Synthesis of 9-allyl-10-hydroxycamptothecin via Suzuki reaction

Article abstract of DOI:10.1002/jhet.1549

A facile and eco-friendly approach for synthesizing 9-allyl-10- hydroxycamptothecin (2), a key intermediate for the preparation of camptothecin analogs, is described. The product was obtained in good yield and high purity (≥99% HPLC) under mild Suzuki reaction condition.

Full text of DOI:10.1002/jhet.1549

July 2014
Synthesis of 9-Allyl-10-hydroxycamptothecin via Suzuki Reaction
1133
b
b
a
a
*
Yu Luo, Shanbao Yu, Qingqing Huang, and Wei Lu
aInstitute of Drug Discovery and Development, East China Normal University, Shanghai 200062, China
bDepartment of Chemistry, East China Normal University, Shanghai 200062, China
*
E-mail: wlu@chem.ecnu.edu.cn
Received September 19, 2011
DOI 10.1002/jhet.1549
Published online 9 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
I
O
RO
B
O
HO
O
O
RO
N
O
N
N
N
N
CsF, Pd(PPh3)4
75%
N
O
O
O
OH
O
OH
O
OH
O
A facile and eco-friendly approach for synthesizing 9-allyl-10-hydroxycamptothecin (2), a key intermediate
for the preparation of camptothecin analogs, is described. The product was obtained in good yield and high
purity (≥99% HPLC) under mild Suzuki reaction condition.
J Heterocyclic Chem., 51, 1133 (2014).
INTRODUCTION
by column chromatography, the purity of product 2 is still
less than 95.0%. It has been proved that impurity 9 in this
step resulted in low purity of final CPT compounds, so high
purity (≥99.0%) is necessary for compound 2. An alternative
approach involves four steps from compound 7 employing
Stille coupling reaction as the key step (Scheme 3) [13], in
which compound 2 can be obtained in over 99.0% purity.
However, tin is too toxic and not eco-friendly. Thus, a novel
and safer synthetic route for obtaining high purity product 2
(≥99.0%) is still needed.
In 2005 and 2009, Kotha’s [14] and Schmalz’s groups
[15] reported an efficient alkylation of aromatic systems via
Suzuki reaction, employed Pd(PPh3)4 as catalyst, CsF as
base, and allyl boronic acid pinacol ester as key allylic
reagent. The results showed that this efficient Suzuki reaction
afforded the final product in good yield, and no rearrange-
ment was observed, which inspired us to apply this method
to scale up compound 2 with high purity (Scheme 4).
To optimize Suzuki reaction, 9-bromo-10-hydroxycamp-
tothecin, synthesized from compound 7 and NBS in DMF,
was initially chosen as the substrate. However, all attempts,
including varying solvents (e.g., THF, CH3CN, DMF, and
toluene) and bases (e.g., CsF, K2CO3, and NaOH), led to
more or less complicated results, suggesting that the phenol
group probably has a negative impact on Suzuki reaction.
Subsequently, 9-bromo-10-methoxycamptothecin, obtained
from 9-bromo-10-hydroxy-camptothecin and CH3I in
DMF, was used as starting material for Suzuki reaction.
Unfortunately, all the aforementioned attempts were not
successful. Finally, all unsatisfactory results led 9-iodine-
10-methoxycamptothecin (15) as the substrate to screen
Suzuki reaction conditions (Table 1).
Camptothecin (CPT, 1) is a potent antitumor alkaloid first
isolated from the Chinese tree, Camptotheca acuminata (Xi
Shu), by Wani and Wall in 1966 [1]. The primary cellular
target of CPT (1) is the covalent binary complex formed
between DNA and topoisomerase I (Topo I) during DNA
relaxation, and the stabilization of this complex by CPT (1)
is believed to lead to cell death [2]. Because of its remarkable
anticancer activity, numerous synthetic routes and various
derivatives have been developed over the past decades. Some
of its analogs, such as topotecan [3], irinotecan [4], and belo-
tecan [5], have been successfully used in clinical trials [6].
Previous structure–activity relationship studies [7]
revealed that the natural S-configuration at position 20
and the stability of ring E lactone (Fig. 1) are essential for
antitumor activity. Moreover, substitutions at position 7,
9, 10, or 11 have positive effect on antitumor activity.
Interestingly, some derivatives with an additional ring
attached at positions 9 and 10 (e.g., compounds 4, 5a, 5b,
and 6a–6c from our group [8] and compound 3 from You’s
group [9]) showed potent antitumor activities superior to
those of original pentacyclic CPTs. All of these compounds
were obtained from oxidation and cyclization of 9-allyl-10-
hydroxycamptothecin (2), which also displays outstanding
in vitro and in vivo activities (Scheme 1) [10,11]. Therefore,
large-scale synthesis of high purity compound 2 becomes
imperative for further research.
RESULTS AND DISCUSSION
Currently, there are two synthetic routes to construct
compound 2. The two-step approach starting from 10-
hydroxycamptothecin (7) is concise (Scheme 2) [12], but
byproduct 9 is difficult to be removed. Even after purification
As shown in Table 1, reaction solvent, base, temperature,
and time were taken into consideration. The optimum
© 2013 HeteroCorporation

1134
Y. Luo, S. Yu, Q. Huang, and W. Lu
Vol 51
condition preferred to employ anhydrous potassium car-
bonate in refluxing acetonitrile for 6 h.
because the methoxymethyl group might have more elec-
tron-donating ability than methoxyl group. Fortunately,
the addition of CsF instead of K2CO3 afforded 18 in yield
of 75%. Subsequently, compound 18 was hydrolyzed to
give the target compound 2. Purification through column
chromatography on silica gel gave compound 2 with more
than 99.8% purity (single impurity less than 0.1%).
With the aforementioned condition in hand, we started
to synthesize compound 2. Considering the accessibility
of deprotection, methoxymethyl was chosen as the protect-
ing group. As shown in Scheme 5, the hydroxyl group of
iodine 14, obtained from compound 7 and NIS in DMF
in 95% yield, was protected with methoxymethyl to give
17 in 90% yield. Then, compound 17 was reacted with
allylboronic acid pinacol ester via Suzuki reaction by our
optimal condition. However, the yield decreased to 45%
CONCLUSION
In summary, 9-allyl-10-hydroxycamptothecin (2), which
is a key intermediate for preparation of CPT derivatives
drugs, was obtained in good yield and high purity (≥99%
HPLC) under mild Suzuki reaction condition.
9
A
7
5
6
8
O
16
E
10
11
4
17
N
B
N 2
1
C
EXPERIMENTAL
D
13
3
1H NMR spectra were recorded on a DRX-500 (Bruker
Optics-Shanghai, China; 500 MHz). 13 C NMR spectra were
obtained on a JNM-EX400 (JEOL Ltd., Tokyo; 100 MHz). Mass
spectra (MS) were determined on a MAT-95 mass spectrometer
(Finnigan, Waltham, MA). Chemical shifts are reported for signal
center, and coupling constants are given in Hz.
12
O
14
15 20
19
OH
O
CPT (1)
18
Figure 1. The structure of CPT.
Scheme 1. 9-Allyl-10-hydroxycamptothecin as an important intermediate for the synthesis of other CPT derivatives.
O
O
O
O
O
N
N
N
N
O
O
3
4
OH
OH
O
O
HO
O
N
N
O
2
R
R
O
OH O
O
O
O
N
N
N
N
O
O
R=Br, 6a
R=OH, 6b
R=OAc, 6c
R=OH,5a
R=CH3, 5b
OH
O
OH
O
Scheme 2. Reagents and conditions: (a) DMF, K2CO3, and allyl bromide and (b) acetic acid, reflux.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
9-Allyl-10-hydroxycamptothecin via Suzuki Reaction
1135
9-Iodine-10-hydroxycamptothecin (14). To a solution of
collected, washed with water, and dried to afford compound 14
(2.5 g, 95% yield). H NMR (500 MHz, DMSO-d6) d : 0.87 (t,
J = 9.8 Hz, 3H), 1.83–1.90 (m, 2H), 5.26 (s, 2H), 5.40 (s, 2H),
6.44 (s, 1H), 7.25 (s, 1H), 7.52 (d, J = 9.0 Hz, 1H), 8.00 (d,
J = 9.0 Hz, 1H), 8.60 (s, 1H), 11.20 (s, 1H). 13C NMR
1
10-hydroxy-camptothecin (7) (2.0 g, 5.5 mmol) in DMF (50 mL)
at 0ꢀC, NIS (1.24 g, 5.5 mmol) was added. The mixture was
stirred for 2 h at room temperature and poured into ice water
(200 mL), adjusted pH 3–4 with 1N HCl. The precipitate was
Scheme 3. Reagents and conditions: (a) DMF, NBS, 95%; (b) ethyl chloroformate, pyridine, CH2Cl2, 85%; (c) toluene, Pd(PPh3)2Cl2, CsF, allyltri-n-
butyltin, reflux; and (d) KOH, MeOH, H2O.
Scheme 4
Table 1
Optimization of Suzuki reaction.a
Entry
Solvent
THF
THF
THF
Toluene
Toluene
Toluene
DMF
DMF
DMF
Base
CsF
NaOH
K2CO3
NaOH
K2CO3
CsF
Temperature (ꢀC)
Catalyst
Time (h)
Yield (%)b
1
Reflux
Reflux
Reflux
100
100
100
100
100
100
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
15
15
15
10
10
10
4
4
4
6
6
45
—
—
—
40
35
30
26
24
65
70
75
2c
3c
4c
5
6d
7d
8d
9d
10
11
12
CsF
NaOH
K2CO3
CsF
NaOH
K2CO3
Acetonitrile
Acetonitrile
Acetonitrile
Reflux
Reflux
reflux
6
aUnless otherwise indicated, the reaction conditions were as follows: compound 16 (1.0 mmol), Pd(Ph3P)4 (0.1 mmol), and base (3.0 mmol);
bIsolated yields;
cNo reaction occurred.
dMain product is 10-methoxycamptothecin.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Y. Luo, S. Yu, Q. Huang, and W. Lu
Vol 51
Scheme 5. Reagents and conditions: (a) DIPEA, CH2Cl2, 92%, MOMCl; (b) Pd(PPh3)4, CsF, acetonitrile; and (c) HCl(aq).
(125 MHz, DMSO-d6) d : 7.7, 30.3, 50.4, 65.2, 72.3, 83.2, 96.2,
118.5, 121.1, 130.9, 131.1, 131.7, 133.4, 144.0, 145.3, 150.0
(Â2), 156.8, 156.9, 172.4. MS (ESI): m/z = 491[M + H]+. HRMS
(ESI): m/z Calcd for C20H16N2O5I: 491.0104; found: 491.0102.
172.5; MS (EI): m/z = 404 [M]+; HRMS (ESI): m/z Calcd for
C23H20N2O5: 404.1372; found: 404.1374.
9-Iodine-10-methoxymethoxycamptothecin (17).
To a
Acknowledgments. This work was supported by the grants of the
National Natural Science Foundation of China (nos. 81172936
and 21102046), the Shanghai Science and Technology Mission
(10ZR1409600), and the Fundamental Research Funds for the
Central Universities. We also thank the Laboratory of Organic
Functional Molecules, the Sino-French Institute of ECNU
for support.
solution of compound 14 (2.0 g, 4.1 mmol) and N, N-
diisopropylethylamine (1.4 mL, 8.2 mmol) in CH2Cl2 (200 mL)
at room temperature, methyl chloromethyl ether (0.35 mL,
4.5 mmol) was added. The mixture was stirred for 2 h at same
temperature and adjusted to pH = 5 with 1N HCl. The mixture
was extracted with CH2Cl2, dried over anhydrous Na2SO4, and
concentrated to afford 2.0 g compound 17 (92% yield). 1H
NMR (500 MHz, DMSO-d6) d : 0.89 (t, J = 7.0 Hz, 3H), 1.84-
1.90 (m, 2H), 3.48 (s, 3H), 5.32 (s, 2H), 5.43 (s, 2H), 5.50 (s,
2H), 6.51 (s, 1H), 7.31 (s, 1H), 7.80 (d, J = 9.5 Hz, 1H), 8.18 (d,
J = 9.5 Hz, 1H), 8.76 (s, 1H). 13C NMR (125 MHz, DMSO-d6) d
: 7.8, 30.3, 50.5, 56.3, 65.2, 72.3, 88.6, 95.0, 96.6, 119.0,
119.7, 130.7, 131.0, 131.8, 134.4, 144.9, 145.0, 150.0, 151.4,
155.3, 156.7, 172.4; MS (ESI): m/z = 535 [M + H]+; HRMS
(ESI): m/z Calcd for C22H20N2O6I: 535.0366; found: 535.0363.
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9-Allyl-10-hydroxyl-camptothecin (2).
To a mixture of
compound 17 (0.4 g, 0.75 mmol), Pd(PPh3)4 (95 mg), CsF
(0.27 g, 1.8 mmol) in anhydrous acetonitrile (60 mL) at room
temperature under an argon atmosphere, allylboronic acid
pinacol ester (0.28 mL, 1.4 mmol) was added. The reaction
mixture was heated at 90ꢀC for 4 h. Then, the mixture was
cooled to room temperature and evaporated to dryness to give
the crude 18, which was dissolved in 1N HCl (20 mL), and was
heated at 60ꢀC for 5 h. The mixture was cooled to room
temperature and evaporated to dryness to give the crude
compound 2, which was further purified by column
chromatography (CH2Cl2 : MeOH = 50:1) to give pure 2 as a
pale yellow solid (0.2 g, two steps’ yield: 53%). Purity >99.8%
1
(HPLC analysis) and without byproduct 9. H NMR (500 MHz,
DMSO-d6) d : 0.89 (t, J = 7.0 Hz, 3H), 1.84-1.90 (m, 2H), 3.77
(d, J = 5.5 Hz, 2H), 4.95-5.00 (m, 2H), 5.21 (s, 2H), 5.40 (s,
2H), 5.95–6.00 (m, 1H), 6.47 (s, 1H), 7.26 (s, 1H), 7.52 (d,
J = 9.0 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 8.59 (s, 1H), 10.21 (s,
1H); 13C NMR (125 MHz, DMSO-d6) d : 7.7, 28.4, 30.2, 50.3,
65.2, 72.4, 95.8, 115.3, 117.1, 118.1, 122.2, 126.3, 128.4,
128.9, 129.6, 136.3, 143.6, 145.9, 148.9, 150.0, 153.7, 156.8,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet