Synthesis of 1,7-dimethoxy-2-hydroxyxanthone, a natural product with potential activity on erectile dysfunction

Article abstract of DOI:10.1016/j.cclet.2013.03.038

The natural product, 1,7-dimethoxy-2-hydroxyxanthone (1), isolated from Securidaca inappendiculate Hassk, has a potential in the treatment of erectile dysfunction due to its significant relaxation activity on rabbit Corpus cavernosum. However, the isolation of compound 1 is problematic because of its high similarity in structure to its analogs. In this paper, the first synthesis of 1 was reported featuring two key reactions: a copper-catalyzed coupling reaction and an intramolecular cyclization.

Full text of DOI:10.1016/j.cclet.2013.03.038

Chinese Chemical Letters 24 (2013) 515–517
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Chinese Chemical Letters
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Original article
Synthesis of 1,7-dimethoxy-2-hydroxyxanthone, a natural product
with potential activity on erectile dysfunction
a,b,
Wen-Jing Liu a, De-Sheng Mei b, , Wen-Hu Duan
*
*
a School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
b Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
A R T I C L E I N F O
A B S T R A C T
Article history:
The natural product, 1,7-dimethoxy-2-hydroxyxanthone (1), isolated from Securidaca inappendiculate
Hassk, has a potential in the treatment of erectile dysfunction due to its significant relaxation activity on
rabbit Corpus cavernosum. However, the isolation of compound 1 is problematic because of its high
similarity in structure to its analogs. In this paper, the first synthesis of 1 was reported featuring two key
reactions: a copper-catalyzed coupling reaction and an intramolecular cyclization.
ß 2013 De-Sheng Mei, Wen-Hu Duan. Published by Elsevier B.V. on behalf of Chinese Chemical
Society. All rights reserved.
Received 6 January 2013
Received in revised form 13 February 2013
Accepted 7 March 2013
Available online 10 May 2013
Keywords:
1,7-Dimethoxy-2-hydroxyxanthone
Erectile dysfunction
Synthesis
Copper-catalyzed coupling reaction
1. Introduction
2. Experimental
Securidaca inappendiculata Hassk, a traditional Chinese herbal
medicine, is mainly distributed in southern China and other
Asian tropical regions. Its roots and stems are used for anti-
inflammatory, anti-bacterial and anti-rheumatism treatment
[1,2]. To date, many xanthones have been isolated from this
plant, including 1,7-dimethoxy-2-hydroxyxanthone (1) [3], 1,6-
dihydroxyxanthone (2), 1,7-dihydroxy xanthone (3), 1,7-dihy-
droxy-4-methoxyxanthone (4), 1,7-dihydroxy-3,4-dimethoxyx-
ane (5), and 1,3,6-trihydroxy-2,7-dimethoxyxanthone (6) (Fig. 1)
[4]. Among these compounds, 1 displayed significant in vitro
relaxation activity on rabbit Corpus cavernosum [5], which is the
first natural product reported to have smooth muscle relaxation
activity. Our group is very interested in its biological activity,
however, the isolation of compound 1 from its natural source is
difficult due to its high similarity in structure to its analogs [3,4].
Thus, a synthetic source could fulfill the unmet task of providing
useful quantities of the material. Here, we report the first
synthesis of compound 1.
Our synthetic approach to the ‘‘retrosynthesis’’ of xanthone 1
was designed to use an intramolecular cyclization as the key step.
As shown in Fig. 2, ring opening of xanthone 1 would give diphenyl
ether 7, to which a stable protecting group was attached.
Compound 7 could then be prepared via a coupling reaction of
4-methoxyphenol 8 (commercially available) and the substituted
bromobenzoic acid 9.
Synthesis of the key intermediate 9 started with pyrocatechol
10, as shown in Scheme 1. Monobenzylation of 10 [6,7] followed by
a formylation of the mono-benzylated pyrocatechol by a Reimer-
Tiemann reaction gave compound 11 (We envisioned the benzyl
ether in compound 11 would tolerate the reaction conditions in
subsequent transformations and could be removed in the last
step). Then protection of the 2-phenolic hydroxyl group of 11
afforded aldehyde 12, which was brominated with Br2/KBr/H2O to
form compound 13 by using modified literature methods [8]. Next,
the liberation of phenolic hydroxyl of 13 to compound 14 followed
by the methylation of the hydroxyl led to aldehyde 15 [9,10].
Subsequent oxidation of 15 by NaClO2/H2O2 yielded the key
intermediate 9–1 [11].
With the key intermediate 9–1 in hand, we first performed the
coupling reaction of 9–1 with 4-methoxyphenol (8). Copper (II)
oxide facilitated this reaction smoothly to give compound 7–1 [12]
in 62% yield. Finally, the intramolecular Friedel–Crafts reaction
was carried out by trifluoromethanesulfonic anhydride as catalyst.
* Corresponding authors at: Department of Medicinal Chemistry, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
E-mail addresses: meids@mail.shcnc.ac.cn (D.-S. Mei),
whduan@mail.shcnc.ac.cn (W.-H. Duan).
1001-8417/$ – see front matter ß 2013 De-Sheng Mei, Wen-Hu Duan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.03.038

[
W.-J. Liu et al. / Chinese Chemical Letters 24 (2013) 515–517
O
O
OMe
O
OH
O
OH
O
OH
O
OH
O
OH
MeO
OH
HO
HO
HO
MeO
HO
OMe
OH
HO
O
O
OMe
O
2
O
O
3
OMe
OMe
1
5
4
6
Fig. 1. Xanthones from Securidaca inappendiculata Hassk.
[(Fig._2)TD$FIG]
O
OMe
O
OMe
O
OMe
HO
MeO
OP
Coupling reaction
MeO
OH
Cyclization
OP
MeO
HO
+
OH
O
1
Br
O
7
9
8
Fig. 2. Retrosynthesis of 1.
[(Scheme_1)TD$FIG]
CHO
CHO
CHO
CHO
COOH
OMe
CHO
OH
OH
O
OEt
Br
O
OEt
Br
OMe
OBn
Br
f
Br
OH
a
b
c
d
e
O
O
OH
OBn
OBn
OBn
13
OBn
OBn
9-1
15
14
10
11
12
Scheme 1. Reagents and conditions: (a) (i) BnBr, K2CO3, acetone, reflux, 8 h; (ii) NaOH, H2O, CHCl3, reflux, 4 h; (b) ClCO2Et, Et3N, toluene, r.t., 2 h, 45.0% of yield from 10; (c) Br2,
KBr, H2O, r.t., 24 h, 52%; (d) LiOH, THF/H2O (1:3), 6 h, 79%; (e) MeI, DMF, 70 8C, 1 h, 92%; and (f) NaClO2, NaH2PO4, H2O2, CH3CN, H2O, r.t., 1 h, 83%.
[(Scheme_2)TD$FIG]
COOH
OMe
OMe
O
OMe
HOOC
MeO
Br
MeO
OBn
MeO
OH
b
a
+
OH
OBn
O
O
9-1
8
7-1
1
Scheme 2. Reagents and conditions: (a) CuO, K2CO3, pyridine, reflux, 24 h, 62%; (b) (CF3SO2)2O, CH2Cl2, reflux, 1 h, 67.0%.
An unexpected debenzylation occurred simultaneously during the
intramolecular cyclization to free the 2-phenolic hydroxyl group,
leading to our final target compound 1 (Scheme 2). The analytical
data of compound 1 were identical to those of 1 in literatures
[3,13].
4. Conclusion
We have accomplished the first synthesis of 7-dimethoxy-2-
hydroxyxanthone (1) in a convergent fashion using a copper-
catalyzed coupling reaction and an intramolecular cyclization as
the key steps. This work provided a reliable source to a large
quantity of 1 needed for further biological studies and also an
approach to the preparation of analogs of compound 1.
3. Results and discussion
In the synthesis of 13, it was noted that the ethoxycarbonyl
protecting group at 2-phenolic hydroxyl was crucial to formation
of the desired ortho-bromination product 13; and without
protection of 2-phenolic hydroxyl or other protecting groups,
Acknowledgments
Financial support of the National Natural Science Foundation
(Nos. 81102461, 81021062, and 90813034), National Science &
Technology Major Project ‘‘Key New Drug Creation and
Manufacturing Program’’ (Nos. 2012ZX09301001-001 and
2012ZX09103101-024) and the Shanghai Science and Technology
Commission (Nos. 11431921100 and 12DZ1930802) are gratefully
acknowledged.
such as methyl, the bromination procedure gave
a meta-
bromination product, which had the bromine atom at the wrong
position, and no appreciable amount of the ortho-bromination
product 13. We also found that the further deprotection of 13
required
a two-step procedure according to the literature
procedure [8a] because acetal would form by using 10% sodium
hydroxide in methanol. To avoid the formation of acetal, we used
lithium hydroxide in aqueous tetrahydrofuran to liberate phenolic
hydroxyl to give compound 14 in 79% yield.
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