Baker's yeast-mediated enantioselective synthesis of the bisabolane sesquiterpenes (+)-curcuphenol, (+)-xanthorrhizol, (-)-curcuquinone and (+)-curcuhydroquinone

Article abstract of DOI:10.1039/b006141g

Fermenting baker's yeast converts the unsaturated aldehydes 5a-c into the saturated alcohols 6a-c, respectively. The microbial saturation of substrates adsorbed on a nonpolar resin proceeds in high chemical yields and shows complete enantioselectivity in the formation of the (S)-(+) isomers. Enantiopure 6a-c are versatile chiral building blocks for the synthesis of bisabolane sesquiterpenes. Their usefulness is shown in the preparation of (S)-(+)-curcuphenol, (S)-(+)-xanthorrhizol, (S)-(-)-curcuquinone and (S)-(+)-curcuhydroquinone. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b006141g

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Baker’s yeast-mediated enantioselective synthesis of the
bisabolane sesquiterpenes (؉)-curcuphenol, (؉)-xanthorrhizol,
(؊)-curcuquinone and (؉)-curcuhydroquinone
1
Claudio Fuganti and Stefano Serra*
Dipartimento di Chimica del Politecnico, Centro CNR per lo Studio delle Sostanze Organiche
Naturali, Via Mancinelli, 7 I-20131 Milano, Italy
Received (in Cambridge, UK) 28th July 2000, Accepted 11th September 2000
First published as an Advance Article on the web 30th October 2000
Fermenting baker’s yeast converts the unsaturated aldehydes 5a–c into the saturated alcohols 6a–c, respectively. The
microbial saturation of substrates adsorbed on a nonpolar resin proceeds in high chemical yields and shows complete
enantioselectivity in the formation of the (S)-(ϩ) isomers. Enantiopure 6a–c are versatile chiral building blocks for
the synthesis of bisabolane sesquiterpenes. Their usefulness is shown in the preparation of (S)-(ϩ)-curcuphenol,
(S)-(ϩ)-xanthorrhizol, (S)-(Ϫ)-curcuquinone and (S)-(ϩ)-curcuhydroquinone.
ducing a stereogenic center in the benzylic position. We
Introduction
have previously11 shown that the baker’s yeast reduction of
The phenolic sesquiterpenes of the bisabolane family have been
(E)-3-(p-tolyl)but-2-en-1-ol affords enantiopure (S)-(ϩ)-3-(p-
tolyl)butan-1-ol, which is a chiral buiding block for the
synthesis of the most common bisabolane sesquiterpenes.
isolated from many different natural sources.1 Differently from
the non-phenolic bisabolane compounds, which are the olfac-
torally active components of a large number of essential oils,
they show a wide range of biological activities. Curcuphenol 1
(Fig. 1), curcuquinone 3 and curcuhydroquinone 4 were
Further studies on the microbial reduction of (R)- and (S)-
3-(4-methylcyclohex-3-enyl)but-2-enal12 allow us to prepare
enantioselectively the well known bisabolene sesquiterpenes
(ϩ)-epijuvabione and (Ϫ)-juvabione.
isolated from the Caribbean gorgonian Pseudopterogorgia
rigida2 and show antibacterial properties against Staphylo-
Now, as part of a programme of synthesis of phenolic ses-
coccus aureus and Vibrio anguillarum. The closely related
quiterpenes,8c,13 we report on the enantioselective synthesis of
xanthorrhizol 2 was extracted from Curcuma xanthorrhixa3
the title compounds 1–4. Their preparation was based on the
and Iostephane heterophylla4 which are plants of different geo-
graphic origins, used in traditional medicine. Moreover, the
baker’s yeast reduction (Scheme 1) of aldehydes 5a–c, to afford
enantiopure alcohols 6a–c, respectively. These latter are useful
recent isolation of the heliannuols,5 which are a group of
building blocks for the synthesis of phenolic sesquiterpenes of
allelochemical phenolic sesquiterpenes structurally related to 4,
(S) absolute configuration.
spreads the known biological activities of this kind of com-
pound. In addition, opposite enantiomers show different
properties, as in the case of curcuphenol where the (S)-(ϩ)-
enantiomer 1 shows antitumoral activity6 whilst the (R)-(Ϫ)-
enantiomer shows the antibacterial features described above.
Though several approaches have been reported for the con-
struction of the bisabolane skeleton,7 only a few enantio-
selective syntheses of these sesquiterpene phenols have been
reported in the literature8–10 due to the difficulty of intro-
Scheme 1
Results and discussion
Following our previous findings, we were looking for a syn-
thetic method for the preparation of aldehydes 5a–c which are
the substrates of choice for the microbial reduction. As shown
in Scheme 2, they were prepared following a common pathway
from the related esters 9, 15 and 18 by reduction to the allylic
alcohol followed by oxidation. The esters were themselves syn-
thesized from the substituted acetophenones 8, 14 and 17
by Horner–Wadsworth–Emmons reaction with triethyl phos-
phonoacetate (ethyl diethoxyphosphorylacetate) and sodium
hydride.14 Since this latter reaction afforded a mixture of E/Z
isomers in ≈5:1 ratio and the enantioselectivity in the yeast
reduction is lowered by the presence of the Z isomer,12 we
purified the mixture by chromatography in order to submit
the pure (E)-aldehydes 5a–c to the reduction. The synthesis
of the acetophenones 8, 14 and 17 differed depending on the
Fig. 1
3758
J. Chem. Soc., Perkin Trans. 1, 2000, 3758–3764
DOI: 10.1039/b006141g
This journal is © The Royal Society of Chemistry 2000

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Scheme 2 Reagents and conditions: a) Ac2O Py; b) AlCl3; c) Me2SO4 K2CO3, acetone; d) (EtO)2POCH2CO2Et, NaH; e) LiAlH4, THF; f ) MnO2,
CHCl3, reflux; g) baker’s yeast, 4–6 d; h) benzene reflux; i) ClCO2Et, Et3N, THF; then aq. KOH, reflux; j) MeMgCl, THF, 0 ЊC; k) AcCl, CH2Cl2,
SnCl4; l) DIBALH, THF; m) ClCOCOCl, DMSO, CH2Cl2, Et3N.
substitution of the aromatic moiety. 2-Methoxy-4-methylaceto-
phenone 8 was prepared according to the literature15 starting
from m-cresol 7 by acetylation, Fries transposition and
methylation. A similar pathway was used to synthesize 2,5-
dimethoxy-4-methylacetophenone 17. Commercially available
2-methylhydroquinone 16 was methylated with Me2SO4 and
then converted into 17 by treatment with AcCl and SnCl4.16
However, 3-methoxy-4-methylacetophenone 14 was prepared
using a completely different approach. Since the reported pro-
cedure based on a functionalization of p-methylacetophenone17
afforded 14 in only low yield, we decided to construct the
aromatic ring by benzanullation18 of the hexadienoic acid
derivative 12. This latter was prepared from crotonaldehyde
10 by Wittig reaction with ylide 11,19 and then was submitted
to cyclization using ethyl chloroformate and triethylamine as
base. After KOH treatment, we obtained the acid 13, which
was converted into the suitable benzophenone 14 in good yield
by a number of straightforward synthetic steps.
(Scheme 3). To this end, the alcohols were converted into the
related iodides 19–21, respectively, via the tosyl ester derivatives
and substitution with NaI in acetone. The coupling of the
iodides with the Grignard reagent 22 catalyzed by copper()
iodide21 afforded enantiopure 23–25 which show the whole C15
bisabolane framework. The methyl ether functionality of com-
pounds 23 and 24 was cleaved using sodium ethanethiolate in
DMF22 to give (S)-(ϩ)-curcuphenol 1 and (S)-(ϩ)-xanthor-
rhizol 2, respectively, showing the same analytical data as those
reported in the literature for the natural products2–4,6 except for
2, whose sign of rotation was reversed and with similar ampli-
tude of that of the natural (R)-(Ϫ)-xanthorrhizol. The same
procedure performed on a sample of 25 gave unsatisfactory
results since an inseparable mixture with the monomethylated
hydroquinone was obtained. Instead, oxidation of 25 with
cerium() ammonium nitrate (CAN) in aq. MeCN23 smoothly
afforded the (S)-(Ϫ)-curcuquinone 3 which could be easily
reduced with NaBH4 to (S)-(ϩ)-curcuhydroquinone 4. The
spectroscopical data of these two compounds were in good
agreement with those of synthetic10,24 and natural2,25 products,
except for 3 whose sign of rotation was reported2 as (Ϫ) for
the (R) isomer. Since we had synthesized 3 and 4 starting
from the (S) alcohol 6c and we obtained the known (S)-(ϩ)-
curcuhydroquinone, the absolute configuration of 3 was
unambiguously (S).
Following the methodology described above, the three (E)
aldehydes 5a–c were obtained on a multigram scale. In order to
achieve a large-scale preparation of the enantiopure alcohols
6a–c, we performed the microbial reduction by adsorbing the
substrates on a nonpolar resin (XAD 1180). This procedure
allowed us to use a high concentration of substrate (5–10 g LϪ1
)
and the product was recovered by simple filtration of the resin.
Extraction of the latter with a suitable solvent afforded the
crude saturated alcohols 6a–c, which were purified as described
in the Experimental section. The results of the biotransform-
ation showed a high conversion of the aldehydes into the satur-
ated alcohols (49–56% yield as isolated products) in only 4–6
days of incubation. The determination of the optical purity of
alcohols 6a–c was performed by comparing the NMR spectra
of the (Ϫ)-MPTA esters20 of the latter alcohols with those
obtained from racemic 6a–c (see Experimental section). Since
the alcohols 6a–c, obtained from yeast reduction, appeared as
single isomers, we can establish an enantiomeric excess >98%.
The transformation of the C11 (S)-(ϩ)-alcohols 6a–c into the
C15 sesquiterpene skeleton was achieved by an effective pro-
cedure we have previously8c,11 used for this kind of compound
Experimental
Mps were measured on a Reichert melting-point apparatus,
equipped with a Reichert microscope, and are uncorrected.
Optical rotations were measured on a Propol automatic digital
polarimeter, and [α]D-values are given in 10Ϫ1 deg cm2 gϪ1
.
Microanalyses were determined on a Carlo Erba 1106 analyzer.
IR spectra were recorded on a Perkin-Elmer 2000 FTIR spec-
trometer. 1H NMR spectra were recorded in CDCl3 solutions at
room temperature unless otherwise stated, on a Bruker AC-250
1
spectrometer (250 MHz H). The chemical-shift scale is based
on internal tetramethylsilane. J-Values are given in Hz. Mass
spectra were measured on a Finnigan-MAT TSQ 70 spec-
J. Chem. Soc., Perkin Trans. 1, 2000, 3758–3764
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1704, 1647, 1426, 1305, 1233, 1092, 971, 767; δH 1.29 (3H, t,
J 7, OCH2Me), 1.89 (3H, d, J 5.4, MeCHCH), 3.47 (2H, s,
CH2CO2H), 4.22 (2H, q, J 7, OCH2Me), 6.14–6.38 (2H, m,
MeCHCH), 7.34 (1H, d, J 10, CHCCO2Et); m/z (EI) 198 (Mϩ,
3%), 183 (3), 154 (63), 139 (29), 125 (29), 111 (66), 97 (19), 79
(100), 67 (11), 53 (16), 39 (15).
3-Hydroxy-4-methylbenzoic acid 13. ClCO2Et (21 mL, 220
mmol) was added in one portion to a solution of acid 12 (35 g,
177 mmol) in dry THF (200 mL), and then Et3N (75 mL, 538
mmol) was added dropwise, keeping the temperature under
20 ЊC. The mixture was stirred for 15 min and then acidified
with an excess of 5% aq. HCl and extracted with ethyl acetate
(3 × 150 mL). The organic phase was concentrated and the
residue was dissolved in ethanol (80 mL). The resulting solution
was treated with aq. KOH (25 g, 445 mmol in 100 mL) and
heated at reflux for 2 h. After cooling, the mixture was acidified
with conc. HCl and extracted with ethyl acetate (3 × 150 mL).
The combined organic portions were washed with brine (100
mL), dried (Na2SO4), and concentrated under reduced pressure.
The residue was purified by chromatography using hexane–
ethyl acetate (8:2→1:2) as eluent followed by crystalliz-
ation to give pure acid 1326 (23.2 g, 86%), mp 220–221 ЊC (from
hexane–ethyl acetate) (Found: C, 63.06; H, 5.33. C8H8O3
requires C, 63.15; H, 5.30%); νmax(film)/cmϪ1 3377, 1663, 1611,
1586, 1428, 1302, 1232, 1182, 880, 762, 640; δH 2.18 (3H, s,
ArMe), 7.17 (1H, d, J 8, ArH), 7.32 (1H, d, J 8, ArH), 7.40 (1H,
s, ArH), 9.7 (1H, br s, ArOH), 12.6 (1H, br s, CO2H); m/z (EI)
152 (100), 135 (38), 123 (3), 107 (82), 77 (32), 67 (3), 63 (4), 51
(9), 45 (3), 39 (6).
3-Methoxy-4-methylacetophenone 14. Acid 13 (20 g, 132
mmol) as a solution in dry acetone (200 mL) was refluxed for
10 h with Me2SO4 (38 mL, 402 mmol) and dry K2CO3 (65 g,
470 mmol). The resulting mixture was concentrated under
reduced pressure, diluted with water (300 mL) and extracted
with diethyl ether (3 × 150 mL). The organic phase was dried
(Na2SO4), concentrated under reduced pressure, and the residue
was reduced at rt with LiAlH4 (6 g, 158 mmol) in dry THF (150
mL). The reaction was quenched by dropwise addition of ethyl
acetate (200 mL) followed by addition of 5% aq. HCl (200 mL).
The organic phase was separated, and the aqueous layer was
extracted with diethyl ether (3 × 150 mL). The combined
organic phases were washed with brine (200 mL), dried
(Na2SO4), and concentrated under reduced pressure. The
obtained benzylic alcohol was dissolved in CHCl3 (200 mL) and
treated with MnO2 (50 g, 575 mmol) at reflux for 3 h. The
reaction mixture was filtered and the liquid phase was concen-
trated under reduced pressure. The residue was dissolved in dry
THF (150 mL) and treated with MeMgCl (55 mL of a 3 M
solution in THF, 165 mmol) while being stirred under nitrogen
at 0 ЊC for 1 h. Acidic work-up with 5% aq. HCl (200 mL),
extraction with ethyl acetate (3 × 100 mL), and concentration
of the organic phase gave the crude carbinol, which was oxidized
directly with MnO2 (50 g, 575 mmol) in CHCl3 (200 mL) at
reflux for 4 h. Filtration and concentration of the organic phase
gave crude 14. Purification of the latter by chromatography
with hexane→hexane–ethyl acetate 9:1 as eluent, afforded
pure 3-methoxy-4-methylacetophenone 1417 (15.9 g, 73%)
(Found: C, 73.30; H, 7.35. C10H12O2 requires C, 73.15; H,
7.37%); νmax(film)/cmϪ1 1682, 1606, 1579, 1501, 1408, 1271,
1227, 1038, 877; δH 2.26 (3H, s, ArMe), 2.58 (3H, s, ArCOMe),
3.88 (3H, s, OMe), 7.19 (1H, d, J 7.5, ArH), 7.41–7.48 (2H,
m, ArH); m/z (EI) 165 (Mϩ ϩ 1, 6%), 164 (Mϩ, 54), 149 (100),
121 (21), 106 (7), 91 (29), 77 (13), 65 (3), 51 (4), 43 (6).
Scheme3 Reagentsandconditions:a)TsCl, Py, CH2Cl2;b)NaI, acetone,
reflux; c) CuI cat., THF; d) NaSEt, DMF, reflux; e) CAN, aq. MeCN;
f ) NaBH4, MeOH.
trometer. TLC analyses were performed on Merck Kieselgel 60
F254 plates. All the chromatographic separations were carried
out on silica gel columns. Baker’s yeast was obtained from
Gist-brocades (DSM Bakery Ingredients Italy s.p.a.).
Preparation of acetophenones 8, 14 and 17
2-Methoxy-4-methylacetophenone 8. Prepared from 7 accord-
ing to the reported procedure15 and further purified by crystal-
lization from hexane; yield 64%, mp 35–37 ЊC (from hexane)
(Found: C, 73.25; H, 7.39. Calc. for C10H12O2: C, 73.15; H,
7.37%); νmax(film)/cmϪ1 1656, 1605, 1418, 1292, 1259, 1172,
1033, 812, 604; δH 2.36 (3H, s, ArMe), 2.57 (3H, s, ArCOMe),
3.87 (3H, s, OMe), 6.72–6.82 (2H, m, ArH), 7.66 (1H, d, J 8.1,
ArH); m/z (EI) 165 (Mϩ ϩ 1, 2%), 164 (Mϩ, 19), 149 (100), 134
(4), 119 (3), 106 (8), 91 (20), 77 (7), 65 (5), 51 (3), 43 (3).
(E,E )-3-(Ethoxycarbonyl)hepta-3,5-dienoic acid 12. Croton-
aldehyde 10 (18 g, 257 mmol) as a solution in benzene (150 mL)
was treated with 1-ethyl hydrogen 2-(triphenylphosphanyl-
idene)butane-1,4-dioate 11 (100 g, 246 mmol) at reflux for 4 h.
The solvent was removed under reduced pressure, the residue
was dissolved in hexane–diethyl ether (2:1), and the triphenyl-
phosphine oxide eliminated by crystallization. The liquid
phase was concentrated and the remaining oil was purified by
chromatography using hexane–ethyl acetate (95:5→8:2) as
eluent to afford exclusively the acid 12 (36 g, 74%) as a single
(E,E) isomer, mp 72–73 ЊC (from hexane) (Found: C, 60.56; H,
7.14. C10H14O4 requires C, 60.59; H, 7.12%); νmax(film)/cmϪ1
2,5-Dimethoxy-4-methylacetophenone 17. Methylhydro-
quinone 16 (40 g, 322 mmol) as a solution in dry acetone (400
mL) was refluxed for 12 h with Me2SO4 (90 mL, 950 mmol)
and K2CO3 (150 g, 1085 mmol). The resulting mixture was
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J. Chem. Soc., Perkin Trans. 1, 2000, 3758–3764

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concentrated under reduced pressure, diluted with water (500
mL), and extracted with diethyl ether (3 × 250 mL). The organic
phase was washed with brine (300 mL), dried (Na2SO4), and
concentrated under reduced pressure. The residue was dissolved
in CH2Cl2 (150 mL) and was treated with AcCl (28 mL, 394
mmol) followed by the dropwise addition of SnCl4 (38 mL, 325
mmol). The resulting solution was stirred at rt for 2 h and then
was poured in ice–water. The mixture was extracted with diethyl
ether (2 × 300 mL) and the organic phase was washed succes-
sively with 5% aq. NaHCO3 (2 × 200 mL) and brine (200 mL).
Evaporation of the solvent, distillation of the residue, and crys-
tallization of the latter from hexane afforded pure ketone 1716
(49 g, 78%), mp 76 ЊC (from hexane) (Found: C, 67.95; H, 7.28.
C11H14O3 requires C, 68.02; H, 7.27%); νmax(film)/cmϪ1 1661,
1610, 1501, 1398, 1214, 1042, 886, 802, 638, 574; δH 2.26 (3H, s,
ArMe), 2.61 (3H, s, ArCOMe), 3.82 (3H, s, OMe), 3.87 (3H,
s, OMe), 6.79 (1H, s, ArH), 7.29 (1H, s, ArH); m/z (EI) 195
(Mϩ ϩ 1, 6%), 194 (Mϩ, 51), 179 (100), 164 (9), 151 (7), 136
(10), 121 (8), 91 (11), 77 (6), 65 (4), 53 (3), 43 (6).
δH 1.31 (3H, t, J 7.3, OCH2Me), 2.23 (3H, s, ArMe), 2.50 (3H,
d, J 1.3, ArCMe), 3.77 (3H, s, OMe), 3.79 (3H, s, OMe), 4.20
(2H, q, J 7.3, OCH2Me), 5.91 (1H, d, J 1.3, CHCO2Et), 6.64
(1H, s, ArH), 6.72 (1H, s, ArH); m/z (EI) 265 (Mϩ ϩ 1, 7), 264
(Mϩ, 45), 249 (1), 233 (48), 219 (17), 205 (100), 189 (18), 176
(20), 161 (37), 149 (6), 133 (5), 115 (8), 105 (7), 91 (8), 77 (10), 65
(6), 51 (4), 39 (7).
Ethyl
(2Z)-3-(2,5-dimethoxy-4-methylphenyl)but-2-enoate
18Z. Colorless crystals (14%), mp 49–50 ЊC (from hexane)
(Found: C, 67.95; H, 7.60%); νmax(film)/cmϪ1 1720, 1646, 1513,
1468, 1402, 1214, 1167, 1042, 868, 811; δH 1.09 (3H, t, J 7.1,
OCH2Me), 2.15 (3H, d, J 1.5, ArCMe), 2.22 (3H, s, ArMe),
3.74 (3H, s, OMe), 3.76 (3H, s, OMe), 3.99 (2H, q, J 7.1,
OCH2Me), 5.95 (1H, m, CHCO2Et), 6.52 (1H, s, ArH), 6.72
(1H, s, ArH); m/z (EI) identical to 18E.
Preparation of aldehydes 5a–c
(2E)-3-(2-Methoxy-4-methylphenyl)but-2-enal 5a. The ester
9E (50 g, 215 mmol) as a solution in dry THF (300 mL) was
reduced with LiAlH4 (8.2 g, 216 mmol) at 0 ЊC. The reaction
was quenched by dropwise addition of ethyl acetate (300 mL)
followed by addition of 5% aq. HCl (650 mL). The organic
phase was separated, and the aqueous layer was extracted with
ethyl acetate (3 × 200 mL). The combined organic phases were
washed with brine (2 × 200 mL), dried (Na2SO4), and concen-
trated under reduced pressure. The crude allylic alcohol was
dissolved in CHCl3 (250 mL) and treated at reflux with MnO2
(80 g, 920 mmol) for 6 h. The residue obtained upon filtration
and evaporation of the CHCl3 was purified by distillation (bp
125 ЊC/0.1 mmHg) to afford pure aldehyde 5a (32 g, 78%) as a
colorless oil (Found: C, 75.95; H, 7.40. C12H14O2 requires C,
75.76; H, 7.42%); νmax(film)/cmϪ1 2939, 1670, 1610, 1501, 1465,
1411, 1282, 1259, 1169, 1133, 1037, 812; δH 2.37 (3H, s, ArMe),
2.52 (3H, d, J 1.4, ArCMe), 3.82 (3H, s, OMe), 6.14 (1H, dq,
J 8.1 and 1.4, CHCOH), 6.72–6.82 (2H, m, ArH), 7.07 (1H, d,
J 7.8, ArH), 10.14 (1H, d, J 8.1, CHCOH); m/z (EI) 190 (Mϩ,
4%), 175 (19), 159 (100), 147 (10), 131 (8), 115 (14), 91 (15), 77
(7), 65 (3), 51 (3), 39 (3).
Preparation of esters 9, 15 and 18
Ethyl (2E)-3-(2-methoxy-4-methylphenyl)but-2-enoate 9E.
Triethyl phosphonoacetate (72 g, 321 mmol) was added drop-
wise under nitrogen over a period of 2 h to a stirred suspension
of NaH (60% in mineral oil; 13 g, 325 mmol) in dry THF (250
mL) at rt. To the resulting mixture was slowly added a solution
of ketone 8 (45 g, 274 mmol) in dry THF (100 mL) and the
reaction mixture was heated at reflux for 2 h. After cooling, the
mixture was poured onto ice–water and extracted with diethyl
ether (3 × 200 mL). The organic phase was washed with brine
(2 × 100 mL), dried (Na2SO4), and concentrated under reduced
pressure. The residue was chromatographed using hexane–ethyl
acetate 95:5 as eluent (Rf 9E: 0.22; Rf 9Z: 0.11) to afford pure
ester 9E (41 g, 64%) (Found: C, 71.88; H, 7.75. C14H18O3
requires C, 71.77; H, 7.74%); νmax(film)/cmϪ1 2934, 1715, 1630,
1571, 1504, 1465, 1409, 1366, 1340, 1274, 1175, 1041, 875, 812;
δH 1.29 (3H, t, J 7.3, OCH2Me), 2.35 (3H, s, ArMe), 2.48
(3H, d, J 1.4, ArCMe), 3.80 (3H, s, OMe), 4.19 (2H, q, J 7.3,
OCH2Me), 5.89 (1H, d, J 1.4, CHCO2Et), 6.67–6.79 (2H, m,
ArH), 7.03 (1H, d, J 7.9, ArH); m/z (EI) 235 (Mϩ ϩ 1, 5%), 234
(Mϩ, 33), 219 (1), 203 (96), 189 (38), 175 (100), 159 (12), 145
(55), 131 (12), 115 (20), 105 (13), 91 (17), 77 (8), 65 (4), 51 (3), 39
(3). The last eluted fractions gave ethyl (2Z)-3-(2-methoxy-4-
methylphenyl)but-2-enoate 9Z (11 g, 17%) (Found: C, 71.85; H,
7.70%); νmax(film)/cmϪ1 2978, 1728, 1610, 1507, 1466, 1372,
1260, 1174, 1151, 1041, 812; δH 1.09 (3H, t, J 7.3, OCH2Me),
2.13 (3H, d, J 1.4, ArCMe), 2.35 (3H, s, ArMe), 3.78 (3H,
s, OMe), 3.98 (2H, q, J 7.3, OCH2Me), 5.94 (1H, d, J 1.4,
CHCO2Et), 6.70–6.80 (2H, m, ArH), 6.91 (1H, d, J 7.9, ArH);
m/z (EI) identical to 9E.
(2E)-3-(3-Methoxy-4-methylphenyl)but-2-enal 5b. Colorless
oil (81%), bp 130 ЊC/0.3 mmHg (Found: C, 75.92; H, 7.40%);
νmax(film)/cmϪ1 1655, 1509, 1418, 1267, 1238, 1135, 1038, 844,
815; δH 2.25 (3H, s, ArMe), 2.56 (3H, d, J 1.1, ArCMe), 3.86
(3H, s, OMe), 6.41 (1H, dq, J 8 and 1.1, CHCOH), 6.98 (1H, d,
J 1.6, ArH), 7.08 (1H, dd, J 7.9 and 1.6, ArH), 7.17 (1H, d,
J 7.9, ArH), 10.18 (1H, d, J 8, CHCOH); m/z (EI) 190 (Mϩ,
26%), 175 (100), 159 (29), 147 (17), 131 (11), 115 (19), 91 (21),
77 (11), 63 (3), 51 (4), 39 (3).
(2E)-3-(2,5-Dimethoxy-4-methylphenyl)but-2-enal 5c. The
ester 18E (30 g, 114 mmol) as a solution in dry THF (150 mL)
was reduced with DIBALH (170 mL of 1.5 M solution in tolu-
ene) at 0 ЊC. The reaction was quenched by dropwise addition
of ethyl acetate (200 mL) followed by addition of 5% aq. HCl
(400 mL). The organic phase was separated, and the aqueous
layer was extracted with ethyl acetate (3 × 200 mL). The com-
bined organic phases were washed with brine (2 × 200 mL),
dried (Na2SO4), and concentrated under reduced pressure. The
residue was dissolved in CH2Cl2 (50 mL) and dropped into
a Swern oxidant mixture which had been previously prepared
by addition of DMSO (20 g, 256 mmol) to a cooled solution
(Ϫ78 ЊC) of ClCOCOCl (16 g, 126 mmol) in CH2Cl2 (150 mL).
The resulting suspension was treated with Et3N (60 g, 593
mmol) and the reaction mixture was allowed to warm to rt.
After 2 h the mixture was diluted with CH2Cl2 (250 mL),
washed with water (4 × 100 mL), and the organic phase was
concentrated under reduced pressure. The residue was purified
by chromatography, using hexane–ethyl acetate (95:5→8:2) as
Ethyl (2E)-3-(3-methoxy-4-methylphenyl)but-2-enoate 15.17
Obtained exclusively as the E-isomer; colorless oil (81%)
(Found: C, 71.60; H, 7.75%); νmax(film)/cmϪ1 1713, 1626, 1572,
1509, 1465, 1411, 1343, 1293, 1231, 1159, 1042, 851, 814;
δH 1.32 (3H, t, J 6.9, OCH2Me), 2.22 (3H, s, ArMe), 2.57 (3H,
d, J 1.1, ArCMe), 3.86 (3H, s, OMe), 4.22 (2H, q, J 6.9,
OCH2Me), 6.13 (1H, d, J 1.1, CHCO2Et), 6.91 (1H, d, J 1.5,
ArH), 6.99 (1H, dd, J 7.8 and 1.5, ArH), 7.12 (1H, d, J 7.8,
ArH); m/z (EI) 235 (Mϩ ϩ 1, 14%), 234 (Mϩ, 87), 219 (2), 205
(11), 189 (76), 188 (100), 175 (11), 160 (29), 145 (20), 131 (16),
115 (23), 103 (9), 91 (16), 77 (10), 65 (4), 51 (4), 39 (3).
Ethyl
(2E)-3-(2,5-dimethoxy-4-methylphenyl)but-2-enoate
18E. Purified by chromatography using hexane–ethyl acetate
9:1 as eluent (Rf 18E: 0.29; Rf 18Z: 0.19) to give colorless
crystals (71%), mp 61–62 ЊC (from hexane) (Found: C, 67.98;
H, 7.65. C15H20O4 requires C, 68.16; H, 7.63%); νmax(film)/cmϪ1
1710, 1630, 1508, 1468, 1400, 1342, 1213, 1174, 1041, 877, 807;
J. Chem. Soc., Perkin Trans. 1, 2000, 3758–3764
3761

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eluent, to give pure aldehyde 5c (17.6 g, 70%) as a yellow oil
(Found: C, 70.75; H, 7.35. C13H16O3 requires C, 70.89; H,
7.32%); νmax(film)/cmϪ1 2936, 2850, 1667, 1501, 1466, 1398,
1213, 1043, 861, 811, 693; δH 2.24 (3H, s, ArMe), 2.54 (3H, d,
J 1.2, ArCMe), 3.79 (6H, s, OMe), 6.15 (1H, dd, J 8.1 and 1.2,
CHCOH), 6.66 (1H, s, ArH), 6.76 (1H, s, ArH), 10.16 (1H, d,
J 8.1, CHCOH); m/z (EI) 220 (Mϩ, 10%), 205 (2), 189 (100),
174 (8), 161 (6), 145 (5), 137 (3), 115 (6), 105 (3), 91 (7), 77 (4),
65 (2), 51 (1), 39 (2).
H, 8.95. C13H20O3 requires C, 69.61; H, 8.99%); νmax(film)/cmϪ1
3369, 2958, 1505, 1466, 1399, 1209, 1047, 863; δH 1.27 (3H, d,
J 7, ArCHMe), 1.52–1.70 (1H, m, HCHCH2OH), 1.82–1.99
(1H, m, HCHCH2OH), 2.20 (3H, s, ArMe), 2.48 (1H, s, OH),
3.28–3.44 (2H, m, CH2HCHOH ϩ ArCHMe), 3.47–3.59 (1H,
m, CH2HCHOH), 3.79 (6H, s, OMe), 6.67 (1H, s, ArH), 6.70
(1H, s, ArH); m/z (EI) 225 (Mϩ ϩ 1, 8%), 224 (Mϩ, 42), 209 (2),
191 (4), 179 (100), 164 (25), 149 (9), 135 (4), 119 (3), 105 (3), 91
(12), 77 (8), 65 (3), 53 (3), 39 (4).
Determination of the optical purity of alcohols 6a–c
Baker’s yeast reduction of aldehydes 5a–c to alcohols 6a–c
The three alcohols (S)-(ϩ)-6a–c were converted into their
(S)-(Ϫ)-α-methoxy-α-(trifluoromethyl)phenylacetyl esters [(S)-
MTPA esters]. In a typical preparation, a solution of (S)-(Ϫ)-α-
methoxy-α-(trifluoromethyl)phenylacetyl chloride (0.2 mmol)
in CCl4 (0.5 mL) was added to a solution of the substrate
alcohol (0.15 mmol) in CCl4 (0.5 mL) containing dry pyridine
(0.5 ml). The mixture was stirred at rt for 24 h and then was
diluted with diethyl ether (60 mL). The solution was washed
successively with 5% aq. HCl (30 mL), saturated aq. Na2CO3
(30 mL) and brine (30 mL). The organic phase was dried
(Na2SO4) and evaporated under reduced pressure to afford the
(S)-MTPA esters of alcohols (S)-6a–c, which were utilized for
NMR spectral measurement.
The samples of racemic alcohols 6a–c were synthesized from
esters 9, 15 and 18 by hydrogenation (H2, Pd/C) and LiAlH4
reduction. The (S)-MTPA esters of the latter were prepared as
described above.
The NMR (400 MHz; CDCl3) spectra of the esters
derived from the racemic alcohols 6a–c were very different to
those obtained from the optically active ones. We used the
signals due to the benzylic methyl group for determination
of the enantiomerical purity. The relevant signals are listed
below:
A 10 L open cylindrical glass vessel equipped with a mechanical
stirrer was charged with tap water (5 L) and glucose (350 g).
Fresh baker’s yeast (1.5 kg) was added in small pieces to the
stirred mixture and fermentation was allowed to proceed for
2 h. The aldehyde 5a (30 g, 158 mmol), adsorbed on the resin
XAD 1180 (150 g), was added in one portion. Vigorous stirring
was continued for 4 days at room temperature. During this time
more baker’s yeast (250 g) and glucose (100 g) were added after
both 24 and 48 h since commencement of fermentation. The
resin was then separated by filtration on a sintered glass funnel
(porosity 0, >160 µm) and the water phase was extracted
again with further resin (50 g). The combined resin crops were
extracted with ethyl acetate (4 × 150 mL) and the acetate solu-
tion was washed with brine. The dried organic phase (Na2SO4)
was concentrated under reduced pressure to give an oil (34 g).
This latter was composed mainly of saturated alcohol 6a and
the related unsaturated allylic alcohol, also produced by micro-
biological reduction. These two compounds showed identical
Rf -values and were not separable by chromatography. In order
to obtain pure 6a we converted selectively the allylic alcohol
in the starting aldehydes 5a by MnO2 oxidation. The crude mix-
ture was dissolved in CHCl3 and treated with MnO2 (70 g), with
stirring of the mixture at reflux for 6 h. The residue obtained
upon filtration and evaporation of the CHCl3 phase was puri-
fied by column chromatography, using hexane–ethyl acetate
(9:1→3:1) as eluent, to give pure (3S)-3-(2-methoxy-4-methyl-
phenyl)butan-1-ol 6a8c (16.4 g, 53%) as a pale yellow oil; [α]D20
ϩ22.8 (c 4, CHCl3) (Found: C, 74.05; H, 9.35. C12H18O2
requires C, 74.19; H, 9.34%); νmax(film)/cmϪ1 3368, 2959, 1612,
1579, 1506, 1465, 1412, 1258, 1042, 812; δH 1.26 (3H, d, J 6.9,
ArCHMe), 1.60–1.76 (1H, m, HCHCH2OH), 1.82–1.98 (1H,
m, HCHCH2OH), 2.35 (3H, s, ArMe), 2.42 (1H, br s, OH),
3.27–3.46 (2H, m, ArCHMe ϩ CH2HCHOH), 3.49–3.59 (1H,
m, CH2HCHOH), 3.83 (3H, s, OMe), 6.69 (1H, s, ArH), 6.77
(1H, d, J 7.7, ArH), 7.07 (1H, d, J 7.7, ArH); m/z (EI) 195
(Mϩ ϩ 1, 3%), 194 (Mϩ, 25), 179 (1), 161 (6), 149 (100), 135 (7),
119 (11), 105 (8), 91 (13), 77 (5), 65 (2), 51 (1), 39 (1).
( )-6a-(S)-MTPA ester: two doublets, δH 1.208 and 1.214,
J 6.9 each.
( )-6b-(S)-MTPA ester: two doublets, δH 1.247 and 1.255,
J 6.9 each.
( )-6c-(S)-MTPA ester: two doublets, δH 1.228 and 1.235,
J 6.9 each.
(S)-(ϩ)-6a-(S)-MTPA ester: doublet, δH 1.208, J 6.9.
(S)-(ϩ)-6b-(S)-MTPA ester: doublet, δH 1.247, J 6.9.
(S)-(ϩ)-6c-(S)-MTPA ester: doublet, δH 1.228, J 6.9.
Since the latter three samples of 6a–c MTPA esters showed
exclusively the three doublets at δ 1.208, 1.247 and 1.228,
respectively, their ees were >98% (1% of analytical sensitivity).
Preparation of iodides 19, 20 and 21
(3S)-3-(2-Methoxy-4-methylphenyl)butyl iodide 19. A solu-
tion of alcohol 6a (2 g, 10.3 mmol) in CH2Cl2 (10 mL) was
treated with tosyl chloride (2.5 g, 13.1 mmol) and pyridine (1.1
mL, 13.6 mmol) and stirred at room temperature for 5 h. The
mixture was then diluted with diethyl ether (150 mL), washed
with 5% aq. HCl (70 mL), and dried over Na2SO4. The solvent
was removed under reduced pressure and the residue was
treated with NaI (7 g, 46.7 mmol) in dry acetone (80 mL) at
reflux for 2 h. The reaction mixture was diluted with water (200
mL), extracted with diethyl ether, and the organic phase was
washed with a solution (2%; 100 mL) of Na2S2O3, dried
(Na2SO4), and concentrated under reduced pressure. The crude
iodide was purified by chromatography, using hexane→hexane–
ethyl acetate 95:5 as eluent, to give pure iodide 198c as a colorless
oil (2.65 g, 84%); [α]D20 ϩ13.7 (c 2, CHCl3) (Found: C, 47.50; H,
5.60; I, 41.63. C12H17IO requires C, 47.39; H, 5.63; I, 41.72%);
νmax(film)/cmϪ1 2959, 1611, 1579, 1507, 1460, 1259, 1043, 812;
δH 1.21 (3H, d, J 6.9, ArCHMe), 1.97–2.28 (2H, m, CH2CH2I),
2.32 (3H, s, ArMe), 3.01–3.11 (2H, m, CH2CH2I), 3.15–3.31
(1H, m, ArCHMe), 3.80 (3H, s, OMe), 6.67 (1H, s, ArH), 6.73
(1H, d, J 7.7, ArH), 7.02 (1H, d, J 7.7, ArH); m/z (EI) 305
(3S)-3-(3-Methoxy-4-methylphenyl)butan-1-ol 6b.9 Colorless
oil (49%); [α]D20 ϩ26.9 (c 2, CHCl3), [α]D20 ϩ32.8 (c 6, acetone)
(Found: C, 74.02; H, 9.37%); νmax(film)/cmϪ1 3348, 2958, 1612,
1583, 1514, 1465, 1416, 1257, 1136, 1043, 995, 856, 817; δH 1.26
(3H, d, J 6.9, ArCHMe), 1.75–1.89 (3H, m, CH2CH2OH ϩ
OH), 2.18 (3H, s, ArMe), 2.74–2.92 (1H, m, ArCHMe), 3.45–
3.63 (2H, m, CH2CH2OH), 3.81 (3H, s, OMe), 6.62–6.73
(2H, m, ArH), 7.04 (1H, d, J 7.5, ArH); m/z (EI) 195 (Mϩ ϩ 1,
7%), 194 (Mϩ, 55), 163 (10), 150 (100), 149 (92), 135 (56), 123
(8), 119 (14), 117 (15), 105 (9), 91 (26), 77 (11), 65 (4), 51 (3),
41 (3).
(3S)-3-(2,5-Dimethoxy-4-methylphenyl)butan-1-ol 6c. This
compound was obtained by yeast reduction of aldehyde 5c
under the same conditions as described above but prolonging
the fermentation for an additional 36 h. Moreover the saturated
alcohol 6c showed a different Rf-value to that of the unsatur-
ated alcohol, so it was separated from the reaction mixture
directly by chromatography without MnO2 treatment as a pale
yellow oil (56%); [α]D20 ϩ40.7 (c 4, CHCl3) (Found: C, 69.73;
3762
J. Chem. Soc., Perkin Trans. 1, 2000, 3758–3764

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(Mϩ ϩ 1, 3%), 304 (Mϩ, 21), 161 (3), 149 (100), 134 (4), 119
m, ArCHCH2CH2), 1.54 (3H, s, CHCMeMe), 1.67 (3H, s,
(13), 105 (9), 91 (19), 77 (8), 65 (4), 51 (3), 39 (6).
CHCMeMe), 1.82–2.00 (2H, m, ArCHCH2CH2), 2.20 (3H, s,
ArMe), 3.00–3.23 (1H, m, ArCHMe), 3.76 (3H, s, OMe), 3.79
(3H, s, OMe), 5.12 (1H, br t, J 7.1, CHCMeMe), 6.67 (2H, s,
ArH); m/z (EI) 263 (Mϩ ϩ 1, 10%), 262 (Mϩ, 56), 247 (1), 231
(1), 219 (1), 205 (4), 192 (8), 179 (100), 165 (20), 152 (27), 135
(4), 115 (5), 105 (4), 91 (15), 77 (8), 69 (9), 55 (7), 41 (23).
(3S)-3-(3-Methoxy-4-methylphenyl)butyl iodide 20. Colorless
oil (84%); [α]D20 ϩ61.3 (c 2, CHCl3) (Found: C, 47.47; H, 5.61;
I, 41.65%); νmax(film)/cmϪ1 2958, 1612, 1583, 1513, 1464, 1415,
1257, 1135, 1043, 851, 815; δH 1.27 (3H, d, J 6.9, ArCHMe),
2.01–2.12 (2H, m, CH2CH2I), 2.18 (3H, s, ArMe), 2.74–2.90
(1H, m, ArCHMe), 2.90–3.01 (1H, m, CH2HCHI), 3.05–3.17
(1H, m, CH2HCHI), 3.83 (3H, s, OMe), 6.64–6.74 (2H, m,
ArH), 7.05 (1H, d, J 7.3, ArH); m/z (EI) 305 (Mϩ ϩ 1, 6%), 304
(Mϩ, 41), 177 (1), 161 (2), 149 (100), 135 (15), 117 (12), 105 (6),
91 (25), 77 (10), 65 (5), 51 (6), 39 (8).
Demethylation of methyl ethers 23 and 24
(S)-(؉)-Curcuphenol 1. Ethanethiol (1.5 mL, 20.3 mmol) was
added dropwise to a suspension of NaH (60% in mineral oil;
880 mg, 22 mmol) in dry DMF (40 mL) under nitrogen. The
reaction temperature was kept below 20 ЊC by external cooling,
and after the addition was complete the mixture was stirred for
30 min at rt. The methyl ether 23 (900 mg, 3.9 mmol) was then
added and the mixture was heated to reflux for 5 h. After cool-
ing, the mixture was diluted with water (100 mL), neutralized
with conc. HCl, and extracted with diethyl ether (2 × 100 mL).
The organic phase was dried (Na2SO4) and concentrated. The
residue was purified by chromatography using hexane–ethyl
acetate (95:5→8:2) as eluent. Bulb-to-bulb distillation
(oven temperature 120 ЊC/0.1 mmHg) afforded pure (S)-(ϩ)-
curcuphenol 12,6,8 as a pale yellow oil (450 mg, 54%); [α]D20 ϩ24.8
(c 1, CHCl3) (Found: C, 82.74; H, 10.20. Calc. for C15H22O:
C, 82.52; H, 10.16%); νmax(film)/cmϪ1 3450, 2962, 2925, 1620,
1581, 1510, 1453, 1377, 1288, 944, 810; δH 1.23 (3H, d, J 6.9,
ArCHMe), 1.44–1.78 (2H, m, ArCHCH2CH2), 1.54 (3H, s,
CHCMeMe), 1.68 (3H, s, CHCMeMe), 1.85–2.05 (2H, m,
ArCHCH2CH2), 2.27 (3H, s, ArMe), 2.86–3.06 (1H, m,
ArCHMe), 4.70 (1H, s, OH), 5.12 (1H, t with further
unresolved couplings, J 7, CHCMeMe), 6.58 (1H, s, ArH), 6.72
(1H, d, J 7.8, ArH), 7.03 (1H, d, J 7.8, ArH); m/z (EI) 219
(Mϩ ϩ 1, 5%), 218 (Mϩ, 32), 203 (3), 175 (1), 161 (10), 148 (34),
135 (100), 121 (23), 115 (14), 105 (5), 91 (19), 83 (4), 77 (6), 69
(6), 55 (6), 41 (9).
(3S)-3-(2,5-Dimethoxy-4-methylphenyl)butyl iodide 21. Color-
less oil (89%); [α]D20 ϩ44.8 (c 2, CHCl3) (Found: C, 46.89; H,
5.75; I, 37.90. C13H19IO2 requires C, 46.72; H, 5.73; I, 37.97);
νmax(film)/cmϪ1 2958, 1505, 1465, 1399, 1209, 1048, 861; δH 1.24
(3H, d, J 6.9, ArCHMe), 2.03–2.13 (1H, m, HCHCH2I), 2.14–
2.25 (1H, m, HCHCH2I), 2.20 (3H, s, ArMe), 3.02–3.12 (2H,
m, CH2CH2I), 3.18–3.28 (1H, m, ArCHMe), 3.77 (3H, s, OMe),
3.79 (3H, s, OMe), 6.65 (1H, s, ArH), 6.68 (1H, s, ArH); m/z
(EI) 335 (Mϩ ϩ 1, 7%), 334 (Mϩ, 54), 319 (1), 206 (1), 192 (3),
179 (100), 164 (24), 149 (11), 135 (5), 115 (6), 105 (6), 91 (17),
77 (13), 65 (5), 53 (6), 39 (8).
Preparation of compounds 23–25
(S)-(؉)-Curcuphenol methyl ether 23. The iodide 19 (2 g, 6.6
mmol) as a solution in dry THF (40 mL) was cooled to Ϫ60 ЊC
and treated under nitrogen with CuI (140 mg, 0.7 mmol) and
Grignard 22 (10 mmol; 2 M solution in THF). The reaction
mixture was allowed to warm to 0 ЊC and was stirred at this
temperature for 8 h. Work-up with aq. NH4Cl, extraction with
diethyl ether, and concentration of the dried (Na2SO4) organic
phase gave the crude product. The latter was purified by
chromatography with hexane→hexane–ethyl acetate 95:5
as eluent. Bulb-to-bulb distillation (oven temperature 115 ЊC/
0.2 mmHg) afforded pure (S)-(ϩ)-curcuphenol methyl ether
238c as a colorless oil (1.15 g, 76%); [α]D20 ϩ7.8 (c 1, CHCl3)
(Found: C, 82.75; H, 10.38. C16H24O requires C, 82.70; H,
10.41%); νmax(film)/cmϪ1 2960, 2925, 1612, 1579, 1506, 1459,
1260, 1044, 810; δH 1.17 (3H, d, J 6.9, ArCHMe), 1.40–1.75
(2H, m, ArCHCH2CH2), 1.53 (3H, s, CHCMeMe), 1.67 (3H, s,
CHCMeMe), 1.82–2.05 (2H, m, ArCHCH2CH2), 2.32 (3H, s,
ArMe), 3.04–3.21 (1H, m, ArCHMe), 3.79 (3H, s, OMe), 5.11
(1H, br t, J 7, CHCMeMe), 6.66 (1H, s, ArH), 6.74 (1H, d,
J 7.7, ArMe), 7.04 (1H, d, J 7.7, ArH); m/z (EI) 233 (Mϩ ϩ 1,
6%), 232 (Mϩ, 36), 217 (4), 189 (2), 175 (8), 162 (13), 149 (100),
135 (15), 119 (9), 110 (10), 91 (15), 77 (4), 69 (5), 55 (3), 41 (8).
(S)-(؉)-Xanthorrhizol 2.9,22 Yield 90%; pale yellow oil (oven
temperature 125 ЊC/0.1 mmHg); [α]D20 ϩ47.6 (c 2, acetone)
(Found: C, 82.65; H, 10.15%); νmax(film)/cmϪ1 3387, 2961,
2925, 1590, 1450, 1421, 1376, 1251, 1122, 813; δH 1.19 (3H, d,
J 6.9, ArCHMe), 1.50–1.63 (2H, m, ArCHCH2CH2), 1.53
(3H, s, CHCMeMe), 1.67 (3H, s, CHCMeMe), 1.81–1.96 (2H,
m, ArCHCH2CH2), 2.19 (3H, s, ArMe), 2.48–2.68 (1H, m,
ArCHMe), 4.70 (1H, br s, OH), 5.08 (1H, t with further
unresolved couplings, J 7.2, CHCMeMe), 6.60 (1H, d, J 1.5,
ArH), 6.67 (1H, dd, J 7.7 and 1.5, ArH), 7.02 (1H, d, J 7.7,
ArH); m/z (EI) 219 (Mϩ ϩ 1, 7%), 218 (Mϩ, 48), 203 (1), 175
(4), 161 (11), 148 (32), 136 (100), 121 (67), 107 (7), 91 (20), 77
(9), 69 (6), 55 (8), 41 (13).
Preparation of curcuquinone 3 and curcuhydroquinone 4
(S)-(؉)-Xanthorrhizol methyl ether 24.9,22 Yield 85%; color-
less oil (oven temperature 120 ЊC/0.2 mmHg); [α]D20 ϩ42.5 (c 2,
CHCl3), [α]D20 ϩ45.4 (c 5, acetone) (Found: C, 82.62; H, 10.38%);
νmax(film)/cmϪ1 2960, 2925, 1613, 1583, 1513, 1465, 1415, 1257,
1134, 1044, 852, 815; δH 1.23 (3H, d, J 6.9, ArCHMe), 1.50–
1.65 (2H, m, ArCHCH2CH2), 1.53 (3H, s, CHCMeMe), 1.67
(3H, s, CHCMeMe), 1.82–1.96 (2H, m, ArCHCH2CH2), 2.18
(3H, s, ArMe), 2.57–2.73 (1H, m, ArCHMe), 3.82 (3H, s,
OMe), 5.09 (1H, t with further unresolved couplings, J 7.1,
CHCMeMe), 6.65 (1H, s, ArH), 6.68 (1H, dd, J 7.3 and 1.6,
ArH), 7.03 (1H, d, J 7.3, ArH); m/z (EI) 233 (Mϩ ϩ 1, 8%), 232
(Mϩ, 44), 217 (1), 189 (3), 175 (7), 162 (19), 150 (100), 135 (63),
119 (9), 105 (6), 91 (17), 77 (5), 69 (4), 55 (5), 41 (10).
(S)-(؊)-Curcuquinone 3. To a solution of curcuhydroquinone
dimethyl ether 25 (400 mg, 1.5 mmol) in acetonitrile (20 mL)
was added dropwise aq. CAN (2.5 g, 4.6 mmol in 15 mL). After
being stirred for 30 min at rt, the reaction mixture was extracted
with chloroform (2 × 80 mL) and the organic phase was con-
centrated under reduced pressure. The residue was purified by
chromatography using hexane–ethyl acetate (95:5→8:2) as
eluent. Bulb-to-bulb distillation (oven temperature 115 ЊC/0.1
mmHg) afforded pure (S)-(Ϫ)-curcuquinone 32,24 (310 mg,
87%); [α]D20 Ϫ0.9 (c 1, CHCl3), [α]25046 Ϫ15.6 (c 1, CHCl3) (Found:
C, 77.73; H, 8.65. Calc. for C15H20O2: C, 77.55; H, 8.68%);
νmax(film)/cmϪ1 2967, 1656, 1611, 1450, 1377, 1242, 913; δH 1.10
(3H, d, J 6.9, quinoneCHMe), 1.33–1.60 (2H, m, ArCH-
CH2CH2), 1.53 (3H, s, CHCMeMe), 1.64 (3H, s, CHCMeMe),
1.85–2.00 (2H, m, ArCHCH2CH2), 2.02 (3H, d, J 1.6,
quinoneMe), 2.77–2.98 (1H, m, quinoneCHMe), 5.03 (1H, br t,
J 7, CHCMeMe), 6.49 (1H, m, COCHC), 6.57 (1H, q, J 1.6,
MeCCHCO); m/z (EI) 234 (Mϩ ϩ 2, 6%), 232 (Mϩ, 3), 217 (1),
(S)-(؉)-Curcuhydroquinone dimethyl ether 25.24 Yield 89%;
colorless oil (oven temperature 140 ЊC/0.2 mmHg); [α]D20 ϩ40.9
(c 2, CHCl3) (Found: C, 77.70; H, 9.97. C17H26O2 requires C,
77.82; H, 9.99%); νmax(film)/cmϪ1 2960, 2929, 1505, 1466, 1399,
1208, 1049, 861; δH 1.18 (3H, d, J 7, ArCHMe), 1.45–1.75 (2H,
J. Chem. Soc., Perkin Trans. 1, 2000, 3758–3764
3763

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5 F. A. Macias, J. M. G. Molinillo, R. M. Varela and A. Torres, J. Org.
Chem., 1994, 59, 8261.
6 A. E. Wright, S. A. Pomponi, O. J. McConnell, S. Kohmoto and
P. J. McCarthy, J. Nat. Prod., 1987, 50, 976.
189 (2), 175 (3), 164 (5), 151 (100), 137 (4), 122 (32), 107 (5),
91 (6), 79 (6), 69 (7), 55 (6), 41 (13).
(S)-(؉)-Curcuhydroquinone 4. A cooled (0 ЊC) solution of
(S)-(Ϫ)-curcuquinone 3 (350 mg, 1.5 mmol) in MeOH (20 mL)
was stirred with NaBH4 (100 mg, 2.6 mmol). After 15 min, 5%
aq. HCl (40 mL) was added and the mixture was extracted with
ethyl acetate (2 × 70 mL). The organic phase was washed with
brine (50 mL), dried (Na2SO4), and concentrated under reduced
pressure. The residue was purified by chromatography using
hexane–ethyl acetate (9:1→7:3) as eluent to afford pure
curcuhydroquinone 42,10,24 (280 mg, 80%); [α]D20 ϩ47.1 (c 1,
CHCl3) (Found: C, 76.73; H, 9.48. Calc. for C15H22O2: C, 76.88;
H, 9.46%); νmax(film)/cmϪ1 3342, 2963, 2927, 1516, 1456, 1418,
1377, 1306, 1188, 1002, 874, 832; δH 1.19 (3H, d, J 6.9,
ArCHMe), 1.49–1.65 (2H, m, ArCHCH2CH2), 1.53 (3H, s,
CHCMeMe), 1.68 (3H, s, CHCMeMe), 1.86–2.01 (2H, m,
ArCHCH2CH2), 2.16 (3H, s, ArMe), 2.80–3.02 (1H, m,
ArCHMe), 4.48 (2H, br s, OH), 5.12 (1H, br t, J 7.1, CH-
CMeMe), 6.55 (1H, s, ArH), 6.58 (1H, s, ArH); m/z (EI) 235
(Mϩ ϩ 1, 7%), 234 (Mϩ, 51), 191 (2), 177 (6), 164 (16), 151
(100), 137 (21), 124 (8), 107 (3), 95 (8), 77 (5), 69 (6), 55 (6), 41
(8).
7 S. L. Graham, C. H. Heathcock, M. C. Pirrung, F. Plavac and
C. T. White, in The Total Synthesis of Natural Products, ed.
J. ApSimon, Wiley and Sons, New York, 1983, vol. 5, p. 35.
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Acknowledgements
We thank MURST and CNR Progetto Finalizzato Biotec-
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