocannabinol: Implications in
Toxicity. Drug Metab. Rev. 2016, 48, 80–87. (c) Järbe, T. U. C.; Hiltunen,
A. J.; Lander, N.; Mechoulam, R. Cannabimimetic Activity (Δ1-THC Cue)
of Cannabidiol Monomethyl Ether and Two Stereoisomeric Hexahydro-
cannabinols in Rats and Pigeons. Pharmacol. Biochem. Behav. 1986, 25,
393–399. (d) Järbe, T. U. C.; McMillan, D. E. Δ9-THC as a Discriminative
Stimulus in Rats and Pigeons: Generalization to THC Metabolites and SP-
111. Psychopharmacology 1980, 71, 281–289. (e) Harvey, D. J.; Martin, B.
*E-mail: a.chandra@iitgn.ac.in
ORCID
Chandrakumar Appayee: 0000-0003-1165-4918
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors are grateful to the SERB, India for Core Research Grant
(CRG/2018/000575) and IIT Gandhinagar for financial support.
R.; Paton, W. D. Identification of Metabolites of D1- and D1(6)
-
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