A practical formal synthesis of camptothecin

Article abstract of DOI:10.1016/j.tetlet.2007.07.017

The synthesis of the DE ring of camptothecin using simple and inexpensive starting materials, employing an addition elimination reaction and selective esterification of an aliphatic carboxylic acid as key steps is described.

Full text of DOI:10.1016/j.tetlet.2007.07.017

Tetrahedron Letters 48 (2007) 6561–6563
A practical formal synthesis of camptothecin
Subhash P. Chavan,* Ashok B. Pathak and Uttam R. Kalkote
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411 008, India
Received 21 May 2007; revised 25 June 2007; accepted 5 July 2007
Available online 2 August 2007
Abstract—The synthesis of the DE ring of camptothecin using simple and inexpensive starting materials, employing an addition
elimination reaction and selective esterification of an aliphatic carboxylic acid as key steps is described.
Ó 2007 Elsevier Ltd. All rights reserved.
Camptothecin 1 was isolated from the Chinese plant
Camptotheca acuminata by Wall and Wani in 1966.1
Camptothecin and its analogues collectively called
camptothecins, have been isolated from various plant
species,2 and show potent antitumour activity and a
unique mechanism of action, which inhibits DNA topo-
isomerase I. Camptothecin cannot be used as a drug due
to its low solubility and toxic nature but its two
analogues, irinotecan 2 and topotecan 3 are marketed
as anticancer drugs and others are in clinical trials.
Due to its challenging structure and broad spectrum of
activity 1 has attracted significant attention from syn-
thetic and medicinal chemists and pharmacologists.
To date, a number of syntheses of 1 have been reported,
the first total synthesis being described by Stork et al. in
1971.4 However, due to its low availability and high
demand, our group has been interested in developing a
simple and practical synthesis of camptothecin and its
derivatives. Various approaches have been developed
by us,5a–c for the construction of the D ring of campto-
thecin. The clinical use of 1 has been limited by its insol-
ubility and toxicity, but extensive structure activity
relation studies have identified many analogues with
better solubility and with equal or better antitumour
activity. Synthetic approaches towards these analogues
have typically involved syntheses of suitably functional-
ized CDE-rings or DE-rings or precursors thereof,
which have then been coupled with suitable counter-
parts. Recently, Hiroya et al.6 synthesized the DE ring
of camptothecin employing a Lewis acid catalyzed
Michael addition on pyridone, however, selective intro-
duction of a nucleophile at the 4-position was a prob-
lem, which also furnished the product of nucleophilic
addition at C-6 in low yields.
R2 R1
R3
O
A
B
N
C
N
D
E
O
OH
O
1 R1, R2, R3 = H, Camptothecin
2 R1 = Et, R2 = H, R3
=
.HCl 3H2O, Irinotecan
N
OCON
3 R1 = H, R2 = CH2NMe2.HCl, R3 = OH, Topotecan
The main structural feature of camptothecin is, a penta-
cyclic quinoline alkaloid containing an unstable six-
membered a-hydroxy lactone. Camptothecin and its
analogues show significant biological activity against
various cancers and recently one of its analogues Foeti-
dine has been shown to exhibit potent anti-HIV activity.3
Here we report a simple and practical synthesis of the
DE-ring of camptothecin from simple and inexpensive
starting materials employing an addition elimination
reaction on 4-chlorodihydropyridone as the key step
Scheme 1.
The synthesis commenced from 4 as the starting material,
which was prepared according to the literature proce-
dure.7 Ketoester 4 was refluxed with POCl3 in anhydrous
dichloromethane to deliver 4-chlorodihydropyridone 5 in
Keywords: Natural product; Alkaloid; Camptothecin; Anticancer.
*
Corresponding author. Tel.: +91 20 25902289; fax: +91 20
25902629; e-mail: sp.chavan@ncl.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.017

6562
S. P. Chavan et al. / Tetrahedron Letters 48 (2007) 6561–6563
Ph
Ph
Ph
Ph
N
O
N
O
N
O
N
O
d
c
b
a
COOEt
COOEt
COOEt
COOEt
Cl
5
O
4
EtOOC
COOEt
EtOOC
COOEt
6
7
Ph
Ph
Ph
Ph
N
O
N
O
N
O
g
N
O
f
h
e
COOH
COOH
COOH
COOEt
O
COOMe
EtOOC
COOEt
O
9
8
11
10
Ph
H
N
O
N
O
O
N
i
Ref. 11
N
HO
O
HO
O
O
HO
O
O
12
O
1
13
Scheme 1. Reagents and conditions: (a) POCl3 (1.2 equiv), CH2Cl2, reflux, 3 h, 97%. (b) NaH (1.2 equiv), diethyl malonate (1.2 equiv), C6H6, rt,
overnight, 85%. (c) DDQ (1.2 equiv), anhydrous 1,4 dioxane, reflux, 6 h, 96%. (d) K2CO3 (3.0 equiv), ethyl iodide (1.2 equiv), anhydrous acetone,
reflux, 12 h, 91%. (e) LiOH (5.0 equiv), EtOH, rt, 24 h, 84%. (f) NiCl2 (0.1 equiv), MeOH, reflux, 12 h, 76%. (g) (i) Et3N (1.0 equiv), methyl
chloroformate (1.0 equiv), anhydrous THF, 0 °C, 1 h. (ii) NaBH4 (4.0 equiv), À78 °C, 3 h, 10% HCl, rt, 12 h, 84%. (h) CuCl2 (4.0 equiv), Me2NH,
O2, DMF, rt, 24 h, 92%. (i) Pd(OH)2, H2, EtOH, 50 °C, 5 h, 62%.
excellent yield. The addition–elimination reaction of
diethyl malonate was accomplished on 5 using sodium hy-
dride as a base to furnish product 6 in very good yield.
Aromatization of dihydropyridone 6 was carried out
using DDQ in refluxing 1,4-dioxane to furnish pyridone
7 in 96% yield. Alkylation of 7 with ethyl iodide gave
alkylated product 8 in 91% yield. Ester hydrolysis fol-
lowed by decarboxylation was achieved in one-pot using
excess lithium hydroxide at room temperature to furnish
diacid 9. The selective mono esterification of the non-aro-
matic acid in the presence of the aromatic acid was accom-
plished using nickel chloride as the catalyst to deliver
compound 10 in good yield.8 Aromatic acid 10 was sub-
jected to treatment with methyl chloroformate using tri-
ethylamine as base in THF at 0 °C to form a mixed
anhydride and subsequent reduction of the mixed anhy-
dride to the alcohol followed by lactonization was
achieved using NaBH4 to furnish 11 in 84% yield.9 It is
pertinent to mention that compared to our earlier synthe-
sis5a for selective differentiation of an ester, here we
avoided the use of DIBAL-H, which is hazardous, diffi-
cult to handle and involves a tedious workup. Hydroxyl-
ation of 11 was carried out using CuCl2 and a catalytic
amount of dimethylamine under an oxygen atmosphere
to afford a-hydroxy lactone 12 in 98% yield.10 Finally
N-debenzylation of 12 was successfully carried out
employing a catalytic amount of palladium hydroxide
in ethanol under H2 at 50 °C to furnish the desired DE-
ring synthon 13 in 62% yield. The spectral data of com-
pound 13 was in complete agreement with reported
data.11 Since 13 was also an intermediate in Comins’ syn-
thesis of 1,12 this constitutes a formal synthesis of
camptothecin.
In conclusion, we have achieved a practical formal syn-
thesis of camptothecin 1 employing an addition elimina-
tion reaction and selective differentiation of an aliphatic
carboxylic acid over a heteroaromatic carboxylic acid as
the key steps in 22% overall yield. This strategy could
also be useful for the synthesis of the CDE-ring of 1 syn-
thon of camptothecin and its analogues.
Acknowledgement
A.B.P. thanks CSIR, New Delhi, India, for a fellowship
and S.P.C. thanks the DST, New Delhi, India, for
funding.
References and notes
1. Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.;
McPhail, A. T.; Sim, G. A. J. Am. Chem. Soc. 1966, 88,
3888–3890.
2. (a) Hecht, S. M.; Newman, D. J.; Kingston, D. G. I. J.
Nat. Prod. 2000, 63, 1273–1276; (b) Das, B.; Madhusudan,
P.; Reddy, P. V.; Anita, Y. Indian J. Chem. 2001, 40B, 453;
(c) Kitajima, M.; Yoshida, S.; Yamagata, K.; Nakamura,
M.; Takayama, H.; Saito, K.; Seki, H.; Aimi, N. Tetra-
hedron 2002, 58, 9169; (d) Puri, S. C.; Verma, V.; Amna,
T.; Quzi, G. N.; Spiteller, M. J. Nat. Prod. 2005, 68, 1717.
3. Priel, E.; Showalter, S. D.; Blair, D. G. AIDS Res. Hum.
Retroviruses 1991, 7, 65–72.
4. Stork, G.; Schultz, A. G. J. Am. Chem. Soc. 1971, 93,
4074.
5. (a) Chavan, S. P.; Venkatraman, M. S. Tetrahedron Lett.
1998, 39, 6745–6748; (b) Chavan, S. P.; Sivappa, R.

S. P. Chavan et al. / Tetrahedron Letters 48 (2007) 6561–6563
6563
Tetrahedron Lett. 2004, 45, 3113–3115; (c) Chavan, S. P.;
Pasupathy, K.; Venkatraman, M. S.; Kale, R. R. Tetra-
hedron Lett. 2004, 45, 6879–6882.
11. Spectral data of compound 13: Mp: 225 °C (lit. 227 °C);
IR (CHCl3) m: 3273, 2930, 1754, 1651, 1620, 1472, 1470,
1160, 837 cmÀ1
;
1H NMR (CDCl3+CCl4+DMSO-d6,
6. Hiroya, K.; Kawamoto, K.; Sakamoto, T. Synlett 2006,
2636–2640.
7. Ibenmoussa, S.; Chavignon, O.; Teulade, J.-C.; Viols, H.;
Debouzy, J.-C.; Chapat, J.-P.; Gueiffier, A. Heterocycl.
Commun. 1998, 4, 317–324.
8. Ram, R. N.; Charles, I. Tetrahedron 1997, 53, 7335–7340.
9. Su, J.; Qiu, G.; Liang, S.; Hu, X. Synth. Commun. 2005,
35, 1427.
400 MHz) d: 0.98 (t, J = 7.2 Hz, 3H), 1.80 (q, J =
7.2 Hz, 2H), 3.72 (s, 1H), 5.15 (d, J = 16.1 Hz, 1H), 5.55
(d, J = 16.1 Hz, 1H), 6.67 (d, J = 6.8 Hz, 1H), 7.42 (d,
J = 6.8 Hz, 1H); 13C NMR (CDCl3+CCl4+DMSO-d6,
100 MHz) d: 7.8, 30.1, 65.2, 72.1, 102.4, 119.1, 134.8,
150.1, 159.1, 172.7; ESI-MS (m/z): 210 (M+1)+, 232
(M+Na)+; Anal. Calcd for C10H11NO4: C, 57.41; H, 5.30;
N, 6.70. Found: C, 57.39; H, 5.34; N, 6.73.
10. Rapoport, H.; Tang, C. S. F.; Morrow, C. J. J. Am. Chem.
Soc. 1975, 97, 159–167.
12. Comins, D. L.; Hao, H.; Saha, J. K.; Gao, J. J. Org.
Chem. 1994, 59, 5120.