Synthesis of wasabidienone a via a novel acyl rearrangement reaction from carbon to oxygen

Article abstract of DOI:10.1055/s-1998-2083

Wasabidienone A (WA), a tautomeric mixture of 5-hydroxy-3-methoxy-4,6- dimethyl-(6S)-[(2R)-2-methylbutyryloxy]-cyclohexa-2,4-dien-1-one (1a) and 5- hydroxy-3-methoxy-2,6-dimethyl-(6R)-[(2R)-2-methylbutyryloxy]cyclohexa-2,4- dien-1-one (1b) was synthesized via a novel rearrangement reaction of an acyl group from carbon to the β-hydroxy oxygen on the cyclohexadienone ring. This reaction may occur during fermentation of Phoma wasabiae to form WA from WB₁.

Full text of DOI:10.1055/s-1998-2083

June 1998
SYNTHESIS
889
Synthesis of Wasabidienone A via a Novel Acyl Rearrangement Reaction from Carbon
to Oxygen
Shingo Sato,* Heitaro Obara, Katsuhiro Yusa, Kazuhiro Sudo, Masaharu Sando, Hiroyuki Kagaya, Hiroki Ijichi,
Shigeru Matsuba, Toshihiro Kumazawa, Jun-ichi Onodera
Department of Materials Science and Engineering, Faculty of Engineering, Yamagata University, Jonan, Yonezawa, Yamagata 992, Japan
Fax +81(238)263413 ; E-mail: tj419 @dipfr.dip.yz.yamagata-u.ac.jp
Received 6 October 1997; revised 12 November 1997
dimethyl-5-methoxycyclohex-5-ene-1,3-dione (4), which
was elucidated in detail by means of spectroscopic analy-
sis.
Abstract: Wasabidienone A (WA), a tautomeric mixture of
5-hydroxy-3-methoxy-4,6-dimethyl-(6S)-[(2R)-2-methylbutyry-
loxy]-cyclohexa-2,4-dien-1-one (1a) and 5-hydroxy-3-methoxy-
2,6-dimethyl-(6R)-[(2R)-2-methylbutyryloxy]cyclohexa-2,4-dien-
1-one (1b) was synthesized via a novel rearrangement reaction of
an acyl group from carbon to the b–hydroxy oxygen on the cyclo-
hexadienone ring. This reaction may occur during fermentation of
Phoma wasabiae to form WA from WB1.
Key words: wasabidienone A, Phoma wasabiae, oxo-enol tau-
tomer, cyclohexadienone, acyl rearrangement
Wasabidienone A (WA), which is a pale yellow pigment
having a highly oxidized cyclohexa-2,4-dienone skeleton
and exists as a mixture of oxo–enol tautomers, is one of
the potato metabolites of Phoma wasabiae producing a
polyphenol oxidase and a peroxidase.1
Scheme 1
We employed this novel reaction to the other cyclohexa-
dienone compounds (see Table 1). Even when the bulkier
migrating acyl group such as a 3-phenylpropanoyl group
(run 8) or the bulkier alkyl group on the b-carbon such as
iso-propyl and 3-methylbut-2-enyl groups (runs 6 and 9)
was employed, the rearrangement of an acyl group to the
b-positioned tert-alcohol oxygen proceeded. Surprising-
ly, the rearrangement of the 2-methylbutanoyl group pro-
ceeded in good yield (run 10).
Since we were interested in the characteristics and biosyn-
thesis of unique pigments which have a chiral carbon on
the cyclohexadienone ring and show oxo–enol tautomer-
ism such as pigments of safflower petals,2 we were also
interested in the structure and biosynthesis of WA and un-
dertook its synthesis. Herein, we would like to report the
synthesis of WA using a novel acyl rearrangement reac-
tion from carbon to oxygen.
The further crossover experiment was carried out. A mix-
ture of the substrates of runs 2 and 4, and runs 6 and 8
(1:1) gave only the corresponding intramolecular-rear-
rangement products respectively, and none of the intermo-
lecular-rearrangement product. From the above result, it is
suggested that this rearrangement reaction proceeds in-
tramolecularly. The mechanism of this rearrangement re-
action can be explained as follows: the alkoxy anion
generated under alkaline conditions attaches to the b-acyl
carbonyl carbon, giving the rearrangement product of an
acyl group to the b-positioned hydroxy oxygen.3
Figure
During the synthesis of WA, it was found that cyclohexa-
2,5-dienone 2 isomerized to a five-membered ring 3 under
the conditions of deacetylation reaction by refluxing in We then attempted the synthesis of WA using this rear-
HCl solution. This isomerization also easily occurred un- rangement reaction as the key step (Scheme 2). The
der the conditions of UV light irradiation or alkaline solu- Friedel–Crafts acylation of 1,3,4,5-benzenetetrol14 with
tion, and Soga et al.1b–d have also reported that the racemic 2-methylbutanoic acid in the presence of
refluxing of WB1 in benzene afforded the five-membered BF3·OEt2 at 80°C gave a monoacylated product 5 in
ring, WB0 (see Scheme 3). Because of these reasons, after 77.5% yield. The bis-C-methylation of 5 with methyl io-
protection of the C-5 enol hydroxy group of 2 by diazo- dide in the presence of sodium hydride followed by O-
methane treatment, the deacetylation reaction was then methylation with diazomethane provided 5-methoxycy-
examined (Scheme 1). Under the conditions of refluxing clohexa-2,5-dienone 7 as diastereomixtures in 56% yield.
in a 5% Na2CO3 aqueous solution and methanol, 5-O-me- Since 7 was inseparable, the condensation of 7 with an N-
thylated 2 was subjected to deacetylation without isomer- carbobenzyloxy (Cbz)-L-valine was performed to afford
ization and the acetyl group migrated from carbon to the 8a and 8b as a 1:1 mixture retaining the chirality on the
b-positioned hydroxy oxygen, providing 4-acetoxy-4,6- cyclohexadienone ring in a total of 97% yield, which

890
Papers
SYNTHESIS
Table. Acyl Rearrangement Reaction of Cyclohexadienone
identical with the natural specimen. It can be assumed that
natural WA was also produced from the other metabolite,
WB1 via rearrangement reaction of the 2-methylbutanoyl
group to the b-hydroxy group, during fermentation of
Phoma wasabiae, as well as WB0 being produced from
WB1 (Scheme 3).1b–e
Run R1
R2
R3
R4
R5 Reflux Isolated
time (h) yield (%)
1
2
3
4
5
6
7
8
9
Me
Et
H
Et
Me Me
Me Me
Me Me
Me Et
Me Et
Me Me
i-Pr Et
H
H
0.75 18 (30a)
1
30b (33a)
c
Me
Me
Me
i-Pr
H
Me
Me
Me
i-Pr
H
Me >3
H
Me >3
H
H
H
H
–
0.72 53 (7a)
c
–
2.17 40 (39a)
1.5
37 (24a)
Me
3-
Me
3-
Me PhCH2CH2
Me i-Bu
0.80 57d (8a)
5.16 20 (23a)
methyl- methyl-
but-2- but-2-
enyl
Me
enyl
Me
10
Me Et(Me)CH
H
1
90 (5a)
All compounds gave satisfactory spectroscopic data and microanaly-
ses.
a Recovery.
b 50 and d17% of them were their de-O-acylated products, respectively.
c No reaction.
could be easily separated by silica gel column chromatog-
raphy (silica gel TLC, EtOAc/hexane = 2:1, 8a; Rf = 0.6
and 8b; 0.4).5 Each diastereomixture 8a and 8b had a va-
line moiety removed by sodium methoxide to yield 9a and
9b respectively in 74 % yield, each of which was a race-
mic mixture in the 2-methylbutanoyl moiety. Next, the
crucial rearrangement reactions by refluxing of 9a and 9b
in a 5 % Na2CO3 aqueous solution and methanol (12:1)
produced the rearrangement products 10a and 10b in 90%
yield respectively. As the optical activity of diastereomer
10b showed the same positive sign as that of the natural
WA’s methyl ether,1b–d subsequent diazomethane treat-
ment of 10b was carried out, yielding methyl ether 11b
and its regioisomer 12b in total of 79% yield (ratio 1:1.5).
The 1H NMR spectrum of 11b was similar to that of one
of the two methyl ethers derived from the natural WA.6
Upon further HPLC analytic comparison of the diastereo-
meric mixture 11b and the natural one (silica column,
hexane/EtOAc = 80:20, 1 mL/min, retention time; 14.1
and 15.7 min, ratio 1.2:1), the retention time of the first
eluate of 11b was identical with that of the natural methyl
ether. Their specific rotations were also identical. Finally,
regioselective de-O-methylation of the C-5 methoxy
group of the chiral first eluate of 11b which was separated
by preparative HPLC, was performed by using aluminum
chloride and ethanethiol in CH2Cl2 affording the desired
chiral WA in 67% yield. The synthetic WA was unstable
and identical with the natural metabolite in silica gel TLC,
mass, IR and 1H NMR spectra, and further diazomethane
treatment of WA provided two regioisomeric methyl
ethers 11b and 13 (1:1), as well as natural one.1b–d Thus,
it was confirmed that WA derived from the chiral 11b was
Scheme 2
Scheme 3

June 1998
SYNTHESIS
891
Mps were determined on a Yanagimoto micro-melting point appara- 3,4,5-Trihydroxy-4,6-dimethyl-2-(2-methylbutanoyl)cyclohexa-
tus and are uncorrected. Mass spectra were recorded on a JEOL JMS- 2,5-dien-1-one (6):
AX505HA spectrometer and HRMS were recorded on a HX-110 To a solution of 5 (22.1 mmol, 5.00 g) in anhyd DMSO (10 mL) a
spectrometer (The Analytical Center of the Graduate School of Sci- suspension of NaH (55.3 mmol, 1.33 g) in anhyd toluene was added
ence at Tohoku University). Electron spectra were recorded on a Hi- under N2. After stirring until the end of the evolution of H2 (for ca.
tachi 228A spectrometer. IR spectra were recorded on a Horiba FT- 0.5h), MeI (55.3 mmol, 7.85 g) was added slowly to the mixture and
200 IR spectrometer as KBr pellets or neat on NaCl cell. 1H and 13
C
then stirred at r.t. for 2h. The mixture was quenched by adding an
NMR spectra were recorded on a JEOL 270, a Varian Mercury 200 ice cold 2M HCl solution and extracted with EtOAc (3 ´ 80 mL).
and a Varian INOVA 500 spectrometers with TMS as an internal The combined extracts were washed with brine and dried (Na2SO4),
standard. Optical rotations were recorded on a JASCO DIP-360 digi- and then evaporated. The residual product was purified by column
tal polarimeter using a 0.5 dm cell. Analytical TLC was performed on chromatography (EtOAc/hexane) to give 6 as a pale brown oil
Merck silica gel 60 F254 plates. Flash column chromatography was (3.20 g, 57%).
carried out with Merck silica gel 60 (230–400 mesh). HPLC was per- EIMS: m/z = 254(M+).
formed on a Hitachi L-7100 and L-4200H system using the following
conditions; column: GL Sciences Inc., Inertsil SIL 100-5 column (5 ´
3,4-Dihydroxy-5-methoxy-4,6-dimethyl-2-(2-methylbutanoyl)cy-
150 mm), solvent: hexane: EtOAc = 80:20, flow rate: 1 mL/min,
clohexa-2,5-dien-1-one (7):
wave length: UV254 or 250 nm. Preparative HPLC; Inertsil SIL 100-
To a solution of 6 (11.8 mmol, 3.00 g) in EtOAc a solution of dia-
5, 10 ´ 250 mm, hexane:EtOAc = 75:25, 5 mL/min, UV254 nm.
zomethane in Et2O was added dropwise in an ice bath until the disap-
pearance of the material on silica gel TLC monitoring. After
2-Acetyl-3,4,5-trihydroxy-4,6-dimethylcyclohexa-2,5-dien-1-one
(2): colorless prisms, mp 153–154°C (lit.7 150.5–151.5°C).
EIMS: m/z = 212(M+).
UV(EtOH): lmax(loge) = 229(4.18), 321(4.09), 358(4.01) nm.
IR(KBr): n = 3384, 3181, 2985, 1664, 1533, 1479, 1279 cm–1.
1H NMR (CDCl3): d = 1.57 and 1.87 (each 3H, s, CH3 ´ 2), 2.57 (3H,
s, Ac), 18.74 (1H, s, chelated OH).
evaporating of the solvent, the residual syrup was purified by column
chromatography (EtOAc/hexane) to give 7 (3.07 g, 97.0%) as a pale
yellow oil.
EIMS: m/z = 268(M+).
4-O-(N-Benzyloxycarbonyl-L-valyl)-3-hydroxy-4,6-dimethyl-2-
(dl-2-methylbutanoyl)-5-methoxy-(4R- and 4S)cyclohexa-2,5-
dien-1-one (8a and 8b):
Anal. (C10H12O5): Calc. C, 56.60; H, 5.70. Found C, 56.56; H, 5.74.
4-Acetyl-3,4-dihydroxy-2-methylcyclopent-2-en-1-one (3): colorless
prisms, mp 152–154°C.
To a solution of 7 (9.47 mmol, 2.54 g) and N-Cbz-L-valine
(10.4 mmol, 3.54 g) in anhyd CH2Cl2 (3 mL) DCC (13.46 mmol, 2.78
g) and DMAP (1.28 mmol, 156 mg) were added in an ice bath under
Ar. After stirring at r.t. for 5h, EtOAc (10 mL) was added to the mix-
ture and then the precipitates were filtered through a pad of Celite.
The filtrate was evaporated and separated by column chromatography
(toluene/EtOAc/HOAc) to give 8a (2.26 g, 47.6%) and 8b (2.31 g,
48.8%) as a colorless syrup, [a]D22 –231 (c = 1.24, CHCl3).
EIMS: m/z = 170(M+).
UV(EtOH): lmax(loge) = 207 (3.51), 254 (4.12) nm.
IR(KBr) n = 3481, 2935, 1718, 1560, 1410, 1361, 1265 cm–1.
1H NMR (DMSO-d6): d = 1.49 (3H, s, CH3), 2.20 (3H, s, Ac), 2.30
and 2.80 (each 1H, d, J=17Hz, CH2), 6.2 (br s, OH).
13C NMR (DMSO-d6): d = 208.9(s), 192.8(s), 190.6(s), 111.3(s),
84.0(s), 43.3(t), 26.0(q), 6.3(q).
8a: FABMS : m/z = 502(M++H).
IR (neat): n = 3344, 2968, 1716, 1531, 1456 cm–1.
1H NMR (CDCl3): d = 0.86–1.19 (12H, m, CH3 ´ 4), 1.39 (1H, m,
CH2CH3), 1.69 (3H, each s, CH3), 1.71 (1H, m, CH2CH3), 1.95 (3H,
s, CH3), 2.41 (lH, m, CH(CH3)2), 3.74 (lH, m, CH(CH3)CH2CH3),
3.86 (3H, each s, CH3), 4.40 (1H, dd, J=3.9 and 9.3Hz, >CHNH), 5.08
(2H, s, CH2Ph), 7.33 (5H, m, ArH), 19.27 and 19.26 (1H, each s, che-
lated OH).
Anal. (C8H10O4): Calc. C, 56.47; H, 5.92. Found C, 56.35; H, 5.94.
4-Acetoxy-5-methoxy-4,6-dimethylcyclohex-5-ene-1,3-dione (4): pale
yellow prisms, mp 146°C.
EIMS: m/z = 226(M+).
UV(EtOH): lmax(loge) = 247(4.06), 297(sh, 3.65), 347(sh, 3.43) nm.
1H NMR(CDCl3): d = 1.64 and 1.94 (each 3H, s, CH3 ´ 2), 2.13 (3H,
s, OAc), 3.57 (2H, s, COCH2CO, disappeared with D2O), 3.92 (3H, s,
OCH3).
8b: [a]D22 +l28 (c = 1.59, CHCl3).
FABMS: m/z = 502(M++H).
IR (neat): n = 3340, 2968, 1716, 1527, 1456 cm–1.
1H NMR (CDCl3): d = 0.86–l.19 (12H, m, CH3 ´ 4), 1.42 (1H, m,
CH2CH3), 1.55 and 1.56 (3H, each s, CH3), 1.72 (1H, m, CH2CH3),
1.97 (3H, s, CH3), 2.26 (1H, m, CH(CH3)2), 3.78 (1H, m,
CH(CH3)CH2CH3), 4.35 (1H, dd, J=3.9 and 9.3Hz, >CHNH), 5.12
(2H, s, CH2Ph), 7.26 (5H, m, ArH), 19.25 and 19.26 (1H, each s, che-
lated OH).
13C NMR(CDCl3): d = 198.2(s), 191.3(s), 170.1(s), 169.5(s), 119.1(s),
80.1(s), 61.8(q), 50.2(t), 23.4(q), 20.3(q), 10.1(q).
Anal. (C11H14O5): Calc. C, 58.40; H, 6.24. Found C, 58.51; H, 6.43.
2-(dl-2-Methylbutanoyl)benzene-1,3,4,5-tetrol (5):
A mixture of benzenetetrol (35.2 mmol, 5.00 g), dl-2-methylbutano-
ic acid (70.4 mmol, 7.68 mL), BF3·OEt2 (84.5 mmol, 10.4 mL) and
powdered molecular sieves 4Å (1 g) was heated at 80°C under Ar
for 1h. After cooling, the mixture was poured into ice-water and
then extracted with EtOAc (3 ´ 100 mL). The combined extracts
were washed with brine and dried (Na2SO4). After evaporation of
the solvent, the residual reddish brown syrup was purified by col-
umn chromatography (EtOAc/hexane) to give 5 (6.17 g, 77.5%) as
a pale brown oil.
3,4-Dihydroxy-4,6-dimethyl-5-methoxy-2-(dl-2-methylbutanoyl)-
(4R- and 4S)-cyclohexa-2,5-dien-1-one (9a and 9b):
To a stirred solution of 8a (4.107 mmol, 2.058 g) in anhyd MeOH
(5 mL) 28% NaOMe (13 mmol, 2.51 g) was added and then stirred at
r.t. under Ar for 2h. The mixture was poured into the ice cold 2M HCl
solution (30 mL) and extracted with EtOAc (2 ´ 20 mL). The com-
bined extracts were washed with brine and dried (Na2SO4) and then
evaporated. The residual syrup was purified by column chromatogra-
phy (EtOAc/hexane) to give 9a (0.814 g, 74.0%) as a colorless syrup.
9b (0.812 g, 73.8%).
EIMS: m/z = 226(M+).
IR(neat): n = 3377, 2968, 1645, 1456, 1379, 1226 cm–1.
1H NMR (DMSO-d6): d = 0.83(3H, t, J=7.4Hz, CH2CH3), 1.05(3H,
d, J=6.6Hz, >CHCH3), 1.31 and 1.70 (each 1H, m, CH2CH3), 3.78
(1H, m, >CHCH3), 5.87 (1H, s, ArH), 7.88 (1H, br s, OH), 10.09,
11.24 and 12.27 (each 1H, s, OH ´ 3).
EI MS: m/z = 268(M+). 9a; [a]D23 –5.07 (c = 1.10, CHCl3), 9b; [a]D22
+4.38 (c = 1.09, CHCl3).

892
Papers
SYNTHESIS
13C NMR(CDCl3): d = 187.60, 174.84, 170.97, 167.13, 116.90,
100.45, 75.17, 61.40, 56.04, 41.00, 26.43, 25.36, 16.79, 11.62, 9.55.
Anal. (C15H22O5): Calc. C, 63.8l; H, 7.85. Found C, 63.51; H, 7.77.
12b* (The latter eluate on HPLC: Rt = 17.3 min): [a]D22 +69.5 (c =
1.05, CHCl3).
4,5-Dimethyl-5-methoxy-(4R and 4S)-4-(2-methylbutyryloxy)cy-
clohex-5-ene-1,3-dione (10a and 10b):
Compound 9a or 9b (3.32 mmol, 890 mg) was added to a mixture of
a 5% Na2CO3 aqueous solution (21 mL) and MeOH (1.6 mL), and the
mixture was then refluxed for 1h. The mixture was cooled and poured
into an ice cold 1M HCl solution and then extracted with EtOAc (2 ´
20 mL). The combined extracts were washed with brine and dried
(Na2SO4), then evaporated. The residual syrup was purified by col-
umn chromatography (EtOAc/hexane) to give 10a (800 mg, 90%) as
a colorless prisms and recovered 9a (22 mg, 2.5%). 10b (90%), 9b
(2.4%).
1H NMR (CDCl3): d = 0.930 (3H, t, J=7.4 Hz, CH3), 1.149 (3H, d,
J=7.1Hz), 1.483 (1H, m, CH2), 1.614 (3H, s, CH3), 1.688 (1H, m,
CH2), 1.911 (3H, s, CH3), 2.438 (1H, m, >CH), 3.702 (3H, s, OCH3),
3.839 (3H, s, OCH3), 5.529 (1H, s, olefinic H).
13C NMR(CDCl3): d = 187.57, 175.00, 171.02, 167.04, 117.14,
100.39, 75.23, 61.38, 55.96, 40.56, 26.65, 25.33, 16.56, 11.28, 9.51.
10a: HPLC: retention time (Rt) = 17.6 and 18.6 min (1:1). [a]D23 –180
(c = 0.96, CHCl3).
10b: colorless prisms. mp 122°C.
Wasabidienone A: 5-Hydroxy-3-methoxy-4,6-dimethyl-(6R)-
[(2R)-2-methylbutyryloxy]cyclohexa-2,4-dien-1-one (1a) and 5-
Hydroxy-3-methoxy-2,6-dimethyl-(6S)-[(2R)-2-methylbutyry-
loxy]-cyclohexa-2,4-dien-1-one (1b):
HPLC: Rt = 17.4 and 18.2 min (1:1). [a]D23 +155 (c = 1.09, CHCl3).
EIMS: m/z = 268(M+).
To a stirred solution of the chiral first eluate of 11b (127 mg,
0.45 mmol) and EtSH (365 mL, 4.95 mmol) in CH2Cl2 (2 mL), AlCl3
(540 mg, 4.05 mmol) was added at 0°C under Ar and the mixture was
stirred for 18 h at r.t. The mixture was poured into an ice 1M HCl mix-
ture and extracted with EtOAc (3 ´ 10 mL). The combined extracts
were washed with brine and dried (Na2SO4), and then evaporated.
The residue was purified by column chromatography (hexane/EtOAc
= 2:1) to give WA (84 mg, 69%) as a pale yellow oil.
1H NMR (DMSO-d6): d = 0.89 (3H, t, J=7.4Hz, CH2CH3), 1.06 and
1.08 (3H, each d (1:1.2), J = 6.9 Hz, CHCH3), 1.36–1.65 (2H, m,
CH2), 1.76 and 1.77 (3H, each s (1:1.2), CH3), 2.40 (1H, m, >CH),
3.74 and 3.75 (3H, each s (1:1.2), OCH3), 5.32 (1H, s, olefinic H).
Anal. (C11H14O5): Calc. C, 62.67; H, 7.51. Found C, 62.40; H, 7.63.
3,5-Dimethoxy-4,6-dimethyl-(6R)-6-[(2R)-2-methylbutyryloxy]-
cyclohexa-2,4-dien-1-one (11b): and 2,4-Dimethyl-3,5-dimethoxy-
(4S)-4-[(2R and 2S)-2-methylbutyryloxy]cyclohexa-2,5-diene-1-
one (12b, 12b*):
EIMS: m/z = 268(M+).
IR(neat): n = 3450–3200, 2972, 2939, 2879, 1732, 1668, 1614 cm–1,
natural WA : lit.1b–d (CCl4) : n = 3450–3200, 1735, 1675, 1620 cm–1.
To a solution of 9b (2.63 mmol, 705 mg) in EtOAc a solution of di-
azomethane in Et2O was added dropwise in an ice bath until the dis-
appearance of the material on silica gel TLC monitoring. After evap-
orating of the solvent, the residual syrup was purified by column
chromatography (EtOAc/hexane = 1:2) to give 11b (236 mg, 31.8%)
as a pale yellow oil and 12b (354 mg, 47.7%) as colorless prisms.
3,5-Dimethoxy-2,6-dimethyl-(6R)-6-[(2R)-2-methylbutyryloxy]-
cyclohexa-2,4-dien-1-one (13):
A diazomethane treatment of the WA and a subsequent purification
were carried out in a same manner as the synthesis of 11b and 12b,
pale yellow crystals, [a]D24 +93 (c = 0.27, CHCl3), natural : lit.1b–d
+140 (c = 2.0).
11b: (The first eluate on HPLC: Rt = 14.1 min): pale yellow oil. [a]D23
+65.3 (c = 2.10, CHCl3), (natural 11b: +65.1, lit.1b–d +63.6).
EIMS: m/z = 282(M+).
HPLC: Rt = 11.3 min.
EIMS: m/z = 282(M+).
UV(EtOH): lmax(loge) = 221(4.16), 366(3.55) nm.
IR(neat): n = 2968, 2937, 1734, 1653, 1637, 1558, 1373, 1217,
1091 cm–1.
UV(EtOH): lmax(loge) = 215(4.20), 319(3.54) nm.
1H NMR (CDCl3): d = 0.979 (3H, t, J=7.4 Hz, CH2CH3), 1.166 (3H,
d, J=7.1Hz, CHCH3), 1.505 (3H, s, CH3), 1.496 and 1.753 (each 1H,
m, CH2), 1.861 (3H, s, CH3), 2.482 (1H, m, >CH), 3.764 (3H, s,
OCH3), 3.794 (3H, s, OCH3), 5.446 (1H, s, olefinic H).
13C NMR(CDCl3): d = 195.40(s), 175.52(s), 172.70(s), 163.24(s),
112.68(s), 95.99(d), 79.16(s), 61.22(q), 56.20(q), 40.00(d), 26.56(t),
23.97(q), 16.28(q), 11.26(q), 9.48(q).
1H NMR (CDCl3): d = 0.923 (3H, t, J= 7.4 Hz, CH3), 1.15 (3H, d,
J=7.1Hz), 1.49 (3H, s, CH3), 1.50 and 1.69 (each 1H, m, CH2), 1.78
(3H, s, CH3), 2.48 (1H, m, >CH), 3.74 (3H, s, OCH3), 3.91 (3H, s,
OCH3), 5.48 (1H, s, olefinic H).
13C NMR(CDCl3): d = 194.6(s), 175.2(s), 169.2(s), 167.8(s),
106.8(s), 86.1(d), 77.9(s), 55.9(q), 55.8(q), 40.1(d), 26.7(t), 24.9(q),
16.4(q), 11.3(q), 7.3(q).
HRMS: m/z = calc. for C15H22O5 282.1467, found 282.1465.
HRMS: calc. for C15H22O5 282.1467, found 282.1472.
3,5-Dimethoxy-4,6-dimethyl-(6R)-6-[(2S)-2-methylbutyryloxy]-
cyclohexa-2,4-dien-1-one (11b*):
(The latter eluate on HPLC: Rt = 15.7 min). pale yellow oil. [a]D23
+79.5 (c = 1.22, CHCl3).
We are grateful to Professor Mitsuru Nakayama of Osaka Prefecture
University for providing the data of WA. This work was supported by
a Grant-in-Aid for Scientific Research (No. 0865I016) from the Min-
istry of Education, Science, Sports, and Culture.
1H NMR(CDCl3): d = 0.960 (3H, t, J=7.4 Hz, CH2CH3), 1.476 (3H,
d, J=7.1Hz, CHCH3), 1.507 (3H, s, CH3), 1.476 and 1.758 (each 1H,
m, CH2), 1.863 (3H, s, CH3), 2.456 (1H, m, >CH), 3.775 (3H, s,
OCH3), 3.792 (3H, s, OCH3), 5.446 (1H, s, olefinic H).
13C NMR(CDCl3): d = 195.54(s), 175.47(s), 172.89(s), 163.45(s),
112.53(s), 96.04(d), 79.16(s), 61.32(q), 56.28(q), 40.47(d), 26.43(t),
24.11(q), 16.39(q), 11.62(q), 9.58(q).
(1) (a) Soga, O. Z. Naturforsch. 1976, B, 31, 124.
(b) Soga, O.; Iwamoto, H.; Date, S.; Watanabe, T.; Tanaka, K.;
Hata, K.; Takuwa, A.; Nakayama, T.Chem. Lett. 1984, 339.
(c) Soga, O.; Iwamoto, H.; Ota, Y.; Oiie, Y.; Takuwa, A.; Nozai,
H.; Kuramoto, J.; Nakayama, M. 27th Symposium on the Chem.
ofNatural Products Hiroshima, 1985, 687.
12b: (The first eluate on HPLC: Rt – 16.5 min): [a]D22 +36.3 (c = 1.19,
CHCl3). Colorless prisms. mp 37–39°C.
EIMS: m/z = 282(M+).
UV(EtOH): lmax(loge) = 203(3.92), 249(4.23), 291(3.64) nm.
IR(KBr): n = 2968, 2941, 1739, 1666, 1622, 1456, 1375, 1361,
1232 cm–1.
(d) Soga, O.; Iwamoto, H.; Takuwa, A.; Nozaki, H.; Kuramoto,
J.; Nakayama, M. Agric. Biol. Chem. 1987, 51, 283.
(e) Soga, O.; Iwamoto, H.; Takuwa, A.; Takata, T.; Tsugiyama,
Y.; Hamada, K. Fujiwara, T. Nakayama, M. Chem. Lett. 1988,
1535.
1H NMR(CDCl3): d = 0.942 (3H, t, J=7.3 Hz, CH3), 1.066 (3H, d,
J=9.4Hz), 1.450 (1H, m, CH2), 1.613 (3H, s, CH3), 1.713 (1H, m,
CH2), 1.916 (3H, s, CH3), 2.396 (1H, m, >CH), 3.705 (3H, s, OCH3),
3.850 (3H, s, OCH3), 5.530 (1H, s, olefinic H).
(2) Obara, H.; Onodera, J. Chem. Lett. 1979, 201.

June 1998
SYNTHESIS
893
Onodera, J.; Obara, H.; Osone, M.; Maruyama, Y.; Sato, S. Chem. (4) Onodera J.; Obara, H. Nippon Kagaku Kaishi 1973, 1808.
Lett. 1981, 433.
(5) Sato, S.; Obara, H.; Kumazawa, T.; Onodera, J.; Furuhata, K.
Chem. Lett. 1996, 833.
(6) Natural WA was isolated from the potato culture solution of Pho-
ma wasabiae, which was isolated from Eutrema wasabi Maximo-
wicz with black leg disease (Sumi-iri-byô).
Takahashi, Y.; Saito, K.; Yanagiya, M.; lkura, M.; Hikichi, K.;
Matsumoto, T.; Wada, M. Tetrahedron Lett. 1984, 25, 2471.
Onodera, J.; Obara, H.; Hirose, R.; Matsuba, S.; Sato, N.; Sato, S.;
Suzuki, M. Chem. Lett. 1989, 1571.
(3) Mahajan, J. R. Synthesis 1976, 110.
Diazomethane treatment of the isolated natural WA followed by
column chromatography (EtOAc/hexane) afforded two methyl
ether derivatives 10b and 12.1b,c
Mahajan, J. R.; Ferreira, G. A. L.; Araujo, H. C.; Nunes, B. J. Syn-
thesis 1976, 112.
Mahajan, J. R.; Carvalho, H. Synthesis 1979, 518.
Mahajan, J. R.; Araujo, H. C. Synthesis 1980, 64.
Mahajan, J. R.; Resck, I. S. Synthesis 1980, 998.
(7) Champbell, T. W., Coppinger, G. M. J. Am. Chem. Soc. 1951, 73,
1849.