A new synthetic strategy for the synthesis of bioactive stilbene dimers. A direct synthesis of amurensin H

Article abstract of DOI:10.1016/j.tetlet.2009.10.040

2,3-Diarylbenzofurans are efficiently generated by the cyclization of ortho-benzyloxybenzophenones using the hindered phosphazene base P₄-t-Bu.

Full text of DOI:10.1016/j.tetlet.2009.10.040

Tetrahedron Letters 50 (2009) 7180–7183
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Tetrahedron Letters
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A new synthetic strategy for the synthesis of bioactive stilbene dimers. A
direct synthesis of amurensin H
*
George A. Kraus , Vinayak Gupta
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
2,3-Diarylbenzofurans are efficiently generated by the cyclization of ortho-benzyloxybenzophenones
using the hindered phosphazene base P4-t-Bu.
Received 24 July 2009
Revised 6 October 2009
Accepted 7 October 2009
Available online 14 October 2009
Published by Elsevier Ltd.
Stilbene dimers are
a
class of natural products that are
erin, structurally related to 1, has been reported to be a potent
MRP1 transport inhibitor.6
broadly distributed and exhibit diverse biological activity.1 Rep-
resentative examples are shown in Figure 1. Amurensin H (1),
isolated from Vitus amurensis, shows significant anti-inflamma-
tory activity in mice models. Compound 1 may have therapeutic
potential for the treatment of allergic airway inflammation.2 It
has also been reported to treat chronic obstructive pulmonary
disease.2 It has been synthesized by an oxidative coupling reac-
tion according to a biosynthetic pathway.3 Gnetuhainin B (2)
was isolated from Gnetum hainanense which grows only in the
People’s Republic of China.4 Gnetuhainin G (3) is a novel fur-
Several synthetic routes to benzofurans such as 1 are known.7
The majority of these syntheses take place via disconnection A
(Fig. 2). This includes the reaction of ortho-halophenols with acety-
lenes,8 and the oxidative cyclization9 of hydroxy stilbenes. A related
pathway is the palladium-mediated arylation of benzofurans.10 In
contrast, disconnection B has rarely been utilized to prepare diary-
lbenzofurans. A notable example is a photocyclization that takes
place via an intramolecular hydrogen atom abstraction of the ben-
zylic hydrogen atom followed by radical recombination and
dehydration.11
obenzofuran from G. hainanense and is an antioxidant.5
a-Vinif-
HO
HO
O
OMe
HO
HO
HO
OMe
OH
O
OH
OH
O
O
OH
OH
HO
OH
HO
HO
OH
2
1
OH
3
Figure 1. Structures of diarylbenzofurans.
OH
O
O
Ar
O
A
Disconnection A
Disconnection B
Ar
Ar
G
B
A
Ar
Figure 2. Synthetic strategies for benzofurans.
* Corresponding author.
E-mail address: gakraus@iastate.edu (G.A. Kraus).
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.10.040

G. A. Kraus, V. Gupta / Tetrahedron Letters 50 (2009) 7180–7183
7181
In connection with our studies of the synthetic potential of the
hindered base P4-t-Bu,12 we reacted 2-benzyloxybenzophenone
with P4-t-Bu and isolated 4 in 100% yield (Scheme 1). We then
evaluated an array of benzophenones. Our results are depicted in
Table 1.
As the results in Table 1 illustrate, this cyclization is compatible
with a variety of functional groups and represents a convenient en-
try to aryl substituted benzofurans.13 As entry 12 indicates, this
chemistry is extendable to the benzo[1,2-b:5,4-b0]difuran ring sys-
tem in 3. Interestingly, this cyclization proceeds in good yield de-
N
P
N
N
P
N
P
N
P4-t-Bu,
O
O
Ph
O
Benzene, reflux
N
N
N
N
Ph
Ph
100%
N
P
N
Ph
N
N
4
P4-t-Bu
Scheme 1. Synthesis of Benzofuran 4.
Table 1
Synthesis of benzofurans from benzophenones
S. No
Reactant
Time (h)
Product
Yield (%)
100
O
1
3
O
O
O
2
3
4
5
6
75
78
70
72
MeO
MeO
MeO
MeO
O
O
O
6
O
O
O
O
O
O
O
O
O
MeO
MeO
6.5
MeO
MeO
O
O
O
O
O
6
O
O
O
O
O
O
O
O
OMe
OMe
MeO
MeO
MeO
OMe
OMe
6
8
76
MeO
MeO
OMe
O
OBn O
OBn
OMe
MeO
7
7.5
60
O
O
(continued on next page)

7182
G. A. Kraus, V. Gupta / Tetrahedron Letters 50 (2009) 7180–7183
Table 1 (continued)
S. No
Reactant
Time (h)
Product
Yield (%)
OBn O
OMe
OMe
MeO
OMe
OMe
8
7
59
O
OBn
OMe
O
O
9
6.5
66
O
O
CO2Et
O
CO2Et
O
10
7
67
O
O
Cl
Cl
11
12
13
8
12
4.5
72
61
65
O
O
O
O
O
O
O
O
O
O
NO2
O
NO2
spite the presence of two different benzyl groups in the benzophe-
none (entries 7 and 8).
The possible mechanism for these reactions is depicted in
Scheme 2. It is based on the assumption that P4-t-Bu successfully
deprotonate the benzylic position which bears the most acidic
hydrogen. The anion thus generated attacks the carbonyl carbon
giving rise to the alcohol which undergoes dehydration at elevated
temperature to give 2,3-diarylbenzofuran.
O
H
Ar'
H
O
O
Ar'
H
H
O
O
P4-t-Bu
- H2O
Ar'
Ar'
Ar
Ar
Ar
HO
Ar
Product
O
Scheme 2. Possible mechanistic pathway for the formation of 2,3-diarylbenzofurans.

G. A. Kraus, V. Gupta / Tetrahedron Letters 50 (2009) 7180–7183
7183
OMe
MeO
OMe
Br
OMe
MeO
OMe
O
MeO
OMe
OH
n-BuLi, THF
-78 oC - 0 ºC
CHO
MnO2, Benzene
Dean- Stark
OMe
OMe
MeO
OMe
OMe
5
7
6
OMe
OMe
1.0M BBr3,
CH2Cl2
-78 ºC - -50 ºC
MeO
OMe
OMe
RO
O
MeO
OH
O
MeO
O
O
OR
P4-t-Bu,
Benzene,
170 ºC,
OMe
OMe
NaH, DMF
MeO
OR
Br
Sealed Tube
RO
OR
8
OMe
9
OMe
10
R = Me
1.0M BBr3,
CH2Cl2, 0 ºC - RT
1 R = H
Scheme 3. Synthesis of 1.
Zhuanli Shenqing Gongkai Shuomingshu Application: CN 2006-10076299
20060421.
This methodology can be used in a direct total synthesis of amu-
rensin H 1 (Scheme 3). Starting from stilbene 5 (readily available
from 3,5-dimethoxybenzaldehyde),14 metal–halogen exchange fol-
lowed by reaction with 3,5-dimethoxybenzaldehyde gave 6 and
oxidation of 6 with activated manganese dioxide affords a benzo-
phenone 7 in 77% yield from 5. This benzophenone 7 can be selec-
tively demethylated in 88% yield to give 8 using BBr3 solution
(1.0 M in CH2Cl2) at ꢀ50 °C. The resulting phenol 8 is converted
into benzyl ether 9 in 86% yield.
Cyclization of 9 using P4-t-Bu in dry benzene at 170 °C (sealed
tube conditions) provided 10 in 42% yield. The higher temperature
needed to effect the cyclization is likely a result of steric factors. Fi-
nally, the total synthesis of amurensin H 1 was achieved by
exhaustive demethylation of benzofuran 10 using solution (1.0 M
in CH2Cl2) at room temperature in 67% yield. The analytical data
for 1 matched with the previously reported data.3,15
3. Huang, K.-S.; Lin, M.; Wang, Y.-H. Chin. Chem. Lett. 1999, 10, 817–820.
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19, 176–207; Cacchi, S.; Fabrizi, G.; Goggiamani, A. Curr. Org. Chem. 2006,
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13. Representative procedure for the preparation of 2,3-diarylbenzofuran: To
a
solution of 2-benzyloxybenzophenone (0.20 g, 0.69 mmol) in freshly distilled
dry benzene (10 mL), P4-t-Bu solution (0.77 mL, 0.76 mmol) was added at rt
and the reaction mixture was heated to reflux. After the completion of reaction
(3 h), benzene was partially evaporated and reaction mixture was purified by
column chromatography using 10% ethyl acetate: petroleum ether to obtain
pure product (100% yield).2,3-Diphenylbenzo[b]furan (4): Mp 123–124.5 °C;
1HNMR (400 MHz) d 7.23 (t, J = 7.3 Hz, 1H), 7.28–7.35 (m, 4H), 7.38–7.52 (m,
6H), 7.55 (d, J = 8.3 Hz, 1H), 7.65–7.67 (m, 2H); 13CNMR (100 MHz) d 111.1,
117.5, 120.0, 122.9, 124.7, 127.0, 127.6, 128.3, 128.4, 129.0, 129.8, 130.2, 130.7,
132.8, 150.5, 154.0; MS m/z 270 (M+).
Acknowledgment
We thank the Department of Chemistry at Iowa State University
for partial support of this research.
References and notes
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