A versatile approach to oligostilbenoid natural products - Synthesis of permethylated analogues of viniferifuran, malibatol A, and shoreaphenol

Article abstract of DOI:10.1039/b901911a

A highly practical route to oligostilbenoid natural products is described. A regioselective Bi(OTf)₃-catalyzed cyclodehydration provided ready access to 3-arylbenzofuran. Pd-catalyzed direct C-H activation of benzofuran and subsequent cross-cou

Full text of DOI:10.1039/b901911a

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A versatile approach to oligostilbenoid natural products – synthesis of
permethylated analogues of viniferifuran, malibatol A, and shoreaphenol†
Ikyon Kim* and Jihyun Choi
Received 29th January 2009, Accepted 3rd April 2009
First published as an Advance Article on the web 21st May 2009
DOI: 10.1039/b901911a
A highly practical route to oligostilbenoid natural products is described. A regioselective
Bi(OTf)3-catalyzed cyclodehydration provided ready access to 3-arylbenzofuran. Pd-catalyzed direct
C–H activation of benzofuran and subsequent cross-coupling with aryl halide was successfully
implemented for the introduction of aryl group at the C2 position of benzofuran. Further manipulation
of the 2,3-diarylbenzofuran led to the efficient total synthesis of permethylated analogues of
viniferifuran, malibatol A, and shoreaphenol.
Introduction
Oligostilbenes1 are a class of highly oxygenated natural products
comprising more than two stilbene units. A number of oligostil-
benoid natural products are known in the literature, with various
modes of connection of stilbene units, oxidation levels, and the
substitution patterns of aryl groups. These exhibit a wide variety
of pharmacological activities including anti-inflammatory, antiox-
idant, antifungal, antibacterial, anti-HIV, and anticarcinogenic
activities.2 As shown in Fig. 1, highly substituted benzofurans
are also within this family. The structure of viniferifuran was
first identified from Vitis vinifera ‘Kyohou’ on the basis of the
extensive NMR spectroscopic and chemical analysis by Niwa and
coworkers.3,4 Its congener, gnetuhainin B was isolated from the
lianas of Gnetum hainanense by the Lin group.5 In 1998, Boyd
and coworkers at NCI disclosed the structures of two novel
oligostilbenes, malibatols A and B, isolated from the organic
extract of the leaves of Hopea malibato.6 It was revealed that
malibatols A and B exhibit cytotoxicity to the host cells (CEM
SS) in an antiviral assay. Interestingly, an oxidized analogue of
malibatol A, called shoreaphenol or hopeafuran, was isolated from
the bark of Shorea robusta and the stem wood of Hopea utilis.7
Despite their interesting biological activities as well as their unique
carbon framework, few synthetic approaches towards these types
of compounds have been reported.8,9 Here we describe a direct
Fig. 1 Some representative oligostilbenoid natural products.
of handling, compounds 1, 2, and 3 were chosen as our synthetic
approach towards these natural products.
targets to validate our approach.10 A retrosynthetic route to these
compounds is outlined in Scheme 1. We envisioned that aldehyde
4 could be a viable common intermediate for the synthesis of
1, 2, and 3. In order to install the aromatic group at the C2
position of benzofuran 5, a transition metal-catalyzed direct C–H
activation of benzofuran 6 followed by intermolecular coupling
with an appropriate aryl halide 7 was considered. The requisite
benzofuran 6 was conceived to be easily available from the
dehydrative cyclization of aryloxyketone 8.
Results and discussion
At the outset, we hoped to design a synthetic strategy by which
not only natural products but also synthetic analogues would be
accessible. Considering the structural similarity and the easiness
Medicinal Chemistry Research Center, Korea Research Institute of Chem-
ical Technology, Daejeon, 305-600, Republic of Korea. E-mail: ikyon@
krict.re.kr; Fax: +82 42 860 7160; Tel: +82 42 860 7177
We commenced our synthesis with the preparation of aryloxyke-
tone 8, which was easily prepared from the reaction of the phenol
† Electronic supplementary information (ESI) available: Copies of 1H
and 13C spectra of compounds 1–6, 8 and 11–18, and comparison of
spectral data of 1–3 with those of the same compounds derived from
the natural products; crystallographic details and CIF files for 5 and 11
(CCDC reference numbers 713936 and 713937, respectively). For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b901911a
9
11 with a-bromoketone 1012 in the presence of K2CO3 (Scheme 2).
Initially, when this ketone 8 was exposed to BCl3 as described
in our previous communication,13 the desired benzofuran 6 was
obtained in 54–57% yield (entries 1 and 2, Table 1). Several
parameters (concentration, temperatures, and equivalents of BCl3)
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Scheme 1 Retrosynthetic analysis.
Scheme 2
Table 1 Synthesis of 3-arylbenzofuran 6 via cyclodehydration of 8
76% yield of 6 (entry 3). While 8 was inert to both InCl3 and
BiCl3, the desired cyclodehydration took place in the presence of
stoichiometric amount of FeCl3, albeit in modest yield (entries 4,
5, and 7). Use of a catalytic amount of FeCl3 together with mild
heating also allowed the formation of 6 but the starting material
was mostly recovered after 16 h, indicating that the process is not
catalytic (entry 6). Finally, we were pleased to find that exposure
of 8 to Bi(OTf)3 (0.2 equiv) in refluxing dichloromethane afforded
the desired 3-arylbenzofuran in 88% yield (entry 8).15
Entry Reagent
Temperature
Time (h)
Yield (%)
Having established the efficient formation of 6, we focused
our attention to the incorporation of aryl group at the C2 site
of benzofuran. Although preactivation of the C2 position of
benzofuran by replacement of the C2 hydrogen with a halide16
or a trialkyltin moiety17 is a possible route for transition metal-
catalyzed cross-coupling reactions, a more direct method was pur-
sued. Since the pioneering work by Ohta,18 direct C–H activation
of (benzo)furans followed by coupling with aryl halides/triflates
has been achieved by several groups.19,20 Surprisingly, how-
ever, no examples of the direct activation of 3-arylbenzofuran
and subsequent cross-coupling reaction have been reported to
date.
1
2
3
4
5
6
7
8
BCl3 (2 equiv)
BCl3 (1.2 equiv)
-78 ◦C to rt
-78 ◦C to rt
2
2
8
16
3
16
18
16
54
57
CF3CO2H (as solvent)
InCl3 (0.2 equiv)
FeCl3 (1 equiv)
FeCl3 (0.2 equiv)
BiCl3 (0.2 equiv)
Bi(OTf)3 (0.2 equiv)
80 ◦
60 ◦
rt
C
C
76
NRa
59
60 ◦
60 ◦
60 ◦
C
C
C
18b
NRa
88
a No reaction. b Starting material was mainly recovered.
were changed to improve the efficiency, but no satisfactory result
was obtained.14
At this point, other cyclodehydration conditions were examined.
Subjection of 8 to refluxing trifluoroacetic acid resulted in a
When 6 was submitted to the conditions (Pd(OAc)2 (0.2 equiv),
KOAc (2 equiv), and 4-iodoanisole (2 equiv) in DMA, 120 C),
◦
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Table 2 Direct arylation at the C2 site of benzofuran 6
Entry
X
R
Temperature (◦C) Product Yield (%)
1
2
3
4
5
6
7
8
9
I
I
OMe
OMe
OMe
OMe
NO2
F
CF3
CN
CO2Et
120
80
80
80
80
80
80
80
80
5
43
60
65
15
59
52
57
65
51
5
Br
B(OH)2
I
Br
Br
Br
Br
5
5
12
13
14
15
16
43% yield of arylated product 5 was isolated along with the
dimerized product 11 (21%)21 (entry 1, Table 2). It should be
noted that the reaction was carried out open to the air.22 The
structures of 5 and 11 were unambiguously established by X-ray
crystallographic analysis (Figs. 2 and 3).†
Fig. 3 Crystal structure of 11.
excellent overall yield (Scheme 3). Horner–Wadsworth–Emmons-
type olefination of 4 with diethyl 4-methoxybenzylphosphonate
provided 1 in quantitative yield. In order to construct the
seven-membered ring embedded in 2 and 3, a stereoselective
epoxide ring opening via nucleophilic attack by the neighboring
aromatic group was conceived based on the previous study.8
Initial efforts to make epoxide 17 from olefin in 1 using
mCPBA led to a complex mixture,27 but this difficulty was
circumvented by adopting the Corey–Chaykovsky protocol28 for
the synthesis of epoxide 17 (Scheme 4). As anticipated, the
reaction of 4 with dimethyl(4-methoxybenzyl)sulfonium chloride29
in the presence of NaH cleanly furnished trans-epoxide 17,
setting the stage for the stereoselective seven-membered ring
formation.
Fig. 2 Crystal structure of 5.
Lowering the reaction temperature to 80 ◦C increased the
isolated yield of 5 and 11 but with a similar ratio (entry 2). Substi-
tution of 4-iodoanisole by 4-bromoanisole also affected the yield in
a positive manner (entry 3). When 4-methoxyphenylboronic acid
was used as a coupling partner, 5 was obtained in a low yield (15%)
along with the dimer 11 (70%) (entry 4). Despite the substantial
increase in yield of 5, however, we were not able to suppress the
formation of dimer 11.23 Interestingly, when 6 was treated with
Pd(OAc)2 (0.2 equiv) and KOAc (2 equiv) in DMA at 80 ◦C in the
absence of an aryl halide, the dimerized product 11 was isolated
in 80% yield.24 At this point, a variety of other aryl groups was
introduced into 6 using the optimized conditions with a similar
efficiency (entries 5–9).25
Scheme 3
Upon exposure of 17 to a catalytic amount of SnCl4 at
-78 ◦C, TLC revealed rapid formation of several products.
Work-up and chromatography subsequently provided 2 (55%)
and 18 (18%) (entry 1, Table 3). The relative stereochemistry
of two stereogenic centers in 2 and 18 was easily assigned
based on the J values (Fig. 4). In addition, the chemical shifts
With gram quantities of the 2,3-diarylbenzofuran 5 in hand,
the stage was set to incorporate the final aryl moiety to 5.
The ester group in 5 was converted to aldehyde via a two-step
sequence (DIBAL reduction and Dess–Martin oxidation26) in
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Table 3 Epoxide ring opening–cyclization
Entry
Reagent
Temperature
Time
Yield (%)a
Ratio (2:18)b
1
2
3
4
5
6
SnCl4 (0.1 equiv)
PTSA-H2O (0.1 equiv)
PPTS (0.1 equiv)
InCl3 (0.1 equiv)
CH3CN–H2O, 1 : 1 (as solvent)
Bi(OTf)3 (0.1 equiv)
-78 ◦
C
5 min
3 h
5 h
1 h
72 h
1 h
55
33
31
34
25c
74
3 : 1
1 : 1.7
1 : 2
1 : 1.6
1 : 2.2
3 : 1
-78 ◦C to rt
-78 ◦C to rt
0 ◦C to rt
rt
-78 ◦
C
a Isolated yield of 2. b Determined by crude 1H NMR. c Starting material was recovered in 15% yield.
Fig. 4
were formed in 3 : 1 ratio (entry 6).31 It should be mentioned that
the combined yield (2 and 18) were excellent in all cases examined
except with SnCl4.
Subsequent Dess–Martin oxidation of 2 proceeded straight-
forwardly, furnishing a quantitative yield of 3.32 Reduction of
3 with NaBH4 only produced 2, which can be explained by
hydride delivery from the less hindered re face. This stereochemical
outcome was further supported by the conversion of 18 to 2
via 3.33
In summary, we have accomplished the total synthesis of
permethylated analogues of viniferifuran, malibatol A, and shore-
aphenol. For the construction of 2,3-diarylbenzofuran core, a
Bi(OTf)3-catalyzed cyclodehydration and a palladium-catalyzed
direct arylation of benzofuran were employed. The efficient pro-
cedure for the synthesis of C2–C2¢-linked benzofuran homodimers
was also discovered during this study. The route described herein
is very concise and practical, and should be useful for the synthesis
of other oligostilbenoid natural products and their analogues
given the fact that various (hetero)aromatic groups could be
easily introduced at each aromatic ring position of these types
of oligostilbenes. Currently, efforts are being made along these
lines, and these will be reported in due course.
Scheme 4
of two adjacent protons (denoted by *) in 2 match those
of the literature data of the compound derived from natural
malibatol A.31
PTSA also effected ring opening but with a 1 : 1.7 ratio (entry
2). PPTS also gave a similar result (entry 3). InCl3 induced seven-
membered ring closure, slightly favoring 18 (entry 4). Notably,
standing a solution of 17 in CH3CN–H2O (1 : 1) without any
catalyst also triggered the cyclization, affording a mixture of
diastereomers in good overall yield (entry 5). When epoxide 17
was treated with Bi(OTf)3 (0.1 equiv), 2 and its diastereomer 18
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3.81 (s, 6H), 3.32 (s, 3H); 13C NMR (75 MHz, CDCl3) d 168.1,
160.9, 157.7, 157.2, 143.1, 135.3, 125.8, 123.0, 118.7, 113.1, 106.5,
100.3, 99.9, 56.3, 55.6, 51.7; HRMS (EI) calcd for [C19H18O6]+:
m/z 342.1103, found 342.1108.
Experimental section
2-Bromo-3¢,5¢-dimethoxyacetophenone (10)
Method A. To
a stirred solution of 3¢,5¢-dimethoxy-
acetophenone (3.66 g, 20.3 mmol) in 60 mL of Et2O–CHCl3 (4 : 1)
was added Br2 (1.04 mL, 1.0 equiv) at 0 ◦C. After 1 h, the mixture
was stirred at rt for an additional 2 h, and more Br2 (0.4 mL,
0.4 equiv) was added at 0 ◦C. After being stirred at rt for 2 h, the
reaction mixture was diluted with saturated aqueous NaHCO3 at
0 ◦C. After the reaction mixture was concentrated under reduced
pressure, the residue was diluted with ethyl acetate. The organic
layer was washed with brine and the aqueous layer was extracted
with ethyl acetate one more time. The combined organic layers
were dried over MgSO4, filtered, and evaporated in vacuo. The
resulting residue was purified by flash column chromatography
(hexanes–ethyl acetate–dichloromethane = 20 : 1 : 2) to afford
a-bromoketone 10 (3.18 g, 60%).
Methyl 3-(3,5-dimethoxyphenyl)-6-methoxy-2-(4-methoxyphe-
nyl)benzofuran-4-carboxylate (5) and dimethyl 3,3¢-bis(3,5-di-
methoxyphenyl)-6,6¢-dimethoxy-2,2¢-bibenzofuran-4,4¢-dicarbo-
xylate (11). To a solution of 6 (1 g, 2.92 mmol) in DMA (31 mL)
was added 4-bromoanisole (0.73 mL, 2 equiv), Pd(OAc)2 (131 mg,
0.2 equiv), and KOAc (573 mg, 2 equiv) at rt. After being stirred at
80 ◦C for 16 h, the reaction mixture was cooled to rt. The mixture
was concentrated under reduced pressure to give the residue
which was purified by flash column chromatography (hexanes–
ethyl acetate–dichloromethane = 10 : 1 : 2 → 3 : 1 : 2) to afford
1
5 (851 mg, 65%) and 11 (339 mg, 34%). 5: H NMR (300 MHz,
CDCl3) d 7.49 (d, J = 9.0 Hz, 2H), 7.24 (d, J = 2.4 Hz, 1H), 7.21
(d, J = 2.1 Hz, 1H), 6.82 (d, J = 9.0 Hz, 2H), 6.50 (s, 3H) 3.90 (s,
3H), 3.80 (s, 3H), 3.77 (s, 6H), 3.23 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 168.2, 161.3, 159.9, 157.3, 155.5, 151.9, 136.8, 128.4,
125.5, 123.2, 121.9, 115.9, 114.1, 112.6, 107.7, 100.4, 99.8, 56.3,
55.7, 55.5, 51.7; HRMS (EI) calcd for [C26H24O7]+: m/z 448.1522,
Method B. To a solution of 3¢,5¢-dimethoxyacetophenone
(3.19 g, 17.7 mmol) in 60 mL of CHCl3–ethyl acetate (1 : 1)
was added CuBr2 (7.908 g, 2 equiv) at rt. After being refluxed
for 16 h, the reaction mixture was cooled to rt. The mixture
was filtered through Celite and washed with CH2Cl2. The filtrate
was concentrated in vacuo. The residue was suspended in solvent
(hexanes–ethyl acetate = 10 : 1), filtered, and rinsed with small
amount of solvent (hexanes–ethyl acetate = 10:1). The solid 10 was
dried under reduced pressure. The filtrate was concentrated and
the resulting residue was purified by flash column chromatography
(hexanes–ethyl acetate–dichloromethane = 20 : 1 : 2) to give 10
1
found 448.1515. 11: H NMR (300 MHz, CDCl3) d 7.23 (d, J =
2.1 Hz, 2H), 7.18 (d, J = 2.4 Hz, 2H), 6.28 (dd, J = 2.1, 2.4 Hz, 2H),
6.08 (d, J = 2.4 Hz, 4H), 3.90 (s, 6H), 3.65 (s, 12H), 3.16 (s, 6H);
13C NMR (75 MHz, CDCl3) d 167.8, 160.2, 158.2, 156.5, 142.8,
134.3, 126.4, 122.3, 119.3, 113.1, 106.6, 99.7, 99.3, 56.0, 55.2, 51.5;
HRMS (EI) calcd for [C38H34O12]+: m/z 682.2050, found 682.2055.
The compounds 12–16 (Table 2) were prepared under the
optimized conditions above.
1
(total 3.44 g, 75%). H NMR (300 MHz, CDCl3) d 7.11 (d, J =
2.1 Hz, 2H), 6.69 (d, J = 2.1 Hz, 1H), 4.43 (s, 2H), 3.85 (s, 6H)
Methyl 3-(3,5-dimethoxyphenyl)-6-methoxy-2-(4-nitrophenyl)-
benzofuran-4-carboxylate (12). 1H NMR (300 MHz, CDCl3) d
8.14 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H), 7.30 (d, J =
2.1 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 6.56 (dd, J = 2.1, 2.4 Hz,
1H), 6.49 (d, J = 2.1 Hz, 2H), 3.93 (s, 3H), 3.79 (s, 6H), 3.26 (s, 3H);
13C NMR (75 MHz, CDCl3) d 167.6, 161.7, 158.7, 156.1, 148.9,
147.0, 136.6, 135.6, 127.0, 126.7, 124.0, 121.3, 121.0, 114.0, 107.4,
100.6, 99.5, 56.3, 55.7, 51.8; HRMS (EI) calcd for [C25H21NO8]+:
m/z 463.1267, found 463.1265.
Methyl 3-(2-(3,5-dimethoxyphenyl)-2-oxoethoxy)-5-methoxy-
benzoate (8). To a solution of 9 (1.406 g, 7.72 mmol) and 10
(2 g, 7.72 mmol) in acetone (40 mL) was added K2CO3 (3.2 g,
3 equiv). The reaction mixture was heated to reflux for 2 h. After
being cooled to rt, the solvent was evaporated under reduced
pressure. The residue was diluted with ethyl acetate and washed
with H2O and brine, successively. The organic layer was dried over
MgSO4, filtered, and evaporated to give a crude residue which
was purified by flash column chromatography (hexanes–ethyl
acetate–dichloromethane = 7 : 1 : 2 → 5 : 1 : 2) to afford 8 (2.67 g,
Methyl 3-(3,5-dimethoxyphenyl)-2-(4-fluorophenyl)-6-methoxy-
benzofuran-4-carboxylate (13). 1H NMR (300 MHz, CDCl3) d
7.54-7.50 (m, 2H), 7.26 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 2.1 Hz,
1H), 7.01-6.95 (m, 2H), 6.53-6.48 (m, 3H), 3.90 (s, 3H), 3.77 (s,
6H), 3.25 (s, 3H); 13C NMR (75 MHz, CDCl3) d 167.8, 164.2, 161.2,
160.9, 157.4, 155.4, 150.6, 136.1, 128.7, 128.6, 126.5, 126.4, 125.6,
121.2, 116.9, 115.6, 115.3, 112.7, 107.3, 100.1, 99.5, 56.0, 55.5,
51.5; HRMS (EI) calcd for [C25H21FO6]+: m/z 436.1322, found
436.1325.
1
96%). H NMR (300 MHz, CDCl3) d 7.23 (d, J = 1.2 Hz, 1H),
7.22 (d, J = 1.2 Hz, 1H), 7.19 (dd, J = 1.2, 2.1 Hz, 2H), 6.74
(dd, J = 2.1, 2.4 Hz, 1H), 6.70 (dd, J = 2.1, 2.4 Hz, 1H), 5.28 (s,
2H), 3.90 (s, 3H), 3.85 (s, 6H), 3.83 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 193.5, 166.8, 161.3, 160.9, 159.2, 136.4, 132.4, 108.6,
107.7, 106.9, 106.3, 106.0, 70.9, 55.9, 55.8, 52.5; HRMS (EI) calcd
for [C19H20O7]+: m/z 360.1209, found 360.1213.
Methyl 3-(3,5-dimethoxyphenyl)-6-methoxybenzofuran-4-car-
boxylate (6). To a solution of 8 (2 g, 5.556 mmol) in CH2Cl2
(56 mL) was added Bi(OTf)3 (729 mg, 0.2 equiv) at rt. After
Methyl
3-(3,5-dimethoxyphenyl)-6-methoxy-2-(4-(trifluoro-
(14). 1H
NMR
methyl)phenyl)benzofuran-4-carboxylate
(300 MHz, CDCl3) d 7.65 (d, J = 8.1 Hz, 2H), 7.53 (d,
J = 8.7 Hz, 2H), 7.28 (d, J = 2.1 Hz, 1H), 7.24 (d, J = 2.4 Hz,
1H), 6.53 (dd, J = 2.1, 2.4 Hz, 1H), 6.49 (d, J = 2.1 Hz, 2H), 3.92
(s, 3H), 3.78 (s, 6H), 3.25 (s, 3H); 13C NMR (75 MHz, CDCl3) d
167.8, 161.5, 158.2, 155.8, 149.9, 136.0, 133.9, 130.2, 129.7, 126.9,
126.3, 126.0, 125.6, 125.56, 125.5, 125.46, 122.4, 121.2, 119.5,
113.5, 107.5, 100.5, 99.6, 56.3, 55.7, 51.8; HRMS (EI) calcd for
[C26H21F3O6]+: m/z 486.1290, found 486.1293.
◦
being stirred at 60 C for 16 h, the reaction mixture was cooled
to rt. The mixture was filtered through a pad of Celite and
the filtrate was evaporated in vacuo to give the residue which
was purified by flash column chromatography (hexanes–ethyl
acetate–dichloromethane = 10 : 1 : 2) to afford 6 (1.672 g, 88%).
1H NMR (300 MHz, CDCl3) d 7.62 (s, 1H), 7.33 (d, J = 2.4 Hz,
1H), 7.21 (d, J = 2.4 Hz, 1H), 6.50-6.46 (m, 3H), 3.90 (s, 3H),
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Methyl 2-(4-cyanophenyl)-3-(3,5-dimethoxyphenyl)-6-methoxy-
benzofuran-4-carboxylate (15). 1H NMR (300 MHz, CDCl3) d
7.63 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.28 (d, J =
2.4 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 6.54 (d, J = 2.1 Hz, 1H),
warmed to rt for 16 h, the mixture was quenched with H2O at 0 ◦C
and extracted with ethyl acetate. The organic layer was dried over
MgSO4, filtered, and evaporated to give a crude residue which was
purified by flash column chromatography (hexanes–ethyl acetate–
dichloromethane = 15 : 1 : 2) to afford 1 (62 mg, 100%). 1H NMR
(300 MHz, CDCl3) d 7.53 (d, J = 9.0 Hz, 2H), 7.11 (d, J = 2.1 Hz,
1H), 7.04 (s, 1H), 7.01 (s, 2H), 6.87 (s, 2H), 6.82 (d, J = 8.7 Hz,
2H), 6.78 (d, J = 8.7 Hz, 2H), 6.65 (s, 2H), 6.63 (t, J = 2.1 Hz,
1H), 3.92 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.74 (s, 6H);1H NMR
(700 MHz, CDCl3) d 7.52 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 2.1 Hz,
1H), 7.01 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 2.1 Hz, 1H), 6.87 (d,
J = 16.3 Hz, 1H), 6.84 (d, J = 16.3 Hz, 1H), 6.81 (d, J = 8.9 Hz,
2H), 6.77 (d, J = 8.7 Hz, 2H), 6.65 (d, J = 2.3 Hz, 2H), 6.63 (t, J =
2.3 Hz, 1H), 3.91 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.74 (s, 6H);
13C NMR (75 MHz, CDCl3) d 161.7, 159.5, 159.4, 158.3, 155.2,
150.0, 137.2, 132.3, 130.5, 128.8, 127.9, 127.8, 123.8, 123.4, 122.3,
116.6, 114.2, 114.1, 108.8, 106.9, 100.7, 95.1, 56.1, 55.7, 55.5, 55.4;
HRMS (EI) calcd for [C33H30O6]+: m/z 522.2042, found 522.2045.
6.48 (d, J = 2.1 Hz, 2H), 3.92 (s, 3H), 3.79 (s, 6H), 3.25 (s, 3H); 13
C
NMR (75 MHz, CDCl3) d 167.7, 161.6, 158.5, 156.0, 149.2, 135.7,
134.7, 132.3, 126.9, 126.6, 121.1, 120.6, 119.0, 113.8, 111.4, 107.4,
100.6, 99.5, 56.3, 55.7, 51.8; HRMS (EI) calcd for [C26H21NO6]+:
m/z 443.1369, found 443.1362.
Methyl 3-(3,5-dimethoxyphenyl)-2-(4-(ethoxycarbonyl)phenyl)-
6-methoxybenzofuran-4-carboxylate (16). 1H NMR (300 MHz,
CDCl3) d 7.95 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.27
(d, J = 2.4 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 6.53 (dd, J = 2.1,
2.4 Hz, 1H), 6.50 (d, J = 2.4 Hz, 2H), 4.36 (q, J = 7.2 Hz, 2H),
3.91 (s, 3H), 3.78 (s, 6H), 3.25 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3) d 167.9, 166.4, 161.5, 158.2, 155.9,
150.4, 136.1, 134.6, 130.0, 129.8, 126.5, 126.3, 121.3, 119.5, 113.4,
107.5, 100.6, 99.6, 61.2, 56.3, 55.7, 51.8, 14.5; HRMS (EI) calcd
for [C28H26O8]+: m/z 490.1628, found 490.1631.
3-(3,5-Dimethoxyphenyl)-6-methoxy-2-(4-methoxyphenyl)-4-
((2R,3R)-3-(4-methoxyphenyl)oxiran-2-yl)benzofuran (17). To a
stirred suspension of 4 (370 mg, 0.88 mmol) and dimethyl(4-
methoxybenzyl)sulfonium chloride (387 mg, 2 equiv) in 6 mL
of THF/DMF (1/1) was added 60% NaH (141 mg, 4 equiv) at
0 ◦C. After being stirred at 0 ◦C for 1 h, the mixture was quenched
with H2O at 0 ◦C and extracted with ethyl acetate. The organic
layer was dried over MgSO4, filtered, and evaporated to give a
crude residue which was purified by flash column chromatography
(hexanes–ethyl acetate–dichloromethane = 10 : 1 : 2 → 7 : 1 : 2)
3-(3,5-Dimethoxyphenyl)-6-methoxy-2-(4-methoxyphenyl)ben-
zofuran-4-carbaldehyde (4). To a solution of 5 (664 mg,
1.482 mmol) in CH2Cl2 (17 mL) was added DIBAL (1 M
solution in toluene, 5.9 mL, 4 equiv) at -78 ◦C. After being
stirred at -78 ◦C for 1 h, the reaction mixture was quenched
with MeOH at -78 ◦C. After being stirred at rt for 30 min, the
mixture was filtered through a pad of Celite and the filtrate was
concentrated under reduced pressure to give the residue which was
purified by flash column chromatography (hexanes–ethyl acetate–
dichloromethane = 5 : 1 : 2 → 3 : 1 : 2) to afford alcohol (623 mg,
100%). 1H NMR (300 MHz, CDCl3) d 7.45 (dd, J = 2.1, 6.9 Hz,
2H), 7.00 (d, J = 2.1 Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H), 6.79 (dd,
J = 2.1, 6.9 Hz, 2H), 6.60 (d, J = 2.1 Hz, 2H), 6.55 (d, J = 2.4 Hz,
1H), 4.45 (d, J = 4.2 Hz, 2H), 3.86 (s, 3H), 3.78 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 161.6, 159.5, 158.2, 154.9, 150.1, 136.8, 135.0,
127.6, 123.6, 121.5, 115.7, 114.1, 111.1, 108.3, 100.7, 95.3, 62.6,
56.0, 55.7, 55.5; HRMS (EI) calcd for [C25H24O6]+: m/z 420.1573,
found 420.1572.
1
to afford 17 (443 mg, 93%). H NMR (300 MHz, CDCl3) d 7.46
(d, J = 8.9 Hz, 2H), 7.03 (d, J = 2.1 Hz, 1H), 6.91-6.86 (m, 3H),
6.80-6.76 (m, 4H), 6.53 (br s, 1H), 6.32 (br s, 1H), 6.18 (dd, J =
2.1, 2.4 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.78 (d, J = 1.8 Hz,
1H), 3.75 (s, 3H), 3.74 (br s, 3H), 3.53 (d, J = 1.8 Hz, 1H), 3.32
(br s, 3H); 13C NMR (75 MHz, CDCl3) d 161.3, 160.0, 159.5, 158.5,
154.6, 150.0, 136.3, 131.8, 128.8, 127.6, 127.2, 123.6, 122.8, 115.7,
114.1, 113.9, 108.1, 106.3, 100.1, 95.7, 63.4, 59.4, 56.1, 55.6, 55.5;
HRMS (EI) calcd for [C33H30O7]+: m/z 538.1992, found 538.1996.
Pentamethyl ether of malibatol A (2) and its diastereomer 18. To
a stirred solution of 17 (38 mg, 0.071 mmol) in CH2Cl2 (3mL) was
added Bi(OTf)3 (5 mg, 0.1 equiv) at -78 ◦C. After being stirred at
-78 ◦C for 1 h, the mixture was quenched with aqueous NaHCO3
at -78 ◦C and extracted with dichloromethane. The organic
layer was dried over MgSO4, filtered, and evaporated to give a
crude residue which was purified by flash column chromatography
(hexanes–ethyl acetate–dichloromethane = 7 : 1 : 2 → 5 : 1 : 2) to
afford 2 (28 mg, 74%) and 18 (9 mg, 24%). 2: 1H NMR (300 MHz,
CDCl3) d 7.62 (d, J = 9.0 Hz, 2H), 7.12-7.10 (m, 3H), 6.94 (d, J =
9.0 Hz, 2H), 6.79 (d, J = 2.4 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H),
6.52 (d, J = 9.0 Hz, 2H), 6.41 (d, J = 2.7 Hz, 1H), 5.57 (d, J =
2.4 Hz, 1H), 5.40 (d, J = 6.0 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H),
To a solution of alcohol (147 mg, 0.35 mmol) in CH2Cl2
(3 mL) was added Dess–Martin periodinane (178 mg, 1.2 equiv)
at 0 ◦C. After being stirred at rt for 1 h, the reaction mixture
was filtered through Celite and the filtrate was concentrated under
reduced pressure to give the residue which was purified by flash col-
umn chromatography (hexanes–ethyl acetate–dichloromethane =
10 : 1 : 2 → 7 : 1 : 2) to afford aldehyde 4 (145 mg, 99%). 1H NMR
(300 MHz, CDCl3) d 9.78 (s, 1H), 7.53 (d, J = 9.0 Hz, 2H), 7.46
(d, J = 2.1 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 6.84 (d, J = 9.0 Hz,
2H), 6.61 (d, J = 2.1 Hz, 2H), 6.56 (dd, J = 2.1, 2.4 Hz, 1H), 3.92
(s, 3H), 3.81 (s, 3H), 3.79 (s, 6H); 13C NMR (75 MHz, CDCl3) d
189.9, 162.1, 160.1, 157.7, 155.5, 152.4, 136.6, 129.6, 128.2, 127.0,
122.8, 115.1, 114.3, 108.1, 107.7, 103.4, 100.8, 56.3, 55.7, 55.5;
HRMS (EI) calcd for [C25H22O6]+: m/z 418.1416, found 418.1420.
3.81 (s, 3H), 3.60 (s, 3H), 3.46 (s, 3H), 2.59 (d, J = 6.9 Hz, 1H); 13
C
NMR (75 MHz, CDCl3) d 160.2, 158.8, 158.5, 158.3, 157.7, 154.2,
151.1, 137.5, 134.4, 132.0, 130.5, 129.8, 124.6, 122.1, 118.2, 116.5,
114.2, 113.3, 108.4, 106.2, 98.3, 94.1, 73.8, 56.2, 55.9, 55.6, 55.2,
55.1, 47.9; HRMS (EI) calcd for [C33H30O7]+: m/z 538.1992, found
538.1995. 18: 1H NMR (300 MHz, CDCl3) d 7.67 (d, J = 8.7 Hz,
2H), 6.97 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 8.1 Hz, 2H), 6.88 (d,
J = 1.8 Hz, 1H), 6.84 (d, J = 2.1 Hz, 1H), 6.78 (d, J = 2.1 Hz,
(E)-3-(3,5-Dimethoxyphenyl)-6-methoxy-2-(4-methoxyphenyl)-
4-(4-methoxystyryl)benzofuran (1). To a stirred solution of di-
ethyl 4-methoxybenzylphosphonate (0.031 mL, 1.5 equiv) in 1 mL
of THF was added KOt-Bu (19 mg, 1.4 equiv) at 0 ◦C. After
5 min, a solution of 4 (50 mg, 0.12 mmol) in THF (1 + 1 mL
for rinse) was added to this mixture at -78 ◦C. After being slowly
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1H), 6.53 (d, J = 8.7 Hz, 2H), 6.48 (d, J = 2.4 Hz, 1H), 5.78 (d,
J = 6.3 Hz, 1H), 5.47 (t, J = 7.2 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H),
3.83 (s, 3H), 3.61 (s, 3H), 3.49 (s, 3H), 1.72 (d, J = 8.7 Hz, 1H);
13C NMR (75 MHz, CDCl3) d 161.1, 160.4, 158.9, 158.0, 157.5,
154.8, 151.9, 135.4, 135.2, 132.6, 130.5, 128.5, 124.4, 119.6, 117.7,
115.6, 114.3, 113.4, 113.1, 106.4, 98.5, 95.5, 74.6, 56.4, 56.0, 55.6,
55.2, 55.1, 44.4; HRMS (EI) calcd for [C33H30O7]+: m/z 538.1992,
found 538.1991.
T. Ito, M. Iinuma and H. Nozaki, Chem. Pharm. Bull., 2006, 54, 354;
(l) M. Yamada, K.-i. Hayashi, S. Ikeda, K. Tsutsui, T. Ito, M. Iinuma
and H. Nozaki, Biol. Pharm. Bull., 2006, 29, 1504.
3 J. Ito, Y. Takaya, Y. Oshima and M. Niwa, Tetrahedron, 1999, 55, 2529.
4 A compound with the same structure as that of viniferifuran was
isolated from Vitis amurensis Rupr., named amurensin H, and found
to exhibit anti-inflammatory activity: K. S. Huang, M. Lin and Y. H.
Wang, Chin. Chem. Lett., 1999, 10, 817.
5 K.-S. Huang, Y.-H. Wang, R.-L. Li and M. Lin, J. Nat. Prod., 2000,
63, 86.
6 J.-R. Dai, Y. F. Hallock, J. H. Cardellina, II and M. R. Boyd, J. Nat.
Prod., 1998, 61, 351.
Pentamethyl ether of shoreaphenol (3) and alcohol 2 from 3. To
a solution of 2 (16 mg, 0.03 mmol) in CH2Cl2 (2 mL) was added
Dess–Martin periodinane (15 mg, 1.2 equiv) at 0 ◦C. After being
stirred at rt for 1 h, the reaction mixture was filtered through Celite
and the filtrate was concentrated under reduced pressure to give
the residue which was purified by flash column chromatography
(hexanes–ethyl acetate–dichloromethane = 7 : 1 : 2) to afford
ketone 3 (16 mg, 100%). Alcohol 18 was also converted to ketone
3 in a similar manner. 1H NMR (300 MHz, CDCl3) d 7.77 (d, J =
9.0 Hz, 2H), 7.44 (d, J = 2.1 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H),
6.98 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.75 (d, J =
2.1 Hz, 1H), 6.55 (d, J = 8.7 Hz, 2H), 6.50 (d, J = 2.4 Hz, 1H),
6.20 (s, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.87 (s, 3H), 3.61(s, 3H),
3.52 (s, 3H); 13C NMR (75 MHz, CDCl3) d 196.3, 160.9, 159.9,
159.2, 158.0, 157.9, 154.2, 153.1, 134.3, 130.8, 130.4, 130.2, 127.8,
123.5, 122.7, 116.5, 116.1, 114.4, 113.5, 109.9, 105.8, 101.5, 98.8,
56.4, 56.3, 55.6, 55.3, 55.2; HRMS (EI) calcd for [C33H28O7]+: m/z
536.1835, found 536.1833.
7 (a) For the isolation of shoreaphenol, see: A. Saraswathy, K. K. Pu-
rushothaman, A. Patra, A. K. Dey and A. B. Kundu, Phytochemistry,
1992, 31, 2561; (b) For the isolation of hopeafuran, see: T. Tanaka, T.
Ito, Y. Ido, K. Nakaya, M. Iinuma and V. Chelladurai, Chem. Pharm.
Bull., 2001, 49, 785.
8 G. A. Kraus and I. Kim, Org. Lett., 2003, 5, 1191.
9 (a) C.-S. Yao, L.-X. Zhou and M. Lin, Chem. Pharm. Bull., 2004,
52, 238; (b) Y. Takaya, K. Terashima, J. Ito, Y.-H. He, M. Tateoka,
N. Yamaguchi and M. Niwa, Tetrahedron, 2005, 61, 10285; (c) S. A.
Snyder, A. L. Zografos and Y. Lin, Angew. Chem., Int. Ed., 2007, 46,
8186; (d) S. S. Velu, I. Buniyamin, L. K. Ching, F. Feroz, I. Noorbatcha,
L. C. Gee, K. Awang, Abd., I. Wahab and J.-F. F. Weber, Chem. Eur. J.,
2008, 14, 11376.
10 Permethylations of viniferifuran, malibatol A, and shoreaphenol were
carried out in the course of their structure elucidations. Thus, the
spectral data of 1, 2, and 3 are known in the literature. See refs. 3
and 7b.
11 (a) T. K. Chakraborty and G. V. Reddy, J. Org. Chem., 1992, 57, 5462;
(b) N. Hoffmann and J.-P. Pete, Synthesis, 2001, 1236; (c) S. Inoue,
C. Nakagawa, H. Hayakawa, F. Iwasaki, Y. Hoshino and K. Honda,
Synlett, 2006, 1363.
12 Br2 was used for a-bromination of 3¢,5¢-dimethoxyacetophenone:
R. Apodaca, A. J. Barbier, N. I. Carruthers, L. A. Gomez, J. M. Keith,
T. W. Lovenberg and R. L. Wolin, World Pat. WO 2006138604 A1.
However, CuBr2 was found to give a better result: L. Chen, Q. Ding,
P. Gillespie, K. Kim, A. J. Lovey, W. W. McComas, J. G. Mullin and
A. Perrota, World Pat. WO 02057261 A2. See the Experimental Section
for more details.
13 I. Kim, S.-H. Lee and S. Lee, Tetrahedron Lett., 2008, 49, 6579.
14 This is surprising because a similar substrate A was smoothly converted
to the corresponding benzofuran B in very good yield. See ref 13.
To a solution of 3 (15 mg, 0.028 mmol) in 3 mL of MeOH/THF
(1/1) was added NaBH4 (2.6 mg, 2.5 equiv) at 0 ◦C. After 30 min,
the mixture was quenched with saturated NH4Cl at 0 ◦C. After the
mixture was concentrated in vacuo, the residue was diluted with
ethyl acetate and washed with brine. The organic layer was dried
over MgSO4, filtered, and evaporated in vacuo to give 2 (15 mg,
100%). Characterisation data identical to that described earlier.
Acknowledgements
We thank the Korea Research Institute of Chemical Technology
for supporting this work. We also thank Dr. Chong-Hyeak Kim
for X-ray crystallographic analysis of compounds 5 and 11.
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23 Other parameters (solvents (toluene, TFA), bases (AgOAc), and ligand
(PPh3)) were briefly examined but all gave inferior results.
24 To the best of our knowledge, no report on the synthesis of ho-
mocoupled benzofuran dimers by direct C–H activation has been
disclosed. The scope of these results will be reported elsewhere. For
furan homodimers, see: T. Itahara, M. Hashimoto and H. Yumisashi,
Synthesis, 1984, 255.
25 Benzofuran homodimer 11 was also isolated in 20–25% yield in the
cases of 12–16.
26 D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155.
27 For comparison, see: Y. Takaya, K.-X. Yan, K. Terashima, J. Ito and M.
Niwa, Tetrahedron, 2002, 58, 7259W. hile epoxidation of (+)-e-viniferin
failed to yield its corresponding epoxide, its pentaacetate analogue was
converted to the corresponding epoxide as a mixture of diastereomers.
28 E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1965, 87,
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29 N. Buckley and N. J. Oppenheimer, J. Org. Chem., 1994, 59,
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30 See ref. 7b.
31 No other isomers were found in epoxide ring opening, indicating that
six-membered ring formation through 6-exo-tet attack is difficult in this
system.
21 For examples of C2–C2¢-linked benzofuran dimers, see: (a) J. Guil-
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32 In order to obtain shoreaphenol, global deprotection of 3 with BBr3
was attempted, only giving a complex mixture.
33 In addition, a crude mixture of diastereomers (2 + 18) resulting from
treatment of 17 with Bi(OTf)3 was directly subjected to Dess–Martin
oxidation conditions, affording 3 in 98% two-step overall yield.
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The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 2788–2795 | 2795
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