Facile synthesis of (±)-parahigginone methyl ether and (±)-curcuphenol

Article abstract of DOI:10.1002/jccs.200400087

Using Grinard coupling as a key step, a facile synthetic approach to (±)-parahigginone methyl ether 1 and (±)-curcuphenol 2 has been achieved by five steps with 42.3% and 58.6% overall yield, respectively.

Full text of DOI:10.1002/jccs.200400087

Journal of the Chinese Chemical Society, 2004, 51, 571-574
571
Facile Synthesis of (±)-Parahigginone Methyl Ether and (±)-Curcuphenol
Zhen-Ting Du (
), An-Pai Li (
), Kun Peng (
),
Tong-Xing Wu (
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
) and Xin-Fu Pan* (
)
Using Grinard coupling as a key step, a facile synthetic approach to (±)-parahigginone methyl ether 1 and
(±)-curcuphenol 2 has been achieved by five steps with 42.3% and 58.6% overall yield, respectively.
Keywords: Synthesis; Parahigginone; Curcuphenol.
INTRODUCTION
A variety of phenolic sesquiterpenes of the bisabolane
phenol shows antifungal biological activities. (-)-Curcu-
phenol, a cytotoxic bisabolane sesquiterpene, was firstly dis-
covered in a metabolite of the gorgonian soft coral Pseudo-
pterogorgia rigida7 and possesses antibacterial activity
against Staphylococcus aureus.3 Due to their interesting bio-
logical activities, a number of synthetic approaches have
been reported.8 Ono described a methodology in synthesis of
a series of such sesquiterpenes by enantioselective hydrolysis
resolution of (±)-4-aryl-5-hydroxy-(2E)-pentenoate by im-
mobilized lipase.8b,8c,8d Based on the baker yeast’s enantio-
selective reduction ability on some special structures, Fuganti
constructed the key benzyl chiral carbon successfully.8h,8j Ho
and coworkers exploited an oxidative cleavage of bicyclic
benzocycloheptane derivatives pathway to synthesize (±)-
curcuphenol methyl ether;8e and very recently Sugahara and
coworkers synthesized (+)-curcuphenol by using a concur-
rent retro-Diels-Alder reaction and Claisen rearrangement.8f
(±)-Curcuphenol methyl ether was also used as a key inter-
mediate to synthesize (±)-a-Cedrene8k by Wender owing to
its characteristic structure.
family (Scheme I) have been isolated from many different
natural resources.1 They are the olfactorally active compo-
nents of a large number of essential oils and show a wide
range of biological activities. These compounds are attrac-
tive synthetic targets especially to verify the usefulness of
newly developed synthetic methodology.
(+)-Parahigginone was firstly separated as an aromatic
bisabolane sesquiterpene by Imai from the spice turmeric2 in
1990, and was detected again by Shen and coworkers from
the Taiwan marine sponges Parahigginsia ps in 1999, and it
shows modest antitumor activity.3 Sharma depicted a route to
parahigginone 1 in racemic form.4 Using the BINOL as the
chiral ligand, Tanaka reported a synthetic approach to (+)-
parahigginone.5
(+)-Curcuphenol bearing the same skeleton was iso-
lated from the marine organisms in both deep and shallow
water collection of the sponge Didiscus flavis.6 (+)-Curcu-
Scheme I
OMe
14
OH
OMe
3
OMe
7
Met
2
1
Grinard
8
oxidation
deprotection
4
9
+
5
coupling
O
O
OH
15
10
6
O
11
12
13
(±)-parahigginone
3-methyl
crotonaldehyde
OH
OMe
OMe
Br
Grinard
deprotection
+
Met
coupling
isoprenyl
bromide
(±)-curcuphenol

572 J. Chin. Chem. Soc., Vol. 51, No. 3, 2004
Du et al.
As an extension of our continuous effort to synthesize
these kinds of naturally occurring products,9 herein, we re-
port a facile synthesis of (±)-parahigginone methyl ether 1
and (±)-curcuphenol 2 through five chemical operations us-
ing cheap starting materials.
Compound 7 after hydroboration oxidization reaction
2-arylpropane-1-ol 6 can be furnished in 97% yield. This al-
cohol can be easily converted into bromide 5 through carbon
tetrabromide and triphenyl phospine in methylene chloride.
But when PBr3 was used as an alternative method, the rear-
ranged product 5a was found in nearly quantitative amounts.
The mechanism of rearrangement has been discussed by
Hauser.10
Our retro-synthetic plan is outlined in Scheme I. The
hydroxyl group should be protected firstly, and the two mole-
cules can be disconnected between C-9 and C-10. Leading by
this strategy, parahigginone can be divided into two parts:
3-methyl crotonaldehyde and a metalized alkyl bromide.
Curcuphenol methyl ether can be divided into prenyl bromide
and metalized alkyl bromide moiety.
With this key intermediate in hand, compound 5 was
treated with Mg powder to afford corresponding Grinard re-
agent. It should be noted that the addition of some methyl io-
dide is very helpful in preparing the Grinard reagent. 3-
Methyl-crotonaldehyde reacted with this Grinard reagent at
-20 °C to afford the intermediate 4 which included a pair of
diastereomers. Both were oxidized with MnO2 in carbon tet-
rachloride to afford parahigginone methyl ether 1 in 95%.
On the other hand, prenyl bromide can be coupled with
the Grinard reagent prepared from 5 in the presence of CuI in
THF at -20 °C to give curcuphenol methyl ether 3, which was
subjected to demethylation to afford (±)-curcuphenol 2 by
EtSNa at 130 °C.
RESULTS AND DISCUSSION
As shown in Scheme II, 2-methoxy-4-methyl aceto-
phenone 8 was used as starting material, which was treated
with methyl magnesium iodide to give a tertiary alcohol. This
alcohol was dehydrated in the presence of p-toluic acid in
benzene to give styrene derivative 7. It should be noted that
the dehydration reaction should be performed under an argon
atmosphere in low concentration, otherwise the dimer of sty-
rene would be produced whose mass spectrum displayed a
double M+ (324). The mechanism of polymerization was
studied in progress.
In summary, we have developed a novel route to con-
struct bisabolane skeleton with Grinard coupling as the key
step reaction. In our approach, the bisabolane sesquiterpenes
which have a C-9 oxidative state can be obtained easily.
Spectroscopic data of synthetic 1 and 2 agree with those re-
ported before.3,8d
Scheme II
OMe
OMe
OMe
EXPERIMENTAL SECTION
General Methods
a
c
b
O
OH
8
7
6
1
The H-NMR and 13C-NMR data were recorded in
OMe
OMe
OMe
CDCl3 solution with a Bruker AC 200 MHz or Virian BB 300
MHz spectrometer, if not noted otherwise. The chemical
shifts are referenced on TMS in ppm on the ‘d’ scale. Mass
spectra were recorded on a HP-5988 mass spectrometer (EI).
Standard flash chromatography was employed to purify the
crude reaction mixture using 200-300 mesh silica gel under a
positive nitrogen pressure.
e
d
f
OH
Br
O
5
4
1
OMe
OH
OMe
g
Br
5a
3
2
2-(2-Methoxy-4-methylphenyl)propene (7)
To a suspension of magnesium (1.0 g, 45.6 mmol) in ab-
solute ether (70 mL) was added methyl iodide (2.8 mL, 45.6
mmol) in ether (30 mL) dropwise over a half hour; then the
mixture was refluxed for 1 hour. Then the mixture was cooled
with an ice-salt bath and then 2-methoxy-4-methyl aceto-
phenone 8 (5 g, 30 mmol) in ether (20 mL) was added
Reagents and Conditions: (a) i, 1.5 eq MeMgI, -20 °C; ii,
p-TosOH, Benzene, reflux, 93%; (b) BH3qTHF, 0 °C, then
aqueous NaOH, 30% H2O2, reflux, 97%; (c) PPh3, CBr4,
CH2Cl2, 95%; (d) Mg powder, 3-methyl-crotonaldehyde, -20
°C, 52%; (e) MnO2, CCl4, reflux, 95%; (f) Mg powder, CuI,
then prenyl bromide, 76%; (g) EtSNa, DMF, 130 °C, 95%.

Synthesis of Two Bisabolane Sesquiterpenes
J. Chin. Chem. Soc., Vol. 51, No. 3, 2004 573
dropwise over 1 hour. The system was quenched with satu-
rated ammonium chloride and extracted with ether (3 ´ 100
mL). The combined organic layers were washed with brine
and dried over Na2SO4. After evaporation in vacuo the crude
product (tertiary alcohol) was obtained. This compound was
not purified further for the next reaction directly. The crude
product was dissolved in benzene (150 mL) and a catalytic
p-toluic acid was added and then equipped with a Dean-Stark
trap. This solution was refluxed for 3 hours, and then another
100 mL benzene was added to dilute the system. The mixture
was washed with saturated sodium hydrogen carbonate and
brine and then dried over Na2SO4. After evaporation, the resi-
due was purified through column chromatography to give 7
(4.5 g, 93%) as colorless oil. 1H-NMR: 2.15 (3H, s), 2.39 (3H,
s), 3.86 (3H, s), 5.09 (1H, br s), 5.16 (1H, br s), 6.74 (1H, s),
6.77 (1H, d, J = 8.0 Hz), 7.13 (1H, d, J = 8.0 Hz), MS (EI):
162 (M+, 42) 147 (86), 119 (100), 91 (37).
(21), 149 (100), 135 (44).
2-Bromo-1-(2-methoxy-4-methylphenyl)propane (5a)
To a solution of 2-(2-methoxy-4-methyl-phenyl)pro-
pyl-1-ol 6 (243 mg, 1 mmol) in anhydrous CH2Cl2 (5 mL),
PBr3 (91 mg, 0.33 mmol) in anhydrous CH2Cl2 (5 mL) was
added dropwise. After 5 minutes, CH2Cl2 (20 mL) was added
to the solution and the organic layer was washed by saturated
NaHCO3 and brine. After evaporation 5a was given quantita-
tively as colorless oil. 1H-NMR: 1.70 (3H, d, J = 6.6 Hz), 2.37
(3H, s), 3.08 (1H, dd, J = 7.2 Hz, J = 13.5 Hz), 3.22 (1H, dd, J
= 7.2 Hz, J = 13.5 Hz), 3.83 (3H, s), 4.42-4.49 (1H, m), 6.70
(1H, br s), 6.75 (1H, d, J = 7.8 Hz), 7.05 (1H, d, J = 7.8 Hz).
MS (EI): 242 (M+, 18), 163 (21), 149 (15), 135 (100), 105
(43).
2-Methyl-6-(2-methoxy-4-methylphenyl)-hept-2-ene-3-ol
(4)
2-(2-Methoxy-4-methylphenyl)propane-1-ol (6)
To a suspension of magnesium powder (70 mg, 2.9
mmol) in absolute ether, 0.05 mL methyl iodide was added to
start the reaction, and then bromide 5 (486 mg, 2 mmol) in
ether (10 mL) was introduced slowly. After addition the reac-
tion mixture was stirred for 3 hours at room temperature then
was cooled with an ice-salt bath to -20 °C. 3-Methyl-croton-
aldehyde (0.3 mL, 3.1 mmol) was added to the corresponding
Grinard reagent over 30 minutes. The ice-salt bath was re-
moved and the mixture was refluxed for 3 hours. Saturated
ammonium chloride was added through a syringe to quench
the reaction. The reaction mixture was extracted with ether (3
´ 20 mL) and then washed with brine and dried over Na2SO4.
After evaporation the residue was purified through column
chromatography to give 4 (258 mg, 52%) as colorless oil.
1H-NMR: 1.20 (3H, d, J = 7.2 Hz), 1.47 (3H, s), 1.51-1.59
(1H, m), 1.74 (3H, s), 1.75-1.83 (1H, m), 2.34 (3H, s),
3.30-3.35 (1H, m), 3.80 (3H, s), 3.98-4.05 (1H, m), 5.16 (1H,
d, J = 8 Hz), 6.70 (1H, s), 6.78 (1H, d, J = 7.5 Hz), 7.01 (1H, d,
J = 7.5 Hz). MS (EI): 248 (M+, 3), 230 (1), 215, (1), 187, (1),
163 (5), 149 (100), 153 (14), 105 (8). HRMS: Required
C16H24O2 248.1776, found 248.2010.
To a solution of styrene derivative 7 (3.0 g, 18.5 mmol)
in THF (15 mL) was added in borane THF (1 M, 19 mL)
dropwise at 0 °C. After 2 hours, 30% NaOH solution (12 mL)
and 30% H2O2 (12 mL) was added to the reaction system. The
mixture was refluxed for 2 hours and then saturated by the ad-
dition of solid sodium chloride. The reaction mixture was ex-
tracted with ethyl acetate and ether (v/v: 1:3, 3 ´ 100 mL).
The combined organic layers were washed with brine and
dried over Na2SO4. After evaporation, the residue was puri-
fied through column chromatography to give 6 (3.2 g, 97%)
as colorless oil. 1H-NMR: 1.26 (3H, d, J = 7.0 Hz), 1.64 (1H,
br s), 2.35 (3H, s), 3.35-3.45 (1H, m), 3.61-3.73 (2H, m), 3.90
(3H, s), 6.71 (1H, s), 6.77 (1H, d, J = 7.6 Hz), 7.08 (1H, d, J =
7.6 Hz). MS (EI): 180 (M+, 14), 149 (100), 134 (6), 119 (15).
1-Bromo-2-(2-methoxy-4-methylphenyl)propane (5)
To a solution of 2-(2-methoxy-4-methyl-phenyl)pro-
pyl-1-ol 6 (1.8 g, 10 mmol) in anhydrous methylene chloride
(15 mL) was added triphenyl phospine (3.14 g, 12 mmol) and
carbon tetrabromide (4.1 g, 12 mmol) portionwise at 0 °C.
The solution was stirred for 5 hours and methanol (2 mL) was
added to quench the reaction. An additional 100 mL of meth-
ylene chloride was introduced to above mixture and then
washed with sodium hydrogen carbonate and brine. After
evaporation, the residue was purified through column chro-
matography to give 5 (3.24 g, 95%) as colorless oil. 1H-NMR:
1.43 (3H, d, J = 7.2 Hz), 2.40 (3H, s), 3.47-3.65 (2H, m),
3.61-3.78 (1H, m), 3.88 (3H, s), 6.76 (1H, s), 6.86 (1H, d, J =
7.6 Hz), 7.11 (1H, d, J = 7.6 Hz). MS (EI): 242 (M+, 5), 163
(±)-Parahigginone methyl ether (1)
To a solution of 2-methyl-6-(2-methoxy-4-methyl-
phenyl)-hept-2-ene-3-ol 4 (100 mg, 0.4 mmol) in carbon tet-
rachloride (5 mL) was added activated manganese oxide (1
g). The reaction mixture was refluxed for 3 hours. Then the
manganese oxide was filtered; the filtrated was evaporated
and the residue was purified by column chromatography to
give parahigginone methyl ether 1 (92 mg, 95%) as colorless

574 J. Chin. Chem. Soc., Vol. 51, No. 3, 2004
Du et al.
oil. IR (film): 2925, 1625, 1560, 1067. 1H-NMR: 1.20 (3H, d,
J = 7.2 Hz), 2.12 (3H, s), 2.32 (3H, s), 2.36 (3H, s), 2.50-2.62
(1H, m), 2.67-2.78 (1H, m), 3.62-3.72 (1H, m), 3.81 (3H, s),
6.08 (1H, s), 6.68 (1H, s), 6.78 (1H, d, J = 7.5 Hz), 7.02 (1H,
d, J = 7.5 Hz). 13C-NMR: 20.11, 20.43, 20.65, 27.64, 29.04,
51.48, 55.25, 111.51, 121.07, 124.07, 126.68, 131.66,
136.80, 154.54, 156.68, 200.59. MS (EI): 246 (M+, 8), 231
(4), 163 (12), 149 (100) and 83 (81). HRMS: required
C16H23O2 147.1693, found 247.1689.
found 219.1743.
ACKNOWLEDGEMENTS
We are grateful to the National Science Foundation of
China (No. 20172023) for financial support.
Received August 4, 2003.
(±)-Curcuphenol methyl ether (3)
To a suspension of CuI (38 mg, 0.2 mmol) in THF (8
mL), the Grinard reagent prepared from 5 (486 mg, 2 mmol)
was added, and then prenyl bromide (300 mg, 2 mmol) in
THF (2 mL) was added dropwise at -20 °C. After 24 hours the
mixture was poured into 5 mL water and extracted with ether
(3 ´ 20 mL). The combined organic layers were washed with
brine and dried over Na2SO4. After evaporation, the residue
was purified through column chromatography to give 3 (353
mg, 76%) as colorless oil. 1H-NMR: 1.19 (3H, d, J = 7.0 Hz),
1.48-1.65 (2H, m), 1.55 (3H, s), 1.69 (3H, s), 1.88-2.07 (2H,
m), 2.35 (3H, s), 3.15 (1H, sex, J = 7.0 Hz), 3.82 (3H, s), 5.13
(1H, br s, J = 7.0 Hz), 6.69 (1H, s), 6.75 (1H, d, J = 7.8 Hz),
7.06 (1H, d, J = 7.8 Hz). 13C-NMR: 17.6, 21.1, 21.4, 25.7,
26.3, 31.4, 37.2, 55.3, 111.5, 121.1, 124.9, 126.6, 132.9,
136.2, 156.9. MS (EI): 232 (M+, 20), 217 (3), 189 (6), 175 (5),
162 (13), 149 (100). HRMS: required C16H25O 233.1906,
found 233.1990.
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(±)-Curcuphenol (2)
To DMF (3 mL) was added ethanethiol (147 mg, 2.36
mmol) and NaH in 60% mineral oil (94 mg, 2.36 mmol), after
hydrogen evolved ceased (about 30 minutes) then compound
3 (110 mg, 0.47 mmol) in DMF (1 mL) was added. The mix-
ture was warmed to 130 °C and stirred for 4 hours. The reac-
tion was quenched by saturated ammonium chloride and ex-
tracted with ether (3 ´ 20 mL); the combined organic layers
were washed with brine and dried over Na2SO4. After evapo-
ration the residue was purified through column chromatogra-
phy to give 1 (98 mg, 95%) as colorless oil. IR: 3537, 2965,
2935, 2866, 1664, 1617, 1421, 808. 1H-NMR: 1.22 (3H, d, J =
7.0 Hz), 1.54 (3H, s), 1.55-1.69 (2H, m), 1.68 (3H, s), 1.89-
1.97 (2H, m), 2.27 (3H, s), 2.96 (1H, sextet, J = 7.0 Hz), 4.67
(1H, s, OH), 5.13 (1H, br t, J = 7.0 Hz), 6.59 (1H, brs), 6.72
(1H, d, J = 8.0 Hz), 7.03 (1H, d, J = 8.0 Hz). 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 (M+, 4), 203 (3), 161
(8), 148 (33), 135 (100). HRMS: required C15H23O, 219.1751,
10. Hauser, C. R.; Skell, P. S.; Bright, K. D.; Refrow, W. B. J.
Am. Chem. Soc. 1947, 69, 591.