Facile synthesis of norwogonin, isoscutellarein, and herbacetin

Article abstract of DOI:10.1016/j.tetlet.2016.06.085

An expeditious synthesis of norwogonin, isoscutellarein, and herbacetin, has been accomplished by a strategy featuring a borylation of sterically hindered aryl iodide and a one-pot oxidation to generate the C-3 and C-8 OH groups. The total synthesis gives excellent yields and conventional flash column chromatography is not needed for purification.

Full text of DOI:10.1016/j.tetlet.2016.06.085

Accepted Manuscript
Facile synthesis of norwogonin, isoscutellarein, and herbacetin
Hu Yuan, Ji Ye, Hao Chen, Zeng Zhao, Xukai Luo, Weidong Zhang, Qingyan
Sun
PII:
S0040-4039(16)30752-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.085
TETL 47812
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
26 April 2016
15 June 2016
20 June 2016
Please cite this article as: Yuan, H., Ye, J., Chen, H., Zhao, Z., Luo, X., Zhang, W., Sun, Q., Facile synthesis of
norwogonin, isoscutellarein, and herbacetin, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.06.085
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Facile synthesis of norwogonin,
isoscutellarein, and herbacetin
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Hu Yuana , Ji Yeb , Hao Chenb , Zeng Zhaob , Xukai Luoa , Weidong Zhanga, b,  and Qingyan Suna, 
a Shanghai Institute of Pharmaceutical Industry, Shanghai 200040, PR China.
b Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.

1
Tetrahedron Letters
Facile synthesis of norwogonin, isoscutellarein, and herbacetin
Hu Yuana , Ji Yeb , Hao Chenb , Zeng Zhaob , Xukai Luoa , Weidong Zhanga, b,  and Qingyan Suna, 
a Shanghai Institute of Pharmaceutical Industry, Shanghai 200040, PR China.
b Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An expeditious synthesis of norwogonin, isoscutellarein, and herbacetin, has been accomplished
by a strategy featuring a borylation of sterically hindered aryl iodide and a one-pot oxidation to
generate the C-3 and C-8 OH groups. The total synthesis gives excellent yields and conventional
flash column chromatography is not needed for purification.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
5,7,8-trihydroxyflavone
synthesis
borylation
oxidation
1. Introduction
The diverse biological activities exhibited by 5,7,8-
trihydroxyflavones have made them of particular synthetic
Flavones have antioxidant, anti-proliferative, anti-tumor, anti-
microbial, antibacterial, anti-inflammatory activities, and are also
used in cardiovascular disease and neurodegenerative disorders.
Flavones have been an indispensable anchor for the development
of new therapeutic agents, and some flavones have undergone
clinical studies.1 Norwogonin (1), isoscutellarein (2), and
herbacetin (3) are a class of 5,7,8-trihydroxyflavone originally
isolated from Scutellaria baicalensis, which is an active
component of the Traditional Chinese Medicine (TCM) extract
from Huang Qin. They have been reported to present anti-
inflammatory,2 insecticidal and antifungal,3 anticancer,4
antidepressant,5 free radical scavenging, and antioxidant effects.6
Additionally, they were found to exhibit potent influenza virus
inhibitory activity in vivo and in vitro.7
interest. Norwogonin (1), isoscutellarein (2), and herbacetin (3)
only occur at low levels in natural plants, and this has negatively
influenced further evaluation of their biological activities.
Therefore, the chemical synthesis of 1, 2, and 3 would be a very
important way of addressing the problem of their availability. As
such, several methods for the synthesis of 5,7,8-
trihydroxyflavones are available (Scheme 1, A), which broadly
can be categorized into two groups involving oxidative
cyclization of chalcones or acid-catalyzed cyclization of 1,3-
diketones using 3,4,5-trimethoxyphenol or 2-hydroxy-3-alkoxy-
4,5-trimethoxyacetophenone as the starting material8 and
selective bromination at the C-6 position of 5-hydroxy-7-
methoxyflavone, followed by methanolysis with CuBr and
MeONa.9 Further deprotection and oxidation yielded the related
5,7,8-trihydroxyflavone and 3,5,7,8-tetrahydroxyflavone.
Figure 1. Chemical structures of norwogonin, isoscutellarein,
and herbacetin.
———
 Corresponding author. Tel.: +86-21-81871246; fax: +86-21-81871246; e-mail: sqy_2000@163.com
 Corresponding author. Tel.: +86-21-81871244; fax: +86-21-81871244; e-mail: wdzhangy@hotmail.com

2
Tetrahedron Letters
Scheme 1. Reported methods for the synthesis of 5,7,8-
trihydroxyflavones (A) and our approach (B).
Scheme 2. Synthesis of norwogonin (1), isoscutellarein (2)
and herbacetin (3).
In general, these approaches suffered either from low overall
yields and tedious work-up or from uncommercially available
starting materials and harsh reaction conditions. In this paper, we
introduce the C-8 OH groups of 5,7,8-trihydroxyflavone and
3,5,7,8-tetrahydroxyflavone via an borylation of 8-iodonated
flavone and a subsequent oxidation.
Table 1
Borylation at C-8 position of 9b
Entry
Reaction conditions
Yield/%
0 a
1
2
PdCl2(dppf), B2Pin2, KOAc/DMSO, 80 ºC
PdCl2(dppf), B2Pin2, TEA/dioxane, 90 ºC
(a) n-BuLi, (b) B(OMe)3, (c) HCl, (d) pinacol
PdCl2(dppf), pinBH, TEA/dioxane, 90 ºC
PdCl2(dppf), pinBH, TEA/dioxane, 70 ºC
PdBr2, P(o-Tol)3, pinBH, TEA/THF, 70 ºC
PdCl2, PPh3, pinBH, TEA/THF, 70 ºC
0 a
2. Results and discussion
b
23
28
66
49
85
63
43
3
Our synthetic efforts (Scheme 2) commenced with 2,4-
dibenzyloxy-6-hydroxy phenylacetone 5. Condensation of 5 with
benzaldehyde (6a or 6b) was achieved via a Claisen-Schmidt
reaction10 to give the chalcone (7a or 7b) in >95% yield.
Chalcone (7 or 7b) was cyclized in the presence of catalytic
iodine in DMSO at 110 °C to give benzyl-protected flavones (8a
or 8b) in high yields. 8-iodonated flavones (9a and 9b) were
readily prepared by reacting 8a and 8b with AgOTf/I2 under mild
conditions.11 Borylation of 9a and 9b with classical Miyaura
borylation reaction12 employing bis(pinacolato)diboron (B2pin2)
as boron source failed to yield corresponding boronic esters, only
dehalogenated byproducts were obtained (Table 1, entries 12),
which might be attributed to the large steric effect. The attempt to
convert 9b into 10b with halogen-lithium exchange to form
boronic acid and subsequent esterification with pinacol afforded
a complex mixture (Table 1, entry 3).13 We next screened the
effect of the palladium source, ligand and boron source on the
borylation reaction of the model substrate (9b). To our delight,
simple variation of boron source showed that pinacolborane
(pinBH) led to much improved reactivity. Several catalytic
systems were found to be efficient for the borylation reaction of
9b, while a Pd(AcO)2/P(o-Tol)3 system provided the highest
yield (Table 1, entries 410). Borylation of 9a with the same
reaction condition also smoothly afforded corresponding boronic
ester 10a in 88% yield.
4
5
6
7
8
Pd(AcO)2, P(o-Tol)3, pinBH, TEA/THF, 60 ºC
Pd(AcO)2, P(o-Tol)3, pinBH, TEA/dioxane, 85 ºC
Pd(AcO)2, PPh3, pinBH, TEA/dioxane, 85 ºC
9
10
a >95% dehalogenated product was observed.
b Complex mixture.
With the boronic esters (10a and 10b) in hand, the
corresponding phenols (11a and 11b) were obtained in high
yields by oxidation with NaBO3·4H2O14 within 60 minutes.
Removal of the benzyl groups of 11a and 11b by hydrogenolysis
or BCl3 furnished norwogonin (1)15 and isoscutellarein (2)16 in
>90% yield. Oxidization of 10b to generate C-3 and C-8 OH
groups in one-pot was readily accomplished in 76% yield by
treatment with dimethyldioxirane (DMDO),17 generated in situ
from Oxone and acetone at low temperature, followed by
opening of the resulting epoxide with catalytic p-toluenesulfonic
acid (p-TSA). Debenzylation of 12 with BCl3 provided
herbacetin (3) whose spectral data were in agreement with those
reported in literature.18 Additionally, the desired product in each
step could be purified via recrystallization, and conventional
flash column chromatography is not needed.
In summary, an exceedingly efficient synthesis of
norwogonin, isoscutellarein, and herbacetin has been
accomplished, which provided >50% overall yield. The most
striking maneuver in this synthesis is the borylation of sterically
hindered aryl iodides and a one-pot oxidation to generate the
hydroxyl groups. This efficient and flexible entry should offer
opportunities for the construction of many other norwogonin,
isoscutellarein, and herbacetin analogues for chemical biology
investigations.

3
Bull. 2003, 51, 339340; (b) Hattori, K. Acta Phytochimica 1931, 5,
Acknowledgments
219226; (c) Parmar, V. S.; Gupta, S.; Sinha, R.; Sharma, S.
K. Indian. J. Chem. B. 1993, 32, 244256; (d) Rao, P. R.; Seshadri, T.
R. Proc. Ind. Acad. Sci. 1946, 24, 243252; (e) Horie, T.; Kourai, H.;
Fujita, N.; Bull. Chem. Soc. Jpn. 1983, 56, 37733780; (f) Horie, T.;
Tsukayama, M.; Kourai, H.; Yokoyama, C.; Furukawa, M.; Yoshimoto,
T.; Yamamoto, S.; Watanabe-Kohno, S.; Ohata, K. J. Med. Chem.
1986, 29, 22562262; (g) Iinuma, M.; Matsuura, S.; Kurogochi, K.;
Tanaka, T. Chem. Pharm. Bull. 1980, 28, 717722.
The work was supported by Professor of Chang Jiang Scholars
Program, NSFC(81520108030, 81573318, 81373301, 1302658),
Shanghai Leading Academic Discipline Project (B906), Shanghai
Engineering Research Center for the Preparation of Bioactive
Natural Products (10DZ2251300), and the Fundamental Research
Funds for the Central Universities of China.
9.
Righi, G.; Antonioletti, R.; Silvestri, I. P.; D'Antona, N.; Lambusta, D.;
Bovicelli, P. Tetrahedron 2010, 66, 12941298.
10. Sharma, P. K.; He, M.; Jurayj, J.; Gou, D. M.; Lombardy, R.;
Romanczyk, L. J., Jr.; Schroeter, H. Molecules 2010, 15, 55955619.
11. Joncour, A.; Decor, A.; Thoret, S.; Chiaroni, A.; Baudoin,
O. Angew. Chem. Int. Ed. 2006, 45, 41494152.
12. (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995,
60, 75087510; (b) Kohari, Y.; Hoshino, Y.; Matsuyama, H.; Nakano,
H. Heterocycles 2010, 81, 18711879.
13. Li, B.; Li, J.; Fu, Y.; Bo, Z. J. Am. Chem. Soc. 2004, 126, 34303431.
14. Takagi, A.; Ikawa, T.; Kurita, Y.; Saito, K.; Azechi, K.; Egi, M.; Itoh,
Y.; Tokiwa, H.; Kita, Y.; Akai, S. Tetrahedron 2013, 69, 43384352.
15. Siddikov, G. U.; Yuldashev, M. P.; Aripova, S. F.; Vdovin, A. D.;
Abdullaev, N. D.; Botirov, E. K. Chem. Nat. Compd. 2008, 44, 2830.
16. Yoon, K. D.; Jeong, D. G.; Hwang, Y. H.; Ryu, J. M.; Kim, J. J. Nat.
Prod. 2007, 70, 20292032.
17. Adams, T. E. ; El Sous, M. ; Hawkins, B. C.; Hirner, S.; Holloway, G.;
Khoo, M. L.; Owen, D. J.; Savage, G. P.; Scammells, P. J.; Rizzacasa,
M. A. J. Am. Chem. Soc. 2009, 131, 16071616.
References and notes
1.
(a) Singh, M.; Kaur, M.; Silakari, O. Eur. J. Med. Chem. 2014, 84,
206239; (b) Verma, A. K.; Pratap, R. Tetrahedron 2012, 68,
85238538.
2.
3.
Li, L.; Sapkota, M.; Kim, S.; Soh, Y. Eur. J. Pharmacol. 2015, 765,
115123.
(a) Xing, S.; Wang, M.; Peng, Y.; Chen, D.; Li , X. J. Ethnopharmacol.
2014, 152, 183–189; (b) Morimoto, M.; Tanimoto, K.; Nakano, S.;
Ozaki, Y.; Nakano, A.; Komai, K. J. Agric. Food Chem. 2003, 51,
389393; (c) Miyasaki, Y.; Rabenstein, J. D.; Rhea, J.; Crouch, M. L.;
Mocek, U. M.; Emmett Kittell, P.; Morgan, M. A.; Stephan Nichols,
W.; Van Benschoten, M. M.; Hardy, W. D.; Liu, G. Y. Plos One 2013,
8, e61594.
4.
(a) Choi, Y. O.; Song, H. H.; Kim, Y. M.; Kang, N. S.; Han, S. Y.;
Chin, Y. W. Bull. Korean Chem. Soc. 2015, 36, 402–405; (b) Qiao, Y.;
Xiang, Q.; Yuan, L.; Xu, L.; Liu, Z.; Liu, X. Food Chem. Toxicol. 2013,
51, 426433; (c) Hyuga, S.; Hyuga, M.; Yoshimura, M.; Amakura, Y.;
Goda, Y.; Hanawa, T. Planta Med. 2013, 79, 15251530.
Liu, X.; Chan, C. B.; Jang, S. W.; Pradoldej, S.; Huang, J.; He, K.;
Phun, L. H.; France, S.; Xiao, G.; Jia, Y.; Luo, H. R.; Ye, K. A. J. Med.
Chem. 2010, 53, 8274–8286.
(a) Hyun, J.; Woo, Y.; Hwang, D. S.; Jo, G.; Eom, S.; Lee, Y.; Park, J.
C.; Lim, Y. Bioorg. Med. Chem. Lett. 2010, 20, 5510–5513; (b)
Olennikov, D. N.; Kashchenko, N. I.; Chirikova, N. K. Molecules 2014,
19, 1829618316.
18. Jeong, H. J.; Ryu, Y. B.; Park, S. J.; Kim, J. H.; Kwon, H. J.; Kim, J.
H.; Park, K. H.; Rho, M. C.; Lee, W. S. Bioorgan. Med.
Chem. 2009, 17, 68166823.
5.
6.
Supplementary Material
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process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
7.
8.
(a) Nagai, T.; Miyaichi, Y.; Tomimori, T.; Suzuki, Y.; Yamada, H.
Chem. Pharm. Bull. 1990, 38, 13291332; (b) Nagai, T., Miyaichi, Y.,
Tomimori, T., Suzuki, Y.; Yamada, H. Antivir. Res. 1992, 19, 207217;
(c) Jeong, H. J.; Ryu, Y. B.; Park, S. J.; Kim, J. H.; Kwon, H. J.; Kim, J.
H.; Park, K. H.; Rho, M. C.; Lee, W. S. Bioorgan. Med. Chem. 2009,
17, 68166823.
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(a) Huang, W. H.; Chien, P. Y.; Yang, C. H.; Lee, A. R. Chem. Pharm.

4
Tetrahedron
 A new approach to 5,7,8-trihydroxyflavones
is provided.
 Satisfactory
yields
of
norwogonin,
isoscutellarein, and herbacetin are obtained.
 Borylation of sterically hindered aryl iodides is
developed.
 NO column chromatography is needed for
purification.