A protecting group-free synthesis of the antineoplastic agent combretastatin A4

Article abstract of DOI:10.3184/174751911X13024592068428

The synthesis of combretastatin A4 (CA4) from commercially available inexpensive materials has been achieved via the Wittig reaction followed by irradiation of the (Z)/(E)-CA4 reaction mixture with sunlight. The method resulted in (Z)-CA4 in high yield. This method does not require protection of the phenolic hydroxy group. The synthesis is operationally simple and cost-efficient.

Full text of DOI:10.3184/174751911X13024592068428

JOURNAL OF CHEMICAL RESEARCH 2011
APRIL, 229–230
RESEARCH PAPER 229
A protecting group-free synthesis of the antineoplastic agent
combretastatin A4
Xiaotao Guo, Dan Zhang, Zhifang Yu*, Tianzhen Liu, Dachang Li and Chunbao Li
Department of Chemistry, College of Science, Tianjin University, Tianjin 300072, P. R. China
The synthesis of combretastatin A4 (CA4) from commercially available inexpensive materials has been achieved via
the Wittig reaction followed by irradiation of the (Z)/(E)-CA4 reaction mixture with sunlight. The method resulted in
(Z)-CA4 in high yield. This method does not require protection of the phenolic hydroxy group. The synthesis is
operationally simple and cost-efficient.
Keywords: antineoplastic agent, combretastatin A4, synthesis, Wittig reaction, irradiation
Combretastatin A4 (CA4) is one of the most potent antineo-
isovanillin and the ylide derived from the phosphonium salt 2
1,2
plastic agents and its phosphate, CA4P, has produced posi-
tive results in clinical trials. CA4 is a natural product that
comes from the bark of the African tree Combretum caffrum.
The availability of CA4 is limited and therefore a practical
synthesis of CA4 is needed to provide enough of the compound
for further research and possible large scale production.
Several reports have described the synthesis of CA4, such as,
a Perkin condensation between 3,4,5-timethoxyphenylacetic
was conducted in a series of solvents using different bases
and the results are summarised in Table 1. Good yields were
obtained for all the reactions (entries 1–13). EtOH/KOH
(entry 1), EtOH/Cs CO (entry 12), and EtOH/DBU (entry 13)
2
3
gave almost quantitative yields of the (E)/(Z)-CA4 mixture and
the latter two reactions were completed in shorter times (3 h).
In other solvents (water, acetone, acetonitrile or THF), the
yields were also high. In all the reactions, the Z:E ratios are
roughly 1:1. Fortunately, part of the (Z)-CA4 can be crystal-
lised from a mixture of ethyl acetate and n-hexane. The mother
liquor was then concentrated and dissolved in ethanol in a
Pyrex flask and irradiated by sunlight. This produced another
batch of (Z)-CA4 which was then isolated via a second crystal-
lisation. After repeating the process twice, an 84%yield of
(Z)-CA4 was achieved. It has been reported that (Z)-CA4 is
3
acid and vanillin followed by elimination, a one-pot hydrosi-
4
lylation-protodesilylation of diaryl alkynes, alkyne hydrobo-
5
6
ration, partial alkyne hydrogenation using Lindlar’s catalyst,
7,8
the Wittig reaction, the Ramberg–Bäcklund reaction via a
sulfone, and hydrolysis of the Ti(II)-alkyne complexes formed
from an alkyne and Ti(OiPr) /n-BuLi.
9
1
0
4
In most of these methods, the hydroxyl group on the phenol
ring must be protected or the reactions have to be conducted
3
converted to (E)-CA4 in the presence of iodine. However, this
1
1
3
under harsh conditions, such as –78 °C, 230 °C or under
is the first report of the transformation of (E)-CA4 to (Z)-CA4
using sunlight. The possible reason is that (E)-CA4 can absorb
sunlight and be converted to the excited state to become (Z)-
1
2
anhydrous conditions. These latter conditions would substan-
tially add to the cost of production of CA4. In this work, CA4
has been synthesised from the commercially available isovan-
illin via the Wittig reaction without the need for protection
and deprotection steps and the byproduct (E)-CA4 has been
transformed into (Z)-CA4 in high yield.
CA4. This agrees with the UV spectra of (E)-CA4 (λ = 207
max
−
1
nm, 328 nm, c = 0.1 mmol L in EtOH) and (Z)-CA4 (λ
=
max
207 nm, 296 nm, c = 0.1 mmol L− in EtOH). The overall yield
1
3
,14,15
is similar to other synthetic routes in the literature,
but
The synthesis of CA4 is outlined in Scheme 1. Treatment of
the present procedure is operationally simpler and more cost-
efficient.
3
,4,5-trimethoxybenzyl alcohol 1 with triphenylphosphonium
bromide in refluxing acetonitrile yielded phosphonium salt 2
Following this route, a reaction starting with isovanillyl
1
2
in 92% yield. This step avoids the need to prepare unstable
alcohol 5 lead to 6, which was reacted with 3,4,5-trimethoxy-
1
3
3
,4,5-trimethoxybenzylbromide. TheWittigreactionbetween
benzaldehyde to yield CA4 as outlined in Scheme 2. The
Scheme 1 Synthesis of (Z)-CA4 using 3,4,5-trimethoxybenzyl alcohol and isovanillin. Reagents and conditions: (a) acetonitrile,
reflux, 10 h, 92%; (b) isovanillin (0.8 equiv.), see Table 1 for other details; (c) sunlight, 4 h, 84%.
*
Correspondent. E-mail: zfyu@tju.edu.cn

2
30 JOURNAL OF CHEMICAL RESEARCH 2011
Scheme 2 Synthesis of (Z)-CA4 using isovanillyl alcohol and 3,4,5-trimethoxybenzaldehyde. Reagents and conditions:
a) acetonitrile, reflux, 6 h, 84%; (b) 3,4,5-trimethoxybenzaldehyde (0.67 equiv.), see Table 2 for other details; (c) sunlight, 4 h, 84%.
(
Table 1 Reaction conditions and results for the synthesis of
CA4 using 2 and isovanilin
Table 2 Reaction conditions and results for the synthesis of
CA4 using 6 and 3,4,5-trimethoxybenzaldehyde
Entry Reaction Solvent
time/h
Base
Z:E /% Yield/%
Entry
Reaction Solvent
time /h
Base
Z:E /%
Yield /%
1
2
3
4
5
6
7
8
9
6
6
Ethanol
Ethanol
Ethanol
Ethanol
Water
KOH
55:45
56:44
52:48
53:47
56:44
51:49
54:46
58:42
54:46
53:47
52:48
56:44
57:43
97
93
90
96
76
73
71
70
82
78
74
98
99
1
2
5
5
6
6
6
6
8
8
7
6
7
8
5
Ethanol
Ethanol
Ethanol
Ethanol
Water
KOH
26:74
21:79
49:51
40:60
52:48
55:45
56:44
59:41
57:43
54:46
56:44
55:45
52:48
90
89
85
88
76
75
72
70
91
90
79
77
86
NaOH
NaOH
8
Na
2
2
CO
CO
KOH
NaOH
3
3
3
Na
2
2
CO
CO
KOH
NaOH
3
3
8
K
3
4
K
3
8
5
8
Water
6
Water
10
10
7
Water
Water
Acetone
Acetonitrile
THF
Ethanol
Ethanol
K
2
CO
3
7
Water
K
2
CO
3
Na
2
CO
8
Water
Na
2
CO
KOH
KOH
KOH
9
Acetone
KOH
1
0
1
2
3
8
10
11
12
13
Acetonitrile KOH
1,4-dioxane KOH
1
1
1
9
3
Cs
2
CO
3
THF
Methanol
KOH
KOH
3
DBU
Reaction conditions: 2 (1.0 equiv.), isovanilin (0.8 equiv.), base
1.2 equiv.), in refluxing solvents, under N
Reaction conditions: 6 (1.0 equiv.), 3,4,5-trimethoxybenzalde-
(
2
.
hyde (0.67 equiv.), base (1.0 equiv.), in refluxing solvents,
2
under N .
results are summarised in Table 2. All the yields were good
entries 1–13) and the reactions using stronger bases (entries
,2,9,10) lead to higher yields and shorter reaction times. The
resulting mixture of 3 and 4 was readily transformed into 3
evaporation of the mother liquor provided crops of (Z)-CA4 (0.145 g)
and (Z)-CA4 (0.198 g). The total yield of (Z)-CA4 was 84%.
(
1
Electronic Supplementary Information
1
[
(Z)-CA4] in high yields via sunlight irradiation.
Detailed H NMR assignments and IR data for both (Z)-CA4 and (E)-
In summary, a new synthesis of CA4, starting from com-
CA4 have been deposited in the ESI available through stl.publisher.
ingentaconnect.com/content/stl/jcr/supp-data.
mercially available and inexpensive materials has been carried
out. Protection and deprotection steps are not required in this
synthesis. For the first time, the transformation of (E)-CA4 to
We thank TJMSTC for the financial support
(
05YFGPGX07500).
(
Z)-CA4 has been realised using sunlight irradiation. This is
a cost-efficient and green method and all the steps involved
are operationally simple. This method represents a practical
synthesis for CA4.
Received 21 December 2011; accepted 23 March 2011
Paper 100489 doi: 10.3184/174751911X13024592068428
Published online: 3 May 2011
Experimental
References
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1
2
3
4
5
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chromatography (eluent: PE-EtOAc 5: 1) to give a (Z)/(E)-CA4
mixture (0.800 g). The mixture was crystallised from ethyl acetate and
hexane to yield (Z)-CA4 (0.150 g). The mother liquor was concen-
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1
1
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4
5
1
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6
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1
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