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17. (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2005, 61,
11771; (b) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000,
100, 3009; (c) Tietze, L. F.; Stewart, S. G.; Polomska, M. E.;
Modi, A.; Zeeck, A. Chem. Eur. J. 2004, 10, 5233; (d) Tietze, L.
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This method for the analysis of thalidomide analogues
provides an accurate, simple and more targeted method
for the determination of the effects on signalling through
the NFjB inflammatory pathway as measured by inhibi-
tion of TNF transcriptional activity, with the added
advantage of concurrently assessing cytotoxicity of each
derivative. The Heck cross coupling was proven to be an
excellent method for the attachment of olefins to the
thalidomide and phthalimide ring frameworks. Of the
newly produced analogues the compounds 22, 29, 33
and 37 which had a TNF expression inhibitory activity
50%, 69%, 52% and 50%, respectively, showed the great-
est potential.
18. Nicolaou, K. C.; Bulger, P. G.; Saralah, D. Angew. Chem.
Int. Ed. 2005, 44, 4442.
19. (a) Muller, G. W.; Konnecke, W. E.; Smith, A. M.; Khetani,
V.D. Org. ProcessRes.Dev. 1999, 3, 139;(b)Capitosti,S. M.;
Hansen, T. P.; Brown, M. L. Org. Lett. 2003, 5, 2865.
20. Kayser, M. M.; Soucy, C.; Favreau, D. J. Org. Chem.
1987, 52, 129.
22. General Heck cross coupling procedure: (E)-methyl 3-(2-
(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acrylate
(20). Pd2(dba)3 (11.9 mg, 0.013 mmol) was added to a
solution of HP(t-Bu)3BF4 (7.5 mg, 0.026 mmol) and
Cy2NMe (32.5 lL, 0.15 mmol) in dioxane (0.5 mL), the
solution was degassed and stirred at room temperature for
1 h. The resulting mixture was treated with phthalimide 4
(50 mg, 0.13 mmol), methyl acrylate (27.5 lL, 0.30 mmol)
and heated to 50 ꢁC for 3 h. The reaction mixture was
cooled to room temperature, dissolved in CHCl3 (60 mL),
washed with saturated NH4Cl (5· 1 mL), dried (MgSO4),
filtrated and concentrated under reduced pressure to
afford dark brown solid. Subjection of this crude product
to gradient flash chromatography (1:1 ! 3:7 Hexane/
EtOAc) and concentration of appropriate fractions pro-
duced desired ester 20 (33 mg, 73%) as a colourless solid.
m.p. = 244–248 ꢁC. Rf = 0.16 (1:1 hexane/EtOAc) IR
(KBr, cmꢀ1) v: 1719.1 (C=O), 1642.5 (C=C), 1397.3,
1199.0 (O-CH3), 748.6. 1H NMR (500 MHz, DMSO-d6): d
At varying concentrations the O-Bu derivative 29 re-
mains a better TNF expression inhibitor than thalido-
mide itself. At 10 lM the inhibition drops to 52%
while thalidomide (1) is at 35%. At 1 lM, inhibition
due to derivative 29 and thalidomide (1) is closer, at
32% and 31%, respectively.
Acknowledgments
The authors thank the University of Western Australia
for the award of a UWA research grant. A scholarship
for M.S. from Temasek Polytechnic is also gratefully
acknowledged.
References and notes
0
0
0
0
2.03–2.10 (m, 1H, H4 =H5 Þ, 2.50–2.64 (m, 2H, H4 =H5 Þ,
0
0
2.85–2.94 (m, 1H, H4 =H5 Þ, 3.77 (s, 3H, CH3), 5.17 (dd,
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0
J = 12.8, 5.5 Hz, 1H, H3 ), 6.99 (d, J = 16.3 Hz, 1H, HA),
7.87–7.98 (m, 2H, Ar-H), 8.36 (d, J = 7.6 Hz, 1H, Ar-H),
8.53 (d, J = 16.3 Hz, 1H, HB), 11.14 (s, 1H, N-H). 13C
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¨
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R R
P
Pd
O
Pd
O
O
O
P
´
´
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.
R = o-Tol
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