Synthesis of (±)-camptothecin using a [3+2] nitrone cycloaddition to construct the CDE ring moiety

Article abstract of DOI:10.1016/j.tetlet.2004.08.025

A novel synthesis to camptothecin is described. A Friedlander condensation of o-aminobenzaldehye with tricylclic ketone affords camptothecin after further elaboration. Tricyclic ketone is prepared via a route employing a [3+2] nitrone cycloaddition and an intramolecular Knoevenagel condensation. A novel synthesis to camptothecin is described. A Friedlander condensation of o-aminobenzaldehye 2 with tricylclic ketone 3 affords camptothecin after further elaboration. Tricyclic ketone 3 is prepared via a route employing a [3+2] nitrone cycloaddition and an intramolecular Knoevenagel condensation.

Full text of DOI:10.1016/j.tetlet.2004.08.025

Tetrahedron
Letters
Tetrahedron Letters45 (2004) 7247–7250
Synthesis of ( )-camptothecin using a [3+2] nitrone cycloaddition
to construct the CDE ring moiety
Jurong Yu,* Jeffrey DePue and David Kronenthal
Department of Process Research and Development, Bristol-Myers Squibb, Pharmaceutical Research Institute,
One Squibb Drive, NewBrunswick, NJ 08903-0191, USA
Received 7 July 2004; accepted 4 August 2004
Available online 21 August 2004
Abstract—A novel synthesis to camptothecin is described. A Friedlander condensation of o-aminobenzaldehye 2 with tricylclic
ketone 3 affordscamptothecin after further elaboration. Tricyclic ketone 3 isprepared via a route employing a [3+2] nitrone cyclo-
addition and an intramolecular Knoevenagel condensation.
Ó 2004 Elsevier Ltd. All rights reserved.
Camptothecin is an alkaloid with a novel ring system,
which was first isolated from Camptotheca acuminata
by Wall et al. in 1966.1 For a number of years, it at-
tracted much attention because of its significant cyto-
toxic activity against a range of tumor cell lines.2
Recently, camptothecin and related compoundshave
returned to the forefront of experimental cancer treat-
ment.3 We became interested in developing a new syn-
thesis of camptothecin that would allow for the facile
incorporation of a variety of substituents on the A
and B rings. Herein, we report a new synthesis of ( )-
camptothecin involving a novel construction of the
CDE ring precursor 3 via a [3+2] nitrone cycloaddition
and an intramolecular Knoevenagel condensation
(Scheme 1).
the construction of camptothecin with the proper stere-
ochemistry at C-20. Further elaboration of the cycload-
dition
adducts,
including
an
intramolecular
Knoevenagel condensation, would provide an efficient
synthesis of 3 (see Scheme 3).
Nitrone 4 wasprepared from tetronic acid 6 (Scheme 2).
Protection of 6 followed by reduction with LiAlH4
afforded diol 7. The latter wasconverted to the corres-
ponding bis-mesylate, which was then treated with
hydroxylamine hydrochloride in triethylamine to give
hydroxylamine 8. Regioselective oxidation of 8 by mer-
cury(II) oxide at 0°C exclusively afforded the desired
nitrone 4.5,6
The [3+2] cycloaddition of nitrone 4 with racemic 5 pro-
ceeded regioselectively to produce a 1:1 mixture of dia-
stereomers 9A and 9B (Scheme 3).7,8 Both 9A and 9B
were ultimately transformed into 3. The two newly
created asymmetric centers (at C-3 and C-5) were con-
verted into sp2 carbons, thereby obviating the need to
separate the diastereomers. Initially, 9A and 9B were
separated by silica gel chromatography in order to
explore the subsequent steps using the pure diastereo-
mers. After these steps were examined preparative work
was carried out on the mixture of diastereomers. The
mixture of 9A and 9B wastreated with zinc in acetic acid
to cleave the N–O bond,9 and the resulting amino-
alcoholswere then acylated to afford 10 asa diastereo-
meric mixture. A one-pot conversion of alcohol 10 to
lactone 11 wasachieved by Swern oxidation, followed
Our synthesis of camptothecin took the ÔclassicalÕ Fried-
lander condensation approach, wherein the AB ring was
created by the condensation of o-aminobenzaldehyde 2
with tricyclic ketone 3.4 The synthesis of 3 wasbaesd
on the [3+2] cycloaddition of nitrone 4 with allylic alco-
hol 5. This approach would allow for a unique assembly
of the CDE ring of camptothecin, wherein the stereo-
chemistry present in the a-hydroxyamide moiety in 5
would be preserved, and this, in turn, would result in
Keywords: Camptothecin; Synthesis; [3+2] Nitrone cycloaddition;
CDE ring moiety.
*
Corresponding author. Tel.: +1 732 227 7485; fax: +1 732 227
3938; e-mail: jurong.yu@bms.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.025

7248
J. Yu et al. / Tetrahedron Letters 45 (2004) 7247–7250
O
O
E
B
N
C
A
N
A
B
N
C
O
D
D
N
O
O
-
C 20
CONEt2
OH O
( ) -Camptothecin (1)
13
O
O
O
O
N
C
A
B
N
O
CHO
NH2
D
N
+
O
CONEt2
O
CONEt2
13
2
3
O
-
O
O
+
O
O
N
N
NEt2
+
O
OH
O
CONEt2
O
3
4
5
Scheme 1.
-
OH
+
OH
O
O
N
N
O
OH
O
i, ii
iii, iv
50%
v
O
O
O
60%
O
70%
O
O
6
7
8
4
Scheme 2. Reagentsand conditions: (i) HO(CH 2)3OH/TsOH, EDC, 120°C, 5h; (ii) LAH (1.3equiv), THF, 0°C to rt, 3h; (iii) MsCl/NEt3, DCM,
À45°C, 3h; (iv) NH2OH/NEt3, 90°C, 5h; (v) HgO, DCM, 0°C, 24h.
+
O
-
O
O
O
OH
9B
H
3
O
O
N
H
3
N
N
5
5
NEt2
i
NEt2
NEt2
O
+
+
O
O
O
OH
O
H
OH
H
O
O
60%
9A
4
5
O
O
O
N
N
OEt
CONEt2
iv, v
ii, iii
75%
O
H
9A/B
55%
O
O
O
HO
O
O
CONEt2
H
OH
11
10
O
O
O
O
O
O
N
vii, viii
79%
N
vi
N
O
O
+
11
O
O
O
CONEt2
CONEt2
O
CONEt2
O
Br
3
12A
12B
Scheme 3. Reagentsand conditions: (i) THF, 80 °C, 24h; (ii) Zn, HOAc/THF/H2O (2:1:1), 0°C, 3h; (iii) (a) EtO2CCH2CO2H/EDAC, DCM, 25°C,
3h, (b) K2CO3/EtOH, 25°C, 3h; (iv) (COCl)2/DMSO/NEt3, DCM, À78°C to 25°C, 2h; (v) KOBut/EtOH, 25°C, 1h; (vi) KHMDS/NBS, À78°C to
25°C, 3h; (vii) Bu3SnH/AIBN, THF, 65°C, 17h; (viii) TFA/H2O (4:1), 25°C, 3h.
by intramolecular Knoevenagel condensation.10 Bromi-
nation/dehydrobromination using 2equiv of KHMDS
and NBS converted compound 11 to a 1:1 mixture of
the pyridone 12A and the over-brominated derivative

J. Yu et al. / Tetrahedron Letters 45 (2004) 7247–7250
7249
O
O
N
N
OH
O
i
ii
N
N
2 + 3
78%
O
O
13
14
CONEt2
CONEt2
O
O
N
N
iv
OAlX2
OAlX2
CONEt2
iii
N
N
28%
(from 13)
O
15
( ) 1
O
OH
Scheme 4. Reagentsand conditions: (i) PhMe, 25 °C, 1h; 80°C, 15h; (ii) (a) Dibal-H (7.5equiv), À78°C, 1h; (b) HOAc (10equiv), 25°C, 1h; (iii)
Dibal-H (10equiv), 50°C, 3h; (iv) 1N HCl, 85°C, 15h.
12B.11 Treatment of thismixture with Bu SnH/AIBN
3. For previous synthesis of camptothecin, see: (a) Chavan,
3
S. P.; Sivappa, R. Tetrahedron Lett. 2004, 45, 3113–3115;
left compound 12A undisturbed and reduced 12B to
(b) Blagg, B. S. J.; Boger, D. L. Tetrahedron 2002, 58,
6343–6349, and referencescited therein; For camptothecin
12A. Ketal hydrolysis then afforded tricyclic ketone 3.
related compounds, see: (c) Curran, D. P. The Campto-
thecins––A Reborn Family of Antitumor Agents. J. Chin.
Chem. Soc. 1993, 40, 1; (d) Potmesil, M. Cancer Res. 1994,
54, 1431; (e) Camptothecin: NewAnticancer Agents ;
Friedlander condensation of 2 and 3 generated lactone
13 (Scheme 4).12 Surprisingly, the reduction of 13
proved to be the most difficult step in this synthesis. A
number of hydride-reducing agentsand different condi-
3a,13
Potmesil, M., Pinedo, H., Eds.; CRC: Boca Raton, 1995.
4. (a) Synthesis of camptothecin via Friedlander condensa-
tion, see: Stork, G.; Schutz, A. G. J. Am. Chem. Soc. 1971,
93, 4074; (b) Volkmann, R.; Danishefsky, S.; Eggler, J.;
Solomon, D. M. J. Am. Chem. Soc. 1971, 93, 5576; (c)
Ejima, A.; Terasawa, H.; Sugimori, M.; Tagawa, H.
Tetrahedron Lett. 1989, 30, 2639; (d) Ejima, A.; Terasawa,
H.; Sugimori, M.; Tagawa, H. J. Chem. Soc., Perkin
Trans. 1 1990, 27; (e) Imura, A.; Itoh, M.; Miyadera, A.
Tetrahedron: Asymmetry 1998, 9, 2285.
tionswere examined for thistransformation.
How-
ever, most conditions resulted in the overreduction of
the quinoline and/or pyridone unit or decarbonylative
loss of the amide group, and, in general, mixtures of
such compounds were formed.13b Eventually, a one-
pot conversion of lactone 13 to ( )-camptothecin was
developed. Reduction of 13 with Dibal-H followed by
quenching with acetic acid generated lactol 14 in situ
(cf. Ref. 4a). Further treatment with additional Dibal-
H, generated 15, which wasthen cyclized to ( )-campt-
othecin 1 by exposure to 1N HCl.14 The proton NMR,
HPLC, and mass spectrum of the isolated, synthetic 1
were identical to those obtained from a commercially
available sample of camptothecin.15
5. Cicchi, S.; Goti, A.; Brandi, A. J. Org. Chem. 1995, 60,
4743.
6. The preparation of nitrone 16 and itscycloaddition has
been reported by Tufariello, J.; Lee, G. J. Am Chem. Soc.
1980, 102, 373. However, we found 16 to be unstable to
the conditionsrequired for the cycloaddition with 5(b).
When the HgO oxidation wasrun at room temperature,
ꢀ5% of the regioisomeric nitrone 17 wasproduced.
Acknowledgements
+
O
We thank Drs. Jeffrey Bien, Gerry Crispino, Jack Venit,
John Wasylyk, Bogdan Mudryk, and Edward Delaney
for many helpful discussions.
N
-
O
+
N
O
O
MeO
OMe
16
17
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.
7. Reviews: (a) Tufariello, J. J. In 1,3 Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley-Interscience: New York,
1984; Vol. 2, Chapter 9, pp 83–168; (b) De March, P.;
Figueredo, M.; Font, J. Heterocycles 1999, 50(2), 1213.
8. Racemic 5 wasprepared from N,N-diethyl 2-ketobutyr-
amide with vinyl magnesium bromide.
9. Chackalamannil, S.; Wang, Y. Tetrahedron 1997, 53(32),
11203.
10. Texier-Boullet, F.; Foucand, A. Tetrahedron Lett. 1982,
23, 4927.
11. Vinyl bromide 12B islikely formed through dibromide 20 .
12. (a) Wani, M. C.; Ronman, P. E.; Lindley, J. T.; Wall, M.
E. J. Med. Chem. 1980, 23, 554; (b) Yaegashi, T.; Sawada,
S.; Nagata, H.; Furuta, T.; Yokokura, T.; Miyasaka, T.
Chem. Pharm. Bull. 1994, 42, 2518.
2. Leading referencesand reviews: (a) Wall, M. E.; Wani, M.
C. Cancer Res. 1995, 55, 753; (b) Wall, M. E.; Wani, M. C.
In The Chemistry of Heterocyclic Compounds: Monoterp-
enoid Indole Alkaloids; Saxton, J. E., Ed.; John Wiley &
Sons: Chichester, UK, 1994; Vol. 25(4), pp 689–713; (c)
Wall, M. E.; Wani, M. C.; Nicholas, A. W.; Manikuma,
G.; Tele, C.; Moore, L.; Truesdale, A.; Leitner, P.;
Besterman, J. M. J. Med. Chem. 1993, 36, 2689; (d)
Suffness, M.; Cordell, G. A. In The Alkaloids; Brossi, A.,
Ed.; Academic: Orlando, FL, 1985; Vol. 25, Chapter 1,
See esp. p 75 ff; (e) Wall, M. E.; Wani, M. C.; Taylor, H.
Cancer Chemother. Rep. 1976, 60, 1011.

7250
J. Yu et al. / Tetrahedron Letters 45 (2004) 7247–7250
O
O
O
N
H
N
H
N
H
-HBr
-HBr
11
12B
12A
Br
Br
Br
Br
18
20
19
13. For the reduction of similar systems, see: (a) Schultz, A.
Chem. Rev. 1973, 73, 385; (b) Ciufolini, M. A.; Rosc-
hangar, F. Tetrahedron 1997, 53(32), 11049, The use of
NaBH4/CeCl3 wasreported in the quantitative reduction
of a lactone similar to 13. However, NaBH4/CeCl3
resulted in over-reduction of 13.
14. The major by-productswere 21 and 22 with the combi-
nation of these impurities typically comprising greater
than 20% of the total reaction mixture.
CDCl3) d 7.27 (s, 1H), 3.97–4.25 (m, 6H), 3.88–3.97 (m,
1H), 3.49–3.59 (m, 1H), 3.17–3.28 (m, 1H), 3.06–3.15 (m,
1H), 2.54–2.67 (m, 2H), 2.34–2.45 (m, 1H), 2.17–2.29
(m, 1H), 2.01–2.11 (m, 1H), 1.58–1.64 (m, 1H), 1.21 (t,
J = 8Hz, 3H), 1.14 (t, J = 8Hz, 3H), 0.88 (t, J = 84Hz,
3H); 13C NMR (500MHz, CDCl3) d 7.69, 12.40, 14.78,
25.12, 30.04, 32.17, 42.67, 42.75, 45.60, 61.95, 62.16, 88.51,
98.08, 105.29, 112.41, 155.77, 155.90, 166.18, 166.47,
169.09. 3: 1H NMR (400MHz, CDCl3) d 7.40 (s, 1H),
4.42–4.55 (m, 1H), 4.37 (t, J = 9Hz, 2H), 3.92–4.0 (m, 1H),
3.40–3.52 (m, 1H), 3.22–3.32 (m, 1H), 3.12–3.21 (m, 1H),
3.03 (t, J = 9Hz, 2H), 2.35–2.42 (m, 1H), 1.24 (t,
J = 8.5Hz, 3H), 1.15 (t, J = 8.5Hz, 3H), 0.87 (t,
J = 8.5Hz, 3H). 13: 1H NMR (400MHz, CDCl3) d 8.43
(s, 1H), 8.24 (d, J = 8Hz, 1H), 7.95 (d, J = 8Hz, 1H), 7.90
(s, 1H), 7.85 (t, J = 8Hz, 1H), 7.70 (t, J = 8Hz, 1H), 5.38
(d, J = 23.8Hz, 1H), 5.32 (d, J = 23.8Hz, 1H), 3.85–4.00
(m, 1H), 3.45–3.55 (m, 1H), 3.25–3.35 (m, 1H), 3.15–3.25
(m, 1H), 2.42–2.52 (m, 1H), 2.17–2.28 (m, 1H), 1.26
(t, J = 9Hz, 3H), 1.15 (t, J = 9Hz, 3H), 0.92 (t, J = 9Hz,
3H).
O
O
N
N
O
N
N
Me
OH
O
21
22
Et
CONEt2
Et
15. Spectral data for key intermediates: 4: 1HNMR (400MHz,
CDCl3) d 7.44 (s, 1H), 3.7–4.1 (m, 6H), 2.44 (m, 2H), 1.9–
2.1 (m, 1H), 1.55–1.75 (m, 1H). 12A: 1H NMR (500MHz,