Regioselective Biomimetic Synthesis of Dimeric Oxyresveratrol Derivatives

Article abstract of DOI:10.1055/s-0040-1707257

Oxyresveratrol and its methylated derivative as coupling precursors were efficiently prepared in four steps, with Wittig reactions and subsequent isomerization reactions as the key steps. The coupling reactions of oxyresveratrol under various oxidative conditions gave a complex and inseparable mixture of coupling products. The oxidative dimerizations of methylated oxyresveratrols catalyzed by horseradish peroxidase-H ₂O ₂or FeCl ₃·6H ₂O in an acetone system predominantly produced the 8-5-coupled and 8-10-coupled dihydrobenzofuran-type dimers, respectively. This regioselective biomimetic strategy might be useful in synthesizing other dimeric oxyresveratrol derivatives.

Full text of DOI:10.1055/s-0040-1707257

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2
020, 31, A–D
letter
A
en
Synlett
L. Ran et al.
Letter
Regioselective Biomimetic Synthesis of Dimeric Oxyresveratrol
Derivatives
Lu Ran
HO
OMe
Hongpeng Li
Ge Chao
O
OMe
2 2
HRP–H O
OH
HO
Xiaodong Kang
Tian Lei
Wenling Li*
acetone–H O
2
OH
62%
OH
–5-coupling dimer
OMe
8
OH
HO
OMe
O
School of Chemical and Biological Engineering,
Lanzhou Jiaotong University, Lanzhou 730070,
P. R. of China
FeCl ·6H O
3
2
OH
HO
OH
acetone
5%
liwl@mail.lzjtu.cn
HO
4
OH
OMe
Corresponding Author
WSe Mc he ano i ol i nl i ogw f Ll C@i h me ma i li .cl az lj t au n. cd nBiological Engineering, Lanzhou Jiaotong University, Lanzhou 730070, P. R. of China
8
–10-coupling dimer
OH
Received: 08.07.2020
Accepted: 03.08.2020
Published online: 01.09.2020
DOI: 10.1055/s-0040-1707257; Art ID: st-2020-k0389-l
Three routes are available for the construction of the
trans-double bond in monomer 2: palladium-catalyzed
5
Heck coupling, as reported by Li’s group; Perkin condensa-
6
tion, as conducted by Zou and co-workers, or a Wittig reac-
Abstract Oxyresveratrol and its methylated derivative as coupling
precursors were efficiently prepared in four steps, with Wittig reactions
and subsequent isomerization reactions as the key steps. The coupling
reactions of oxyresveratrol under various oxidative conditions gave a
complex and inseparable mixture of coupling products. The oxidative
dimerizations of methylated oxyresveratrols catalyzed by horseradish
peroxidase–H O or FeCl ·6H O in an acetone system predominantly
7a
7b
tion, as performed by Lee et al. and by Reimann. Process-
es for the synthesis of the natural oligomers of 2 have been
rarely reported, apart from an acid-catalyzed dimerization
OH
2
2
3
2
produced the 8–5-coupled and 8–10-coupled dihydrobenzofuran-type
dimers, respectively. This regioselective biomimetic strategy might be
useful in synthesizing other dimeric oxyresveratrol derivatives.
HO
HO
OH
OH
5
O
R
7
OH
8
Key words oxyresveratrol, biomimetic synthesis, oligostilbenes, oxi-
OH
10
dative coupling, dimerization, regioselectivity
OH
HO
OH
R = H, resveratrol (1)
R = OH, oxyresveratrol (2)
gnetumontainin A (3)
Oxyresveratrol (2; Figure 1), as a 2-hydroxy-substituted
derivative of resveratrol (1), is found in the roots, leaves,
stems, and fruits of the widely distributed plant families,
HO
OH
OH
OH
1
including Moraceae, Liliaceae, and Gnetaceae, in China. It
O
OH
HO
possesses wide-ranging pharmacological properties, in-
cluding antiherpetic, anti-HIV, antiinflammatory, antioxi-
dative, antiapoptotic, and neuroprotective activities, as well
OH
HO
OH
OH
OH
OH
as strong skin-depigmenting effects, because it is similar to
OH
HO
2
HO
1
in structure. Oxyresveratrol (2) also shows potential in
artogomezianol (4)
parvifolol C (5)
the production of medicines, cosmetics, and health supple-
ments because of its low toxicity and good water solubility.
However, the scarcity and high cost of extracting 2 and its
oligomers have greatly restricted investigations on their
structure–activity relationships and on their further devel-
opment and application. Chemical synthesis is an effective
way to solve the scarcity of 2 and its oligomers. However,
HO
OH
OMe
OH
MeO
OMe
HO
MeO
OH
OH
OMe
OMe
OH
OMe
MeO
OH
alboctalol (6)
3
efforts to synthesize 2 and its natural dimers, such as 3–6,
7
have been scarce in comparison with those for 1 and its
oligomers.
4
Figure 1 Oxyresveratrol (2) and several representative dimers 3–7
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
L. Ran et al.
Letter
of tetramethylated oxyresveratrol for the preparation of the
octamethyl ether of alboctalol (6) in 6% yield and a multi-
step chemical transformation for the assignment of the
terns or that subsequent intramolecular cyclizations of cou-
pling intermediates occurred, considerably increasing the
structural complexity of the coupling products. We there-
fore attempted to protect the C-2 hydroxy group of 2 selec-
tively to enhance regioselective control of its oxidative cou-
pling reaction by using oxyresveratrol 2-methyl ether (15)
as a coupling precursor.
The synthetic route to 15 is shown in Scheme 2. Com-
mercially available 2-methoxy-4-hydroxybenzaldehyde
(12) was benzylated to give aldehyde 13. Wittig reaction of
benzaldehyde 13 with phosphonium salt 10 in refluxing
toluene afforded an isomeric mixture of (Z)-14 and (E)-14
in 91% yield. The mixture was then treated with (PhS)2–
AIBN in THF to give (E)-14 in 86% yield. The target precursor
8
configuration of dimer 7. Difficulties encountered in the
syntheses of oligomers of 2 are due to a lack of general regio-
selective methods. To explore the biomimetic synthesis of
oligostilbenes and to prepare natural stilbene dimers, we
prepared the precursor 2 and its derivatives, and we ex-
plored their coupling reactions under various oxidative
conditions. Several oxyresveratrol dimers were synthe-
9
sized.
Our study began with the preparation of oxyresveratrol
(
2; Scheme 1). First, 2,4-dihydroxybenzaldehyde (8) as a
starting material was protected with benzyl groups to give
aldehyde 9. Phosphonium salt 10 was prepared according to
a previously reported procedure.10 The key Wittig reaction
between aldehyde 9 and phosphonium salt 10 in refluxing
toluene for 12 hours gave a 74% yield of mixture of (Z)-11
and (E)-11 in a 1:1 molar ratio. Isomers (Z)-11 and (E)-11
were obtained in 2:9 molar ratio and an 88% yield when the
reaction was conducted in dry tetrahydrofuran (THF) at
room temperature for six hours. The resulting mixture of
stilbenes 11 was subjected to isomerization in the presence
of (MeCN) PdCl in dichloromethane at room temperature
15 was synthesized in 90% yield through AlCl -promoted
3
14
debenzylation of 14.
OH
OBn
1) 10, n-BuLi
toluene, reflux
BnCl, K
OMe DMF, reflux
3%
2 3
CO
9
1%
OMe 2) Ph2S , AIBN
2
9
THF, reflux
CHO
CHO
86%
1
2
13
OBn
OH
2
2
for 24 hours to afford (E)-11 in 65% yield.11 The yield of (E)-
1 increased to 90% when the isomerization was performed
OMe
OMe
AlCl
3
, PhNMe
2
1
DCM, r.t.
90%
with the (PhS) –azodiisobutyronitrile (AIBN)–THF system
2
at the reflux for eight hours.12 Finally, the desired monomer
BnO
OBn
HO
OH
2
was synthesized in 85% yield through global debenzyla-
(
E)-14
15
tion (E)-11.
Scheme 2 Synthetic route to precursor 15
2 3
CH PPh Cl
OH
OBn
Oxidative coupling of monomer 15 was initially carried
BnCl, K
2 3
CO
BnO
OBn
out by using HRP–H O in an acetone–water system
2
2
10
DMF, reflux
OH
OBn
(Scheme 3). Dominant coupling between the radicals M8
n-BuLi, toluene, reflux
9
5%
CHO
CHO
or 10, n-BuLi, THF, r.t.
and M gave a quinone intermediate, that underwent se-
5
8
9
quential intramolecular cyclization and rearrangement to
OBn
15
OBn
give the dihydrobenzofuran-type dimer 16 in 62% yield.
Direct demethylation of 16 to give the target compound 17
did not proceed because of the insolubility of 16 in a BBr3–
dichloromethane system. Moreover, an attempt at global
acetylation of 16 and sequential deacetylation and demeth-
ylation in one pot for the preparation of 17 was fruitless
owing to the formation of a complex product mixture con-
taining a small amount of dimer 16.
OBn
OBn
(
MeCN)
2
PdCl
2
(II), DCM, r.t.
AlCl3, PhNMe
2
2
or Ph
2
S
2
, AIBN, THF, reflux
DCM, r.t.
85%
BnO
OBn
BnO
OBn
(
Z)-11 + (E)-11
(E)-11
Scheme 1 Preparation of stilbene 2
Subsequently, oxidation of precursor 15 by FeCl ·6H O
3
2
in acetone at room temperature gave 8–10-coupled dihyd-
1
6
Next, the oxidative coupling reactions of 2 were con-
ducted under various oxidative conditions. However, a com-
plex mixture of products rapidly formed regardless of
whether we used horseradish peroxidase (HRP) and H O in
robenzofuran 18 (Scheme 4). The yield of 18 was largely
influenced by the amount of oxidant and the reaction time.
Dimer 18 was isolated in 45% yield as the major coupling
product by using 3.5 equivalents of FeCl ·6H O and allowing
2
3
2
3
2
1
aqueous acetone or a FeCl ·6H O–acetone system. The
the coupling reaction to proceed for ten hours.
3
2
complex product was isolated and characterized. We specu-
lated that the reactive phenolic oxygen atom at the C-2 po-
sition in monomer 2 was involved in various coupling pat-
In conclusion, the efficient syntheses of 2 and stilbene
15 were accomplished by using a Wittig reaction of the pro-
tected benzaldehyde 9 or 13, respectively, with phosphoni-
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
Synlett
L. Ran et al.
Letter
um salt 10 as a key step. The direct oxidation of precursor 2
promoted by various catalysts invariably led to the produc-
tion of a complex product mixture, possibly because of the
involvement of the reactive hydroxy group at C-2. Oxidative
dimerization of monomer 15 by HRP–H O in aqueous ace-
uct. These results showed that selective protection of the 2-
hydroxy group in 2 substantially improves the regioselec-
tivity of the oxidative coupling reactions of stilbene 15. This
biomimetic strategy might be applicable to the synthesis of
other oligomers of 2; this work is currently ongoing in our
laboratory.
2
2
tone afforded the 8–5-coupled dihydrobenzofuran 16 mod-
erate yield, whereas the oxidative coupling of 15 by Fe-
Cl ·6H O gave the 8–10-coupled dimer 18 as the main prod-
3
2
Funding Information
O
OMe
O
OMe
This research work was financially supported by the National Natural
Science Foundation of China (No. 21462024).Natio
n
al Natural Science Fo
u
n
d
ati
o
n
o
f
C
h
ina(2
1
4
6
2
0
2)
HRP–H
2
O
2
HO
1
5
OH
acetone–H
2
O
Supporting Information
OH
M8
OH
M5
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707257. Su
p
p
orting Inform atio
n
Su
p
p
orting Inform atio
n
O
OMe
O
OMe
cyclization
References and Notes
HO
H
OH
(
1) (a) Hu, S. T.; Zheng, Z. P.; Zhang, X. C.; Chen, F.; Wang, M. F.
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Huang, X. Int. J. Pharmacol. 2014, 10, 44.
OH
OH
HO
HO
OMe
O
OMe
(
2) (a) Aftaba, N.; Likhitwitayawuid, K.; Vieira, A. Nat. Prod. Res.
2
010, 24, 1726. (b) Chatsumpun, N.; Chuanasa, T.; Sritularak, B.;
6
2%
OH
Lipipun, V.; Jongbunprasert, V.; Ruchirawat, S.; Ploypradith, P.;
Likhitwitayawuid, K. Molecules 2016, 21, 489. (c) Galindo, I.;
Hernáez, B.; Berná, J.; Fenoll, J.; Cenis, J. L.; Escribano, J. M.;
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Sornsute, A.; Sritularak, B.; Ploypradith, P. Bioorg. Med. Chem.
Lett. 2006, 16, 5650.
OH
HO
1
6
OH
OH
OH
O
1
) Ac
2
O, pyridine
HO
2
) BBr
3
, DCM, r.t.
OH
(
(
3) (a) Likhitwitayawuid, K.; Sritularak, B. J. Nat. Prod. 2001, 64,
1457. (b) Choa, H. M.; Haa, T. K. Q.; Phama, H. T. T.; Ana, J.-P.;
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OH
1
7
OH
1
65, 112044. (c) Tanaka, T.; Iliya, I.; Ito, T.; Furusawa, M.;
Scheme 3 HRP–H O -mediated oxidative dimerization of monomer 15
2
2
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4
2
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O
OMe O
OH
4) For reviews, see: (a) Sotheeswaran, S.; Pasupathy, V. Phytochem-
istry 1993, 32, 1083. (b) Lin, M.; Yao, C.-S. Stud. Nat. Prod. Chem.
FeCl3·6H
acetone
2
O
cyclization
HO
1
5
2
006, 33, 601. (c) Shen, T.; Wang, X.-N.; Lou, H.-X. Nat. Prod.
OMe
Rep. 2009, 26, 916. (d) Quideau, S.; Deffieux, D.; Douat-Casas-
sus, C.; Pouységu, L. Angew. Chem. Int. Ed. 2011, 50, 586.
(e) Snyder, S. A.; ElSohly, A. M.; Kontes, F. Nat. Prod. Rep. 2011,
OH
M8
M10
OH
2
8, 897. (f) Synder, S. A. Recent Adv. Polyphenol Res. 2012, 3, 311.
HO
OMe
(g) Velu, S. S.; Thomas, N. F.; Weber, J. F. Curr. Org. Chem. 2012,
O
OMe
1
2
6, 605. (h) Li, W. L.; Zang, P.; Li, H. F.; Yang, S. X. Prog. Chem.
012, 24, 545. (i) Li, W.; Lv, T.; Yang, Y.; Yang, Y. Youji Huaxue
O
OH
O
OH
HO
HO
2013, 33, 2443. (j) Keylor, M. H.; Matsurra, B. S.; Stephenson, C.
R. J. Chem. Rev. 2015, 115, 8976. (k) Wang, X.-F.; Yao, C.-S. J.
Asian Nat. Prod. Res. 2016, 18, 376.
H
4
5%
OH
OMe
OH
OMe
(
5) Li, Z.; Kang, S.; Chen, L.; Wang, Y.; Li, J. Youji Huaxue 2016, 36,
1
143.
18
OH
OH
(6) (a) Sun, H.-Y.; Xiao, C.-F.; Wei, W.; Chen, Y.; Lü, Z.-L.; Zou, Y.
Youji Huaxue 2010, 30, 1574. (b) Sun, H.-Y.; Xiao, C.-F.; Cai, Y.-C.;
Scheme 4 FeCl ·6H O-induced oxidative dimerization of precursor 15
3
2
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
Synlett
L. Ran et al.
Letter
Chen, Y.; Wei, W.; Liu, X.-K.; Lv, Z.-L.; Zou, Y. Chem. Pharm. Bull.
010, 58, 1492.
7) (a) Lee, S. K.; Nam, K. A.; Hoe, Y. H.; Min, H.-Y.; Kim, E.-Y.; Ko, H.;
(15) 5-{(E)-2-[3-(3,5-Dihydroxyphenyl)-2-(4-hydroxy-2-
2
methoxyphenyl)-6-methoxy-2,3-dihydro-1-benzofuran-5-
yl]ethenyl}benzene-1,3-diol (16)
(
1
Song, S.; Lee, T.; Kim, S. Arch. Pharm. Res. 2003, 26, 253.
Yellowish amorphous powder; yield: 31 mg (62%). H NMR (500
(
b) Reimann, E. Tetrahedron Lett. 1970, 4051.
MHz, acetone-d ):  = 3.77 (s, 3 H), 3.94 (s, 3 H), 4.36 (d, J = 5.0
6
(
8) (a) Bates, R. B.; Caldera, S.; Deshpande, V. H.; Malik, B. L.;
Paknikar, S. K. J. Nat. Prod. 1997, 60, 1041. (b) Alesso, E. N.;
Finkielsztein, L. M.; Lantaño, B.; Aguirre, J. M.; Iglesias, G. Y. M. J.
Chem. Res., Synop. 1999, 23, 302.
Hz, 1 H), 5.73 (d, J = 5.0 Hz, 1 H), 6.21 (d, J = 2.0 Hz, 2 H), 6.23 (t,
J = 2.0 Hz, 1 H), 6.24 (t, J = 2.0 Hz, 1 H), 6.40 (dd, J = 8.5, 2.0 Hz, 1
H), 6.50 (d, J = 2.0 Hz, 2 H), 6.52 (d, J = 2.0 Hz, 1 H), 6.64 (d, J =
2.0 Hz, 1 H), 6.84 (d, J = 16.5 Hz, 1 H), 7.12 (d, J = 8.5 Hz, 1 H),
7.32 (d, J = 2.0 Hz, 1 H), 7.35 (d, J = 16.5 Hz, 1 H), 8.15 (br s, 2 H),
(9) (a) Li, W.; Li, H.; Luo, Y.; Yang, Y.; Wang, N. Synlett 2010, 1247.
(b) Li, W.; Luo, Y.; Li, H.; Zang, P.; Han, X. Synthesis 2010, 3822.
c) Li, W.; Yang, S.; Lv, T.; Yang, Y. Org. Biomol. Chem. 2014, 12,
8.16 (br s, 2 H), 8.46 (br s, 1 H). 13C NMR (125 MHz, acetone-d ):
6
(
 = 55.7, 56.2, 89.8, 94.3, 100.0, 102.0, 102.5, 105.5, 105.6 (2 C),
2273. (d) Yang, Y.; Liu, Q.; Chen, P.; Li, W. Tetrahedron Lett. 2014,
107.0, 107.1 (2 C), 107.6, 119.8, 121.2, 122.9 (2 C), 123.4, 123.9,
5
5, 4455. (e) Li, W.; Chen, P.; Yang, Y.; Liu, X.; Dong, T. Tetrahe-
126.8, 128.1, 141.4, 147.2, 159.0, 159.1, 159.5, 159.6 (2 C),
+
dron 2016, 72, 210. (f) Li, W.; Dong, T.; Chen, P. L.; Liu, X.; Liu,
M.; Han, X. Tetrahedron 2017, 73, 3056. (g) Liu, M.; Guan, X.;
Shao, Z.; Li, W. Tetrahedron 2018, 74, 4013. (h) Guan, X.; Liu, M.;
Shao, Z.; Li, H.; Ran, L.; Li, W. Synthesis 2019, 51, 1825.
162.2. HRMS (ESI): m/z [M – H] calcd for C30H25O : 513.15549;
8
found: 513.15547.
(16) 5-{6-Hydroxy-2-(4-hydroxy-2-methoxyphenyl)-5-[(E)-2-(3-
hydroxy-5-methoxyphenyl)ethenyl]-2,3-dihydro-1-benzofu-
ran-3-yl}benzene-1,3-diol (18)
(
(
(
(
10) Li, W.; Li, H.; Li, Y.; Hou, Z. Angew. Chem. Int. Ed. 2006, 45, 7609.
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13) (a) Correa, A.; Mancheño O, G.; Bolm, C. Chem. Soc. Rev. 2008,
1
Yellowish amorphous powder; yield: 15 mg (45%). H NMR (500
MHz, acetone-d ):  = 3.76 (s, 3 H), 3.83 (s, 3 H), 4.36 (d, J = 5.0
6
Hz, 1 H), 5.67 (d, J = 5.0 Hz, 1 H), 6.20 (dd, J = 8.5, 2.0 Hz, 1 H),
6.26 (d, J = 2.0 Hz, 2 H), 6.34 (dd, J = 8.0, 2.0 Hz, 1 H), 6.36 (d, J =
2.0 Hz, 2 H), 6.41 (d, J = 2.0 Hz, 1 H), 6.51 (d, J = 2.0 Hz, 1 H), 6.68
(d, J = 2.0 Hz, 1 H), 6.76 (d, J = 16.5 Hz, 1 H), 7.05 (d, J = 8.0 Hz, 1
3
7, 1108. (b) Bauer, I.; Knölker, H.-J. Chem. Rev. 2015, 115, 3170.
14) 5-[(E)-2-(4-Hydroxy-2-methoxyphenyl)ethenyl]benzene-
,3-diol [(E)-15]
(
1
1
13
Pale-yellow oil; yield: 1.77 g (91%). H NMR (500 MHz, acetone-
d6):  = 3.85 (s, 3 H), 6.24 (t, J = 2.0 Hz, 1 H), 6.46 (dd, J = 8.5, 2.0
Hz, 1 H), 6.49 (d, J = 2.0 Hz, 1 H), 6.52 (d, J = 2.0 Hz, 2 H), 6.88 (d,
J = 16.5 Hz, 1 H), 7.30 (d, J = 16.5 Hz, 1 H), 7.45 (d, J = 8.5 Hz, 1
H), 7.15 (d, J = 16.5 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1 H). C NMR
(125 MHz, acetone-d ):  = 55.6, 55.7, 55.8, 89.1, 99.7, 99.8,
6
103.9, 107.0, 107.3, 108.3, 118.6, 120.1, 122.3, 123.8, 125.3,
125.6, 127.2, 127.8, 128.1, 128.4, 137.2, 148.1, 151.9, 158.5 (2
C), 159.3 (2 C), 159.5, 162.8 (2 C). HRMS (ESI): m/z [M – H]+
1
3
H), 8.16 (br s, 2 H), 8.51 (br s, 1 H). C NMR (125 MHz, acetone-
d6):  = 55.8, 99.8, 99.9, 102.4, 105.5 (2 C), 108.5, 118.7, 123.9,
1
calcd for C30H25O : 513.15549; found: 513.15546.
8
26.8, 127.9, 141.5, 159.2, 159.5, 159.6. HRMS (ESI): m/z [M –H]+
calcd for C15H13O : 257.08193; found: 257.08191.
4
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–D