A facile and practical total synthetic route for ampelopsin F and permethylated ?-viniferin

Article abstract of DOI:10.1055/s-0035-1561419

Stilbene dimers (±)-ampelospin F and permethylated (±)-?-viniferin were synthesized by a practical synthetic route with overall yields of 10% and 27%. This route involves triethylsilane-mediated reduction of the 2,3-diarylbenzofuran, and BBr₃-mediated one-pot demethylation and cascade intramolecular cyclization reaction.

Full text of DOI:10.1055/s-0035-1561419

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
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2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
J. Zhang et al.
Letter
Synlett
A Facile and Practical Total Synthetic Route for Ampelopsin F and
Permethylated ε-Viniferin
MeO
Jifa Zhang
OH
Jianqiao Zhang
MeO
HO
O
MSA
Pd(OAc)2/KOAc
TES/TFA
Yulong Kang
Jiangong Shi
Chunsuo Yao*
COOH
OMe
OH
BBr3
OMe
H
HO
HO
OH
HO
OH
O
MeO
OH
OH
State Key Laboratory of Bioactive Substance and Function
of Natural Medicines, Institute of Materia Medica, Chinese
Academy of Medical Sciences & Peking Union Medical
College, Beijing 100050, P. R. of China
yaocs@imm.ac.cn
Received: 10.01.2016
OH
Accepted after revision: 26.02.2016
Published online: 30.03.2016
DOI: 10.1055/s-0035-1561419; Art ID: st-2016-w0019-l
OH
HO
OH
4a
4b
HO
OH
Abstract Stilbene dimers (±)-ampelospin F and permethylated (±)-ε-
viniferin were synthesized by a practical synthetic route with overall
yields of 10% and 27% . This route involves triethylsilane-mediated re-
duction of the 2,3-diarylbenzofuran,, and BBr3-mediated one-pot de-
methylation and cascade intramolecular cyclization reaction.
1b
7b
OH
1a
10b
7a
8a
H
9a
OH
12b
HO
O
HO
OH
10a
2
8b
12a
14b
OH
OH
HO
Key words total synthesis, ampelopsin F, ε-viniferin, stilbene dimer,
BBr3
1
3
Figure 1 Structures of natural products 1–3
(±)-Ampelopsin F (1), a resveratrol dimer containing a
dibenzobicyclo[3.2.1]octadiene skeleton (Figure 1), is dis-
tributed in Vitaceaeous plants, such as Vitis amurensin, V.
vinifera, and Ampelopsis brevipedunculata.1 Biological stud-
ies have demonstrated that 1 exhibits antioxidative, antilip-
id peroxidation, and antimicrobial activities.2 (±)-ε-Vinifer-
in (2), another natural stilbene dimer (Figure 1) containing
a dihydrobenzofuran skeleton, is distributed in Vitaceaeous
plants and displays potent anti-inflammatory, antioxidant,
antifungal, antibacterial, anticancer, and neuroprotective
activities.3 Nevertheless, given that these dimers are exclu-
sively obtained through extraction from natural sources,
studies on their biological properties are limited by their
extreme scarcity, making their synthesis a recent research
hotspot.
Despite their interesting biological activities, as well as
their unique carbon framework, few synthetic approaches
for these two compounds have been reported.4 Most at-
tempts to prepare 1 and 2 have been derived from their
presumed biogenesis, that is, the process involving genera-
tion of radicals or carbocations through exposure to differ-
ent chemicals or enzymes, especially the biomimetic syn-
thesis of 2 by an oxidative dimerization of resveratrol (3).5
In these reactions, complex mixtures of products typically
resulted in tedious separation and low yields. In some rare
cases,6 when regioselectivity was achieved, the limited sub-
strate scope and modification sites hampered its applica-
tion in conducting analogue synthesis.
Snyder et al. constructed a common building block to
obtain 1 in 11 steps with an overall yield of 5%. Moreover,
Elofsson et al. recently reported the synthesis of 2 in 15
steps with 5% overall yield.4 However, long reaction steps
render these approaches not suitable for specific alterations
of the substitution patterns.
In this study, we report a facile and practical total syn-
thetic approach to obtained 1 and permethylated 2 – a
framework of great biological significance in high yield.
During synthesis, direct construction of the complex
highly strained dibenzobicyclo[3.2.1]octadiene embedded
in 1 is apparently a big challenge. By contrast, from a bioge-
netic viewpoint, 1 evolved from 2 via a cation-based rear-
rangement, as reported in the literature.7 Thus, 2 may be
chosen as the key synthetic precursor of 1. The retrosyn-
thetic route to natural product 1 is outlined in Scheme 1.
The precursor 2 could be produced by olefination of the key
intermediate dihydrobenzofuran aldehyde 4, which could
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
J. Zhang et al.
Letter
Synlett
OH
OH
OH
MeO
MeO
HO
HO
OMe
OMe
MeOOC
OH
CHO
HO
OMe
OMe
OH
O
O
MeO
MeO
OH
HO
O
OH
5
4
1
2
MeO
MeO
OMe
OMe
MeOOC
MeOOC
MeO
O
Br
OMe
O
O
MeO
6
6a
7
Scheme 1 Retrosynthetic analysis of ampelopsin F (1)
be hypothesized to be available through hydrogenation re-
duction of benzofuran 5. According to Kim’s method,8
structural feature of active naturally oligostilbenes (e.g.,
maximol A, scirpusin A).9 However, synthetic methods for
reducing 2,3-diarylbenzofuran to the corresponding 2,3-di-
aryl-2,3-dihydrobenzofuran are scare. Recently, Elofsson et
al.4 employed catalytic hydrogenation over Pd/C in EtOAc–
MeOH at 20 °C for three days to synthesize a cis-methyl
3-[3,5-bis(cyclopropylmethoxy)phenyl]-6-(cyclopropylme-
thoxy)-2-[4-(cyclopropylmethoxy)phenyl]-2,3-dihydrobenzo-
furan-4-carboxylate in 80% yield. While catalytic reduction
of 2,3-diarylbenzofuran systems has provided cis-dihydro-
benzofurans, to our knowledge, no methods for reducing
the fused-ring system to the corresponding trans-2,3-dia-
ryl-2,3-dihydrobenzofuran have been reported so far. Sev-
eral attempts to this reduction were unsuccessful because
of the large steric hindrance of two adjacent aryls. First, the
magnesium-mediated reduction of 5 in tetrahydrofuran
and methanol did not produce the desired 11;10 instead, the
methyl ester group was unexpectedly reduced to benzyl al-
cohol. Then compound 5 was treated with 10% Pd/C under
hydrogen atmosphere in methanol at 50 °C for ten hours,
5
could be prepared via a transition-metal-catalyzed direct
C–H activation of benzofuran 6 followed by intermolecular
coupling with an aryl halide 6a. Finally, the requisite 6 was
conceived to be available from the dehydrative cyclization
of aryloxyketone 7, which can be conveniently prepared
from the commercially available 3,5-dihydroxybenzoic acid
(8a) and 3,5-dihydroxyacetophenone (8b).
As delineated in Scheme 2, we commenced our synthe-
sis with the preparation of aryloxyketone intermediate 7
from 9a and 9b in the presence of potassium carbonate,
which were easily prepared from 8a and 8b. 3-Aryl benzo-
furan 6 was prepared through cyclodehydration reaction of
7 in the presence of Bi(OTf)3 or methanesulfonic acid (MSA)
in 83% or 72% yield, respectively. Subsequently, when 6 was
exposed to the conditions [Pd(OAc)2 (0.2 equiv), KOAc (2
equiv), and 4-bromoanisole (10 equiv) in DMA, 120 °C] as
reported by Kim et al., the desired benzofuran 5 was suc-
cessfully obtained at 57% yield.8
1
With 2,3-diarylbenzofuran 5 in hand, we explored the
synthesis of the key intermediate 2,3-dihydrobenzofuran
11 by hydrogenation reduction of the 2,3-diarylbenzofuran
ring. 2,3-Diaryl-2,3-dihydrobenzofurans are a common
and 11b was obtained in low yield (18%). In the H NMR
spectrum, the coupling constant of 8 Hz between H-2 and
H-3 indicates a cis orientation of 2,3-diaryl groups. Fortu-
nately, when we used triethylsilane in trifluoroacetic acid
COOMe
COOH
MeO
MeO
MeO
1) MeOH/H2SO4
2) MeI
Pd(OAc)2,
KOAc/DMA
120 °C;
OMe
Br
MeO
OH
HO
OH
OMe
MeOOC
K2CO3/acetone
MeOOC
MSA/DCM
MeOOC
OMe
O
8a
9a
18 h, 57%
Br
40 °C, 72%
MeO
reflux, 3 h, 98%
MeO
OMe
OMe
MeO
O
O
O
O
O
6
5
7
1) MeI
2) CuBr2
HO
OH
MeO
OMe
9b
8b
Scheme 2 Construction of diarylbenzofuran intermediate 5
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
J. Zhang et al.
Letter
Synlett
MeO
MeO
MeO
OMe
OMe
OMe
CH2OH
CO2Me
CO2Me
Mg/NH4Cl/THF/MeOH
r.t., 3 h, 27%
TES/TFA
r.t., overnight, 96%
OMe
OMe
OMe
O
O
O
MeO
MeO
MeO
5
11a
11
Pd-C/H2/MeOH
50 °C, 10 h,18%
MeO
OMe
CO2Me
OMe
O
MeO
11b
Scheme 3 Reduction of the diarylbenzofuran intermediate 5
following the procedure described by Lau and co-workers,11
the reduction process proceeded smoothly to form racemic
dihydrobenzofuran 11 with an excellent yield of 96% in 12
hours (Scheme 3); the coupling constant of 4.3 Hz for H-2
and H-3 suggests a trans configuration for 2,3-diaryl
groups. According to the ionic hydrogenation with TES/TFA,
the mechanism of this reduction has been shown to entail
the initial protonation of the benzofuran at C-3 by the tri-
fluoroacetic acid, followed by the transfer of hydride from
the triethylsilane to C-2. Generally, ionic hydrogenation re-
sults in the formation of the thermodynamically more sta-
ble trans isomer. This means that the proton and the hy-
dride ion are added trans to the alkenic bond, which result-
ed in the products with trans configuration.12
converted into 1 at 39% yield rather than into the desired 2
(Scheme 5). This finding indicates that, being a Lewis acid,
BBr3 is sufficiently strong to facilitate demethylation and
cascade intramolecular cyclization simultaneously. At this
point, to prepare the natural product 2 from 12, many a
methods have been explored, such as BBr3/DCM, BBr3/ben-
zene, BBr3/toluene, TMSI, MeSO3H/methionine, and
TMSI/quinoline. Unfortunately, all of these attempts failed
to obtain compound 2.
Comparison revealed that the 1H NMR and 13C NMR
spectral data of compound 1 are consistent with those of
the natural product ampelopsin F isolated from A. brevipe-
duncularu var. hancei reported by Yoshiteru Oshima
et al.1,14
After preparing 11, we subsequently incorporated the
final aryl moiety into 11. The ester group in 11 was reduced
with LiAlH4 followed by oxidation with Dess–Martin perio-
dinane to produce aldehyde 4 in an excellent overall yield of
92% over two steps. The Horner–Wadsworth–Emmons-
type olefination of 4 with 4-methoxybenzylphosphonate
successfully provided the permethylated (±)-ε-viniferin
(12) with a yield of 98% (Scheme 4).13
In view of the isomerization reaction mechanisms of
(+)-ε-viniferin reported by Niwa et al.,7 the possible forma-
tion mechanism of 1 may be rationalized as shown in
Scheme 6.
Initially, 12 was demethylated by BBr3 in dichlorometh-
ane to produce 2. Then under the Lewis acid BBr3 condi-
tions, the unstable dihydrofuran ring was opened, followed
by nucleophilic attack of the double bond to form a five-
membered ring intermediate. Afterwards, the second nuc-
leophilic attack of the double bond against the intermediate
and the subsequent deprotonation generate the ultimate
product 1. All of the reactions mentioned above should be
carried out concertedly. To the best of our knowledge, the
According to the method described by Niwa et al.,7 com-
pound 1 can be obtained by treating 2 with protonic acid.
Therefore, we hypothesized that 2 can be initially prepared
through BBr3-induced cleavage of the five methyl ethers of
12. When 12 was treated with BBr3 in dichloromethane at
–50 °C to 5 °C for 12 hours, it was unexpectedly directly
MeO
MeO
MeO
MeO
PO(OEt)2
OMe
OMe
MeO
OMe
CO2Me
CHO
1) LiAlH4/THF, r.t., 2 h
2) Dess–Martin periodinane/DCM
r.t., 2 h, 92% for two steps
OMe
OMe
t-BuOK/THF, r.t., 24 h, 98%
MeO
OMe
O
O
MeO
MeO
O
4
11
12
Scheme 4 Synthesis of permethylated (±)-ε-viniferin (12)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
J. Zhang et al.
Letter
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MeO
OH
OH
HO
MeO
HO
OH
OMe
OH
BBr3/DCM
H
HO
–50 to 5°C
overnight
39%
OMe
OH
OH
O
O
12
MeO
HO
OH
1
2
Scheme 5 BBr3-mediated one-pot demethylation and cascade intramolecular cyclization reaction of 12
OH
OH
OH
MeO
HO
HO
HO
MeO
OH
OH
OH
BBr3
OMe
H
HO
HO
OH
OMe
OH
OH
O
BBr3
HO
O
MeO
OH
OH
12
7
1
Scheme 6 Proposed mechanism of the unusual BBr3-mediated one pot demethylation and cascade intramolecular cyclization.
BBr3-mediated cascade intramolecular cyclization reaction
of 12 to form the complex dibenzobicyclo[3.2.1]octadiene
derivative was reported herein for the first time.
Mohamad, S. A. S.; Low, A. L. M.; Sufian, A. S.; Yusof, M.; Latip, J.
J. Nat. Prod. Res. 2014, 16, 1099. (c) Oshima, Y.; Ueno, Y.;
Hisamichi, K.; Takeshita, M. Tetrahedron 1993, 49, 5801.
(2) (a) Ha, D. T.; Kim, H. J.; Thuong, P. T.; Ngoc, T. M.; Lee, I.; Hung,
N. D.; Bae, K. J. Ethnopharmacol. 2009, 125, 304. (b) Yim, N.;
Trung, T. N.; Kim, J. P.; Lee, S.; Na, M.; Jung, H.; Kim, H. S.; Kim,
Y. H.; Bae, K. Bioorg. Med. Chem. Lett. 2010, 20, 1165.
(3) (a) Privat, C.; Telo, J. P.; Bernardes-Genisson, V.; Vieira, A.;
Souchard, J. P.; Nepveu, F. J. Agric. Food Chem. 2002, 50, 1213.
(b) Schnee, S.; Queiroz, E. F.; Voinesco, F.; Marcourt, L.; Dubuis,
P. H.; Wolfender, J. L.; Gindro, K. J. Agric. Food Chem. 2013, 61,
5459. (c) Yáñez, M.; Fraiz, N.; Cano, E.; Orallo, F. Eur. J. Pharma-
col. 2006, 542, 54. (d) Zghonda, N.; Yoshida, S.; Ezaki, S.; Otake,
Y.; Murakami, C.; Mliki, A.; Ghorbel, A.; Miyazaki, H. Biosci. Bio-
technol. Biochem. 2012, 76, 954. (e) Lin, M.; Yao, C. S. Stud. Nat.
Prod. Chem. 2006, 33, 601.
In summary, a facile and practical total synthetic ap-
proach to produce the natural occurring stilbenoids 1 and
12 was achieved in ten steps with overall yields of 10% and
27%, respectively. The total synthetic route involves trieth-
ylsilane-mediated reduction of the 2,3-diarylbenzofuran
ring, and BBr3-induced one-pot demethylation and cascade
intramolecular cyclization reaction of 12. The route de-
scribed herein is concise and practical and should be useful
for the synthesis of 1, 2, and their analogues. Synthesis of 2
is in progress and will be reported in due course.
(4) (a) Snyder, S. A.; Zografos, A. L.; Lin, Y. Angew. Chem. Int. Ed.
2007, 46, 8186. (b) Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin,
Y.; Zografos, A. L. J. Am. Chem. Soc. 2009, 131, 1753. (c) Lindgren,
A. E. G.; Öberg, C. T.; Hillgren, J. M.; Elofsson, M. Eur. J. Org.
Chem. 2016, 426.
(5) (a) Huang, K. S.; Lin, M.; Wang, Y. H. Chin. Chem. Lett. 1999, 10,
817. (b) Yao, C. S.; Lin, M.; Wang, Y. H. Chin. J. Chem. 2004, 22,
1350. (c) Takaya, Y.; Terashima, K.; Ito, J.; He, Y. H.; Tateoka, M.;
Yamaguchi, N.; Niwa, M. Tetrahedron 2005, 61, 10285. (d) Wang,
G. W.; Wang, H. L.; Capretto, D. A.; Han, Q.; Hu, R. B.; Yang, S. D.
Tetrahedron 2012, 68, 5216.
Acknowledgment
We are grateful to the department of Instrumental Analysis, Institute
of Materia Medica, Chinese Academy of Medical Sciences and Peking
Union Medical College for measuring the NMR and MS spectra.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561419.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(6) Li, W.; Li, H.; Luo, Y.; Yang, Y.; Wang, N. Synlett 2010, 1247.
(7) Takaya, Y.; Yan, K. X.; Terashima, K.; Ito, J.; Niwa, M. Tetrahedron
2002, 58, 7259.
References and Notes
(8) Kim, I.; Choi, J. Org. Biomol. Chem. 2009, 7, 2788.
(9) Wang, X. F.; Yao, C. S. J. Asian Nat. Prod. Res. 2016, 18, in press;
DOI: 10.1080/10286020.2015.1094464.
(10) Fischer, J.; Savage, G. P.; Coster, M. J. Org. Lett. 2011, 13, 3376.
(1) (a) Ha, D. T.; Chen, Q. C.; Hung, T. M.; Youn, U. J.; Ngoc, T. M.;
Thuong, P. T.; Kim, H. J.; Seong, Y. H.; Min, B. S.; Bae, K. H. Arch.
Pharm. Res. 2009, 32, 177. (b) Ahmat, N.; Wibowo, A.;
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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J. Zhang et al.
Letter
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(11) (a) Rupprecht, K. M.; Boger, J.; Hoogsteen, K.; Nachbar, R. B.;
Springer, J. P. J. Org. Chem. 1991, 56, 6180. (b) Lau, C. K.;
Belanger, P. C.; Dufresne, C.; Scheigetz, J.; Therien, M.;
Fitzsimmons, B.; Young, R. N.; Ford-Hutchinson, A. W.;
Riendeau, D.; Denis, D.; Guay, J.; Charleson, S.; Piechuta, H.;
McFarlane, C. S.; Chiu, S.-H. L.; Chiu, D.; Eline, R. F.; Alvaro, G.;
Miwa, J.; Walsh, L. J. Med. Chem. 1992, 35, 1299.
(12) (a) Lanzilotti, A. E.; Littell, R.; Fanshawe, W. J.; Mckenzie, T. C.;
Lovell, F. M. J. Org. Chem. 1979, 44, 4809. (b) Kursanov, D. N.;
Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633.
(13) General Procedure for the Synthesis of Compound 12
t-BuOK (303 mg, 2.73 mmol) was added to a stirred solution of
diethyl(4-methoxyphenyl)phosphonate (659 mg, 2.70 mmol) in
THF (15 mL) at –40 °C. Then compound 4 (810 mg, 1.93 mmol)
in THF (20 mL) was added, and the mixture was stirred at room
temperature for 24 h. After the solvent was removed under
reduced pressure, the mixture was diluted with EtOAc, washed
with brine and water, dried over anhydrous Na2SO4, and con-
centrated in vacuo. The residue was purified by column chro-
matography over silica gel to afford compound 12.
acetone-d6): δ = 162.34 (4 C), 160.61, 160.54, 147.20, 136.26,
134.72, 130.89, 130.23, 128.61 (2 C), 127.87 (2 C), 123.97,
121.03, 114.86 (2 C), 114.79 (2 C), 106.79 (2 C), 102.95, 99.33,
95.77, 93.65, 57.19, 55.84, 55.62 (2 C), 55.57 (2 C). ESI-HRMS:
m/z calcd for C33H33O6Na: 547.2097; found: 547.2103.
(14) General Procedure for the Synthesis of Compound 1
To a solution of compound 12 (200 mg, 0.38 mmol) in CH2Cl2
(20 mL), a solution of BBr3 (4.6 mmol) in dichloromethane (20
mL) was added at –50 °C. The mixture was warmed up to –20 °C
and stirred for 4 h. After stirred overnight at 5 °C, MeOH (5 mL)
was added at –50 °C to quench the reaction. The solution was
diluted with EtOAc, washed with water, dried over anhydrous
Na2SO4, and evaporated under reduced pressure to afford a red
residue, which was then purified through silica gel column
chromatography and Sephadex LH-20 to afford compound 1.
Analytical Cata of Compound 1
25
Yield 39%, reddish solid, mp 218.5–222.1 °C; [α]D 0 (c 0.1,
MeOH). 1H NMR (500 MHz, CD3OD): δ = 7.02 (d, J = 8.5 Hz, 2 H),
6.72 (d, J = 8.5 Hz, 2 H), 6.69 (d, J = 8.5 Hz, 2 H), 6.51 (d, J = 8.6
Hz, 2 H), 6.38 (d, J = 2.0 Hz, 1 H), 6.36 (d, J = 2.4 Hz, 1 H), 6.08 (d,
J = 2.4 Hz, 1 H), 6.01 (d, J = 2.0 Hz, 1 H), 4.09 (d, J = 1.5 Hz, 1 H),
4.03 (s, 1 H), 3.56 (s, 1 H), 3.23 (s, 1 H). 13C NMR (125 MHz,
CD3OD): δ = 158.48 (s), 158.08 (s), 157.12 (s), 156.13, 156.11,
153.16 (s), 147.85 (s), 147.53 (s), 139.07 (s), 136.09 (s), 130.08
(2 C), 129.37 (2 C), 128.72 (s), 115.76 (2 C), 115.59 (2 C), 114.11
(s), 105.78, 104.32, 102.01, 101.92, 59.28, 50.95, 49.85, 47.65.
ESI-HRMS: m/z calcd for C28H21O6: 453.1338; found: 453.1351
[M – H]–.
Analytical Data of Compound 12
Yield 98%, colorless oil; [α]D 0 (c 0.07, MeOH). 1H NMR (500
25
MHz, acetone-d6): δ = 7.31 (d, J = 8.7 Hz, 2 H), 7.26 (d, J = 8.7 Hz,
2 H), 7.04 (d, J = 16.4 Hz, 1 H), 6.94 (d, J = 8.7 Hz, 2 H), 6.83 (d, J =
8.7 Hz, 2 H), 6.82 (d, J = 2.4 Hz, 1 H), 6.79 (d, J = 16.4 Hz, 1 H),
6.48 (d, J = 2.4 Hz, 2 H), 6.46 (d, J = 2.4 Hz, 1 H), 6.39 (t, J = 2.4 Hz,
1 H), 5.57 (d, J = 5.5 Hz, 1 H), 4.66 (d, J = 5.5 Hz, 1 H), 3.85 (s, 3
H), 3.80 (s, 3 H), 3.77 (s, 3 H), 3.74 (s, 6 H). 13C NMR (125 MHz,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E