Total syntheses of isonaamine C and isonaamidine e

Article abstract of DOI:10.1016/j.tetlet.2011.08.030

The total syntheses of two alkaloids isolated from a marine sponge of the Leucetta sp. have been accomplished in 6 and 7 steps starting from a 4,5-diiodoimidazole derivative. Grignard mediated halogen-metal exchange was used to install the benzyl side cha

Full text of DOI:10.1016/j.tetlet.2011.08.030

Tetrahedron Letters 52 (2011) 5725–5727
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Tetrahedron Letters
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Total syntheses of isonaamine C and isonaamidine E
⇑
Heather M. Lima, Beatriz J. Garcia-Barboza , Nicole N. Khatibi , Carl J. Lovely
Department of Chemistry & Biochemistry, University of Texas at Arlington, Arlington, TX 76019, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The total syntheses of two alkaloids isolated from a marine sponge of the Leucetta sp. have been accom-
plished in 6 and 7 steps starting from a 4,5-diiodoimidazole derivative. Grignard mediated halogen–
metal exchange was used to install the benzyl side chain. C2 substitution was accomplished via lithiation
followed by quenching with trisyl azide which provided isonaamine C after hydrogenation. Isonaamidine
E was then prepared from isonaamine C via introduction of the hydantoin ring by reaction with an acti-
vated parabanic acid derivative.
Received 14 July 2011
Revised 2 August 2011
Accepted 3 August 2011
Available online 11 August 2011
Keywords:
Leucetta
Ó 2011 Elsevier Ltd. All rights reserved.
2-Aminoimidazole
4,5-Diiodoimidazole
Azidation
Methylparabanic acid
Marine sponges of the Leucetta and Clathrina genera produce a
number of imidazole-containing alkaloids that are characterized
by a 2-amino or N-imidazolidinedionyl group at C2, and varying
benzyl substitution at C4 and C5 on the imidazole.1,2 Isonaamine
C (1)3 and isonaamidine E (2) isolated by Wright in 2002,4 among
others, are representative examples of this class of natural prod-
ucts (Fig. 1).5 Calcaridine A (5)6,7 is an example of the more highly
oxidized members of this family. Many of these alkaloids have
been reported to exhibit varying biological activities including
those of interest in this manuscript. Both isonaamine C (1) and
isonaamidine E (2) were found to be cytotoxic against stomach
(HM02) and liver (HepG2 and Huh7) cancer cell lines with GI50 val-
O
H3C
O
N
N
N
OCH3
OCH3
N
OCH3
OCH3
H2N
HN
N
N
OCH3
OCH3
2: Isonaamidine E
ues in the range of 1.3–7.0 l
g/mL.4
1: Isonaamine C
N
A robust, efficient, and adaptable synthetic strategy was devel-
oped by our lab to access this family of natural products centers
around the functionalization of 4,5-diiodoimidazoles via halogen-
metal exchange of Grignard reagents to prepare the benzyl substi-
tuted framework.2 C2 substitution using n-BuLi and TsN3 or TrisN3
to ultimately lead to the 2-amino substituted target following
reduction has been a very effective method as evidenced by the
successes in our own lab7–9 and in numerous other examples. This
manuscript will detail the application of this approach in the total
syntheses of isonaamine C (1) and isonaamidine E (2).
O
N
H3C
O
N
H2N
HN
OCH3
N
O
O
HN
N
CH3
OCH3
3: Naamine D
4: Clathridine A
HO
The sequential functionalization of 4,5-dihaloimidazoles with
Grignard reagents has been well documented, and follows the or-
der of C5, then C4.10–12 However, C4 functionalization of N-benzyl
substituted derivatives leading to C4 benzyl substitution has not
OCH3
N
H2N
N
OCH3
O
⇑
CH3
Corresponding author. Tel.: +1 817 272 5446; fax: +1 817 272 3808.
E-mail address: lovely@uta.edu (C.J. Lovely).
Undergraduate coworkers.
Figure 1. Examples of Leucetta alkaloids.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.030

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H. M. Lima et al. / Tetrahedron Letters 52 (2011) 5725–5727
1. EtMgBr, THF,
rt, 1h; then 9,
rt, 18 h
1. EtMgBr, CH2Cl2
rt, 1 h
1. NaH, THF,
0° C, 1 h
N
I
N
I
N
I
N
N
N
2. PMB-Cl, 55 °C,
12 h, 91%
2. NaBH4, MeOH,
rt, 3 h, 73%
2. H2O, rt, 2 h, 83%
I
I
H
6
OCH3
8
OCH3
7
O
H
OCH3
OCH3
OH
Et3SiH, TFA, CHCl3,
60 °C, 18 h, 86%
N
N
OCH3
OCH3
OCH3
OCH3
9
N
N
OCH3
10
OCH3
11
Scheme 1. Substitution of 4,5-diiodoimidazole.
O
OH
Ar
BuLi, THF, -78 °C,
N
7 min; then Tris-N3,
1 h, 65%
OCH3
OCH3
N
N
N
I
EtMgBr, THF,
rt, 1h; then 9,
rt, 18h
N3
Ar
11
+
N
N
N
N
OCH3
13
OCH3
12
OCH3
10
OCH3
8
Pd/C, H2, MeOH, rt,
10 h, 86%
Ar = 3,4-dimethoxyphenyl
L
L
ı
Mg
H
O
O
1: Isonaamine C
Oppenauer-like transition state
leading to ketone 12
Ar
H3C
O
H3C
O
O
O
Im
Ar
BSA,
toluene, 85 °C,
12 h, 51%
N
N
CH3CN, 45 °C
H
NH
N
TMS
O
O
14
Scheme 2. Grignard reaction leading to 10 and 12.
O
been demonstrated before, and the occurrence of competitive lat-
eral metalation of the N-benzyl side chain is a possible complica-
tion.13,14 Therefore, the application of this synthetic strategy to
isonaamine C provides the first example of selective C4 metalation
in the presence of an N-benzyl substituent. Going forward, 4,5-
diiodoimidazole (6) was treated with NaH, then 4-methoxybenzyl
chloride to give the PMB-protected imidazole 7. Treatment of 7
with EtMgBr induced a halogen–metal exchange at C5 selectively
which when quenched with water resulted in an overall reduction
leading to the 4-iodoimidazole intermediate 8 (Scheme 1).
Treatment of 8 with another round of EtMgBr followed by 3,4-
dimethoxybenzaldehyde (9) led to a mixture of alcohol 10 and the
corresponding ketone 12, which is thought to form via an Oppe-
nauer-type oxidation as a result of coordination through the mag-
nesium alkoxide salt and the benzaldehyde 9 (Scheme 2).15–17
However, it was found that the formation of the ketone by-product
could be minimized by the addition of the prepared Grignard re-
agent to a dilute solution of the aldehyde at room temperature.
In addition, the crude mixture of products isolated from the Grig-
nard reaction could be treated with NaBH4 in MeOH to provide
10 in 73% yield over the two steps.
H3C
N
N
O
N
OCH3
OCH3
HN
N
OCH3
2: Isonaamidine E
Scheme 3. Total synthesis of isonaamine C and isonaamidine E.
duced by treatment of 11 with n-BuLi and quenched with TrisN3 to
give 13 which was reduced via hydrogenation on Pd/C resulting in
isonaamine C (1) in 86% yield. The hydantoin ring of isonaamidine
E was introduced following the literature procedure involving the
reaction of 1-methylparabanic acid and BSA leading to the activated
acid 14.8,9,18,19 Upon treatment of 1 with 14, isonaamidine E (2) was
isolated in 51% yield from 1 (Scheme 3). In both cases, the spectro-
scopic data for compounds 1 and 2 agree with the reported values.4
In conclusion, isonaamine C (27% overall) and isonaamidine E
(14% overall) have been synthesized in 6 and 7 steps, respectively,
Reduction of 10 with Et3SiH and TFA7–9 led to 11 allowing access
to the necessary bis-benzyl substituted framework of isonaamine C
and isonaamidine E (Scheme 1). The 2-amino substituent was intro-

H. M. Lima et al. / Tetrahedron Letters 52 (2011) 5725–5727
5727
from 7 following a general synthetic route developed by us to ac-
References and notes
cess this family of natural products. Central to this approach is
the application of the chemoselective reactivity of 4,5-dihaloimi-
dazole substitution that has allowed for the controlled elaboration
of imidazoles, including those having N-benzyl substituents, lead-
ing to the desired benzyl substituted core of the target alkaloids. To
date a number of bioactive Leucetta and Clathrina alkaloids have
been synthesized following this strategy attesting not only to its
versatile and efficient nature, but also to its potential applicability
in medicinal chemistry projects.
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Acknowledgments
This work was supported by the Robert A. Welch Foundation (Y-
1362) and in part by the NIH (GM066503). The NSF (CHE-0840509,
CHE-0234811) is thanked for partial funding of the purchases of
the NMR spectrometers used in this work.
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Supplementary data
Supplementary data (experimental procedures and copies of 1H
and 13C NMR data for all new compounds) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.08.030.