An improved method for the synthesis of γ-DDB

Article abstract of DOI:10.1016/j.bmcl.2010.01.166

A mild and efficient method for the synthesis γ-DDB has been developed through anhydride-linker assisted intramolecular Ullmann reaction. Highly regioselective bromination of differentially protected gallate was realized by virtue of the introduction of NBS.

Full text of DOI:10.1016/j.bmcl.2010.01.166

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2297–2298
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
An improved method for the synthesis of c-DDB
*
*
Chuanjun Song , Peng Zhao, Zhiqiang Hu, Shuai Shi, Yanmei Cui, Junbiao Chang
Department of Chemistry, Zhengzhou University, Zhengzhou 450001, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient method for the synthesis
assisted intramolecular Ullmann reaction. Highly regioselective bromination of differentially protected
gallate was realized by virtue of the introduction of NBS.
c
-DDB has been developed through anhydride-linker
Received 15 December 2009
Revised 28 January 2010
Accepted 30 January 2010
Available online 6 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
c
-DDB
Ullmann reaction
Anhydride-linker
Selective bromination
Families of DDB (compounds with dimethylenedioxybiphenyl
group) are known for their interesting biological activities, for
example, antihepatotoxic, antitumor, anti-HIV and antifungal
properties.1–4 They are also useful building blocks for access to
Schisandrin-type lignans.
OMe
CO2Me
O
O
O
O
O
O
O
O
MeO
MeO
CO2Me MeO
CO2Me
CO2Me
CO2Me
CO2Me
O
The synthesis of symmetrical
a- or b-DDB (Fig. 1) is easily
O
achieved through intermolecular Ullmann reaction5 between two
identical bromobenzene units.2a,6–10 However, this approach is
O
O
OMe
α-DDB
OMe
γ-DDB
β-DDB
not suitable for unsymmetrical
two required bromobenzene units were performed, mixtures of
-DDB, b-DDB and -DDB would be obtained.
A reasonable way to avoid competitive homocoupling is to build
c-DDB. If Ullmann coupling of the
Figure 1.
a
c
yield, uncontaminated by significant amounts of the 6-brominated
or dibrominated products. Methylation of the hydroxy group in 3,
followed by saponification gave 5, the first component for the syn-
a linker between the two different coupling units, an intramolecu-
lar coupling reaction could then be realised. We previously re-
ported an ester-linker directed intramolecular Ullmann reaction
thesis of
c-DDB. In comparison to our previous strategy for the
for the synthesis of
c
-DDB.11 Whilst the desired unsymmetrical
introduction of the bromo group by application of a regioselective
product was obtained, a disappointing yield of 25% was obtained.
Newman and Cella reported Ullmann reactions between coupling
partners joined by an anhydride rather than ester-linker.12 Indeed,
by applying such a linker, intramolecular Ullmann reaction of 10
(vide infra) was achieved with high yield. Also, the reaction could
be carried out at 60–70 °C rather than the high temperature gener-
ally required. We now report the full detail of our improved meth-
CO2Me
OH
CO2Me
OH
CO2Me
Br
CO2Me
Br
i
ii
iii
HO
OH
O
O
OMe
O
OH
O
O
3
O
1
2
4
od for the synthesis of c-DDB.
CO2H
Br
As shown in Scheme 1, regioselective bromination of 3-hydro-
xy-4,5-methylenedioxybenzoate 2 using 1 equiv of NBS added
slowly to the reaction mixture gave bromide 3 in 79% isolated
iv
OMe
O
O
5
* Corresponding authors. Tel.: +86 0371 67781588 (C.S.); +86 0371 67783017
(J.C.).
Scheme 1. Reagents and conditions: (i) CH2I2, K2CO3, DMF, 40 °C, 20 h, 49%; (ii)
NBS, THF, rt, 0.5 h, 79%; (iii) Me2SO4, K2CO3, acetone, reflux, 4 h, 90%; (iv) (a) KOH
(aq), reflux, 5 h; (b) H+, 95%.
E-mail addresses: chjsong@zzu.edu.cn (C. Song), changjunbiao@zzu.edu.cn
(J. Chang).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.166

2298
C. Song et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2297–2298
the yield for regioselective bromination and intramolecular Ull-
mann reaction, the two key steps of the synthesis, were greatly
improved.
CO2Me
CO2Me
CO2Me
CO2Me
OMe
Br
Br
i
ii
OMe
OMeiii
HO
OH
HO
HO
O
OH
O
OH
OH
1
6
7
8
Acknowledgment
O
O
O
O
J. Chang is grateful to NSFC (Outstanding Young Scholarship,
#30825043) for financial support.
COCl
OMe
O
Br
O
O
O
vi MeO
O
CO2Me
CO2Me
OMe v
iv
Br Br
O
OMe
O
O
Supplementary data
O
10
9
OMe
11
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.01.166.
Scheme 2. Reagents and conditions: (i) Ref. 11; (ii) NBS, THF, rt, 0.5 h, 89%; (iii)
CH2I2, K2CO3, acetone, reflux, 5 h, 78%; (iv) Ref. 11, 77%; (v) 5, pyridine, THF, 0 °C,
0.5 h, 86%; (vi) (a) Cu (powder), DMF, 60–70 °C, 1.5 h; (b) KOH, MeOH/H2O, reflux,
20 min; (c) H+; (d) MeOH, concd H2SO4, reflux, 10 h, 40% over the four steps.
References and notes
1. (a) Xie, J. X.; Zhou, J.; Zhang, C. Z. Acta Pharm. Sin. 1982, 17, 23; (b) Chen, D. F.;
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2003, 86, 2239; (b) Guo, R. Y.; Chang, J. B.; Chen, R. F.; Fan, X. L.; Xie, J. X. Acta
Pharm. Sinica 1999, 34, 439; (c) Chang, J. B.; Reiner, J.; Xie, J. X. Chem. Rev. 2005,
105, 4581.
nitration–reduction-Sandmeyer reaction sequence,11 use of NBS as
the regioselective bromination agent gave a greatly improved yield
(79% vs 18%).
3. Kou, Y. H.; Kou, L. Y.; Chen, C. F. J. Org. Chem. 1997, 62, 3242.
4. Xie, L.; Xie, J. X.; Kashiwada, Y. J. Med. Chem. 1995, 38, 3003.
5. For a review of the Ullmann coupling, see: Fanta, P. E. Synthesis 1974, 9.
6. (a) Cheng, S. X.; Wang, L. M.; Chang, J. B.; Qu, L. B.; Chen, R. F.; Xie, J. X. Chin.
Chem. Lett. 2005, 16, 167; (b) Cheng, S. X.; Wang, L. M.; Chang, J. B.; Qu, L. B.;
Chen, X. L.; Chen, R. F. Youji Huaxue 2004, 24, 691; (c) Guo, R. Y.; Chang, J. B.;
Chen, R. F.; Xie, J. X.; Yan, D. Y. Chin. Chem. Lett. 2001, 12, 491; (d) Guo, R. Y.; He,
J.; Chang, J. B.; Chen, R. F.; Xie, J. X.; Ge, Y. H.; Liu, H. Q. Gaodeng Xuexiao Huaxue
Xuebao 2001, 22, 2018.
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1909.
Mono-methylation of triol 1 gave 6 (Scheme 2), which was bro-
minated in the 6-position with NBS to give compound 7 in excel-
lent yield. In the production of 3 and 7, we observed bromination
with NBS occurring regioselectively ortho to the hydroxy substitu-
ent. Similar results were also observed by Tsuboi10 using DBDMH
as the brominating agent. Following a similar strategy described
for the synthesis of 5, benzoyl chloride 9 was obtained in good
overall yield from 7. Compound 10, the key precursor for intramo-
lecular Ullmann reaction was then prepared by anhydride forma-
tion between 5 and 9. Subsequent studies showed that the
anhydride-linker directed intramolecular Ullmann reaction of 10
could be performed at 60–70 °C, instead of the high temperatures
generally required for this reaction, and gave, after hydrolysis
11. Chang, J.; Guo, X.; Cheng, S.; Guo, R.; Chen, R.; Zhao, K. Bioorg. Med. Chem. Lett.
2004, 14, 2131.
12. Newman, M. S.; Cella, J. A. J. Org. Chem. 1974, 39, 2084.
and ester formation,
In conclusion, we have developed a mild and efficient method
for the synthesis of -DDB. Compared to our previous method,
c-DDB 11 in good overall yield.
c