Synthesis of novel polycyclic indolyldiamines

Article abstract of DOI:10.1021/ol047408b

(Chemical Equation Presented) A rapid and stereoselective access to novel polycyclic indolyldiamines is described. The key step involves simple chemoselective transformations of a common bicyclic aminal intermediate, easily available on a large scale from

Full text of DOI:10.1021/ol047408b

ORGANIC
LETTERS
2005
Vol. 7, No. 10
1911-1913
Synthesis of Novel Polycyclic
Indolyldiamines
Sabrina Cutri,† Anna Diez,*,‡ Martine Bonin,*,† Laurent Micouin,† and
Henri-Philippe Husson†
Laboratoire de Chimie The´rapeutique, Faculte´ des Sciences Pharmaceutiques et
Biologiques, UMR 8638 associe´e au CNRS et a` l’UniVersite´ Rene´ Descartes, 4 aV de
l’ObserVatoire, 75270 Paris Cedex 06, France, and Parc Cient´ıfic de Barcelona,
c/Josep Samitier, 1-5 08028 Barcelona, Spain
martine.bonin@uniV-paris5.fr
Received December 17, 2004
ABSTRACT
A rapid and stereoselective access to novel polycyclic indolyldiamines is described. The key step involves simple chemoselective transformations
of a common bicyclic aminal intermediate, easily available on a large scale from an enantiomerically pure cyano oxazolopiperidine precursor.
The design and synthesis of structurally diverse, optically
pure diamines continues to be an area of intense research in
medicinal and coordination chemistry, as well as in asym-
metric catalysis.1 In medicinal chemistry particularly, intro-
duction of heteroaromatic motifs on ethylenediamines in-
creases their pharmaceutical value.2 Considering the growing
interest in bioactive indole derivatives, we decided to
investigate the introduction of this nucleus on conform-
ationally restricted diamines.
enlargement of bridged bicyclic intermediates in a totally
regio- and diastereoselective manner (Figure 1). Although
In the context of our synthetic studies on constrained
diamine systems, we recently reported a simple route to
enantiopure mono- or disubstituted 3-aminoazepanes 3 or
5, respectively, starting from 2-cyano-6-oxazolopiperidine
1.3 The key step involved reductive or alkylative ring-
† l’Universite´ Rene´ Descartes.
‡ Parc Cient´ıfic de Barcelona.
Figure 1. General strategy for the synthesis of polysubstituted
(1) For a recent review, see: (a) Lucet, D.; Le Gall, T.; Mioskowski, C.
Angew. Chem., Int. Ed. 1998, 37, 2581. For selected leading references,
see: (b) Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem. Soc. 2002,
124, 5640. (c) Bloch, R. Chem. ReV. 1998, 98, 1407. (d) Kobayashi, S.;
Ishitani, H. Chem. ReV. 1999, 99, 1069. (e) Ellman, J. A.; Owens, T. D.;
Tang, T. P. Acc. Chem. Res. 2002, 35, 984.
azepanes.
various indole derivatives from natural or synthetic sources
are known to exhibit interesting biological activities, very
few examples that include an azepane core have been
(2) (a) Michalson, E. T.; Szmuszkovicz, J. Prog. Drug Res. 1989, 33,
135. (b) Wong, E.; Giandomenico, C. M. Chem. ReV. 1999, 99, 2451.
10.1021/ol047408b CCC: $30.25
© 2005 American Chemical Society
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described.4 Reports of bioactive carba analogues of eudis-
tomines5 prompted us to test the reactivity of bicyclic indole
derivatives 2 or 4 toward the synthesis of new polycyclic
scaffolds.
reactions involving reactive iminium species.6 Side chain
O-protection was first performed to avoid any competitive
morpholine formation (Scheme 2).7,8 Subsequent imine
We first focused on the preparation of 2-substituted
3-aminoazepane 3 in the N-methyl indole series. The imino
bicyclic compound 6 can be prepared in multigram quantities
using Et2O-TMEDA as the solvent system. High and
reproducible yields were obtained following an optimized
sonication procedure. Standard reductive conditions were
then applied to achieve diastereoselective access to the
3-aminoazepane core.
Scheme 2. Chemoselective Activation of Bicyclic Aminal 8
Although ring enlargement in the phenyl or furyl series
proceeded at room temperature,3b harsher reaction conditions
(an excess of reagent in refluxing isopropyl ether) were
needed to achieve ring enlargement in the indole series
(Scheme 1). Thus, unprotected 2-substituted 3-aminoazepane
Scheme 1. Reductive Ring Enlargement in the Indole Series
reduction was conducted using LAH under mild conditions,
leading to compound 8 in a diastereomerically pure form.9
Methylmagnesium bromide was used as the external
nucleophilic reagent for the alkylative ring-enlargement
process. Best results were obtained using a slight excess (3.5
equiv) of Grignard reagent in refluxing Et2O, leading to
compound 9 in 51% yield as a single diastereomer. Its 2,7-
trans relative configuration could be assigned by comparison
to previous spectroscopic data in the phenyl series.3b
Compound 10, resulting from the intramolecular nucleo-
philic attack of indole C3, was never detected in the ring
enlargement reaction mixture, indicating a fully chemo-
selective seven-membered iminium ion formation. However,
this bridged heterocycle was isolated when aminal 8 was
purified by chromatography on silica gel and could also be
obtained in modest but reproducible yield by adding SiO2
directly to a solution of aminal 8.
As a nonprotected indole moiety could be of interest in
the search for bioactive products, we applied our initial
alkylation step using N-phenylsulfonylindole (Scheme 3).
Lithiated sulfonylindole proved to be unreactive with
compound 1 in Et2O but, in THF, led to a new bridged
tetracycle 11 characterized by an exo imine function (carbon
peak at 165.3 ppm) and a deshielded H-6 proton signal (δ
) 5.52 ppm). Interestingly, a desulfonylation of the indole
moiety occurred during this synthetic transformation.10 The
same compound could be obtained using the carboxylated
indole as a nucleophilic species under the standard conditions
reported by Katritzky and co-workers.11 The formation of
the tetracycle 11 can be easily explained by an intramolecular
attack of the transient N-lithiated indole species on the
derivative 7 was obtained in 74% overall yield from 1 after
hydrogenolysis of the chiral appendage. The trans relative
configuration was assigned by comparison with previously
reported structures (J2,3 ) 9.6 Hz).3
Intra- or intermolecular nucleophilic attack was then
evaluated on the bicyclic aminal system 8. The indole nucleus
was expected to compete with an external nucleophile in
(3) (a) Cutri, S.; Bonin, M.; Micouin, L.; Froelich, O.; Quirion, J.-C.;
Husson, H.-P. Tetrahedron Lett. 2000, 41, 1179. (b) Cutri, S.; Bonin, M.;
Micouin, L.; Chiaroni, A.; Husson, H.-P. J. Org. Chem. 2003, 68, 2645.
(4) (a) Ennis, M. D.; Hoffman, R. L.; Ghazal, N. B.; Olson, R. M.;
Knauer, C. S.; Chio, C. L.; Hyslop, D. K.; Campbell, J. E.; Fitzgerald, L.
W.; Nichols, N. F.; Svensson, K. A.; McCall, R. B.; Haber, C. L.; Kagey,
M. L.; Dinh, D. M. Bioorg. Med. Chem. Lett. 2003, 2369. (b) Fre´de´rich,
M.; Jacquier, M.-J.; The´penier, P.; De Mol, P.; Philippe, G.; Delaude, C.;
Angenot, L.; Ze`ches-Hanrot, M. J. Nat. Prod. 2002, 65, 1382. (c) Bennasar,
M.-L.; Jimenez, J.-M.; Vidal, B.; Sufi, A.; Bosch, J. J. Org. Chem. 1999,
64, 9605.
(5) Isolation eudistomins: (a) Rinehart, K. L., Jr.; Kobayashi, J.; Harbour,
G. C.; Hughes, R. G., Jr.; Mizsak, S. A.; Scahill, T. A. J. Am. Chem. Soc.
1984, 106, 1524. Biological activities: (b) Van Maerseveen, J. H.;
Hermkens, P. H. H.; De Clercq, E.; Balzarini, J.; Scheeren, H. W.; Kruse,
C. G. J. Med. Chem. 1992, 35, 3223. Synthesis and analogues: (c) Van
Maerseveen, J. H.; Scheeren, H. W.; De Clercq, E.; Balzarini, J.; Kruse, C.
G. Bioorg. Med. Chem. 1997, 5, 955. (d) Liu, J.-J.; Hino, T.; Tsuruoka, A.;
Nakagawa, M. J. Chem. Soc., Perkin Trans. 1 2000, 3487. (e) Yamashita,
T.; Tokuyama, H.; Fukuyama, T. Synlett 2003, 5, 738. (f) Kurihara, T.;
Sakamoto, Y.; Kimura, T.; Ohishi, H.; Harusawa, S.; Yoneda, R.; Suzutani,
T.; Azuma, M. Chem. Pharm. Bull. 1996, 44, 900.
(6) For a recent review on the synthesis of heterocycles based on iminium
ion cyclizations, see: Royer, J.; Bonin, M.; Micouin, L. Chem. ReV. 2004,
104, 2311.
(7) Froelich, O.; Desos, P.; Bonin, M.; Quirion, J.-C.; Husson, H.-P. J.
Org. Chem. 1996, 61, 6700.
(8) Compound 8 could be characterized by NMR, but all attempts of
chromatographic purifications led to its rearrangement or degradation.
(9) Absolute configuration of the newly created center was determined
unambiguously by chemical correlation with the corresponding O-silylated
piperidine.3b
(10) Sundberg, R. J.; Broome, R.; PowersWalters, C.; Schnur, D. J.
Heterocycl. Chem. 1981, 18, 807.
(11) Katritzky, A. R.; Akutagawa, K. Tetrahedron Lett. 1985, 26, 5935.
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Org. Lett., Vol. 7, No. 10, 2005

target tetracyclic core by building the C ring using a bis-
electrophile. Although this synthetic pathway is well docu-
mented,13 it has mainly been applied to unprotected indole
precursors. As expected, despite its major nucleophilicity on
C3, the indole N-methylated substrate was difficult to cyclize
in comparison to unprotected derivatives, since the anion
cannot be formed. Finally, protection of the exocyclic amino
group as a phthalimide and subsequent reaction using glyoxal
as the bridging agent14 led to the formation of the eudistomine
analogue 14.
Scheme 3. Rearrangements of Indolic Aminals
Interestingly, when the o-nosyl protective group and the
chloroacetamide precursor were used in the presence of K2-
CO3 as the scavenger (Scheme 5),15 compound 15 yielded
transient iminium ion delivered by the oxazolidine ring.
Although this compound proved to be quite stable, even
under chromatographic purification conditions, an N to C
rearrangement occurred during its reduction by LAH, leading
to 12 as a single diastereomer.12 The same relative config-
uration was assigned to compounds 10 and 12 on the basis
of the consistency of their 1H and 13C NMR chemical shifts.
In the course of this general reactivity study, we investi-
gated the use of derivative 7 as a starting material for the
synthesis of carba analogues of eudistomines 13 (Scheme
4). Previous structure-activity relationships had shown
Scheme 5. Cyclization to Piperazinones
a Yield was 70% on the basis of recovered unreacted material.
the bridged piperazinone 16.
In summary, we have established a rapid and stereoselec-
tive access to several new indolyldiamine polycyclic systems.
These scaffolds can be obtained using simple chemoselective
transformations of a common bicyclic aminal intermediate
and could be of interest in a diversity-oriented search for
new bioactive substances.
Scheme 4. Preparation of Tetracyclic Azepanes
Acknowledgment. We thank the Ligue Nationale contre
le Cancer and MRT (Picasso action) for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization for compounds 6, 7, 9-12, and
14-16. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL047408B
(13) For selected examples, see: (a) Melnyck, P.; Legrand, B.; Gasche,
J.; Ducrot, P.; Thal, C. Tetrahedron 1995, 51, 1941. (b) Suzuki, H.; Iwata,
C.; Sakurai, K.; Tokumoto, K.; Takahashi, H.; Hanada, M.; Yokoyama,
Y.; Murakami, Y. Tetrahedron 1997, 53, 1593. (c) Suzuki, H.; Yokoyama,
Y.; Miyagi, C.; Murakami, Y. Chem. Pharm. Bull. 1991, 39, 2170.
(14) For an example of the use of glyoxal as a bridging agent, see:
Alexakis, A.; Tranchier, J.-P.; Lensen, N.; Mangeney, P. J. Am. Chem. Soc.
1995, 117, 10767 and references therein.
significant antiviral and antitumoral activities of tetracyclic
indole derivatives of this type.5 We planned to obtain this
(12) For a similar desulfonylation reaction, followed by an N to C
rearrangement, see: (a) Rubiralta, M.; Diez, A.; Vila, C. Tetrahedron 1990,
46, 4443. (b) Rubiralta, M.; Diez, A.; Bosch, J.; Solans, X. J. Org. Chem.
1989, 54, 5591.
(15) (a) Dinsmore, C. J.; Beshore, D. C. Org. Prep. Proced. Int. 2002,
34, 367. (b) Dinsmore, C. J.; Bergman, J. M.; Bogusky, M. J.; Culberson,
J. C.; Hamilton, K. A.; Graham, S. L. Org. Lett. 2001, 3, 865.
Org. Lett., Vol. 7, No. 10, 2005
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