Total syntheses of brominated marine sponge alkaloids

Article abstract of DOI:10.1021/ol701626m

Total syntheses of six brominated marine sponge bis(indole) alkaloids of the hamacanthin, spongotine, and topsentin classes are described. Retrosynthetic analysis shows that their structures all include the 1-(6′-bromoindol- 3′-yl)-1,2-diaminoethane unit 13a. This key moiety has been prepared from brominated indolic N-hydroxylamine 5b via synthetic intermediate 8b.

Full text of DOI:10.1021/ol701626m

ORGANIC
LETTERS
2007
Vol. 9, No. 19
3761-3764
Total Syntheses of Brominated Marine
Sponge Alkaloids
Xavier Guinchard, Yannick Valle´e, and Jean-Noe1l Denis*
De´partement de Chimie Mole´culaire (SERCO), UMR-5250, ICMG FR-2607,
CNRS, UniVersite´ Joseph Fourier, BP-53, 38041 Grenoble Cedex 9, France
jean-noel.denis@ujf-grenoble.fr
Received July 11, 2007
ABSTRACT
Total syntheses of six brominated marine sponge bis(indole) alkaloids of the hamacanthin, spongotine, and topsentin classes are described.
Retrosynthetic analysis shows that their structures all include the 1-(6 -bromoindol-3 -yl)-1,2-diaminoethane unit 13a. This key moiety has
been prepared from brominated indolic N-hydroxylamine 5b via synthetic intermediate 8b.
′
′
Natural products of marine origin still continue to fascinate
organic chemists due to the wide diversity of their structural
features and biologists for their potent biological properties.1
Many of these compounds are implicated in chemical defense
against predators or biofouling2 and possess a panel of
biological properties.3 In particular, compounds belonging
to the bis(indole) alkaloids class, such as hamacanthins 1,4-6
spongotines 2,4,5,7 topsentins 3,4,5,8 nortopsentins,4 and drag-
macidins,4 isolated from marine sponges, have received a
lot of attention because some of them exhibit various potent
bioactivities such as cytotoxic, antiviral, antitumor, and anti-
inflammatory activities.5,6b,9 These properties have made them
attractive targets for biomedical purposes.10
In this context, we noticed that hamacanthins 1, spongo-
tines 2, and topsentins 3 include the 1-(indol-3′-yl)-1,2-
diaminoethane unit 13 (Figure 1), a common key moeity that
(6) (a) For the first isolation of (S)-(+)-hamacanthin 1a, see: Gunasekera,
S. P.; Mccarthy, P. J.; Kelly-Borges, M. J. Nat. Prod. 1994, 57, 1437. (b)
For the first isolation of (R)-(-)-hamacanthins 1b and 1c, see: Bao, B.;
Sun, Q.; Yao, X.; Hong, J.; Lee, C.-O.; Ya Sim, C.; Sik Im, K.; Jung, J. H.
J. Nat. Prod. 2005, 68, 711. (c) For the first isolation of (S)-(+)-hamacanthin
1d, see ref 5.
(7) (a) For the first isolation of the (-)-spongotine A 2a, see: Tsujii,
S.; Rinehart, K. L.; Gunasekera, S. P.; Kashman, Y.; Cross, S. S.; Lui, M.
S.; Pomponi, S. A.; Diaz, M. C. J. Org. Chem. 1988, 53, 5446. (b) For the
first isolation of the (-)-spongotine C 2b, see ref 5.
(8) (a) For the first isolation of topsentin 3a, see: Shin, J.; Seo, Y.; Cho,
K. W.; Rho, J.-R.; Sim, C. J. J. Nat. Prod. 1999, 62, 647. (b) For the first
isolation of topsentin 3b, see ref 6b.
(1) (a) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2005, 22, 15 and earlier reviews cited therein.
(b) Sipkema, D.; Franssen, M. C. R.; Osinga, R.; Tramper, J.; Wijffels, R.
H. Mar. Biotechnol. 2005, 7, 142. (c) Alvarez, M.; Salas, M. Heterocycles
1991, 32, 1391.
(2) (a) Braekman, J. C.; Daloze, D. Pure Appl. Chem. 1986, 58, 357.
(b) Henrikson, A. A.; Pawlik, J. R. J. Exp. Mar. Biol. Ecol. 1995, 194,
157. (c) Henrikson, A. A.; Pawlik, J. R. Biofouling 1996, 12, 245. (d) Pawlik,
J. R.; McFall, G.; Zea, Z. J. Chem. Ecol. 2002, 28, 1103.
(3) (a) Aygu¨n, A.; Pindur, U. Curr. Med. Chem. 2003, 10, 1113. (b)
Gul, W.; Hamann, M. T. Life Sci. 2005, 78, 442. (c) Pawlik, J. R. Chem.
ReV. 1993, 93, 1911. (d) Butler, A. Curr. Opin. Chem. Biol. 1998, 2, 279.
(4) For a review on bis(indole) metabolites, see: Yang, C.-G.; Huang,
H.; Jiang, B. Curr. Org. Chem. 2004, 8, 1691.
(5) In a recent article, Jung et al. described the structural elucidation
and/or biological activities of all natural products described herein except
3b. See: Bao, B.; Sun, Q.; Yao, X.; Hong, J.; Lee, C.-O.; Cho, H. Y.;
Jung, J. H. J. Nat. Prod. 2007, 70, 2.
(9) Oh, K.-B.; Mar, W.; Kim, S.; Kim, J.-Y.; Lee, T.-H.; Kim, J.-G.;
Shin, D.; Sim, C. J.; Shin, J. Biol. Pharm. Bull. 2006, 29, 570.
(10) For patent literature, see: (a) Gunasekera, S. P.; Cross, S. S.;
Kashman, Y.; Lui, M. S. Eur. Patent 272 810, 1988; Chem. Abstr. 1988,
109, 129417q. (b) Gunasekera, S. P.; Cross, S. S. Eur. Patent 304 157,
1989; Chem. Abstr. 1989, 111, 160196g. (c) Gunasekera, S. P.; Cross, S.
S.; Kashman, Y.; Lui, M. S.; Rinehart, K. L.; Tsujii, S. U.S. Patent 4 866
084, 1989; Chem. Abstr. 1990, 112, 185775d. (d) Sun, H. H.; Sakemi, S.;
Gunasekera, S.; Kashman, Y.; Lui, M.; Burres, N.; McCarthy, P. U.S. Patent
4 970 226, 1990; Chem. Abstr. 1991, 115, 35701z. (e) McConnell, O. J.;
Saucy, G.; Jacobs, R. U.S. Patent 5 290 777, 1994; Chem. Abstr. 1994,
120, 236178m. (f) Wright, A. E.; Mattern, R.; Jacobs, R. S. Patent WO
2000002857, 2000.
10.1021/ol701626m CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/18/2007

Figure 1. Retrosynthetic analysis and structures of synthesized bis(indole) alkaloids.
could be elaborated by a reaction of R-amino nitrones with
the appropriate indolic core.11 However, the few reported
total syntheses of these alkaloids12,13 1 and 3 do not use
precursors containing this indolic 1,2-diaminoethane moiety.
Moreover, the synthesis of spongotines 2 was not described
until our recent report14 describing the total synthesis of two
(()-spongotines 2 and three topsentins 3 from nonbrominated
N-hydroxylamine 5c (R ) H). However, this strategy could
not be applied to the brominated bis(indole) alkaloids because
debromination occurred during the debenzylation step. We
consequently sought a strategy compatible with the bro-
moindolyl moiety.
of all these alkaloids except (()-hamacanthin 1a and
topsentin 3a.12,13
Scheme 1
In this paper, we wish to report the recent developments
of our methodology which allow access to building blocks
4b and 8b from brominated N-hydroxylamine 5b11 and its
application to the total syntheses of (()-hamacanthins 1a,c,
(()-spongotines 2a,b, and topsentins 3a,b. This new meth-
odology has been applied to the 6-bromoindolyl, 5-bromo-
indolyl, and indolyl series as shown in Scheme 1. The
synthesis of (()-hamacanthins 1b and 1d (R * Br) from
indolic N-hydroxylamine 5c is also reported. To the best of
our knowledge, we describe herein the first total syntheses
(11) For the preparation of indolic N-hydroxylamines, see: (a) Chalaye-
Mauger, H.; Denis, J.-N.; Averbuch-Pouchot, M.-T.; Valle´e, Y. Tetrahedron
2000, 56, 791. (b) Denis, J.-N.; Mauger, H.; Valle´e, Y. Tetrahedron Lett.
1997, 38, 8515.
(12) For the synthesis of (()- and (S)-(+)-hamacanthins A 1a, see: (a)
Yang, C.-G.; Wang, J.; Tang, X.-X.; Jiang, B. Tetrahedron: Asymmetry
2002, 13, 383. (b) Kouko, T.; Matsumura, K.; Kawasaki, T. Tetrahedron
2005, 61, 2309. (c) Kawasaki, T.; Kouko, T.; Totsuka, H.; Hiramatsu, K.
Tetrahedron Lett. 2003, 44, 8849. (d) Miyake, F. Y.; Yakushijin, K.; Horne,
D. A. Org. Lett. 2000, 2, 2121. For the synthesis of non-natural (R)-(-)-
hamacanthin A, see: Jiang, B.; Yang, C.-G.; Wang, J. J. Org. Chem. 2001,
66, 4865.
(13) For the synthesis of topsentin A (3, R ) R′ ) H), see: (a) Braekman,
J. C.; Daloze, D.; Stoller, C. Bull. Soc. Chim. Belg. 1987, 96, 809. (b)
Kawasaki, I.; Katsuma, H.; Nakayama, Y.; Yamashita, M.; Ohta, S.
Heterocycl. Commun. 1996, 2, 189. (c) Achab, S. Tetrahedron Lett. 1996,
37, 5503. (d) Kawasaki, I.; Katsuma, H.; Nakayama, Y.; Yamashita, M.;
Ohta, S. Heterocycles 1998, 48, 1887. For the synthesis of topsentin 3a,
see ref 13c.
First, the indolic N-hydroxylamines 5a-c have been
oxidized to nitrones 6a-c by using manganese dioxide15 at
100 °C during 10 min in toluene. The nitrones 6a-c are
obtained with 70%, 77%, and 58% yields, respectively. We
observed that the more activated the indolic core was, the
lower the yield was. In particular, we got 0% yield with 5d
(complete degradation of the reaction mixture). We then
performed the hydroxyaminolysis of indolic nitrones 6a-c
with hydroxylamine hydrochloride in MeOH at room tem-
perature. Primary N-hydroxylamines 7a-c have been ob-
tained in good yields. Finally, these N-hydroxylamines 7a-c
(14) Guinchard, X.; Valle´e, Y.; Denis, J.-N. J. Org. Chem. 2007, 72,
3972.
(15) Cicchi, S.; Marradi, M.; Goti, A.; Brandi, A. Tetrahedron Lett. 2001,
42, 6503.
3762
Org. Lett., Vol. 9, No. 19, 2007

have been reduced with 2 equiv of titanium trichloride in
MeOH16 to afford the corresponding monoprotected diamines
8a-c in 83-97% yields. The benzyl group has consequently
been removed in a three-step sequence via a strategy of
oxidation-hydroxyaminolysis-reduction, providing the free
amines 8a, 8b, and 8c in 45%, 51%, and 26% overall yields,
respectively.
Scheme 3
Amines 8a-c have been deprotected with a 8% solution
of hydrochloric acid in dry MeOH14,17 affording quantita-
tively the corresponding indolic 1,2-diamine salts 4a-c
(Scheme 2). These salts are stable and could be stored at
Scheme 2
in the starting indolic N-hydroxylamines 5b,c, which can be
eliminated in different conditions.
The salt 4b was reacted with S-methylthioimidate salts14
12a and 12b in MeOH in the presence of triethylamine. The
desired natural spongotines 2a and 2b were obtained in 76%
and 64% yields, respectively. As recently reported,5 broading
1
and/or doubling of H NMR signals of compounds 2a and
2b were observed in neutral DMSO-d6 solution due to slow
interconversion of R-keto imidazoline tautomers and/or
rotamers. The H NMR spectrum of spongotine A 2a with
TFA in DMSO-d6 solution is in agreement with the one
described in this paper.5
0 °C over long periods without any degradation. However,
when we tried to obtain the basic 5- and 6-bromoindolic 1,2-
diamino compounds by basic treatment of 4a and 4b,
respectively, degradation occurred quickly. On the other
hand, amines 8b,c have been reacted with R-ketoacid
chlorides 9, prepared from the corresponding indoles,18
providing the amides 10a-d in excellent yields.
Amides 10 were then refluxed during 40 h in a 3/7 mixture
of HCOOH/1,2-dichloroethane to afford hamacanthins 1a-d
in good yields (Scheme 3). Deprotection by formic acid
generates in situ the primary amines 11a-d, which cyclized
by reaction with the carbonyl to provide the expected
hamacanthins 1. This transformation has surprisingly shown
total chemoselectivity toward hamacanthins of A series 1a-d
contrary to what was reported in similar synthetic strategies.12c,d
No traces of any hamacanthin of B series were detected.
1
Finally, oxidation of these imidazoline derivatives 2a,b
with IBX in DMSO19 afforded the natural bromodeoxy-
topsentin 3a and dibromodeoxytopsentin 3b with 78% and
90% yields, respectively. Spectroscopic data for 3a and 3b
are in agreement with those previously reported in the
literature.8,20 As expected, mixtures of slowly interconverting
1
tautomers were observed in H and 13C NMR in neutral
solution (CD3COCD3). We observed a splitting of all signals
that could be suppressed by addition of 1% of CF3COOD
into the deuterated solvent.
In summary, we have developed the first synthesis of the
original indolic 1,2-diamino derivatives 4a,b and 8a,b,
brominated on either position 5 or 6 of the indole core from
the corresponding indolic N-benzyl-N-hydroxylamines 5a,b.
The indolic 1,2-diamino compounds 8b,c have then been
(17) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. Tetrahedron:
Asymmetry 1997, 8, 2381.
(18) (a) Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002,
124, 13179. (b) Shaw, K. N. F.; McMillan, A.; Gudmundson, A. G.;
Armstrong, M. D. J. Org. Chem. 1958, 23, 1171. (c) Hashem, M. A.;
Sultana, I.; Hai, M. A. Indian J. Chem., Sect. B 1999, 38, 789.
(19) (a) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. Angew.
Chem., Int. Ed. 2003, 42, 4077. (b) Nicolaou, K. C.; Mathison, C. J. N.;
Montagnon, T. J. Am. Chem. Soc. 2004, 126, 5192.
These syntheses of hamacanthins 1a-d take advantage
of the orthogonality of the benzyl and Boc protecting groups
(16) (a) Murahashi, S.-I.; Kodera, Y. Tetrahedron Lett. 1985, 26, 4633.
(b) Kodera, Y.; Watanabe, S.; Imada, Y.; Murahashi, S.-I. Bull. Chem. Soc.
Jpn. 1994, 67, 2542.
(20) Casapullo, A.; Bifulco, G.; Bruno, I.; Riccio, R. J. Nat. Prod. 2000,
63, 447.
Org. Lett., Vol. 9, No. 19, 2007
3763

Scheme 4
engaged as building blocks in the total synthesis of (()-
Acknowledgment. We thank the Association de la
Recherche contre le Cancer (ARC) and ACI no. 02L0525,
Nouvelles approches the´rapeutiques du cancer, for their
financial support. This work was supported by a grant from
the Ministe`re de la Jeunesse, de l’Education Nationale et de
la Recherche to X.G.
hamacanthins 1a-d (obtained in 37%, 23%, 15%, and 21%
overall yields, respectively, in five steps from N-hydroxy-
lamines 5b,c), (()-spongotines 2a,b (obtained in 38% and
33% overall yields, respectively, in five steps from N-
hydroxylamine 5b), and topsentins 3a,b (both obtained in
29% overall yield in six steps from N-hydroxylamine 5b).
To the best of our knowledge, these are the first described
total syntheses of (()-hamacanthins 1b-d, (()-spongotines
2a,b, and topsentin 3b. This strategy is versatile and allows
access to a large number of indolic alkaloids bearing different
subsituents. Moreover, this strategy is smooth enough to
avoid protecting groups on the nitrogen atom of the indolic
cores.
Supporting Information Available: Experimental pro-
cedures and characterization data for all products, 1H NMR
and/or 13C NMR spectra of all new compounds, hamacan-
thins 1a-d, spongotines 2a,b, and topsentins 3a,b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL701626M
3764
Org. Lett., Vol. 9, No. 19, 2007