Total synthesis of epiberberine

Article abstract of DOI:10.1080/10286020.2012.701621

Epiberberine, a natural bioactive protoberberine alkaloid, was totally synthesized in short, convenient and low-cost, four-step reactions including cyclization, condensation, reduction, and ring-closing, with an overall yield of 26.1%.

Full text of DOI:10.1080/10286020.2012.701621

This article was downloaded by: [University of Connecticut]
On: 06 January 2014, At: 20:07
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Journal of Asian Natural Products
Research
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/ganp20
Total synthesis of epiberberine
Zi-Ming Lu a b , Jun-Qing Liang b , Hong-Tao Wang b , Shao-Hua
Zhao b , Hao Zhang c & Peng-Fei Tu a
a State Key Laboratory of Natural and Biomimetic Drugs, School
of Pharmaceutical Sciences, Peking University , Beijing , 100191 ,
China
b Beijing Yiling Pharmaceutical Co., Ltd , Beijing , 100027 , China
c West China School of Pharmacy, Sichuan University , Chengdu ,
610041 , China
Published online: 28 Aug 2012.
To cite this article: Zi-Ming Lu , Jun-Qing Liang , Hong-Tao Wang , Shao-Hua Zhao , Hao Zhang &
Peng-Fei Tu (2012) Total synthesis of epiberberine, Journal of Asian Natural Products Research, 14:9,
873-876, DOI: 10.1080/10286020.2012.701621
To link to this article: http://dx.doi.org/10.1080/10286020.2012.701621
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Journal of Asian Natural Products Research
Vol. 14, No. 9, September 2012, 873–876
Total synthesis of epiberberine
Zi-Ming Luab, Jun-Qing Liangb, Hong-Tao Wangb, Shao-Hua Zhaob, Hao Zhangc and
Peng-Fei Tua*
aState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences,
Peking University, Beijing 100191, China; bBeijing Yiling Pharmaceutical Co., Ltd, Beijing 100027,
China; West China School of Pharmacy, Sichuan University, Chengdu 610041, China
c
(Received 8 May 2012; final version received 7 June 2012)
Epiberberine, a natural bioactive protoberberine alkaloid, was totally synthesized in
short, convenient and low-cost, four-step reactions including cyclization, condensation,
reduction, and ring-closing, with an overall yield of 26.1%.
Keywords: epiberberine; protoberberine alkaloids; total synthesis
1. Introduction
reported the preparation of epiberberine
[13]. However, this approach was uneco-
nomical and tedious for the reactions of
nine steps to form the side product
epiberberine with low efficiency, as well
as the use of expensive intermediates and
several toxic reagents (CH2N2, PCl5, etc.)
(Scheme 1).
Epiberberine is a natural quaternary
berberine alkaloid isolated from Coptis
chinensis [1] and other plants [2–5]. It
exhibited broad biological activities, such
as inhibition activity on CYP2D6 (one of
cytochrome p450 isoforms) [6] and aldose
reductase [7], a-adrenoceptor blocking
action [8], in vitro hypoglycemic effect
[9], etc. Recently, Jun et al. [10] have
reported that epiberberine exhibited
acetylcholinesterase (AChE), butyrylcho-
linesterase, and b-site amyloid precursor
protein cleaving enzyme 1 inhibitory
activities. The result indicated that epiber-
berine had beneficial use in the develop-
ment of therapeutic and preventive agents
for Alzheimer’s disease (AD). The berber-
ine structure has been used as a template to
synthesize more potent AChE inhibitors
[11]. However, low yields (0.5–2%) [12]
made epiberberine mainly be used as
reference substance in content determi-
nation and difficultly be purchased in
market, which restricted the further study
and application in pharmacology and
clinic, and so on. So far only one literature
Therefore, increasing interest has been
attracted by developing convenient syn-
thetic route to get epiberberine and its
natural and artificial derivatives in con-
tinuation of our ongoing program of the
protoberberine and berberine alkaloids
[14] on AD study. Herein, we report the
total synthesis of epiberberine (Scheme 2).
2. Results and discussion
As shown in Scheme 2, intermediate 1 was
formed by cyclization reaction of 2,3-
dihydroxybenzaldehyde with CH2Br2 in
75.0% yield after column chromatography,
and 2 was synthesized by condensation of
1 and 3,4-dimethoxyphenethylamine in
98.7% yield. Compound 3 was obtained
by reduction reaction of 2 and NaBH4.
Ring-closing reaction of 3 and glyoxal
*Corresponding author. Email: pengfeitu@bjmu.edu.cn
ISSN 1028-6020 print/ISSN 1477-2213 online
q 2012 Taylor & Francis
http://dx.doi.org/10.1080/10286020.2012.701621
http://www.tandfonline.com

874
Z.-M. Lu et al.
Br
Br
Br
n-BuNO2
P2O5
NOH
COOH Benzene
O
O
O
O
O
O
O
O
Br
Br
1.PCl5/ether
O
COOH
COOH
2.MeOH-KOH
3.MeOH-KOH-Pd/C H2
O
O
O
O
O
O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
N
O
N
N
O
H
H
O
O
O
O
HO2C
H
HO2C
H
CH2N2
CH3O
CH3O
CH3O
N
O
N
O
N
CH3O
O
H3CO
O
CH3O
H
CH3O2C
H
O
O
HOH2C
H
H
O
O
Scheme 1. Synthesis route of epiberberine in Ref. [13].
produced the target chemical agent 4,
epiberberine, and so on. Thus, a short,
convenient and low-cost synthesis route of
epiberberine including four-step reactions
was established with an overall yield of
26.1%, and was suitable for synthesis in
batch. Further pharmacokinetic profiles
and in vivo pharmacology studies on AD
are ongoing in our group. The synthesis of
epiberberine derivatives is underway.
a
Yanoco micro-melting apparatus
(Yanagimoto Co., Tokyo, Japan) and are
uncorrected. NMR spectra were recorded
on Brucker AM-500 spectrometer (Bruker
Instruments, Inc., Billerica, MA, USA).
1
Chemical shifts of H were referenced to
the NMR solvents. Mass spectra were
obtained on a VGZAB-2F spectrometer
(VG Mircromas Ltd, Manchester, UK).
TLC was carried out on silica gel (GF254
)
(Yantai Chemical Industry Research Insti-
tute, Yantai, China). Column chromato-
graphy was run on silica gel (200–300
mesh) (Qingdao Ocean Chemical Factory,
Qingdao, China). The samples were
visualized by spraying with Dragendorff
reagent to produce an orange spot.
3. Experimental
3.1 General experimental procedures
All the reagents were obtained commer-
cially and used without further purifi-
cation. Melting points were determined on

Journal of Asian Natural Products Research
875
CHO
HO
HO
CHO
O
O
(a)
CH3O
CH3O
N
1
(b)
O
O
CH3O
CH3O
2
NH2
CH3O
CH3O
CH3O
CH3O
(c)
HN
(d)
N
O
O
O
O
3
4
Scheme 2. Conditions and reagents: (a) CH2Br2, anhydrous K2CO3, DMF, reflux, 24 h, 75.0%;
(b) 3,4-dimethoxyphenethylamine, triethylamine, CH2Cl2, MgSO4, reflux, 5 h, 98.7%; (c) NaBH4,
anhydrous ethyl alcohol, 10 h, 98.4%; (d) glyoxal, NaCl, CuSO4 · 5H2O, 708C, acetic anhydride,
HAc, 20 h, 35.8%.
3.2 General procedures for the
synthetic compounds
58mmol), CH2Cl2 (100 ml), triethylamine
(6.82 g, 67 mmol), and anhydrous MgSO4
(10 g) were stirred and refluxed for 5 h. The
reaction progress was monitored by TLC.
After the completion of reaction, the mixture
was filtered, and the filtrate was evaporated
and cooled for crystallization. The precipi-
tate was washed well with methanol.
Compound 2 was obtained as white square
crystal (17.6 g, yield 98.7%). Compound 2:
m.p.41–438C. 1H NMR(CDCl3, 500 MHz):
d (ppm) 8.23 (1H, s, NvCH-Ar), 6.86 (1H,
d, J ¼ 8.0 Hz, ArH), 6.85 (1H, J ¼ 8.0 Hz,
ArH), 6.79 (1H, t, J ¼ 8.0 Hz, ArH), 6.76
(2H, d, J ¼ 8.0 Hz, ArH), 6.04 (1H, s, ArH),
5.90 (2H, s, ZOCH2OZ), 3.85 (3H, s,
ZOCH3), 3.82 (3H, s, ZOCH3), 3.85 (2H, t,
J ¼ 7.0 Hz, CH2), 2.96 (2H, t, J ¼ 7.0 Hz,
CH2). EI-MS m/z: 313.1 [M]þ.
3.2.1 Compound 1
A mixture of 2,3-dihydroxy benzaldehyde
(13.8 g, 100 mmol), anhydrous K2CO3
(20.8 g, 151 mmol), CH2Br2 (28.3 g,
163 mmol), and DMF (50 ml) were stirred
and refluxed for 24 h. During the reaction,
the detection was performed by TLC.
EtOAc was used for extraction
(3 £ 150 ml). The organic phase was
combined and dried over Na2SO4 over
night and evaporated to give the crude
product which was purified by column
chromatography (PE:EtOAc; 20:1, v/v).
Compound 1 was obtained as colorless
needle (11.2 g, yield 75.0%). Compound 1:
m.p. 30–318C. 1H NMR (CDCl3,
500 MHz): d (ppm) 10.09 (1H, s, 1-CHO),
7.25 (1H, d, J ¼ 7.5 Hz, ArH), 7.02 (1H, d,
J ¼ 6.5 Hz, ArH), 6.95 (1H, dd, J ¼ 7.5,
6.5 Hz, ArH), 6.11 (2H, s, ZOCH2OZ)
[15,16]. EI-MS m/z: 150.1 [M]þ.
3.2.3 Compound 3
Compound 2 (17.6 g) was heated and
dissolved in anhydrous ethanol (100 ml).
NaBH4 (5.0 g, 66 mmol) was added in
batches. After the addition, the mixture
was refluxed for 10 h and monitored by
TLC. Then, the reaction product was
3.2.2 Compound 2
A
mixture of
2,3-dimethoxyphenethylamine (10.6 g,
1 (8.51 g, 57 mmol),

876
Z.-M. Lu et al.
evaporated to remove the solvent. To the
residue, water (150 ml) and EtOAc
(3 £ 150 ml) were added which were
used for extraction. The organic phase
was combined and dried over Na2SO4 over
night and evaporated. Compound 3 was
obtained as yellow oil (17.4 g, yield
H-6), 3.95 (3H, s, 2-OCH3), 3.88 (3H,
s, 3-OCH3), 3.22 (2H, t, J ¼ 5.6 Hz, H-5).
EI-MS m/z: 339.1 [M]þ [5,13].
Acknowledgments
1
We are grateful to the Major Scientific and
Technological Specialized Project for Signifi-
cant New Formulation of New Drugs
(2011ZX09401-020) for financial support.
98.4%). Compound 3: H NMR (CDCl3,
500 MHz): d (ppm) 6.71–6.80 (6H, m,
ArH), 5.90 (2H, s, ZOCH2OZ), 3.85 (3H,
s, ZOCH3), 3.84 (3H, s, ZOCH3),
3.79 (2H, s, NZCH2ZAr), 2.87 (2H, t,
J ¼ 7.0 Hz, CH2), 2.77 (2H, t, J ¼ 7.0 Hz,
CH2). EI-MS m/z: 315.1 [M]þ.
References
[1] J. Lan, S.L. Yang, Y.Q. Zheng, J.B. Shao,
and Y. Li, Chin. Tradit. Herb Drugs 12,
1139 (2001).
[2] H. Itokawa and A. Ikuta, Phytochemistry
7, 2143 (1988).
[3] R. Chatterjee, A. Banerjee, and
A.K. Barua, J. Ind. Chem. Soc. 28, 225
(1951).
[4] S.F. Cooper, J.A. Mockle, and J. Beliveau,
Planta Med. 19, 23 (1970).
[5] M. Mizuno, H. Kojima, M. Linuma,
T. Tanaka, and K. Goto, Phytochemistry
2, 717 (1992).
[6] Y.L. Han, H.L. Yu, D. Li, X.L. Meng,
Z.Y. Zhou, Q. Yu, X.Y. Zhang, F.J. Wang,
and C. Guo, Phytother. Res. 21, 3475
(2011).
[7] H.A. Jun, N.Y. Yoon, H.J. Bae, B.S. Min,
and J.S. Choi, Arch. Pharm. Res. 11, 1405
(2008).
[8] J.L. Wang and D.C. Fang, Acta Pharm.
Sin. 4, 289 (1990).
[9] X.F. Jiang, L.J. Wang, X.G. Li, Z.Q. Zhao,
and J.Y. Zhu, Guizhou Agric. Sci. 9, 44
(2011).
[10] H.A. Jun, B.S. Min, T. Yokazawa,
J.H. Lee, Y.S. Kim, and J.S. Choi,
Biol. Pharm. Bull. 8, 1433 (2009).
[11] P. Williams, A. Sorribasab, and M.J.R.
Howes, Nat. Prod. Rep. 28, 48 (2011).
[12] Q.M. Fang, H. Zhang, and Z.C. Li,
W. C. J. P. S 18, 290 (2003).
[13] B.R. Pai, S. Natarajan, H. Suguna,
S. Rajeswari, S. Chandrasekaran, and
K. Nagarajan, Indian J. Chem. Sect. B 21,
607 (1982).
[14] Z.M. Lu, W.X. Sun, X.H. Duan,
Z.Y. Yang, Y.D. Liu, and P.F. Tu,
China J. Chin. Mat. Med. 2, 232 (2012).
[15] P.Y. Ding and D.Q. Yu, Acta Pharm. Sin.
10, 796 (1995).
3.2.4 Epiberberine
In 500 ml three-necked bottle, CuSO4 · 5-
H2O (16.1 g), NaCl (16.3 g), and 40%
glyoxal (24.1 g) were added under stir, and
the mixture was heated to 708C for 2 h.
Following the addition of compound 3
(17.4 g, 55 mmol), acetic anhydride
(30 ml) and HAc (100 ml) were added.
The mixture was stirred and heated to
1008C for 20 h. Additional water (250 ml)
was added, and the mixture was kept at
908C and stood for 1 h. After the mixture
was removed from the bottle, it was
neutralized to pH 7 with saturated NaCO3
solution. The precipitate was collected and
washed with water till the washing water
showed light yellow. Then, the precipitate
was added in HCl–95% ethanol (5:95, v:v,
20 ml), and heated for 1 h, then cooled and
filtered. The cake was purified by column
chromatography (CHCl3:MeOH; 9:1, v:v).
Epiberberine was obtained by recrystalli-
zation in 95% ethanol as hydrochlorate of
orange amorphous powder (7.3 g, yield
35.8%), and it showed the identical TLC
behavior with the reference substance.
Epiberberine: m.p. 259–2608C (dec.)
([13], 2608C(dec.)). 1H NMR (DMSO-
d6): d (ppm) 9.91 (1H, s, H-8), 9.04 (1H, s,
H-13), 8.03 (1H, d, J ¼ 8.4 Hz, H-11),
7.86 (1H, d, J ¼ 8.4 Hz, H-12), 7.71 (1H,
s, H-l), 7.09 (1H, s, H-4), 6.55 (2H, s,
ZOCH2OZ), 4.94 (2H, t, J ¼ 5.6 Hz,
[16] S. Chen, Y.F. Tong, and S. Wu,
Chin. J. Chem. 4, 512 (2009).