Acetylation of Camptothecins Using Lithium Bromide as Catalyst

Article abstract of DOI:10.1081/SCC-120026340

Camptothecin and 9-Methoxycamptothecin, two promising naturally occurring anticancer alkaloids containing a tertiary hydroxy group, were acetylated with acetic anhydride at room temperature in the presence of lithium bromide as catalyst. The similar method was followed for acetylation of other two related natural alkaloids, mappicine and 9-methoxymappicine.

Full text of DOI:10.1081/SCC-120026340

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Acetylation of Camptothecins Using Lithium Bromide as
Catalyst
a
a
a
a
N. Ravindranath , C. Ramesh , M. Ravinder Reddy , K. V. N. S. Srinivas & Scientist
a
Biswanath Das
a
Organic Chemistry Division-I , Indian Institute of Chemical Technology , Hyderabad, India
Published online: 16 Aug 2006.
To cite this article: N. Ravindranath , C. Ramesh , M. Ravinder Reddy , K. V. N. S. Srinivas & Scientist Biswanath Das (2003)
Acetylation of Camptothecins Using Lithium Bromide as Catalyst, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 33:23, 4029-4035, DOI: 10.1081/SCC-120026340
To link to this article: http://dx.doi.org/10.1081/SCC-120026340
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 23, pp. 4029–4035, 2003
Acetylation of Camptothecins Using Lithium
Bromide as Catalyst
y,#
N. Ravindranath, C. Ramesh, M. Ravinder Reddy,
K. V. N. S. Srinivas, and Biswanath Das*
Organic Chemistry Division-I, Indian Institute of
Chemical Technology, Hyderabad, India
ABSTRACT
Camptothecin and 9-Methoxycamptothecin, two promising naturally
occurring anticancer alkaloids containing a tertiary hydroxy group,
were acetylated with acetic anhydride at room temperature in the
presence of lithium bromide as catalyst. The similar method was
followed for acetylation of other two related natural alkaloids,
mappicine and 9-methoxymappicine.
y
The article is dedicated with best regards in memory of (Late) Professor
T. R. Govindachari who taught us what camptothecins are.
#
[1]
See Ref.
Correspondence: Biswanath Das, Scientist, Organic Chemistry Division-I,
*
Indian Institute of Chemical Technology, Uppal Road, Hyderabad-500 007,
India; E-mail: biswanathdas@yahoo.com.
4
029
DOI: 10.1081/SCC-120026340
Copyright & 2003 by Marcel Dekker, Inc.
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Ravindranath et al.
Key Words: Camptothecin; 9-Methoxycamptothecin; Mappicine;
-Methoxymappicine; Acetylation; LiBr.
9
[2]
Camptothecin (1), a naturally occurring novel pyrrolo(3,4-b)-
quinoline alkaloid, is one of the most impressive anticancer molecules
of the recent years. The interesting feature of the compound is that it
contains a hydroxylactone ring (E-ring) with 20(S)-configuration and the
hydroxyl group is tertiary in nature. The compound exhibits remarkable
[
2–4]
antitumor and antileukamic properties.
It acts as an inhibitor of
[6]
[5]
DNA topoisomerase I. It also possesses significant anti-HIV activity.
More recently, it has been shown promising results against parasitic
[
trypanosome and Leishmania. The acetyl derivative of camptothecin,
7]
2
abundance is low.
, is also a naturally occurring anticancer alkaloid but its natural
[8]
[
8b,9]
In connection with our work
alkaloids we required acetyl derivative of these compounds. Campto-
thecin acetate (2) was previously prepared by prolonged treatment
of camptothecin (1) with acetic anhydride and pyridine. In an experiment
on camptothecin (1) and related
[
2,8b,10]
the mixture of camptothecin, Ac O and pyridine was refluxed for 24 h
2
ꢀ
and kept at 60 C for 72 h more to obtain camptothecin acetate in 63%
[
10]
yield.
Two other methods for acetylation of camptothecin involving nitronium
Thus the total time is long. Moreover, pyridine is highly toxic.
[
11]
tetrafluoroborate and trichloroethane have also been reported. In the
ꢀ
first method the reaction mixture was stirred at 80 C for 24 h while in the
second method concentrated H SO was used with the reaction mixture
2
4
ꢀ
at 50 C for the same period of time.
We have recently developed a mild and convenient method for
acetylation of camptothecin using LiBr as catalyst. LiBr has applied
in organic synthesis as an effective Lewis acid catalyst for a variety
[
12a]
of reactions such as rearrangement of epoxides,
Friedal Craft
[12d]
Knoevenagel condensation,
[12b]
[12c]
acylation,
dithioacetalization of aldehyde,
transesterification,
[
12e]
[12f ]
Preparation of acylals and mono-
We have treated camptothecin (1) with
[
12g]
thioacetalization of acetals.
Ac O in the presence of LiBr at room temperature for 24 h. The product,
camptothecin acetate (2) was obtained in 68% yield. 9-Methoxycamp-
2
[8b,10]
tothecin (3),
was also acylated in the similar way to produce 9-methoxycamptothecin
another naturally occurring camptothecin analogue,
[
acetate (4) (yield 62%). Both camptothecin acetate (2) and 9-methoxy-
8]
[9f ]
camptothecin acetate (4) have been reported from natural source.
Several E-ring modified natural analogues of camptothecin are also
well-known. One of such compounds is mappicine (5)
[
13]
which can be

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Acetylation of Camptothecins
4031
exploited for the preparation of different derivatives of camptothecin (1).
[
10e]
Mappicine (5) as well as its natural analogue, 9-methoxymappicine (7)
contains a hydroxyl group (secondary) at C-20. Both the compounds, 5
and 7 were acetylated at room temperature by treatment with Ac O in the
2
[
9d]
presence of LiBr as catalyst to the corresponding acetates 6
8
(yields
0%) and 8 (yield 76%) respectively by following the method reported
earlier.
The structures of all the acetates (2, 4,
[9c]
[
8]
[9f ]
[9d]
[9e]
6,
and 8 ) were
established by comparison of their spectral properties with those reported
earlier as well as by direct comparison with authentic samples available in
the laboratory.
In conclusion, we have developed a mild and convenient method
for acetylation of camptothecin and related alkaloids using LiBr as
catalyst. The experimental procedure is simple and the catalyst is easily
available. The procedure may be utilized for the preparation of other
esters of these compounds.
EXPERIMENTAL SECTION
Melting points were determined on a Buchi-510 apparatus and are
uncorrect. IR spectra were recorded on a Perkin–Elmer spectro-
1
photometer, H NMR spectra on a Varian Gemini-200 MHz, and mass

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032
Ravindranath et al.
spectra on a VG Micromass 7070H (70 eV) spectrometers. Column
chromatography was performed with silica gel (100–200 mesh) and TLC
with silica gel G. Natural alkaloids, camptothecin, 9-methoxycampto-
[
9e]
thecin, mappicine, and 9-methoxymappicine were isolated earlier from
the stems of Nathapodytes foetida and were available in our laboratory.
General Procedure for Acetylation of Camptothecins
To a mixture of camptothecin (1, 98 mg, 0.25 mmol) and Ac O
2
(
perature for 24 h. H O (10 mL) was added and the suspension was
4 mL) LiBr (100 mg) was added. The mixture was stirred at room tem-
2
extracted with EtOAc (4 ꢁ 10 mL). The extract was concentrated and
purified by column chromatography to obtain camptothecin acetate (2,
7
3 mg, 68%).
For mappicine (5) and 9-methoxymappicine (7) the reaction was
carried out for 12 h.
[
8]
ꢂ1 1
Camptothecin acetate (2). IR: ꢀmax (KBr) 1738, 1610 cm . H NMR
CDCl ): ꢁ 8.38 (1H, s, H-7), 8.21 (1H, dd, J ¼ 8.0, 1.2 Hz, H-12), 7.92
(
(
(
3
1H, dd, J ¼ 8.0, 1.2 Hz, H-9), 7.81 (1H, td, J ¼ 8.0, 1.2 Hz, H-11), 7.64
1H, td, J ¼ 8.0, 1.2 Hz, H-10), 7.20 (1H, s, H-14), 5.65 (1H, d,
J ¼ 17.0 Hz, H-17), 5.38 (1H, d, J ¼ 17.0 Hz, H-17), 5.29 (2H, s, H -5),
2
2
.34–2.08 (2H, m, H -19), 2.22 (3H, s, -OAc), 0.95 (3H, t, J ¼ 7.5 Hz,
2
þꢃ
Me-18). MS: m/z 390 (M ), 330, 315, 302.
[
9f]
9
-Methoxycamptothecin acetate (4).
1
IR: ꢀmax (KBr) 1750, 1666,
617, 1596 cm . H NMR (CDCl ): ꢁ 8.74 (lH, s, H-7), 7.73–7.65 (2H,
ꢂ1
1
3
m, H-11, H-12), 7.14 (1H, s, H-14), 6.92 (1H, dd, J ¼ 7.0, 1.5 Hz, H-10),
.66 (1H, d, J ¼ 17.0, H-17), 5.38 (1H, d, J ¼ 17.0 Hz, H-17), 5.18 (2H,
s, H -5), 4.00 (3H, s, -OMe), 2.25–2.10 (2H, m, H -19), 2.18 (3H, s,
5
2
2
þꢃ
-
3
OAc), 0.97 (3H, t, J ¼ 7.5 Hz, Me-18). MS: m/z 420 (M ), 360, 345,
32, 317, 256.
Mappicine acetate (6).
[
9d]
ꢂ1
IR: ꢀmax (KBr) 1733, 1655, 1598 cm
.
1
H NMR (CDCl ): ꢁ 8.29 (1H, s, H-7), 8.19 (1H, dd, J ¼ 8.5, 1.5 Hz,
3
H-12), 7.85 (1H, dd, J ¼ 8.5, 1.5 Hz, H-9), 7.78 (1H, dt, J ¼ 8.5, 1.5 Hz,
H-11), 7.58 (1H, dd, J ¼ 8.5, 1.5 Hz, H-10), 7.29 (1H, s, H-14), 5.86 (1H,
dd, J ¼ 7.5, 5.5 Hz, H-20), 5.20 (2H, s, H -5), 2.32 (3H, s, -OAc), 2.18
2
(
MS: m/z 348 (M ), 305, 289, 288, 273, 248, 219.
3H, s, Me-17), 2.02–1.78 (2H, m, H -19), 1.03 (3H, t, J ¼ 7.0 Hz, Me-18).
2
þꢃ
[
9e]
9
-Methoxymappicine acetate (8).
ꢂ1
IR: ꢀmax (KBr) 1736, 1654,
617 cm . H NMR (CDCl ): ꢁ 8.79 (1H, s, H-7), 7.80–7.67 (2H, m, H-
1
1
3
1
1, H-12), 7.42 (1H, s, H-14), 6.93 (1H, dd, J ¼ 6.0, 2.5 Hz, H-10), 5.89
(
1H, t, J ¼ 7.5 Hz, H-20), 5.24 (2H, s, H -5), 4.02 (3H, s, -OMe), 2.36 (3H,
2

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Acetylation of Camptothecins
4033
s, -OAc), 2.13 (3H, s, Me-17), 2.10–1.70 (2H, m, H -19), 1.01 (3H, t,
2
þꢃ
J ¼ 7.0 Hz, Me-18). MS: m/z 378 (M ), 335, 320, 319, 306, 379, 206.
ACKNOWLEDGMENTS
The authors thank UGC and CSIR, New Delhi for financial
assistance.
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Acetylation of Camptothecins
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Received in India June 13, 2003

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