A novel, expeditious synthesis of racemic camptothecin

Article abstract of DOI:10.1021/ol0509641

(Chemical Equation Presented) A novel and efficient synthesis of racemic camptothecin, starting from a readily accessible hydroxy pyridone, is presented. Key steps include a Claisen rearrangement of a functionalized allylic ether, a hindered Heck coupling

Full text of DOI:10.1021/ol0509641

ORGANIC
LETTERS
2
005
Vol. 7, No. 14
989-2991
A Novel, Expeditious Synthesis of
Racemic Camptothecin
2
Regan J. Anderson, Gajendra B. Raolji, Alice Kanazawa,* and Andrew E. Greene
UniVersit e´ Joseph Fourier de Grenoble, Chimie Recherche (LEDSS),
38041 Grenoble, France
alice.kanazawa@ujf-grenoble.fr
Received April 29, 2005
ABSTRACT
A novel and efficient synthesis of racemic camptothecin, starting from a readily accessible hydroxy pyridone, is presented. Key steps include
a Claisen rearrangement of a functionalized allylic ether, a hindered Heck coupling, and a Friedlander condensation.
1
Isolated from the Chinese plant Camptotheca acuminata by
Wall and co-workers in 1966, camptothecin (1) elicited
widespread interest due to its potent antitumor activity.
currently in clinical and preclinical trials.
1
,2
The initial excitement quickly waned, however, because of
problems associated with its insolubility and toxicity. Several
3
years later, though, it was reported that camptothecin had a
unique mechanism of action that involved selective inhibition
of DNA topoisomerase I. This disclosure served to rekindle
4
interest in camptothecinoids and has led to topotecan (2a)
and irinotecan (2b), as well as several other analogues
5
6
The camptothecinoids and camptothecin in particular have
been targeted by numerous research groups, which has
resulted in many imaginative syntheses over the past several
(
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, 3888-3890.
2) For reviews on camptothecin and its derivatives, see: (a) Du, W.
Tetrahedron 2003, 59, 8649-8687. (b) Lansiaux, A.; Bailly, C. Bull. Cancer
003, 90, 239-245. (c) Camptothecins: New Anticancer Agents; Potmesil,
2
decades. Although several of the approaches are direct and
(
high-yielding, for the most part they are not open to facile
variation. We have previously described a route to the
2
M., Pinedo, H., Eds.; CRC Press: Boca Raton, 1995. (d) Sawada, S.;
Yokokura, T.; Miyasaka, T. Curr. Pharm. Des. 1995, 1, 113-132. (e) Torck,
M.; Pinkas, M. J. Pharm. Belg. 1996, 51, 200-207. (f) Hutchinson, C. R.
Tetrahedron 1981, 37, 1047-1065.
7
camptothecinoids based on a bicyclization strategy. In this
communication we wish to disclose a conceptually different
8
approach founded on a 1,3-dipolar cycloaddition. This new
(3) Hsiang, Y. H.; Hertzberg, R.; Hecht, S.; Liu, L. F. J. Biol. Chem.
camptothecinoid approach, now demonstrated by the prepa-
1
8
985, 260, 14873-14878. See also: Rothenberg, M. L. Ann. Oncol. 1997,
, 837-855. Pommier, Y.; Pourquier, P.; Fan, Y.; Strumberg, D. Biochim.
Biophys. Acta 1998, 1400, 83-105. Palumbo, M.; Gatto, B.; Sissi, C. In
DNA and RNA Binders; Demeunynck, M., Bailly, C., Wilson, W. D., Eds.;
Wiley: Weinheim, 2003; Vol. 2, Chapter 19.
(5) 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, 1164-1168. Kawato, Y.; Aonuma, M.; Hirota, Y.; Kuga,
H.; Sato, K. Cancer Res. 1991, 51, 4187-4191.
(6) Cragg, G. M.; Newman, D. J. J. Nat. Prod. 2004, 67, 232-244.
Butler, M. S. Nat. Prod. Rep. 2005, 22, 162-195.
(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, 98-107.
1
0.1021/ol0509641 CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/10/2005

ration of camptothecin (as its racemate), is convergent at
several points, which should make it well-suited for eventual
structural modification of the natural product.
Scheme 3
Padwa and co-workers have developed over the past
several years elegant chemistry based on isom u¨ nchnone
cycloadditions.9 In a particularly interesting example,
,10
9a
diazo imide 3 was converted into isom u¨ nchnone 4, which
underwent cycloaddition in situ with methyl acrylate to
furnish, ultimately, hydroxy pyridone 5a; treatment of 5a
with acid readily yielded hydroxy pyridone 5b (Scheme 1).
Scheme 1
and cesium carbonate to give derivative 5c, in preparation
for a Claisen rearrangement to introduce a substituent in the
â position (Scheme 3). This etherification proved uneventful,
as did the subsequent thermally induced Claisen rearrange-
ment, and hydroxy pyridone 6a could be secured in good
yield. Hydrogenation of 6a over Pd/C then afforded hydroxy
pyridone 6b, in which the desired â substituent was now in
place.
We felt that this hydroxy pyridone might serve as a
precursor of a wide range of camptothecinoids if (1)
appropriate appendages for eventual hydroxy lactone con-
struction could be joined to 5b at the R and â positions to
give I; (2) benzylic-type oxidation could be achieved at some
point in the presence of existing functionality to produce II;
1
2
The introduction of the R substituent proved to be much
more problematic. The derived triflate 7a failed to yield
serviceable amounts of R coupled product with a large array
of palladium catalysts, ligands, and tin and boron reagents.
Several standard Heck procedures with styrene or methyl
acrylate were also examined for this transformation but
afforded the desired product in, at best, moderate yield.
Fortunately, however, greater success was achieved under
(
3) Friedl a¨ nder condensation and eventual hydroxyl-group
deprotection could be accomplished (Scheme 2).
Scheme 2
13
Jeffery’s conditions: palladium acetate in conjunction with
tetrabutylammonium acetate in acetonitrile at 80 °C delivered
the styryl derivative 7b in a remarkable 83% yield.
Lactone construction was completed by treatment of 7b
with ozone in the presence of pyridine at -100 °C, followed
by reduction of the resultant aldehyde with sodium borohy-
dride, which provided lactone 8 in 80% overall yield (Scheme
4
). Of the protocols examined for benzylic-type oxidation
The synthesis began with etherification of hydroxy pyri-
done 5b with (Z)-methyl 4-chloro-2-methoxybut-2-enoate
of lactone 8 or other intermediates (e.g., R-formyl and
R-styryl derivatives), selenium dioxide with 8 proved to
1
1
14
(
7) Mekouar, K.; G e´ nisson, Y.; Leue, S.; Greene, A. E. FR 99 06757,
May, 1999. Leue, S.; Gar c¸ on, S.; Greene, A. E.; G e´ nisson, Y.; L e´ on, P. FR
0 11769, September, 2000. Leue, S.; Miao, W.; Kanazawa, A.; G e´ nisson,
Y.; Gar c¸ on, S.; Greene, A. E. J. Chem. Soc., Perkin Trans. 1 2001, 2903-
905.
8) The present work represents a significant extension of our earlier
(10) For reviews on isom u¨ nchnone cycloadditions, see: McMills, M.
C.; Wright, D. In The Chemistry of Heterocyclic Compounds: Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles
and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley and
Sons: New York, 2002; pp 253-314. Mehta, G.; Muthusamy, S.
Tetrahedron 2002, 58, 9477-9504. Padwa, A. Top. Curr. Chem. 1997, 189,
121-158. Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223-269.
Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis, 1994, 123-141.
Padwa, A. Acc. Chem. Res. 1991, 24, 22-28.
0
2
(
mappicine ketone (nothapodytine B) synthesis. See: Raolji, G. B.; Gar c¸ on,
S.; Greene, A. E.; Kanazawa, A. Angew. Chem., Int. Ed. 2003, 42, 5059-
5
061.
(9) (a) Padwa, A.; Sheehan, S. M.; Straub, C. S. J. Org. Chem. 1999,
(11) Farina, C.; Gagliardi, S.; Parini, C.; Pinza, M.; Nadler, G.;
Marguerite, M. G.; Morvan, M. J-M. PCT Int. Appl. WO 9621644, 1996.
(12) For reviews on the Claisen rearrangement, see: Rhoads, S. J.;
Raulins, N. R. Org. React. 1975, 22, 1-252. Blechert, S. Synthesis 1989,
71-82. Martin Castro, A. M. Chem. ReV. 2004, 104, 2939-3002.
(13) Jeffery, T. Tetrahedron 1996, 52, 10113-10130. For Pd couplings
on related substrates, see: Earl, R. A.; Vollhardt, K. P. C. J. Org. Chem.
1984, 49, 4786-4800 and ref 9a.
6
4, 8648-8659. See, also: (b) Hertzog, D. L.; Austin, D. J.; Nadler, W.
R.; Padwa, A. Tetrahedron Lett. 1992, 33, 4731-4734. (c) Padwa, A.;
Hertzog, D. L.; Nadler, W. R.; Osterhout, M. H.; Price, A. T. J. Org. Chem.
1
994, 59, 1418-1427. (d) Marino, J. P., Jr.; Osterhout, M. H.; Price, A.
T.; Semones, M. A.; Padwa, A. J. Org. Chem. 1994, 59, 5518-5520. (e)
Padwa, A.; Hertzog, D. L.; Nadler, W. R. J. Org. Chem. 1994, 59, 7072-
7
1
6
084. (f) Marino, J. P., Jr.; Osterhout, M. H.; Padwa, A. J. Org. Chem.
995, 60, 2704-2713. (g) Sheehan, S. M.; Padwa, A. J. Org. Chem. 1997,
2, 438-439. (h) Harris, J. M.; Padwa, A. Org. Lett. 2003, 5, 4195-4197.
(14) Shen, W.; Coburn, C. A.; Bornmann, W. G.; Danishefsky, S. J. J.
Org. Chem. 1993, 58, 611-617.
2990
Org. Lett., Vol. 7, No. 14, 2005

cleave the methyl protecting group in 10, which indeed
smoothly provided camptothecin in 86% yield. The synthetic
material (mp 264-265 °C, dec) was chromatographically
and spectroscopically identical with an authentic sample of
the natural product.
Scheme 4
To summarize, a new approach to camptothecin and its
congeners, which is both concise and efficient, has been
developed from readily available hydroxy pyridone 5b. The
approach offers excellent opportunities for asymmetric
1
7
induction; these modifications, as well as other aspects,
are presently being studied and will be discussed in a future
publication.
Acknowledgment. We thank Professor P. Dumy for his
interest in our work. Financial support from the Universite´
Joseph Fourier and the CNRS (UMR 5616, FR 2607) is
gratefully acknowledged.
be the most efficacious and afforded the hydroxy derivative
15
9
in 62% yield (68% brsm). As the corresponding crude
Supporting Information Available: Complete experi-
mental procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
ketone, formed with the Dess-Martin periodinane, proved
unstable to purification, it was directly subjected to Fried-
l a¨ nder condensation1 with an o-aminobenzaldehyde sur-
rogate to afford quinoline 10 in 77% yield (2 steps). Since
we had previously found camptothecin to be surprisingly
stable in hot aqueous HBr, these conditions were applied to
4,16
OL0509641
(16) For a review on the Friedl a¨ nder quinoline synthesis, see: Cheng,
C.-C.; Yan, S. J. Org. React. 1982, 28, 37-201.
(17) See: Nubbemeyer, U. Synthesis 2003, 961-1008. Abraham, L.;
K o¨ rner, M.; Hiersemann, M. Tetrahedron Lett. 2004, 45, 3647-3650 and
references therein.
(
15) Selenium dioxide oxidation of styryl derivative 7b proceeded more
rapidly, but the hydroxy product was less stable to SiO2 purification, which
resulted in a lower isolated yield.
Org. Lett., Vol. 7, No. 14, 2005
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