Debromodispacamides B and D: Isolation from the marine sponge Agelas mauritiana and stereoselective synthesis using a biomimetic proline route

Article abstract of DOI:10.1021/ol702866m

New debromopyrrole-2-aminoimidazolones, debromodispacamide B (1) and debromodispacamide D (2) were isolated from the sponge Agelas mauritiana, collected in the Solomon Islands. A biomimetic one-step reaction from pseudopeptides 5 and 13 in presence of air oxygen and guanidine gave the chiral form of the natural product stereoselectively.

Full text of DOI:10.1021/ol702866m

ORGANIC
LETTERS
2008
Vol. 10, No. 3
493-496
Debromodispacamides B and D:
Isolation from the Marine Sponge
Agelas mauritiana and Stereoselective
Synthesis Using a Biomimetic Proline
Route
Carine Vergne,† Je´roˆme Appenzeller,† Ce´line Ratinaud,† Marie-The´re`se Martin,†
Ce´cile Debitus,‡ Anne Zaparucha,† and Ali Al-Mourabit*,†
Institut de Chimie des Substances Naturelles du CNRS, AVenue de la Terrasse,
91198 Gif-sur-YVette, France, and UMR 152 IRD-UniVersite´ Paul Sabatier Toulouse
III, Faculte´ des Sciences Pharmaceutiques, 31062 Toulouse cedex 9, France
ali.almourabit@icsn.cnrs-gif.fr
Received November 27, 2007
ABSTRACT
New debromopyrrole-2-aminoimidazolones, debromodispacamide B (1) and debromodispacamide D (2) were isolated from the sponge Agelas
mauritiana, collected in the Solomon Islands. A biomimetic one-step reaction from pseudopeptides 5 and 13 in presence of air oxygen and
guanidine gave the chiral form of the natural product stereoselectively.
Marine sponges are a rich source of bromopyrrole alkaloids.1
In particular the sponge families Agelasidae and Axinellidae
widely contain brominated pyrrole-2-aminoimidazole alka-
loids.2 As part of our ongoing biogenetic investigations
through the exhaustive isolation and synthesis of the pyrrole-
2-aminoimidazole (P-2-AI) metabolite family, we investi-
gated the polar extract of the sponge Agelas mauritiana.
collected off the Solomon Islands. Here we described the
isolation and the biomimetic synthesis of two new non-
brominated P-2-AI belonging to the dispacamide family.
Specimens of Agelas mauritiana (Demospongiae, order
Agelasida, family Agelasidae) were collected by scuba divers
on Guadalcanal reefs off the Solomon Islands (18 to 30 m
depth, June 2004). Freshly collected sponges were frozen
and lyophilized. The sponge was sucessively extracted with
dichloromethane and methanol. Methanolic crude extract was
partitioned between n-butanol and water. The n-butanol-
soluble material was subjected to silica gel column chroma-
tography using dichloromethane/methanol gradient as eluent.
The fraction containing P-2-AI alkaloids obtained with 15%
methanol in dichloromethane was further purified by pre-
parative HPLC to yield 3 mgeach of debromodispacamide
B (1) and debromodispacamide D (2) (Figure 1).
† Institut de Chimie des Substances Naturelles du CNRS.
‡ UMR 152 IRD-Universite´ Paul Sabatier Toulouse III, Faculte´ des
Sciences Pharmaceutiques.
(1) (a) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1-48. (b) Al-Mourabit,
A.; Potier, P. Eur. J. Org. Chem. 2001, 237-243.
Debromodispacamide B (1) presents a HRMS (M + H)+
ion at m/z 248.1122, indicating the formula of C11H12N5O2.
The 1H NMR spectrum showed strong similarities to the data
(2) (a) Braeckman, J.-C.; Daloze, D.; Stoller, C.; Van Soest, R. W. M.
Biochem. Syst. Ecol. 1992, 20, 417-431. (b) Erpenbeck, D.; van Soest, R.
W. Mar. Biotechnol. 2007, 9, 2-19.
10.1021/ol702866m CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/03/2008

The synthesis of 1 and 2 was designed according to our
previous proposed biogenetic hypothesis based on the new
oxidative transformation of the pyrrole-proline pseudopeptide
5 and guanidine into hydroxyimidazolidinone 9 presenting
the pyrrole-2-aminoimidazole skeleton (Scheme 1).6
Scheme 1. Debromodispacamide B Synthesis
Figure 1. Debromodispacamides and dispacamides B and D.
for the known compound dispacamide B (3) isolated from
an Agelas sp.3 The only differences between 1 and 3 were
the presence of the pyrrolic H-3 at 6.17 ppm besides H-2
and H-4 appearing as doublets of doublets at 6.86 and 6.72
ppm, respectively, indicating the presence of a nonsubstituted
pyrrole unit. The HMBC correlation of the olefinic proton
H-10 at 5.71 ppm with C-12 at 168.4 ppm and the coupling
constant (3JC-H ) 4.3 Hz) confirmed the cis relationship
between the olefinic proton and the carbonyle function,
meaning a (Z) configuration of the double bond. The
configuration of the exocyclic double bound was correlated
with the 3JC-H coupling constants by Branko Stanovnik and
co-workers.4 The systematically measured coupling constants
of various imidazolones were between 2 and 6 Hz for nuclei
with cis-configuration ((Z)-isomers), instead between 8 and
12 Hz for nuclei with trans-configuration ((E)-isomers)
(Figure 2).
The mechanistic studies regarding the general oxidative
transformations of pseudopeptide derivatives such as 5 will
be published elsewhere.
During our survey, we found that the one-pot reaction of
the pseudopeptide pyrrole-proline methyl ester 5 with air
oxygen in the presence of guanidine carbonate and 4 Å
molecular sieves, in DMF at 90 °C for 45 min, afforded
stereoselectively the desired debromodispacamide B (1) in
56% yield, together with the spiropyrrolidine aminoimida-
zolone7 10 in 12% yield (Scheme 1). The mechanism of
the reaction could be explained through the formation of
the intermediates 11 or 12 followed by the nucleophilic
attack of the guanidinic or amidic nitrogens, respectively
(Scheme 1).
Following the same strategy, the stereospecific synthesis
of the (+)-debromodispacamide D (2) started with the
pseudodipeptide pyrrole-hydroxyproline methyl ester 13.
Reaction of the commercially available trans-L-4-hydroxy-
proline methyl ester with the 2-pyrrolecarboxylic acid in the
presence of a coupling reagent (EDCI) gave the pseudo-
dipeptide 13 together with the O-acylated product 14, in 71%
and 9% yields, respectively. The reaction of the guanidine
carbonate with 13 in DMF in the presence of 4 Å molecular
sieves at 90 °C for 30 min led to the formation of
Figure 2. Comparison of 3JC-H coupling constants of (E) and (Z)-
isomers and the (Z) configuration of 1 and 2.
The molecular formula of debromodispacamide D (2) was
confirmed as C11H12N5O3 by HRMS. The comparison of
NMR spectral data with the data of the known brominated
dispacamide D (4)5 and its two-dimensional (2D) NMR
analysis gave the non-brominated and hydroxylated molecule
2. The configuration of the double bond was similarly
assigned to be (Z) (3JC-H ) 4.2 Hz). The only uncertainty
remaining to be solved was the configuration of C-9 of the
side chain. The specific rotation [R]25D 0° (c ) 0.28, MeOH)
indicated that 2 was a racemate that was confirmed by the
stereoselective synthesis described in the following section
of this letter.
(6) (a) Travert, N.; Al-Mourabit, A. J. Am. Chem. Soc. 2004, 126,
10252-10253. (b) Vergne, C.; Boury-Esnault, N.; Perez, T.; Martin, M.-
T.; Adeline, M.-T.; Tran Huu Dau, E.; Al-Mourabit, A. Org. Lett. 2006, 8,
2421-2424.
(7) For the synthesis of spiropyrrolidine imidazolones see : Fresneda,
P. M.; Castaneda, M.; Sanz, M. A.; Bautista, D.; Molina, P. Tetrahedron
2007, 63, 1849-1856.
(3) Cafieri, F.; Fattorusso, E.; Taglialatela-Scafati, O. Tetrahedron Lett.
1996, 37, 3587-3590.
(4) Jakse, R.; Recnik, S.; Svete, J.; Golobic, A.; Golic, L.; Stanovnik,
B. Tetrahedron 2001, 57, 8395-8403.
(5) Cafieri, F.; Carnussio, R.; Fattorusso, E.; Taglialatela-Scafati, O.;
Vallefuoco, T. Bioorg. Med. Chem. Lett. 1997, 7, 2283-2288.
494
Org. Lett., Vol. 10, No. 3, 2008

debromodispacamide D (2) as the (R) enantiomer in 27%
yield, together with the spiropyrrolidine aminoimidazolone
15 in 2% isolated yield (Scheme 2).
We wanted to probe the stability of the chirality of
(+)-debromodispacamide D (2) in an acidic condition.
Treatment with trifluoroacetic acid of 2 (50 mg) at 60 °C
gave a complex mixture of compounds from which the
1/1 mixture of oxazolines (Z)-17a (3JC-H ) 4.1 Hz) and
(E)-17b (3JC-H ) 9.0 Hz) were isolated in 21% yield
(Scheme 3). The structures were determined by 2D-NMR
Scheme 2. Debromodispacamide D Synthesis
Scheme 3. Racemization of the Natural Compound
The stereochemistry of the minor compound 15 was
assigned according to NOESY experiments (Figure 3). Its
including coupling constants mesurements as for the natural
products 1 and 2 described above.
If the pH-dependent isomerization takes place through 16a
and 16b, then the hydrolysis of the oxazolines 17a and 17b
should lead to the (()2. To unambiguously confirm the
common pathway, 17a and 17b were subjected to various
attempts of hydrolysis/isomerization. By heating the 1/1
mixture (Z)-17a + (E)-17b in EtOH/1 N HCl: (2/1) at 60
°C for 2.5 h, (E)-17b was transformed into (Z)-17a quan-
titatively. Regarding the latter result, it is tempting to consider
that the transient isomers 16a and 16b play an important
role in both formation of oxazolines and racemization. This
may explain why the natural product is racemic. The simple
experiment consisting in the stirring of the synthetic material
(+)2 in 6 N HCl for 2 h at room temperature led to a
complex reaction mixture. To prevent the degradation, the
same experiment was repeated for 15 min at room temper-
ature. After the purification, the recovered starting material
Figure 3. Stereochemistry of the spirocompound 15. NOESY
correlations.
formation could be explained by a similar mechanism as for
10 (Scheme 1).
The optical rotation obtained for the synthetic material of
(+)-debromodispacamide D (2) [R]25 +41.7° (c ) 0.34,
D
MeOH) indicated that the natural material [R]25 0° (c )
D
0.28, MeOH) that we have isolated was a racemate. The
optical rotations of the other natural members of natural
dispacamide family indicated that the absolute configuration
at C9 is not stable. The examples of the brominated
derivatives dispacamides C and D described by Fattorusso
([R]D 0°)5 and tauroacidins A ([R]D -4.3°) and B ([R]D +5°)8
are in favor of a racemization during the purification
processes. Kobayashi has even described the same dipaca-
mide D ()mukanadin A, [R]D +5°)9 for a 7:3 mixture of
enantiomers.
2 (60% yield) showed a similar [R]25 +40° (c ) 1.29,
D
MeOH) as for the starting material. Finaly, the experiments
that we have conducted on the synthetic material do not
support any clean racemization in acidic or basic conditions.
The degradation of the starting material is the major process
that we have observed.
In summary, we have isolated two new non-brominated
pyrrole-2-aminoimidazolone metabolites 1 and 2 from the
marine sponge Agelas mauritiana collected in the Solomon
Islands. The straightforward stereoselective synthesis reported
here underlines the likelihood of our biogenetic hypothesis
based on the oxidative rearrangement of the proline and
hydroxyproline units. We believe that the formation of
pyrrole-2-aminoimidazolones metabolites from pyrrole con-
(8) Kobayashi, J.; Inaba, K.; Tsuda, M. Tetrahedron 1999, 49, 16679-
16682.
(9) Dispacamide D described in ref 5 has been named mukanadin A (2
years later)! Uemoto, H.; Tsuda, M.; and Kobayashi, J. J. Nat. Prod. 1999,
62, 1581-1583.
Org. Lett., Vol. 10, No. 3, 2008
495

taining diketopiperazines by spontaneous air oxidation and
skeletal rearrangement is of high significance for the bio-
synthesis of this family of marine metabolites. Further studies
of the reactivity and biomimetic reactions concerning pyrrole-
2-aminoimidazolones will be reported in due course.
edge the field team of the IRD centre in Noume´a for the
collection of the sponge, Nicole Boury Esnault (CNRS,
Marseille) and John Hooper (Queensland Museum, Brisbane)
for the identification of the sample.
Supporting Information Available: Extraction proce-
1
dure, isolation, and characterization data (including H and
Acknowledgment. This work is part of the CRISP project
(Coral Reef Initiative in the South Pacific) and was granted
by the AFD (Agence Franc¸aise pour le De´veloppement). We
thank the Solomon government for permitting us to collect
there, the Fisheries Department and R. Sulu (University of
the South Pacific) for their help and assistance. We acknowl-
13C NMR spectra) for compounds 1 and 2. Experimental and
NMR spectra for synthetic compounds 1 and 2 and for
compounds 10, 13-15, and 17a + 17b. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL702866M
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Org. Lett., Vol. 10, No. 3, 2008