Regioselective biomimetic oxidation of halogenated resveratrol for the synthesis of (±)-ε-viniferin and its analogues

Article abstract of DOI:10.1016/j.tet.2018.06.005

FeCl₃·6H₂O-promoted biomimetic oxidations of 3,5-dihalogeno-resveratrol in different acetone systems produced several coupling intermediates bearing distinct dimeric skeletons with moderate yields. The subsequent deprotection reactio

Full text of DOI:10.1016/j.tet.2018.06.005

Tetrahedron xxx (2018) 1e7
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Regioselective biomimetic oxidation of halogenated resveratrol for the
synthesis of (±)-ε-viniferin and its analogues
*
Meijie Liu, Tao Dong, Xingchao Guan, Zhibo Shao, Wenling Li
School of Chemical and Biological Engineering, Lanzhou Jiaotong University, Lanzhou, 730070, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 March 2018
Received in revised form
FeCl $6H O-promoted biomimetic oxidations of 3,5-dihalogeno-resveratrol in different acetone systems
3
2
produced several coupling intermediates bearing distinct dimeric skeletons with moderate yields. The
subsequent deprotection reactions of brominated coupling products achieved the efficient synthesis of
natural products (±)-ε-viniferin, (±)-ampelosin B, and (±)-gnetins F, as well as an unnatural oligostilbene.
The coupling mechanisms for the formation of different dimeric structures were also proposed.
3
June 2018
Accepted 5 June 2018
Available online xxx
©
2018 Published by Elsevier Ltd.
Keywords:
Resveratrol
Oxidative coupling
Oligostilbenes
Debromination
Biomimetic synthesis
1. Introduction
conditions by using tert-butyl-protected stilbenes, such as 8, as the
coupling precursor. However, dihydrobenzofuran-type dimeric
7
Since ε-viniferin (2), a dehydrodimer of resveratrol (1), was first
discovered by Langcake and Pryce in 1977, more than three hun-
stilbenes, such as 2e4, were rarely observed in coupling products.
In view of the adverse effects of acidic debutylation conditions on
the structural stability of dimeric products, we recently used
brominated resveratrol 9 as an alternative precursor. The different
enzyme-catalyzed oxidation of 9 followed by the debromination
reactions facilitated the total synthesis of several novel resveratrol
1
dred natural oligostilbenes with complicated structures and diverse
biological activities have been isolated and studied in the past four
2
decades (Fig. 1). Some resveratrol oligomers, such as dimers 3e7,
have been prepared through efficient chemical synthesis or various
3
8
biomimetic oxidations. However, the exploration on the prepara-
dimers in addition to the natural products 5e7. Encouraged by this
tion of 2 has rarely succeeded except in a few biosynthetic reports
because of its structural instability. In 1999, Lin et al. successfully
finding, we intended to further investigate the regioselective
coupling reactions of halogenated resveratrol precursors oxidized
4
synthesized (±)-2 from 1 with 30.5% yield under the FeCl
oxidative condition and Yao’ team in 2017 conducted the
FeCl $6H O-promoted oxidation of 1 in aqueous methanol to form
±)-2 with 13.5% yield. Niwa's group synthesized 2 as the sole
3
-MeOH
by FeCl
natural dimer 2.
3 2
$6H O in various solvent systems to finally synthesize
3
2
5
(
2. Results and discussion
coupling product of 1 with 30% yield by using Ti(NO
3
)
3
as a catalyst
ꢁ
at ꢀ50 C and prepared the dimeric mixture including 2, with 22%
We first studied the oxidative coupling reactions of brominated
6
3 6
overall yield in the K Fe(CN) -oxidized alkaline methanol solution.
resveratrol (9) promoted by FeCl
tems. As illustrated in Scheme 1 and Table 1, the treatment of
precursor 9 with 6.5 equimolar amount of FeCl $6H O in acetone
for 24 h generated the dihydrobenzofuran-type product 10 with
8% yield and another unexpected dimer 11 with 32% yield.
Increasing the amount of FeCl $6H O or prolonging the reaction
3 2
$6H O in different solvent sys-
Considering the importance of 2 as the biogenic precursor for a
majority of the natural resveratrol oligomers and existing synthetic
challenge, our group has been devoted to the regioselective bio-
mimetic synthesis of oligostilbenes under a variety of oxidative
3
2
3
3
2
time resulted in considerably decrease in the isolated yields of 10
and 11 owing to the formation of complex polar products. When
the same oxidative condition and reaction time were applied in the
*
Corresponding author.
E-mail address: liwl@mail.lzjtu.cn (W. Li).
https://doi.org/10.1016/j.tet.2018.06.005
040-4020/© 2018 Published by Elsevier Ltd.
0
Please cite this article in press as: Liu M, et al., Regioselective biomimetic oxidation of halogenated resveratrol for the synthesis of (±)-ε-viniferin
and its analogues, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.06.005

2
M. Liu et al. / Tetrahedron xxx (2018) 1e7
sequential intramolecular cyclization rearrangement leading to the
9
dihydrobenzofuran skeleton 10. The 8e8-coupled bis-quinone
methide underwent further nucleophilic cyclization to form the
dimeric structure 14. Electron-rich C10 of the intermediate 14
attacked the electrophilic carbonyl group of acetone solvent, which
further nucleophilic attacked C7 of quinone methide to construct
the bicyclic dimer 11. The indanes 12a/12b and 13 were formed
through different intramolecular cyclization paths of the initial
8
e8-coupled bis-quinone methide, as hypothesized in our previous
8
report.
On the basis of the above research results, we continued to
examine the oxidative coupling reactions of another halogenated
stilbene precursor, 3,5-diiodo-resveratrol (18), which was prepared
through the key Wittig reaction of phosphonium salt 15 with 3,5-
diiodo-4-hydroxyl-benzaldehyde (16) followed by the debenzyla-
tion reaction of stilbene 17 (Scheme 3). The coupling reactions of
stilbene 18 were carried out under similar oxidative conditions as
those of precursor 9, but the catalyst amount and reaction time
were optimized to achieve increased product yields. As shown in
Fig. 1. Resveratrol and several representative natural dimers.
3 2
Scheme 3 and Table 2, 18 was oxidized by 3 equiv. FeCl $6H O for
coupling reaction of 9 in acetoneebenzene system, dimeric prod-
ucts 10 and 11 were still dominant, but their yields decreased to
18 h, which resulted in the 8e10-coupled dimer 19 and 8e8-
coupled intermediate 20 either in acetone or acetoneebenzene
system with 65%e72% total yield. However, the coupling reaction
2
8%. Large volume ratio of acetoneebenzene (from 1:1 to 1:4) led
to decreased total yields of 10 and 11. Next, we investigated the
effect of the acetoneeH O solvent system on the coupling reaction
2
of 18 in acetoneeH O or acetoneebuffer system only formed the
2
8e8-coupled indane 21a in 45% or 35% yield, and its isomer 21b
was rarely isolated from the product mixture. After the catalyst
amount was increased and the reaction time was prolonged, the
mixture of 21a and 21b with 1:2 molar ratio with 32% yield and
pallidol-type dimer 22 with 10% yield were finally produced (entry
of 9. As shown in entry 3, the isomeric mixture of 12a and 12b with
nearly 1:1 molar ratio was obtained with 41% yield, and dimer 13
was also generated with 25% yield. When the same oxidation re-
action was conducted in acetoneebuffer system, only the isomers
12a and 12b were isolated with 31% yield in the reaction mixture.
5). This result indicated the increased stereoselectivity of iodine
The reaction mechanisms of coupling dimers 10 and 11 were
proposed as shown in Scheme 2. Precursor 9 mediated by one-
atoms as positional protecting groups compared with bromine in
FeCl $6H Oemediated coupling reactions.
3 2
With these coupling products, we carried out the reductive
debromination reactions of 10 and 11 to prepare several natural
resveratrol dimers. As shown in Scheme 4, 10 was subjected to 70
10
electron oxidation using FeCl
semiquinone radical M . The radical M
monomer 9 to form 8-10-coupled intermediate, which underwent
3
$6H
2
O primarily resulted in the
8
8
reacted directly with
Scheme 1. Structures of coupling products from the oxidation of 9.
Table 1
Coupling products of precursor 9 in different oxidative systems.
Entry
FeCl
3 2
$6H O (Equiv.)
Solvents (Volume ratio)
Time (h)
Coupling products (isolated yield %)
10
11
12a/12b (molar ratio)a
13
1
2
3
4
6.5
6.5
6.0
6.0
acetone
acetoneebenzene (2:1)
acetoneeH
acetoneebuffer (pH ¼ 5.4) (2:1)
24
24
30
30
36
28
e
32
28
e
e
e
e
e
2
O (2:1)
41 (1:1)
31 (1:1)
25
e
e
e
a
Determined by a crude 1H NMR spectrum.
Please cite this article in press as: Liu M, et al., Regioselective biomimetic oxidation of halogenated resveratrol for the synthesis of (±)-ε-viniferin
and its analogues, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.06.005

M. Liu et al. / Tetrahedron xxx (2018) 1e7
3
In summary, the oxidative coupling reactions of halogenated
resveratrol 9 and 18 promoted by FeCl $6H O in different acetone
3
2
systems were investigated in detail. We obtained several dimeric
intermediates with distinct skeletons, including 8e10-coupled
dihydrobenzofurans 10 and 19, 8e8-coupled indanes 11e12 and
20e21, as well as 8e8-coupled structure 13 and 22. These experi-
mental results confirmed the similar regioselectively controlled
effects of bromine or iodine atoms as positional protecting groups
on the coupling reactions of stilbenes 9 and 18. The undesired 8e5-
coupling form was efficiently impeded, and the yields of 8e10-
coupling or 8e8-coupling products substantially improved. After-
ward, we selected the brominated coupling dimers to conduct the
deprotection reactions under various reductive conditions. The
debromination reaction of dimer 10 mediated by different amounts
of LiAlH
4
yielded the expected product (±)-ε-viniferin (2) and the
N-catalyzed hy-
unexpected (±)-ampelosin B (4). The PdeCeEt
3
drogenated reduction of 10 yielded the natural (±)-gnetins F (3).
The unnatural resveratrol dimer 23 was first synthesized by the
hydrogenated debromination reaction of 11. This regioselective
biomimetic strategy is applicable for the efficient synthesis of other
oligostilbenes, and this work is ongoing in our laboratory.
3. Experimental section
3.1. General methods
Structural determinations of the isolated compounds were
based on H, C NMR, NOESY, H- H COSY, HMBC spectra, and
HRMS analysis. All NMR spectra were recorded on a Varian Mercury
Scheme 2. Proposed mechanisms for the formation of 10 and 11.
1
13
1
1
ꢁ
equiv. LiAlH
4
in tetrahydrofuran at 50 C for 18 h, which smoothly
4
00 MHz instrument in a solvent as indicated. HRMS spectra were
afforded the sole deprotection product (±)-viniferin (2) with 61%
yield. Unexpectedly, a natural dimer (±)-ampelosin B (4) was
formed when 10 was treated with a large excess amount of LiAlH
at reflux for 48 h. This dimer was considered as a further intra-
molecular cyclization product of 2 under reductive condition. Next,
measured on an Autostec-3090 mass spectrometer. All solvents
were freshly purified and dried by standard techniques prior to use.
Purification of products was performed by column chromatography
CC) on silica gel (200e300 mush), purchased from Qingdao Marine
Chemical Co. (Qingdao, China).
4
(
3
the PdeCeEt Necatalyzed hydrogenation of 10 easily achieved
debromination and reduction of double bonds to synthesize the
natural (±)-gnetins F (3) with 89% high yield. The unnatural
resveratrol dimer 23 was also obtained with 88% yield through the
3
3
.2. Synthesis of coupling dimers 10 and 11
11
.2.1. Procedure 1
FeCl $6H O (290 mg, 1.08 mmol) was slowly added to the solu-
3 2
3
hydrogenated debromination reaction of 11. The PdeCeEt N-
mediated debromination reactions of intermediates 12e13 to form
tion of stilbene 9 (70 mg, 0.18 mmol) in acetone (8 mL). The reaction
mixture was kept out of sun and stirred at room temperature under
8
natural products 5e7 has been reported in our previous work.
Scheme 3. Preparation of 18 and its oxidative coupling products 19e22.
Please cite this article in press as: Liu M, et al., Regioselective biomimetic oxidation of halogenated resveratrol for the synthesis of (±)-ε-viniferin
and its analogues, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.06.005

4
M. Liu et al. / Tetrahedron xxx (2018) 1e7
Table 2
Coupling products of precursor 18 in different oxidative systems.
Entry
FeCl
3
$6H
2
O (Equiv.)
Solvents (Volume ratio)
Time (h)
Coupling products (isolated yield %)
19
20
21a/21b (molar ratio)a
22
1
2
3
4
5
3.0
3.0
3.0
3.0
5.0
acetone
acetone-benzene(2:1)
acetone-H
acetone-buffer (pH ¼ 5.4) (2:1)
acetone-H O(2:1)
18
18
18
24
36
38
35
e
34
30
e
e
e
e
e
2
O(2:1)
45 (1:0)
35 (1:0)
32 (1:2)
e
e
e
e
2
e
e
10
a
Determined by crude 1H NMR spectrum.
argon atmosphere for 24 h. After the removal of the acetone under
reduced pressure, the resulting residue was extracted with EtOAc
three times. The combined organic layer was washed with brine,
evaporated in vacuo. The crude products was subjected to silica gel
column chromatography (CH Cl
unreacted 9 (39.5 mg), the dimer 10 (11.3 mg, 28%) and 11 (12.2 mg,
2
2
:
MeOH ¼ 30:1) to give the
dried over anhydrous MgSO
products was subjected to silica gel column chromatography
CH Cl
4
and evaporated in vacuo. The crude
28%) both as amorphous powder.
(
2
2
: MeOH ¼ 30:1) to give the unreacted 9 (21.3 mg), the dimer
3.2.3. 10
1H NMR (600 MHz,
D
-acetone):
d
¼ 4.64 (d, J ¼ 5.4 Hz, 1H), 5.49
10 (17.6 mg, 36%) and 11 (16.8 mg, 32%) both as amorphous powder.
(
(
6
(
d, J ¼ 5.4 Hz,1H), 6.26 (d, J ¼ 1.8 Hz, 2H), 6.28 (t, J ¼ 1.8 Hz,1H), 6.43
d, J ¼ 1.8 Hz, 1H), 6.76 (d, J ¼ 1.8 Hz, 1H), 6.80 (d, J ¼ 16.2 Hz, 1H),
3
.2.2. Procedure 2
FeCl $6H O (338 mg, 1.26 mmol) was slowly added to the solu-
tion of stilbene 9 (80 mg, 0.21 mmol) in acetone (6 mL) and water
3 mL). The reaction mixture was kept out of sun and stirred at
room temperature under argon atmosphere for 24 h. After the
removal of the acetone under reduced pressure, the resulting res-
idue was extracted with EtOAc three times. The combined organic
13
.88 (d, J ¼ 16.2 Hz,1H), 7.48 (br s, 2H), 7.56 (br s, 2H) ppm; C NMR
3
2
150 MHz,
D-acetone):
d
¼ 55.8, 91.0, 96.7, 101.4, 104.4, 106.0 (2C),
1
10.7, 110.9, 118.8, 125.7, 126.5, 129.6 (3C), 130.1 (3C), 132.3, 132.4,
(
1
34.8,136.3,145.7,150.0,150.4,158.8,159.0,161.2 ppm; HRMS (ESI):
m/z calcd. for C28
H18Br
4
O
6
þH: 770.7869; found: 770.7884.
3.2.4. 11
4
layer was washed with brine, dried over anhydrous MgSO and
1H NMR (600 MHz,
D-acetone):
d
¼ 1.62 (s, 3H), 1.68 (s, 3H), 2.99
(
dd, J ¼ 10.2, 10.2 Hz, 1H), 3.35 (dd, J ¼ 10.2, 10.2 Hz, 1H), 4.18 (d,
J ¼ 10.2 Hz, 1H), 4.61 (d, J ¼ 10.2 Hz, 1H), 5.95 (d, J ¼ 1.8 Hz, 2H), 5.99
13
(
t, J ¼ 1.8 Hz, 1H), 6.32 (s, 1H), 7.10 (br s, 2H), 7.35 (br s, 2H) ppm;
NMR (150 MHz, -acetone):
¼ 25.2, 27.8, 52.9, 56.5, 62.9, 75.6,
5.7, 100.7, 103.2, 106.4, 109.5, 109.9, 117.7, 128.6, 129.7 (2C), 131.1
4C), 131.7 (3C), 132.6, 135.1, 138.0, 142.3, 143.1, 148.6, 149.3, 153.3,
54.0, 157.9 ppm; HRMS (ESI): m/z calcd. for C31
C
D
d
7
(
1
H24Br
4
O
7
þNa:
8
3
3
50.8107; found: 850.8126.
.3. Synthesis of coupling dimers 12a/12b and 13
.3.1. Procedure 1
FeCl
which was slowly added to the solution of stilbene 9 (50 mg,
.13 mmol) in acetone (4 mL). The reaction mixture was kept out of
sun and stirred at room temperature under argon atmosphere for
0 h. After quenching with the ice water, the resulting residue was
extracted with EtOAc three times. The combined organic layer was
washed with brine, dried over anhydrous MgSO and evaporated in
vacuo. The crude products was subjected to silica gel column
chromatography (CH Cl
15 mg), the dimeric mixture 12a/12b (14.7 mg, 41%) and 13
8.7 mg, 25%) both as amorphous powder.
3 2
$6H O (209 mg, 0.78 mmol) was dissolved in water (2 mL),
0
3
4
2
2
: MeOH ¼ 30:1) to give the unreacted 9
(
(
3.3.2. Procedure 2
FeCl $6H O (209 mg, 0.78 mmol) was dissolved in buffer solu-
3
2
tion (pH ¼ 5.4, 2 mL), which was slowly added to the solution of
stilbene 9 (50 mg, 0.13 mmol) in acetone (4 mL). The reaction
mixture was kept out of sun and stirred at room temperature under
argon atmosphere for 30 h. After quenching with the ice water, the
resulting residue was extracted with EtOAc three times. The com-
bined organic layer was washed with brine, dried over anhydrous
MgSO
4
and evaporated in vacuo. The crude products was subjected
Cl
to silica gel column chromatography (CH
the unreacted 9 (23.5 mg) and the dimeric mixture 12a/12b
2
2
: MeOH ¼ 30:1) to give
Scheme 4. Deprotection products of 10 and 11.
(8.4 mg, 31%) as an amorphous powder.
Please cite this article in press as: Liu M, et al., Regioselective biomimetic oxidation of halogenated resveratrol for the synthesis of (±)-ε-viniferin
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M. Liu et al. / Tetrahedron xxx (2018) 1e7
5
3
.3.3. 12a
J ¼ 1.8 Hz, 1H), 6.57 (d, J ¼ 1.8 Hz, 2H), 6.93 (d, J ¼ 16.2 Hz, 1H), 7.03
1H NMR (400 MHz,
D
-acetone):
d
¼ 3.05 (dd, J ¼ 4.4, 5.2 Hz, 1H),
(d, J ¼ 16.2 Hz, 1H), 7.98 (br s, 2H), 8.20 (br s, 3H) ppm; C NMR
13
3
.51 (dd, J ¼ 5.2, 5.6 Hz, 1H), 4.20 (d, J ¼ 4.4 Hz, 1H), 4.65 (d,
(150 MHz,
D
-acetone):
d
¼ 83.9, 105.2 (2C), 124.8 (2C), 129.1 (2C),
J ¼ 4.8 Hz, 1H), 4.76 (dd, J ¼ 5.6, 4.8 Hz, 1H), 6.04 (d, J ¼ 2.0 Hz, 2H),
134.2, 137.3 (3C), 139.2, 154.4, 158.7 ppm; HRMS (ESI): m/z calcd. for
þH: 480.8792; found: 480.8797.
6
.13 (d, J ¼ 2.0 Hz,1H), 6.14 (d, J ¼ 2.0 Hz,1H), 6.29 (d, J ¼ 2.0 Hz,1H),
14 11 2 3
C H I O
13
7
(
1
1
.18 (d, J ¼ 2.0 Hz, 2H), 7.41 (d, J ¼ 2.0 Hz, 2H) ppm; C NMR
100 MHz, -acetone):
¼ 56.1, 58.0, 62.0, 75.0, 101.4, 102.8, 104.8,
06.2 (2C), 110.8, 111.1, 122.2, 131.9 (2C), 132.2 (3C), 139.0, 141.9 (2C),
47.1 (2C), 149.4, 150.1, 150.4, 155.2, 159.5 (2C) ppm; HRMS (ESI)
calcd for C28
þNa: 810.7794; found: 810.7780.
D
d
3.6. Synthesis of coupling dimers 19 and 20
3.6.1. Procedure 1
H20Br
4
O
7
3 2
FeCl $6H O (236 mg, 0.87 mmol) was slowly added to the so-
lution of stilbene 18 (140 mg, 0.29 mmol) in acetone (6 mL). The
reaction mixture was kept out of sun and stirred at room temper-
ature under argon atmosphere for 18 h. After the removal of the
acetone under reduced pressure, the resulting residue was extrac-
ted with EtOAc three times. The combined organic layer was
3
.3.4. 12b
1H NMR (400 MHz,
.55 (dd, J ¼ 5.2, 5.6 Hz, 1H), 4.19 (d, J ¼ 5.2 Hz, 1H), 4.59 (d,
D
-acetone):
d
¼ 3.35 (dd, J ¼ 5.2, 5.2 Hz, 1H),
3
J ¼ 4.8 Hz, 1H), 4.74 (dd, J ¼ 5.2, 4.8 Hz, 1H), 6.03 (d, J ¼ 2.0 Hz, 2H),
.17 (d, J ¼ 2.0 Hz,1H), 6.31 (d, J ¼ 2.0 Hz,1H), 6.41 (d, J ¼ 2.0 Hz,1H),
6
washed with brine, dried over anhydrous MgSO
vacuo. The crude products was subjected to silica gel column
chromatography (CH Cl
4
and evaporated in
13
7
(
1
1
.09 (d, J ¼ 2.0 Hz, 2H), 7.29 (d, J ¼ 2.0 Hz, 2H) ppm; C NMR
100 MHz, -acetone):
¼ 55.8, 59.5, 61.2, 75.1, 101.6, 102.9, 105.4,
06.4 (2C), 111.0, 111.1, 121.6, 131.5 (2C), 132.0 (3C), 139.3, 141.2 (2C),
47.6 (2C), 149.1, 149.5, 150.4, 155.2, 159.5 (2C) ppm; HRMS (ESI): m/
z calcd for C28
þNa: 810.7794; found: 810.7780.
D
d
2
2
: MeOH ¼ 30:1) to give the unreacted 18
(38 mg), the dimer 19 (38.7 mg, 38%) and 20 (36.7 mg, 34%) both as
amorphous powder.
4 7
H20Br O
3.6.2. Procedure 2
3
.3.5. 13
1H NMR (400 MHz,
.23 (br s, 4H), 6.71 (br s, 2H), 7.33 (br s, 4H) ppm; C NMR
-acetone):
FeCl $6H O (113 mg, 0.42 mmol) was slowly added to the solu-
3
2
D
-acetone):
d
¼ 3.95 (br s, 2H), 4.58 (br s, 2H),
tion of stilbene 18 (70 mg, 0.14 mmol) in acetone (4 mL) and water
(2 mL). The reaction mixture was kept out of sun and stirred at
room temperature under argon atmosphere for 18 h. After the
removal of the acetone under reduced pressure, the resulting res-
idue was extracted with EtOAc three times. The combined organic
13
6
(
(
(
100 MHz,
D
d
¼ 53.4 (2C), 59.9 (2C), 102.3 (2C), 103.3
2C), 111.1 (2C), 122.2 (2C), 131.9 (4C), 141.8 (4C), 149.6 (2C), 150.3
4C), 155.8 (2C), 159.7 (2C) ppm; HRMS (ESI): m/z calcd for
C
28
H
18Br
4
O
6
þH: 770.7869; found: 770.7859.
layer was washed with brine, dried over anhydrous MgSO
evaporated in vacuo. The crude products was subjected to silica gel
column chromatography (CH Cl
4
and
3.4. Synthesis of stilbene 17
2
2
:
MeOH ¼ 30:1) to give the
unreacted 18 (21 mg), the dimer 19 (17.1 mg, 35%) and 20 (15.5 mg,
The stirred solution of phosphorus ylide 15 (1.3 g, 2.2 mmol) in
30%) both as amorphous powder.
dry toluene (40 mL) under argon atmosphere was added to a so-
lution of n-BuLi (2.2 mL, 12.0 mmol) in n-hexane. After stirring for
3.6.3. 19
3
0 min, aldehyde 16 (0.7 g, 1.8 mmol) was added and then stirred
1H NMR (600 MHz,
D
-acetone):
d
¼ 4.62 (d, J ¼ 5.4 Hz, 1H), 5.43
ꢁ
for an additional 6 h under refluxing at 110 C, after which ethanol
(d, J ¼ 5.4 Hz,1H), 6.24 (d, J ¼ 1.8 Hz, 2H), 6.28 (t, J ¼ 1.8 Hz,1H), 6.41
(
10 mL) was added. The reaction mixture was concentrated and
extracted with EtOAc (50 mL) for three times, washed with water,
brine and then dried over anhydrous MgSO . The solvent was
(d, J ¼ 1.8 Hz, 1H), 6.74 (d, J ¼ 1.8 Hz, 1H), 6.76 (d, J ¼ 16.2 Hz, 1H),
13
6.83 (d, J ¼ 16.2 Hz,1H), 7.70 (br s, 2H), 7.78 (br s, 2H) ppm; C NMR
4
(150 MHz,
D
-acetone):
d
¼ 55.8, 83.6, 83.7, 90.6, 96.6, 101.5, 104.4,
removed under reduced pressure and the residue was purified on a
silica gel column chromatography (petroleum ether: EtOAc ¼ 8:1)
106.0 (2C), 118.8, 125.5, 126.1, 134.0, 134.9, 136.9 (3C), 137.4 (2C),
137.8, 139.7, 145.6, 154.5, 154.9, 158.8, 159.1, 161.2 (2C) ppm; HRMS
(ESI): m/z calcd. for C28
1
to give stilbene 17 (0.96 g, 81%) as a pale white solid. H NMR
H
18
I
4
O
6
þH: 958.7355; found: 958.7360.
(
(
7
400 MHz,
D
-acetone):
d
¼ 5.14 (s, 4H), 6.61 (t, J ¼ 2.0 Hz, 1H), 6.96
d, J ¼ 2.0 Hz, 2H), 7.06 (d, J ¼ 16.4 Hz, 1H), 7.14 (d, J ¼ 16.4 Hz, 1H),
3.6.4. 20
1
3
1H NMR (600 MHz,
.33e7.50 (m, 10H), 8.01 (br s, 2H) ppm; C NMR (100 MHz,
D-
D-acetone):
d
¼ 1.61 (s, 3H), 1.67 (s, 3H), 2.94
acetone):
d
¼ 74.8 (2C), 89.1, 106.8, 110.9 (2C), 130.8, 132.8 (5C),
(dd, J ¼ 10.2, 10.2 Hz, 1H), 3.35 (dd, J ¼ 10.2, 10.2 Hz, 1H), 4.14 (d,
1
33.0 (3C), 133.6 (5C), 133.8, 139.2, 142.6 (4C), 144.5, 159.8, 165.5
2C) ppm; HRMS (ESI): m/z calcd. for C28
þH: 660.9731;
found: 660.9725.
J ¼ 10.2 Hz,1H), 4.56 (d, J ¼ 10.2 Hz,1H), 5.93 (d, J ¼ 1.8 Hz, 2H), 6.00
13
(
H
22
2
I O
3
(t, J ¼ 1.8 Hz,1H), 6.31 (s, 1H), 7.33 (br s, 2H), 7.58 (br s, 2H) ppm;
C
NMR (150 MHz,
5.6, 82.1, 82.8, 100.8, 103.1, 106.4 (2C), 117.7, 118.0, 136.5, 138.5 (3C),
139.0 (2C), 139.4, 142.3, 143.1, 151.8, 152.9 (2C), 153.7 (2C), 157.9 (2C)
D-acetone):
d
¼ 25.2, 27.8, 52.8, 56.1, 59.6, 75.2,
7
3.5. Synthesis of coupling precursor 18
ppm; HRMS (ESI): m/z calcd. for C31
1016.7761.
H I
24 4
O
7
þH: 1016.7774; found:
N, N-dimethylaniline (11.6 mL, 0.15 mol) was added to a well-
stirred solution of stilbene 17 (1.98 g, 3 mmol) in dry methylene
ꢁ
chloride (50 mL) at 0 C. After 5 min, anhydrous AlCl
3
(2.4 g,
3.7. Synthesis of coupling dimers 21a and 21b
5
6.6 mmol) was added to the reaction mixture. After stirring for
additional 8 h at room temperature, the reaction mixture was
quenched with water at 0 C and poured into a 2.0 M solution of HCl
3.7.1. Procedure 1
ꢁ
3 2
FeCl $6H O (84 mg, 0.3 mmol) was dissolved in water (2 mL),
(
(
15 mL). The resulting mixture was extracted with EtOAc
3 ꢂ 40 mL), washed with saturated brine and then dried over
which was slowly added to the solution of stilbene 18 (50 mg,
0.10 mmol) in acetone (4 mL). The reaction mixture was kept out of
sun and stirred at room temperature under argon atmosphere for
18 h. After quenching with the ice water, the resulting residue was
extracted with EtOAc three times. The combined organic layer was
4
anhydrous MgSO . The solvent was removed under reduced pres-
sure and the residue purified on a silica gel column chromatog-
raphy (petroleum ether: EtOAc ¼ 3:1) to give stilbene 18 (1.1 g, 79%)
as pale yellow oil. 1H NMR (600 MHz,
D-acetone):
d
¼ 6.30 (t,
4
washed with brine, dried over anhydrous MgSO and evaporated in
Please cite this article in press as: Liu M, et al., Regioselective biomimetic oxidation of halogenated resveratrol for the synthesis of (±)-ε-viniferin
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6
M. Liu et al. / Tetrahedron xxx (2018) 1e7
vacuo. The crude products was subjected to silica gel column
chromatography (CH Cl
: MeOH ¼ 25:1) to give the unreacted 18
20 mg) and the dimer 21a (13.7 mg, 45%) as an amorphous powder.
temperature under argon atmosphere and the mixture continued
to stir at 50 C for 18 h. The ice water was slowly added to quench
the reaction and the resulting mixture was extracted with EtOAc
three times (10 mL). The combined organic layer was washed with
ꢁ
2
2
(
3
.7.2. Procedure 2
brine, dried over anhydrous MgSO
crude products were subjected to silica gel column chromatog-
raphy (CH Cl
: MeOH ¼ 15:1) to give (±)-ε-viniferin (2) (10.8 mg,
61%) as an yellowish oil. H NMR (400 MHz,
4
and evaporated in vacuo. The
FeCl $6H O (168 mg, 0.63 mmol) was dissolved in buffer solu-
3
2
tion (pH ¼ 5.4, 3 mL), which was slowly added to the solution of
stilbene 18 (100 mg, 0.21 mmol) in acetone (6 mL). The reaction
mixture was kept out of sun and stirred at room temperature under
argon atmosphere for 24 h. After quenching with the ice water, the
resulting residue was extracted with EtOAc three times. The com-
bined organic layer was washed with brine, dried over anhydrous
2
2
1
D-acetone):
d
¼ 4.48 (d,
J ¼ 5.2 Hz, 1H), 5.43 (d, J ¼ 5.2 Hz, 1H), 6.24 (br s, 3H), 6.33 (t,
J ¼ 1.6 Hz, 1H), 6.71 (d, J ¼ 16.4 Hz, 1H), 6.73 (d, J ¼ 1.6 Hz, 1H), 6.74
(d, J ¼ 8.4 Hz, 2H), 6.84 (d, J ¼ 8.4 Hz, 2H), 6.92 (d, J ¼ 16.4 Hz, 1H),
13
7.18 (d, J ¼ 8.4 Hz, 2H), 7.21 (d, J ¼ 8.4 Hz, 2H) ppm; C NMR
MgSO
4
and evaporated in vacuo. The crude products was subjected
Cl
(150 MHz,
D
-acetone):
d
¼ 57.1, 93.9, 96.8, 102.1, 104.2, 107.0 (2C),
to silica gel column chromatography (CH
the unreacted 18 (60 mg) and the dimer 21a (14.2 mg, 35%) as an
2
2
: MeOH ¼ 25:1) to give
116.1 (2C), 116.3 (2C), 119.8, 123.5, 127.9 (2C), 128.7 (2C), 130.1 (2C),
133.9, 136.4, 147.4, 158.2 (2C), 159.6, 159.9 (2C), 162.5 ppm; HRMS
amorphous powder.
(ESI): m/z calcd. for C28
22
H O
6
þH: 455.1489; found: 455.1490.
3
.7.3. Procedure 3
FeCl $6H O (282 mg, 1.05 mmol) was dissolved in water (4 mL),
which was slowly added to the solution of stilbene 18 (100 mg,
.21 mmol) in acetone (8 mL). The reaction mixture was kept out of
sun and stirred at room temperature under argon atmosphere for
6 h. After quenching with the ice water, the resulting residue was
extracted with EtOAc three times. The combined organic layer was
washed with brine, dried over anhydrous MgSO and evaporated in
vacuo. The crude products was subjected to silica gel column
chromatography (CH Cl
: MeOH ¼ 25:1) to give the unreacted 18
36 mg) and the dimeric mixture of 21a and 21b (20.8 mg, 32%), as
well as the dimer 22 (10 mg, 10%) both as amorphous powder.
3.8.2. Procedure 2
3
2
4
Large Excess LiAlH (0.33 g, 8.7 mmol) was added to a solution of
dimer 10 (45 mg, 0.058 mmol) in dry THF (5 mL) at room temper-
ature under argon atmosphere and the mixture continued to stir at
reflux for 48 h. The ice water was slowly added to quench the re-
action and the resulting mixture was extracted with EtOAc three
times (10 mL). The combined organic layer was washed with brine,
0
3
4
dried over anhydrous MgSO
products were subjected to silica gel column chromatography
(CH Cl
: MeOH ¼ 15:1) to give (±)-ampelopsin B (4) (15.6 mg, 59%)
as an yellowish oil. H NMR (400 MHz,
4
and evaporated in vacuo. The crude
2
2
2
2
1
(
D
-acetone):
d
¼ 3.18 (dd,
J ¼ 18.0, 4.0 Hz, 1H), 3.59 (dd, J ¼ 18.0, 4.0 Hz, 1H), 4.17 (d,
J ¼ 11.2 Hz, 1H), 5.21 (t, J ¼ 4.0 Hz, 1H), 5.72 (d, J ¼ 11.2 Hz, 1H), 6.05
(d, J ¼ 2.0 Hz, 1H), 6.24 (d, J ¼ 2.0 Hz, 1H), 6.33 (d, J ¼ 2.0 Hz, 1H),
6.43 (d, J ¼ 2.0 Hz, 1H), 6.65 (d, J ¼ 8.4 Hz, 2H), 6.76 (d, J ¼ 8.4 Hz,
3
.7.4. 21a
1H NMR (600 MHz,
.48 (dd, J ¼ 5.6, 6.0 Hz, 1H), 4.17 (d, J ¼ 4.8 Hz, 1H), 4.62 (d,
D
-acetone):
d
¼ 2.99 (dd, J ¼ 5.4, 4.8 Hz, 1H),
13
3
2H), 6.94 (d, J ¼ 8.4 Hz, 2H), 7.09 (d, J ¼ 8.4 Hz, 2H) ppm; C NMR
J ¼ 6.0 Hz, 1H), 5.99 (d, J ¼ 1.8 Hz, 2H), 6.17 (t, J ¼ 1.8 Hz, 1H), 6.31 (d,
J ¼ 1.8 Hz, 1H), 6.44 (d, J ¼ 1.8 Hz, 1H), 7.37 (br s, 2H), 7.52 (br s, 2H)
(100 MHz,
D
-acetone):
d
¼ 33.8, 36.2, 49.3, 88.3, 95.7, 101.5, 105.4,
109.0, 115.6 (2C), 116.0 (2C), 119.0, 122.8, 128.6 (2C), 130.0 (2C),
131.0, 134.8, 138.1, 142.6, 156.1, 156.6, 157.2, 158.5, 158.7, 160.4 ppm;
HRMS (ESI): m/z calcd. for C28
13
ppm; C NMR (150 MHz,
D
-acetone):
d
¼ 54.4, 58.8, 60.3, 74.0, 82.9,
8
1
3.3, 100.6, 101.7, 104.6, 105.3 (2C), 120.6, 138.0 (3C), 138.4 (3C),
40.0, 141.8, 146.9, 148.3, 152.9, 153.8, 154.2, 158.4, 158.5 (2C) ppm;
HRMS (ESI): m/z calcd. for C28
H
22
O
6
þH: 455.1489; found: 455.1486.
H
20
I
4
O
7
þH: 976.7460; found:
3.9. Hydrogenation debromination of dimer 10
9
3
3
76.7457.
After two vaccum/H
flask, a suspension of dimer 10 (31 mg, 0.04 mmol), 10% Pd/C
(30 mg), and Et N (0.5 mL) in MeOH (5 mL) was vigorously stirred
2
cycles to remove air from a round bottom
.7.5. 21b
1H NMR (600 MHz,
.44 (dd, J ¼ 6.6, 4.2 Hz, 1H), 4.19 (d, J ¼ 3.6 Hz, 1H), 4.63 (d,
D
-acetone):
d
¼ 3.38 (dd, J ¼ 4.2, 3.6 Hz, 1H),
3
using a stir bar under hydrogen atmosphere at ambient tempera-
ture. After stirring for 14 h, the reaction mixture was filtered. The
filtrate was washed with diluted HCl and then extracted with EtOAc
(2 ꢂ 10 mL). The combined organic layer was washed with satu-
J ¼ 6.6 Hz, 1H), 6.00 (d, J ¼ 1.8 Hz,1H), 6.06 (d, J ¼ 1.8 Hz, 2H), 6.15 (t,
J ¼ 1.8 Hz, 1H), 6.28 (d, J ¼ 1.8 Hz, 1H), 7.45 (br s, 2H), 7.65 (br s, 2H)
13
ppm; C NMR (150 MHz,
D
-acetone):
d
¼ 54.5, 57.3, 61.3, 74.1, 83.0,
8
1
3.5, 100.5, 101.9, 104.2, 105.2 (2C), 121.3, 138.3 (3C), 138.6 (3C),
39.5, 142.5, 146.1, 149.4, 153.1, 154.2 (2C), 158.4, 158.5 (2C) ppm;
HRMS (ESI): m/z calcd. for C28
4
rated brine and then dried over MgSO . The solvent was removed
under reduced pressure and the residue was purified on a silica gel
(CH Cl
: MeOH ¼ 18:1) to obtain (±)-gnetins F (3) (16.2 mg, 89%) as
light yellowish oil. H NMR (400 MHz,
H
20
I
4
O
7
þH: 976.7460; found:
2
2
1
9
3
6
76.7457.
D
-acetone):
d
¼ 2.26e2.55
(
m, 4H), 4.18 (d, J ¼ 6.0 Hz, 1H), 5.33 (d, J ¼ 6.0 Hz, 1H), 6.18 (br s,
.7.6. 22
2H), 6.25 (br s, 1H), 6.26 (br s, 1H), 6.28 (br s, 1H), 6.65 (d, J ¼ 8.4 Hz,
1H NMR (600 MHz,
D
-acetone):
d
¼ 3.91 (br s, 2H), 4.54 (br s, 2H),
2H), 6.81 (d, J ¼ 7.6 Hz, 2H), 6.83 (d, J ¼ 7.6 Hz, 2H), 7.13 (d,
13
.23 (d, J ¼ 1.8 Hz, 2H), 6.69 (d, J ¼ 1.8 Hz, 2H), 7.56 (br s, 4H) ppm;
J ¼ 8.4 Hz, 2H) ppm; C NMR (100 MHz,
D-acetone):
d
¼ 35.5, 35.8,
1
3
C NMR (150 MHz,
D-acetone):
d
¼ 53.2 (2C), 59.9 (2C), 102.7 (2C),
56.4, 93.3, 94.8, 101.3, 106.3 (2C), 108.5, 115,0 (2C), 115.4 (2C), 119.5,
127.4 (2C), 129.5 (2C), 132.8, 133.2, 140.3, 146.7, 155.6, 157.5, 158.8,
103.6 (2C), 107.3 (2C), 121.9 (2C), 138.3 (2C), 139.2 (6C), 149.9 (2C),
1
C
55.2 (2C), 159.5 (2C), 159.8 (2C) ppm; HRMS (ESI): m/z calcd for
159.1 (2C), 161.4 ppm; HRMS (ESI): m/z calcd. for C28
457.1646; found: 457.1643.
H O
24 6
þH:
H
28 18
I
4
O
6
þH: 957.7381; found: 957.7659.
3.8. Reductive debromination reaction of dimer 10
3.10. Hydrogenation debromination of dimer 11
3
.8.1. Procedure 1
After two vaccum/H
flask, a suspension of dimer 11 (40 mg, 0.039 mmol), 10% Pd/C
(40 mg), and Et N (0.5 mL) in MeOH (5 mL) was vigorously stirred
2
cycles to remove air from a round bottom
4
Excess LiAlH (0.10 g, 2.73 mmol) was added to a solution of
dimer 10 (30 mg, 0.039 mmol) in dry THF (4 mL) at room
3
Please cite this article in press as: Liu M, et al., Regioselective biomimetic oxidation of halogenated resveratrol for the synthesis of (±)-ε-viniferin
and its analogues, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.06.005

M. Liu et al. / Tetrahedron xxx (2018) 1e7
7
using a stir bar under hydrogen atmosphere at ambient tempera-
ture. After stirring for 14 h, the reaction mixture was filtered. The
filtrate was washed with diluted HCl and then extracted with EtOAc
(e) Keylor MH, Matsurra BS, Stephenson CRJ. Chem Rev. 2015;115:8976e9027;
f) Wang X-F, Yao C-S. J Asian Nat Prod Res. 2016;18:376e407.
. (a) Kurihara H, Kawabata J, Ichikawa S, Mizutani J. Agric Biol Chem. 1990;54:
097e1099;
(b) Vo DD, Elofsson M. Synth Catal. 2016;358:4085e4092;
c) Lindgren AEG, Oberg CT, Hillgren JM, Elofsson M. Eur J Org Chem. 2016;3:
26e429;
d) Wang G-W, Wang H-L, Capretto DA, Han Q, Hu R-B, Yang S-D. Tetrahedron.
(
3
1
(
2 ꢂ 10 mL). The combined organic layer was washed with satu-
rated brine and then dried over MgSO . The solvent was removed
under reduced pressure and the residue was purified on a silica gel
CH Cl
: MeOH ¼ 18:1) to obtain (±)-23 (17.6 mg, 88%) as light
yellowish oil. H NMR (400 MHz,
(
4
(
4
(
2
2
2012;68:5216e5222;
(e) Xie J-S, Wen J, Wang X-F, et al. Molecules. 2015;20:22662e22673;
1
D
-acetone):
d
¼ 1.61 (s, 3H), 1.65 (s,
(f) Takaya Y, Yan K-X, Terashima K, Ito J, Niwa M. Tetrahedron. 2002;58:
3
4
2
H), 2.82 (dd, J ¼ 10.0, 9.6 Hz, 1H), 3.43 (dd, J ¼ 10.0, 10.0 Hz, 1H),
7259e7265;
.21 (d, J ¼ 9.6 Hz, 1H), 4.46 (d, J ¼ 9.6 Hz, 1H), 5.87 (d, J ¼ 1.6 Hz,
H), 5.92 (t, J ¼ 1.8 Hz, 1H), 6.26 (s, 1H), 6.47 (d, J ¼ 8.4 Hz, 2H), 6.63
(g) Matsurra BS, Keylor MH, Li B, Lin Y, Allison S, Stephenson CRJ. Angew Chem
Int Ed. 2015;54:3754e3757;
(h) Li C, Lu J, Xu XF, Hu RL, Pan Y. J Green Chem. 2012;14:3281e3284;
(
d, J ¼ 8.4 Hz, 2H), 6.79 (d, J ¼ 8.4 Hz, 2H), 6.99 (d, J ¼ 8.4 Hz, 2H)
(i) Snyder SA, Breazzano SP, Ross AG, Lin Y-Q, Zografos AL. J Am Chem Soc.
13
ppm; C NMR (100 MHz,
0.2, 82.8, 105.2, 108.0, 111.8 (2C), 119.1 (2C), 119.8 (2C), 123.4, 123.8,
33.8 (2C), 134.0 (2C), 136.6, 138.7, 148.6, 148.8, 156.8, 158.2, 160.8,
61.3, 162.5 (2C) ppm; HRMS (ESI): m/z calcd. for C31
þH:
13.1907; found: 513.1908.
D
-acetone):
d
¼ 30.4, 33.1, 57.9, 62.2, 68.6,
2009;131:1753e1765;
j) Tamboli VF, Re N, Coletti C, Defant A, Mancini I, Tosi P. Int J Mass Spectrom.
012;319e320:55e63;
k) Klotter F, Studer A. Angew Chem Int Ed. 2014;53:2473e2476;
(
2
(
8
1
1
5
28
H O
7
(l) Mora-Pale M, Bhan N, Masuko S, et al. Biotechnol Bioeng. 2015;112(12):
2418e2428;
(
(
m) Szewczuk LM, Lee SH, Blair IA, Penning TM. J Nat Prod. 2005;68:36e42;
n) Tang M-L, Peng P, Liu Z-Y, Zhang J, Yu J-M, Sun X. Chem Eur J. 2016;22:
Acknowledgements
14535e14539;
(
(
o) Yao C-S, Lin M, Wang Y-H. Chin J Chem. 2004;22:1350e1355;
p) Takaya Y, Terashima K, Ito J, et al. Tetrahedron. 2005;61:10285e10290.
This research work was financially supported by the National
Natural Science Foundation of China (No. 21462024).
4
. (a) Wu ZF, Li H, Zhu XJ, et al. Catalysts. 2017;7, 188-130;
b) Zhang JF, Zhang JQ, Kang YL, Shi JG, Yao CS. Synlett. 2016;27:1587e1591.
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19e831.
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(
5
(
8
Appendix A. Supplementary data
6
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.06.005.
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(b) Li WL, Luo YL, Li HF, Zang P, Han XQ. Synthesis. 2010;22:3822e3826;
(c) Li WL, Li HF, Luo YL, Yang YH, Wang N. Synlett. 2010;21:1247e1250;
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Please cite this article in press as: Liu M, et al., Regioselective biomimetic oxidation of halogenated resveratrol for the synthesis of (±)-ε-viniferin
and its analogues, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.06.005