A facile synthesis of dragmacidin B and 2,5-bis(6′-bromo-3′-indolyl)piperazine

Article abstract of DOI:10.1021/ol0001970

(matrix presented) A short synthesis of dragmacidin B (1), 2,5-bis(6′-bromo-3′-indolyl)piperazine (2), and corresponding didebromo analogues 8 and 9 is described. The key steps involve the dimerization of oxotryptamines 4 and 11 to give bis(indolyl)pyrazines 5 and 12, which upon selective reduction and reductive methylation with sodium cyanoborohydride afforded the requisite piperazine natural products.

Full text of DOI:10.1021/ol0001970

ORGANIC
LETTERS
2000
Vol. 2, No. 20
3185-3187
A Facile Synthesis of Dragmacidin B
and
2,5-Bis(6′-bromo-3′-indolyl)piperazine
Fumiko Y. Miyake, Kenichi Yakushijin, and David A. Horne*
Oregon State UniVersity, Department of Chemistry, CorVallis, Oregon 97331
horned@ucs.orst.edu
Received July 26, 2000
ABSTRACT
A short synthesis of dragmacidin B (1), 2,5-bis(6′-bromo-3′-indolyl)piperazine (2), and corresponding didebromo analogues 8 and 9 is described.
The key steps involve the dimerization of oxotryptamines 4 and 11 to give bis(indolyl)pyrazines 5 and 12, which upon selective reduction and
reductive methylation with sodium cyanoborohydride afforded the requisite piperazine natural products.
Marine sponges produce a number of bioactive bisindole
metabolites containing either an imidazole or piperazine
derived spacer unit.1 The 2,5-bis(3′-indolyl)piperazine alka-
loids, dragmacidin B (1)2 (from the sponge, Hexadella sp.)
and 2,5-bis(6′-bromo-3′-indolyl)piperazine (2)3 (from the
tunicate, Didemnum candidum), are representative of a group
of bisindole metabolites containing a piperazine linker.4
Despite the broad range of biological activity exerted by the
class of bis(indolyl)piperazines, which includes cytoxicity,
only two reports have described the successful construction
of the piperazine ring system.5 In both reports, access to the
substituted piperazines was achieved via diborane reduction
of diketopiperazine intermediates.
(1) Faulkner, D. J. Nat. Prod. Rep. 2000, 17, 7 and previous reports in
this series.
(2) Morris, S. A.; Andersen, R. J. Tetrahedron 1990, 46, 715. Although
originally named dragmacidon B, this metabolite also has been referred to
as dragmacidin B.5a We prefer the use of dragmacidin B because of its
structural similarity to dragmacidin, the first isolated bisindole piperazine
metabolite.4a
(3) Fahy, E.; Potts, B. C. M.; Faulkner, D. J. Smith, K. J. Nat. Prod.
1991, 54, 564.
(4) For related bisindole natural products, see (a) Kohmoto, S.; Kashman,
Y.; McConnell, O. J.; Rinehart, K. L.; Wright, A.; Koehn, F. J. Org. Chem.
1988, 53, 3116. (b) Wright, A. E.; Pomponi, S. A.; Cross, S. S.; McCarthy,
P. J. Org. Chem. 1992, 57, 4772. (c) Gunasekera, S. P.; McCarthy, P. J.;
Kelly-Borges, M. J. Nat. Prod. 1994, 57, 1437. (d) Capon, R. J.; Rooney,
F.; Murray, L. M.; Collins, E.; Sim, A. T. R.; Rostas, J. A. P.; Butler, M.
S.; Carroll, A. R. J. Nat. Prod. 1998, 61, 660. (e) Casapullo, A.; Bifulco,
G.; Bruno, I.; Riccio, R. J. Nat. Prod. 2000, 63, 447. (f) Cutignano, A.;
Bifulco, G.; Bruno, I.; Casapullo, A.; Gomez-Paloma, L.; Riccio, R.
Tetrahedron 2000, 56, 3743.
Biosynthetically, dragmacidin B and the related bisindole
imidazole, topsentin A, are conceivably derived by the
condensation of two tryptamine derivatives in either a head-
10.1021/ol0001970 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/14/2000

to-head (topsentins) or head-to-tail (dragmacidins) orienta-
tion. Recently, we reported a concise synthesis of topsentin
A that proceeded through the facile preparation of oxo-
tryptamine 4 and its head-to-head condensation in the
presence of ammonia and air.6 In this communication, we
describe a simple synthesis of dragmacidin B (1), 2,5-bis-
(6′-bromo-3′-indolyl)piperazine (2), and debromo analogues
8 and 9 via head-to-tail dimerizations of oxotryptamines 4
and 11. In addition, we disclose a useful method for the
preparation of substituted piperazines from pyrazines via
selective reduction and reductive methylation with sodium
cyanoborohydride.
cyanide 3 with LAH8 gave the expected amino alcohol 6.9
Heating 6 under analogous conditions (e.g., 4 to 5) produced
a complicated mixture of products, none of which appeared
to contain a piperazine ring. Instead, symmetrical dimer 7
and indole were isolated as the principle components but
only in modest amounts. These results suggest that a retro-
type aldol mechanism is operative under these conditions
that precludes the desired dimerization event. Biosyntheti-
cally, it is interesting to speculate that a related type of
degradative process may be occurring during the formation
of 4- and 6-bromo-substituted indole metabolites that lack
substituents at the 3-position.10
Next, reduction of the pyrazine ring in 5 to the requisite
piperazine system was investigated (Scheme 2). In relevant
Our approach to the piperazine ring system begins with
acyl cyanide 3 (Scheme 1). Hydrogenation over Pd/C gave
Scheme 2
Scheme 1
indole chemistry, Gribble and co-workers have shown that
indoles can be readily reduced to indolines using borohy-
drides and carboxylic acids.11 By adopting this set of reaction
conditions, pyrazine 5 underwent clean conversion to pip-
erazine 8 using NaBH3CN in acetic acid. Only the thermo-
dynamically more stable trans diequatorial isomer was
detected. Using formic acid as solvent, piperazine 5 under-
went reductive methylation to afford dimethyl piperazine 9
in satisfactory yield. In both cases, reduction of the indole
double bond was not observed. These results suggest that
the initial reduction of pyrazine to piperazine prevents
reduction of the indole double bond, possibly through steric
factors.12
oxotryptamine 4 in excellent yield.6 There is ample literature
precedent suggesting that R-amino ketones such as 4 can
undergo dimerization to pyrazines.7 Upon heating 4 in a
xylene/EtOH (4:1) solution under a sealed atmosphere of
argon followed by exposure to air and filtration, pyrazine 5
was obtained in good yield as a yellow solid. The success
of this result prompted us to pursue the dimerization of
hydroxy tryptamine 6, which in principle would lead directly
to the desired piperazine ring system. Reduction of acyl
With the synthetic approach and methodology in hand for
the debromo dragmacidin analogues 8 and 9, our attention
turned to the natural products, dragmacidin B (1) and 2,5-
bis(6′-bromo-3′-indolyl)piperazine (2) (Scheme 3). Both
substituted piperazines 1 and 2 contain a 6-bromoindole
(8) Burger, A.; Hornbaker, E. D. J. Am. Chem. Soc. 1952, 74, 5514.
(9) All new compounds gave satisfactory spectral data (1H and 13C NMR
and HRMS).
(10) (a) Higa, T.; Ichiba, T.; Okuda, K. Experientia 1985, 41, 1487. (b)
Kobayashi, J.; Ishibashi, M. In The Alkaloids; Brossi, A., Cordell, G. A.,
Ed.; Academic Press, New York, 1992; Vol. 41, p 51.
(11) Gribble, G. W.; Lord, P. D.; Skotnicki, J.; Dietz, S. E.; Eaton, J.
T.; Johnson, J. L. J. Am. Chem. Soc. 1974, 96, 7812.
(12) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc.
1971, 93, 2897.
(5) (a) Whitlock, C. R.; Cava, M. P. Tetrahedron Lett. 1994, 35, 371.
(b) Jiang, B.; Smallheer, J. M.; Amaral-Ly, C.; Wuonola, M. A. J. Org.
Chem. 1994, 59, 6823.
(6) Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Org. Lett. 2000, 2, 2121.
(7) Sato, N. In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A.
R., Rees, C. W., Scriven, E. F. V., Boulton, A. J., Eds.; Pergamon: New
York, 1996; Vol. 2, p 266.
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Org. Lett., Vol. 2, No. 20, 2000

mixture of 5- and 6-substituted indole derivatives 10 and 11
in an approximate 2:1 ratio, respectively. Bromoindoles 10
and 11 can be separated by flash chromatography. Conden-
sation of 11 under thermal conditions gave pyrazine 12 in
good yield. Selective reduction of the pyrazine ring using
NaBH3CN in formic or acetic acid (23 °C, 24 h) afforded
dragmacidin B (1) and 2,5-bis(6′-bromo-3′-indolyl)piperazine
(2), respectively. Spectral data for synthetic 1 and 2 were
consistent with those reported for the corresponding natural
material.
Scheme 3
In summary, a short synthesis of bis(indolyl)piperazine
natural products 1 and 2 has been achieved. The synthesis
is highly convergent and highlights a useful preparation of
piperazines from pyrazines under convenient reaction condi-
tions.
Acknowledgment. We thank Professor John Faulkner for
helpful discussions on bioactivity and Mr. Rodger Kohnert
for assistance with NMR. Financial support from the National
Institutes of Health (GM 50929) is gratefully acknowledged.
moiety. Accordingly, the introduction of bromine directly
to the 6-position of oxotryptamine 4 was viewed as the most
direct approach in our synthetic scheme. This approach is
based on the successful incorporation of bromine to 3-cy-
anoindole, which produced 6-bromo-3-cyanoindole as the
major product.6 In the present case, however, bromination
(23 °C, 12 h) of oxotryptamine 4 produced an isomeric
Supporting Information Available: 1H and 13C NMR
spectra for compounds 5-12, dragmacidin B (1), and 2,5-
bis(6′-bromo-3′-indolyl)piperazine (2). This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
OL0001970
Org. Lett., Vol. 2, No. 20, 2000
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