ketone.5 However, due to the reactivity of 1 and the presence
of the unsaturated side-chain at position 4, effort is required
to secure an alternative and more direct strategy for its
synthesis.
As a part of our program to develop new syntheses and
to understand the biomimetic reactivity of 2-aminoimidazole
marine metabolites, for which compound 1, as a central
precursor, is of great interest for biogenetic considerations,6
we describe here a new biogenetically inspired synthesis of
1 and the study of its tautomeric behavior.
The C6N4 derivatives of 1 such as girolline (2),7 pyraxinine
(3),8 and 49 were isolated from the Axinellidae and
Agelasidae families of sponges. Although pyraxinine is a
pyridine derivative, it may be biogenetically considered as
being derived from the same intermediate 1 as girolline
(Figure 1). Thus, cyclization of 1, cleavage of the result-
ing aminal 5, and aromatization to pyridine could occur to
afford pyraxinine (3). This is presumed to be a minor process,
since girolline is accompanied by only small amounts of
pyraxinine. However, the significance of the chemical
connection between 1 and 3 oriented us to use pyridine for
the synthesis of the natural compound 1.
We reasoned that if 1 and 3 were connected to the inter-
mediate relay 5, then the synthesis of 1 should be accessible
from pyridine through a bicyclic compound of type 5. Our
approach would involve a preparation of 7 from guanidine
derivatives and the known N-alkylcarbamoyl 1,2 dihydro-
pyridine (6) (Scheme 1) followed by the unprecedented ring
borohydride reagents.10 Despite the instability of dihydro-
pyridines, Fowler reported that an N-carboalkyloxy substitu-
ent stabilizes the dihydropyridine and permits its use for
preparative chemistry. We studied the reaction of various
free and protected guanidines with the carbomethoxydi-
hydropyridine (10) in the presence of bromine or NBS. The
expected bicyclic product 13 was obtained when 3-4 equiv
of Boc-guanidine11 were added to the dihydropyridine 10 in
a mixture of DMF/MeCN in the presence of bromine.
Removal of the Boc protecting group by direct treatment of
nonseparated regioisomers 11 and 12 with 2 M HCl afforded
compound 13 in 71% yield. Compounds 11 and 12 could
be isolated by flash chromatography on silica gel. Cis-fused
bicyclic 13 was fully characterized by NMR spectroscopy.12
Interestingly, when the reaction was carried out using 1 or
2 equiv of Boc-guanidine, only moderate yields of 13 were
obtained. The regioselective cleavage of the aminal bond
N1-C2 of 13 into 14 was achieved in 85% yield by boiling
for 5 min in aqueous 1 M NaOH. However, the yield of the
reaction was dramatically time and temperature dependent.
The yield of reaction decreased when scaled up to multigram
quantities. The instability of the allylic amine 14 under basic
conditions thus limits its preparation in large quantities.13
Assuming the manifold pH-dependent reactivity of 2-amino-
imidazoles substituted by an allylamine at position 4, we
have investigated the chemical behavior of 14 under acidic
and basic conditions.
If we consider the natural product 1, there are four
tautomeric forms that implicate the protons H1, H3, H5, and
H7 (Figure 2). The low relative energy differences between
Scheme 1. Targeted 2-Aminoimidazole Derivatives from
1,2-Dihydropyridine
cleavage reaction of 7 into 8, affording the appropriately
substituted (Z)-isomer of the 2-aminoimidazole precursor of
1. We assumed that both of the two new reaction steps (6
f 7 and 7f 8) would require special focus. The electron-
withdrawing alkyl or aryl-carbamoyl group should assist the
regioselective aminal cleavage and afford the aromatic
2-aminoimidazole derivative 8.
Figure 2. Ab initio calculations of the four tautomers of 1: total
energies (a.u.) at the 6-316* level with relative energies in
parentheses (kcal/mol).
the four tautomers (<1.40 Kcal/mol) obtained by ab initio
calculations14 at the 6-316* level suggest the possible
coexistence of the tautomers under the same conditions. In
our previous paper, we outlined that the reactivity of the
tautomers is probably at the origin of the molecular diversity
A literature survey revealed that dihydropyridine 6 is
accessible from pyridinium salts by careful reduction with
(4) (a) Daninos, S.; Al-Mourabit, A.; Ahond, A.; Zurita, M. B.; Poupat,
C.; Potier, P. Bull. Soc. Chim. Fr. 1994, 131, 590-599. (b) Olofson, A.;
Yakushjin, K.; Horne. D. A. J. Org. Chem. 1997, 62, 7918-7919. (c) Berre´e,
F.; Bleis, P. G.-L.; Carboni, B. Tetrahedron Lett. 2002, 43, 4935-5138.
(5) Little, T. L.; Webber, S. E.; J. Org. Chem. 1994, 59, 7299-7305.
(6) Al-Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237-243 and
references therein.
(7) Ahond, A.; Bedoya-Zurita, M.; Colin, M.; Fizames, C.; Laboute, P.;
Lavelle, F.; Laurent, D.; Poupat, C.; Pusset, M.; Pusset, J.; Thoison, O.;
Potier, P. C. R. Acad. Sci. Paris, Se´rie II 1981, 307, 145-148.
(8) Al-Mourabit, A.; Pusset, M.; Chtourou, M.; Gaigne, C. Ahond, A.
Poupat, C.; Potier, P. J. Nat Prod. 1997, 60, 290-291.
(9) Scheuer, P. J. Marine Natural Products; Academic Press: London
New York, 1981; Vol. IV, pp 70-73.
(10) Fowler, F. W. J. Org. Chem. 1972, 37, 1321-1323.
(11) Boc-guanidine was prepared by the adaptation of the method
reported by Goodman: Zapf, C. W.; Creighton, C. J.; Tomioka, M.;
Goodman, M. Org. Lett. 2001, 3, 1133-1136.
(12) Compound 7 gave satisfactory one- and two-dimensional NMR
spectra. The stereochemistry of the cis-fused structure was elucidated by
two-dimensional NOESY experiments.
(13) Efforts to optimize this step have demonstrated that different
N-substitutions on the guanidine and dihydropyridine groups are important.
To evaluate the scope of the method, a general study of the reaction
including urea derivatives and N-acyldihydropyridines will be reported
elsewhere.
3934
Org. Lett., Vol. 6, No. 22, 2004