Syntheses of (±)-curcuphenol, (±)-curcudiol and (±)-curcuhydroquinone: A Johnson-Claisen rearrangement approach

Article abstract of DOI:10.1002/jccs.201000059

The synthesis of (±)-curcuphenol 1, (±)-curcudiol 2, (±)-curcuhydroquinone 3 and (±)-curcuquinone 4 had been achieved, in which the Johnson-Claisen rearrangement was used as key step.

Full text of DOI:10.1002/jccs.201000059

Journal of the Chinese Chemical Society, 2010, 57, 399-403
399
Syntheses of (±)-Curcuphenol, (±)-Curcudiol and (±)-Curcuhydroquinone:
A Johnson-Claisen Rearrangement Approach
Zhen-Ting Dua,* (
), Hong-Rui Yua (
), Yan Xua (
),
Qi-Liang Songa (
) and An-Pai Lib,* (
)
aNorthwest A&F University, College of Science, Yangling, Shaanxi, 712100, P. R. China
bSynthetics Technologica Pte Ltd., 3 Phillip Street, #18-00 Commerce Point, 048693, Singapore
The synthesis of (±)-curcuphenol 1, (±)-curcudiol 2, (±)-curcuhydroquinone 3 and (±)-curcuquinone
4 had been achieved, in which the Johnson-Claisen rearrangement was used as key step.
Keywords: (±)-Curcuphenol; (±)-Curcudiol; (±)-Curcuhydroquinone; (±)-Curcuquinone; Syn-
thesis.
INTRODUCTION
Sesquiterpenes are a big family naturally occurring
ness of newly developed synthetic methodology. Although
several report of the synthesis this kind of compounds can
be found in literature, the existent routes are either long or
inefficient.7
compounds which could be found in many kinds of plants
or microorganisms.1,4 The aromatic bisabolane sesquiter-
penes are a small branch of them which have the simplest
monocarbocyclic skeleton and have been popular synthetic
targets globally in last 30 years.2 Their parent hydrocar-
bons skeleton is shown in Figure 1, and many of them had
been recognized as odor component of many plant essen-
tial oils.3 (+)-Curcuphenol and (+)-curcudiol were firstly
isolated from the water collection of the sponge Didiscus
flavus. (+)-Curcuphenol was found to be an inhibitor of
gastric H, K-ATPase and to have antitumor and antifungal
activities.4 (-)-Curcuphenol, (-)-curcuhydroquinone and
(-)-curcuquinone were isolated from the Caribbean gor-
gonian Pseudopterogorgia rigida and showed antibacterial
activity against Staphylococcus aureus and the marine
pathogen Vibro anguillarum.5 Curcuhydroquinone and
curcuquinone have been used for synthesis of some heli-
annuols,6 one kind of allelochemicals isolated from sun-
flower Helianthus annuus leaves bearing significant bio-
logical activity. Because of their wide range of biological
activities, these compounds and their derivatives are attrac-
tive synthetic targets, and especially to verify the useful-
Johnson-Claisen rearrangement is a powerful tool in
synthesis of naturally occurring products in which a key in-
termediate of derivatives of -unsaturated pentanoic acid
was involved.8 As an extension of our continuous effort to
synthesize those kinds of naturally occurring products and
to evaluate their potential in agrochemicals,9 herein, we
wish to report the synthesis of (±)-curcuphenol 1, (±)-cur-
cudiol 2, (±)-curcuhydroquinone 3 and (±)-curcuquinone 4
through a Johnson-Claisen rearrangement approach.
RESULTS AND DISSCUSION
As shown in Scheme I, our synthesis commenced at
acetophenones 10a and 10b, carbinols 9a and 9b will be
given after a Grignard addition in 90 and 93% yield, re-
spectively. If anhydrous CeCl3 was not used, the yield is
low, relatively. The carbinols underwent a Johnson-Claisen
rearrangement in CH3C(OEt)3 and at the catalysis of pro-
panoic acid at 170 °C for 3 days, to give compound 8a and
8b in good yield as an E/Z mixtures in which the ratio of E
and Z isomer is in ca. 3:1. If the rearrangement was per-
formed in a microwave oven with irradiation, the reaction
duration can be reduced to 15-30 minutes without loss of
yields. With this key intermediate in hand, the double
bonds were reduced after catalytic hydrogen to furnish 7a
and 7b in excellent yields. Compounds 7a and 7b were sub-
jected to an excess MeMgI addition to afford the tertiary al-
cohol 6a and 6b. (±)-Curcudiol 2 was obtained after a
Fig. 1. Aromatic bisabolane sesquiterpenes skeleton.

400 J. Chin. Chem. Soc., Vol. 57, No. 3A, 2010
Du et al.
Scheme I
demethylation step of compound 6b using NaSEt in 96%
yield. The dehydrated products 5b and 5b were got in very
high yield at dehydration protocol at presence I2, respec-
tively. Compounds 5a and 5b can be converted to (±)-cur-
cuphenol 1, (±)-curcuhydroquinone 3 and using a NaSEt
demethylation protocol in 95 and 90% yields, respectively.
(±)-Cucuquinone 4 can be obtained through oxidation of
5b on the basis of the reference reported by Ono and co-
workers.7a The spectrums of target molecules are identical
to the ones in literature. It is obvious that our synthetic
route is terse and effective.
EXPERIMENTAL
General
The IR spectra were recorded on a Perkin-Elmer 2000
FTIR spectrometer. 1H and 13C NMR data were recorded in
CDCl3 with Bruker-400 or Virian 300 spectrometers if not
noted otherwise. The chemical shifts were reported in ppm
relative to TMS. Mass spectra were recorded on a HP-5988
mass spectrometer (EI). HRMS (ESI) were performed on a
Bruker FT-MS analyzer. Column chromatography were
generally performed on silica gel (200-300 mesh) eluting
with petroleum ether:EtOAc (100:1-10:1 v/v) and TLC in-
spections on silica gel GF254 plates with petroleum ether:
EtOAc (20:1-5:1 v/v) if not noted otherwise.
CONCLUSION
In summary, we have achieved an effective and facile
route to synthesis of (±)-curcuphenol 1, (±)-curcudiol 2,
(±)-curcuhydroquinone 3 and (±)-curcuquinone 4 in higher
yield using cheap starting materials. The Johnson-Claisen
rearrangement was used to build up the key intermediate is
our salient characteristic of our approach.
2-(2-Methoxy-4-methylphenyl)but-3-en-2-ol 9a: To
a solution of 2-methoxy-4-methylphenoacetone (6.4 g,
0.04 mol) in anhydrous THF (60 mL) was added anhydrous
CeCl3 (3.94 g, 0.016 mol) and then added magnesium vinyl
bromide (80 mL, 1 mol/L in THF) dropwise at -30 °C, and
the resulting mixture was stirred for 2 hours and warmed to

Synthesis of Sesquiterpenes
J. Chin. Chem. Soc., Vol. 57, No. 3A, 2010 401
room temperature. The saturated NH4Cl was introduced to
quench the reaction. The reaction mixture was extracted
with ethyl acetate (3 ´ 100 mL); the combined organic lay-
ers were washed with brine and dried with anhydrous
Na2SO4. The solvent was evaporated in vacuum and the
residue was purified through column chromatography to
give 9a (6.9 g, 90%) as a pale yellow oil. 1H-NMR: 1.66 (s,
3H), 2.35 (s, 3H), 3.87 (s, 3H), 4.42 (s, 1H), 5.04, (dd, 1H, J
= 10.8 Hz, J = 1.2 Hz), 5.14 (dd, 1H, J = 17.2 Hz, J = 1.2
Hz), 6.18 (dd, 1H, J = 17.6 Hz, J = 10.8 Hz), 6.751 (s, 1H),
6.77 (d, 1H, J = 8 Hz), 7.20 (d, 1H, J = 8 Hz). 13C-NMR:
22.3, 27.2, 55.4, 74.7, 111.3, 112.5, 121.4, 126.4, 130.8,
138.5, 145.0, 156.9. ESI-MS: M+Na = 175.2.
Ethyl 5-(4-methyl-2,5-dimethoxylphenyl)hexanoate
7b was obtained from 8b by above method similarly as a
pale yellow oil in 95% yield. 1H-NMR: 1.17 (d, 3H, J = 7.2
Hz), 1.25 (t, 3H, J = 7.2 Hz), 2.20 (s, 3H), 2.27-2.29 (m,
2H), 3.16-3.25 (m, 1H), 3.77 (s, 3H), 3.80 (s, 3H), 4.11 (q,
2H, J = 7.2 Hz), 6.67 (s, 1H), 6.70 (s, 1H). 13C-NMR: 14.2,
16.1, 21.1, 23.1, 31.6, 34.3, 36.7, 56.1, 56.3, 60.1, 109.6,
114.2, 124.3, 133.4, 150.7, 151.8, 173.8. ESI-MS: M+ =
294.
2-Methyl-6-(4-methyl-2-methoxylphenyl)-2-hepta-
nol 6a: To a suspension of power Mg (1.45 g, 60 mmol) in
50 mL of anhydrous diethyl ether was added slowly iodo-
methane (6.39 g, 45 mmol) in 50 mL of anhydrous diethyl
ether at reflux. After completion, the reaction mixture was
stirred at reflux for 1 h and was cooled to room tempera-
ture. A solution of compound 7a (2.25 g, 9 mmol) in anhy-
drous diethyl ether (30 mL) was added slowly to the above
reaction mixture at room temperature. The reaction was
refluxed for 1 h and quenched with saturated NH4Cl and
extracted with ethyl acetate (3 ´ 70 mL). The combined or-
ganic layer was washed with saturated NaHCO3 and brine,
dried with anhydrous MgSO4. The solvent was evaporated
in vacuum and the residue was purified through column
chromatography to give 6a (2.10 g, 93%) as colorless oil.
1H-NMR: 1.14 (s, 3H), 1.18 (s, 3H), 1.21 (d, J = 7.2 Hz,
3H), 1.30-1.65 (m, 6H), 2.33 (s, 3H), 3.18-3.25 (m, 1H),
3.84 (s, 3H), 6.71 (s, 1H), 6.78 (d, 1H, J = 7.8 Hz), 7.01 (d,
1H, J = 7.8 Hz). 13C-NMR: 21.0, 21.2, 22.3, 29.0, 29.1,
31.2, 37.6, 43.8, 55.2, 70.8, 111.4, 121.1, 126.4, 132.8,
136.1, 156.7. EIMS (m/z): 250, 235, 232, 217, 175, 162,
149, 119, 91.
2-(2,5-Dimethoxy-4-methylphenyl)but-3-en-2-ol
9b: 9b was obtained from 10b by method similar to 9a as a
yellowish oil in 93% yield. 1H-NMR: 1.68 (s, 3H), 2.22 (s,
3H), 3.80 (s, 3H), 3.83 (s, 3H), 4.44 (s, 1H), 5.07 (dd, 1H, J
= 10.8 Hz, J = 1.2 Hz), 5.16 (dd, 1H, J = 17.2 Hz, J = 1.2
Hz), 6.18 (dd, 1H, J = 17.2 Hz, J = 10.8 Hz), 6.75 (s, 1H),
6.84 (s, 1H). 13C-NMR: 16.0, 27.3, 56.0, 56.1, 74.7, 109.5,
111.5, 114.9, 126.2, 131.8, 144.9, 150.5, 151.6. ESI-MS:
M+H-H2O = 205.3.
Ethyl 5-(2-methoxy-4-methylphenyl)hexenoate 8a:
A mixture of 9a (7.69 g, 0.04 mol), triethyl orthoacetate
(32.7 g, 0.2 mol), propanoic acid (0.15 g, 2 mmol) was
warmed to 170 °C for 3 days. The reaction mixture was
separated through column chromatography directly to af-
ford crude 8a (mixtures of E and Z) as pale yellow oil
(80%). ESI-MS: M+H = 263.3.
Ehyl 5-(2,5-dimethoxy-4-methylphenyl)hexenoate
8b: 8b was obtained from 9b similarly in 84% yield. ESI-
MS: M+Na = 315.3.
2-Methyl-6-(4-methyl-2,5-dimethoxylphenyl)-2-
heptanol 6b was obtained from 7b by method similar to 6a
(89%) as colorless oil. 1H-NMR: 1.18 (s, 3H), 1.20 (s, 3H),
1.23 (d, J = 7.2 Hz, 3H), 1.30-1.65 (m, 6H), 2.34 (s, 3H),
3.18-3.26 (m, 1H), 3.83 (s, 3H), 3.87 (s, 3H), 6.65 (s, 1H),
6.74 (s, 1H). 13C-NMR: 16.0, 17.9, 21.1, 22.3, 29.0, 31.7,
37.4, 43.9, 56.1, 56.3, 70.9, 109.7, 114.3, 124.2, 134.0,
150.7, 151.8. EIMS (m/z): 280, 265, 262, 247, 205, 192,
179, 149, 119, 91.
Ethyl 5-(4-methyl-2-methoxylphenyl)hexanoate 7a:
To the solution of 8a (2.62 g, 10 mmol) in a mixture of ethyl
acetate (70 mL) and acetic acid (10 mL) was added 10%
Pd/C (200 mg). The atmosphere was excavated by H2 three
times, and the reaction mixture was stirred for 24 h at the at-
mosphere of 1.5 atm H2. The Pd/C was filtered and the fil-
trate was evaporated in vacuum and the residue was puri-
fied through column chromatography to give 7a (2.45 g,
1
98%) as a pale yellow oil. H-NMR: 1.19 (d, 3H, J = 7.2
2-Methyl-6-(4-methyl-2-methoxylphenyl)-2-hep-
tene 5a: To a solution of compound 6a (2.00 g, 8 mmol) in
benzene (100 mL) was added p-TosOH acid (100 mg) and
equipped a Dead-Stark trap. The reaction mixture was re-
fluxed for 6 h and then diluted with ethyl acetate (100 mL).
The organic layer was washed with saturated NaHCO3 and
brine, dried with anhydrous MgSO4. The solvent was evap-
Hz), 1.25 (t, 3H, J = 7.2 Hz), 1.53-1.61 (m, 4H), 2.26-2.29
(m, 2H), 2.33 (s, 3H), 3.14-3.18 (m, 1H), 3.80 (s, 1H), 4.11
(q, 2H, J = 7.2 Hz), 6.68 (s, 1H), 6.75 (d, 1H, J = 7.6 Hz),
7.03 (d, 1H, J = 7.6 Hz). 13C-NMR: 14.2, 21.0, 21.4, 23.1,
31.1, 34.4, 36.6, 55.3, 60.0, 111.4, 121.1, 126.4, 132.3,
136.4, 156.8, 174.8. ESI-MS: M+ = 264.

402 J. Chin. Chem. Soc., Vol. 57, No. 3A, 2010
Du et al.
orated in vacuum and the residue was purified through col-
umn chromatography to give 5a (1.76 g, 95%) as a color-
less oil. 1H-NMR: 1.19 (d, J = 7.0 Hz, 3H), 1.48-1.65 (m,
2H), 1.55 (s, 3H), 1.69 (s, 3H), 1.88-2.07 (m, 2H), 2.35 (s,
3H), 3.15 (sex, J = 7.0 Hz, 1H), 3.82 (s, 3H), 5.13 (t, J = 7.0
Hz, 1H), 6.69 (s, 1H), 6.75 (d, J = 7.8 Hz, 1H), 7.06 (d, J =
7.8 Hz, 1H). 13C-NMR: 17.6, 21.1, 21.4, 25.7, 26.3, 31.4,
37.2, 55.3, 111.5, 112.1, 124.9, 126.6, 128.7, 132.9, 136.2,
156.9. EIMS (m/z): 232, 217, 189, 175, 162, 149, 119, 91.
HRMS: required C16H24O 232.2996, found 232.2990.
2-Methyl-6-(4-methyl-2,5-dimethoxylphenyl)-2-
heptene 5b was obtained from 6b by method similar to 5a
(96%) as a colorless oil. 1H-NMR: 1.28 (d, J = 7.2 Hz, 3H),
1.56 (s, 3H), 1.57-1.59 (m, 2H), 1.75 (s, 3H), 1.96-2.04 (m,
2H), 2.33 (s, 3H), 3.21-3.26 (m, 1H), 3.87 (s, 3H), 3.88 (s,
3H), 5.22 (t, J = 6.9 Hz, 1H), 6.67 (s, 1H), 6.70 (s, 1H).
13C-NMR: 16.0, 17.5, 21.2, 25.6, 26.3, 31.8, 37.3, 56.0,
56.3, 111.6, 112.5, 122.0, 125.0, 126.7, 133.1, 136.8,
157.1. EIMS (m/z): 262, 247, 219, 192, 179, 149, 119, 91.
HRMS: required C17H27O2 262.2013, found 262.2009.
(±)-Curcuphenol 1: To DMF (3 mL) was added eth-
anethiol (147 mg, 2.36 mmol) and NaH in 60% mineral oil
(94 mg, 2.36 mmol), after hydrogen evolved ceased (about
30 minutes) and then compound 5a (110 mg, 0.47 mmol) in
DMF (1 mL) was added. The mixture was heated to 130 °C
and stirred for 4 h. The reaction was cooled to room tem-
perature, quenched by saturated ammonium chloride and
extracted with diethyl ether (3 ´ 20 mL). The combined or-
ganic layers were washed with brine and dried over Na2SO4.
After evaporation, the residue was purified through column
chromatography to give 1 (98 mg, 95%) as a colorless oil.
IR (neat): 3537, 2965, 2935, 2866, 1664, 1617, 1421, 808
extracted with diethyl ether (3 ´ 20 mL). The combined or-
ganic layers were washed with brine and dried over Na2SO4.
After evaporation, the residue was purified through column
chromatography to give 2 (82 mg, 96%) as a colorless oil.
IR (neat): 1070, 1420, 1254, 1619, 1711, 2859, 2924 cm-1.
1H-NMR: 1.18 (s, 3H), 1.20 (s, 3H), 1.30 (d, J = 7.8 Hz,
3H), 1.33-1.72 (m, 6H), 2.05 (br, 1H), 2.23 (s, 3H), 3.15-
3.18 (m, 1H), 5.02 (br, 1H), 6.61 (s, 1H), 6.78 (d, J = 7.8
Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H). 13C-NMR: 21.16, 22.23,
28.99, 29.61, 31.47, 37.96, 43.75, 71.93, 116.60, 121.40,
126.97, 131.07, 136.40, 153.70. MS (EI): 236, 218, 203, 161,
148, 135, 121, 91. HRMS: required C15H24O2, 236.1856,
found 236.1853.
(±)-Curcuhydroquinone 3: To a suspension Mg (1.45
g, 60 mmol) in 10 mL of anhydrous diethyl ether was added
slowly iodomethane (6.35 g, 45 mmol) in anhydrous di-
ethyl ether at room temperature. After completion, the re-
action mixture was refluxed for 1 h and then the mixture
was evaporated in vacuum. The neat compound 5b (393
mg, 1.5 mmol) was added to the above residue and heated
to 180 °C for 15 minutes, after cooled to room temperature
and 100 mL 1.0 M HCl was added to quench the reaction.
The mixture was extracted EtOAc (3 ´ 20 mL); the com-
bined organic layer was washed with brine and dried over
Na2SO4. After evaporation the residue was purified through
column chromatography to give 3 (316 mg, 90%) as a col-
orless oil. IR (neat): 3545, 2966, 2927, 1666, 1615, 1456,
1
1417, 1377, 1306, 1187, 1003, 875, 833 cm-1. H-NMR:
1.20 (d, J = 7.2 Hz, 3H), 1.53 (s, 3H), 1.50-1.63 (m, 2H),
1.68 (s, 3H), 1.92-1.95 (m, 2H), 2.17 (s, 3H), 2.94 (m, 1H),
4.65 (br, 1H), 5.15 (br, 1H), 6.56 (br, 1H), 6.71 (br, 1H),
7.02 (d, J = 7.9 Hz, 1H). 13C-NMR (CDCl3, 300 MHz):
15.4, 17.7, 21.1, 25.7, 26.0, 31.5, 37.4, 113.5, 118.0, 121.8,
124.6, 131.8, 132.1, 146.7, 147.8. MS (EI): 235 (M+ + 1),
234, 217, 191, 177, 164, 151, 137, 124, 107, 95, 77.
HRMS: required C15H22O2, 234.1700, found 234.1703.
1
cm-1. H-NMR: 1.22 (d, J = 7.0 Hz, 3H), 1.54 (s, 3H),
1.55-1.69 (m, 2H), 1.68 (s, 3H), 1.89-1.97 (m, 2H), 2.27 (s,
3H), 2.96 (sextet, J = 7.0 Hz, 1H), 4.67 (s, 1H), 5.13 (br,
1H), 6.59 (br, 1H), 6.72 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.0
Hz, 1H). 13C-NMR: 17.7, 20.8, 21.1, 25.7, 26.1, 31.4, 37.3,
116.2, 121.7, 124.6, 126.8, 130.0, 132.0, 136.5, 152.8. MS
(EI): 218, 203, 161, 148, 138, 119, 91, 77. HRMS: required
C15H22O, 218.1751, found 218.1743.
ACKNOWLEDGMENTS
Financial support from the Program for Excellent
Young Talents in Northwest A&F University (2111020712)
as well as the National Natural Science Foundation of
China (20802058) is greatly appreciated.
(±)-Curcudiol 2: To DMF (3 mL) was added ethane-
thiol (150 mg, 2.37 mmol) and NaH in 60% mineral oil (95
mg, 2.37 mmol), after hydrogen evolved ceased (about 30
minutes) and then compound 6a (89 mg, 0.36 mmol) in
DMF (1 mL) was added. The mixture was heated to 130 °C
and stirred for 4 h. The reaction was cooled to room tem-
perature, quenched by saturated ammonium chloride and
Received February 7, 2010.
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