Novel route for preparation of 7-methyl-camptothecin and its possible mechanism

Article abstract of DOI:10.1080/00397910500283263

A novel route for preparation of 7-methyl-camptothecin is described. Its possible mechanism is discussed. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500283263

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Novel Route for Preparation of
7‐Methyl‐camptothecin and Its Possible
Mechanism
a
a
a
a
Xin Wang , Jiwu Wen , Gang Li & Tianpa You
a
Department of Chemistry , University of Science and Technology of China ,
Hefei, Anhui, China
Published online: 20 Aug 2006.
To cite this article: Xin Wang , Jiwu Wen , Gang Li & Tianpa You (2005) Novel Route for Preparation of
7‐Methyl‐camptothecin and Its Possible Mechanism, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 35:24, 3163-3166
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Synthetic Communications , 35: 3163–3166, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500283263
Novel Route for Preparation of 7-Methyl-
camptothecin and Its Possible Mechanism
Xin Wang, Jiwu Wen, Gang Li, and Tianpa You
Department of Chemistry, University of Science and Technology
of China, Hefei, Anhui, China
Abstract: A novel route for preparation of 7-methyl-camptothecin is described. Its
possible mechanism is discussed.
Keywords: Mechanism, 7-methyl-camptothecin, novel route, preparation
INTRODUCTION
[
1]
Camptothecin (CPT), a pentacyclic alkaloid isolated from the Chinese tree
Camptotheca acuminata by Wall et al. in 1966, was shown to have strong
antitumor activity against colon, mammary, leukemia, and ovarian tumor
models. The discovery of its unique mechanism of action, trapping a
[2]
cleavable complex between topoisomerase I and DNA,
revived the
research interest in CPT and its analogs as antitumor agents. A number of
CPT analogs have been developed. SAR studies had indicated that a lipophilic
group in position 7 such as 7-alkyl-camptothecins are substantially more
[
3–5]
cytotoxic than CPT.
was the most potent in inhibiting tumor cell growth.
-Methyl-camptothecin was previously prepared by treatment of CPT
Among 7-alkyl-camptothecins, 7-methyl-camptothecin
[5]
7
[5]
.
with H O , FeSO 7H O, and CH CHO in aq. H SO
(
camptothecin by treatment of CPT with FeSO4, HCONH2, and
in moderate yield
,70%). We have found a novel route for preparation of 7-methyl-
2
2
4
2
3
2
4
Received in Japan May 23, 2005
Address correspondence to Tianpa You, Department of Chemistry, University of
Science and Technology of China, No. 96, Jinzhai Road, Hefei, Anhui 230026,
China. Tel.: þ 86 551 3606944; Fax: þ86 551 3606168; E-mail: ytp@ustc.edu.cn
3
163

3
164
X. Wang et al.
(
CH ) COOH under acidic conditions. The present procedure offers
3
3
several advantages such as much higher yields (96.1%), easy purification of
the product (do not need to use column chromatography), and fast reaction
time (within 1 h to complete the reaction). This provides an alternative
method.
EXPERIMENTAL
Camptothecin (0.1 g, 0.29 mmol) was suspended in a mixture of CF COOH
3
.
3.5 ml) and H SO (1.2 ml). FeSO 7H O (0.21 g, 0.76 mmol) and H O
2 4 4 2 2
(
(
6 ml) were added successively. After cooling to 58C, HCONH (0.2 ml)
2
was added. To the mixture, 65% (CH ) COOH (0.1 ml, 0.68 mmol) was
3
3
added dropwise at 28C. The mixture was stirred for 1 h at 08C and then
poured into ice water. The precipitated material in the solution was
collected by suction, washed with water, and dried in vacuo. Yellow
powder (0.100 g) was obtained. Yield: 96.1%. IR (KBr) nmax: 3430, 1750,
2
1 1
1
653, 1602 cm . H NMR (DMSO-d ) d: 0.91 (3H, t, J ¼ 7.20 Hz, C18-
6
methyl protons), 1.83–1.96 (2H, m, C19-methylene protons), 2.81 (3H, s,
C7-CH ), 5.31 (2H, s, C5-methylene protons), 5.47 (2H, s, C17-methylene
3
protons), 7.35 (1H, s, C14-H), 7.75 (1H, t, J ¼ 7.36 Hz, C10-H), 7.89 (1H,
t, J ¼ 7.06 Hz, C11-H), 8.17 (1H, d, J ¼ 8.12 Hz, C9-H), 8.26 (1H, d,
J ¼ 8.45 Hz, C12-H). Anal. calcd. for C H N O : C, 69.60; H, 5.01; N,
2
1 18 2 4
7.73%. Found: C, 69.40; H, 4.75; N, 7.58%. HRMS (EI) m/z calcd. for
C H N O : 362.127; found: 362.129.
21 18 2 4
DISCUSSION
[
6,7]
According to the literature,
media is presumably a radical mechanism.
methylation in the 7 position of CPT in acidic
The only possible source of methyl radical in Scheme 1 must come from
t-butyl hydroperoxide. As Richardson had pointed out,
[8]
when t-butyl
Scheme 1.

7-Methyl-camptothecin
3165
hydroperoxide was used with transition-metal salt, a t-butoxy radical was
usually produced.
2
þ
FeðOHÞ2þ þ ðCH3Þ CO†
Fe þ ðCH3Þ COOH
!
ð1Þ
3
3
As a common fragmentation, t-butoxy radical split into methyl radical
[
9]
and acetone:
ðCH Þ CO†
!
The methyl radical acted with CPT to afford the methylated species as
†CH þ ðCH Þ CO
ð2Þ
3
3
3
3 2
[
6,7]
shown in reaction (3):
It is important to add CF COOH to the solvent system because that
3
remarkably improves the solubility of CPT and results in high yield.
However, the function of HCONH remained unknown. The fact is that no
2
target product is obtained without the assistance of HCONH . We think the
2
function of HCONH may be to stabilize the methyl radical.
2
REFERENCES
1
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Plant antitumor agents. The isolation and structure of camptothecin, a novel
alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata. J. Am.
Chem. Soc. 1966, 88 (16), 3888–3890.
2
3
4
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linked breaks via mammalian DNA topoisomerase I. J. Biol. Chem. 1985, 260,
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6
. Lei, Y. J.; Zhu, C. H.; Wang, Z. Q.; Liu, H. The improved synthesis of 7-ethyl-
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7
8
9. Gray, P.; Williams, A. The thermochemistry and reactivity of alkoxyl radicals.
Chem. Rev. 1959, 59, 239.