COMMUNICATION
DOI: 10.1002/chem.201202701
A Convergent Approach to (À)-Callystatin A Based on Local Symmetry
Mathieu Candy,[a] Loꢀc Tomas,[a] Sabrina Parat,[a] Virginie Heran,[a] Hugues Bienaymꢁ,[b]
Jean-Marc Pons,*[a] and Cyril Bressy*[a]
(À)-Callystatin A 1 is a natural polypropionate belonging
to the Leptomycin family that was isolated by Kobayashi
et al. in 1997[1] from a marine sponge, Callyspongia truncata,
in very small amounts (1 mg for 1 kg of sponge). This natu-
ral product exhibits picomolar cytotoxic activity against sev-
eral cancer cell lines (IC50 =10 pgmLÀ1 against the KB cell
line and 20 pgmLÀ1 against the L1210 cell line). The mode
of action of (À)-callystatin A, common to the leptomycin
family, consists in the specific inhibition of the CRM1 (chro-
mosome region maintenance 1) protein, which is responsible
for the exportation of macromolecules from the nucleus to
the cytoplasm of eukaryotic cells. Mechanistically, the d-lac-
tone moiety acts as a Michael acceptor with the cysteine 528
residue of CRM1.[2] The covalent adduct then prevents the
formation of the exporting complex formed between CRM1,
proach based on the formation of the diene segments
through metal-mediated cross-coupling and/or olefination
reactions and hence on the disconnection of the natural
product in three fragments. Chiral pool and diastereoselec-
tive aldolization reactions with chiral auxiliaries were exten-
sively used to control the stereogenic centers. However, a
chiral pool could be particularly expensive in some cases
and to resort to chiral auxiliaries requires additional steps
for their introduction and removal. Among the enantioselec-
tive solutions to control stereogenic centers, catalytic desym-
metrizations of prochiral or meso compounds avoid these
drawbacks. Hence, the exploitation of hidden symmetry in
the target molecule represents a valuable alternative ap-
proach for the synthetic chemist.[5] We recently demonstrat-
ed the strength of hidden-symmetry-based strategy in the
synthesis of polypropionate natural products.[6] This straight-
forward approach provides valuable building blocks bearing
several stereogenic centers[7] by desymmetrization of a meso
intermediate.
the macromolecule to be exported, and
a cofactor,
RanGTP.[3] The structure of (À)-callystatin A includes an
unsaturated d-lactone, two (Z,E)- and (E,E)-1,3-diene units,
an isolated stereogenic center at C10 and a polypropionate
fragment including four stereogenic centers (Figure 1).
Herein, we report a new synthetic approach en route to
the synthesis of (À)-callystatin A exploiting the local sym-
metry. We particularly focused our efforts on the catalytic
enantiocontrol of strategic stereogenic centers, thus avoiding
the need for a chiral pool or chiral auxiliaries. In this pre-
liminary study, the synthesis of each fragment is described
and their coupling is examined.
Due to the sensitivity of the unsaturated d-lactone, we
planned a late construction of this subunit (Scheme 1).
Akitaꢀs procedure of isomerization/lactonization,[8] which
converts E-d-hydroxy-a,b-unsaturated carboxylic acids di-
rectly into dihydropyrones, led us to consider compound 2
as a plausible intermediate to reach the natural product.
From that, two strategic disconnections could be proposed:
Figure 1. Structure of (À)-callystatin A 1.
Due to its remarkable cytotoxic activity combined with its
complex structure, several groups[4] have focused their atten-
tion to the synthesis of (À)-callystatin A. Nearly all the re-
ported total syntheses have employed a convergent ap-
À
the C7 C8 bond (formed through a Stille cross-coupling)
À
and the C12 C13 bond (formed through a modified Julia
olefination), leading to three fragments. The pivotal local
symmetry present on the west fragment 3 would arise from
the meso diol 6. The central fragment 4 and the east frag-
ment 5 could come from itaconic acid 7 and enyne 8, respec-
tively.
[a] Dr. M. Candy, Dr. L. Tomas, Dr. S. Parat, Dr. V. Heran,
Prof. Dr. J.-M. Pons, Dr. C. Bressy
Aix-Marseille Universitꢁ, CNRS, iSm2 UMR7313
13397 Marseille Cedex 20 - Service 532 (France)
Fax : (+33)04-91-28-91-87
The synthesis of the west fragment 3 started with the en-
zymatic desymmetrization of meso diol 6, which was ob-
tained in three steps from methacroleine 9[9] (Scheme 2).
The conditions of asymmetric acetylation, described by ChÞ-
nevert and Courchesne[10] employing Candida rugosa, were
slightly modified to furnish monoacetate 10 quantitatively
[b] Dr. H. Bienaymꢁ
TARGEON, 65 rue Rambuteau
75004 Paris (France)
Supporting information for this article is available on the WWW
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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