Biomimetic synthesis of grossularines-1

Article abstract of DOI:10.1002/anie.200500055

(Chemical Equation Presented) Like a sea squirt: An efficient biomimetic synthesis of the antitumor α-carboline marine alkaloids grossularine-1 (1) and N,N-didesmethylgrossularine-1 (2) is based on a novel oxidative dimerization of 2-amino-4-(3-indolyl)imidazole.

Full text of DOI:10.1002/anie.200500055

Communications
Biomimetic Synthesis
novel oxidative dimerization–electrocyclization sequence of
-amino-4-(3-indolyl)imidazoles 5 and 6 derived from oxo-
2
Biomimetic Synthesis of Grossularines-1**
tryptamine (3).
Oxotryptamine (3) continues to serve as an important
cornerstone in indole heterocyclic construction. In previous
work reported by our research group, a practical procedure
for the preparation of 3 was developed that avoids the use of
protecting groups and DDQ oxidation, and was applied to the
Fumiko Y. Miyake, Kenichi Yakushijin, and
David A. Horne*
Dedicated to Professor Peter B. Dervan
on the occasion of his 60th birthday
[
5]
synthesis of various bis-indole marine natural products. In a
formal sense, grossularine 1 and its didesmethyl congener 2
consist of two oxotryptamine units that are linked by an
oxidative coupling between the two carbon centers of the
amino-bearing termini. Although such a mode of dimeriza-
tion is difficult to envisage with oxotryptamine per se, the use
of an electron-rich aromatic surrogate based on 2-amino-
imidazoles 5 and 6 seemed plausible, particularly in view of
the oxidized analogue, 2-dimethylamino-5-(3-indolyl)imida-
Isolated in only small amounts from the Britannia marine
tunicate Dendrodoa grossularia (Styelidae), grossularine-1
(1) represents one of the more structurally intriguing
members of a relatively small but potent class of a-carboline
metabolites that exhibit pronounced effects against solid
[
1]
human tumor cell lines. The limited material available from
nature as well as synthetic sources, however, have hampered
further investigations in vivo. Closely related to 1 is N,N-
didesmethylgrossularine-1 (2) (from the Chuuk Atoll tunicate
Polycarpa aurata) whose structure was established by X-ray
[
6]
zol-4-one (4). This derivative was co-isolated with 1 from
the same tunicate. The presence of this oxidized metabolite
[
2]
crystallographic analysis.
along with the fact that 2-aminoimidazoles are readily
[
7]
converted into imidazolones through oxidation [Eq. (1)],
suggests that 2-aminoimidazoles 5 and 6 could serve as
potential biosynthetic forerunners.
In contrast to the well-known class of b-carboline-derived
natural products, grossularines represent the first examples of
naturally occurring a-carbolines. Despite the promising
biological activity of 1, only one total synthesis has been
[
3]
completed. In the approach of Hibino and co-workers, the
construction of the tetracyclic pyrido[2,3-b]indole ring system
proceeded in a linear manner through the use of Pd-catalyzed
cross-coupling reactions of halogenated indoles and metal-
lated imidazoles. A formal synthesis of 1 has been reported by
Molina et al. that intersects the key intermediate reported
by Hibino and co-workers. Herein we describe a remarkably
concise biomimetic synthesis of 1 and 2 that is based on a
The synthesis begins with the preparation of 2-amino-
[
4]
imidazoles 5 and 6 by using the classical cyclocondensation of
[
8]
a-amino carbonyl compounds and cyanamide (Scheme 1).
Condensation of oxotryptamine (3) and dimethylcyanamide
in the absence of air produced 2-dimethylamino-4-(3-in-
[
9,10]
dolyl)imidazole (5).
Attempts to purify 5 as the free base
[
*] F. Y. Miyake, Dr. K. Yakushijin, Dr. D. A. Horne
Department of Chemistry, Oregon State University
Corvallis, OR 97331 (USA)
by flash chromatography were unsuccessful owing to its
instability; however, 5 can be obtained in relatively pure form
Fax: (+1)541-737-2062
E-mail: horned@onid.orst.edu
[**] Financial support from the National Institutes of Health
(
GM71985) and Chugai Pharmaceutical Co. is gratefully acknowl-
edged. We thank Rodger Kohnert for assistance with NMR
spectroscopic data acquisition and Jeff Morre of the Mass
Spectrometry Facility of the Environmental Health Science Center
(
NIEHS P30 ES00210) at Oregon State University for recording
mass data.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 1. Preparation of 2-amino-4-(3-indolyl)imidazoles (5) and (6).
3
280
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200500055
Angew. Chem. Int. Ed. 2005, 44, 3280 –3282

Angewandte
Chemie
as the hydrochloride salt. On the other hand, 2-amino-4-(3-
indolyl)imidazole (6), which lacks the dimethyl substituent,
can be secured as the free base by the condensation of 3 with
cyanamide followed by chromatographic purification over
silica. These findings are consistent with observations made
by Snyder and co-workers during their investigations of
Diels–Alder reactions of 2-aminoimidazoles, in which greater
thermal and air sensitivity of 2-dimethylaminoimidazole was
intermediate 7b to 7c followed by facile aminolysis results in
the loss of dimethylguanidine and the formation of a-carbo-
line 8. The sequence is remarkably efficient, delivering 8
directly in one pot and good overall yield from 5. Aromatic
imine 8 was found to be quite stable and required fairly
rigorous hydrolysis conditions to yield grossularine-1 (1) as a
yellow solid. All spectral data of synthetic 1 were in excellent
[
1]
agreement with data reported for the natural product.
[
11]
observed.
Similarly, treatment of 6 under analogous MeOH–NH3
conditions produced fused pentacyclic dimer 9 as a dark violet
to black solid (Scheme 3). Upon further standing in MeOH–
The instability of 5 normally would not be judged very
significant on its own; however, further investigation was
inspired by the fact that this 2-aminoimidazole derivative is
quite sensitive to air and that an oxidative coupling event
could, in principle, deliver conjoined indole units as a means
to potentially access the a-carboline core. We were quite
surprised to find that upon exposure of 5·HCl to a methanol
solution saturated with ammonia, a-carboline 8 was produced
[
12]
(
Scheme 2).
During the course of the reaction, dimer 7
partially precipitated from solution after 1 day as a dark violet
solid. Collection and resubjection of 7 to the reaction
conditions afforded 8. To explain these results, one mecha-
nistic pathway might involve initial oxidative dimerization of
5
to yield dimer 7. Upon standing in a methanol-saturated
ammonia solution, 7 undergoes an electrocyclization–aroma-
tization event via tautomer 7a. Oxidation of the resulting
Scheme 3. Synthesis of N,N-didesmethylgrossularine-1 (2).
NH , 9 underwent aminolysis to afford imine 10.
3
Hydrolysis of the imine functionality of 10 gave N,N-
didesmethylgrossularine-1 (2). Alternatively, 2 can
be obtained directly from the hydrolysis of 9. All
spectral data of synthetic 2 were in excellent agree-
[
2]
ment with those reported for the natural product.
In noting differences between dimethylaminoimid-
azole 5 and its didesmethylamino analogue 6, the
precyclized desmethylamino dimer corresponding to
7
was not obtained in the case of 6. This outcome is
attributed to the greater solubility of the putative
desmethyl intermediate in methanolic ammonia. In
the case of 5, the N,N-dimethylamino analogue 7c
corresponding to 9 also was not obtained. The
greater propensity toward aminolysis of this putative
guanidinium ion intermediate explains this result.
Although electron-rich aromatic heterocycles
such as indoles are known to undergo autoxidative
[
13]
coupling, the oxidative dimerization of 2-amino-
imidazoles under simple aerobic conditions is unpre-
cedented. The structurally and biologically signifi-
cant a-carboline natural products 1 and 2 were
produced in excellent overall yields with an opera-
tionally simple, three-pot sequence starting from
oxotryptamine. The chemistry and brevity of this
novel sequence support a plausible biogenetic con-
Scheme 2. Synthesis of grossularine-1 (1).
Angew. Chem. Int. Ed. 2005, 44, 3280 –3282
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3281

Communications
nection that explains these and several other structurally
related members this a-carboline family.
Received: January 6, 2005
Published online: April 28, 2005
Keywords: alkaloids · biomimetic synthesis · dimerization ·
.
natural products · oxidation
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3
282
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2005, 44, 3280 –3282