The new shortcut synthesis of 8-oxocoptisine

Article abstract of DOI:10.1016/j.cclet.2010.05.019

8-Oxocoptisine 1, a natural protoberberine alkaloid, can be more easily achieved starting from readily available and inexpensive berberine hydrochlorate 2. The structure of the target compound 1 was confirmed by melting point, ¹H NMR, IR, MS and elemental analysis.

Full text of DOI:10.1016/j.cclet.2010.05.019

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 1281–1282
www.elsevier.com/locate/cclet
The new shortcut synthesis of 8-oxocoptisine
*
Xiang Juan Cui, Ying Ying Lu, Min Zhao, Shan Qian, Yong Wu
Key Laboratory of Drug Targeting of Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Received 24 February 2010
Abstract
-Oxocoptisine 1, a natural protoberberine alkaloid, can be more easily achieved starting from readily available and inexpensive
8
berberine hydrochlorate 2. The structure of the target compound 1 was confirmed by melting point, H NMR, IR, MS and elemental
1
analysis.
#
2010 Yong Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 8-Oxocoptisine; Protoberberine alkaloid; Berberine hydrochlorate; Synthesis
8
-Oxocoptisine 1, a natural protoberberine alkaloid isolated from Coptidis rhizome [1] and other primitive plant
families [2–7], exhibits broad biological activities, such as antitumor [8], antiviral [9] and antimicrobacterial activities
10]. It is worth mentioning that the multidrug resistance (MDR) inhibition activity of 1 is similar to verapamil, which
[
is an active inhibitor of the P-glycol protein induced MDR [11]. However, low yields (0.07%) [1] make the obtaining
of 1 from nature arduous. Therefore, increasing interest has been attracted by developing convenient synthetic route to
get the natural and artificial 8-oxocoptisine derivatives.
Le and Cho [12] have reported the preparation of 8-oxocoptisine 1. However, this approach was uneconomical and
tedious, because it included multi-step and low yield (only 3% for six steps). In addition, the starting materials were
not commercial products. Maria [13] has also reported a complicated synthetic method. Similarly the raw materials
were non-commercially available. Eberhard and Fritz [14] have used isoquinoline derivative as the starting material to
synthesize compound 1 with total yield of 10% for six steps. This method, however, was low efficiency, and moreover
used several toxic reagents (NaBH CN, KCN, etc.). Recently, Dost a´ l et al. [15] have converted coptisine to compound
3
1
[
during the research of the oxidation of protoberberine alkaloids. But the content of coptisine in natural plant was rare
16] (0.03%). Based on the favorable biological activity of 1, we searched for efficient synthetic route and modified its
structure to discover more potential derivatives. Considering that berberine hydrochloride 2, an inexpensive and
commercial product, possessed similar structure skeleton to 8-oxocoptisine 1, we assumed that 2 could be transformed
to 1 by demethylation, etherification and oxidation, sequentially. Moreover, this approach would enable us to
introduce different substituents and thereby facilitate the preparation of 8-oxocoptisine derivatives for studying their
MDR inhibition activity.
*
Corresponding author.
E-mail address: wyong@scu.edu.cn (Y. Wu).
1001-8417/$ – see front matter # 2010 Yong Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.05.019

[(Scheme_1)TD$FIG]
1
282
X.J. Cui et al. / Chinese Chemical Letters 21 (2010) 1281–1282
3 2 2
Scheme 1. The synthetic route of the compound 1. Conditions and reagents: (a) AlCl , o-xylene, 150 8C, 4 h, 70%; (b) CH Cl , DMSO, 50% KOH,
90 8C, 5 h; (c). 50% KOH, 80 8C, 5 h, 25% for two steps.
We attempted to get phenol 3 by selectional demethylation from berberine hydrochloride 2 under the agents of
CH ) SiI, PCl , BBr , HI and AlCl [17–21], respectively. We failed to get phenol 3, while tetrahydroxyl berberine
hydrochlorate 4 was generated. Because compounds 3 and 4 were transformed to the same product 5 by etherification,
(
3
3
5
3
3
we directly utilized AlCl to get 4 with good yield, as shown in Scheme 1. Subsequently, we probed different
3
etherification methods to obtain ether 5 from phenol 4. Avariety of alkylation agents (CH Cl , CH Br , CH I ), alkalis
2
2
2
2
2 2
(
DMAP, KOH, etc.) and different solvents (DMF, DMSO, etc.) were employed to promote the etherification. As a
result, only CH Cl , KOH and DMSO could effectively carry out this etherification. Finally, coptisine hydrochlorate 5
2
2
was easily transformed into the target compound 1 [22] by the reported method [15].
In summary, we report new synthetic strategy in three steps with good yields of 18%, starting from readily available
and inexpensive berberine hydrochloride 2, for the preparation of 8-oxocoptisine 1. The synthesis of 8-oxocoptisine
derivatives and their MDR inhibition activity are underway.
References
[
[
[
[
[
[
[
[
[
1] W. Wang, Q.W. Zhang, W.C. Ye, et al. Chin. J. Nat. Med. 5 (2007) 5.
2] M. Zhu, P.G. Xiao, Chin. Bull. Bot. 9 (1992) 55.
3] J.Y. Zhou, B.Z. Chen, X.J. Tong, et al. Chin. Herbal Med. 20 (1989) 2.
4] V. Preininger, R.S. Thakur, F. Santav, J. Pharm. Sci. 65 (1976) 294.
5] M. Li, X. Chen, Q.M. Tang, et al. Planta Med. 67 (2001) 189.
6] A.U. Rahman, S. Ahmad, K. Bhatti, et al. Phytochemistry 40 (1995) 593.
7] S. Paelka, J. Kovar, C. Czeoh, Chem. Commun. 41 (1976) 3654.
8] M. Naito, T. Tsuruo, Cancer Res. 49 (1989) 1452.
9] M.A. Rashid, K.R. Gustafson, Y. Kashman, Nat. Prod. Lett. 6 (1995) 153.
[
[
[
[
[
[
[
[
[
[
[
[
[
10] F.C. Huang, T.M. Kutchan, Phytochemistry 53 (2000) 555.
11] Y.D. Min, M.C. Yang, K.H. Lee, et al. Arch. Pharm. Res. 29 (2006) 757.
12] T.N. Le, S.G. Gang, W.J. Cho, J. Org. Chem. 69 (2004) 2768.
13] C. Maria, J. Nat. Prod. 58 (1995) 401.
14] R. Eberhard, G. Fritz, P. Kurt, Monatsh. Chem. 134 (2003) 991.
15] J. Dost a´ l, S. Man, P. Seckarova, et al. J. Mol. Struct. 687 (2004) 135.
16] B. S¸ ener, J. Nat. Prod. 48 (1985) 670.
17] S.B. Ian, J.H. David, W. Susan, et al. Tetrahedron Lett. 35 (1994) 3367.
18] R. Sharma, K.H. Bhushan, B. Pandya, et al. WO 2006040645 (2006.04.20).
19] G. Thota, T. Pahk, L. Li, et al. Biol. Med. Chem. Lett. 18 (2008) 4982.
20] L. Canonica, B. Rindone, E. Santaniello, et al. Tetrahedron 28 (1972) 4395.
21] J.H. Kim, T.N. Jhong, Y.K. Paik, et al. US 6255317 (2001.07.03).
1
22] The data of target compound 1. Orange solid; mp 289–291 8C; H NMR (400 MHz, CDCl
3
): d 7.21 (s, 1H, H-1), 7.17 (d, 1H, J = 8.0 Hz, H-11),
–O–), 6.01 (s, 2H, –O–CH –O–), 4.28 (t, 2H,
J = 6.4 Hz, H-6), 2.89 (t, 2H, J = 6.4 Hz, H-5); IR (KBr, cm ): ymax 2924, 1654, 1594, 1482, 1384, 1268, 1226, 1100. Anal. Calcd. for
7
.05 (d, 1H, J = 8.0 Hz, H-12), 6.75 (s, 1H, H-4), 6.71 (s, 1H, H-13), 6.22 (s, 2H, –O–CH
2
2
À1
+
19 5
C H13NO : C 68.06, H 3.91, N 4.18. Found C 68.32, H 3.76, N 4.21. ESI-MS m/z: 336.0 (M+H) .