Oxidative cross-coupling approach to the biomimetic synthesis of the heterodimers of resveratrol and isorhapontigenin

Article abstract of DOI:10.1016/j.tetlet.2020.152239

The regioselective oxidative cross-coupling reactions of two different stilbene precursors catalyzed by FeCl₃ or horseradish peroxidase-H₂O₂ in acetone solvent produced three dihydrobenzofuran-type heterodimers. The reductive debrominations of these cross-coupled dimers synthesized two heterodimers of resveratrol and isorhapontigenin, an analogue of (±)-scirpusin A and (±)-gnetuhainin Q.

Full text of DOI:10.1016/j.tetlet.2020.152239

Journal Pre-proofs
Oxidative cross-coupling approach to the biomimetic synthesis of the hetero‐
dimers of resveratrol and isorhapontigenin
Hongpeng Li, Lu Ran, Meijie Liu, Tian Lei, Xiaodong Kang, Wenling Li
PII:
S0040-4039(20)30706-1
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152239
TETL 152239
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
29 January 2020
2 July 2020
9 July 2020
Please cite this article as: Li, H., Ran, L., Liu, M., Lei, T., Kang, X., Li, W., Oxidative cross-coupling approach to
the biomimetic synthesis of the heterodimers of resveratrol and isorhapontigenin, Tetrahedron Letters (2020),
doi: https://doi.org/10.1016/j.tetlet.2020.152239
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version
will undergo additional copyediting, typesetting and review before it is published in its final form, but we are
providing this version to give early visibility of the article. Please note that, during the production process, errors
may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Elsevier Ltd. All rights reserved.

Graphical Abstract
Oxidative Cross-Coupling Approach to the Biomimetic
Synthesis of the Heterodimers of Resveratrol and
Isorhapontigenin
Leave this area blank for abstract info.
Hongpeng Li, Lu Ran, Meijie Liu, Tian Lei, Xiaodong Kang, Wenling Li*
School of Chemical and Biological Engineering, Lanzhou Jiaotong University, Lanzhou, 730070, China
OMe
HO
O
OH
HO
1) FeCl3 acetone
OH
OH
2) debromination
OMe
Br
OH
scirpusin A analogue
+
OH
OMe
HO
HO
OH
OH
HO
O
1) HRP-H2O2 acetone
OH
HO
2) debromination
OH
OH
gnetuhainin Q

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Oxidative Cross-Coupling Approach to the Biomimetic Synthesis of the
Heterodimers of Resveratrol and Isorhapontigenin
Hongpeng Li, Lu Ran, Meijie Liu, Tian Lei, Xiaodong Kang, Wenling Li*
School of Chemical and Biological Engineering, Lanzhou Jiaotong University, Lanzhou, 730070, China
ARTICLE INFO
ABSTRACT
The regioselective oxidative cross-coupling reactions of two different stilbene precursors
catalyzed by FeCl3 or horseradish peroxidase-H2O2 in acetone solvent produced three
dihydrobenzofuran-type heterodimers. The reductive debrominations of these cross-coupled
dimers synthesized two heterodimers of resveratrol and isorhapontigenin, an analogue of (±)-
scirpusin A and (±)-gnetuhainin Q.
Article history:
Received
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Resveratrol
Isorhapontigenin
Oxidative cross-coupling
Biomimetic synthesis
———
*Corresponding author. Tel.: +86 0931 4938 755; Fax: +86 0931 4938 755; E-mail: liwl@mail.lzjtu.cn.

2
Tetrahedron Letters
1. Introduction
resveratrol (8) or 5-bromo-isorhapontigenin (9) in acetone
followed by the debromination of the dimer 10 or 11 (Scheme
1).7f,7h Based on this result, we primarily selected the brominated
stilbenes 8 and 9 as the coupling precursors to conduct the
Natural oligostilbenes are a special group of plant polyphenols
possessing complex structures and diverse biological activities.1
Among them are more than 300 homooligomers of stilbene units
including resveratrol (1), isorhapontigenin (2), piceatannol (3)
and oxyresveratrol (4); and tens of novel oligomers polymerized
from the different monomers, such as the heterodimer 5−7
(Figure 1).2 Many chemists have focused on synthesizing these
natural polyphenolic products over the past four decades.3
Notably, the resveratrol oligomers with diverse skeletons were
efficiently constructed via traditional biomimetic oxidations or
well-designed chemical transformations.4 However, little
attention has been given to the heterooligomers of different
stilbenes, and few synthetic efforts toward them have been
reported thus far. Although the oxidative coupling reactions of
the hetero-monomers were known the most concise approach to
the diverse structures of heterooligomers, this strategy was
mostly applied in the biomimetic synthesis of lignans and
stilbenolignans.5 Only Lin et al. in 2006 conducted the
FeCl3·6H2O-catalyzed oxidative cross-coupling reaction of
stilbenes 1 and 2 in acetone and identified nine oligomeric
products, including two homodimers and seven heterooligomers
without definite isolated yields indicated.1b In addition, Queiroz’s
team investigated the enzyme-mediated biotransformation of the
mixture of 1 and pterostilbene and isolated five homodimers and
four heterodimers.6 These findings revealed the considerable
challenge in the efficient synthesis of heterodimers, such as 5–7,
due to the lack of regioselective control in the oxidative cross-
coupling reactions of stilbenes.
oxidative cross-coupling reaction.
R
OH
HO
Br
R
O
OH
Br
FeCl3 6H2O
HO
acetone
OH
OH
HO
R
Br
R = Br, 10
R =OMe, 11
OH
R = Br, 8
R =OMe, 9
R
HO
HO
O
OH
LiAlH4
THF
OH
R
OH
R = H,
-viniferin (12)
R =OMe, bisisorhapontigenin A (13)
Scheme 1. Synthesis of oligostilbenes from the oxidative coupling of
precursor 8 or 9
When the FeCl3·6H2O-oxidized cross-coupling reaction of
monomer 8 and 9 (molar ratio 1:1) was performed in acetone, 9
was quickly consumed, and the 8-10-coupled homodimer 11 was
formed as major product. The amount of dimer 10 was gradually
increased with prolonged time, and almost no heterodimer was
found in the reaction mixture. As such, the reactivity of 9 is
higher than that of 8 in the same oxidative system. The coupling
reaction condition was constantly optimized to enhance the
possibility of cross-coupling pattern. A small amount of 8-10-
coupled heterodimer 14 was finally found in the product mixture
when twice equivalent amount of 9 was slowly added in batch to
the acetone solution of FeCl3·6H2O and 8 (Scheme 2). Although
the low yield of 14 (<11%) and the difficulty in the isolation and
purification because of the similar polarity of 14 with 11
restricted its further application, the formation of 14 implied the
potential of the oxidative cross-coupling strategy for the
synthesis of the heterodimers.
OMe
OH
HO
O
HO
OH
OH
HO
R1
R1= R2= H, resveratrol (1)
R2
OH
OH
OH
R1= OMe, R2= H, isorhapontigenin (2)
R1= OH, R2= H, piceatanol (3)
R1= H, R2= OH, oxyresveratrol (4)
gnetuhainin Q£¨5£©
OH
HO
HO
HO
OH
O
OH
O
HO
OH
O
OH
Br
R
O
OH
OH
scirpusin A (6)
gnetuhainins A (7)
OH
10
FeCl3 6H2O
Figure 1. Natural stilbenes and several representative heterodimers
8
9
8
+
acetone
r.t., 48 h
Given the high interest in the biomimetic synthesis of
oligostilbenes, our group have efficiently prepared tens of
homodimers of 1 and 2 through their regioselective oxidative
coupling reactions under varied oxidative conditions.7 The
introduction of the positional protecting groups such as tert-butyl
group or halogen atoms into the stilbene precursors significantly
improved the coupling yields of 8-8-coupled or 8-10-coupled
products. Based on this efficient synthetic strategy, this work
aimed to explore the oxidative cross-coupling reactions of two
different stilbenes to synthesize several heterooligomers of 1 and
2.
HO
OH
R
Br
OH
M8
M10
R =OMe, or Br
OMe
HO
O
OH
Br
HO
+
10
11
+
OH
14
2. Results and Discussion
Br
Br
OH
38% isolated yield
(molar ratio of 10: 11: 14 =1:6:3)
We recently synthesized natural (±)-ε-viniferin (12) and (±)-
bisisorhapontigenin A (13) through the FeCl3·6H2O-catalyzed
regioselective oxidative coupling reaction of 3,5-dibromo-
Scheme 2. FeCl3▪6H2O-oxidized cross-coupling reaction of stilbenes
8 and 9

3
In view of the significant difference of stilbenes 1 and 9 in the
structure and reactivity, they were used as the coupling
precursors to perform the cross-coupling reaction (Scheme 3).
However, the coupling dimerization of 9 to 11 was achieved
under FeCl3-promoted or FeCl3·6H2O-catalyzed condition; the
oxidation of 1 to 12 proceeded smoothly only in FeCl3-acetone
system. Thus, the FeCl3-catalyzed cross-coupling reaction of 1
and 9 was conducted in anhydrous acetone solvent. The yield of
the expected 8-10-coupled heterodimer 15 was largely influenced
by the molar ratio and the addition sequence of two precursors, as
well as the amount of FeCl3 oxidant. We continuously optimized
the reaction condition to increase the coupling yield of
heterodimer 15. We found when six equivalents of FeCl3 was
added to acetone solution of 1 and 9 (molar ratio 1.5:1) and the
reaction continued for 4 hr until 9 was completely consumed, the
heterodimer 15 with 43% maximum yield and the homodimer 12
with 13% yield were isolated. Only a trace amount of 11 was
formed in the reaction mixture.
O
R1
R2
O
5
HRP-H2O2
8
OH
9
1
+
acetone-H2O
r.t., 1 h
HO
OH
OH
M5
M8
R1 = R2 = H, 1
R1 =OMe, R2 = Br, 9
HO
HO
OMe
HO
O
O
OH
+
Br
HO
OH
OH
OH

-viniferin (16)
(44% yield)
OH
17
OH
(42% yield)
O
R1
R2
Scheme 4. HRP-H2O2-promoted cross-coupling products of stilbenes
1 and 9
O
OH
FeCl3
10
1
9
+
8
With the heterodimeric intermediates 14, 15 and 17 in hand,
we attempted to remove their protecting groups for the synthesis
of several natural oligostilbenes. As shown in scheme 5, the
LiAlH4-catalyzed reductive debromination reactions of dimer 14
or 15 smoothly gave rise to unnatural product 18 with 70% or
75% yields. The subsequent direct demethylation of 18 for the
synthesis of natural scirpusin A (6) did not proceed because of
the insolubility of 18 in the BBr3-dichloromethane system.2d The
global acetylation of 18 followed by the deacetylation and
demethylation in one-pot finally led to the complex and
inseparable product mixture. The natural (±)-gnetuhainin Q (5)
was firstly synthesized by the debromination of 17 under the
LiAlH4-THF reductive condition.2e
acetone
r.t., 4 h
HO
OH
M8
R1 = R2 = H, 1
OH
M10
R1 =OMe, R2 = Br, 9
OMe
HO
O
OH
Br
HO
+
12
(13% yield)
OH
OH
OMe
15
HO
HO
(43% yield)
OH
O
OH
O
OH
HO
Scheme 3. FeCl3-catalyzed cross-coupling products of monomers 1
and 9
LiAlH4
HO
1) Ac2O, Pyrinde
2) BBr3, DCM
14 or 15
THF, r.t.
OH
70% or 75% yield
OH
The formation of the 8-10-coupled heterodimer 14 or 15 in the
ferric chloride-oxidized cross-coupling reactions verified the
higher reactivity of the M8 radical mesomer of stilbene 9 in
comparison to that of 1 or 8, which preferentially participated in
the cross-coupling dimerizations under the optimized reaction
conditions. Based on the above results and our previous
achievements on the enzyme-mediated coupling reactions of 1 or
9,7e,7g we explored the oxidative cross-coupling reaction of 1 and
18
scirpusin A (6)
OH
OH
OMe
HO
O
LiAlH4
17
OH
HO
THF, r.t.
73.5% yield
9
under the horseradish peroxidase (HRP)-H2O2-catalyzed
OH
OH
condition (Scheme 4).
gnetuhainin Q (5)
In the aqueous acetone solution of HRP-H2O2 and equivalent
amounts of coupling precursors, the oxidation of 1 was obviously
faster than that of 9 and mostly produced the homodimer of 1, δ-
viniferin (16) and small amount of 8-5-coupled heterodimer 17.
Under the most optimum reaction condition, 1.5 equivalents of 1
and 3% H2O2 was added dropwise into the reaction mixture
within 40 min and the reaction continued for 1 hr at room
temperature utill two precursors disappeared, the homodimer 16
with 44% yield, heterodimer 17 with 42% maximum yield, and a
small quantity of the homodimer 11 were isolated from the
product mixture. The results confirmed that the yield of
heterodimer 17 can be effectively increased by the optimization
of the molar ratio and addition sequence of precursors 1 and 9.
Scheme 5. Reductive debromination products of heterodimers 14, 15
or 17
In summary, we explored the biomimetic cross-coupling
reactions of two different stilbene monomers under several
oxidative conditions. The key to the regioselective synthesis of
heterodimers 14, 15 or 17 lies in the significant difference in the
reactivity of brominated isorhapontigenin 9 and resveratrol (1) or
brominated resveratrol 8 in the same oxidative system and the
appropriate molar ratios and addition sequences of two coupling
precursors. The formation of 8-10-coupled dimer 15 or 8-5-
coupled product 17 with moderate yield under the optimized

4
Tetrahedron Letters
FeCl3- or HRP-H2O2-catalyzed reaction condition confirmed
that this strategy is practicable for the regioselective synthesis of
the heterodimeric stilbenes. The scirpusin A (6) analogue, 18,
and (±)-gnetuhainin Q (5) were firstly synthesized by the
reductive debromination reactions of heterodimers 14, 15 or 17.
The application of this regioselective biomimetic strategy for the
preparation of other natural stilbene heterooligomers is ongoing
in our laboratory.
Acknowledgements
This research work was financially supported by the National
Natural Science Foundation of China (No. 21462024).
References and Notes
1
For the reviews, see: (a) Sotheeswaran, S.; Pasupathy, V. Phytochemistry
1993, 32, 1083-1092; (b) Lin, M.; Yao, C. S. Stud. Nat. Prod. Chem. 2006,
33, 601-644; (c) Shen, T.; Wang, X.-N.; Lou, H.-X. Nat. Prod. Rep. 2009,
26, 916-935; (d) Quideau, S.; Deffieux, D.; Douat-Casassus, C.; Pouysegu,
L. Angew. Chem., Int. Ed. 2011, 50, 586-621.
2
(a) Huang, K.-S., Wang ,Y.-H., Li, R. –L.; Lin, M. J. Nat. Prod. 2000, 63,
86-89; (b) Li, X. M.; Wang, Y. H.; Lin, M. Chin. Chem. Lett. 2001, 12,
611-612; (c) Syaha, Y. M.; Achmada, S. A.; Ghisalbertib, E. L.; Hakima,
E. H.; Makmura, L.; Soekamtoa, N. H. J. Chem. Res. 2004, 5, 339–340;
(d) Kong, Q. J.; Ren, X. Y.; Jiang, L. Y.;, Pan, Y. J.; Sun, C. R. J. Sci.
Food Agric. 2010; 90, 823–828; (e) Wang, Y.-H.; Huang, K.-S.; Lin, M.
J. Asian Nat. Prod. Res. 2006, 3, 169-176;
3
4
5
For the reviews, see: (a) Snyder, S. A.; Elsohly, A. M.; Kontes, F. Nat.
Prod. Rep., 2011, 28, 897-924; (b) Synder, S. A. Recent Advances in
Polyphenol Research, 2012, 3, 311-350; (c) Velu, S. S.; Thomas,N. F.;
Weber, J. F. Curr. Org. Chem. 2012, 16, 605-662; (d) Li, W. L.; Zang, P.;
Li, H. F.; Yang, S. X. Prog. Chem. 2012, 24, 545-554; (e) Li, W. L.; Lv, T.;
Yang, Y. H.; Yang, Y. D. Chin. J. Org. Chem. 2013, 33, 2443-2459; (f)
Keylor, M. H.; Matsurra, B. S.; Stephenson, C. R. J. Chem. Rev. 2015, 115,
8976-9027; (g) Wang, X.-F.; Yao, C.-S. J. Asian Nat. Prod. Res. 2016, 18,
376-407.
(a) He, S.; Wu, B.; Pan, Y. J.; Jiang, L. Y. J. Org. Chem. 2008, 73, 5233-
5241; (b) Hong, F.-J.; Low, Y.-Y.; Chong, K.-W.; Thomas, N. F.; Kam, T.-
S. J. Org. Chem. 2014, 79, 4528-4543; (c) Hong, F.-J.; Chong, K.-W.;
Low, Y.-Y.; Thomas, N. F.; Kam, T.-S. Chem. Asian J. 2015, 10, 2207-
2220; (d) Matsurra, B. S.; Keylor, M. H.; Li, B.; Lin, Y.; Allison, S.;
Stephenson, C. R. J. Angew.Chem. Int. Ed. 2015, 54, 3754-3757; (e)
Keylor, M.; Matsuura, B. S.; Griesser, M.; Chauvin, J.-P. R.; Harding, R.
A.; Kirillova, M. S.; Zhu, X.; Fischer, O. J.; Pratt, D. A.; Stephenson, C. R.
J. Science 2016, 354, 1260-1265.
(a) Setälä, H.; Pajunen, A.; Rummakko, P.; Sipilä, J.; Brunow, G. J. Chem.
Soc., Perkin Trans. 1, 1999, 461-464; (b) Syrjänen, K.; Brunow, G. J.
Chem. Soc. Perkin Trans. 1 2000, 183-187; (c) Syrjänen, K.; Brunow, G.
Tetrahedron 2001, 57, 365-370; (d) Lu, F.; Ralph, J.; Morreel, K.;
Messensc, E.; Boerjan, W. Org. Biomol. Chem. 2004, 2, 2888-2890; (e)
Yao, C.-S.; Lin, M.; Wang, L. Chem. Pharm. Bull. 2006, 54(7), 1053-1057;
(f) Arrieta-Baez, D.; Stark, R. E. Phytochemistry 2006, 67, 743-753; (g)
Saliu, F.; Tolppa, E.-L.; Zoia, L.; Orlandi, M.; Tetrahedron Letters 2011,
52, 3856-3860; (h) Yao, C. S.; Lin, M.; Yang, Q. Y. Acta Pharmaceutica
Sinica B 2013, 3(2), 102-108.
6
7
Gindro, K.; Schnee, S.; Righi, D.; Marcourt, L.; Ebrahimi, S. N.; Codina,
J. M.; Voinesco, F.; Michellod, E.; Wolfender, J.-L.; Queiroz, E. F. J. Nat.
Prod. 2017, 80, 887−898.
(a) Li, W. L.; Li, H. F.; Luo, Y. L.; Yang, Y. H.; Wang, N. Synlett. 2010,
21, 1247-1250; (b) Li, W. L.; Luo, Y. L.; Li, H. F.; Zang, P.; Han, X. Q.
Synthesis 2010, 22, 3822-3826; (c) Li, W. L.; Yang, S. X.; Lv, T.; Yang,
Y. D. Org. Biomol. Chem. 2014, 12, 2273-2279; (d) Yang, Y. D.; Liu, Q.;
Chen, P. L.; Li, W. L. Tetrahedron Letters 2014, 55, 4455-4457; (e) Li,
W. L.; Chen, P. L.; Yang, Y. D.; Liu, X. L.; Dong, T. Tetrahedron 2016,
72, 210-215. (f) Li, W. L.; Dong T.; Chen, P. L.; Liu, X. L.; Liu, M. J.;
Han, X. Q. Tetrahedron 2017, 73, 3056-3065; (g) Liu, M. J.; Guan, X. C.;
Shao, Z. B.; Li, W. L. Tetrahedron 2018, 74, 4013-4019. (h) Guan, X. C.;
Liu, M. J.; Shao, Z. B.; Li, H. P.; Ran, L. Synthesis 2019, 51, 1825-1831.

5
Highlights:



Three dihydrobenzofuran-type stilbene heterodimers
were prepared.
(±)-Gnetuhainin Q and an analogue of (±)-scirpusin A
were firstly synthesized.
The oxidative cross-coupling reactions of two
different stilbenes were explored.