Microwave-assisted synthesis of taxol side-chain precursor from malonic acid

Article abstract of DOI:10.14233/ajchem.2013.13532

Being a complex diterpenoid, the potent anticancer drug, taxol requires complicated multistep for its synthesis. Due to the chemical complexity of taxol, its commercial production by total synthesis is not likely to be economical. Another natural product, 10-deacetyl baccatin 111 is readily available in higher yield. Several methods have been reported for the synthesis of taxol by coupling baccatin 111 and the N-benzoyl-β-phenyl isoserine side chain. In this study, a simple precursor of side chain has been synthesized under microwave radiation by the condensation of benzaldehyde, ammonium acetate and malonic acid. The time required for the resulting β-amino acid was remarkably reduced from 6 h to 30 s only along with rapid, easy, simple and safe methodology. The structure elucidation of synthesized compound was done by its melting point, solubility, TLC techniques and spectral analyses.

Full text of DOI:10.14233/ajchem.2013.13532

Asian Journal of Chemistry; Vol. 25, No. 5 (2013), 2929-2930
http://dx.doi.org/10.14233/ajchem.2013.13532
NOTE
Microwave-Assisted Synthesis of Taxol Side-Chain Precursor from Malonic Acid
1
,*
1
2
S. EHSAN , B. KHAN and J. ARA
1
Department of Chemistry, Lahore College for Women University, Lahore, Pakistan
Department of Chemistry, Queen Merry College for Women, Lahore, Pakistan
2
*
Corresponding author: Fax: +92 42 992038077; Tel: +92 42 99203801-9; E-mail: shahana_organic@hotmail.com
Received: 30 January 2012; Accepted: 30 November 2012)
(
AJC-12484
Being a complex diterpenoid, the potent anticancer drug, taxol requires complicated multistep for its synthesis. Due to the chemical
complexity of taxol, its commercial production by total synthesis is not likely to be economical. Another natural product, 10-deacetyl
baccatin 111 is readily available in higher yield. Several methods have been reported for the synthesis of taxol by coupling baccatin 111
and the N-benzoyl-β-phenyl isoserine side chain. In this study, a simple precursor of side chain has been synthesized under microwave
radiation by the condensation of benzaldehyde, ammonium acetate and malonic acid. The time required for the resulting β-amino acid
was remarkably reduced from 6 h to 30 s only along with rapid, easy, simple and safe methodology. The structure elucidation of synthe-
sized compound was done by its melting point, solubility, TLC techniques and spectral analyses.
Key Words: Taxol, Diterpenoid, 10-deacetyl baccatin III, β-Amino acid, Microwave.
Taxol (Paclitaxel) is one of the natural diterpenoid
alkaloids isolated primarily from the bark of the WesternYew
Several methods have been reported for the semi synthesis
of taxol by coupling baccatin III and the side chain of taxol.
It is known that C-13 side chain, i.e. N-benzoyl-(2R, 3S)-3-
phenylisoserine (Fig. 2) moiety is crucial for the activity of
1
tree (Taxusbrevifolia) (Fig. 1).
6
AcO
O
taxol .
OH
O
O
O
Ph
NH
O
O
O
Ph
NH
H
Ph
HO
C H OCO
OAc
OH
Fig. 1. Structure of Taxol
O
Ph
6
5
OH
Fig. 2. Structure of taxol side-chain
Because it can kill tumor cell by enhancing the assembly
2
of microtubules and inhibiting depolymerization , taxol has
7
Semi-synthetic taxol work has generated a demand for
been well established and approved by the food and drug ad-
ministration (FDA) as a very important effective chemothera-
new stereoselective synthesis of isoserine type structure. The
C-13 contains a complex N-benzoyl phenyl isoserine ester
group, which is known as the taxol side-chain. The aim of the
work is to improve and provides an efficient and rapid method
for the synthesis of taxol side-chain.
3
peutic agent against a wide range of tumors since .
However, the supply of taxol has been limited since the
discovery of this natural product and with increasing demands
in chemotherapy; the availability and cost of the drug will
All chemicals used in the synthesis were of analytical
grade from Merck and Fluka. Melting points of synthesized
compounds were determined using Gallenkamp melting
apparatus. Ultraviolet spectra were recorded within the range
4
remain an important issue .
However, it has been found that 10-deacetyl baccatin III,
the abundant constituent of the needles of the European yew
5
tree species Taxusbaccata, is more readily obtained .
2
00-500 nm on Hitachi U-2800 spectrophotometer. FTIR

2
930 Ehsan et al.
Asian J. Chem.
TABLE-1
CONVENTIONAL HEATING VERSUS MICROWAVE RADIATION FOR THE SYNTHESIS OF TAXOL SIDE-CHAIN PRECURSOR
Conventional heating
Time (min) Yield (%)
Microwave irradiation
Time (sec) Yield (%)
S. No.
Substrate
Product
NH2
O
CHO
COOH
COOH
OH
H C
2
+
1.
360
70
30
80
β-Amino acid
Benzaldehyde malonic acid
ammonium acetate
TABLE-2
FTIR ANALYSIS
-
1
S. No.
Compound
Bands (cm ) and Intensity
-amino-3-phenyl Conventional: 3156, 1980 w, 1725 s, 1614 w, 1402 s, 1283 m, 1105 m, 887 w, 664 m.
propanoic acid
Microwave: 4471 w, 3938 w, 3736 w, 3409 w, 3205 w,b, 2925 w, 2351 w, 1566 s, 1408 s, 1121 m, 714 m, 657 w.
3
1.
-
1
spectra were recorded within the range 4000-400 cm as KBr
pellets on a Midac M-2000 spectrometer (USA) while mass
data were recorded on GC-MS Schimadzo QP-2010 spectro-
meter (Japan). For the microwave-assisted synthesis of comp-
ound, microwave oven DW-180, 2450 MHz, 950 W was used.
ion peak at m/z = 136 shows the fragmentation which contain
amino group.
TABLE-3
GC-MS OF TAXOL-SIDE CHAIN PRECURSOR
S.
No.
Base
Peak
Molecular ion
+
Peak M
Synthesis of 3-phenyl-3-amino-amino acid
Compound
Formula
Conventional: A mixture of benzaldehyde (2.0 mL),
malonic acid (2.08 g), ammonium acetate (3.08 g) in ethanol
Taxol side-chain
precursor
1.
C H N O
2
91
136
9
11
(
30 mL) was refluxed for 6 h. The compound was precipitated
from the reaction mixture after cooling. The white solid thus
obtained was separated by simple filtration.Yield (70 %), m.p.
Conclusion
Taxol side-chain precursor has been prepared from cheap
and inexpensivestarting materials and reagents by utilizing the
application of microwave. The time required for this synthesis
was reduced from 6 h to 30 sec only with good yield. So by
selecting such a novel method, a large number of medicinally
important compounds can be prepared within a short time.
2
20 ºC
Microwave: A mixture of benzaldehyde (1.0 mL),
malonic acid (1.04 g), ammonium acetate (1.5 g) in ethanol
15 mL) was irradiated for 30 s. to give β-amino acid, which
(
was washed and dried. Yield ( 80 %), m.p. 218 ºC
The present study has made an attempt to synthesize
side-chain precursor β-amino acid, by both methods i.e.
conventional and microwave-assisted. It was observed that the
time required for the synthesis of 3-amino-3-phenyl propanoic
acid (β-amino acid) under microwave radiation was remark-
ably reduced from 6 h to thirty seconds with better yield as
shown in Table-1.
REFERENCES
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M.C. Wani, H.L. Taylor and M.E. Wall, J. Am. Chem. Soc., 93, 2325
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In taxol-side chain precursor the amino group showed
-1
medium absorption near 3200 cm and carboxyl group gave
6
.
a) C. Swindell and N.E. Krauss, J. Med. Chem., 34, 1176 (1991); b) F.
Gueritte and D. Guenard, J. Med. Chem., 34, 992 (1991).
-
1
bending vib. frequency at 1600 cm and stretching vib. near
-
1
7. a) D. Hart, Chem. Rev., 89, 1447 (1989); b) G.I. George, Tetrahedron
Lett., 25, 3779 (1984).
3
300 cm as given in Table-2.
Mass spectrum of taxol side chain precursor is recorded
in Table-3. The base peak which appeared at m/z = 91 shows
+
the presence of benzyliccation C H CH while the molecular
6 5 2