Total syntheses of naamidine G and 14-methoxynaamidine G

Article abstract of DOI:10.1016/j.tetlet.2009.10.117

Simple total syntheses of two Leucetta-derived marine alkaloids have been developed using position-specific halogen-metal exchange of polyhaloimidazoles to introduce the benzyl substituted sidechains. Introduction of the C2 amine group by lithiation and trapping with tosyl azide provides amines on catalytic hydrogenation, which can be converted to naamidine G and 14-methoxynaamidine G using a procedure described in the literature.

Full text of DOI:10.1016/j.tetlet.2009.10.117

Tetrahedron Letters 51 (2010) 164–166
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Tetrahedron Letters
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Total syntheses of naamidine G and 14-methoxynaamidine G
*
Panduka B. Koswatta, Carl J. Lovely
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019-0065, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple total syntheses of two Leucetta-derived marine alkaloids have been developed using position-spe-
cific halogen-metal exchange of polyhaloimidazoles to introduce the benzyl substituted sidechains. Intro-
duction of the C2 amine group by lithiation and trapping with tosyl azide provides amines on catalytic
hydrogenation, which can be converted to naamidine G and 14-methoxynaamidine G using a procedure
described in the literature.
Received 24 September 2009
Revised 19 October 2009
Accepted 23 October 2009
Available online 30 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
2-Aminoimidazole alkaloids have recently attracted the atten-
tion of the synthetic community, in particular several members of
the oroidin family of alkaloids.1,2 A less well-explored group of 2-
aminoimidazole-containing natural products are found in sponges
of the Leucettidae family of sponges. The Leucetta family of alkaloids
is characterized by the presence of a 2-aminoimidazole moiety
which is substituted at various positions around the heterocycle
and possesses typically one or two benzylic fragments (1–6,
Fig. 1).1b They range in complexity from the fairly simple clathri-
dine A (1)3 via naamine/naamidine type systems (e.g., naamine D
(2), naamidine G (3), and 14-methoxynaamidine G (5))4 to the more
elaborate and highly oxygenated members such as calcaridine A (4)
and spiroleucettadine (6).5 From a medicinal chemistry perspective,
several of these alkaloids have been reported to exhibit activity as
antibiotics,6 nitric oxide synthase inhibitors,7 and cytotoxicity,8
but in general their broad scale pharmacological evaluation has
not been addressed. Although these molecules are not overly
complex or challenging targets, they are potentially attractive
scaffolds for evaluation in high-throughput screening programs.1b
Our laboratory has developed a number of synthetic methods
for the total synthesis of 2-aminoimidazole alkaloids using poly-
haloimidazoles as the starting point, utilizing this strategy en route
to the total synthesis of members of both the oroidin and Leucetta
families of alkaloids.2,9 Following earlier reports,10 we and others
have demonstrated that 4,5-dihaloimidazoles can be functional-
ized in a sequential and controlled manner in the order of
C5?C4?C2 using Grignard reagents (for functionalization at the
4- and 5-positions) and n-BuLi (for C2).9,11,12 This manuscript de-
scribes the application of this strategy in the total syntheses of
naamidine G (3) and 14-methoxynaamidine G (5).
that the crude extract possess mild cytotoxicity (against KB cells)
and activity against Candida albicans, but apparently the purified
compounds were not further evaluated.4b Our approach to these
natural products was patterned after
a similar sequence of
reactions used en route to calcaridine A9a starting from 4,5-diio-
do-l-methylimidazole (7). Specifically, 7 was converted to the
corresponding 4-iodoimidazole 8 by treatment with EtMgBr and
then p-anisaldehyde (Scheme 1).9a After ionic reduction of the ben-
O
O
O
Me
OMe
OMe
N
N
N
H2N
N
N
O
N
H
HN
Me
1: Clathridine A
2: Naamine D
HO
Me
O
N
O
OMe
OMe
OMe
N
N
N
N
N
HN
H2N
O
OMe
Me
Me
4: Calcaridine A
OMe
3: Naamidine G
Me
N
O
O
OMe
OMe
OMe
N
N
N
Me
N
HN
O
Naamidine G (3) and 14-methoxynaamidine G (5) were isolated
and described by Pietra in 1995, but little in terms of biological
activity of these natural products was reported.4b It is mentioned
O
O
Me
N
H
NHMe
6: (-)-Spiroleucettadine
Figure 1. Selected Leucetta alkaloids.
5: 14-Methoxynaamidine G
* Corresponding author. Tel.: +1 817 272 5446; fax: +1 817 272 3808.
E-mail address: lovely@uta.edu (C.J. Lovely).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.117

P. B. Koswatta, C. J. Lovely / Tetrahedron Letters 51 (2010) 164–166
165
I
I
CHO
OMe
I
I
N
N
EtMgBr
CH2Cl2
then
N
N
N
N
N
N
Et3SiH, TFA
EtMgBr/THF
p-MeOC6H4MgBr
then 10
CH2Cl2
reflux
97%
OH
THF, reflux
98%
85%
p-anisaldehyde Me
Me
Me
Me
7
95%
8
9
11
OMe
OMe
CHO
N
Me
10
OH
N
N
N
N
N
N
Et3SiH, TFA
°
C
n-BuLi, THF,-78
then,TsN3
N3
CH2Cl2, rt
81%
OMe
OMe
OMe
89%
Me
Me
Me
O
Me
N
OMe
OMe
OMe
NH
12
13
14
O
Pd-C, H2
EtOH, 95%
O
O
BSA, MeCN,
Me
O
OMe
°
45
C
N
N
TMS
O
N
N
Me
O
H2N
N
NH
N
°
PhMe, 80 C,
OMe
OMe
N
N
78%
Me
O
Me
3
15
OMe
Scheme 1. Total synthesis of naamidine G (3).
zylic hydroxyl group in 8 with Et3SiH and TFA, the resulting 4-iod-
oimidazole was reacted with EtMgBr to effect formation of the
imidazol-4-yl Grignard reagent which was treated with N-methyl-
formanilide (10) to provide the aldehyde 11. Reaction of this alde-
hyde with p-MeOC6H4MgBr provided the desired alcohol 12,
which is the key intermediate for both naamidine G and 14-meth-
oxynaamidine G (Scheme 2). Removal of the doubly benzylic alco-
hol in 12 was achieved by reduction with Et3SiH and TFA at room
temperature affording 13. Lithiation at C2 was accomplished with
n-BuLi and the resulting organolithium species was treated with
TsN3 to install an azide moiety, which was subjected to the catalytic
hydrogenation to provide 1-methylnaamine D (15). This was then
converted to naamidine G (3) using the procedure reported earlier
with TMS-activated methyl parabanic acid13,9b to complete the
total synthesis of 3 in 41% overall yields in eight steps.
OH
OMe
OMe
N
N
N
N
MeOH, TFA
reflux
95%
OMe
OMe
Me
Me
16
OMe
12
n-BuLi, THF,
°
-78 C, then
TsN3
67%
OMe
OMe
Pd-C, H2
EtOH, 98%
N
N
N
N
H2N
N3
OMe
OMe
Me
Me
The total synthesis of 14-methoxynaamidine G (5) commenced
with the conversion of alcohol 12 to methyl ether 16 with methanol
and TFA (Scheme 2). Introduction of C2 azide was accomplished by
metalation and reaction with TsN3 provided 17, which was con-
verted to amine 18 by catalytic hydrogenation. Following the same
reaction as above, TMS-activated methyl parabanic acid provided
14-methoxynaamidine G (5) in low yield. Initially it was assumed
that the TMS source used (BSA = N,O-bis trimethylsilylacetamide)
might cause the decomposition of the starting material. Therefore,
the introduction of hydantoin moiety was attempted with other
methods reported in the literature.14 However, these methods
failed to give the product and only the decomposition of the starting
material was observed. The reason for the low yield from these
reactions is still under investigation, but presumably is a result of
competitive silylation and ionization of the methyl ether.
17
18
OMe
OMe
O
O
Me
Me
BSA, MeCN,
N
N
NH
°
PhMe, 80 C,
N
°
45
C
10%
O
O
O
OTMS
OMe
O
Me
N
NH
N
OMe
N
N
O
OMe
The spectroscopic data of the synthetic compounds were in
agreement with the data reported for the natural products.
However the melting point of the synthetic naamidine G was
195–196 °C in contrast to the natural product (94 °C).4b
Me
5
Scheme 2. Total synthesis of 14-methoxynaamidine G (5).

166
P. B. Koswatta, C. J. Lovely / Tetrahedron Letters 51 (2010) 164–166
4. For isolation see: (a) Dunbar, D. C.; Rimoldi, J. M.; Clark, A. M.; Kelly, M.;
In summary, we have developed high yielding eight-step
Hamann, M. T. Tetrahedron 2000, 56, 8795–8798; (b) Mancini, I.; Guella, G.;
Debitus, C.; Pietra, F. Helv. Chim. Acta 1995, 78, 1178.
syntheses of the Leucetta alkaloids naamidine G (3) and 14-meth-
oxynaamidine G (5) using a sequential chemoselective halogen-
magnesium exchange, permitting the selective installation of the
C5 and C4-benzyl groups without protection of the more acidic
C2-position. Subsequent lithiation at C2 and electrophilic trapping
leads to introduction 2-amino moiety. We are actively exploring
the synthesis of other members of the Leucetta family of alkaloids,
and their analogs for medicinal chemistry programs.
5. (a) Edrada, R. A.; Stessman, C. C.; Crews, P. J. Nat. Prod. 2003, 66, 939; (b) Ralifo,
P.; Crews, P. J. Org. Chem. 2004, 69, 9025; (c) White, K. N.; Amagata, T.; Oliver, A.
G.; Tenney, K.; Wenzel, P. J.; Crews, P. J. Org. Chem. 2008, 73, 8719.
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Chem. 1990, 55, 1944.
7. Dunbar, D. C.; Rimoldi, J. M.; Clark, A. M.; Kelly, M.; Hamann, M. T. Tetrahedron
2000, 56, 8795.
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C. M. J. Med. Chem. 1998, 41, 3909; (b) Aberle, N. S.; Catimel, J.; Nice, E. C.;
Watson, K. G. Bioorg. Med. Chem. Lett. 2007, 17, 3741.
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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-9601771,
CHE-0234811) is thanked for partial funding of the purchases of
the NMR spectrometers used in this work.
12. (a) Dehmel, F.; Abarbri, M.; Knochel, P. Synlett 2000, 345; (b) Abarbri, M.;
Thibonnet, J.; Bérillon, L.; Dehmel, F.; Rottländer, M.; Knochel, P. J. Org. Chem.
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X.; Knochel, P. Chem. Commun. 2006, 2170.
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References and notes
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