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
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
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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.
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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