Concise synthesis of anhydrovinblastine from leurosine.

Article abstract of DOI:10.1021/ol025560c

[reaction: see text] The Cp(2)TiCl-mediated deoxygenation of leurosine (1) afforded anhydrovinblastine (4) in good yield. Furthermore, as the reaction proceeded via a carbon-centered radical intermediate, this transient was also trapped by a hydrogen-atom donor to afford selectively reduced alkaloid 10.

Full text of DOI:10.1021/ol025560c

ORGANIC
LETTERS
2
002
Vol. 4, No. 7
151-1153
Concise Synthesis of
Anhydrovinblastine from Leurosine
1
Christophe Hardouin, Eric Doris,* Bernard Rousseau, and Charles Mioskowski
CEA/Saclay, SerVice de Marquage Mol e´ culaire et de Chimie Bioorganique, B aˆ t. 547,
D e´ partement de Biologie Joliot-Curie, 91191 Gif sur YVette Cedex, France
eric.doris@cea.fr
Received January 15, 2002
ABSTRACT
The Cp
via a carbon-centered radical intermediate, this transient was also trapped by a hydrogen-atom donor to afford selectively reduced alkaloid
0.
2
TiCl-mediated deoxygenation of leurosine (1) afforded anhydrovinblastine (4) in good yield. Furthermore, as the reaction proceeded
1
1
Leurosine (1) is one of the most abundant bisindole alkaloids
isolated from the leaves of the Madagascan periwinkle
Catharantus roseus. It was formerly classified in the family
of Vinca alkaloids, which also included vinblastine (2),
inhibit mitosis by binding to tubuline, thus allowing a broad
spectrum of activity in the treatment of various carcinomas.2
The synthesis of Navelbine (5) requires two steps: the
biomimetic coupling of two monomers (catharanthine (6) and
vindoline (7)) to afford anhydrovinblastine 4, followed by
,4
2
vincristine (3), and anhydrovinblastine (4) (Scheme 1).
Together with vinorelbine (5) (Navelbine), a semisynthetic
3
5
contraction of the latter’s C′ ring (Scheme 2). Anhydrovin-
derivative currently on the market, these dimeric alkaloids
blastine is thus the key intermediate in the synthesis of the
anticancer drug Navelbine. Herein, we would like to report
a one-step procedure for the synthesis of anhydrovinblastine
(
4) starting from the parent alkaloid leurosine (1). Since the
Scheme 1
alkaloids 1 and 4 differ only by the presence of an epoxide
on the “northern” portion of leurosine, the selective deoxy-
(
1) For an X-ray structure of leurosine methiodide, see: Hardouin, C.;
Doris, E.; Rousseau, B.; Mioskowski, C.; Nierlich, M. Acta Crystallogr.
000, C56, 225-226.
2) The Alkaloids. Antitumor Bisindole Alkaloids from Catharanthus
Roseus (L.). Brossi, A., Suffness, M., Eds.; Academic Press: San Diego,
2
(
1
990; Vol. 37.
3) Langlois, N.; Gu e´ ritte, F.; Langlois, Y.; Potier, P. J. Am. Chem. Soc.
976, 98, 7017-7024.
(
1
(4) Zavala, F.; Gu e´ nard, D.; Potier, P. Experientia 1978, 34, 1497-1499.
Gu e´ ritte, F.; Pouilh e` s, A.; Mangeney, P.; Andriamialisoa, R. Z.; Langlois,
N.; Langlois, Y.; Potier, P. Eur. J. Med. Chem.-Chim. Ther. 1983, 18, 419-
4
6
24. Lobert, S.; Vulevic, B.; Correia, J. J. Biochemistry 1996, 35, 6806-
814.
(5) Mangeney, P.; Andriamialisoa, R. Z.; Lallemand, J. Y.; Langlois,
N.; Langlois, Y.; Potier, P. Tetrahedron 1979, 35, 2175-2179. Andriami-
alisoa, R. Z.; Langlois, N.; Langlois, Y.; Potier, P. Tetrahedron 1980, 36,
3053-3060.
1
0.1021/ol025560c CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/05/2002

4
unambiguously by spectroscopic and chromatographic
comparison with an authentic sample.
Scheme 2
A postulated reaction mechanism is illustrated in Scheme
4. In the first step, the sequential single electron transfer from
Scheme 4
Cp TiCl to the oxirane and homolysis of the C-O bond
2
generate the â-alkoxy radical 8. The relative stability of the
carbon-centered radical intermediate (for example, tertiary
>
secondary > primary) governs the regiochemistry of the
ring opening. Upon reaction with a second equivalent of Cp
2
-
genation of the cyclic ether should thus provide direct access
to anhydrovinblastine, as previously demonstrated by Atta-
ur-Rahman (Scheme 3).6
TiCl, the â-alkoxy carbanion 9 results. Subsequent elimina-
tion of a titanium-oxo byproduct finally delivers deoxy-
genated anhydrovinblastine 4.
The intermediacy of a radical species similar to 8 prompted
us to trap this transient by a hydrogen-atom donor.10 Such
radical capture would produce a vinblastine-type alkaloid
analogous to 10 by selective reduction of the epoxide
Scheme 3
(Scheme 5). To corroborate this hypothesis, a THF solution
Scheme 5
Our strategy involves the utilization of a low-valent
titanium species for the key deoxygenation step. Indeed,
7
Nugent and RajanBabu reported that Cp
2
TiCl efficiently
promotes the conversion of epoxides to the corresponding
8
olefins under mild conditions. Leurosine (1) was therefore
reacted with Cp
The low-valent titanium(III) complex was readily prepared
by the in situ reduction of 2.5 equiv of Cp TiCl with 5 equiv
2
TiCl for 15 min at room temperature in THF.
of Cp
2
TiCl was added dropwise to a mixture of leurosine
(1) and a 10-fold excess of 2-methyl-2-propanethiol. Inverse
2
2
addition of the titanium reagent to the epoxide was advanta-
9
of powdered zinc for 45 min. The reaction produced
anhydrovinblastine (4) cleanly in 70% yield; we identified
(8) RajanBabu, T. V.; Nugent, W. A.; Beattie, M. S. J. Am. Chem. Soc.
1
990, 112, 6408-6409. RajanBabu, T. V.; Nugent, W. A. J. Am. Chem.
Soc. 1994, 116, 986-997. See also: Schobert, R. Angew. Chem., Int. Ed.
(6) Atta-ur-Rahman; Perveen, S. J. Nat. Prod. 1988, 51, 1271-1272.
7) Gans a¨ uer, A.; Bluhm, H. Chem. ReV. 2000, 100, 2771-2788. Li, J.
Engl. 1988, 27, 855-856.
(
(9) Hardouin, C.; Chevallier, F.; Rousseau, B.; Doris, E. J. Org. Chem.
2001, 66, 1046-1048.
J. Tetrahedron 2001, 57, 1-24.
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Org. Lett., Vol. 4, No. 7, 2002

geous to minimize the competing deoxygenation to anhy-
drovinblastine. This furnished an alkaloid derivative to which
we tentatively assign the structure of the bisindole 10. It
should be noted that we obtained this product only in modest
yield (11%) and as a single diastereomer, albeit with
unknown stereochemistry of the ethyl group.
of a vinblastine-type alkaloid by selective reduction of the
epoxide moiety of leurosine.
1
1
Acknowledgment. This work is part of a collaboration
between Pierre Fabre M e´ dicament/CEA-Direction des Sci-
ences du Vivant. Dr. J. Albert Ferreira is gratefully acknowl-
edged for reviewing this manuscript.
In conclusion, we have shown that the low-valent Cp
2
-
TiCl efficiently deoxygenates leurosine to anhydrovinblas-
1
2
tine. A modified procedure was also applied to the synthesis
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 4 and 10. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
10) Gans a¨ uer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem. Soc. 1998,
20, 12849-12859. Gans a¨ uer, A. Synlett 1998, 801-809.
11) Kutney, J. P.; Honda, T.; Kazmaier, P. M.; Lewis, N. J.; Worth, B.
R. HelV. Chim. Acta 1980, 63, 366-374.
12) Sz a´ ntay, C., Jr.; Bal a´ zs, M.; B o¨ lcskei, H.; Sz a´ ntay, C. Tetrahedron
991, 47, 1265-1274.
1
(
(
1
OL025560C
Org. Lett., Vol. 4, No. 7, 2002
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