Regioselective Oxidative Coupling of 4-Hydroxystilbenes: Synthesis of Resveratrol and ε-Viniferin (E)-Dehydrodimers

Article abstract of DOI:10.1021/jo035791c

Treatment of 5-[2-(4-hydroxyphenyl)vinyl]benzene-1,3-diol (resveratrol) with an equimolar amount of silver(I) acetate in dry MeOH at 50 °C for 1 h followed by chromatographic purification with a short silica gel column allowed the isolation of its (E)-deh

Full text of DOI:10.1021/jo035791c

We describe a nonenzymatic and efficient method for
the preparation of the dehydrodimer 2 involving the
simple treatment of resveratrol (1) with silver(I) acetate
(AgOAc) under mild conditions followed by chromato-
graphic purification using a short silica gel column. The
present method is, in principle, applicable to the oxidative
dimerization of 4-hydroxystilbenes and 4-hydroxysty-
renes leading to the corresponding 2-(4-hydroxyphenyl)-
2,3-dihydrobenzofurans possessing various types of bio-
logical activities.8
Regioselective Oxid a tive Cou p lin g of
4-Hyd r oxystilben es: Syn th esis of
Resver a tr ol a n d E-Vin ifer in
(E)-Deh yd r od im er s
Magoichi Sako,* Hiroyuki Hosokawa, Tetsuro Ito, and
Munekazu Iinuma
Gifu Pharmaceutical University, 5-6-1, Mitahora-higashi,
Gifu 502-8585, J apan
When the mixture of resveratrol (1) with an equimolar
amount of AgOAc in dry MeOH was heated at 50 °C for
1 h and the resulting mixtures were purified by silica
gel column chromatography, the desired dehydrodimer
2 was obtained as an optically inactive product in almost
quantitative yield. The structure of the product 2 was
confirmed by comparison with the previously reported
UV, mass, and 1H NMR spectral data,1-4,7 e.g., its 1H
NMR spectrum showed characteristic signals for the
dihydrobenzofuran ring protons at δ 4.45 (d, J ) 8.0 Hz)
and δ 5.44 (d, J ) 8.0 Hz) and for the trans-stilbene vinyl
protons at δ 6.94 (d) and δ 7.05 (d) with a large coupling
constant (J ) 16.4 Hz).1,7 Thus, the present oxidative
dimerization proceeded regioselectively to give 2, though
the starting 1 has both the 4-hydroxyphenyl and 3,5-
dihydroxyphenyl groups in the molecule, i.e., no forma-
tion of the structural isomer, 5-{6-hydroxy-2-(4-hydroxy-
phenyl)-4-[2-(4-hydroxyphenyl)vinyl]-2,3-dihydrobenzo-
furan-3-yl}benzene-1,3-diol (ꢀ-viniferin) (3), in this reac-
tion was observed. The efficiency of this reaction signifi-
cantly depended upon the employed solvent because of
the low solubility of AgOAc in an organic solvent, i.e.,
the use of MeOH as a solvent was the most effective for
the smooth formation of the dehydrodimer 2 among the
examined solvents that involved acetone, MeCN, and
THF. Under the employed conditions, it changed to an
ash color because the reaction mixture is colorless during
the initial stage and then the formation of a silver mirror
on the inside of the used flask was observed, indicating
sako@gifu-pu.ac.jp
Received December 7, 2003
Abstr a ct: Treatment of 5-[2-(4-hydroxyphenyl)vinyl]ben-
zene-1,3-diol (resveratrol) with an equimolar amount of
silver(I) acetate in dry MeOH at 50 °C for 1 h followed by
chromatographic purification with a short silica gel column
allowed the isolation of its (E)-dehydrodimer, 5-{5-[2-(3,5-
dihydroxyphenyl)vinyl]-2-(4-hydroxyphenyl)-2,3-dihydroben-
zofuran-3-yl}benzene-1,3-diol, as a racemic mixture in high
yield. The present method was applicable to the oxidative
dimerization of 4-hydroxystilbenes such as trans-styrylphe-
nol and 5-{6-hydroxy-2-(4-hydroxyphenyl)-4-[2-(4-hydroxy-
phenyl)vinyl]-2,3-dihydrobenzofuran-3-yl}benzene-1,3-diol
(ꢀ-viniferin) leading to the corresponding 2-(4-hydroxyphen-
yl)-2,3-dihydrobenzofurans possessing various types of bio-
logical activities.
5-{5-[2-(3,5-Dihydroxyphenyl)vinyl]-2-(4-hydroxyphen-
yl)-2,3-dihydrobenzofuran-3-yl}benzene-1,3-diol [resvera-
trol (E)-dehydrodimer] (2) is a polyphenolic phytoalexin
isolated from grapevines,1 the lianas of Gnetum hainan-
ense,2 Vitis vinifera cell cultures,3 and the roots of Rheum
maximowiczii.4 Recently, this compound has been docu-
mented to exhibit interesting biological activities such
as antimicrobial,1 cyclooxygenase (I and II) inhibitory,3,5
and 5R-reductase inhibitory activities,6 and cytotoxicity
against human lymphoblastoid cells.5 The dehydrodimer
2 can be obtained as a racemic mixture by the enzymatic
oxidations of commercially available 5-[2-(4-hydroxyphen-
yl)vinyl]benzene-1,3-diol (resveratrol) (1) with a horse-
radish peroxidase-H2O2 system1,6 and a laccase-like
stilbene oxidase of Botrytis cinerea.5,7 However, to study
the molecular mechanisms that explain its biological
effects, a more convenient preparative method for 2 and
its analogues was required.
that the redox reaction between the starting 1 [Eox
)
p
+1.14 V vs SCE in MeCN] and silver(I) cation is involved
in this reaction.
On the basis of these facts, the formation of the
dehydrodimer 2 in the reaction of resveratrol (1) with
AgOAc can be reasonably explained by virtue of a single-
electron transfer from 1 to the silver(I) cation, a regiose-
lective coupling of the phenoxyl radicals (A and A′)
generated by deprotonation of the 4-hydroxystilbene
cation radical, and subsequent intramolecular cyclization
leading to 2 as the ultimate product as shown in Scheme
1.
(1) Langcake, P.; Pryce, R. J . Experientia 1977, 33, 151-152.
Langcake, P.; Pryce, R. J . J . Chem. Soc., Chem. Commun. 1977, 208-
210. Langcake, P.; Pryce, R. J . Physiol. Plant Pathol. 1976, 9, 77-86.
(2) Huang, K.-S.; Wang, Y.-H.; Li, R.-L.; Lin, M. J . Nat. Prod. 2000,
63, 86-89.
(3) Waffo-Teguo, P.; Lee, D.; Cuendet, M.; Merillon, J .-M.; Pezzuto,
J . M.; Kinghorn, A. D. J . Nat. Prod. 2001, 64, 136-138.
(4) Shikishima, Y.; Takaishi, Y.; Honda, G.; Ito, M.; Takeda, Y.;
Kodzhimatov, O. K.; Ashurmetov, O. Phytochemistry 2001, 56, 377-
381.
(5) Cichewicz, R. H.; Kouzi, S. A.; Hamann, M. T. J . Nat. Prod. 2000,
63, 29-33.
(6) Hirano, Y.; Kondo, R.; Sakai, K. J . Wood Sci. 2002, 48, 64-68.
(7) Breuil, A.-C.; Adrian, M.; Pirio, N.; Meunier, P.; Bessis, R.;
J eandet, P. Tetrahedron Lett. 1998, 39, 537-540. Sbaghi, M.; J eandet,
P.; Bessis, R.; Lereux, P. Plant Pathol. 1996, 45, 139-144.
Analogous results were obtained with metallic oxidants
such as Ag2O,9 Ag2CO3,10 AgNO3, Mn(OAc)3,11 Cu(OAc)n
(8) Roemer, K.; Mahyar-Roemer, M. Drugs Today 2002, 38, 571-
580. Wolter, F.; Stein, J . Drugs Future 2002, 27, 949-959.
(9) Zhou, L.-X.; Lin, M. Chinese Chem. Lett. 2000, 11, 515-516.
Antus, S.; Gottsegen, A.; Kolonits, P.; Wagner, H. Liebigs Ann. Chem.
1989, 593-594. Antus, S.; Bauer, R.; Gottsegen, A.; Seligmann, O.;
Wagner, H. Liebigs Ann. Chem. 1987, 357-360.
(10) Fernandes, E. G. R.; Pinto, M. M. M.; Silva, A. M. S.; Cavaleiro,
J . A. S.; Gottlieb, O. R. Heterocycles 1999, 51, 821-828.
10.1021/jo035791c CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/02/2004
2598
J . Org. Chem. 2004, 69, 2598-2600

F IGURE 1. Resveratrol (1), ꢀ-viniferin (3), and their dehydrodimers (2 and 4).
TABLE 1. Oxid a tive Dim er iza tion of Resver a tr ol (1)
SCHEME 1. A Most P la u sible Mech a n ism for th e
Oxid a tive Dim er iza tion of Resver a tr ol (1)
yield (%)b
conditionsa unchanged 1 dehydrodimer 2
metallic
oxidant
reaction
entry
1
2
3
4
5
6
7
8
AgOAc
Ag2O
Ag2CO3
AgNO3
Mn(OAc)3
CuOAc
a
a
a
a
a
a
a
b
∼1
97
76
56
4
55
24
22
40
8
37
95
19
57
62
32
Cu(OAc)2
K3Fe(CN)6
a
Reaction conditions: (a) MeOH, 50 °C, 1 h; (b) 0.1 M phosphate
b
buffer (pH 5.5)-MeCN (1/1), 50 °C, 1 h. Estimated by TLC
densitometry.
iferin (3) [Eox ) +1.15 V vs SCE in MeCN] was very
p
unstable under the employed oxidation conditions and
smoothly dimerized to give 5-{6′-hydroxy-2′-(4-hydroxy-
phenyl)-5-[2-[3-(3,5-dihydroxyphenyl)-6-hydroxy-2-(4-hy-
droxyphenyl)-4-yl]]vinyl-2′,3-bis(4-hydroxyphenyl)-2,3,-
2′,3′-tetrahydro[3,4′]bibenzofuranyl-3′-yl}benzene-1,3-
diol (vitisin B, a (E)-dehydrodimer of ꢀ-viniferin) (4),14
together with another undetermined dimeric product.
Thus, the 4-hydroxystyrene moiety is required for the
formation of the 2,3-dihydrobenzofuran ring in the
present reaction. An analogous oxidative dimerization
was observed for the reaction of trans-4-styrylphenol with
AgOAc in MeOH.1,15
Among these results, the selective formation of the
resveratrol (E)-dehydrodimer 2 during the Fe3+-oxidation
of resveratrol (1) is interesting in relation to the mech-
anisms for the enzymatic formation of the polyphenolic
phytoalexins, possessing a 2,3-dihydrobenzofuran ring in
(n ) 1, 2), and K3Fe(CN)6 (in pH 5.5 phosphate buffer-
MeCN)12 in place of AgOAc as an oxidant, and also of
13
organic oxidants such as PhI(OAc)2 and DDQ in place
of the metallic oxidant, though their efficiencies were
dependent upon their solubility in the solvents and the
oxidation ability of the employed oxidants (see Table 1
and Experimental Section). The dimeric product
2
[Eox ) +1.12 V vs SCE in MeCN] was very stable under
p
the oxidation conditions; the treatment with AgOAc at
50 °C in MeOH resulted in the recovery of the unchanged
2 even after a prolonged reaction time (ex after 3 h). In
sharp contrast to this fact, the structural isomer ꢀ-vin-
(11) Snider, B. B.; Han, L.; Xie, C. J . Org. Chem. 1997, 62, 6978-
6984.
(12) Wasserman, H. H.; Brunner, R. K.; Buynak, J . D.; Carter, C.
G.; Oku, T.; Robinson, R. P. J . Am. Chem. Soc. 1985, 107, 519-521.
(13) J uhasz, L.; Kuerti, L.; Antus, S. J . Nat. Prod. 2000, 63, 866-
870.
(14) Ito, J .; Niwa, M. Tetrahedron 1996, 52, 9991-9998. Oshima,
Y.; Kamijou, A.; Ohizumi, Y.; Niwa, M.; Ito, J .; Hisamichi, K.;
Takeshita, M. Tetrahedron 1995, 51, 11979-11986.
(15) Schultz, T. P.; Hubbard, T. F., J r.; Lin, L.; Fisher, T. H.;
Nicholas, D. D. Phytochemistry 1990, 29, 1501-1507.
J . Org. Chem, Vol. 69, No. 7, 2004 2599

and the dehydrodimer 2 estimated by TLC densitometry are
summarized in Table 1. The starting compound 1, however, was
unchanged after treatment with an equivalent amount of Hg-
(OAc)2, Cd(OAc)2, or Pd(OAc)2 in dry MeOH at 50 °C for 1 h.
the molecule such as the dehydrodimers 2 and ꢀ-viniferin
(3), in grapes and peanuts as a natural fungicide.1,6,16
Exp er im en ta l Section
A mixture of 1 (11.4 mg, 0.05 mmol) and K3Fe(CN)6 (16.5 mg,
0.05 mmol) in 0.1 M phosphate buffer (pH 5.5)-MeCN (1/1) (2.0
mL) was stirred at 50 °C for 1 h. After being diluted with water
(10 mL) and adjusted to pH 3 with 0.1 M HCl, the mixture was
extracted with ethyl acetate (20 mL, two times). The obtained
residue after evaporation of the extract was subjected to column
chromatography by eluting with chloroform-MeOH (10/1) to
separate the starting 1 (2.9 mg, 25%) and the dehydrodimer 2
(3.4 mg, 30%), together with undetermined products (0.5 mg).
The melting points are uncorrected. Mass spectra were
determined at an ionizing voltage of 70 eV. 1H NMR spectra were
obtained at 400 MHz, using deuterioacetone unless otherwise
noted as the solvent. For the thin-layer chromatographic (TLC)
analyses, Merck precoated TLC plates (Merck No. 5715; silica
gel 60-F254) were used. Column chromatography was performed
on silica gel (Cica Merck No. 9385; silica gel 60). ꢀ-Viniferin (3)
was isolated from the stem bark of Vateria indica.17 Unless
otherwise noted, the materials obtained from commercial sup-
pliers were used without further purification.
(c) With Or ga n ic Oxid a n ts. To a solution of 1 (4.6 mg, 0.02
mmol) in dry MeCN (0.5 mL) was added PhI(OAc)2 (3.3 mg, 0.01
mmol) or DDQ (2.3 mg, 0.01 mmol) and the mixture was heated
at 50 °C for 1 h. TLC densitometric analyses of the resulting
mixtures showed the formation of 2 in 25% and 7% yields,
respectively, with the recovery of 1 in 17% [PhI(OAc)2] and 49%
(DDQ) yields. In these reactions, the formation of highly polar
polymeric products was observed at the spotted position and the
employment of an equivalent amount of the oxidants caused the
significant decrease in the formation of 2.
Oxid a tion of Resver a tr ol (1): (a ) With Ag+ Oxid a n ts. A
mixture of resveratrol (1) (SIGMA, 99% purity; 9.2 mg, 0.04
mmol) and AgOAc (Kishida Chemicals, >99.0% purity; 6.8 mg,
0.04 mmol) in dry MeOH (2.0 mL) was heated at 50 °C for 1 h.
The reaction mixture turned to an ash color with time and the
formation of a silver mirror was observed on the inside of the
employed flask. After removal of the solvent under reduced
pressure, the resulting residue was subjected to column chro-
matography by eluting with chloroform-MeOH (10/1) to isolate
the optically inactive 5-{5-[2-(3,5-dihydroxyphenyl)vinyl]-2-(4-
hydroxyphenyl)-2,3-dihydrobenzofuran-3-yl}benzene-1,3-diol [res-
veratrol (E)-dehydrodimer] (2) (7.8 mg, 86%) as a colorless
amorphous powder: mp 156-157 °C (from chloroform) (lit.3 mp
150-152 °C); IR (KBr) 3400, 1602, 1509, 1489 cm-1; UV (MeOH)
320, 310, 220 (sh) nm; mass m/z (rel intensity) 454 (M+, 100),
408 (4), 360 (12), 347 (12), 228 (12); 1H NMR δ 4.45 (1H, d, J )
8.0 Hz), 5.44 (1H, d, J ) 8.0 Hz), 6.18 (2H, d, J ) 2.0 Hz), 6.24
(1H, t, J ) 2.0 Hz), 6.27 (1H, t, J ) 2.0 Hz), 6.52 (2H, d, J ) 2.0
Hz), 6.84 (2H, d, J ) 8.8 Hz), 6.87 (1H, d, J ) 8.8 Hz), 6.90 (1H,
d, J ) 16.4 Hz), 7.05 (1H, d, J ) 16.4 Hz), 7.25 (2H, d, J ) 8.3
Hz), 7.25 (1H, br s), 7.42 (1H, br d, J ) 8.3 Hz), 8.17 (2H, s),
8.20 (2H, s), 8.44 (1H, s); anal. calcd for C28H22O6 m/z 454.1417,
found m/z 454.1423. TLC analyses of the reaction mixtures
obtained after the AgOAc oxidation of resveratrol (1) showed
the complete consumption of 1 and almost quantitative conver-
sion to the dehydrodimer 2.
The oxidation of 1 (2.3 mg, 0.01 mmol) in dry MeOH (0.5 mL)
was carried out with Ag2O, Ag2CO3, or AgNO3 in place of AgOAc
as the oxidant. TLC densitometric analyses (detection at 320
nm) of the mixtures obtained after the reactions (at 50 °C for
1 h) showed the formation of the dehydrodimer 2, with recovery
of the starting 1 and with the concurrent formation of a small
amount of an undetermined more polar product. The yields of
the unchanged 1 and the dehydrodimer 2 are summarized in
Table 1. TLC analyses of the reaction mixtures obtained after
the oxidation of 1 (2.3 mg, 0.01 mmol) with AgOAc in dry
acetone, MeCN, and THF (each 2.0 mL) (at 50 °C, for 1 h) showed
the formation of 2 in 90%, 86%, and 19% yields, respectively,
with recovery of the starting 1 and with the formation of a trace
amount of an undetermined polar product.
AgOAc Oxid a tion of E-Vin ifer in (3). A mixture of 3 (22.8
mg, 0.05 mmol) and AgOAc (8.4 mg, 0.05 mmol) in dry MeOH
(5.0 mL) was heated at 50 °C for 2 h. The formation of a silver
mirror during the reaction was observed. After removal of the
solvent under reduced pressure, the resulting residue was
subjected to column chromatography by eluting with chloroform-
MeOH (10/1) to isolate 5-{6′-hydroxy-2′-(4- hydroxyphenyl)-5-
[2-[3-(3,5-dihydroxyphenyl)-6-hydroxy-2-(4-hydroxyphenyl)-4-yl]]-
vinyl-2,3′-bis(4-hydroxyphenyl)-2,3,2′,3′-tetrahydro[3,4′]bibenzo-
furanyl-3′-yl}benzene-1,3-diol (vitisin B, a (E)-dehydrodimer of
ꢀ-viniferin) (4);13 9.0 mg, 40%) as a colorless amorphous powder
[mp 225-227 °C (from chloroform); FABMS m/z 907 (MH+), 906
(MH+ - 1), 854, 810; IR (KBr) 3402, 1609, 1514, 1484, 1451 cm-1
;
UV (MeOH) 321, 298, 287, 223 nm; 1H NMR δ 4.31 (1H, d, J )
4.4 Hz), 4.44 (1H, d, J ) 5.4 Hz), 4.52 (1H, d, J ) 4.4 Hz), 5.40
(2H, d, J ) 4.4 Hz), 5.52 (1H, d, J ) 5.4 Hz), 6.10 (2H, d, J )
2.0 Hz), 6.18 (1H, d, J ) 2.0 Hz), 6.19-6.24 (5H, m), 6.30 (2H,
d, J ) 2.0 Hz), 6.55-6.80 (4H, m), 6.59 (2H, d, J ) 8.8 Hz), 6.62
(1H, d, J ) 16.0 Hz), 6.76 (1H, d, J ) 16.0 Hz), 6.82 (2H, d, J )
8.8 Hz), 6.90 (2H, d, J ) 8.8 Hz), 7.13 (1H, d, J ) 8.3 Hz), 7.19
(2H, d, J ) 8.8 Hz), 7.24 (2H, d, J ) 8.8 Hz), 8.07 (2H, s), 8.11
(2H, s), 8.13 (1H, s), 8.26 (1H, s), 8.30 (1H, s), 8.34 (1H, s), 8.52
(1H, s); anal. calcd for C56H43O12 m/z 907.2754 [MH+], found m/z
907.2751] and an undetermined isomeric dehydrodimer (7.2 mg,
32%) as a less polar product [FAB MS m/z 907 (MH+), 906
(MH+ - 1), 853; IR (KBr) 3393, 1611, 1516, 1483, 1451 cm-1
;
UV (MeOH) 320, 298, 287, 223 nm; 1H NMR δ 3.77 (1H, d, J )
4.9 Hz), 4.32 (1H, d, J ) 8.8 Hz), 4.50 (1H, d, J ) 4.9 Hz), 5.23
(1H, d, J ) 4.9 Hz), 5.28 (1H, d, J ) 8.8 Hz), 5.39 (1H, d, J )
4.9 Hz), 5.96 (2H, d, J ) 2.0 Hz), 6.10 (1H, d, J ) 16 Hz), 6.30
(1H, d, J ) 16 Hz), 6.22-6.32 (5H, m), 6.66-6.83 (13H, m), 7.02
(2H, d, J ) 8.8 Hz), 7.15 (1H, d, J ) 8.8 Hz), 7.20 (2H, d, J )
8.8 Hz), 8.12 (2H, s), 8.20 (2H, s), 8.26 (1H, s), 8.34 (1H, s), 8.37
(2H, br s), 8.39 (1H, s); anal. calcd for C56H43O12 m/z 907.2754
(MH+), found m/z 907.2749].
(b) With Oth er Meta llic Oxid a n ts. The use of an equivalent
amount of Mn(OAc)3, CuOAc, and Cu(OAc)2 in place of AgOAc
for the oxidation of 1 (2.3 mg, 0.01 mmol) allowed the formation
of 2 in moderate to low yields. The yields of the unchanged 1
(16) For pertinent reviews for the phytoalexins see: Fregoni, C.;
Bavaresco, L. Vignevini 2002, 29, 58-60. J eandet, P.; Douillet-Breuil,
A.-C.; Bessis, R.; Debord, S.; Sbaghi, M.; Adrian, M. J . Agr. Food Chem.
2002, 50, 2731-2741. Hain, R. Spec. Publ. R. Soc. Chem. (Pestic. Chem.
Biosci.) 1999, 233, 190-203.
(17) Ito, T.; Tanaka, T.; Iinuma, M.; Nakaya, K.; Takahashi, Y.;
Sawa, R.; Naganawa, H.; Chelladurai, V. Tetrahedron 2003, 59, 1255-
1264.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure and characterization data for the (E)-dehydrodimer of
trans-4-styrylphenol and 1H NMR, IR, UV, and MS spectral
data for 2, 4, and the isomeric compound of 4. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O035791C
2600 J . Org. Chem., Vol. 69, No. 7, 2004