Total synthesis of the active resveratrol dimer dehydro-δ-viniferin

Article abstract of DOI:10.1080/10286020.2020.1776267

A new approach for the total synthesis of the active stilbene dimer dehydro-δ-viniferin has been achieved in 9 steps with methyl 4-hydroxybenzoate and 3,5-dihydroxyacetophenone as starting materials. The key feature of the method is the amberlyst 15-mediated cyclodehydration of α-aryloxyketone.

Full text of DOI:10.1080/10286020.2020.1776267

Journal of Asian Natural Products Research
ISSN: 1028-6020 (Print) 1477-2213 (Online) Journal homepage: https://www.tandfonline.com/loi/ganp20
Total synthesis of the active resveratrol dimer
dehydro-δ-viniferin
Bin-Hao Teng, Qi-Bin Zhu, Yi-Yao Fan & Chun-Suo Yao
To cite this article: Bin-Hao Teng, Qi-Bin Zhu, Yi-Yao Fan & Chun-Suo Yao (2020): Total
synthesis of the active resveratrol dimer dehydro-δ-viniferin, Journal of Asian Natural Products
Research, DOI: 10.1080/10286020.2020.1776267
To link to this article: https://doi.org/10.1080/10286020.2020.1776267
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JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
https://doi.org/10.1080/10286020.2020.1776267
Total synthesis of the active resveratrol dimer
dehydro-d-viniferin
ꢀ
ꢀ
Bin-Hao Teng , Qi-Bin Zhu , Yi-Yao Fan and Chun-Suo Yao
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
ABSTRACT
ARTICLE HISTORY
A new approach for the total synthesis of the active stilbene
dimer dehydro-d-viniferin has been achieved in 9 steps with
methyl 4-hydroxybenzoate and 3,5-dihydroxyacetophenone as
starting materials. The key feature of the method is the amberlyst
Received 27 April 2020
Accepted 27 May 2020
KEYWORDS
Stilbene dimer; dehydro-
d-viniferin; total synthesis;
amberlyst 15
15-mediated cyclodehydration of a-aryloxyketone.
1. Introduction
A number of hydroxylated stilbenoids derived from natural sources have been
described over the past three decades due to their intriguing structures and diverse
biological activities [1–3]. Oligomeric stilbenes have been described as potentially
important antimicrobial, anti-oxidant and anti-inflammatory agents in recent years
[
4]. Stilbene dimers with benzofuran nucleus, an interesting chemical skeleton, is
prevalent in a wide variety of biologically active natural and unnatural compounds.
,3-Diaryl benzofuran stilbenoids are of interest because they exhibit a wide range of
biological activities, such as anti-cancer, anti-inflammatory, anti-oxidant, and so on
5]. Due to the structural diversity and attractiveness of stilbene dimers, several syn-
2
[
thetic approaches to this class of compounds have been introduced up to now [6–7].
Of particular significance are the works on biomimetic dimerization approaches and
on rational synthetic approaches.
Dehydro-d-viniferin (1) is a resveratrol dimer with 2,3-diarylbenzofuran skeleton
with multifaced bioactivities, such as anti-inflammatory and liver-protective activities.
CONTACT Chun-Suo Yao
yaocs@imm.ac.cn
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
Supplemental data for this article is available online at https://doi.org/10.1080/10286020.2020.1776267.
These authors contributed equally to this work.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group
ꢀ

2
B.-H. TENG ET AL.
Scheme 1. Retrosynthetic analysis of dehydro-d-viniferin.
Recently dehydro-d-viniferin was found to show potent inhibition on the T3SS, better
efficacy to rescue eukaryotic cells from infection, and toxicity towards the eukaryotic
cells [8]. It was also reported to show significant antibacterial activity against S. aur-
eus and comparable antiradical activities [9–10]. Owing to its fascinating structures
and unexplored potential in medicine, it has become an attractive target for total syn-
thesis. As reported in the literature [10], compound 1 was semi-synthesized by lac-
case-biocatalyzed dimerization of resveratrol followed by dehydrogenation of
d-viniferin. Its total synthesis was achieved by one pot two-step Sonogashira cyclyza-
tion of o-iodophenol and 4-ethynylanisole [11]. Our continuous medicinal chemistry
research on stilbene dimers has enabled us to pursue efficient and versatile total syn-
thesis of this acitive compound. Herein, a new and facile total synthetic approach for
synthesizing 1 has been achieved. The method and strategy described have the poten-
tial of being applicable in syntheses of the dehydro-d-viniferin analogues to establish
structure-activity relationships.
2. Results and discussion
At the outset, we wish to design a synthetic strategy by which not only 1 but also its
synthetic ananlogues would be accessible. The critical issues need to be addressed for
the synthesis of dehydro-d-viniferin is the construction of the intermediate benzo-
furan 2. We envision that cyclodehydration reaction catalyzed by transition metal and
Lewis acid could be a viable method as reported in the literatue [12–13]. Therefore,
the retrosynthetic route to active product 1 is outlined in Scheme 1. According to the
method reported, compound 1 could be produced by olefination of the key inter-
mediate 2,3-diarylbenzofuran aldehyde 2, which could be be available through hydro-
genation reduction of benzofuran 3. Intermediate 3 could be prepared via Heck
reaction of benzofuran 4 followed by intermolecular coupling with 4-bromoanisole 5.
At last, the requisite 4 was envisioned to be accessible from the dehydrative cyclyza-
tion of aryloxyketone 6, which can be easily assembled from the commercially avail-
able methyl 4-hydroxybenzoate 7 and 3,5-dihydroxyacetophenone 8.

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
3
Scheme 2. Synthesis of intermediate 6.
Scheme 3. Cyclodehydration reaction of aryloxyketone 6.
As delineated in Scheme 2, we started our synthesis with the preparation of the
intermediate a-aryloxyketone 6 from the reaction of the phenol 7 with a-bromoke-
tone 9 in the presence of potassium carbonate, which was easily prepared from 3,5-
dihydroxyacetophenone 8. With compound 6 in hand, we explored the synthesis of
the key intermediate 3-arylbenzofuran 4. As reported in the literature [12–13], subjec-
tion of 10 to refluxing toluene in the presence of Bi(OTf) or CH SO H resulted in
3
3
3
8
8% or 72% yield of 11. However, when ketone 6 was exposed to Bi(OTf) or
3
CH SO H as the same method described, instead of the desired benzofuran 4, only
3
3
degradation products were observed in the reaction mixture (Scheme 3). Several
attempts to this cyclodehydration reaction were then carried out, and a number of
other catalysts, such as FeCl , CF COOH, and CH SO H, were found to be inert to
3
3
3
3
the reaction. Finally, we were pleased to find that exposure of 6 to amberlyst 15 (0.3
ꢁ
equiv) in refluxing toluene at 150 C affored the desired 3-arylbenzofuran 4, albeit in
low yield of 14%. Whereafter, several parameters (concentration, temperatures, and
equivalents of catalysts) were changed to improve the efficiency, but no satisfactory
result was obtained. Analysis of the difference between 10 and 6 indicated that a
meta-methoxy in a-aryloxyketone 10 played a significant role in the process. Higher
reactivity of the benzene ring caused by an electron-donating group of compound 10
resulted in the cyclodehydration reaction took place at ortho- and para-position of
the alkoxies. However, in this reaction, the lack of meta-methoxy at benzene ring of
6
led to the lower reactivity, which prevented the reaction from occurring.

4
B.-H. TENG ET AL.
Scheme 4. Synthesis of permethylated dehydro-d-viniferin.
Scheme 5. BBr -mediated demethylation of permethylated dehydro-d-viniferin.
3
Afterwards, 4 was exposed to the conditions [Pd(OAc) (0.2 equiv), KOAc (2
2
ꢁ
equiv), and 4-bromoanisole (10 equiv) in DMA, 120 C] to generate the arylated
product 3 in 60.1% yield. Reduction of the ester group in 3 with LiAlH followed by
4
oxidation with Dess-Martin periodinane resulted in the generation of aldehyde 2 in
an overall yield of 99% over two steps. The Horner-Wadsworth-Emmons-type olefi-
nation of 2 with diethyl 3,5-dimethoxybenzylphosphonate (12) produced the perme-
thylated dehydro-d-viniferin (13) in quantitative yield (Scheme 4) [13]. When 13 was
ꢁ
treated with BBr in dichloromethane at -45 C to room temperature for 12 hours, the
3
target compoud 1 was obtained in 65.1% yield. Additionally, when 13 was treated in
ꢁ
ꢁ
the same way at -45 C to 0 C, dimethoxydehydro-d-viniferin 14 was obtained
smoothly in 56.7% yiled (Scheme 5).
In conclusion, a new strategy for the total synthesis of active stilbene dimer
dehydro-d-viniferin 1 was achieved in 9 steps with commercially available methyl
4
1
-hydroxybenzoate and 3,5-dihydroxyacetophenone as starting materials. Amberlyst
5-mediated cyclodehydration of a-aryloxyketone was employed to construct the key
intermediate 3-arylbenzofuran. The route reported here should be useful for the syn-
thesis of dehydro-d-viniferin analogues to establish structure-activity relationships.
3. Experimental
3.1. General experimental procedures
All commercially available reagents were used without further purification. Solvents
were dried prior to use following the standard procedures. THF and toluene were
dried by Na. CH Cl was dried by CaSO or P O . HR-MS-ESI and ESI spectra were
2
2
4
2 5

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
5
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). The reaction pro-
gress was detected by TLC. TLC was carried out with glass precoated silica gel GF254
plates (Qingdao Marine Chemical, Inc., Qingdao, China). Spots were visualized under
1
13
UV light. H and C NMR spectra for all compounds were recorded at 500 and
25 MHz (Bruker Corporation, Karlsruhe, Germany), respectively, and the chemical
1
shifts are reported in ppm. In most of the cases, yields refer to isolated yields after
purification.
3
.2. Preparation of 2-bromo-1-(3,5-dimethoxyphenyl)-ethanone (9)
2
-Bromo-1-(3,5-dimethoxyphenyl)-ethanone (9) was prepared as a dark red solid via
ꢁ
1
a method similar to the literature [12] with a yield of 77.0%. Mp 54.3 - 57.1 C. H
NMR (500 MHz, acetone-d ): d 7.17 (d, J ¼ 2.2 Hz, 2H), 6.76 (t, J ¼ 2.2 Hz, 1H), 4.75
6
þ
(
s, 2H), 3.86 (s, 6H). ESI-MS m/z 281.0 [M þ Na] .
3
.3. Preparation of methyl 4-(2-(3,5-dimethoxyphenyl)-2-oxoethoxy)-
benzoate (6)
Powdered K CO (10.64 g 77.0 mmol) was added to a stirred solution of 7 (5.87 g,
2
3
38.5 mmol) and 9 (10 g, 38.5 mmol) in acetone (300 ml). The mixture was stirred at
room temperature for 1 hour before refluxed for five hours. Then the mixture was
cooled to ambient temperature, filtered through celite and washed with acetone. The
organic layer was removed by reduced pressure and the residue was purified by silica
gel column chromatography (petroleum ether: ethyl acetate: dichloromethane ¼ 50: 2:
1
5
) to afford compound 6 (12.45 g, 98.0%) as a white amorphous powder. H NMR
(
500 MHz, CDCl ) d 7.99 (d, J ¼ 8.8 Hz, 2H), 7.11 (d, J ¼ 2.2 Hz, 2H), 6.94 (d,
3
J ¼ 8.9 Hz, 2H), 6.71 (t, J ¼ 2.3 Hz, 1H), 5.31 (s, 2H), 3.88 (s, 3H), 3.85 (s, 6H).
þ
(þ)-HRESIMS: m/z 331.1179 [M þ H] (calcd for C H O , 331.1176).
18
19 6
3
.4. Preparation of methyl 3-(3,5-dimethoxyphenyl)benzofuran-5-carboxylate (4)
Amberlyst 15 (15 g) was added to a stirred solution of 6 (5.00 g, 15.1 mmol) in tolu-
ꢁ
ene (300 ml). The mixture was stirred at 150 C in a sealed tube for 30 h. After com-
pletion, the reaction mixture was filtered and concentrated in vaccuo. The residue
was then purified by silica gel column chromatography (petroleum ether: ethyl acet-
ate: dichloromethane ¼ 80: 5: 2) to afford a yellowish amorphous powder 4 (0.66 g,
1
1
1
4.0%). H NMR (500 MHz, CDCl ) d 8.55 (d, J ¼ 1.8 Hz, 1H), 8.08 (dd, J ¼ 8.7,
3
.7 Hz, 1H), 7.84 (s, 1H), 7.57 (d, J ¼ 8.7 Hz, 1H), 6.78 (d, J ¼ 2.3 Hz, 2H), 6.52 (t,
13
J ¼ 2.2 Hz, 1H), 3.95 (s, 3H), 3.87 (s, 6H). C NMR (125 MHz, CD Cl ) d 167.3,
3
3
1
(
61.5 (2 ꢂ C), 158.4, 142.8, 133.2, 130.0, 128.2, 126.7, 125.6, 123.2, 111.8, 106.1
þ
2 ꢂ C), 99.8, 55.7, 55.6, 52.3. (þ)-HRESIMS: m/z 313.1073 [M þ H] (calcd for
C H O , 313.1071).
1
8
17 5

6
B.-H. TENG ET AL.
3.5. Preparation of methyl 3-(3,5-dimethoxyphenyl)-2-(4-
methoxyphenyl)benzofuran-4-carboxylate (3)
KOAc (2.19 g, 22.4 mmol), Pd(OAc) (500 mg, 2.3 mmol) and 4-bromoanisole (5,
2
20.95 g, 112.0 mmol) were added in sequence to a stirred solution of 4 (3.50 g,
1
1.2 mmol) in DMA (200 ml) at room temperature. The mixture was stirred in a
ꢁ
sealed tube (500 ml) filled with dry nitrogen at 120 C for 20 h. Then the mixture was
filtered through celite and washed with ethyl acetate. The organic layer was concen-
trated under reduced pressure, and the left residue was dissolved in ethyl acetate,
washed with water, and dried over Na SO . After removing the solvent, the residue
2
4
was purified by silica gel column chromatography (petroleum ether: ethyl acetate:
dichloromethane ¼ 90: 2: 5) to afford a colorless crystal 3 (acetone, 2.82 g, 60.1%).
1
H NMR (500 MHz, CDCl ) d 8.22 (d, J ¼ 1.6 Hz, 1H), 8.06 (dd, J ¼ 8.6, 1.7 Hz, 1H),
3
7
.66 (d, J ¼ 8.9 Hz, 2H), 7.57 (d, J ¼ 8.6 Hz, 1H), 6.90 (d, J ¼ 9.0 Hz, 2H), 6.65 (d,
13
J ¼ 2.3 Hz, 2H), 6.56 (t, J ¼ 2.3 Hz, 1H). C NMR (150 MHz, CDCl ) d 167.4, 161.5
3
(
1
2 ꢂ C), 160.2, 156.4, 152.2, 134.3, 130.7, 128.7 (2 ꢂ C), 126.3, 125.4, 122.7, 122.4,
16.3 (2 ꢂ C), 114.1, 110.9, 107.8 (2 ꢂ C), 100.3, 55.6, 55.5, 55.4, 52.2. (þ)-HRESIMS:
þ
m/z 419.1492 [M þ H] (calcd for C H O , 419.1490).
2
5
23 6
3
.6. Preparation of 3-(3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)-5-
benzofuranmethanol (2a)
To a stirred solution of compound 3 (2.80 g, 6.7 mmol) in freshly redistilled THF
(
50 ml) was added LiAlH (508 mg, 13.4 mmol), and the resulted suspension was
4
allowed to stir at room temperature for 2 h. After TLC detection revealed a comple-
tion of the reaction, 600 ml of water, 1800 ml of 15% NaOH solution and 600 ml of
water were added successively to the suspension very slowly and was then allowed to
stir for 15 min. Subsequently, the mixture was filtered through celite, the filtrate was
dried over anhydrous Na SO , and evaporated in vacuo to give a colorless oil 2a
2
4
1
(
2.61 g, 99.8%). H NMR (500 MHz, CDCl ) d 7.64 (d, J ¼ 8.9 Hz, 2H), 7.51 (d,
3
J ¼ 8.4 Hz, 1H), 7.49 (d, J ¼ 1.6 Hz, 1H), 7.32 (dd, J ¼ 8.3, 1.8 Hz, 1H), 6.87 (d,
J ¼ 8.9 Hz, 2H), 6.63 (d, J ¼ 2.3 Hz, 2H), 6.52 (t, J ¼ 2.3 Hz, 1H), 4.75 (s, 2H), 3.82 (s,
1
3
3
1
1
H), 3.78 (s, 6H). C NMR (150 MHz, CDCl ) d 161.4 (2 ꢂ C), 160.0, 153.5, 151.5,
3
35.9, 135.0, 130.7 (2 ꢂ C), 128.6, 124.0, 123.2, 118.7, 116.1, 114.1 (2 ꢂ C), 111.2,
þ
07.9, 107.9, 100.0, 65.9, 55.6 (2 ꢂ C), 55.4. (þ)-HRESIMS: m/z 391.1542 [M þ H]
(
calcd for C H O , 391.1540).
24 23 5
3
.7. Preparation of 3-(3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)benzofuran-5-
carbaldehyde (2)
Dess-Martin periodinane (5.4 g, 12.8 mmol) was added to a stirred solution of 2a
(2.50 g, 6.4 mmol) in redistilled dichloromethane (80 ml). TLC detection demonstrated
that the reaction completed within 8 h. The solution was washed successively with
saturated NaHCO , and saturated NaS O solution, dried over anhydrous Na SO
4
3
2
3
2
and evaporated under reduced pressure. The residue was purified by column chroma-
tography over silica gel using petroleum ether and acetone (20: 1, v/v) as the eluent

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
7
1
to afford compound 2 as a light yellowish oil (2.37 g, 95.2%). H NMR (500 MHz,
CDCl ) d 10.03 (s, 1H), 8.02 (d, J ¼ 1.6 Hz, 1H), 7.87 (dd, J ¼ 8.4, 1.7 Hz, 1H), 7.65
3
(
d, J ¼ 8.9 Hz, 2H), 7.63 (d, J ¼ 8.5 Hz, 1H), 6.88 (d, J ¼ 8.9 Hz, 2H), 6.63 (d,
13
J ¼ 2.3 Hz, 2H), 6.55 (t, J ¼ 2.3 Hz, 1H), 3.83 (s, 3H), 3.80 (s, 6H). C NMR
(
1
125 MHz, CDCl ) d 191.9, 161.5 (2 ꢂ C), 160.4, 157.3, 152.7, 134.1, 132.5, 131.3,
3
28.8 (2 ꢂ C), 126.0, 123.3, 122.5, 116.3, 114.2 (2 ꢂ C), 111.8, 107.8, 107.8, 100.2, 55.6
þ
(
2 ꢂ C), 55.6. (þ)-HRESIMS: m/z 389.1387 [M þ H] (calcd for C H O , 389.1384).
24
21 5
3
.8. Preparation of 3-(3,5-dimethoxyphenyl)-5-[(1E)-2-(3,5-
dimethoxyphenyl)ethenyl]-2-(4-methoxyphenyl)benzofuran (13)
t-BuOK (290 mg, 2.58 mmol) was added to a stirred solution of diethyl (3,5-dime-
thoxyphenyl) phosphonate (559 mg, 1.94 mmol) in freshly redistilled THF (15 ml) at
ꢁ
-
40 C, and then the mixture was stirred at this temperature for 20 min. Subsequently,
compound 2 (500 mg, 1.29 mmol) in freshly redistilled THF (15 ml) was added, and
the mixture was allowed to warm to room temperature slowly and was stirred for
another 24 h. After the solvent was removed under reduced pressure, the mixture was
diluted with ethyl acetate, washed with saturated aqueous NaCl and water, dried over
anhydrous Na SO , and concentrated in vacuo. The residue was then purified by col-
2
4
umn chromatography over silica gel with petroleum ether and acetone (15: 1, v/v) as
1
the eluent to afford compound 13 as a colorless oil (671 mg, 99.2%). H NMR
(
500 MHz, CDCl ) d 7.64 (d, J ¼ 8.8 Hz, 2H), 7.58 (s, 1H), 7.50 (br s, 2H), 7.17 (d,
3
J ¼ 16.2 Hz, 1H), 7.00 (d, J ¼ 16.2 Hz, 1H), 6.87 (d, J ¼ 8.9 Hz, 2H), 6.66 - 6.67 (m,
H), 6.54 (t, J ¼ 2.3 Hz, 1H), 6.38 (t, J ¼ 2.2 Hz, 1H), 3.83 (s, 6H), 3.83 (s, 3H), 3.80
4
1
3
(
s, 6H). C NMR (125 MHz, CDCl ) d 161.4 (2 ꢂ C), 161.1 (2 ꢂ C), 160.0, 153.7,
3
1
1
5
51.5, 139.7, 135.0, 132.6, 131.0, 129.7, 128.6, 128.6, 127.7, 123.2, 123.2, 118.0, 118.0,
16.1, 114.0, 111.3, 107.9, 107.9, 104.5, 104.5, 100.1 (2 ꢂ C), 55.7 (2 ꢂ C), 55.6, 55.6,
þ
5.5. (þ)-HRESIMS: m/z 523.2120 [M þ H] (calcd for C H O , 523.2115).
33
31 6
3
.9. Preparation of 5-[5-[(1E)-2-(3,5-dihydroxyphenyl)ethenyl]-2-(4-
hydroxyphenyl)-3-benzofuranyl]-1,3-benzenediol (1)
To a solution of compound 13 (200 mg, 0.38 mmol) in redistilled dichloromethane
(
20 ml), a solution of BBr (4.6 mmol) in redistilled dichloromethane (20 ml) was
3
added dropwise at -45 ˚C within 30 min, and the mixture was stirred for 2 h at the
ꢁ
ꢁ
same temperature. Then the mixture was warmed up to react at -25 C, ꢃ10 C, and
ꢁ
0
C for 2 h sequentially. After stirred overnight at room temperature, methanol
(5 ml) was added dropwise at -45 ˚C to quench the reaction. The solution was diluted
with 120 ml ethyl acetate, washed with water, dried over anhydrous Na SO , and
2
4
evaporated under reduced pressure to afford a red residue, which was then purified
through silica gel column chromatography (dichloromethane: MeOH ¼ 40: 1, v/v)
and Sephadex LH-20 (MeOH) to afford compound 1 as a white amorphous powder
1
(
112.7 mg, 65.1%). H NMR (500 MHz, CD OD) d 7.56 (d, J ¼ 1.6 Hz, 1H), 7.54 (d,
3
J ¼ 8.8 Hz, 2H), 7.52 - 7.49 (m, 1H), 7.48 (d, J ¼ 8.5 Hz, 1H), 7.13 (d, J ¼ 16.2 Hz,
H), 6.95 (d, J ¼ 16.2 Hz, 1H), 6.77 (d, J ¼ 8.7 Hz, 2H), 6.49 (d, J ¼ 2.2 Hz, 2H), 6.43
1

8
B.-H. TENG ET AL.
1
3
(
(
1
1
d, J ¼ 2.2 Hz, 2H), 6.35 (t, J ¼ 2.2 Hz, 1H), 6.18 (t, J ¼ 2.2 Hz, 1H). C NMR
125 MHz, CD OD) d 160.3 (2 ꢂ C), 159.7 (2 ꢂ C), 159.6, 154.8, 152.9, 141.0, 136.0,
3
34.1, 132.1, 129.8, 129.7 (2 ꢂ C), 128.8, 123.9, 123.0, 118.6, 116.8, 116.4 (2 ꢂ C),
11.8, 109.2 (2 ꢂ C), 106.0 (2 ꢂ C), 103.0, 103.0. (þ)-HRESIMS: m/z 453.1336
þ
[
M þ H] (calcd for C H O , 453.1333).
2
8
21 6
3
.10. Preparation of 5-[5-[(1E)-2-(3,5-dimethoxyphenyl)ethenyl]-2-(4-
hydroxyphenyl)-3-benzofuranyl]-1,3-benzenediol (14)
To a solution of compound 13 (200 mg, 0.38 mmol) in redistilled dichloromethane
(
20 ml), a solution of BBr (4.6 mmol) in redistilled dichloromethane (20 ml) was
3
added dropwise at -45 ˚C within 30 min, and the mixture was stirred for 2 h at the
ꢁ
ꢁ
same temperature. Then the mixture was warmed up to -25 C, ꢃ10 C and stirred
ꢁ
for another 2 h, respectively. After stirred overnight at 0 C, methanol (5 ml) was
added dropwise at -45 C to quench the reaction. The solution was diluted with
ꢁ
1
20 ml ethyl acetate, washed with water, dried over anhydrous Na SO , and evapo-
2 4
rated under reduced pressure to afford a red residue, which was then purified
through silica gel column chromatography (dichloromethane: MeOH ¼ 50: 1, v/v) to
1
afford compound 14 as a white amorphous powder (104.3 mg, 56.7%). H NMR
(
500 MHz, CD OD) d 7.61 (d, J ¼ 1.6 Hz, 1H), 7.56 (d, J ¼ 8.8 Hz, 2H), 7.53 (d,
3
J ¼ 1.7 Hz, 1H), 7.49 (d, J ¼ 8.5 Hz, 1H), 7.23 (d, J ¼ 16.2 Hz, 1H), 7.04 (d, J ¼ 16.2 Hz,
1
6
(
1
1
H), 6.80 (d, J ¼ 8.7 Hz, 2H), 6.72 (d, J ¼ 2.2 Hz, 2H), 6.47 (d, J ¼ 2.2 Hz, 2H), 6.37 -
13
.39 (m, 2H), 3.81 (s, 6H). C NMR (125 MHz, CD OD) d 162.5 (2 ꢂ C), 160.2
3
2 ꢂ C), 159.2, 154.9, 152.9, 141.1, 136.0, 133.9, 132.1, 130.5, 129.7 (2 ꢂ C), 128.6,
24.1, 123.2, 118.7, 116.8, 116.3 (2 ꢂ C), 111.9, 109.2 (2 ꢂ C), 105.4 (2 ꢂ C), 103.0,
þ
00.7, 55.8. (þ)-HRESIMS: m/z 481.1647 [M þ H] (calcd for C H O , 481.1646).
30
25 6
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
The work was financially supported by the National Natural Science Fund of China (NNSFC
1630094), the CAMS Innovation Fund for Medical Sciences (CIFMS 2016-I2M-2-002), and
8
the Drug Innovation Major Project (2018ZX09711-001-005 and 2018ZX09711001-001-003).
References
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