Concise total synthesis of naamine G and naamidine H

Article abstract of DOI:10.1039/b926285g

Total syntheses of the cytotoxic Leucetta-derived 2-aminoimidazoles, naamine G and naamidine H, have been accomplished using a position selective metalation-benzylation sequence with a 4,5-diiodoimidazole derivative. The Royal Society of Chemistry.

Full text of DOI:10.1039/b926285g

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Concise total synthesis of naamine G and naamidine Hw
Panduka B. Koswatta and Carl J. Lovely*
Received (in College Park, MD, USA) 14th December 2009, Accepted 22nd January 2010
First published as an Advance Article on the web 9th February 2010
DOI: 10.1039/b926285g
Total syntheses of the cytotoxic Leucetta-derived 2-amino-
imidazoles, naamine G and naamidine H, have been accomplished
using a position selective metalation–benzylation sequence with
a 4,5-diiodoimidazole derivative.
derivatives naamidine H and I (3 and 4) have been found to
be cytotoxic against HeLa cells with IC50 values of 5.6 and
15 mg mlÀ1, respectively.4
As a part of a continuation of our programs towards the
synthesis of 2-aminoimidazole natural products,9 in this
communication we describe the total synthesis of the bio-
logically active alkaloids, naamine G (2) and naamidine H (3).
Following earlier reports,10 we and others have demonstrated
that N-protected 4,5-diiodoimidazoles can be systematically
functionalized in a position specific order of C5-C4-C2
using Grignard reagents (C5, C4) and n-BuLi (C2 position)
and appropriate electrophiles.11–13 Using these protocols we
envisioned the disconnections to 3 as depicted in Fig. 2.
Removal of C2 hydantoin moiety and amino group from 3
would give disubstituted imidazole (5) which can be obtained
by sequential benzylation of methylimidazole 7 via the mono-
substituted imidazole 6.
More than fifty Leucetta and Clathrina-derived alkaloids,
containing a 2-aminoimidazole moiety, have been isolated
during the last three decades.1 These natural products are
characterized by the presence of one (1)2 or two benzylic
fragments (2–4),3,4 and in some cases, they contain additional
substitution on the C2-amino group, typically in the form of a
hydantoin moiety (e.g., 1, 3–4, Fig. 1). Several of these
alkaloids were reported to exhibit biological activity, including
antibiotic activity,5 nitric acid synthase inhibition,6 cytotoxicity,7
leukotriene B4 receptor antagonist activity8 and inhibition of
epidermal growth factor (EGF) receptor activities.7a
Recently, several new members of this family of alkaloids,
naamine G (2),3 naamidine H (3) and I (4),4 were isolated from
an Indonesian variant of the sponge Leucetta chagosensis.
Naamine G (2) was reported to exhibit strong antifungal
activity against the phytopathogenic fungus Cladosporium
herbarum (20 mg per disk) and mild cytotoxicity against mouse
lymphoma (L5178Y) and human cervix carcinoma (HeLa) cell
lines at a concentration of 10 mg mlÀ1 (46% and 29% growth
inhibition, respectively, vs. control).3 Similarly, the N-substituted
Our synthetic endeavors begin by treating 4,5-diiodo-
1-methyl-1H-imidazole (7) with EtMgBr followed by
benzaldehyde
8 to provide alcohol 9 in 95% yield
(Scheme 1).11a Ionic reduction of this alcohol was attempted
using well known conditions with Et3SiH and TFA, conditions
that we have used successfully on several occasions.11,14
Surprisingly, this reaction did not work well at room temperature,
nor did increasing the reaction temperature (reflux in CH2Cl2
or CHCl3) increase the efficiency, providing 6 in only 28%
yield. We have also used BF3ÁOEt2 in combination with
Et3SiH to effect related reductions, but this tactic failed to
provide the desired product. It has been observed in the course
of related reactions that the solution typically becomes red or
orange when the carbocation formed and it slowly disappears
upon reacting with Et3SiH. However, in this case the reaction
turned only pale yellow, which presumably indicates the
absence or little formation of carbocation from the alcohol.
Rather than spend time finding conditions to reduce the
alcohol at this stage, it was decided to push the synthesis
Fig. 1 Selected Leucetta and Clathrina alkaloids.
Department of Chemistry and Biochemistry, The University of Texas
at Arlington, TX 76019-006, Arlington, USA.
E-mail: lovely@uta.edu; Fax: +1 817-272-3808;
Tel: +1 817-272-5446
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for all new compounds. See
DOI: 10.1039/b926285g
Fig. 2 Retrosynthetic approach to naamidine H.
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to be good substrates in this reaction,11c and we noted in the
Lindell reports that electron withdrawing protecting groups
were employed, therefore we decided to switch protecting
groups.10
We have used the N,N-dimethylaminosulfonyl (DMAS)
group at the N1 position of a variety of imidazoles and in a
variety of chemistries; thus it was anticipated that this would
be suitable in the present context.12 An additional factor
driving this choice of protecting group was the recent report
from Delest et al.,15 describing an efficient method for
methylating DMAS-protected imidazoles with transposition,
which we envisioned being useful for our synthesis. Accordingly,
imidazole 1512 was treated with EtMgBr followed by freshly
prepared CuCNÁ2LiCl and p-methoxybenzyl bromide to
produce the iodoimidazole 16 in 65% yield (Scheme 2).10,12
Repetition of this sequence of reactions, EtMgBr, CuCNÁ
2LiCl followed by benzyl bromide 10, was performed to
produce the 4,5-dibenzylimidazole (17) in 70% yield.9
At this stage the DMAS-protecting group needed to be
removed and replaced with an N-methyl group in a position
specific manner. This could be easily achieved via formation of
the methyl imidazolium salt 18, which facilitates the removal
Scheme 1 First generation approach to naamidine H.
forward by introducing the C4 p-methoxybenzyl group. To
accomplish this, alcohol 9 was formylated by treatment with
2 equiv. of EtMgBr and then 3 equiv. of N-methylformanilide
(11) affording aldehyde 12 in 77% (Scheme 1). Subsequent
treatment of 12 with excess p-MeOC6H4MgBr produced
diol 13, which was then subjected to ionic reduction with
Et3SiH–TFA. In contrast to alcohol 9, the diol was readily
soluble in CH2Cl2, and after the addition of TFA, the solution
became highly colored. Analysis of the reaction mixture
indicated complete consumption of diol 13, but rather than
reduction to provide 5, the imidazonaphthalene derivative 14
was formed. The formation of 14 can be readily understood in
terms of an intramolecular Friedel–Crafts cyclization of the
electron rich aromatic D-ring onto the carbocation produced
by ionization of the C12 alcohol and then dehydration. Similar
cyclizations have been reported previously also under acidic
conditions.14
Since all attempts via alcohols failed to give key intermediate 5
en route to naamidine H, the synthetic strategy required
redesigning to avoid the intermediacy of benzylic alcohols
related to 9. Lindell and co-workers have reported that it is
possible to directly alkylate imidazolyl cuprate derivatives
with benzylic bromides and thus we pursued this strategy.10
However, treating imidazole 7 with EtMgBr, then trans-
metalation with CuCNÁ2LiCl (1.0 M in THF) followed by
exposure to 4-benzyloxy-3,5-dimethoxybenzyl bromide (10),
did not provide an isolable product. We have observed
previously that methyl substituted imidazoles do not appear
Scheme 2 Total synthesis of naamidine H.
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of DMAS protection at N1-position.15 Following literature
precedent,15 disubstituted imidazole 17 was treated with
methyl triflate in dichloromethane to provide the imidazolium
ion 18, the formation of which was observed by TLC and
confirmed by 1H NMR spectroscopy of the crude reaction
mixture. After removing the solvent, this intermediate was
reacted with benzylamine in refluxing acetonitrile to provide
the methylimidazole 5 in 90% overall yield. When 5 was
treated with n-BuLi and TsN3, tosyl derivative 19 was isolated
as the only substitution product in addition to large amount of
recovered starting material. This was a somewhat surprising
result since we and others have used this approach for the
azidation of imidazole C2 position.11,12b,16 Fortunately the
preparation of azide 20 was achieved in 63% yield simply by
treating imidazole 5 with n-BuLi and followed by trisyl azide
at À78 1C. Catalytic hydrogenation of this material converted
the azide to the amine and simultaneously removed the benzyl
protecting group and provided of naamine G (2) in 95% yield.
Conversion of 2 to naamidine H (3) was accomplished using
Watson’s modification of the Ohta protocol17 for introduction
of methyl parabanic acid moiety (via 21) completing the total
synthesis of naamidine H in 20% overall yields from 15 in
6 steps.
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In summary, we have successfully used a position selective
transmetalation reaction to incorporate two benzyl fragments
to access two Leucetta-derived alkaloids naamine G and
naamidine H. The synthesis also employs a position selective
exchange of nitrogen substituents via an imidazolium salt. We
are currently investigating the biological activity of these
natural products and analogs and will describe these studies
elsewhere.
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Notes and references
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2150 | Chem. Commun., 2010, 46, 2148–2150