Facile syntheses of (±)-curcuphenol-(±)-curcudiol-±)- curcuhydroquinone, and (±)-curcuquinone

Article abstract of DOI:10.1080/00397910903174382

The syntheses of (±)-curcuphenol 1, (±)-curcudiol 2, (±)-curcuhydroquinone 3, and (±)-curcuquinone 4 have been achieved. The key steps involved in the syntheses were the Reformatsky reaction and hydrogenation reaction. Copyright

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Facile Syntheses of (±)-Curcuphenol, (±)-
Curcudiol, (±)-Curcuhydroquinone, and
(±)-Curcuquinone
Zhenting Du a , Yong Li a , Yin Wang a , Lichun Ding a & Jinming Gao a
a College of Science, Northwest A&F University , Yangling, Shaanxi,
China
Published online: 08 Jun 2010.
To cite this article: Zhenting Du , Yong Li , Yin Wang , Lichun Ding & Jinming Gao (2010) Facile
Syntheses of (±)-Curcuphenol, (±)-Curcudiol, (±)-Curcuhydroquinone, and (±)-Curcuquinone, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:13, 1920-1926, DOI: 10.1080/00397910903174382
To link to this article: http://dx.doi.org/10.1080/00397910903174382
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Synthetic Communications1, 40: 1920–1926, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903174382
FACILE SYNTHESES OF (ꢀ)-CURCUPHENOL,
(ꢀ)-CURCUDIOL, (ꢀ)-CURCUHYDROQUINONE,
AND (ꢀ)-CURCUQUINONE
Zhenting Du, Yong Li, Yin Wang, Lichun Ding, and
Jinming Gao
College of Science, Northwest A&F University, Yangling,
Shaanxi, China
The syntheses of (ꢀ)-curcuphenol 1, (ꢀ)-curcudiol 2, (ꢀ)-curcuhydroquinone 3, and (ꢀ)-
curcuquinone 4 have been achieved. The key steps involved in the syntheses were the
Reformatsky reaction and hydrogenation reaction.
Keywords: Bisabolane sesquiterpene; (ꢀ)-curcudiol; (ꢀ)-curcuhydroquinone; (ꢀ)-curcuphenol; (ꢀ)-
curcuquinone; synthesis
INTRODUCTION
The bisabolane compounds are a small family of sesquiterpenes having the
simplest monocarbocyclic skeleton. (þ)-Curcuphenol 1 and (þ)-curcudiol 2 were
isolated from the water collection of the sponge Didiscus flavus.[1] (þ)-Curcuphenol
1 was found to be an inhibitor of gastric H, K-ATPase and to have antitumor and
antifungal activities.[1] (–)-Curcuphenol 1, (–)-curcuhydroquinone 3, and (–)-
curcuquinone 4 were isolated from the Caribbean gorgonian Pseudopterogorgia
rigida and showed antibacterial activity against Staphylococcus aureus and the
marine pathogen Vibro anguillarum.[2] Compounds 3 and 4 have been used for
synthesis of some heliannuols, allelochemicals isolated from sunflower leaves, that
bear significant biological activity.[3] Because of their wide range of biological
activities, these compounds and their derivatives are attractive synthetic targets,[4]
especially to verify the usefulness of newly developed synthetic methodology.
As an extension of our continuous effort to synthesize those kinds of naturally
occurring products,[5] herein we report facile syntheses of (ꢀ)-curcuphenol 1, (ꢀ)-
curcudiol 2, (ꢀ)-curcuquinone 3, and (ꢀ)-curcuhydroquinone 4 through four or five
chemical operations.
Received May 13, 2008.
Address correspondence to Zhenting Du, College of Science, Northwest A&F University,
Yangling, Shaanxi, China. E-mail: jamesduh@gmail.com
1920

SYNTHESIS OF BISABOLANE SESQUITERPENES
1921
RESULTS AND DISCUSSION
The well-known Reformatsky reaction[6] consists of the zinc-induced formation
of b-hydroxy esters by the reaction of a-halogenated esters with aldehydes or
ketones. The Reformatsky reaction has been considered as the most useful method
for the formation of CꢁC bonds and an important alternative to the base-induced
aldol reactions. Therefore, we first applied the Reformatsky reaction for the
synthesis of bisabolane sesquiterpenes. To this end, commercial starting materials
acetophenone derivatives 13=14 were employed as electrophiles, which underwent
the Reformatsky addition with methyl bromocrotonate in the presence of Zn dust[6d]
to provide the 13 carbons motifs 11=12, respectively, in moderate yields, as shown in
(Scheme 1). No attempt was made to separate the a-adduct.[7] The carbinols 11=12
were subjected to palladium=carbon-catalytic hydrogenation to furnish the desirable
reduced products 9=10 in almost quantitative yields in a single step.[8] The hydroxyl
group at the benzyl position and the double bond was reduced in one pot. Treatment
of the esters 9=10 with methyl magnesium iodide in anhydrous diethyl ether delivered
the corresponding tertiary alcohols 7=8.
(ꢀ)-Curcudiol 2 was obtained by the demethylation of the alcohol 7 with
ethanethiol in the presence of sodium hydride and dimethylformamide (DMF) at
130 ꢂC.[9] On the other hand, compound 7 was dehydrated to yield curcuphenol
Scheme 1. Reagents and conditions: (a) methyl 4-bromocortonate, Zn dust, THF, reflux; 65% for 11, 58%
for 12; (b) 10% Pd=C, HOAc=EtOAc, H2; 98% for 9, 95% for 10; (c) MeMgI, THF, 0 ꢂC; 93% for 7, 89%
for 8; (d) EtSH, NaH, DMF, 130 ꢂC; 95% for 1, 96% for 2, 95% for 3; (e) TosOH, PhH, reflux; 95% for 5,
96% for 6.

1922
Z. DU ET AL.
methyl ether 5, which was converted into (ꢀ)-curcuphenol 1 under the mentioned
demethylation conditions. The alcohol 8 was transformed into compound 6 by the
same dehydration, and subsequent demethylation of the key intermediate 6
furnished (ꢀ)-curcuhydroquinone 3. Finally, (ꢀ)-cucuquinone 4 can be prepared
by oxidation of compound 6 according to the literature method described by Ono
and coworkers.[4c] All synthesized compounds have been characterized by means
1
of H and 13C NMR, infrared (IR), and mass spectral (MS) data as well as by
comparison with those reported in the literature.
In summary, we report an effective and facile route to synthesis of (ꢀ)-
curcuphenol 1, (ꢀ)-curcudiol 2, (ꢀ)-curcuhydroquinone 3, and (ꢀ)-curcuquinone 4
in greater yield using cheap starting materials.
EXPERIMENTAL
General
The IR spectra were recorded on a Perkin-Elmer 2000 Fourier transform (FT)–
1
IR spectrometer. H and 13C NMR data were recorded in CDCl3 with Varian 300
spectrometers if not noted otherwise. The chemical shifts were reported in parts
per million (ppm) relative to tetramethylsilane (TMS). MS data were recorded on
a HP-5988 mass spectrometer (electron impact). High-resolution HRMS (electro-
spray ionization) were performed on a Bruker FT-MS analyzer. Column chromato-
graphy were generally performed on silica gel (200–300 mesh) eluting with petroleum
ether=EtOAc (100:1–10:1 v=v) and thin-layer chromatography (TLC) inspections on
silica-gel GF254 plates with petroleum ether=EtOAc (20:1–5:1 v=v) if not noted
otherwise.
Methyl 5-(4-Methyl-2-methoxylphenyl)-5-hydroxylhex-2-enoate 11
4-Methyl-2-methoxyacetophenone 13 (3.28 g, 20 mmol) and methyl 4-bromo-
crotonate (7.10 g, 40 mmol) in 50 mL of anhydrous benzene were added to a suspen-
sion of Zn (2.00 g, 30 mmol) in anhydrous benzene (20 mL) at reflux. The reaction was
initiated, and then the other portion of solution was added dropwise to the reaction
mixture. The mixture was stirred for 2 h. The reaction was quenched with 50 mL of
10% AcOH. The reaction mixture was extracted with ethyl acetate (3 ꢃ 100 mL);
the combined organic layers 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 11 (3.43 g, 65%) as a pale yellow oil. 1H NMR: 1.55
(s, 3H), 2.33 (s, 3H), 2.74 (dd, J ¼ 7.5 Hz, J ¼ 12.1 Hz, 1H), 2.84 (dd, J ¼ 7.5 Hz,
J ¼ 12.1 Hz, 1H), 3.67 (s, 3H), 3.87 (s, 3H), 4.15 (s, 1H), 5.80 (d, J ¼ 15.9 Hz, 1H),
6.73 (s, 1H), 6.75 (d, J ¼ 8.0 Hz, 1H), 6.85 (d, J ¼ 15.9 Hz, 1H), 7.00 (d, J ¼ 8.0 Hz,
1H). 13C NMR: 21.2, 27.3, 45.2, 51.3, 55.2, 74.2, 112.2, 121.5, 123.1, 126.3, 130.6,
138.5, 145.7, 156.5, 166.7. EIMS (m=z): 264, 249, 215, 187, 165, 147, 135, 119, 91.
Methyl 5-(4-Methyl-2,5-dimethoxylphenyl)-5-hydroxylhex-2-enoate
12. This compound was obtained from 14 by a method similar that used for 11.
1
Yield 58% as a pale yellow oil. H NMR: 1.55 (s, 3H), 2.33 (s, 3H), 2.74 (dd,
J ¼ 7.5 Hz, J ¼ 12.1 Hz, 1H), 2.84 (dd, J ¼ 7.5 Hz, J ¼ 12.1 Hz, 1H), 3.67 (s, 3H),

SYNTHESIS OF BISABOLANE SESQUITERPENES
1923
3.85 (s, 3H), 3.87 (s, 3H), 4.15 (s, 1H), 5.80 (d, J ¼ 15.9 Hz, 1H), 6.73 (s, 1H), 6.78 (s,
1H), 6.85 (d, J ¼ 15.9 Hz, 1H). 13C NMR: 15.99, 26.46, 45.23, 51.34, 55.83, 56.15,
65.70, 110.47, 114.51, 124.91, 126.37, 131.66, 141.58, 149.76, 150.66, 163.94. EIMS
(m=z): 294, 279, 245, 195, 187, 149, 91.
Methyl 5-(4-Methyl-2-methoxylphenyl)hexanoate 9. To the solution of
11 (2.64 g, 10 mmol) in a mixture of ethyl acetate (70 mL) and acetic acid (10 mL),
10% Pd=C (200 mg) was added. The atmosphere was excavated by H2 three times,
and the reaction mixture was stirred for 24 h at 2 atm H2. The Pd=C was filtered,
the filtrate was evaporated in vacuum, and the residue was purified through column
1
chromatography to give 9 (2.45 g, 98%) as a pale yellow oil. H NMR: 1.55 (d,
J ¼ 7.2 Hz 3H), 1.13 (d, J ¼ 7.2 Hz, 3H), 1.50–1.62 (m, 4H), 2.26–2.94 (m, 2H),
2.33 (s, 3H), 3.15–3.18 (m, 1H), 3.67 (s, 3H), 3.87 (s, 3H), 6.68 (s, 1H), 6.73 (d,
J ¼ 8.0 Hz, 1H), 7.02 (d, J ¼ 8.0 Hz, 1H). 13C NMR: 20.98, 21.38, 23.09, 31.18,
34.15, 36.61, 51.37, 55.29, 111.46, 121.12, 126.47, 132.20, 136.40, 156.77, 174.17.
EIMS (m=z): 250, 235, 219, 201, 175, 149, 119, 91.
Methyl 5-(4-Methyl-2,5-dimethoxylphenyl) hexanoate 10. Compound 10
was obtained from 12 by method similar to that used for 9. Yield 95% as a pale
1
yellow oil. H NMR: 1.17 (d, J ¼ 7.2 Hz 3H), 1.16 (d, J ¼ 6.8 Hz, 3H), 1.51–1.63
(m, 4H), 2.20 (s, 3H), 2.27–2.30 (m, 2H), 3.18–3.21 (m, 1H), 3.69 (s, 3H), 3.89 (m,
6H), 6.67 (s, 1H), 6.77 (s, 1H). 13C NMR: 20.96, 21.41, 24.12, 31.17, 34.14, 36.63,
51.35, 55.28, 55.42, 111.45, 121.23, 126.42, 132.23, 136.41, 156.82, 174.42. EIMS
(m=z): 280, 265, 249, 231, 119, 91.
2-Methyl-6-(4-methyl-2-methoxylphenyl)-2-heptanol 7. Iodomethane
(6.39 g, 45 mmol) in 50 mL of anhydrous diethyl ether was added slowly to a suspen-
sion of power Mg (1.45 g, 60 mmol) in 50 mL of anhydrous diethyl ether at reflux.
Once the addition was complete, the reaction mixture was stirred at reflux for 1 h
and was cooled to room temperature. A solution of compound 9 (2.25 g, 9 mmol)
in anhydrous diethyl ether (30 mL) was added slowly to the reaction mixture at room
temperature. The reaction was refluxed for 1 h, quenched with sat. NH4Cl, and
extracted with ethyl acetate (3 ꢃ 70 mL). The combined organic layer was washed
with sat. NaHCO3 and brine, then dried over anhydrous MgSO4. The solvent was
evaporated in vacuum, and the residue was purified through column chromatography
to give 7 (2.10 g, 93%) as a colorless oil. 1H NMR: 1.14 (s, 3H), 1.18 (s, 3H), 1.18 (s,
3H), 1.21 (d, J ¼ 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, J ¼ 7.8 Hz, 1H), 7.01 (d, J ¼ 7.8 Hz, 1H). 13C NMR:
20.97, 21.24, 22.27, 28.98, 29.07, 31.25, 37.57, 43.85, 55.20, 70.84, 111.40, 121.08,
126.40, 132.76, 136.05, 156.70. EIMS (m=z): 250, 235, 232, 217, 175, 162, 149, 119, 91.
2-Methyl-6-(4-methyl-2,5-dimethoxylphenyl)-2-heptanol 8. Compound
8 was obtained from 10 by method similar to that used for 7. Yield 89% as a colorless
oil. 1H NMR: 1.18 (s, 3H), 1.20 (s, 3H), 1.23 (d, J ¼ 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: 15.97, 17.85, 21.10, 22.32, 29.04, 31.73, 37.38, 43.86, 56.07, 56.34, 70.89,
109.67, 114.33, 124.18, 133.96, 150.70, 151.87. EIMS (m=z): 280, 265, 262, 247, 205,
192, 179, 149, 119, 91.

1924
Z. DU ET AL.
2-Methyl-6-(4-methyl-2-methoxylphenyl)-2-heptene 5. p-TsOH acid
(100 mg) was added to a solution of compound 7 (2.00 g, 8 mmol) in benzene
(100 mL) equipped with a Dean–Stark trap. The reaction mixture was refluxed for
6 h and then diluted with ethyl acetate (100 mL). The organic layer was washed with
sat. NaHCO3 and brine, then dried over anhydrous MgSO4. The solvent was evapo-
rated in vacuum, and the residue was purified through column chromatography
to give 5 (1.76 g, 95%) as a colorless oil. 1H NMR: 1.19 (d, J ¼ 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 ¼ 7.0 Hz, 1H), 3.82 (s, 3H), 5.13 (t, J ¼ 7.0 Hz, 1H), 6.69 (s, 1H), 6.75
(d, J ¼ 7.8 Hz, 1H), 7.06 (d, J ¼ 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 6. Compound 6
was obtained from 8 by a method similar to that used for 5. Yield 96% as a colorless
oil. 1H NMR: 1.28 (d, J ¼ 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 ¼ 6.9 Hz, 1H), 6.67 (s, 1H), 6.70 (s, 1H). 13C NMR: 15.99, 17.53, 21.22,
25.64, 26.30, 31.85, 37.27, 56.01, 56.24, 111.65, 112.46, 122.04, 125.03, 126.71,
133.12, 136.85, 157.13. EIMS (m=z): 262, 247, 219, 192, 179, 149, 119, 91. HRMS:
required C17H27O2 262.2013; found 262.2009.
(ꢀ)-Curcuphenol 1. Ethanethiol (147 mg, 2.36 mmol) and NaH in 60%
mineral oil (94 mg, 2.36 mmol) were added to DMF (3 mL), after hydrogen evolved
ceased (about 30 min), and then compound 5 (110 mg, 0.47 mmol) in DMF (1 mL)
was added. The mixture was heated to 130 ꢂC and stirred for 4 h. The reaction
was cooled to room temperature, quenched by sat. ammonium chloride, and
extracted with diethyl ether (3 ꢃ 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 1 (98 mg, 95%) as a colorless oil. IR (neat):
1
3537, 2965, 2935, 2866, 1664, 1617, 1421, 808 cmꢁ1. H NMR: 1.22 (d, J ¼ 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 ¼ 7.0 Hz, 1H), 4.67 (s, 1H), 5.13 (br, 1H), 6.59 (br, 1H), 6.72 (d,
J ¼ 8.0 Hz, 1H), 7.03 (d, J ¼ 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.
(ꢀ)-Curcudiol 2. Compound 2 was obtained from 7 by a method similar to
that used for 1. Yield 96% as a colorless oil. IR (neat): 1070, 1420, 1254, 1619,
1
1711, 2859, 2924 cmꢁ1. H NMR: 1.18 (s, 3H), 1.20 (s, 3H), 1.30 (d, J ¼ 7.2 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 ¼ 7.8 Hz, 1H), 7.01 (d, J ¼ 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. Compound 3 was obtained from 6 by a method
similar to that used for 1. Yield 95% as a colorless oil. IR (neat): 3545, 2966, 2927,

SYNTHESIS OF BISABOLANE SESQUITERPENES
1925
1
1666, 1615, 1456, 1417, 1377, 1306, 1187, 1003, 875, 833 cmꢁ1. H NMR: 1.20 (d,
J ¼ 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 ¼ 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
(Mþ þ 1), 234, 217, 191, 177, 164, 151, 137, 124, 107, 95, 77. HRMS: required
C15H22O2 234.1700; found 234.1703.
ACKNOWLEDGMENTS
This work was supported by Starting Funds Programs of Doctor at Northwest
A&F University as well as by the Program for New Century Excellent Talents in
University (NCET-05-0852).
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