LETTER
Synthesis of Combretastatin A-4
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also allowed the synthesis of original cis-stilbenes such as
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1
In each case, the Z/E ratio was determined by H NMR,
and it was possible to isolate the pure Z-isomers using sil-
ica gel column chromatography.
Finally, for the sake of evaluating the scope and limita-
tions of this methodology, a series of various substituted
(Z)-stilbenes was synthesized. The results are presented in
Table 3.
The reaction sequence provided different results depend-
ing on the substitution of the phenyl ring of the arylpro-
panoic acid 2. Unsubstituted acids (entries 1–3) gave good
yields and excellent Z/E ratios (ca. 95:5). The presence of
electron-withdrawing (entry 4) or electron-donating (en-
try 6) groups lead to a loss of the stereoselectivity and
yield. In the case of the nitro derivative (entry 4), the de-
crease of both yield and selectivity is probably due to a
loss of reactivity during the Suzuki step since the first step
afforded the (Z)-b-bromostyrene in a high stereoselectivi-
ty as reported.13,16
In conclusion, we have developed a new and efficient
microwave-promoted synthesis of cis-stilbenes, CA-4 an-
alogues, using trans-cinnamic acids as starting materials.
The scope and limitations of this new methodology has
been studied. Our procedure proved to be very useful to
prepare a library of CA-4 analogues whose biological
evaluation is in progress.
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Acknowledgment
Dr. Rémi Legay is gratefully acknowledged for his assistance in
measurement of mass spectra.
(12) Uenishi, J.; Kawahama, R.; Shiga, Y.; Yonemitsu, O.; Tsuji,
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(1) Current address: Université de Nantes, Nantes Atlantique
Universités, IICiMed EA1155, UFR des Sciences
Pharmaceutiques, Laboratoire de Chimie Thérapeutique, 1
Rue Gaston Veil, BP 53508, 44000 Nantes, France.
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In a 10 mL microwave vial were introduced a magnetic stir
Synlett 2009, No. 17, 2789–2794 © Thieme Stuttgart · New York