Biomimetic synthesis of resveratrol trimers catalyzed by horseradish peroxidase

Article abstract of DOI:10.3390/molecules22050819

Biotransformation of trans-resveratrol and synthetic (±)-viniferin in aqueous acetone using horseradish peroxidase and hydrogen peroxide as oxidants resulted in the isolation of two new resveratrol trimers (3 and 4), one new resveratrol derivative (5) with a dihydrobenzofuran skeleton, together with two known stilbene trimers (6 and 7), and six known stilbene dimers (8-13). Their structures and relative configurations were identified through spectral analysis and possible formation mechanisms were also discussed. Among these oligomers, trimers 6 and 7 were obtained for the first time through direct transformation from resveratrol. Results indicated that this reaction is suitable for the preparation of resveratrol oligomers with a complex structure.

Full text of DOI:10.3390/molecules22050819

molecules
Article
Biomimetic Synthesis of Resveratrol Trimers
Catalyzed by Horseradish Peroxidase
Jian-Qiao Zhang , Gan-Peng Li , Yu-Long Kang , Bin-Hao Teng and Chun-Suo Yao 1,*
1
2
1
1
1
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, China;
jqzhang@imm.ac.cn (J.-Q.Z.); kangyulongzyy@imm.ac.cn (Y.-L.K.); tengbh@imm.ac.cn (B.-H.T.)
Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry
2
of Education, Yunnan Minzu University, Kunming 650500, China; ganpeng_li@sina.com
*
Correspondence: yaocs@imm.ac.cn; Tel.: +86-10-6021-2110; Fax: +86-10-6301-7757
Academic Editor: Derek J. McPhee
Received: 31 March 2017; Accepted: 11 May 2017; Published: 17 May 2017
Abstract: Biotransformation of trans-resveratrol and synthetic (
using horseradish peroxidase and hydrogen peroxide as oxidants resulted in the isolation of
two new resveratrol trimers ( and ), one new resveratrol derivative ( ) with a dihydrobenzofuran
skeleton, together with two known stilbene trimers ( and ), and six known stilbene dimers ( 13).
Their structures and relative configurations were identified through spectral analysis and possible
formation mechanisms were also discussed. Among these oligomers, trimers and were obtained
±
)-ε-viniferin in aqueous acetone
3
4
5
6
7
8–
6
7
for the first time through direct transformation from resveratrol. Results indicated that this reaction
is suitable for the preparation of resveratrol oligomers with a complex structure.
Keywords: horseradish peroxidase; ε-viniferin; resveratrol trimer; biotransformation; radical reaction
1
. Introduction
Stilbenes are a class of plant polyphenols that can be divided into two categories, namely,
monomeric and oligomeric stilbenes. Resveratrol oligomers possess novel structures and exhibit
various biological activities, such as anticarcinogenesis, anti-inflammation, and tyrosinase activity
inhibition. These oligomers can be used to treat cancer, AIDS, bacterial infections, and other diseases.
Some oligostilbenes exhibit more potent bioactivities than their monomers do [1–3].
Various resveratrol oligomers exist in nature, especially in grapevine. However, the structures
of minor stilbene oligomers have yet to be elucidated because sufficient amounts of these minor
components are difficult to isolate for subsequent structural characterization. In recent years,
some researchers focused their attention on the synthesis of these oligomers and total synthetic
routes of numerous resveratrol oligomers, including dimers, trimers, and tetramers, have been
reported in literature [4–10], but long reaction steps render these approaches unsuitable for specific
preparations of the complex oligomers. Therefore, biomimetic synthesis is still a concise and practical
alternative for the preparation of oligostilbenes with intricate structures. The natural biotransformation
of stilbene oligomers in nature can be simulated in vitro by transformation with biological enzymes,
unorganized fermentation, metal oxidants, light, acids and alkali [2,11]. In combination with
diverse separation methods, transformation can induce the accumulation of large amounts of minor
compounds. Using this approach, a number of known natural stilbene oligomers and new stilbene
oligomers have been obtained, and their structures have also been identified successfully [11].
The oxidative coupling of resveratrol, including its analogs, has been examined under different
conditions since
ε-viniferin was first isolated in 1977 by Langcake and Pryce [12]. Nevertheless,
the in vitro biocatalyzed oxidation of stilbenes has rarely been explored, and studies on biocatalyzed
Molecules 2017, 22, 819; doi:10.3390/molecules22050819
www.mdpi.com/journal/molecules

Molecules 2017, 22, 819
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enzymes have focused on horseradish peroxidase (HRP) and laccase [13
,14], which indicated that
dimers, such as dihydrobenzofuran-like dimers, are the main products of reactions mediated by these
enzymes. As reported in the literature [12 15], -viniferin, which would be synthesized enzymatically in
plant tissues, seems to be a biogenetically important precursor of many oligostilbenes in plants, such as
davidiol A, davidiol B, hopeaphenol, ampelopsin E, and so on. So, biotransformation of -viniferin
is a promising way to prepare these oligomers. Wilkens et al. [16] reported the transformation of
resveratrol and ( )- -viniferin catalyzed by HRP produces different stilbene oligomers, including
,
ε
ε
−
ε
dimers, trimers, tetramers, and polymeric products. In addition to two trimeric stilbenes obtained
in a pure form, other oligomers only have been detected through HPLC-PDA or HPLC-ESI-MS/MS.
Many resveratrol trimers and tetramers can be possibly obtained by further investigating this
reaction. As an extension of the preliminary work, this study demonstrated the biotransformation
of trans-resveratrol (
peroxide as oxidants. Thus, two new resveratrol trimers (
) with a dihydrobenzofuran skeleton, together with two known natural stilbene trimers (
and six known natural stilbene dimers ( 13) were isolated and structurally identified (Figure 1).
Among these substances, trimers and were obtained for the first time through direct transformation
1) and synthetic (
±
)-ε
-viniferin (
2
) in aqueous acetone with HRP and hydrogen
and ), one new resveratrol derivative
and ),
3
4
(5
6
7
8
–
6
7
from resveratrol. Moreover, their potential formation mechanisms were also discussed.
OH
HO 4
3a
OH
4a
a
A1 1a
2a
1a
O 11b
A1
12b
HO13b
7a
HO
11b
1bO 1a
7a
2a
HO13b
O
7a
8a
HO
4
4a
HO
1
HO
11a
B2 13bOH
B2
H
OH
A1
3b
OH
13a
b
4b
H
8a
O
OH
4b
10b
9b
8b
A2 9a
13a
9b
1a
B1
9b
A2
6a
7a
3b
H
H
1b
9a
1b
H
8a
9a
12a
8b
4b
10a
2b
H
H
OH
1b
7
b
H
7c
11a
H1
0c
OH
B1
6b
7b
8
c
7c
HO
3c
HO
H
8c
9c
OH
7b
1b
A2
1c
OH
HO1
H
O
c
12a
HO11c
1c
1c C1
14a
H
1c C2
8c
9c
4
OH
4c OH
C1
12c
1
3c
OH
13c
C2 13c OH
1c
OH
4c
OH
1
OH
5
HO
Davidiol B (6)
3
4
HO 4
a
1
a
O
11b
7
a
3bOH
HO
HO
1
1
1a
HO
9
a
9b
O
HO
O
1
3a
OH
1
b
4b
OH
HO
3c
7b
HO
1
c
HO
8c
O
c
4
9
c
OH
13c
OH
OH
OH
1
1c
HO
HO
Resveratrol-cis-dehydrodimer (9)
Resveratrol-trans-dehydrodimer (8)
rel-(7aS,8aS,7bS,8bS)-cis-Diptoindonesin B (7)
HO
HO
4
a
4
a
OH
OH
OH
3b
1
a
H
O
1
a
HO
O
1
OH
7a
OH
11b HO
7a
OH
OH
7a
HO 4a
1a
13b
HO
9a
HO
8a
10b
8
a
H9a
9b
1
3a
9b
13a
8b
9
b
H
7b
8b
7
b
1
0a
13b
11a
11b
1
3a
7b
1b
1b
HO
1
0a
1b
OH
OH
OH
OH
OH
OH
4b
4
b
4b
OH
OH
Leachianol G (10)
OH
Leachianol F (11)
OH
Parthenostilbenin B (12)
Ampelopsin B (13)
Figure 1. Structures of compounds 3–13.

Molecules 2017, 22, 819
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2
. Results and Discussion
2
.1. Synthesis of 2 with Resveratrol as a Starting Material and HRP and Hydrogen Peroxide-Catalyzed
Biotransformation of 1 and 2
In this study, semisynthetic (
as the starting material for biotransformation. According to the method reported in our previous
±
)-
ε
-viniferin (
2
) under the procedure shown in Figure 2 was used
paper [17], trans-resveratrol was subjected to an oxidative coupling reaction in aqueous methanol
using FeCl3 6H O as an oxidant, and this procedure was performed in combination with column
·
2
chromatography on silica gel. Thus, 2 with 13.5% yield was produced.
HO
HO
OH
O
OH
HO
FeCl3 6H O
2
OH
OH
OH
2
1
Figure 2. Semi-synthetic route of compound 2.
Successively, biotransformation of
and hydrogen peroxide generated a major product peak
Supplementary Materials), which resulted in the isolation and identification of four resveratrol trimers
1
and
2
in aqueous acetone catalyzed by horseradish peroxidase
8
and a complicated mixture (Figure S30 in
(
(
3
8
,
–
4
,
6
, and
7, where 3 and 4 are new ones), one new resveratrol derivative 5, and six known dimers
13) (Figure 1). Their structures and stereochemistry were elucidated by analyzing spectroscopic data.
2
.2. Structure Elucidation of Biotransformation Products
Compound
3
was obtained as a brown amorphous powder. The negative ion peak at m/z 697.2076
−
[
M
−
H] (cacld. for C H O , 697.2079) in its HR-ESI-MS (Figure S7) corresponded to the molecular
42
33 10
formula of C H O and indicated that 3 could be a resveratrol trimer. The IR spectrum (Figure S9)
42
34 10
−
1
revealed the presence of hydroxyls (νmax = 3395 and 3187 cm ) and aromatic rings (νmax = 1600,
513, and 1469 cm ). Absorption bands were also observed at λmax (log
and 283 (3.92) nm in the UV spectrum (Figure S8). The H-NMR spectrum (Figure S1, Table 1) showed
−
1
1
ε
) 203 (5.14), 231 (4.66),
1
three sets of A B systems for rings A1, B1, and C1 at
δ of 6.83 (2H, d, J = 8.4 Hz, H-3(5)a), 7.24 (2H, d,
H
2
2
J = 8.4 Hz, H-2(6)a), 6.54 (2H, d, J = 8.4 Hz, H-3(5)b), 6.34 (2H, d, J = 8.4 Hz, H-2(6)b); 6.68 (2H, d,
J = 8.4 Hz, H-3(5)c), and 6.85 (2H, d, J = 8.4 Hz, H-2(6)c); one set of AB system for ring A2 at of
δ
H
2
6
.36 (1H, t, J = 2.4 Hz, H-12a) and 6.20 (2H, d, J = 2.4 Hz, H-10(14)a); two sets of meta-coupled aromatic
protons for rings B2 and C2 at
δ
of 5.98 (1H, d, J = 2.4 Hz, H-14b) and 6.19 (1H, d, J = 2.4 Hz, H-12b),
H
1
and
δ
5.17 (1H, d, J = 1.8 Hz, H-14c) and 6.24 (1H, d, J = 1.8 Hz, H-12c). The H-NMR spectrum
H
also displayed the presence of two mutually coupled benzyl methine protons at
δ of 5.33 (1H, d,
H
J = 3.0 Hz, H-7a) and 4.83 (1H, d, J = 3.0 Hz, H-8a) and a sequence of successively coupled benzyl
methine protons at of 4.30 (1H, brs, H-7b), 3.76 (1H, brs, H-8b), 4.02 (1H, dd, J = 4.2, 3.0 Hz, H-7c),
δ
H
and 2.96 (1H, m, H-8c). Moreover, the HSQC spectrum (Figure S4) supplied the complete assignment
of all protonated carbon, as shown in Table 1. The 13C-NMR spectrum (Figure S2, Table 1) of
revealed
the presence of six aliphatic carbons at of 52.64, 54.45, 65.07, 77.10, 54.73, and 93.78 ppm and 36
3
δ
C
aromatic carbons. The aliphatic carbon at
δ of 77.10 ppm was due to an alcohol carbon. The carbon
C
signals at
δ of 54.73 and 93.78 ppm and proton signals at δ of 5.33 and 4.83 suggested the presence
C H
of dihydroxybenzofuran ring. The three remaining aliphatic protons and three carbon atoms indicated

Molecules 2017, 22, 819
4 of 12
the presence of an indane ring. This group of evidence demonstrated that
3
possessed a skeleton
similar to that of davidiol B [18
shifts of H-2(6)a, H-7a, H-8a, H-10(14)a, H-8b, and H-2(6)c in
and +0.50 ppm) caused by the anisotropic effect of the aromatic ring suggested that
c-empimer of davidiol B [20]. In the HMBC spectrum (Figure S5 and Figure 3a) of , the correlations
,
19]. In addition, compared with those of davidiol B, the downfield
∆δH +0.24, +0.28, +1.72, +0.29, +0.95,
could be a
3
(
3
7
3
of H-2c, H-6c, H-14c, and C-7c, which were attached to the hydroxyl group, showed that C-7c was
excluded from the additional ring, and ring C1 was attached at C-7c. The correlations between H-7b,
H-8b, H-5b, and C-1b verified that ring B1 was connected at C-7b. Moreover, the correlations between
H-7a and C-10(14)a and H-8a and C-2(6)a substantiated that ring A1 was linked at C-7a, and ring A2
was linked at C-8a. Comparison of the spectral data with those of davidiol B and the analysis of DEPT,
HMBC, and HSQC (Figures S3~S5) correlations determined the planar structure of 3 (Figure 1).
Table 1. H- and 13C-NMR spectroscopic data of compounds 3–5 *.
1
No.
3
4
5
1
(6)a
(5)a
a
134.69s
128.25d
116.04d
158.11s
93.78d
133.85s
128.80d
116.36d
158.58s
95.00d
131.98s
127.59d
115.14d
157.36s
92.53d
2
3
7.24 (d, 8.4)
6.83 (d, 8.4)
7.00 (d, 9.0)
6.80 (d, 9.0)
7.20 (d, 8.5)
6.82 (d, 8.5)
4
7
8
9
a
a
a
a
5.33 (d, 3.0)
4.83 (d, 3.0)
5.22 (d, 6.1)
3.85 (d, 6.1).
5.34 (d, 8.3)
4.36 (d, 8.3)
54.73d
57.8d
57.66d
149.28s
107.13d
159.93s
101.82d
159.93s
107.13d
137.41s
129.35d
115.48d
155.85s
115.48d
129.35d
52.64d
147.28s
107.27d
159.56s
101.90d
159.56s
107.27d
131.87s
128.53d
116.30d
158.69s
116.30d
128.53d
94.86dd
58.78d
144.29s
106.51d
158.79s
101.34d
158.79
106.51d
153.02s
131.30s
112.10d
151.57s
109.08d
114.69d
1
0a
1a
2a
3a
4a
6.20 (d, 2.4)
6.36 (t, 2.4)
6.20 (d, 2.4)
5.94 (d, 2.4)
6.09 (t, 2.4)
5.94 (d,2.4)
6.16 (d, 2.1)
6.25 (t, 2.1)
6.16 (d, 2.1)
1
1
1
1
1
2
b
b
b
b
b
b
b
b
b
6.34 (d, 8.4)
6.54 (d, 8.4)
7.14 (d, 8.4)
6.75 (d, 8.4)
3
4
5
6
7
8
9
6.47 (d, 2.2)
6.54 (d, 8.4)
6.34 (d, 8.4)
4.30 (s, 1H)
3.76 (s, 1H)
6.75 (d, 8.4)
7.14 (d, 8.4)
5.30 (d, 8.4)
4.30 (d, 8.4)
6.67 (brs)
6.67 (brs)
54.45d
147.43s
119.71s
161.56s
95.45d
159.93s
104.82d
136.42s
129.22d
115.33d
157.34s
115.33d
129.22d
77.10d
145.04s
120.40s
162.74s
96.83d
1
1
1
1
1
0b
1b
2b
3b
4b
6.19 (d, 2.4)
5.98 (d, 2.4)
6.23 (d, 2.4)
6.25 (d, 2.4)
6.76 (d, 2.4)
159.48s
109.40d
131.51s
127.36d
132.74s
160.43s
109.85d
130.09d
131.70d
127.04d
137.54s
107.71d
159.79s
102.54d
159.79s
107.71d
1
2
c
c
c
c
c
c
c
c
c
6.85 (d, 8.4)
6.68(d, 8.4)
3
4
5
6
7
8
9
6.68 (d, 8.4)
6.85 (d, 8.4)
4.02 (dd, 4.2, 3.0)
2.96 (m)
6.65 (d, 8.4)
6.98 (dd, 8.4, 2.4)
6.21 (d, 12.0)
65.07d
6.05 (d, 12.0)
148.34s
123.66s
154.66s
102.22d
158.38s
106.66d
1
1
1
1
1
0c
1c
2c
3c
4c
6.03 (d, 2.4)
6.17 (t, 2.4)
6.03 (d, 2.4)
6.24 (d, 1.8)
5.17 (d, 1.8)
Data (δH) were measured in MeOD for H-NMR at 600 MHz and for 13C-NMR at 150 MHz. The assignments were
1
*
1
1
based on DEPT, H- H COSY, HSQC, HMBC, and NOESY experiments, respectively.

Molecules 2017, 22, 819
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OH
HO
H
OH
O
A1
HO
H
H
HO
O
HO
B2
B1
OH
OH
H
H
H
A2
H
H
H
H
OH
OH
HO
H
HO
H
OH
OH
C2
C1
OH
OH
OH
OH
a
b
Figure 3. Important HMBC (a) and NOESY (b) interactions of 3.
The stereochemistry of
3 was determined by analyzing the NOESY spectrum (Figure S6 and
Figure 3b). The interactions among H-2(6)b and H-7b, H-8b suggested a trans orientation of rings
B1 and B2. The NOE interactions among H-7c and H-2(6)c, H-2(6)b suggested a cis orientation of
rings C1 and B1. The NOE interactions between H-8a and H-2(6)a and between H-7a and H-10(14)a
indicated a trans orientation between rings A1 and A2. Furthermore, the NOE interactions among
H-14c and H-2(6)c, H-8c revealed that ring C1 could be located near ring C2. The downfield shift
of H-14c (6.68–6.65 (m, 1H)) and upfield shift of H-8b (2.81 (s, 1H)) in
davidiol B further substantiated this observation. Therefore, the structure of
shown in Figure 1.
3
compared with those of
was determined as
3
Compound
HR-ESI-MS (Figure S4) m/z 679.1973 [M
formula of C H O , which implied that
4 was obtained as a light brown amorphous powder. Its corresponding negative
−
H] (cacld. for C H O , 679.1968) showed a molecular
42 31 9
−
4
could be a resveratrol trimer. The UV (λmax = 203.4 (4.99),
42
31
9
−
1
2
28 (4.69), and 281 (4.22) nm) and IR (νmax = 3335, 1604, 1516, 1487, 1449, 1004, and 836 cm ) spectra
(
Figures S18 and S19) of
4
displayed the presence of a phenolic oligostilbene containing a cis olefinic
1
13
1
1
bond [21]. The H- and C-NMR spectral data (Figures S10 and S11, Table 1) of
4, along with H- H
COSY, DEPT, HSQC, and HMBC spectra (Figures S12~S14 and S16), revealed resonances attributable
to two 4-hydroxyphenyl groups (rings A1 and B1), two 3,5-dihydroxyphenyl groups (rings A2 and
C2), a 3,5-dihydroxy-1,2-disubstituted benzene ring (ring B2), and a 4-hydroxy-1,3-disubstituted
1
benzene ring (ring C1). The H-NMR spectral data also suggested the presence of two sets of aliphatic
signals at
δ of 5.22 (1H, d, J = 6.1 Hz, H-7a) and 3.85 (1H, d, J = 6.1 Hz, H-8a). These signals are
H
characteristic of a 2,3-diaryldihydrobenzofuran moiety, except a cis-1,2-disubstituted olefinic bond at
6.21 (1H, d, J = 12.0 Hz, H-7c) and 6.05 (1H, d, J = 12.0 Hz, H-8c). Our comparison revealed that the
δ
H
NMR spectroscopic data of
literature [21], which suggested that
In the HMBC spectrum (Figure S14 and Figure 4a) of
4
were remarkably similar to those of cis-diptoindonesin B reported in the
possessed the same planar structure as cis-diptoindonesin B.
, the significant correlations of H-7a/C-2(6)a,
4
4
C-9a, and C-11b; H-8a/C-10(14)a, C-1a, and C-9b; H-7b/C-2(6)b, and C-9b; and H-8b/C-1b, C-2c,
and C-4c; H-7c/C-5c; H-8c/C-2(6)c, in combination with their shifts, further supported the planar
structure of 4 as shown in Figure 1.
The relative stereochemistry of H-7a/H-8a and H-7b/H-8b was determined by analyzing the
NOESY spectrum of
4 (Figure S15 and Figure 4b). The NOE interactions among H-7a and H-2(6)a,
H-10(14)a and those among H-8a and H-2(6)a, H-10(14a) suggested a trans orientation between H-7a
and H-8a. Similarly, the NOE interactions between H-8b and H-2(6)b also suggested a trans relationship
of H-7b and H-8b. Despite that
their difference indicated that could be a stereoisomer of cis-diptoindonesin B. The comparison of the
NMR data of with cis-diptoindonesin B demonstrated that H-8a, H-8c, and H-10(14)c and C-8b, C-9b,
C-8c, and C-9c in were shifted by ∆δH of +0.36, 0.24, 0.19 and ∆δC of +3.3, +4.7, 2.5, and 3.5
ppm, respectively. This evidence demonstrated that the relative configurations of C-7b and C-8b in
4 exhibited a planar structure similar to that of cis-diptoindonesin B,
4
4
4
−
−
−
−
4
could be 7bR and 8bR instead of 7bS and 8bS in cis-diptoindonesin B, respectively [21]. In contrast to the
relative configuration of rel-(7aS, 8aS, 7bS, and 8bS) in cis-diptoindonesin B, the relative configurations
of
4 for C-7a, C-8a, C-7b, and C-8b were determined as rel-(7aS, 8aS, 7bR, and 8bR), respectively

Molecules 2017, 22, 819
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(Figure 1). This conjecture was confirmed by the fact that H-8a and H-2(6)b were deshielded because
of anisotropic effects induced by rings B2 and C1. On the contrary, H-7c, H-8c, and H-10(14)c were
shielded due to anisotropic effects elicited by rings B2.
HO
HO
H
A1
O
O
OH
OH
HO
HO
B1
H
A2
OH
H
OH
B2
HO
HO
C1
O
O H
C2
OH
OH
HO
HO
a
b
Figure 4. Significant HMBC (a) and NOESY (b) correlations of compound 4.
Compound
5
was obtained as brown amorphous powder. The corresponding positive ion
+
HR-ESI-MS (Figure S27) peak at m/z 337.1073 [M + H] (cacld. for C H O , 337.1071) provided the
20
17
5
molecular formula of C H O . The IR spectrum (Figure S29) displayed the presence of hydroxyls
2
0
16
5
−
1
−1
1
(
3337 cm ) and aromatic rings (1615, 1517, and 1464 cm ). The H-NMR spectrum (Figure S20,
Table 1) showed one A2B2 system at of 7.20 (2H, d, J = 8.5 Hz, H-3(5)a) and 6.82 (2H, d, J = 8.5 Hz,
δ
H
H-3(5)a), one AB2 system at
δ of 6.25 (1H, t, J = 2.1 Hz, H-12a) and 6.16 (2H, d, J = 2.1 Hz, H-10(14)a),
H
one ABX system at
δ of 6.47 (1H, d, J = 2.2 Hz, H-3b) and 6.67 (2H, brs, H-5b, H-6b), and two mutually
H
coupled benzyl methine protons at
δ of 5.34 (1H, d, J = 8.3 Hz, H-7a) and 4.36 (1H, d, J = 8.3 Hz, H-7a).
H
In addition, the carbon signals at
δ
of 54.66 and 92.53 ppm in 13C-NMR (Figure S21, Table 1), together
C
with the proton signals at
δ of 5.34 and 4.36 ppm, suggested the presence of dihydroxybenzofuran
H
ring. Accordingly,
5 was identified as a resveratrol derivative with benzofuran skeleton, as shown
in Figure 1, which was confirmed by DEPT, HSQC, HMBC, COSY, and UV spectra (Figures S22~S26
and S28). In HMBC spectrum (Figure S24 and Figure 5a), the correlations between H-7a and C-2(6)a,
C-9a, C-2b and H-8a and C-10(14)a, C-1a, C-6b suggested that ring A1 could be linked at C-7a, and ring
A2 could be linked at C-8a. In NOESY experiment (Figure S25 and Figure 5b), the NOE enhancements
between H-7a and H-2(6)a/H-10(14)a and H-8a and H-10(14)a/H-2(6)a suggested a trans orientation
of rings A1 and A2. Therefore, the structure of 5 was determined as shown in Figure 1.
HO
HO
O
A1
O
OH
OH
HO
HO
A2
OH
OH
a
b
Figure 5. Significant HMBC (a) and NOESY (b) correlations of compound 5.
In addition to these three compounds, two known resveratrol trimers, namely, davidiol B (6) [18]
and rel-(7aS,8aS,7bS,8bS)-cis-diptoindonesin B (
7
) [21], and six known dimers, namely, (
±
)-resveratrol-
26],
trans-dehydrodimer ( ) [22 23], ( )-resveratrol-cis-dehydrodimer (
8
,
±
9
) [23 24], leachianol G (10) [25,
,

Molecules 2017, 22, 819
7 of 12
leachianol F (11) [25
,26], parthenostilbenin B (12) [20], and ampelopsin B (13) [27
,
28], were identified
by comparing their physical and spectroscopic data with those reported in previous studies. Among
them, trimers and , which are difficult to obtain by common organic reactions, were obtained for
the first time by direct biotransformation from resveratrol.
6
7
2
.3. Probable Coupling Reaction Mechanisms
Considering the obtained results, a mechanism on how different trimeric derivatives formed were
proposed. HRP-catalyzed biotransformation is presumed on the basis of radical reaction [13
,14,29].
Induced by hydrogen peroxide, resveratrol, and ( )- -viniferin were dehydrogenated and rearranged
±
ε
to form different radicals (Figure 6). Afterward, these HRP-catalyzed radicals were combined to
produce different dimers and trimers. The coupling of one radical D and one radical A, and subsequent
tautomeric rearrangement and intramolecular nucleophilic attack to the intermediate quinone yielded
the dihydrofuran trimers
explained by the coupling of one radical D with one radical B and subsequent addition of a water
molecule to the intermediate quinone (Figure 8). Furthermore, may be formed through the oxidation
of ( )- -viniferin by H O and HRP, but an appropriate account for the reactivity cannot be established
4 and 7 (Figure 7). Consequently, the formation of 3 and 6 can be easily
5
±
ε
2
2
with this evidence. In addition, the formation mechanisms of the dimers obtained in this work are the
same as those reported in our previous paper [26,30,31].
HO
HO
HO
HO
OH
HO
OH HO
OH
O
OH
O
OH
O
OH
HO
HO
HO
HRP/H O
HRP/H O
2 2
2
2
HO
HO
HO
OH
O
O
2
OH
O
O
radical "A"
radical "A"
radical "B"
1
radical "C"
radical "D"
Figure 6. Plausible radical intermediates from 1 and 2 by horseradish peroxidase and hydrogen peroxide.
HO
HO
O
HO
HO
O
O
OH
O
O
OH
HO
OH
OH
HO
HO
HO
OH
HO
H
O
HO
OH
HO
OH
HO
HO
O
O
O
HO
OH
O
HO
HO
OH
radical "D"
radical "A"
HO
compounds 4 and 7
Figure 7. Proposed formation mechanisms for compounds 4 and 7.
HO
HO
HO
HO
HO
HO
HO
HO
O
OH HO
OH
O
OH
O
OH
O
OH
O
OH
OH
H
H
O
HO
HO
H
OH
HO
O
HO
HO
HO
HO
OH
O
OH
HO
O
O
HO
HO
compounds 3 and 6
radical "D"
radical "B"
Figure 8. Proposed formation mechanisms for compounds 3 and 6.

Molecules 2017, 22, 819
8 of 12
3
. Materials and Methods
3
.1. Materials and Instrumentation
Optical rotations were measured on P2000 polarimeter (JASCO, Tokyo, Japan). UV spectra
were obtained on a JASCOP650 spectrometer (JASCO). IR spectra were recorded on a Nicolet
5
700 FT-IR microscope instrument (FT-IR microscope transmission, Thermo Electron Corporation,
1
Madison, WI, USA). 1D and 2D NMR spectra were acquired at 500 or 600 MHz for H and 125 or
1
(
50 MHz for 13C, respectively, on Varian INOVA 500 MHz, or Bruker AVANCE III HD 600 MHz
Bruker Corporation, Karlsruhe, Germany), in acetone-d or methanol-d , with solvent peaks as
6
4
references. ESI-MS and HR-ESI-MS data were measured using an AccuToFCS JMST100CS spectrometer
Agilent Technologies, Ltd., Santa Clara, CA, USA). Column chromatography (CC) was performed
with silica gel (200–300 mesh, Qingdao Marine Chemical Inc., Qingdao, China). HPLC separation
was performed on an instrument consisting of a Waters 515 pump and a Waters 2487 dual
absorbance detector (Waters Corporation, Milford, MA, USA) with a YMC semi-preparative column
250 × 10 mm i.d.) packed with C18 (5 M). TLC was carried out with glass precoated silica gel GF254
plates (Qingdao Marine Chemical, Inc., Qingdao, China). Spots were visualized under UV light or by
spraying with 7% H SO in 95% EtOH followed by heating.
(
λ
(
µ
2
4
3
.2. Synthesis of Compoud 2
The solution of FeCl3 6H O (380 g, 1.43 mol) in H O (100 mL) was added to a solution of 1
·
2 2
(
300 g, 1.32 mol) in methanol (500 mL) under stirring at room temperature, and the mixture was stirred
for 60 h at room temperature. After removing of methanol in vacuo, water was added to the mixture,
and the mixture was extracted with EtOAc. Subsequently, the obtained organic layer was washed with
brine and water, dried over anhydrous Na SO for 24 h, then concentrated in vacuo to give a residue,
2
4
which was further chromatographed on silica gel column with CHCl –MeOH (15:1, v/v) as eluent to
3
provide unreacted resveratrol 130 g and product 2 (23 g, yield 13.5%).
1
Compound 2: grey amorphous powder. H-NMR(CD COCD , 500 MHz)
δ: 8.41 (OH), 8.38 (OH),
3
3
8
6
6
6
4
.33 (OH), 8.17 (2H, 2
×
OH), 7.20 (2H, d, J = 9.0 Hz, H-2a, 6a), 7.16 (2H, d, J = 8.5 H, H-2b, 6b),
.90 (1H, d, J = 16.0 Hz, H-7b), 6.82 (2H, d, J = 9.0 Hz, H-3a, 5a), 6.73 (2H, d, J = 8.5 Hz, H-3b, 5b),
.72 (2H, d, J = 2.0 Hz, H-10a, 14a), 6.70 (1H, d, J = 16.0 Hz, H-8b), 6.32 (1H, d, J = 2.0 Hz, H-12b),
.23 (2H, br s, H-12a, 14b), 5.41 (1H, d, J = 5.5 Hz, H-7a), 4.47 (1H, d, J = 5.5 Hz, H-8a); (+)-ESI m/z:
+
77 [M + Na] .
3
.3. Treatment of 1 and 2 with Horseradish Peroxidase/Hydrogen Peroxide
To a mixed solution of
1 (3000 mg, 13.2 mmol) and 2 (1500 mg, 3.3 mmol) in acetone (240 mL),
50 mL of water was added under stirring at room temperature. After that, a solution of HRP (10.0 mg)
in water (30 mL) was added slowly. The reactant was stirred for 5 min, 30% H O (1.4 mL) was then
2
2
added. The reactant was stirred for another 7 h at room temperature. Finally, the reaction mixture
was suspended in water, and extracted with ethyl acetate. The organic layer was dried on anhydrous
Na SO for 24 h, and concentrated in vacuo to yield a residue.
2
4
The residue was subjected to column chromatography over ODS, eluting with a gradient of
increasing methanol in water (15~100%) to provide nine fractions (R-I~R-IX) on the basis of HPLC
analysis. R-VI (2.5 g) was further fractionated via silica gel column chromatography (CC), eluting with
CHCl –MeOH (17:1, v/v) to yield
8
(0.493 g, 16.5%) and R-VI-2~R-VI-4. R-VI-3 was then separated
by semi-preparative Rp-HPLC (column, Rp-18, 250 10 mm, 5 m) eluted using methanol/water
56:44, v/v) to afford (2 mg, 0.07%); 30 mg R-I (total 280 mg) was separated by semi-preparative
Rp-HPLC using a mobile phase of methanol/water (16:84, v/v) to afford 10 (9 mg, 2.7%) and 11
4 mg, 1.2%). R-II (30 mg) was further purified by semi-preparative Rp-HPLC eluted with a mobile
phase of MeOH–H O (30:70, v/v) to afford (1.7 mg). 300 mg R-III (total amount 600 mg) was
3
×
µ
(
9
(
5
2

Molecules 2017, 22, 819
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resolved by Rp-MPLC with a gradient of increasing MeOH (18~30%) in water to give R-III-1~R-III-3.
Among them, Fraction R-III-2 (34 mg) were subsequently separated by Rp-HPLC with a mobile phase of
methanol/water (40:60, v/v) to afford 6 (5 mg, 0.43%) and 3 (3 mg, 0.26%); R-III-1 and R-III-3 were dealt
with the same manner to provide 13 (13 mg, 0.87%), and 12 (7 mg, 0.44%), respectively. Furthermore,
R-VII (600 mg) was subjected to Rp-MPLC eluting with methanol–water (49:51, v/v) to yield R-VII-1
and R-VII-2; subsequently, R-VII-1 was purified by semi-preparative Rp-HPLC using a mobile phase
of methanol–water (46:54, v/v) to provide
7 (2 mg); R-VII-2 was dealt with methanol–water (54:46, v/v)
by semi-preparative Rp-HPLC in the same manner to give 4 (6 mg).
Compound : Brown amorphous powder. UV (MeOH) λmax (log ): 203 (5.14), 231.2 (4.66), 283 (3.92) nm;
3
ε
IR (film) νmax: 3395, 3187, 2921, 2850, 1646, 1513, 1469, 1420, 1342, 1245, 1120, 1005, 834, 722,
−
1
1
13
6
7
6
48 cm ; H-NMR (600 MHz, MeOD) and C-NMR (150 MHz, MeOD), see Table 1; (+)-ESI m/z:
21.0 [M + Na]+, 736.9 [M + K] ; (
97.2076, [M − H] (cacld. for C H O , 697.2079).
+
−
)-ESI m/z: 696.9 [M
−
− −
H] , 732.9 [M + Cl] ; HR-ESI-MS m/z:
−
42
33 10
Compound 4: Light brown amorphous powder. UV (MeOH) λmax (log ε): 203.4 (4.99), 228 (4.69),
2
6
7
81 (4.22) nm; IR (film) νmax: 3335, 2924, 2852, 1604, 1516, 1487, 1449, 1349, 1241, 1169, 1004, 836,
−
1
1
13
94 cm ; H-NMR (600 MHz, MeOD) and C-NMR (150 MHz, MeOD), see Table 1; (+)-ESI m/z:
+
−
−
−
H]
03.3 [M + Na] ; (
−
)-ESI m/z: 678.9 [M
−
H] , 715.8 [M + Cl] ; HR-ESI-MS m/z: 679.1973, [M
−
(cacld. for C H O , 679.1968).
42 31 9
Compound
5: Brown amorphous powder. UV (MeOH) λmax (log ε): 203.4 (4.73), 229.8 (4.29),
2
83 (3.70) nm; IR (film) νmax: 3337, 2921, 2852, 1615, 1517, 1488, 1464, 1351, 1235, 1198, 1157, 1105,
−
1 1
13
1
000, 836, 778, 746, 691 cm ; H-NMR (600 MHz, acetone-d ) and C-NMR (150 MHz, acetone-d6),
6
+
see Table 1; HR-ESI-MS m/z: 337.1073 [M + H] (cacld. for C H O , 337.1071).
20
17
5
1
Davidiol B (
6): Brown amorphous powder. H-NMR (600 MHz, acetone-d ), δ: 7.00 (2H, d, J = 8.5 Hz,
6
H-2(6)a), 6.87 (2H, d, J = 8.5 tHz, H-3(5)a), 6.68–6.65 (1H, m, H-14c), 6.53 (2H, d, J = 8.6 Hz, H-3(5)b),
6
6
.45 (2H, d, J = 8.5 Hz, H-3(5)c), 6.38 (1H, d, J = 2.1 Hz, H-12c), 6.35 (2H, d, J = 8.4 Hz, H-2(6)c),
.31 (1H, t, J = 2.2 Hz, H-12a), 6.16 (1H, d, J = 2.1 Hz, H-12b), 6.13 (2H, d, J = 8.4 Hz, H-2(6)b), 5.99 (1H,
d, J = 2.1 Hz, H-14b), 5.91 (2H, d, J = 2.0 Hz, H-10(14)a), 5.05 (1H, d, J = 2.3 Hz, H-7a), 4.10 (1H, s,
H-7b), 3.95 (1H, d, J = 10.1 Hz, H-7c), 3.11 (1H, d, J = 2.4 Hz, H-8a), 2.90 (1H, d, J = 10.1 Hz, H-8c), 2.81
(
1
(
1H, s, H-8b). 13C-NMR (150 MHz, acetone-d6),
δ
: 161.74s (C-11b), 159.94s (C-11(13)a), 159.83s (C-13b),
58.71s (C-13c), 157.90s (C-4a), 157.48s (C-4c), 155.84s (C-4b), 154.98s (11c), 150.15s (C-9c), 148.81s
C-9a), 148.01s (C-9b), 136.55s (C-1b), 136.18s (C-1c), 134.35s (C-1a), 129.72d (C-2(6)b), 128.66d (C-2(6)c),
1
1
5
6
27.57d (C-2(6)a), 122.69s (C-10c), 118.50s (C-10b), 116.41d (C-3(5)c), 116.02d (C-3(5)a), 115.18d (C-3(5)b),
07.41d (C-14c), 106.90d (C-10(14)a), 104.52d (C-14b), 102.11d (C-12c), 101.70d (C-12a), 63.97d (C-8c),
+
+
4.57d (C-8b), 54.46d (C-8a), 53.24d (C-7b). (+)-ESI m/z: 721.0 [M + Na] , 736.9 [M + K] ; ( )-ESI m/z:
−
−
−
96.9 [M − H] , 732.9 [M + Cl] .
1
cis-Diptoindonesin B (7): Brown amorphous powder. H-NMR (600 MHz, methanol-d ), δ: 7.09 (1H, d,
4
J = 8.6 Hz, H-6c), 6.99 (2H, d, J = 8.6 Hz, H-2(6)b(, 6.92 (2H, d, J = 8.5 Hz, H-2(6)a), 6.75 (2H, d,
J = 8.6 Hz, H-3(5)a), 6.68 (2H, d, J = 8.5 Hz, H-3(5)b), 6.63 (1H, brs, H-2c), 6.60 (1H, d, J = 8.3 Hz, H-5c),
6
.37 (1H, d, J = 12.2 Hz, H-7c), 6.31 (1H, d, J = 12.2 Hz, H-8c), 6.25 (1H, d, J = 2.1 Hz, H-12b), 6.22 (2H, d,
J = 2.2 Hz, H-10(14)c), 6.19 (1H, d, J = 2.1 Hz, H-14b), 6.12 (1H, t, J = 2.2 Hz, H-12c), 6.10 (1H, t,
J = 2.2 Hz, H-12a), 5.85 (2H, d, J = 2.2 Hz, H-10(14)a), 5.15 (1H, d, J = 10.0 Hz, H-7b), 5.14 (1H, d,
13
J = 5.2 Hz, H-7a), 4.29 (1H, d, J = 10.0 Hz, H-8b), 3.49 (1H, d, J = 5.2 Hz, H-8a). C-NMR (150 MHz,
methanol-d4), : 162.61s (C-11b), 160.55s (C-4c), 160.25s (C-13b), 159.86s (C-11(13)a), 159.12s (C-11(13)c),
58.81s (C-4b), 158.41s (C-4a), 147.58s (C-9a), 140.93s (C-9c), 140.29s (C-9b), 133.87s (C-1a), 131.92s
C-1b), 131.73s (C-1c), 131.12s (C-3c), 130.32d (C-6c), 129.53d (C-8c), 128.94d (C-2(6)b), 128.17d (C-2(6)a),
δ
1
(
1
1
27.23d (C-2c), 122.03s (C-10b), 116.36d (C-3(5)b), 116.28d (C-3(5)a), 109.68d (C-5c), 108.53d (C-10(14)c),
08.13d (C-14b), 107.09d (C-10(14)a), 102.56d (C-12c), 102.18d (C-12a), 96.83d (C-12b), 94.99d (C-7b),

Molecules 2017, 22, 819
10 of 12
+
+
9
4.55d (C-7a), 56.84d (C-8a), 55.52d (C-8b). (+)-ESI-MS m/z: 681.0 [M + H] , 703.0 [M + Na] ; ( )-ESI
−
−
−
m/z: 678.9 [M − H] , 714.9 [M + Cl] .
Ampelopsin B (13): Brown amorphous powder. 1H-NMR (500 MHz, methanol-d4),
δ
: 7.02 (2H, d,
J = 8.6 Hz, H-2(6)b), 6.89 (2H, d, J = 7.9 Hz, H-2(6)a), 6.69 (2H, d, J = 8.6 Hz, H-3(5)b), 6.60 (2H, d,
J = 8.6 Hz, H-3(5)a), 6.30 (1H, d, J = 2.2 Hz, H-12b), 6.27 (1H, d, J = 1.9 Hz, H-14a), 6.09 (1H, d, J = 1.8 Hz,
H-14b), 6.01 (1H, d, J = 2.0 Hz, H-12a), 5.65 (1H, d, J = 11.4 Hz, H-7b), 5.14 (1H, t, J = 3.8 Hz, H-7a),
4
.05 (1H, d, J = 11.4 Hz, H-8b), 3.53 (1H, dd, J = 17.4, 4.1 Hz, H-8aα), 3.17 (1H, brd, J = 17.4 Hz, H-8aβ).
+
+
−
−
(
+)-ESI m/z: 455.0 [M + H] , 477.0 [M + Na] ; (−)-ESI m/z: 453.0 [M − H] , 489.0 [M + Cl] .
. Conclusions
The HRP-catalyzed biotransformation of
4
1
and
2
produced various resveratrol stilbene oligomers,
, and ),
including dimers, trimers, and tetramers. In this reaction mixture, four resveratrol trimers (
one new resveratrol derivative ( ) with a dihydrofuran skeleton, and six dimers ( 13) were isolated
and identified. Among these compounds, and were newly identified in our study. The raceme
3,
4,
6
7
5
8–
3
4
nature of the dimers was indicated by the zero values of their optical rotations, and this finding
suggested that a radical mechanism was involved in HRP-catalyzed biotransformation. Our study
favored the enzymatic biotransformation of stilbenes by HRP as a prominent method to produce
oligomeric stilbenes for research activity. Considering that these new compounds may occur naturally
as minor constituents, we observed that our reference data provided a basis for the detection of the
presence of these stilbene oligomers in future investigations. Oligostilbenes were reported to show
various activities [1,2]. Therefore, these products should be further examined, and results will be
reported in our future research.
1
13
Supplementary Materials: The following are available online. Figures S1~S9: H-NMR, C-NMR, DEPT, HSQC,
1
13
HMBC, NOESY, HRESIMS, UV, and IR spectra in CD COCD of
3
. Figures S10~S19: H-NMR, C-NMR, DEPT,
3
3
1
HSQC, HMBC, NOESY, COSY, HRESIMS, UV, and IR spectra in CD COCD of
4
. Figures S20~S29: H-NMR,
3
3
1
3
C-NMR, DEPT, HSQC, HMBC, NOESY, COSY, HRESIMS, UV, and IR spectra in CD COCD of 5. Figure S30:
3
3
HPLC chromatogram of biotransformation products of 1 and 2.
Acknowledgments: This study was conducted with grants from the Key Project of National Natural Science
Funds of China (No. 81630094) and the CAMS Innovation Fund for Medical Sciences (No. 2016-I2M-2-002). 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 IR, NMR, and MS spectra.
Author Contributions: C.-S.Y. and J.-Q.Z. conceived, designed the experiments and wrote the paper; J.-Q.Z.,
Y.-L.K. and B.-H.T. performed the experiments; C.-S.Y. and G.-P.L. analyzed the data. All authors read and
approved the final manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
3.
Yao, C.S.; Wang, X.F. Naturally active oligostilbenes. J. Asian Nat. Prod. Res. 2016, 18, 376–407.
Lin, M.; Yao, C.S. Natural oligostilbenes. Stud. Nat. Prod. Chem. 2006, 33, 601–644.
Shen, T.; Wang, X.N.; Lou, H.X. Natural stilbenes: An overview. Nat. Prod. Rep. 2009, 26, 916–935. [CrossRef]
[PubMed]
4.
5.
6.
Lindgren, A.E.G.; Oberg, C.T.; Hillgren, J.M.; Elofsson, M. Total synthesis of the resveratrol oligomers
(
±)-ampelopsin B and (±)-ε-viniferin. Eur. J. Org. Chem. 2016, 3, 426–429. [CrossRef]
Snyder, S.A.; Gollner, A.; Chiriac, M. Regioselective reactions for programmable resveratrol oligomer
synthesis. Nature 2011, 474, 461–466. [CrossRef] [PubMed]
Snyder, S.A.; Breazzano, S.P.; Ross, A.G.; Lin, Y.; Zografos, A.L. Total synthesis of diverse carbogenic
complexity within the resveratrol class from a common building block. J. Am. Chem. Soc. 2009, 131, 1753–1765.
[CrossRef] [PubMed]

Molecules 2017, 22, 819
11 of 12
7
.
Kim, I.; Choi, J. A versatile approach to oligostilbenoid natural products-synthesis of permethylated
analogues of viniferifuran, malibatol A, and shoreaphenol. Org. Biomol. Chem. 2009, 7, 2788–2795. [CrossRef]
[
PubMed]
Jeffrey, J.L.; Sarpong, R. Concise synthesis of pauciflorol F using a larock annulation. Org. Lett. 2009, 11,
450–5453. [CrossRef] [PubMed]
8
9
1
.
.
5
Snyder, S.A.; Zografos, A.L.; Lin, Y. Total synthesis of resveratrol-based natural products: A chemoselective
solution. Angew. Chem. Int. Ed. 2007, 46, 8186–8191. [CrossRef] [PubMed]
0. Li, W.; Li, H.; Li, Y.; Hou, Z. Total synthesis of (
609–7611. [CrossRef] [PubMed]
±
)-quadrangularin A. Angew. Chem. Int. Ed. 2006, 45,
7
1
1
1. Li, W.L.; Zang, P.; Li, H.F.; Yang, S. Biomimetic synthesis of oligostilbenes. Prog. Chem. 2012, 24, 545–555.
2. Langcake, P.; Pryce, R.J. Oxidative dimerization of 4-hydroxystilbenes in vitro: Production of a grapevine
phytoalexin mimic. J. Chem. Soc. Chem. Commun. 1977, 7, 208–210. [CrossRef]
1
3. Wan, X.; Wang, X.B.; Yang, M.H.; Wang, J.S.; Kong, L.Y. Dimerization of peceatannol by Momordica charantia
peroxidase and
α-glucosidase inhibitory activity of the biotransformation products. Bioorg. Med. Chem. 2011,
1
9, 5085–5092. [CrossRef] [PubMed]
1
1
1
4. Ponzoni, C.; Beneventi, E.; Cramarossa, M.R.; Raimondi, S.; Trevisi, G.; Pagnoni, U.M.; Riva, S.; Forti, L.
Laccase-catalyzed dimerization of hydroxystilbenes. Adv. Synth. Catal. 2007, 349, 1497–1506. [CrossRef]
5. He, Y.H.; Takaya, Y.; Terashima, K.; Niwa, M. Determination of absolute structure of (+)-davidiol A.
Heterocycles 2006, 68, 93–100. [CrossRef]
6. Wilkens, A.; Paulsen, J.; Wray, V.; Winterhalter, P. Structures of two novel trimeric stilbenes obtained by
horseradish peroxidase catalyzed by biotransformtion of trans-resveratrol and (
Food Chem. 2010, 58, 6754–6761. [CrossRef] [PubMed]
−
)-ε-viniferin. J. Agric.
1
1
1
2
2
7. Yao, C.S.; Lin, M.; Wang, Y.H. Synthesis of the active stilbenoids by photooxidation reaction of
trans-ε-viniferin. Chin. J. Chem. 2004, 22, 1350–1355. [CrossRef]
8. Tanaka, T.; Ito, T.; Iinuma, M.; Ohyama, M.; Ichise, M.; Tateishi, Y. Stiblbene oligomers in roots of
Sophora davidii. Phytochemistry 2000, 53, 1009–1014. [CrossRef]
9. Ito, T.; Tanaka, T.; Iinuma, M.; Iliya, I.; Nakaya, K.; Ali, Z.; Takahashi, Y.; Sawa, R.; Shirataki, Y.; Murata, J.; et al.
New resveratrol oligomers in the stem bark of Vatica pauciflora. Tetrahedron 2003, 59, 5347–5363. [CrossRef]
0. Kim, H.J.; Saleem, M.; Seo, S.H.; Jin, C.; Lee, Y.S. Two new antioxidant stilbene dimers, parthenostilbenins A
and B from Parthenocissus tricuspidata. Planta Med. 2005, 71, 973–976. [CrossRef] [PubMed]
1. Syah, Y.M.; Aminah, N.S.; Hakim, E.H.; Aimi, N.; Kitajima, M.; Takayama, H.; Achmad, S.A.
Two oligostilbenes, cis and trans-diptoindonein B, from Dryobalanops oblongifolia. Phytochemistry 2003, 63,
9
13–917. [CrossRef]
2
2
2. Roger, P.; Camille, P.; Junlien, B.J.; Raffaele, T.; Kartia, G.; Oliver, V. δ-viniferin, a resveratrol dehydromer:
One of the major stilbenes synthesized by stressed grapevine leaves. J. Agric. Food Chem. 2003, 51, 5488–5492.
3. Pilar, R.B.; Lorena, M.C.; Jose, M.L.; Francisco, G.C. Kinetic mechanism and product characterization of the
enzymatic peroxidation of pterostilbene as model of the detoxification process of stilbene-type phytoalexins.
Phytochemistry 2011, 72, 100–108.
2
2
2
4. Hirano, Y.; Kondo, R.; Skai, K. 5 alpha-reductase inhibitory compounds produced by polymerization of
resveratrol with horseradish peroxidase. J. Wood Sci. 2002, 48, 64–68. [CrossRef]
5. Ohyama, M.; Tanaka, T.; Iinuma, M. Five resveratrol oligomers from Roots of Sophara leachiana. Phytochemistry
1
995, 38, 733–740. [CrossRef]
6. Xie, J.S.; Wen, J.; Wang, X.F.; Zhang, J.Q.; Zhang, J.F.; Kang, Y.L.; Hui, Y.W.; Zheng, W.S.; Yao, C.S.
Potassium hexacyanoferrate (III)-catalyzed dimerization of hydroxystilbene: Biomimetic synthesis of indane
stilbene dimers. Molecules 2015, 20, 22662–22673. [CrossRef] [PubMed]
2
7. Takaya, Y.; Yan, K.X.; Terashima, K.; Ito, J.; Niwa, M. Chemical determination of the absolute structures of
resveratrol dimers, ampelopsin A, B. C, D and F. Tetrahedron 2002, 58, 7259–7265. [CrossRef]
8. Keckeis, K.; Sarker, S.D.; Dinan, L. Resveratrol-type oligostilbenes from Iris clarkei antagonize
2
2
0-hydroxyecdysone action in the Drosophila melanogaster B cell line. Cell. Mol Life Sci. 2000, 57, 333–336.
II
[CrossRef] [PubMed]
2
9. Takaya, Y.; Yan, K.X.; Terashima, K.; He, Y.H.; Niwa, M. Biogenetic reactions on stilbene tetramers from
Vitaceaeous plants. Tetrahedron 2002, 58, 9265–9271. [CrossRef]

Molecules 2017, 22, 819
12 of 12
3
3
0. Zhang, Y.; Wang, X.F.; Lin, M.B.; Hou, Q.; Yao, C.S.; Shi, J.G. Preparation of active resveratrol dimeric
derivatives by oxidative coupling reaction using AgOAc as oxidant. Chin. J. Org. Chem. 2014, 34, 886–892.
CrossRef]
[
1. Wang, X.F.; Zhang, Y.; Lin, M.B.; Hou, Q.; Yao, C.S.; Shi, J.G. Biomimetic synthesis of active isorhapontigenin
dimers. J. Asian Nat. Prod. Res. 2014, 16, 511–521. [CrossRef] [PubMed]
Sample Availability: Samples of the compounds are not available from the authors.
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