Direct access to marine pyrrole-2-aminoimidazoles, oroidin, and derivatives, via new acyl-1,2-dihydropyridin intermediates

Article abstract of DOI:10.1021/ol0608451

A short synthesis of the C₁₁N₅ oroidin derivatives is reported. The key step of the strategy is a one-pot oxidative bromine-mediated addition of protected guanidines to the N-acyl-1,2-dihydropyridines 9a-c. The new N-acyl-1,2-dihydropyridines were prepared directly from pyridine and pyrrole-2-carbonyl chloride by reduction with borohydride reagent in one step.

Full text of DOI:10.1021/ol0608451

ORGANIC
LETTERS
2006
Vol. 8, No. 14
2961-2964
Direct Access to Marine
Pyrrole-2-aminoimidazoles, Oroidin, and
Derivatives, via New
Acyl-1,2-dihydropyridin Intermediates
Cosima Schroif-Gregoire, Nathalie Travert, Anne Zaparucha, and Ali Al-Mourabit*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette, France
Ali.Almourabit@icsn.cnrs-gif.fr
Received April 7, 2006
ABSTRACT
A short synthesis of the C11N5 oroidin derivatives is reported. The key step of the strategy is a one-pot oxidative bromine-mediated addition
of protected guanidines to the N-acyl-1,2-dihydropyridines 9a c. The new N-acyl-1,2-dihydropyridines were prepared directly from pyridine
−
and pyrrole-2-carbonyl chloride by reduction with borohydride reagent in one step.
Current interest in the group of pyrrole-2-aminoimidazole
marine metabolites, which includes the important putative
biogenetic intermediates oroidin (1),1 hymenidin (2),2 and
clathrodine (3)3 (Figure 1), has been concerned not only with
Scheme 1. Targeted 2-Aminoimidazole Derivatives from
1,2-Dihydropyridine
Figure 1. Structures of the marine metabolites oroidin, hymenidin,
clathrodine, and dibromoagelaspongine.
oxidative addition of Boc-guanidine to the N-carbomethoxy-
dihydropyridine 5.6
preparative synthesis and biological activities4 but also with
their biomimetic chemical reactivity.5
On the basis of our studies on the synthesis of various
N-substituted 1,2-dihydropyridines and their reactivity with
We have recently described a new preparation of the
2-aminoimidazole derivative 7 (Scheme 1) bearing the allylic
amine substituent on the C4(5) position, using a bromine
(1) (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.
10.1021/ol0608451 CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/10/2006

guanidine, we planned to use this procedure for a rapid and
straightforward preparation of the natural products 1-3 and
their derivatives.7 Our synthetic strategies are inspired from
a global analysis of the structures and reactivities of the
natural metabolites. The structure of dibromoagelaspongine
(4), isolated from the sponge Agelas sp.,8 exhibits a structural
proximity with oroidin (1) suggesting a common chemical
approach via a dihydropyridine intermediate.
It then appears clearly that the cyclic clathrodine derivative
10a was the relevant target via the dihydropyridine inter-
mediate 9a (Scheme 1). However, it is of special interest to
note that in contrast with N-carbomethoxydihydropyridine
5, described by Fowler,9 the N-acyl-1,2-dihydropyridines
such as 9a were not readily available from pyridine via the
reduction of the corresponding pyridinium salts.10 Moreover,
the preparation of N-substituted 1,2-dihydropyridines is
hampered by a regioselectivity problem leading to formation
of the 1,4-dihydropyridine regioisomer.11
is determinant for the reduction of the N-acyl pyridinium
salt intermediate; thus, the optimization to minimize side
products was conducted by varying the quantities of MeOH,
pyridine, and NaBH4. It was found that the use of 0.15 mL
of MeOH per millimole of 11a, 2 equiv of pyridine, and 0.5
equiv of NaBH4 was optimal for obtaining the best yield
(38% of isolated 9a). Although the yield of N-acyl-dihydro-
pyridine is apparently low, we can say that this is the first
and shortest preparation of 9a.
With the optimized reaction conditions in hand, we next
examined the formation of the brominated derivatives 9b,c.
We observed that the yield of the major product decreases
with the bromination degree of the pyrrole ring (Scheme 2).
N-Acyl-1,2-dihydropyridine 9a smoothly underwent reac-
tion with 4 equiv of Boc-guanidine in the presence of 1 equiv
of bromine, affording the bicyclic product 14a (38%) and
its regioisomer 14b (5%) (Scheme 3). It is noteworthy that
This article expands to the first report of the acyldihy-
dropyridine 9a synthesis based on the reduction of the
pyrrolic N-acyl-pyridinium 8 and further short synthesis of
the C11N5 clathrodine (3) and derivatives.
Scheme 3. Clathrodine (3) Synthesis from 9a.
Our retrosynthetic approach is depicted in Scheme 1.
Extension of Fowler’s methodology to the reduction of
N-acylpyridinium 8 should afford dihydropyridine intermedi-
ate 9a. Subsequent nucleophilic addition of a protected
guanidine in oxidative conditions would lead to the formation
of the bicyclic compound 10a. We anticipated that 10a might
have reactivity similar to that of 6 to undergo aminal opening,
affording the natural 2-aminoimidazolic clathrodine (3).
To prepare the requisite pyrrolic dihydropyridines 9a-c,
we investigated the reaction conditions for the reduction,
starting from pyridine and pyrrole-2-carbonyl chloride (11a)-
(Scheme 2). After preliminary assays, it appeared that the
the use of 2 or 3 equiv of bromine led to a mixture of pyrrole
brominated derivatives of 14a,b. Deprotection of 14a,b in
the presence of TFA gave 10a in 21% isolated yield.
Clathrodine (3) was obtained directly from 9a using the same
conditions followed by 6 N HCl treatment in methanol for
6 h. Deprotection, cleavage of the aminal, and Z f E
isomerization of the double bond were conducted without
any purification of the intermediates. Despite the low yields
of the reactions, clathrodine (3) was quickly obtained in 9%
overall yield.
Scheme 2. Reduction of N-Acyl-dihydropyridinium Salts into
N-Acyl-dihydropyridines
(4) For recent reviews of synthetic efforts, see: (a) Hoffmann, H.; Lindel,
T. Synthesis 2003, 1753-1783. (b) Jacquot, D. E. N.; Lindel, T. Curr. Org.
Chem. 2005, 9, 1551-1565 and references therein.
(5) (a) Al-Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237-243.
(b) Baran, P. S.; O’Malley, D. P.; Zografos, A. L. Angew. Chem., Int. Ed.
2004, 43, 2674-2677.
(6) (a) Abou-Jneid, R.; Ghoulami, S.; Martin, M.-T.; Tran Huu Dau, E.;
Travert, N.; Al-Mourabit, A. Org. Lett. 2004, 6, 3933-3936. (b) Sanchez
Salvatory, M. del R.; Abou-Jneid, R.; Ghoulami, S.; Martin, M.-T.;
Zaparucha, A.; Al-mourabit, A. J. Org. Chem. 2005, 70, 8208-8211.
(7) Al-Mourabit, A.; Travert, N.; Abou-Jneid, R.; Ghoulami, S. WO 2004/
101573 A1, 25.11.2004, Demande PCT/Fr2004/001059 30.04.2004.
(8) Fedoreyev, S. A.; Il’yin, S. G.; Utkina, N. K.; Maximov, O. B.;
Reshetnyak, M. V.; Antipin, Mu. Y.; Struchkov, Yu. T. Tetrahedron 1989,
45, 3487-3492.
desired major product 1,2-dihydropyridine 9a was formed
along with the contaminants 1,4-dihydropyridine 12a and
methyl-2-pyrrole carboxylate (13a). The presence of MeOH
(9) Fowler, F. W. J. Org. Chem. 1972, 37, 1321-1323.
(10) Whyle, M. J.; Fowler, F. W. J. Org. Chem. 1984, 49, 4025-4029.
(11) (a) Ref 8. (b) Knaus, E. E.; Redda, K. Can. J. Chem. 1977, 55,
1788-1791.
(2) Kobayashi, J.; Ohizumi, Y.; Nakamura, H.; Hirata, Y. Experientia
1986, 42, 1176-1177.
(3) Morales, J. J.; Rodriguez, A. D. J. Nat. Prod. 1991, 54, 629-631.
2962
Org. Lett., Vol. 8, No. 14, 2006

Surprisingly, treatment of the dibromodihydropyridine 9c
(Scheme 2) under the same oxidative conditions did not
provide the desired bicyclic adduct, but a mixture of unstable
compounds from which tricyclic dihydropyridine 1512 was
the only identifiable product in 14% yield. The dibromopy-
rrole moiety appeared to promote intramolecular nucleophilic
attack of the bromonium intermediate by the nitrogen of the
pyrrole ring, instead of the intermolecular addition of the
protected guanidine. To circumvent this problem, we needed
a more nucleophilic guanidine derivative than N-Boc-
guanidine. For this purpose, we selected 2-aminopyrimidine
(2-AP) as a readily available protected guanidine. Initially,
the reactivity of 2-AP in the coupling reaction in the pres-
ence of bromine was examined using the Fowler dihydro-
pyridine 5 (Scheme 4). Indeed, with 2 equiv of bromine,
electronic influence of the bromine atoms destabilizes 10c
which undergoes aminal opening immediately after the
deprotection of 18c. The ratio of these two products was
found to be time dependent. Z f E isomerization of 19 using
TFA/CH2Cl2 provided oroidin (1) in 71% yield.15 Applying
the same treatment to the bicyclic compounds 10a,b resulted
in the formation of clathrodine (3) and hymenidin (2) in 40%
and 42% yields, respectively.
Pyrrole-2-aminoimidazole (P-2-AI) derivatives are very
sensitive to variations in pH and atmospheric oxygen. Thus,
the yields of the reactions were closely dependent on the
reaction time and purification processes. For example, when
compound 10b was heated at 50 °C for 3 h, the oxidized
side product 24 was isolated in 13% yield (Scheme 6). The
Scheme 6
Scheme 4
tricyclic ring system 17 was obtained via the intermediate
16 in 62% yield.
Running the reaction on the pyrrolic dihydropyridines
9a-c afforded condensation products 18a-c in acceptable
isolated yields without any trace of the tricyclic compounds
related to 15 (Scheme 5).13
latter compound was not observed when running the reaction
under argon.
Scheme 5. Targeted 2-Aminoimidazole Derivatives from
1,2-Dihydropyridine
Compound 24 was the result of an unexpected competitive
air oxidation, as the consequence of the isomerization of the
Z-hymenidin 21 into the natural E stereoisomer 2. The
important intermediate 23, pointed out in our earlier paper,6a
could also be oxidized by atmospheric oxygen to give 24.
The tautomerism relating 10a, 21, and 22 is created by the
ambivalent reactivity of the 2-aminoimidazole part of these
metabolites.5 Regarding the sensitivity of oroidin derivatives
to atmospheric oxygen, Lindel and co-workers have recently
(12) Structure of compound 15.
(13) In the case of 9a, small amounts of two brominated compounds
18b (6%) and 20 (5%) were isolated and identified.
The guanidine motif was revealed by treatment of the
tricyclic 18a and the monobrominated 18b with hydroxyl-
amine14 to give 10a,b in 51% and 66% yield, respectively.
The dibrominated derivative 18c afforded 10c in only 6%
yield along with the Z-oroidin (1) in 47% yield. The
(14) Fajgelj, S.; Stanovnik, B.; Tister, M. Heterocycles 1986, 24, 379-
386.
(15) For an alternative synthesis of Z-oroidin, see: Lindel, T.; Hochgu¨rtel,
M. J. Org. Chem. 2000, 65, 2806-2809.
Org. Lett., Vol. 8, No. 14, 2006
2963

reported similar oxidation by treatment of sventrine with
TFA/CHCl3.16
into account the overall yield and the overall time required
for the synthesis.
To avoid the formation of the side products by repetitive
manipulations, preparation of hymenidin (2) from 9b was
tested without any purification of the intermediates. This
revealed an interesting economy of time. Thus, hymenidin
(2) was prepared from 9b, in 1 day, in 33% overall yield
(Scheme 7). Although the yield of 9b is low, we can say
that the global yield is favorable. This is obvious if we take
In summary, a short and original method for the prepara-
tion of P-2-AI marine metabolites from the new N-acyl-1,2-
dihydropyridines has been developed. Our current studies
are directed toward extension of the preparative scope,
development of analogues of P-2-AI synthesis for further
biomimetic synthesis of more challenging congeners, and
biological testing.
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data,
including 1H and 13C NMR spectra for all described
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Scheme 7
OL0608451
(16) Lindel, T.; Breckle, G.; Hochgu¨rtel, M.; Volk, C.; Ko¨ck, M.
Tetrahedron Lett. 2004, 45, 8149-8152.
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