The first total synthesis of kwakhurin, a characteristic component of a rejuvenating plant, "kwao keur": Toward an efficient synthetic route to phytoestrogenic isoflavones

Article abstract of DOI:10.1039/b414955f

A convergent synthesis of kwakhurin (5), a characteristic estrogen-like isoflavone of Pueraria mirifica (Leguminosae), is described. Isoflavone skeleton 31 was constructed by Suzuki-Miyaura coupling of 3-bromochromone 26 (AC-ring) and arylboronic acid 30

Full text of DOI:10.1039/b414955f

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A R T I C L E
The first total synthesis of kwakhurin, a characteristic component of
a rejuvenating plant, “kwao keur”: toward an efficient synthetic route
to phytoestrogenic isoflavones
Fumihiro Ito,a Misako Iwasaki,a Toshiko Watanabe,*a Tsutomu Ishikawa*a and
Yoshihiro Higuchib
a Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba,
263-8522, Japan. E-mail: toshiw@p.chiba-u.ac.jp
b Central Research Laboratory, Shiratori Pharmaceutical Co. Ltd., 6-11-24 Tsudanuma,
Narashino, Chiba, 275-0016, Japan
Received 27th September 2004, Accepted 9th December 2004
First published as an Advance Article on the web 24th January 2005
A convergent synthesis of kwakhurin (5), a characteristic estrogen-like isoflavone of Pueraria mirifica (Leguminosae),
is described. Isoflavone skeleton 31 was constructed by Suzuki–Miyaura coupling of 3-bromochromone 26 (AC-ring)
and arylboronic acid 30 (B-ring) in the presence of TBAB as an additive. Microwave-assisted coupling was also
examined, but did not improve the yield. Baeyer–Villiger oxidation, followed by propargylation and reduction
afforded 1,1-dimethylallyl ether 37. 6ꢀ-Prenylisoflavone 34 was obtained in high yield by Claisen rearrangement of 37
in N,N-diethylaniline. On the other hand, 1,3-rearrangement of prenyl ether 33 with clay gave 34 in poor yield.
Successive methylation of 34 and deprotection yielded the target kwakhurin (5) in 12% overall yield from
2,4-dihydroxybenzaldehyde (23).
to artificially obtain 5 and, in the previous paper,5 reported
a stepwise approach to 5 via deoxybenzoin 8 as outlined in
Scheme 1. However, the final deprotection of the isopropyl (IP)
groups in 6 was unsuccessful. In this paper we report the first
total synthesis of kwakhurin (5) by a convergent route using a
methoxyethoxymethyl (MEM) group for phenol protection in
addition to further trials of the deoxybenzoin route.
Introduction
A medicinal plant “kwao keur” has been locally considered to
be a rejuvenating drug in Thailand and Burma and at present
is commercially available in some countries including Japan.
Therefore, the relationship between the chemical constituents
(e.g. 1–5, Fig. 1) and estrogenic activity has been widely
studied.1,2 The source of “kwao keur” is the tuberous root of
Pueraria mirifica (Leguminosae); however, the quality of the
commercial product is occasionally in doubt, because the aerial
parts are very similar to those of other vine legume species.
Results and discussion
We first examined the deoxybenzoin route by changing the
protecting group from the IP group to a triisopropylsilyl (TIPS)
group (Scheme 2). After benzoylation of triisopropoxyphenol5
11, replacement of the IP group in 12 with TIPS afforded tri-
TIPS isoflavone 14. Trials of the debenzoylation of 14 with either
a base (KOH, NaOMe, or K2CO3) or a hydride reagent (NaBH4,
LiAlH4, or NaH) yielded phenol 15; however, a partially TIPS-
deprotected compound 16 was always formed as a co-product.
Therefore, we decided to change the synthetic strategy.
Therefore, it is necessary to determine whether the commercial
“kwao keur” is genuine or not. We have focused on kwakhurin3
(5) as an index of quality standard because 5 is not only
a characteristic component of P. mirifica showing estrogenic
2b
activity but also an isolated peak with a long retention time
due to 5 is observed in HPLC.4
As the amount of kwakhurin (5) as a natural source is not
enough to examine the quality of “kwao keur”, we planned
Two other possible pathways would be available from the
literature:6 1) the oxidative rearrangement of chalcones and
flavanones and 2) the arylation of a pre-formed chromanone
ring. The latter coupling pathway was adopted because of its
potential application to various types of isoflavones and an easily
removable methoxyethoxymethyl (MEM) group was chosen for
phenol protection. The retrosynthesis is shown in Scheme 3.
6ꢀ-Prenylisoflavones, which are obtained from aldehyde 19 via
Baeyer–Villiger oxidation, can be afforded by 1,3- or 3,3-
rearrangement of O-allyl ethers 17. The isoflavone skeleton
19 is constructed by palladium catalyzed cross-coupling from
chromone ring 20 (AC-ring) and arylboronic acid 21 (B-ring).
The chromone 26 and the arylboronic acid 30 were prepared
from 2,4-dihydroxyacetophenone (22) and 2,4-dihydro-
xybenzaldehyde (23), respectively, as shown in Scheme 4. After
selective alkylation of 22 with MEMCl, the resulting mono-
MEM ketone7 24 was then converted into enaminoketone 25
with DMF–dimethylacetal (DMF–DMA) in good yield. Treat-
ment of 25 with bromine in CHCl38 afforded 3-bromochromone
26 in 60–70% yield. It was found that an easily handled N-
bromosuccinimide (NBS)–SiO2 system9 was also effective. On
the other hand, B-ring unit 30 was prepared from 23 by
Fig. 1 Selected chemical constituents of Pueraria mirifica.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 7 4 – 6 8 1
6 7 4
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Scheme 1
Scheme 2 Reagents and conditions: a, BzCl, Et3N, CH2Cl2, −20 ◦C, 5 h,
100%; b, BCl3, CH2Cl2, −50 ◦C, 9 h, 80%; c, TIPSCl, imidazole, DMF,
rt, 2 h, 64%.
Scheme 4 Reagents and conditions: a, DMF–DMA, 90 ◦C, 2 h, 92%;
b, NBS, SiO2, CHCl3, 0 ◦C, 0.5 h, 64%; c, NBS, SiO2, CHCl3, 30 ◦C,
20 h, 73%; d, NH4Cl, HC(OEt)3, EtOH, 90 ◦C, 2 h, 100%; e, i) n-BuLi,
B(OiPr)3, THF, −78 ◦C to rt, 1 h, ii) 1% HCl aq., 0 ◦C, 20 min, 74%.
successive reaction of bromination with NBS–SiO2, after
MEM protection of phenolic functions, ketalization with
HC(OEt)3, and metallation with n-BuLi and B(OiPr)3.
Next, Suzuki–Miyaura cross-coupling of chromone 26 with
arylboronic acid 30 was examined for the construction of
the isoflavone skeleton (Table 1). Although application of
microwave10 (MW)-assisted metal-free coupling reaction ac-
cording to the Leadbeater and Marco11 conditions failed
(entry 1), in the presence of a palladium catalyst the MW-
assisted reaction was completed in only 6 min to afford the
desired isoflavone 31 in moderate yield (entry 2). In contrast,
under conventional conditions better results were obtained even
though a longer reaction time was needed. The presence of
tetrabutylammonium bromide (TBAB) as an additive12 led to
a satisfactory yield (entry 4). Thus, in this coupling reaction,
MW irradiation strongly accelerated the reaction rate, but was
not necessarily effective.
The formyl group of 31 was then converted to a phenolic
function by Baeyer–Villiger oxidation followed by alkaline
hydrolysis. In the previous paper5 we used prenyl 1,3-migration
of 5ꢀ-(3,3-dimethylallyloxy)isoflavone with montmorillonite clay
for the introduction of a C5-unit. Thus, we investigated the
Scheme 3 Retrosynthetic analysis of kwakhurin (5) by a convergent
route.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 7 4 – 6 8 1
6 7 5

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Table 1 Preparation of isoflavone 31 by Suzuki–Miyaura coupling
Conditions
Microwave
Entry
Catalyst
Solvents
Additive
Conventional
Yield of 31 (%)
1
2
3
4
None
H2O
TBAB
None
None
TBAB
100 W, 130 ◦C, 2 min
—
—
Complex mixture
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
H2O–DME–EtOH (2 : 4 : 1)
Benzene
Benzene
55 W, 90 ◦C, 6 min
51
63
89
—
—
80 ◦C, 6 h
80 ◦C, 3 h
TBAB = tetrabutylammonium bromide.
migration of a prenyl ether 33 derived from 32. Treatment
with montmorillonite KSF5,13 in benzene gave poor yield (4%)
of the desired prenylated isoflavone 34. Further trials using
montmorillonite K1014 or Florisil15 showed no improvement in
the yield of 34, presumably because of lability of the MEM group
in 33 under these conditions (Scheme 5).
Scheme 6 Reagents and conditions: a, CuCl2, DBU, CH3CN, 0 ◦C, 6.5 h,
70%; b, H2, Lindlar’s cat., quinoline, EtOH, rt, 40 min, 88%.
Table 2 Solvent effect on Claisen rearrangement of 37
Conditions
Entry
Solvents
Temp.
Time/h
Yield of 34 (%)
1
2
3
4
Benzene
Toluene
Xylene
Reflux
Reflux
Reflux
180 ◦C
2
4
4
4
0
50
56
89
Scheme 5 Reagents and conditions: a, i) mCPBA, NaHCO3, CH2Cl2,
−10 ◦C, 25 min, ii) KOH, MeOH, rt, 30 min, 80%; b, prenyl bromide,
K2CO3, acetone, rt, 22 h, 78%; c, montmorillonite K10, CH2Cl2, 0 ◦C,
2 d then rt, 2 d.
PhNEt2
Therefore, we changed the migration mode to thermal re-
arrangement of 1,1-dimethylallyl ether. Alkylation of phenol
32 with propargyl carbonate 35 in the presence of a copper
catalyst16 yielded ether 36 followed by hydrogenation to afford
1,1-dimethylallyl ether 37 in high yield (Scheme 6).
As shown in Table 2, the Claisen rearrangement of 37 afforded
a prenyl isoflavone 34 in good yield when N,N-diethylaniline was
used as a solvent (entry 4).
Although conventional methylation (dimethyl sulfate–
K2CO3–DMF) of phenol 34 gave 38 in moderate yield (64%),
methylation of 34 using a phase transfer catalyst (PTC) yielded
38 in more satisfactory yield (89%). The final stage was achieved
by deprotection of 38 with 10% aqueous solution of HCl in
MeOH to afford the target kwakhurin (5) in 81% yield, the
physical and spectral data of which, including the HPLC peak,
were identical with those of the natural product (Scheme 7).
Full assignments for the hydroxy groups in synthetic 5 were
determined by HMBC experiments (Fig. 2).
In summary, we have achieved the total synthesis of
kwakhurin (5) via a convergent pathway in 10 steps from 22
and 11 steps from 23 in 10% and 12% overall yields, respectively.
A structurally related mirificoumestan17 (39) was also isolated
from P. mirifica along with kwakhurin (5). The hydrogenative
cyclization followed by oxidation of the isoflavone skeleton
to coumestan has been reported.18 It is suggested that our
synthetic method could be applied to the synthesis of 39 after
modification of the reaction conditions (Scheme 8). Thus, this
synthetic method could provide an efficient route to isoflavones
6 7 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 7 4 – 6 8 1

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(Merck) was used. Microwave-assisted reaction was carried out
in a CEM Discover instrument.
5ꢀ-Benzoyloxy-7,2ꢀ,4ꢀ-triisopropoxyisoflavone (12)
To a solution of 5ꢀ-hydroxyisoflavone5 11 (2.19 g, 5.30 mmol) in
CH2Cl2 (22 mL) were added Et3N (0.74 mL, 5.31 mmol) and
benzoyl chloride (0.65 mL, 5.60 mmol) under ice–salt cooling
and the whole mixture was stirred at −20 ◦C for 5 h. The reaction
mixture was diluted with CHCl3 (100 mL) followed by successive
washing with H2O (30 mL), saturated aqueous solution of
NaHCO3 (30 mL), H2O (30 mL), 1 M aqueous solution of
HCl (30 mL) and brine (30 mL), then dried over MgSO4 and
evaporated to dryness in vacuo to afford a yellow oil (3.15 g). The
crude product was purified by column chromatography using
hexane–AcOEt (20 : 1 to 3 : 1) as eluent to give 12 as a colourless
oil (2.74 g, 100%) (Found: C, 72.2; H, 6.3. C31H32O7 requires
C, 72.1; H, 6.2%); mmax (neat)/cm−1 1655 and 1637 (C O); dH
=
(400 MHz) 1.27 [6 H, d, J 6.0, CH(CH3)2], 1.28 [6 H, d, J 6.0,
CH(CH3)2], 1.41 [6 H, d, J 6.0, CH(CH3)2], 4.41 [1 H, sep, J 6.0,
OCH(CH3)2], 4.49 [1 H, sep, J 6.0, OCH(CH3)2], 4.67 [1 H, sep,
J 6.0, OCH(CH3)2], 6.66 (1 H, s, 3ꢀ-H), 6.84 (1 H, d, J 2.2, 8-H),
6.94 (1 H, dd, J 9.0 and 2.2, 6-H), 7.27 (1 H, s, 6ꢀ-H), 7.49 (2 H,
dd, J 7.9 and 7.9, benzoyl-3,5-H), 7.61 (1 H, dd, J 7.9 and 7.9,
benzoyl-4-H), 8.02 (1 H, s, 2-H), 8.17 (1 H, d, J 9.0, 5-H) and
8.19–8.21 (2 H, m, benzoyl-2,6-H); m/z: (EI) 516 (M+, 34%),
474 (12), 432 (7), 369 (10), 327 (31), 285 (13) and 105 (100).
Scheme 7 Reagents and conditions: a, Me2SO4, PhCH2Bu3NCl, 2%
NaOH aq., benzene, rt, 30 min, 89%; b, 10% HCl, MeOH, 70 ◦C, 1 h,
81%.
5ꢀ-Benzoyloxy-7,2ꢀ,4ꢀ-trihydroxyisoflavone (13)
To a solution of triisopropoxyisoflavone 12 (0.659 g, 1.28 mmol)
in CH2Cl2 (3.3 mL) was added a solution of 0.3 M BCl3
in CH2Cl2 (42.5 mL, 12.8 mmol; prepared from commercial
1 M solution) at −78 ◦C. The whole mixture was stirred at
−50 ◦C for 9 h under an argon atmosphere and poured into
H2O (170 mL). The resulting precipitates were collected by
filtration, washed with H2O and CHCl3, and dried to afford
a pale yellow solid (0.544 g). The crude solid was purified by
column chromatography using CHCl3–MeOH (30 : 1) as eluent
to give 13 as a pale yellow powder (0.398 g, 80%), mp 152–
Fig. 2 Selected HMBC correlation and assignments for 7-, 2ꢀ-, and
4ꢀ-hydroxy groups of kwakhurin (5). Chemical shift values (d, ppm) of
each hydroxy group are given in parentheses.
154 ◦C. mmax (Nujol)/cm−1 3313 (OH), 1718 and 1655 (C O);
=
dH (400 MHz; CDCl3 + 1 drop of CD3OD) 6.68 (1 H, s, 3ꢀ-H),
6.88 (1 H, d, J 2.2, 8-H), 6.98 (1 H, s, 6ꢀ-H), 6.99 (1 H, dd, J 9.0
and 2.2, 6-H), 7.51 (2 H, dd, J 8.4 and 8.4, benzoyl-3,5-H), 7.64
(1 H, dd, J 8.4 and 8.4, benzoyl-4-H), 8.09 (1 H, s, 2-H), 8.18
(1 H, d, J 9.0, 5-H) and 8.23 (2 H, d, J 8.4, benzoyl-2,6-H); m/z:
(FAB) 391 (MH+), 390 (M+) and 105; found (FAB): 391.0804
(MH+). C22H15O7 requires 391.0818.
Scheme 8
5ꢀ-Benzoyloxy-7,2ꢀ,4ꢀ-tris(triisopropylsilyloxy)isoflavone (14)
and coumestans to examine the structure–activity relationship
of their estrogenic activity.
To a solution of trihydroxyisoflavone 13 (0.398 g, 1.02 mmol)
and imidazole (0.487 g, 7.14 mmol) in DMF (1 mL) was added
TIPSCl (0.74 mL, 3.35 mmol). The whole mixture was stirred at
room temperature for 2 h under an argon atmosphere, diluted
with H2O (10 mL), and extracted with AcOEt (3 × 10 mL).
The organic layer was washed with H2O (2 × 10 mL) and
brine (10 mL), dried over MgSO4, and evaporated to dryness
in vacuo to afford a pale yellow oil (1.27 g). The crude product
was purified by column chromatography using benzene as eluent
to give 14 as pale yellow prisms (0.559 g, 64%), mp 150–155 ◦C.
Experimental
General
All melting points were measured on a melting-point hot
stage MP-3S (Yanaco) and are uncorrected. Infrared spectra
were recorded on a JASCO FT/IR-300E spectrometer. 1H-
and 13C-NMR spectra were recorded in chloroform-d (CDCl3)
unless otherwise stated, on JEOL JNM GSX-400A, GSX-500A,
and ECP-400 spectrometers with tetramethylsilane (TMS) as
internal reference. Low-resolution mass spectra were recorded
on a JEOL JMS-GCmate with electron impact (EI) ionisa-
tion, and JEOL JMS-AX-500 and JMS-HX 110A fast atom
bombardment (FAB) ionisation. High-resolution mass spectra
were recorded on JEOL JMS-HX 110A (FAB) spectrometer.
For column chromatography, silica gel [FL-100D; particle size:
100 lm (Fuji Silysia) or silica gel 60; particle size 63–230 lm
(Kanto Kagaku)] was used unless otherwise stated. For thin-
layer chromatography (TLC), pre-coated silica gel 60 F254
mmax (Nujol)/cm−1 1718 (C O) and 1655 (C O); dH (400 MHz)
1.00 [18 H, d, J 7.5, 3 × CH(CH3)2], 1.02 [18 H, d, J 7.5, 3 ×
CH(CH3)2], 1.13 [18 H, d, J 7.5, 3 × CH(CH3)2], 1.08–1.25
[6 H, sep, J 7.5, 6 × SiCH(CH3)2], 1.32 [3 H, sep, J 7.5, 3 ×
SiCH(CH3)2], 6.55 (1 H, s, 5ꢀ-H), 6.88 (1 H, d, J 2.2, 8-H), 6.92
(1 H, dd, J 8.8 and 2.2, 6-H), 7.20 (1 H, s, 3ꢀ-H), 7.49 (2 H,
dd, J 7.5 and 7.5, benzoyl-3,5-H), 7.59 (1 H, dd, J 7.5 and 7.5,
benzoyl-4-H), 7.98 (1 H, s, 2-H), 8.13 (1 H, d, J 8.8, 5-H) and
8.18 (2 H, d, J 7.5, benzoyl-2,6-H); m/z: (FAB) 859 (MH+), 815,
667, 581, 495 and 105.
=
=
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 7 4 – 6 8 1
6 7 7

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Trials of debenzoylation of 14: 5ꢀ-hydroxy-7,2ꢀ,4ꢀ-tris-
(triisopropylsilyloxy)isoflavone (15) and 5ꢀ-benzoyloxy-
7-hydroxy-2ꢀ,4ꢀ-bis(triisopropylsilyloxy)isoflavone (16)
(C O); dH (400 MHz) 3.37 (3 H, s, OMe), 3.55–3.57 (2 H,
m, OCH2CH2OMe), 3.83–3.86 (2 H, m, OCH2CH2OMe), 5.37
(2 H, s, OCH2O), 7.12 (1 H, dd, J 9.5 and 2.2, 6-H), 7.12
(1 H, d, J 2.2, 8-H), 8.16 (1 H, s, 2-H) and 8.18 (1H, d, J
9.5, 5-H); dC (100 MHz) 59.0 (OMe), 68.2 (OCH2CH2OMe),
71.4 (OCH2CH2OMe), 93.4 (OCH2O), 103.1 (C-8), 110.7 (C-3),
116.2 (C-6), 117.7 (C-4a), 127.8 (C-5), 153.4 (C-2), 157.5 (C-8a),
161.8 (C-7) and 171.6 (C-4); m/z: (FAB) 331 (MH+ + 2) and 329
(MH+); Found (FAB) 329.0016. C13H14BrO5 requires 329.0025.
=
A mixture of tris-TIPS isoflavone 14 (20 mg, 0.024 mmol), NaH
(4 mg, 0.17 mmol) and THF (0.2 mL) was stirred at 20 ◦C
for 2.5 days under an argon atmosphere. The reaction mixture
was poured into H2O (10 mL) and acidified with 10% aqueous
solution of HCl (1.5 mL) followed by extraction with CHCl3
(3 × 10 mL). The organic layer was washed with H2O (10 mL)
and brine (10 mL), dried over MgSO4, and evaporated to dryness
in vacuo to afford a yellow oil (25 mg). The crude product was
purified by preparative TLC (hexane–AcOEt = 3 : 1) to give two
compounds; 15 (Rf ; 0.58) as a colourless amorphous powder
(3 mg, 17%) and 16 (Rf ; 0.25) as a colourless amorphous powder
(2 mg, 11%).
15: dH (400 MHz, CDCl3 + 1 drop of CD3OD) 0.95 [18 H,
d, J 7.4, 3 × CH(CH3)2], 1.10 [18 H, d, J 7.7, 3 × CH(CH3)2],
1.13 [18 H, d, J 7.5, 3 × CH(CH3)2], 1.20–1.34 [9 H, m, 9 ×
SiCH(CH3)2], 6.45 (1 H, s, 3ꢀ-H), 6.81 (1 H, d, J 1.5, 8-H), 6.86
(1 H, s, 6ꢀ-H), 6.89 (1 H, dd, J 8.8 and 1.5, 6-H), 7.89 (1 H, s,
2-H) and 8.09 (1 H, d, J 8.8, 5-H); m/z: (EI) 754 (M+, 73%), 711
(100), 511 (58) and 425 (15).
5-Bromo-2,4-bis(2-methoxyethoxymethoxy)benzaldehyde (28)
To a solution of aldehyde 27 (0.520 g, 1.66 mmol; prepared
from 23 by reported alkylation7 in 82% yield) in CHCl3 (16 mL)
were added silica gel (Fuji Silysia, Microbead 3A, 1.79 g) and
NBS (0.329 g, 1.85 mmol). The whole mixture was stirred at
room temperature for 20 h in the dark. The insoluble material
was filtered off and the filtrate was washed with 10% aqueous
solution of Na2S2O3 (3 × 10 mL) and brine (10 mL), dried
over MgSO4, and evaporated to dryness in vacuo. The crude
product was purified by column chromatography using hexane–
AcOEt (17 : 10) as eluent to give 28 (0.474 g, 73%) as colourless
prisms, mp 56–57 ◦C, which were recrystallised from Et2O–
hexane. (Found: C, 45.6; H, 5.3. C15H21BrO7 requires C, 45.8;
16: dH (400 MHz) 0.98 [18 H, d, J 7.3, 3 × CH(CH3)2], 1.01 [18
H, d, J 7.3, 3 × CH(CH3)2], 1.08–1.23 [6 H, m, 6 × SiCH(CH3)2],
6.55 (1 H, s, 3ꢀ-H), 6.78 (1 H, d, J 2.2, 8-H), 6.88 (1 H, dd, J 8.8
and 2.2, 6-H), 7.25 (1 H, s, 6ꢀ-H), 7.48 (2 H, dd, J 7.6 and 7.6,
benzoyl-3,5-H), 7.61 (1 H, dd, J 7.6 and 7.6, benzoyl-4-H), 7.81
(1 H, s, 2-H), 8.10 (1 H, d, J 8.6, 5-H) and 8.19 (2 H, d, J 7.6,
benzoyl-2,6-H); m/z: (FAB) 704 (MH+), 660, 600 and 511.
H, 5.4%); mmax (Nujol)/cm−1 1665 (C O); dH (400 MHz) 3.37
=
(6 H, s, 2 × OMe), 3.55–3.58 (4 H, m, 2 × OCH2CH2OMe),
3.85–3.88 (4 H, m, 2 × OCH2CH2OMe), 5.38 and 5.40 (each
2 H, s, OCH2O), 7.06 (1 H, s, 3-H), 8.02 (1 H, s, 6-H) and 10.28
(1H, s, CHO); dC (100 MHz) 58.97 and 59.00 (OMe), 68.37 and
68.42 (OCH2CH2OMe), 71.36 and 71.43 (OCH2CH2OMe), 93.9
and 94.0 (OCH2O), 102.5 (C-3), 105.8 (C-5), 121.0 (C-1), 132.7
=
(C-6), 159.2 (C-2), 160.3 (C-4) and 187.2 (C O); m/z: (FAB)
1-[2-Hydroxy-4-(2-methoxyethoxymethoxy)phenyl]-
3-dimethylaminopropen-1-one (25)
395 (MH+ + 2) and 393 (MH+).
A mixture of ketone 24 (0.801 g, 3.33 mmol; prepared from 22 by
reported alkylation7 in 56% yi◦eld) and DMF–DMA (0.66 mL,
5.00 mmol) was stirred at 90 C for 2 h. After removal of the
MeOH formed in vacuo, the residue was extracted with AcOEt
(10 mL). The organic layer was washed with H2O (3 × 2 mL)
and the aqueous layer was extracted again with AcOEt (3 ×
10 mL). The combined organic solution was washed with brine
(10 mL), dried over MgSO4, and evaporated to dryness in vacuo
to give a brown oil (0.972 g). The crude product was purified
with column chromatography using hexane–AcOEt (1 : 2) as
eluent to afford 25 (0.904 g, 92%) as yellow prisms, mp 80–
81 ◦C, which were recrystallised from Et2O–hexane. (Found:
C, 61.0; H, 7.1; N, 4.7. C15H21NO5 requires C, 61.0; H, 7.2;
5ꢀ-Formyl-7,2ꢀ,4ꢀ-tris(2-methoxyethoxymethoxy)isoflavone (31)
i) Ketalization: 5-bromo-2,4-bis(2-methoxyethoxymethoxy)-
benzaldehyde diethylacetal (29). To a solution of aldehyde 28
(1.43 g, 3.64 mmol) and NH4Cl (37 mg, 0.69 mmol; freshly
prepared by sublimation) in dry EtOH (10 mL) was added
HC(OEt)3 (1.8 mL, 11.0 mmol) under an argon atmosphere
and the whole mixture was stirred at 90 ◦C for 2 h. The reaction
mixture was diluted with Et2O (200 mL) and washed with H2O
(50 mL) and brine (50 mL), dried over K2CO3, and evaporated
to dryness in vacuo. Removal of the excess reagent by distillation
◦
(100 C/1 mmHg) gave 29 (1.69 g, 100%) as a yellow oil. mmax
(neat)/cm−1 no characteristic absorption; dH (400 MHz) 1.22
(6 H, t, J 7.2, 2 × CH3CH2O), 3.38 (6 H, s, 2 × OMe), 3.49–3.63
(8 H, m, 2 × OCH2CH2OMe and 2 × CH3CH2O), 3.80–3.83 and
3.86–3.88 (each 2 H, m, OCH2CH2OMe), 5.27 and 5.31 (each
2 H, s, OCH2O), 5.68 [1 H, s, ArCH(OEt)2], 7.00 (1 H, s, 3-H)
and 7.71 (1H, s, 6-H); dC (100 MHz) 15.2 (CH2CH3), 58.9 and
59.0 (OMe), 61.6 (OCH2CH3), 67.8 and 68.0 (OCH2CH2OMe),
71.4 and 71.5 (OCH2CH2OMe), 93.7 and 94.3 (OCH2O), 96.5
(ArCH), 104.0 (C-3), 104.9 (C-5), 123.6 (C-1), 131.4 (C-6),
154.2 (C-2) and 154.7 (C-4); m/z: (FAB) 468 (M++2) and 466
(M+); Found (FAB) 466.1209. C19H31BrO8 requires 466.1202.
This compound was used for the next reaction without further
purification.
N, 4.7%); mmax (Nujol)/cm−1 2923 (OH) and 1627 (C O); dH
=
(400 MHz) 2.96 and 3.18 (each 3 H, br s, NMe2), 3.38 (3 H, s,
OMe), 3.55–3.57 (2 H, m, OCH2CH2OMe), 3.80–3.83 (2 H, m,
OCH2CH2OMe), 5.28 (2 H, s, OCH2O), 5.69 (1 H, d, J 12.2,
2-H), 6.50 (1 H, dd, J 8.8 and 2.5, C5ꢀ-H), 6.58 (1 H, d, J 2.5, 3ꢀ-
H), 7.62 (1 H, d, J 8.8, 6ꢀ-H), 7.85 (1 H, d, J 12.2, 3-H) and 14.3
(1 H, s, OH); dC (100 MHz) 37.2 and 45.2 (NMe2), 58.9 (OMe),
67.8 (OCH2CH2OMe), 71.4 (OCH2CH2OMe), 89.6 (C-3ꢀ), 92.9
(OCH2O), 103.9 (C-2), 106.8 (C-5ꢀ), 114.8 (C-1ꢀ), 129.6 (C-6ꢀ),
154.1 (C-3), 161.6 (C-2ꢀ), 165.0 (C-4ꢀ) and 190.4 (C-1); m/z: (EI)
295 (M+, 47%,), 251 (73), 190 (7.6) and 89 (41).
3-Bromo-7-(2-methoxyethoxymethoxy)chromone (26)
ii) Preparation of arylboronic acid: 5-borono-2,4-bis(2-
methoxyethoxymethoxy)benzaldehyde (30). To a solution of
acetal 29 (0.205 g, 0.438 mmol) in THF (2 mL) was added
n-BuLi (1.26 M solution in hexane, 0.52 mL, 0.655 mmol) at
To a solution of 25 (0.630 g, 2.13 mmol) in CHCl3 (10 mL) were
added silica gel (Fuji Silysia, Microbead 3A, 2.10 g) and NBS
(0.401 g, 2.25 mmol). The whole mixture was vigorously stirred
◦
◦
at 0 C for 30 min. The insoluble material was filtered off and
−78 C for 10 min under an argon atmosphere. After stirring
filtrate was washed with 10% aqueous solution of Na2S2O3 (3 ×
10 mL) and brine (10 mL), dried over MgSO4, and evaporated
to dryness in vacuo. The crude product was purified by column
chromatography using hexane–AcOEt (17 : 10) as eluent to give
26 (0.446 g, 64%) as colourless prisms, mp 75–76 ◦C, which
were recrystallised from Et2O–hexane. mmax (Nujol)/cm−1 1637
for 1 h, B(OiPr)3 (0.2 mL, 0.867 mmol) was added and the
whole mixture was stirred for 20 min and allowed to stand at
room temperature for 1 h. The reaction mixture was poured into
H2O (4 mL), acidified with 1% aqueous solution of HCl, and
the whole mixture was stirred for 20 min followed by dilution
with H2O (10 mL). The mixture was extracted with AcOEt
6 7 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 7 4 – 6 8 1

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(4 × 50 mL). The organic layer was washed with brine (40 mL),
dried over MgSO4, and evaporated to dryness in vacuo under
20 ◦C to give a yellow oil (0.210 g). The crude oil was solidified
and washed with Et2O–hexane to afford arylboronic acid 30
(0.116 g, 74%) as a labile colourless powder. mmax (Nujol)/cm−1
dried over MgSO4 and evaporated to dryness in vacuo to give a
brown oil (0.372 g). The crude product was purified by column
chromatography using AcOEt as eluent to afford phenol 32
(0.236 g, 80%) as a brown oil. mmax (Nujol)/cm−1 3396 (OH)
=
and 1637 (C O); dH (400 MHz) 3.35, 3.39 and 3.42 (each 3
=
3282 (OH) and 1670 (C O); dH (400 MHz) 3.37 (6 H, s, 2 ×
H, s, OMe), 3.51–3.63 (6 H, m, 3 × OCH2CH2OMe), 3.73–3.91
(6 H, m, 3 × OCH2CH2OMe), 5.12, 5.28 and 5.37 (each 2 H, s,
OCH2O), 6.27 (1 H, s, OH), 6.88 (1 H, s, 3ꢀ-H), 7.05 (1H, s, 6ꢀ-H),
7.08 (1 H, dd, J 8.8 and 2.4, 6-H), 7.11 (1 H, d, J 2.4, 8-H), 7.86
(1 H, s, 2-H) and 8.19 (1 H, d, J 8.8, 5-H); dC (100 MHz) 58.95,
59.02 and 59.08 (OMe), 67.6, 68.1 and 68.9 (OCH2CH2OMe),
71.50, 71.58 and 71.64 (OCH2CH2OMe), 93.4, 95.2 and 96.3
(OCH2O), 103.2 (C-3ꢀ), 106.7 (C-8), 115.3 (C-6), 117.2 (C-1ꢀ),
118.1 (C-6ꢀ), 119.2 (C-4a), 122.6 (C-3), 127.8 (C-5), 142.2 (C-
5ꢀ), 145.2 (C-4ꢀ), 149.0 (C-2ꢀ), 153.7 (C-2), 157.7 (C-8a), 161.3
(C-7) and 175.4 (C-4); m/z: (FAB) 551 (MH+); Found (FAB)
551.2109. C27H35O12 requires 551.2129.
OMe), 3.56–3.58 (4 H, m, 2 × OCH2CH2OMe), 3.85–3.88 (4 H,
m, 2 × OCH2CH2OMe), 5.42 and 5.44 (each 2 H, s, OCH2O),
5.53 (2 H, s, 2 × OH), 6.95 (1 H, s, 3-H), 8.36 (1 H, s, 6-H) and
10.33 (1H, s, CHO); dC (100 MHz) 58.97 and 59.01 (OMe), 68.3
and 68.8 (OCH2CH2OMe), 71.4 and 71.6 (OCH2CH2OMe),
93.55 and 93.63 (OCH2O), 99.8 (C-3), 120.2 (C-1 and C-5),
=
138.6 (C-6), 163.2 (C-2), 167.8 (C-4) and 188.4 (C O). This
compound was used for the coupling reaction without further
purification.
iii) Suzuki–Miyaura coupling (conventional method). To a
solution of chromone 26 (0.516 g, 1.57 mmol), arylboronic acid
30 (0.616 g, 1.72 mmol), Pd(PPh3)4 (56 mg, 48 lmol), and TBAB
(0.103 g, 0.318 mmol) in dry benzene (3 mL) was added 2 M
aqueous solution of Na2CO3 (1.6 mL). The whole mixture was
heated at 80 ◦C for 3 h under an argon atmosphere. The reaction
mixture was diluted with AcOEt (100 mL) and washed with
H2O (2 × 30 mL) and brine (30 mL), dried over K2CO3 and
evaporated to dryness in vacuo to afford a red oil (1.12 g). The
crude product was purified by column chromatography [silica
gel 60N (spherical neutral, 63–210 lm); Kanto Kagaku] using
hexane–AcOEt (1 : 14) as eluent to give isoflavone 31 (0.785 g,
89%) as colourless prisms, mp 50–51 ◦C, which were recrys-
tallised from Et2O–benzene. (Found: C, 59.6; H, 6.1. C28H34O12
requires C, 59.8; H, 6.1%); mmax (Nujol)/cm−1 1678 and 1620
7,2ꢀ,4ꢀ-Tris(2-methoxyethoxymethoxy)-5ꢀ-(3,3-
dimethylallyloxy)isoflavone (33)
A mixture of 5ꢀ-hydroxyisoflavone 32 (110 mg, 0.201 mmol), dry
◦
K2CO3 (72 mg, 0.522 mmol; dried at 100 C for 12 h prior to
use), and prenyl bromide (0.07 mL, 0.583 mmol) in dry acetone
(1 mL) was stirred at room temperature for 22 h under an
argon atmosphere. The reaction mixture was poured into H2O
(10 mL) and extracted with Et2O (3 × 20 mL). The organic layer
was washed with 2% aqueous solution of NaOH (10 mL) and
brine (10 mL), dried over K2CO3, and evaporated to dryness in
vacuo to give a yellow solid (129 mg). The crude product was
purified by column chromatography using hexane–AcOEt (1 :
9) as eluent to afford prenyl ether 33 (96 mg, 78%) as colourless
fine needles, mp 61–62 ◦C, which were recrystallised from Et2O.
(Found: C, 61.9; H, 6.75. C32H42O12 requires C, 62.1; H, 6.8%);
=
(C O); dH (400 MHz) 3.35, 3.39 and 3.40 (each 3 H, s, OMe),
3.52–3.60 (6 H, m, 3 × OCH2CH2OMe), 3.77–3.90 (6 H, m, 3 ×
OCH2CH2OMe), 5.29, 5.38 and 5.43 (each 2 H, s, OCH2O), 7.09
(1 H, dd, J 8.8 and 2.3, 6-H), 7.09 (1 H, s, 3ꢀ-H), 7.13 (1 H, d,
J 2.3, 8-H), 7.76 (1 H, s, 6ꢀ-H), 7.85 (1 H, s, 2-H), 8.17 (1 H, d,
J 8.8, 5-H) and 10.36 (1H, s, CHO); dC (100 MHz) 58.9, 59.01
and 59.03 (OMe), 68.09, 68.12 and 68.3 (OCH2CH2OMe), 71.41,
71.44 and 71.5 (OCH2CH2OMe), 93.3, 93.5 and 93.8 (OCH2O),
101.2 (C-3ꢀ), 103.2 (C-8), 115.4 (C-6), 116.3 (C-1ꢀ), 118.9 (C-5ꢀ),
119.7 (C-4a), 122.3 (C-3), 127.7 (C-6ꢀ), 131.4 (C-5), 153.4 (C-2),
mmax (Nujol)/cm−1 1641 (C O); dH (400 MHz)1.70and 1.76 [each
=
=
3 H, s, C(CH3)2], 3.34 (3 H, s, OMe), 3.39 (6 H, s, 2 × OMe),
3.49–3.59 (6 H, m, 3 × OCH2CH2OMe), 3.72–3.90 (6 H, m, 3 ×
OCH2CH2OMe), 4.52 (2 H, d, J 6.7, 1ꢀꢀ-H2), 5.14, 5.32 and 5.38
(each 2 H, s, OCH2O), 5.48-5.52 (1 H, m, 2ꢀꢀ-H), 6.92 (1 H, s,
3ꢀ-H), 7.08 (1 H, dd, J 8.8 and 2.2, 6-H), 7.12 (1 H, d, J 2.2, 8-H),
7.14 (1H, s, 6ꢀ-H), 7.93 (1 H, s, 2-H) and 8.20 (1 H, d, J 8.8, 5-H);
dC (100 MHz) 18.2 (C-4ꢀꢀ), 25.8 (C-5ꢀꢀ), 58.97, 59.03 and 59.09
(OMe), 66.6 (C-1ꢀꢀ), 67.75, 67.83 and 68.16 (OCH2CH2OMe),
71.50, 71.56 and 71.58 (OCH2CH2OMe), 93.4, 94.8 and 95.1
(OCH2O), 103.2 (C-3ꢀ), 107.5 (C-8), 115.4 (C-6), 115.6 (C-1ꢀ),
117.4 (C-6ꢀ), 119.3 (C-4a), 120.0 (C-2ꢀꢀ), 122.1 (C-3), 127.8 (C-5),
137.7 (C-3ꢀꢀ), 144.3 (C-5ꢀ), 147.7 (C-4ꢀ), 149.6 (C-2ꢀ), 154.2 (C-2),
157.7 (C-8a), 161.3 (C-7) and 175.5 (C-4); m/z: (EI) 618 (M+,
11%), 550 (36), 475 (11), 386 (41) and 89 (100).
157.8 (C-8a), 161.4 (C-4ꢀ), 161.6 (C-2ꢀ), 161.7 (C-7), 175.1 (C-4)
+
=
and 188.1 (C O); m/z: (FAB) 563 (MH ).
iv) Suzuki–Miyaura coupling (microwave-assisted method).
A mixture of chromone 26 (0.101 g, 0.308 mmol), aryl boronic
acid 30 (0.123 g, 0.342 mmol), Pd(PPh3)4 (11 mg, 9.3 lmol), and
Na2CO3 (66 mg, 0.621 mmol) in the mixture of H2O (0.6 mL),
EtOH (0.3 mL), and DME (1.2 mL) was stirred in a microwave
instrument (55 W) at 90 ◦C for 6 min. The same work-up
and purification as above gave isoflavone 31 (0.088 g, 51%) as
colourless prisms.
1,3-Rearrangement of 5ꢀ-prenyloxyisoflavone 33: 5ꢀ-hydroxy-
7,2ꢀ,4ꢀ-tris(2-methoxyethoxymethoxy)-6ꢀ-(3,3-
dimethylallyl)isoflavone (34)
5ꢀ-Hydroxy-7,2ꢀ,4ꢀ-tris(2-methoxyethoxymethoxy)isoflavone (32)
A mixture of prenyl ether 33 (52 mg, 0.084 mmol) and
montmorillonite K10 (53 mg) in CH2Cl2 (1 mL) was stirred at
0 ◦C for 2 days under an argon atmosphere. The clay was filtered
off and the filtrate was evaporated to dryness in vacuo to afford a
brown oil (50 mg). The crude product was purified by preparative
TLC (hexane–AcOEt = 2 : 1) to give 34 (2 mg, 4%) as a colourless
oil along with the starting compound 33 (20 mg, 38%), phenol 32
(8 mg, 16%) and an unidentified monodeprotected compound
(3 mg, 7%). The desired compound 34 was identical to the sample
obtained from 37 described later.
To a suspension of 5ꢀ-formylisoflavone 31 (0.301 g, 0.535 mmol)
and NaHCO3 (0.135 g, 1.60 mmol) in CH2Cl2 (3 mL) was added
mCPBA (65%, 0.170 g, 0.641 mmol) and the whole mixture
was vigorously stirred at −10 ◦C for 25 min. After removal
of the solvent in vacuo, the residue was dissolved in AcOEt
(100 mL). The organic solution was washed with saturated
aqueous solution of NaHCO3 (20 mL) and brine (20 mL),
dried over MgSO4 and evaporated to dryness in vacuo to afford
formate (0.429 g) as a brown oil.
The formate was dissolved in MeOH (4 mL), basified (pH 9–
10) with 10% methanolic solution of KOH and the whole mixture
was stirred at room temperature for 30 min. After evaporation of
the solvent in vacuo, the residue was dissolved in H2O (10 mL)
and acidified with 10% aqueous solution of HCl followed by
dilution with H2O (10 mL) and extracted with AcOEt (4 ×
50 mL). The organic layer was washed with brine (20 mL),
7,2ꢀ,4ꢀ-Tris(2-methoxyethoxymethoxy)-5ꢀ-(1,1-
dimethylpropargyloxy)isoflavone (36)
To an ice-cooled mixture of 5ꢀ-hydroxyisoflavone 32 (0.215 g,
0.391 mmol) and CuCl2 (1.9 mg, 0.014 mmol) in dry CH3CN
(7 mL) was added DBU (0.08 mL, 0.535 mmol). After 15 min
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 7 4 – 6 8 1
6 7 9

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carbonate 35 (84.2 mg, 0.592 mmol; freshly prepared by reported
procedure16) was added and the whole mixture was stirred at
room temperature for 6.5 h under an argon atmosphere. The
reaction mixture was poured into H2O (20 mL) and extracted
with Et2O (3 × 40 mL). The organic layer was washed with 10%
aqueous solution of CuSO4 (30 mL) and brine (30 mL), dried
over K2CO3, and evaporated to dryness in vacuo to afford a
brown oil (0.241 g). The crude product was purified by column
chromatography using hexane–AcOEt (1 : 12) as eluent to
give 36 (0.168 g, 70%) as a yellow oil. mmax (neat)/cm−1 3256,
5.31 (each 1 H, d, J 6.8, OCH2O), 5.38 (2 H, s, OCH2O), 6.04
(1 H, s, OH), 6.93 (1 H, s, 3ꢀ-H), 7.08 (1 H, dd, J 8.8 and 2.2, 6-H),
7.12 (1 H, d, J 2.2, 8-H), 7.66 (1 H, s, 2-H) and 8.18 (1 H, d, J 8.8,
5-H); dC (100 MHz) 17.6 (C-5ꢀꢀ), 25.5 (C-4ꢀꢀ), 26.9 (C-1ꢀꢀ), 58.90
(OMe), 59.00, 59.04 and 67.4, 68.1 and 68.6 (OCH2CH2OMe),
71.46, 71.51 and 71.60 (OCH2CH2OMe), 93.4, 94.8 and 95.7
(OCH2O), 103.09 (C-3ꢀ), 103.11 (C-8), 115.2 (C-6), 116.5 (C-1ꢀ),
119.1 (C-4a), 121.2 (C-3), 122.7 (C-2ꢀꢀ), 127.8 (C-5), 128.7 (C-6ꢀ),
131.2 (C-3ꢀꢀ), 140.2 (C-5ꢀ), 144.7 (C-4ꢀ), 149.0 (C-2ꢀ), 153.9 (C-
2), 157.8 (C-8a), 161.3 (C-7) and 175.9 (C-4); m/z: (FAB) 619
(MH+); found (FAB) 619.2747. C32H43O12 requires 619.2755.
=
2110 (terminal alkyne) and 1648 (C O); dH (400 MHz) 1.65
[6 H, s, C(CH3)2], 2.50 (1 H, s, 1ꢀꢀ-H), 3.34, 3.39 and 3.40 (each 3
H, s, OMe), 3.51–3.60 (6 H, m, 3 × OCH2CH2OMe), 3.74–3.89
(6 H, m, 3 × OCH2CH2OMe), 5.18, 5.27 and 5.38 (each 2 H, s,
OCH2O), 7.08 (1 H, dd, J 8.8 and 2.4, 6-H), 7.10 (1 H, s, 3ꢀ-H),
7.12 (1 H, d, J 2.4, 8-H), 7.36 (1H, s, 6ꢀ-H), 7.89 (1 H, s, 2-H) and
8.19 (1 H, d, J 8.8, 5-H); dC (100 MHz) 29.3 (CMe), 58.88, 58.96
and 58.99 (OMe), 67.7, 67.8 and 68.1 (OCH2CH2OMe), 71.41,
71.49 and 71.53 (OCH2CH2OMe), 73.4 (C-1ꢀꢀ), 74.3 (C-3ꢀꢀ), 86.3
(C-2ꢀꢀ), 93.3 (OCH2O), 94.6 (OCH2O), 94.9 (OCH2O), 103.1
(C-3ꢀ), 105.9 (C-8), 115.2 (C-6), 115.4 (C-1ꢀ), 119.2 (C-4a), 122.2
(C-3), 126.8 (C-6ꢀ), 127.7 (C-5), 139.8 (C-5ꢀ), 151.3 (C-4ꢀ), 151.9
(C-2ꢀ), 153.9 (C-2), 157.6 (C-8a), 161.2 (C-7) and 175.2 (C-4);
m/z: (FAB) 617 (MH+); Found (FAB) 617.2600. C32H41O12
requires 617.2598.
5ꢀ-Methoxy-7,2ꢀ,4ꢀ-tris(2-methoxyethoxymethoxy)-6ꢀ-(3,3-
dimethylallyl)isoflavone (38)
To a solution of 6ꢀ-prenylisoflavone 34 (76 mg, 0.123 mmol)
and benzyltributylammonium chloride (36 mg, 0.115 mmol) in
benzene (4 mL) were added 2% aqueous solution of NaOH
(2 mL) and Me2SO4 (0.05 mL, 0.528 mmol). The whole mixture
was stirred at room temperature for 2.5 h under an argon
atmosphere. The excess reagent was quenched with 5% aqueous
solution of NH3 (6 mL) with stirring for 30 min followed by
extraction with AcOEt (2 × 20 mL). The organic layer was
washed with 5% aqueous solution of NH3 (10 mL), H2O (2 ×
10 mL), and brine (10 mL), dried over K2CO3, and evaporated
to dryness in vacuo to afford a brown oil (72 mg, 92%). The
crude product was purified with column chromatography using
hexane–acetone (2 : 1) as eluent to give 38 (70 mg, 89%) as a
7,2ꢀ,4ꢀ-Tris(2-methoxyethoxymethoxy)-5ꢀ-(1,1-
dimethylallyloxy)isoflavone (37)
yellow oil. mmax (neat)/cm−1 1648 (C O); dH (400 MHz) 1.42
=
A mixture of ether 36 (0.180 g, 0.292 mmol) and quinoline
(0.02 mL) in EtOH (2 mL) was hydrogenated over Lindlar’s
catalyst (18 mg) at room temperature for 40 min under ambient
pressure. The reaction mixture was filtered through a Celite
pad. After removal of the solvent a crude product (0.194 g)
was purified by chromatography using hexane–acetone (3 : 1) as
eluent to afford 37 (0.160 g, 88%) as a yellow oil. mmax (neat)/cm−1
(3 H, s, 5ꢀꢀ-H3), 1.55 (3 H, s, 4ꢀꢀ-H3), 3.10 (1 H, dd, J 14.5 and 7.3,
1ꢀꢀ-Ha), 3.33, 3.39 and 3.40 (each 3 H, s, CH2OMe), 3.33–3.42
(1 H, m, 1ꢀꢀ-Hb), 3.47–3.61 (6 H, m, 3 × OCH2CH2OMe), 3.66–
3.90 (6 H, m, 3 × OCH2CH2OMe), 3.79 (3 H, s, 5ꢀ-OMe), 5.00
(1 H, dd, J 7.3 and 6.2, 2ꢀꢀ-H), 5.06 and 5.13 (each 1 H, d, J 6.8,
OCH2O), 5.33 and 5.38 (each 2 H, s, OCH2O), 6.97 (1 H, s, 3ꢀ-H),
7.08 (1 H, dd, J 8.8 and 2.2, 6-H), 7.12 (1 H, d, J 2.2, 8-H), 7.65
(1 H, s, 2-H) and 8.18 (1 H, d, J 8.8, 5-H); dC (100 MHz) 17.6 (C-
5ꢀꢀ), 25.5 (C-4ꢀꢀ), 27.2 (C-1ꢀꢀ), 58.94, 59.06 and 59.08 (OMe), 60.9
(ArOMe), 67.6, 67.9 and 68.2 (OCH2CH2OMe), 71.51, 71.54
and 71.59 (OCH2CH2OMe), 93.41, 94.29 and 94.34 (OCH2O),
102.9 (C-3ꢀ), 103.1 (C-8), 115.2 (C-6), 115.7 (C-1ꢀ), 119.2 (C-4a),
121.2 (C-3), 123.4 (C-2ꢀꢀ), 127.8 (C-5), 131.0 (C-6ꢀ), 136.4 (C-3ꢀꢀ),
143.0 (C-5ꢀ), 150.9 (C-4ꢀ), 152.2 (C-2ꢀ), 154.0 (C-2), 157.8 (C-
8a), 161.3 (C-7) and 176.0 (C-4); m/z: (FAB) 633 (MH+); found
(FAB) 633.2898. C33H45O12 requires 633.2921.
=
1648 (C O); dH (400 MHz) 1.44 (6 H, s, 2 × CCH3), 3.34,
3.39 and 3.40 (each 3 H, s, OMe), 3.50–3.60 (6 H, m, 3 ×
OCH2CH2OMe), 3.73–3.89 (6 H, m, 3 × OCH2CH2OMe), 5.07
(1 H, dd, J 10.8 and 1.1, 1ꢀꢀ-Ha), 5.15 (1 H, dd, J 17.4 and
1.1, 1ꢀꢀ-Hb), 5.16, 5.28 and 5.37 (each 2 H, s, OCH2O), 6.15
(1 H, dd, J 17.4 and 10.8, 2ꢀꢀ-H), 7.02 (1 H, s, 3ꢀ-H), 7.07
(1 H, dd, J 8.8 and 2.4, 6-H), 7.07 (1H, s, 6ꢀ-H), 7.11 (1 H,
d, J 2.4, 8-H), 7.87 (1 H, s, 2-H) and 8.19 (1 H, d, J 8.8,
5-H); dC (100 MHz) 26.5 (CMe), 58.93, 59.00 and 59.05 (OMe),
67.7, 67.9 and 68.1 (OCH2CH2OMe), 71.45, 71.54 and 71.58
(OCH2CH2OMe), 80.9 (C-3ꢀꢀ), 93.3, 94.7 and 95.0 (OCH2O),
103.1 (C-3ꢀ), 106.8 (C-8), 113.3 (C-1ꢀꢀ), 115.2 (C-6), 115.3 (C-1ꢀ),
119.2 (C-4a), 122.0 (C-3), 127.2 (C-6ꢀ), 127.8 (C-5), 140.1 (C-5ꢀ),
144.0 (C-2ꢀꢀ), 151.4 (C-4ꢀ), 151.4 (C-2ꢀ), 154.0 (C-2), 157.6 (C-
8a), 161.2 (C-7) and 175.3 (C-4); m/z: (FAB) 619 (MH+); Found
(FAB) 619.2726. C32H43O12 requires 619.2755.
Kwakhurin (5)
To a solution of tris-MEM-kwakhurin 38 (105 mg, 0.166 mmol)
in MeOH (10 mL) was added 10% aqueous solution of HCl
(2 mL). The whole mixture was stirred at 70 ◦C for 1 h under an
argon atmosphere, diluted with H2O (30 mL) and extracted with
AcOEt (3 × 50 mL). The organic layer was washed with H2O
(30 mL) and brine (30 mL), dried over MgSO4, and evaporated to
dryness in vacuo to afford a brown amorphous solid (61 mg, 99%)
which was washed with CHCl3 to give kwakhurin (5) (50 mg,
Claisen rearrangement of 1,1-dimethylallyloxyisoflavone 37:
5ꢀ-hydroxy-7,2ꢀ,4ꢀ-tris(2-methoxyethoxymethoxy)-6ꢀ-(3,3-
dimethylallyl)isoflavone (34)
A solution of 1,1-dimethylally ether 37 (0.268 g, 0.433 mmol)
in PhNEt2 (2.5 mL) was heated at 180 ◦C for 30 min under
an argon atmosphere. The reaction mixture was diluted with
AcOEt (50 mL), washed with 5% aqueous solution of HCl (8 ×
2 mL) and brine (8 mL), dried over MgSO4, and evaporated
to dryness in vacuo to afford a yellow oil (0.286 g). The crude
product was purified by chromatography using hexane–acetone
(3 : 2) as eluent to afford 34 (0.239 g, 89%) as a yellow oil. mmax
81%) as a labile colourless powdered solid, mp 210–212 ◦C
◦
(lit., no data, lit.,19 209–212 C). (Found: C, 66.9; H, 5.5. 1/10
3b
CHCl3·C21H20O6 requires C, 66.6; H, 5.5%); mmax (KBr)/cm−1
=
3372 (OH) and 1625 (C O); dH (400 MHz; acetone-d6) 1.42
(3 H, s, 5ꢀꢀ-H3), 1.53 (3 H, s, 4ꢀꢀ-H3), 3.12 (1 H, dd, J 14.6 and
7.1, 1ꢀꢀ-Ha), 3.35 (1 H, dd, J 14.6 and 6.7, 1ꢀꢀ-Hb), 3.74 (3 H, s,
OMe), 5.04 (1 H, ddq, J 7.1, 6.7 and 1.2, 2ꢀꢀ-H), 6.43 (1 H, s, 3ꢀ-H),
6.95 (1 H, d, J 2.2, 8-H), 7.02 (1 H, dd, J 8.8 and 2.2, 6-H), 7.89
(1 H, s, 2-H), 7.68 (1 H, br s, 2ꢀ-OH), 7.99 (1 H, br s, 4ꢀ-OH), 8.06
(1 H, d, J 8.8, 5-H) and 9.66 (1 H, br s, 7-OH); dC (100 MHz;
acetone-d6) 17.2 (C-5ꢀꢀ), 25.3 (C-4ꢀꢀ), 27.2 (C-1ꢀꢀ), 60.7 (OMe),
102.2 (C-3ꢀ), 102.8 (C-8), 111.1 (C-1ꢀ), 115.1 (C-6), 118.3 (C-4a),
121.1 (C-3), 124.5 (C-2ꢀꢀ), 127.9 (C-5), 130.5 (C-3ꢀꢀ), 136.0 (C-6ꢀ),
139.8 (C-5ꢀ), 151.1 (C-4ꢀ), 153.0 (C-2ꢀ), 155.5 (C-2), 158.7 (C-8a),
(neat)/cm−1 3373 (OH) and 1647 (C O); dH (400 MHz) 1.44
=
(3 H, s, 5ꢀꢀ-H3), 1.58 (3 H, s, 4ꢀꢀ-H3), 3.08 (1 H, dd, J 14.5 and 7.7,
1ꢀꢀ-Ha), 3.33, 3.39 and 3.42 (each 3 H, s, OMe), 3.33–3.42 (1 H,
m, 1ꢀꢀ-Hb), 3.47–3.62 (6 H, m, 3 × OCH2CH2OMe), 3.65–3.90
(6 H, m, 3 × OCH2CH2OMe), 5.01 (1 H, d, J 6.8, OCH2O), 5.08
(1 H, br t, J 7.7, 2ꢀꢀ-H), 5.09 (1 H, d, J 6.8, OCH2O), 5.28 and
6 8 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 7 4 – 6 8 1

View Article Online
162.7 (C-7) and 176.3 (C-4); m/z: (FAB) 391 (M++Na) and 369
(MH+); Found (FAB) 369.1331. C21H21O6 requires 369.1338.
This compound was completely identical with the natural
5 M. Iwasaki, T. Watanabe, T. Ishikawa, S. Chansakaow, Y. Higuchi
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1
3b
product in all spectral data. Precise assignments in H- and
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4 Retention time 45.3 min for kwakhurin (5) using the following
conditions: column, YMC-Pack ODS-AM-303 (4.6 mm I.D. ×
250 mm L); mobile phase, CH3CN–H2O–CH3CO2H (linear gradient
150 : 850 : 1 to 350 : 650 : 1); flow rate, 1.0 mL min−1; detection,
254 nm; injection volume, 20 lL; column temperature, 35 ◦C. [S.
Shimokawa, T. Kumamoto, T. Ishikawa, M. Takashi and Y. Higuchi,
unpublished result; under these conditions retention time for daizein
(3): 27.3 min and for genistein (4): 38.7 min].
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19 S. Chansakaow, PhD Thesis, 2000, Chiba University, Japan.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 6 7 4 – 6 8 1
6 8 1