A likely biogenetic gateway linking 2-aminoimidazolinone metabolites of sponges to proline: Spontaneous oxidative conversion of the pyrrole-proline- guanidine pseudo-peptide to dispacamide A

Article abstract of DOI:10.1021/ja047574e

A new spontaneous oxidative transformation of the associated pyrrole-proline-guanidine to the natural marine pyrrole 2-aminoimidazolinone derivative has been achieved. The sensitive reaction requires air oxygen and the N-acylation of proline by pyrrole-2-carboxylic acid. Proline metabolism and pyrrole 2-aminoimidazole secondary metabolites formation seem to be related and are utilized by sponges under stress conditions for their defense against predators. A plausible stress-induced oxidative chemical pathway that establishes dispacamide derivatives as the forerunners in the biogenetic synthesis of the key pyrrole 2-aminoimidazole oroidin is proposed. The mechanism of the reaction seems to be another development of the known luciferins' chemiluminescent reactions in bioluminescent marine organisms. Copyright

Full text of DOI:10.1021/ja047574e

Published on Web 08/03/2004
A Likely Biogenetic Gateway Linking 2-Aminoimidazolinone Metabolites of
Sponges to Proline: Spontaneous Oxidative Conversion of the
Pyrrole-Proline-Guanidine Pseudo-peptide to Dispacamide A
Nathalie Travert and Ali Al-Mourabit*
Institut de Chimie des Substances Naturelles du CNRS, BP 1, 91198 Gif-sur-YVette, France
Received April 27, 2004; E-mail: Ali.Almourabit@icsn.cnrs-gif.fr
Scheme 1. Possible Biogenetic Sequences Relating Proline/
Ornithine to Oroidin (1) and Dispacamide (2)
A number of structurally related biologically active pyrrole
2-aminoimidazole metabolites have been isolated worldwide from
marine sponges belonging to the Agelasidae, Axinellidae, and
Halichondriidae families.1 Among these is oroidin (1),2 which is
the formal biogenetic building block and is considered to be the
key precursor in the elaboration of polycyclic C11N5 “oroidin”
derivatives.3 The isolation of dispacamide A (2)4 from phylo-
genetically related sponges raises the question as to which of 1 or
2 is the forerunner. These two compounds are frequently found in
sponges together with their closely related polycyclic derivatives.
Thus, the common metabolic intermediates 1 and 2 are good
candidates for linking amino acid precursors to the pyrrole
2-aminoimidazole family.
Although these compounds are important for their pharmacologi-
cal activities5 and for chemotaxonomic considerations,1 their
biosynthesis remains in question. From an ecological point of view,
the antipredatory role of oroidin-based alkaloids could be their most
important biological function.6 Kitagawa7 and later Braeckman and
Van Soest1 proposed that proline, ornithine, and guanidine are prob-
able precursors of both the bromopyrrole and 2-aminoimidazolinone
moieties (Scheme 1, paths 1 and 2). Ornithine and proline have
been respectively used in the synthesis of “oroidin-based” dibromo-
phakellin by Bu¨chi8 and dibromophakellstatin by Romo.9 Kerr10
has conducted what is so far the only biosynthetic experiment in
cell cultures of the sponge which produces stevensine (odiline).11
The study showed that [14C]-labeled proline, ornithine, and histidine
were incorporated into stevensine. Natural compounds 3 and 4 were
proposed as intermediates. We have considered that the pseudo-
dipeptide pyrrole-proline-guanidine 6 (Scheme 2) could be the
precursor leading to the amide-connected C11N5 pyrrole and
2-aminoimidazolinone sections. Our choice was also influenced by
the intriguing fact that the metabolism of proline in some plants
and microorganisms is known to be stress dependent.12 Although
the ecological role of proline in sponges is not known, one can
suppose that its role under stress conditions is also crucial. Thus,
if proline is involved in C11N5 formation under oxidative conditions,
this would be in accordance with the ecological role of “oroidin-
based” alkaloids used by sponges as a chemical arsenal for their
defense. The first specific step in pyrrole 2-aminoimidazole
biosynthesis would involve proline-based peptide synthesis of 5
(Scheme 2), followed by oxidation of the proline to pyrrole section
and then by the oxidation rearrangement of proline-guanidine
moiety to the 2-aminoimidazolinone (7). We have tested step 2,
considering that the self-catalyzed intramolecular transamination
reaction transforming 6 into 7 would be the critical step of the
biomimetic process.
Scheme 2. Sequential Pyrrole and 2-Aminoimidazolinone
Sections Formation
Scheme 3 a
a Reagents and conditions: (a) CH2Cl2, EDCI, DMAP, 0 °C, 90%; (b)
NaH, THF, 0 °C, 74%; (c) THF, Boc-guanidine, 3 h reflux, 13 + 14 (46%)
and 15 (7%); (d) THF, guanidine (HCl), NaOH (1.2 equiv), 1 h, 6 (44%)
and 12 (42%); (e) CH2Cl2, Boc-guanidine, rt, 1 night, 13 + 14 (42%); (f)
CH2Cl2, TFA, rt, quantitative.
The unsymmetrical compound 11 showed high sensitivity to
nucleophilic agents. To our delight, in the presence of guanidine,
11 gave intermediate 6 in 44% yield, together with the oxidized
2-aminoimidazolinone 12 in 42% yield. Running the same reaction
with Boc-guanidine led to the 2-aminoimidazolinone regioisomers
The required pseudo-peptide 10 (Scheme 3) was prepared from
pyrrole-2-carboxylic acid (8) and L-proline methyl ester (9) using
standard reactions.13,14 Activation of 10 via N1-C cyclization to
11 was cleanly performed in THF in the presence of NaH at 0 °C.
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C O M M U N I C A T I O N S
Scheme 4. Possible Peroxide Intermediates
of air oxygen. This result also points to dispacamide A (2) as the
forerunner of oroidin (1). Natural compounds 3 and 4 are probably
hydrolysis products of oroidin (1) and not the precursors. We are
continuing our investigations in order to deepen our understanding
of the mechanism of the reaction and to discover additional
transformations linking the triad pyrrole-proline-guanidine with
other polycyclic “oroidin-based” alkaloids. The study of the pH-
dependent behavior of the key intermediate 17 is underway and
will be reported in due course.
Scheme 5 a
Acknowledgment. We thank Dr. M.-T. Martin for assistance
with NMR analysis and Dr. A. Zaparucha for fruitful discussions.
Supporting Information Available: Detailed experimental pro-
cedures and characterization for 2, 10-16. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Reagents and conditions: (a) (i) AcOH, Br2, rt, (ii) CH2Cl2, TFA, rt,
74%; (b) CH3SO3H, 80 °C, 65%.
References
(1) Braekman, J.-C.; Daloze, D.; Stoller, C.; Van Soest, R. W. M. Biochem.
Syst. Ecol. 1992, 20, 417-431.
13 + 14 in 42% yield. Direct reaction of methyl ester 10 with Boc-
guanidine also gave 13 + 14 in 46% yield and the decarboxylated
compound 15 in 7% yield. To the best of our knowledge, this is
the first example of an oxidative rearrangement of a proline-
guanidine skeleton into a substituted 2-aminoimidazolinone. Im-
portantly, the transamination reaction occurs under mild conditions
and requires air oxygen. When the reaction with guanidine was
run under argon in degassed solvent, no rearrangement of proline
to 2-aminoimidazolinone was observed.
(2) (a) Forenza, S.; Minale, L.; Riccio, R.; Fattorusso, E. Chem. Commun.
1971, 1129-1130. (b) Garcia, E. E.; Benjamin, L. E.; Fryer, R. I. J. Chem.
Soc., Chem. Commun. 1973, 78-79.
(3) (a) Al-Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237-243. (b)
Hoffmann, H.; Lindel, T. Synthesis 2003, 1753-1753.
(4) Cafieri, F.; Fattorusso, E.; Magoni, A.; Tagliatela-Scafati, O. Tetrahedron
Lett. 1996, 37, 3587-3590.
(5) (a) Ahond, A.; Bedoya Zurita, M.; Colin, M.; Fizames, C.; Laboute, P.;
Lavelle, F.; Laurent, D.; Poupat, C.; Pusset, J.; Pusset, M.; Thoison, O.;
Potier, P. C. R. Acad. Sci. Paris, Se´r. II 1988, 307, 145-148. (b)
D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pusset, J.; Leroy, S.; Pietra,
F. J. Chem. Soc., Chem. Commun. 1993, 1305-1306. (c) Pettit, G. R.;
McNulty, J.; Herald, D. L.; Doubek, D. L.; Chapuis, J.-C.; Schmidt, J.
M.; Tackett, L. P.; Boyd, M. R. J. Nat. Prod. 1997, 60, 180-183. (d)
Kinnel, R. B.; Gehrken, H.-P.; Scheuer, P. J. J. Am. Chem. Soc. 1993,
115, 3376-3377. For a review see ref 3b.
(6) (a) Assmann, M.; Lichte, E.; Pawlik, J.-R.; Ko¨ck, M. Mar. Ecol. Prog.
Ser. 2000, 207, 255-262. (b) Assmann, M.; Van Soest, R. W. M.; Ko¨ck,
M. J. Nat. Prod. 2001, 64, 1345-1347.
(7) Kitagawa, I.; Kobayashi, M.; Kitanaka, K.; Kido, M.; Kyogoku, Y. Chem.
Pharm. Bull. 1983, 31, 2321-2328.
(8) (a) Foley, L. H.; Bu¨chi, G. J. Am. Chem. Soc. 1982, 104, 1776-1777.
(b) The method has been developed by Horne and co-workers: Olofsen,
A.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 1998, 63, 1248-1253.
(9) Poullennec, K.; Romo, D. J. Am. Chem. Soc. 2003, 125, 6344-6345.
(10) Andrade, P.; Willoughby, R.; Pomponi, S. A.; Kerr, R. G. Tetrahedron
Lett. 1999, 40, 4775-4778.
(11) (a) De Nanteuil, G.; Ahond, A.; Guilhem, J.; Poupat, C.; Tran Huu Dau,
E.; Potier, P.; Pusset, M.; Pusset, J.; Laboute, P. Tetrahedron 1985, 41,
6019-6033. (b) Albizati, K. F.; Faulkner, D. J. J. Org. Chem. 1985, 50,
4163-4164.
(12) (a) Hare, P. D.; Cress, P. D. Plant Growth Regul. 1997, 21, 79-102. (b)
Ballantyne, J. S.; Storey, K. B. Comp. Biochem. Physiol. 1983, 76B, 133-
138.
(13) Prepared according to a previously described procedure: (a) McElroy,
A. B.; Clegg, S. P.; Deal, M. J.; Ewan, G. B.; Hagan, R. M.; Ireland, S.
J.; Jordan, C. C.; Porter, B.; Ross, B. C.; Ward, P.; Whittington, A. R. J.
Med. Chem. 1992, 35, 2582-2591. (b) Ishibashi, N.; Kouge, K.; Shinoda,
I.; Kanihisa, H.; Okai, H. Ecol. Biol. Chem. 1988, 52, 819-827.
(14) Travert, N. Ph.D. thesis, Universite´ Paris XI, Orsay, 16 Sept 2003.
(15) (a) McCapra, F.; Chang, Y. C. Chem. Comm. 1966, 522-523 and
references therein. (b) Goto, T.; Kishi, Y. Angew. Chem., Int. Ed. Engl.
1968, 7, 407-414 and references therein. (c) McCapra, F.; Chang, Y. C.;
Francois, V. P. Chem. Commun. 1968, 22-23. (d) Schmidt, S. P.; Schuster,
G. B. J. Am. Chem. Soc. 1978, 100, 1966-1968.
The mechanism of the reaction seems to be close to that described
for bioluminescent reaction involving the formation of dioxetanones
in marine organisms.15
Formation of the byproduct 15 from 10 (Scheme 4) in the
presence of guanidine and air oxygen confirms the suggested
mechanism occurring through the species 16a-e. The presence of
guanidine is important for the catalyzed enolization/oxidation of
10 and 11 to 16a-e. Subsequent dismutation and intramolecular
transamination of 16b and 16c lead to 12 and the regioisomers 13
+ 14 respectively. Loss of CO2 from the dioxetanone 16e gives
15.
This is an efficient aerobic oxidation under atmospheric pressure
and without any catalyst or addition of oxidant. The intramolecular
nucleophilic substitution by guanidine and the dismutation of
peroxide lead to the cleavage of the crucial N-C bond of proline
and the formation of the 2-aminoimidazolinone 12, whose structure
is very close to those of natural dispacamide A (2) and mauritamide
A.16 The dispacamide A (2) synthesis (Scheme 5) was accomplished
by dibromination of the mixture 13 + 14 using 2 equiv of bromine,
followed by TFA-promoted Boc deprotection to 17 in 74% yield
for both steps. Subsequent dehydration by treatment with methane-
sulfonic acid gave dispacamide A (2) in 65% yield.17
In summary, a new biomimetic spontaneous conversion of proline
to 2-aminoimidazolinone derivatives using a self-catalyzed intra-
molecular transamination reaction together with peroxide dis-
mutation as a key step is described. The reaction requires the
N-acylation of proline by pyrrole-2-carboxylic acid and the presence
(16) Jime´nez, C.; Crews, P. Tetrahedron Lett. 1994, 35, 1375-1378.
(17) Note that heating of 12 or the protected derivatives (13 and 14) in TFA
did not lead to the dehydrated compound but to polycyclic derivatives.
The latest results will be published as a full paper in due course.
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