Formal synthesis of (±)-camptothecin via tricyclic lactone as key synthon

Article abstract of DOI:10.1016/j.tetlet.2010.04.019

Formal synthesis of (±)-camptothecin via CDE tricyclic lactone employing tandem Michael addition, Dieckmann condensation and addition-elimination reaction as key steps starting from glycinate is described.

Full text of DOI:10.1016/j.tetlet.2010.04.019

Tetrahedron Letters 51 (2010) 3099–3101
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Formal synthesis of ( )-camptothecin via tricyclic lactone as key synthon
*
Subhash P. Chavan , Abasaheb N. Dhawane, Uttam R. Kalkote
Division of Organic Chemistry, National Chemical Laboratory (CSIR), Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 February 2010
Revised 5 April 2010
Accepted 8 April 2010
Available online 11 April 2010
Formal synthesis of ( )-camptothecin via CDE tricyclic lactone employing tandem Michael addition, Die-
ckmann condensation and addition–elimination reaction as key steps starting from glycinate is
described.
Ó 2010 Elsevier Ltd. All rights reserved.
Camptothecin 1, isolated from the Chinese plant Camptotheca
acuminata by Wall and Wani in 1966,1 elicited extensive interest
due to its potent antitumor activity. The initial excitement quickly
waned, because of problems associated with its insolubility and
toxicity.2 Liu and co-workers in 1985 reported that camptothecin
had an unique mechanism of action that concerned selective inhi-
bition of DNA topoisomerase I.3 This disclosure served to regener-
ate interest in camptothecinoids and has led to the development of
its analogues viz. topotecan4 (Hycamtin) 2 and irinotecan5 (Cam-
ptosar) 3 which are marketed as anticancer drugs. While one of
its analogues foetidine 4 exhibits anti-HIV activity,6 others are in
different stages of clinical trials.7
Due to its excellent biological activity many research groups are
attracted to synthesise camptothecin8,9 and its analogues. How-
ever, most of the reported syntheses have drawbacks, involving
lengthy routes and/or expensive starting materials, hazardous re-
agents or tedious reaction conditions and/or proceed in low overall
yields. To overcome these problems there still exists a need to de-
velop simple, practical and efficient process for the synthesis of
camptothecin.
In keeping with our interest in the synthesis of camptothe-
cin9b,c,f,10 and its analogues, we decided to undertake the synthesis
of CDE tricyclic lactone 5 (Scheme 1) which is the most versatile
synthon to access a variety of camptothecin derivatives. Synthetic
R2 R1
R3
O
O
A
B
N
C N
OH
D
N
N
E
O
O
O
HO
O
OH
O
O
HN
NH
1 Camptothecin R1 , R2 , R3 = H
2. Topotecan R 1=H, R2=CH2NMe2,HCl, R3=OH
3. Irinotecan R1=Et, R2=H, R3=OCOPipPip,HCl 3H2O
4. Foetidine
approaches of the analogues have typically involved synthesis of
suitably functionalised CDE-ring or DE-ring or precursors thereof,
which was then coupled with appropriate counter parts. In this
* Corresponding author. Tel.: +91 20 25902289; fax: +91 20 25902629.
E-mail address: sp.chavan@ncl.res.in (S.P. Chavan).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.019

3100
S. P. Chavan et al. / Tetrahedron Letters 51 (2010) 3099–3101
EtOOC
O
NCbz
O
6
b
c
NCbz
ref 10a
EtOOC
NHCbz
a
-
NCbz
+
O
NH3Cl
O
O
O
O
7
8
9
10
h
O
O
O
O
NCbz
O
g
N
d
f
N
NCbz
+
COOEt
O
O
O
O
COOEt
COOMe
COOMe
COOH
O
14
e
11
12
13
O
O
O
O
O
O
O
N
O
i
N
N
j
k
N
O
O
O
O
CHO
COOEt
COOEt
COOEt
COOEt
COOEt
Cl
O
COOEt
19
EtOOC
EtOOC
EtOOC
R
15
18
16 R = H
17 R = Et
EtOOC
COOEt
X
O
O
O
O
N
N
N
n
l
m
O
N
O
O
O
O
O
HO
EtOOC
20
O
5
( )-1
Scheme 1. Reagents and conditions: (a) NaH (1.2 equiv), ethyl acrylate (1.2 equiv), C6H6, rt 1 h, refluxed 2–3 h, 72%; (b) NaCl (4.0 equiv), DMSO–H2O (3:1), 120–130 °C, 3 h,
78%; (c) 1,2-ethane diol, cat. PTSA, benzene, reflux, 8 h, 90%; (d) (i) OsO4, acetone/water (3:1), NaIO4, 3 h; (ii) oxone, methanol, rt, 16 h; (e) diazomethane, ether 0 °C–rt, 12 h,
95%; (f) (i) Pd/C, ethanol, 60 psi, 2 h; (ii) K2CO3, DCM, ethyl malonyl chloride, 0 °C–rt, 1 h, 88% (over two steps); (g) NaH, ethanol, rt, 3 h, 98%; (h) POCl3, DCM, reflux, 4 h; (i)
NaH, diethylmalonate, anhydrous benzene, rt, overnight, 65%; (j) DDQ, dioxane, reflux, 48 h, 98%; (k) DIBAL-H, THF, À60 °C, 2 h, 83%; (l) NaBH4, methanol, 0 °C, 5 min 90%; (m)
10% HCl, 90–100 °C, 6 h, 82%; (n) Ref. 13.
Letter we wish to report a practical, simple and efficient synthesis
of camptothecin via CDE skeleton which would have the flexibility
to obtain the analogues of camptothecin from inexpensive, com-
mercially available starting materials.
anhydrous benzene at room temperature overnight afforded the
desired compound 16 in 65% yield. Aromatisation of 16 was
achieved by employing DDQ as the oxidant in refluxing dioxane
to furnish pyridone 18 in 98% yield. The next task was to selec-
tively reduce hetero aromatic ester to aldehyde. Earlier10a we have
shown that although this type of transformation could be readily
accomplished by use of DIBAL-H, it may be pointed out that in a re-
lated study conducted recently12 towards the synthesis of DE syn-
thon of camptothecin, the aliphatic ester was preferentially
reduced along with reduction of pyridone ring. It was therefore
heartening to note that when the aromatic ester in pyridone 18
was subjected to selective reduction using 3 equiv of DIBAL-H in
THF as a solvent at À60 °C, it afforded the desired aromatic alde-
hyde 19 in 83% yield. Aldehyde 19 on further treatment with so-
dium borohydride in THF/H2O (9:1) at 0 °C furnished the lactone
20 in 90% yield. Acetal deprotection, ester hydrolysis and decar-
boxylation was carried out in one-pot by refluxing lactone 20 with
10% HCl for 6 h to afford the CDE tricyclic lactone 5 in 82% yield.
The spectral data of compound 5 were in complete agreement with
reported data.13,14 Since 5 was also an intermediate in Shamma’s
synthesis of camptothecin 1,13 this constitutes a formal synthesis
of camptothecin.
Synthesis started from urethane 7 as the starting material,
which was prepared from glycinate 610a described by us. Urethane
7 was subjected to one-pot Michael addition, followed by Dieck-
mann cyclisation with ethyl acrylate using NaH as a base, to afford
the keto ester 8 in 72% yield. Keto ester 8 was subjected to hydro-
lysis-decarboxylation under Krapcho conditions to afford the keto
compound 9, which was protected as acetal using ethylene glycol
to afford urethane 10 in 90% yield. Urethane 10 was subjected to
oxidative cleavage by using catalytic osmium tetraoxide followed
by sodium periodate to afford an intermediate aldehyde. The crude
aldehyde on treatment with oxone11 in methanol at room temper-
ature afforded ester urethane 11 in 60% yield along with acid 12 in
25% yield. Acid 12 was converted into required methyl ester 11 on
treatment with diazomethane in 95% yield.
To synthesise D ring, ester 11 was subjected to benzyl carba-
mate deprotection by using Pd/C at 60 psi pressure followed by
condensation with ethyl malonyl chloride using K2CO3 as a base
in anhydrous DCM to afford the amide 13 in 88% yield over two
steps. Amide 13 was treated with sodium hydride in ethanol at
0 °C to yield the cyclised compound in 98% yield, which existed
in the keto form 14. The keto compound 14 without purification
was treated with POCl3 in anhydrous dichloromethane at reflux
temperature to furnish chloro compound 15.
In conclusion we have described formal synthesis of ( )-cam-
ptothecin via tricyclic lactone employing simple reaction condi-
tions and from cheap, commercially available starting material
with an overall yield of 12.1%.
The resulting chloro compound 15 being unstable was immedi-
ately subjected to addition elimination reaction with diethyl 2-eth-
ylmalonate, it did not furnish the desired product. However, the
reaction of diethyl malonate using sodium hydride as the base in
Acknowledgements
A.N.D. thanks CSIR, New Delhi, India, for a fellowship and S.P.C.
acknowledges funding from DST, New Delhi, India.

S. P. Chavan et al. / Tetrahedron Letters 51 (2010) 3099–3101
3101
N.; Greene, A. E. Synlett 2008, 2275; (e) Liu, G. S.; Dong, Q. L.; Yao, Y.; Yao, Z. Org.
Lett. 2008, 10, 2008; (f) Chavan, S. P.; Dhawane, A. N.; Kalkote, U. R. Synlett
2008, 2781. and references cited therein.
References and notes
1. Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; MacPhail, A. T.; Sim, G. A. J.
Am. Chem. Soc. 1966, 88, 3888.
10. (a) Chavan, S. P.; Venkatraman, M. S. Tetrahedron Lett. 1998, 39, 6745; (b)
Chavan, S. P.; Sivappa, R. Tetrahedron Lett. 2004, 45, 3113; (c) Chavan, S. P.;
Pasupathy, K.; Venkatraman, M. S.; Kale, R. R. Tetrahedron Lett. 2004, 45, 6879;
(d) Chavan, S. P.; Sivappa, R. Tetrahedron Lett. 2004, 45, 3941; (e) Chavan, S. P.;
Venkatraman, M. S. ARKIVOC 2005, 165.
2. (a) Gottlieb, J. A.; Luce, J. K. Cancer Chemother. Rep. 1972, 56, 103; (b) Moertel, C.
G.; Schutt, A. J.; Reitemerier, R. J.; Hahn, R. G. Cancer Chemother. Rep. 1972, 56, 95.
3. (a) Hsiang, Y. H.; Hertzberg, R.; Hecht, S. M.; Liu, L. F. J. Biol. Chem. 1985, 260,
14873; (b) Hsiang, Y. H.; Liu, L. F. Cancer Res. 1988, 48, 1722; (c) Khon, K. W.;
Pommier, Y. Ann. N.Y. Acad. Sci. 2000, 922, 11; (d) Staker, B. L.; Hjerrild, K.;
Feese, M. D.; Behnke, C. A.; Burgin, A. B., Jr.; Stewart, L. Proc. Natl. Acad. Sci.
2002, 99, 15387.
4. Kingsbury, W. D.; Boehm, J. C.; Jakas, D. R.; Holden, K. G.; Hecht, S. M.;
Gallagher, G.; Caranfa, M. J.; McCabe, F. L.; Faucette, L. F.; Johnson, R. K.;
Hertzberg, R. P. J. Med. Chem. 1991, 34, 98.
5. (a) Negoro, S.; Fukuoka, M.; Masuda, N.; Takada, M.; Kusunoki, Y.; Matsui, K.;
Takifuji, N.; Kudoh, S.; Niitani, H.; Taguchi, T. J. Natl. Cancer Inst. 1991, 83, 1164;
(b) Kawato, Y.; Aonuma, M.; Hirata, Y.; Kuga, H.; Sato, K. Cancer Res. 1991, 51,
4187.
6. Priel, E.; Showalter, S. D.; Blair, D. G. AIDS Res. Hum. Retroviruses 1991, 7, 65.
7. (a) Cragg, G. M.; Newman, D. J. J. Nat. Prod. 2004, 67, 232; (b) Butler, M. S. J. Nat.
Prod. 2005, 22, 162.
8. Review on camptothecin and its derivatives, see: (a) Wall, M. E.; Wani, M. C.. In
In the Alkaloids; Cordell, G. A., Ed.; Academic press: San Diego, CA, 1998; Vol. 50,
p 509. Chapter 13; (b) Cuendet, M.; Pezzuto, J. M. In Modern Alkaloids: Structure,
Isolation, Synthesis and Biology; Fattorusso, E., Taglialatela-Scafati, O., Eds.;
Wiley-VCH: Weinheim, 2008; pp 29–33. Chapter 2; (c) Hutchison, C. R.
Tetrahedron 1981, 37, 1047; (d) Du, W. Tetrahedron 2003, 59, 8649; (e) Thomas,
C. J.; Rahier, N. J.; Hecht, S. M. Bioorg. Med. Chem. 2004, 12, 1585.
9. For several recent syntheses of camptothecin, see: (a) Zhou, H. B.; Liu, G. S.;
Yao, Z. J. Org. Lett. 2007, 9, 2003; (b) Chavan, S. P.; Pathak, A. B.; Kalkote, U. R.
Tetrahedron Lett. 2007, 48, 6561; (c) Chavan, S. P.; Pathak, A. B.; Kalkote, U. R.
Synlett 2007, 2635; (d) Kanazawa, A.; Muniz, M. N.; Baumlová, B.; Ljungdahl,
11. Borhan, B.; Hollist, G. O.; Sivakumar, M.; Travis, B. R. Org. Lett. 2003, 5, 1031.
12. Chavan, S. P.; Dhawane, A. N.; Kalkote, U. R. Synlett 2009, 1524.
13. Shamma, M.; Smithers, D. A.; Georgier, V. S. Tetrahedron 1973, 29, 1949.
14. NMR data for selected compound.
Compound 16 1H NMR (CDCl3, 200 MHz): d 1.25–1.38 (m, 9H), 2.04–2.08 (m,
2H), 2.47 (dd, J = 16.8 and 5.05, 1H), 2.66 (dd, J = 13.7 and 16.8 Hz, 1H), 3.48–
3.74 (m, 2H), 3.86 (dd, J = 13.7 and 5.05 Hz, 1H), 3.94–4.03 (m, 4H), 4.19–4.38
(m, 6H), 4.77 (s, 1H); 13C NMR (CDCl3, 50 MHz) d: 13.85, 13.87, 13.9, 25.8, 33.5,
41.9, 55.0, 59.5, 61.6, 62.10, 62.17, 65.2, 113.4, 130.8, 143.2, 159.5, 164.7,
165.7, 166.3 ppm. MS (ESI) m/z: 448 (M+Na)+.
Compound 18 1H NMR (CDCl3, 200 MHz): d 1.28 t, J = 7.20 Hz, 6H), 1.38 (t,
J = 7.07, 3H), 2.39 (t, J = 6.95, 2H), 4.18–4.30 (2q, J = 7.20, 4H), 4.41 (q, J = 7.07,
2H), 4.09–4.17 (m, 6H), 4.88 (s, 1H), 6.47 (s, 1H); 13C NMR (CDCl3, 50 MHz) d:
13.8, 14.0, 33.5, 45.0, 54.4, 61.7, 62.2, 65.5, 100.0, 112.8, 124.7, 144.8, 149.6,
157.9, 165.4, 166.3 ppm. MS (ESI) m/z: 424 (M+H)+, 446 (M+Na)+.
Compound 19 1H NMR (CDCl3, 500 MHz): d 1.28 (t, J = 7.2, 6H), 2.43 (t, J = 6.7,
2H), 4.12–4.18 (m, 6H), 4.24 (q, J = 7.2, 4H), 6.08 (s, 1H), 6.39 (s, 1H), 10.47 (s,
1H); 13C NMR (CDCl3, 125 MHz): d 13.9, 33.4, 45.1, 52.9, 62.1, 65.7, 101.1,
113.0, 121.5, 150.1, 154.0, 161.9, 166.9, 192.1 ppm. MS (ESI) m/z: 380 (M+H)+,
402 (M+Na)+.
Compound 5 1H NMR (CDCl3 + CCl4, 400 MHz): d 2.97 (t, J = 6.7, 2H), 3.66 (s,
2H), 4.35 (t, J = 6.7, 2H), 5.44 (s, 2H), 6.75 (s, 1H); 13C NMR (CDCl3, 100 MHz): d
33.6, 34.1, 42.1, 66.2, 102.5, 126.6, 139.6, 142.4, 157.7, 167.2, 195.8 ppm. MS
(ESI) m/z: 219 (M)+, 242 (M+Na)+.