An approach to the tricyclic core of madangamines based upon a biogenetic scheme

Article abstract of DOI:10.1021/ol050740i

(Chemical Equation Presented) A short synthesis of intermediates possessing the tricyclic core of natural madangamines, bioactive alkaloids found in marine sponges, is described. The key reaction entails the condensation of the sodium salt of diethylaceto

Full text of DOI:10.1021/ol050740i

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2437-2440
An Approach to the Tricyclic Core of
Madangamines Based upon a
Biogenetic Scheme
Han Min Tong, Marie-The´re`se Martin, Ange`le Chiaroni, Michel Be´ne´chie, and
Christian Marazano*
Institut de Chimie des Substances Naturelles, CNRS, 1 AVenue de la Terrasse,
91198 Gif-sur-YVette, France
marazano@icsn.cnrs-gif.fr
Received April 6, 2005
ABSTRACT
A short synthesis of intermediates possessing the tricyclic core of natural madangamines, bioactive alkaloids found in marine sponges, is
described. The key reaction entails the condensation of the sodium salt of diethylacetonedicarboxylate with a dihydropyridinium salt derivative.
This new approach is modeled on a biogenetic proposal linking madangamines to ircinals, related alkaloids occurring in sponges of the same
order.
Madangamine A (Figure 1) is a cytotoxic alkaloid that
exhibits inhibitory activity against a number of tumor cell
lines. It was isolated from the marine sponge Xestospongia
ingens by Andersen in 1994.1 The discovery of madangamine
A was followed by the isolation, from the same sponge, of
four analogues, madangamines B-E.2 These alkaloids belong
to a large family of natural products extracted from sponges
of the order Haplosclerida.3 Their tricyclic core is unprec-
edented, and this original structure has thus encouraged
substantial synthetic efforts. As a result two approaches4 to
the tricyclic core of madangamines have been reported to
date.
Interestingly, a hypothesis has been proposed to explain
the biosynthetic origin of madangamines.1 This hypothesis,
based on the initial proposal of Baldwin and Whitehead
(1) Kong, F.; Andersen, R. J.; Allen, T. M. J. Am. Chem. Soc. 1994,
Figure 1. Structures of madangamines A-E.
116, 6007-6008.
(2) Kong, F.; Graziani, E. I.; Andersen, R. J. J. Nat. Prod. 1998, 61,
267-271.
concerning the biosynthesis of manzamine alkaloids,5 sug-
gests that madangamines can be derived from keramaphidin-
like derivatives.
In this paper we present a related but quite different
pathway that links madangamines to ircinal derivatives
according to Scheme 1. This proposal is based on our
(3) For reviews, see: (a) Matzanke, N.; Gregg, R. J.; Weinreb, S. M.
Org. Prep. Proc. Int. 1998, 30, 3-51. (b) Tsuda, M.; Kobayashi, J.
Heterocycles 1997, 46, 765-794. (c) Andersen, R. J.; Van Soest, R. W.
M.; Kong, F. In Alkaloids: Chemical and Biological PerspectiVes; Pelletier,
S. W., Ed.; Elsevier Science: New York, 1996; Vol. 10, pp 301-355. (d)
Crews, P.; Cheng, X.-C.; Adamczeski, M.; Rodriguez, J.; Jaspar, M.;
Schmitz, F. J.; Traeger, S. C.; Pordesimo, E. O. Tetrahedron 1994, 50,
13567-13574.
10.1021/ol050740i CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/14/2005

Scheme 1. Possible Biogenetic Scenario Linking
Scheme 2. From the Biogenetic Scenario to a Synthetic
Madangamines to Ircinal Derivatives
Strategy
derivatives 9. In this paper we report, as a result of model
experiments, the success of this approach for the construction
of the tricyclic core of madangamines.
The synthesis of dihydropyridinium species corresponding
to 8 started from tetrahydropyridine 10 (Scheme 3), available
Scheme 3. Synthesis of Tetrahydropyridines 16a,b
suggested modification6 of the Baldwin and Whitehead
hypothesis in which manzamine alkaloids can alternatively
be viewed as derived from malondialdehyde and long chain
aminoaldehyde derivatives to give intermediates such as 1
(Scheme 1). Reduction of these intermediates followed by
oxidation can give access to ircinal derivatives such as ircinal
B (n ) 1), precursors of manzamines.
As an alternate pathway, intermediate 1 (n ) 3) was
reduced to give, after double-bond migration, amino aldehyde
2. Ring opening could then occur, leading to the imine
derivative 3 whose reduction would afford secondary amine
4. Cyclization to the corresponding double-iminium salt
derivative 5 could then produce produce pentacyclic inter-
mediate 6, a final double-bond migration affording madan-
gamine C.
Interestingly, intermediate 4 can be considered as being
in equilibrium with dihydropyridinium intermediate 7 via a
retro-vinylogous Mannich reaction (Scheme 2). This obser-
vation is at the origin of our retrosynthetic analysis of the
madangamine core skeleton. Accordingly, we decided to
target the dihydropyridinium salts of general structure 8 and
to study their reaction with acetone dicarboxylate as a
bisnucleophilic reagent in order to access to the tricyclic
in two steps from nicotinic acid methyl ester. Alkylation7
with n-butyl bromide afforded derivative 11, which was
reduced to aldehyde 12. Formation of imine 13 followed by
isomerization to 148 and hydrolysis gave primary amine 15.
Additionaly, reductive amination of aldehyde 12 with n-
butylamine followed by trifluoroacetylation afforded tet-
rahydropyridine 16a. Trifluoroacetylation of amine 15 finally
gave tetrahydropyridine 16b. Treatment of 16a or 16b
(Scheme 4) with m-CPBA afforded N-oxide derivatives 17a
and 17b, respectively, as a mixture of diastereoisomers that
can be separated by chromatography on silica gel (undefined
(4) (a) Matzanke, N.; Gregg, R. J.; Weinreb, S. M.; Parvez, M. J. Org.
Chem. 1997, 62, 1920-1921. (b) Yamazaki, N.; Kusanagi, T.; Kibayashi,
C. Tetrahedron Lett. 2004, 45, 6509-6512. For other synthetic efforts,
see: Vila, X.; Quirante, J.; Paloma, L.; Bonjoch, J. Tetrahedron Lett. 2004,
45, 4661-4664.
(5) Baldwin, J. E.; Whitehead, R. C. Tetrahedron Lett. 1992, 33, 2059-
2062. Baldwin, J. E.; Claridge, T. D. W.; Culshaw, A. J.; Heupel, F. A.;
Lee, V.; Spring, D. R.; Whitehead, R. C. Chem. Eur. J. 1999, 5, 3154-
3161 and references therein.
(7) Herrmann, J. L.; Kieczykowski, G. R.; Schlessinger, R. H. Tetrahe-
dron Lett. 1973, 14, 2433-2436.
(8) De Kimpe, N.; De Smaele, D.; Hofkens, A.; Dejaegher, Y.; Kesteleyn,
B. Tetrahedron 1997, 53, 10803-10816.
(6) Kaiser, A.; Billot, X.; Gateau-Olesker, A.; Marazano, C.; Das, B. C.
J. Am. Chem. Soc. 1998, 120, 8026-8034. Sanchez-Salvatori, M. d. R.;
Marazano, C. J. Org. Chem. 2003, 68, 8883-8889 and references therein.
2438
Org. Lett., Vol. 7, No. 12, 2005

Scheme 4. Synthesis of Salts 18, Analogues of Salts 8, and
Their Reactions with Acetone Dicarboxylate Diethylester as a
Bisnucleophilic Reagent
Figure 2. ORTEP drawing of adduct 19a. Displacement ellipsoids
are shown at the 30% probability level.
from N-oxides 17b and in a 65/35 ratio (Scheme 5). These
products were separated by chromatography on silicagel.
stereochemistry). The desired dihydropyridinium salts 18a
and 18b were, however, obtained using the conditions of
the Polonovski-Potier reaction9 on the corresponding crude
N-oxide diastereoisomeric mixtures.
Scheme 5. Madangamine Tricyclic Core Models
In a preliminary study, salt 18a was treated with the
sodium salt of acetone dicarboxylate diethyl ester at ambient
temperature, and the adducts were purified by chromatog-
raphy on silica gel. Three adducts 19a, 20a, and 21a were
isolated under these conditions in a 42/27/31 ratio, and their
structure was resolved by NMR spectroscopy.10 This struc-
tural attribution was further secured by an X-ray analysis of
adduct 19a, depicted in Figure 2. The results clearly showed
that the stereoselectivity of addition was rather low and in
favor of the undesired isomers 19a and 20a, which cannot,
in principle, form an amide bond with the masked secondary
amine to give the madangamine core.
However, this problem was shown to be easily overcome
on the basis of a study of the reaction starting from
dihydropyridinium salt 18b.
This result demonstrates that the “wrong” isomers 19 and
20 can in fact also give access to the desired tricyclic core
of madangamines via an interesting rearrangement. A simple
mechanism for this rearrangement, explaining the formation
of the tricyclic derivative 23, is depicted in Scheme 6. The
Thus, treatment of salt 18b with the sodium salt of acetone
dicarboxylate diethyl ester resulted in the formation of a
mixture of adducts. Adducts 19b and 21b were detected in
this mixture, but due to a difficult separation, only adduct
19b could be isolated and characterized.
Scheme 6. Proposed Mechanism for the Formation of
Tricyclic Derivative 23
However, when the crude mixture of adducts was treated
with an alkaline solution of EtOH/H2O at reflux, two tricyclic
derivatives 22 and 23 were obtained in 50% overall yield
(9) (a) Grierson, D. S.; Harris, M.; Husson, H.-P. J. Am. Chem. Soc.
1980, 102, 1064-1082. (b) For a review, see: Grierson, D. S. Org. React.
1990, 39, 85-295.
(10) All complex structures were resolved by intensive NMR spectro-
scopic studies, including one- and two-dimensional NMR experiments
(COSY 90, NOESY, HMQC, HMBC).
Org. Lett., Vol. 7, No. 12, 2005
2439

initial adduct 24 (equivalent to 19b and 20b if R ) CO2Et,
but R ) H is also to be considered) is likely to be in
equilibrium with enone 25 by a retro Michael process.
Rotation of the C-C bond adjacent to the quaternary center
then allows amide formation with the benzylic amino group
followed by Michael addition of the primary amine and
decarboxylation to give tricyclic derivative 23.
(10 steps from the readily accessible tetrahydropyridine 11).
Finally, it should be emphasized that the novel “3 + 3”
nucleophilic addition of acetone dicarboxylate esters to
dihydropyridinium salts described here, which gives adducts
such as 19-21, offers a practical access to the 2-azabicyclo-
[3.3.1]nonane framework.
In conclusion, the successful synthesis of madangamine
models 22 and 23 is encouraging for future work concerning
the total synthesis of madangamines based upon our bioge-
netically inspired strategy. The approach is stereoselective
and also offers some flexibility. In addition, this access to
the core skeleton of madangamines competes favorably with
other reported strategies with regard to the number of steps
Supporting Information Available: Experimental pro-
cedures and copies of NMR spectra for compounds 11-15,
16a,b, 17a,b, 18a,b, 19a,b, 20a, 21a, 22, and 23. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL050740I
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Org. Lett., Vol. 7, No. 12, 2005