Novel, efficient total synthesis of natural 20(S)-camptothecin

Article abstract of DOI:10.1039/b611202a

A modular approach to racemic and achiral camptothecinoids from the Padwa hydroxypridone which is based in part on a Claisen rearrangement and a Friedlander condensation was analyzed. The elements necessary for the construction of the chiral hydroxyl lactone derivative would be introduced by a Claisen rearrangement for the β substituent and a Heck coupling for the α substituent. Hydroxypyridone 3 was obtained in high yield from 2 pyrrolidinone and then converted into crotonate 4 in 96% yield through reaction with methyl 4 bromocrotonate. To cleave oxidatively the ethylidene group in 5a, it proved necessary to first deactivate the hydroxypyridone moiety by triflation and this permitted the desired scission to proceed selectively with ozone in dichloromethane to give keto ester 6 in 96% yield. Result shows that a new synthesis of 20 (S)-camptothecin has been developed which is both efficient and flexible.

Full text of DOI:10.1039/b611202a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Novel, efficient total synthesis of natural 20(S)-camptothecin†
Chao-Jun Tang, Matej Babjak, Regan J. Anderson, Andrew E. Greene and Alice Kanazawa*
Received 2nd August 2006, Accepted 6th September 2006
First published as an Advance Article on the web 18th September 2006
DOI: 10.1039/b611202a
Enantiopure 20(S)-camptothecin has been prepared from
a known hydroxypyridone through a novel approach that
involves a Claisen rearrangement, an asymmetric nucleophilic
ethylation, a Heck coupling and a Friedla¨nder condensation
as the key transformations.
of an a-keto ester (or lactone) derivative has yet to be exploited for
this purpose, in spite of the fact that adjacency of an aromatic
ring or an alkoxycarbonyl group tends to impact favorably
on asymmetric addition to keto and aldehydic carbonyls.10 In
this paper an effective asymmetric synthesis of natural 20(S)-
camptothecin through the use of such a strategy is disclosed.
We have recently illustrated a modular approach to racemic and
achiral camptothecinoids from the Padwa hydroxypyridone11 that
Camptotheca acuminata is a tree indigenous to China, where it
is known as xi shu and used in traditional medicine for a wide
spectrum of symptoms.1 Camptothecin (1) (Fig. 1), present in the
fruit, bark, and wood of this plant, was first isolated by Wall and
colleagues in 1958 from its stem wood and structurally elucidated
a few years later.1–3
Preclinical studies of this alkaloid in leukemia and carci-
nosarcoma models proved promising, but its general insolubility
subsequently generated a number of problems, as well as mis-
leading results. However, later elucidation of its in vivo lactone
chemistry and novel mechanism of action, which involves the
selective inhibition of DNA topoisomerase I, rekindled the initial
excitement and has led to several syntheses of camptothecin, as
well as to the preparation of a number of more soluble congeners.
Two such analogs, Irinotecan (2a) and Topotecan (2b), are now
commercially available (ovarian, cervical, colon, colorectal, and
lung cancers) and several others are presently in preclinical and
clinical trials.4,5
is based in part on a Claisen rearrangement and a Friedlander
condensation.12 These are adaptable, highly versatile transfor-
mations that have been retained in our asymmetric approach,
which is outlined retrosynthetically for camptothecin in Chart
1. The natural product was to be secured by deprotection of the
Friedla¨nder product derived from condensation of keto pyridone
II, obtained by oxidation of pyridone I. The elements necessary
for the construction of this chiral hydroxy lactone derivative would
be introduced by a Claisen rearrangement for the b substituent
and a Heck coupling for the a substituent, starting from the
Padwa hydroxypyridone 3, which is readily prepared through
isomu¨nchnone cycloaddition chemistry.13
¨
Chart 1 Retrosynthesis of camptothecin (1).
Hydroxypyridone 3 was obtained in high yield from 2-
pyrrolidinone, as previously described,11 and then converted
into crotonate 4 in 96% yield through reaction with methyl 4-
bromocrotonate (Scheme 1). The crotonate rearranged smoothly
in hot o-dichlorobenzene (DCB) to give the b,c-unsaturated ester
Claisen product,14 which without purification was isomerized
through exposure to piperidine at 20 ◦C to provide the acrylate
derivative 5a (84%, 2 steps).
To cleave oxidatively the ethylidene group in 5a, it proved
necessary to first deactivate the hydroxypyridone moiety by
triflation (98%); this permitted the desired scission to proceed
selectively with ozone in dichloromethane at −90 ◦C to give
keto ester 6 in 96% yield. With this keto ester in hand, the
key asymmetric nucleophilic ethylation was next undertaken. The
method recently described by DiMauro and Kozlowski15 provided
Fig. 1 Camptothecin (1), Irinotecan (2a), and Topotecan (2b).
Published asymmetric syntheses of these molecules have in-
volved a number of different approaches for introducing the 20(S)
configuration, which include the use of chemical and enzymatic
resolutions,6 chiral pool-derived precursors,7 chiral auxiliaries,8
and asymmetric hydroxylation and dihydroxylation reactions.9
Most surprisingly, however, asymmetric nucleophilic ethylation
Chimie Recherche (LEDSS), Universite´ Joseph Fourier, 38041 Grenoble,
France. E-mail: Alice.Kanazawa@ujf-grenoble.fr; Fax: 33 4 76514494;
Tel: 33 4 76514686
† Electronic supplementary information (ESI) available: Experimental
description and product characterization data for the conversion of 3 into
1. See DOI: 10.1039/b611202a
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Scheme 2 Conversion of ester 7b into 20(S)-camptothecin (1).
Acknowledgements
We thank Prof. P. Dumy and Dr G. B. Raolji for their interest in
our work. Financial support from the Universite´ J. Fourier and
the CNRS (UMR 5616, FR2607) is gratefully acknowledged.
Scheme 1 Synthesis of enantiopure ester 7b.
References
an exceptionally pleasing result: a 95% conversion of 6 and an ee of
7a of 90%.16 Equally pleasing was that simple recrystallization of
the product provided pure material (>99% ee, 62% overall yield).
To the best of our knowledge, this is the first application of this
effective method in natural product synthesis.
Methyl ether protection of the C-20 hydroxyl was chosen over
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was discovered that the conditions recently described by Eustache
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methyl ether 7b, an intermediate in our racemic synthesis, but now
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D
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spectroscopically and chromatographically identical with a sample
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was run with 14% catalyst at −90 ◦C. At higher temperatures, there was
significant secondary alcohol formation.
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17 Natural camptothecin was recovered enantiopure18 and in >80% yield
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0.5 mL min−1. tR of R isomer = 41.5 min; tR of S isomer = 34.6 min.
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23 The authentic sample of 20(S)-camptothecin was purchased from
Sigma-Aldrich ([a]20 +43 (c 0.2 in 1 : 4 MeOH : CHCl3), mp 260–
D
261 ◦C, dec.).
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The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 3757–3759 | 3759
©