Expedient total syntheses of preclathridine A and clathridine A

Article abstract of DOI:10.1016/j.tetlet.2009.06.088

A short and operationally simple total synthesis of two Leucetta-derived marine alkaloids has been developed, which rely on position specific halogen-metal exchange to introduce the benzyl-substituted side chain. Introduction of the C2 amine group by lith

Full text of DOI:10.1016/j.tetlet.2009.06.088

Tetrahedron Letters 50 (2009) 4998–5000
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Expedient total syntheses of preclathridine A and clathridine A
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:
A short and operationally simple total synthesis of two Leucetta-derived marine alkaloids has been devel-
oped, which rely on position specific halogen–metal exchange to introduce the benzyl-substituted side
chain. Introduction of the C2 amine group by lithiation and trapping with tosyl azide provides preclathri-
dine A on catalytic hydrogenation, which can be converted to clathridine A by a procedure described in
the literature.
Received 17 April 2009
Revised 4 June 2009
Accepted 16 June 2009
Available online 21 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
2
-Aminoimidazole alkaloids have recently attracted the atten-
O
O
tion of the synthetic community, in particular several members
O
O
of the oroidin family of alkaloids.1 A less well explored group of
,2
O
Me
2
-aminoimidazole-containing natural products is found in sponges
N
N
of the Leucettidae family. The Leucetta family of alkaloids are char-
acterized by the presence of a 2-aminoimidazole moiety which is
substituted at various positions around the heterocycle and con-
tains at least one, but more commonly two benzylic fragments.
They range in complexity from the fairly simple clathridine A
N
N
N
N
O
HN
H N
2
Me
1: Clathridine A
Me
2: Preclathridine A
HO
3
4
(
1), preclathridine A (2), and naamidine type systems (e.g.,
Me
N
5
,6
naamidine A (3)) to the more elaborate and highly oxygenated
members such as calcaridine A (4), spiroleucettadine (5), and
kealiiquinone (6). From a biological perspective, some of these
alkaloids have been reported to exhibit activities as antibiotics, ni-
O
7
7
O
OMe
8
N
OMe
OH
N
N
N
N
9
HN
H N
2
tric oxide synthase inhibitors,9 and are cytotoxic, but in general
their broad scale pharmacological evaluation has not been ad-
dressed. While in some cases these molecules are, relatively speak-
ing, simple targets for total synthesis, they are attractive scaffolds
for evaluation in high throughput screening programs, providing
flexible and efficient synthetic approaches (Fig. 1).
10
O
OMe
Me
Me
3
: Naamidine A
4: Calcaridine A
O
Me
N
OMe
OMe
O
In principle two general approaches to these molecules might
be envisioned, one in which the imidazole ring is constructed in
a de novo fashion, or a second in which a pre-existing imidazole
is elaborated. While both strategies have different strengths and
weaknesses, our laboratory has followed the latter approach using
polyhaloimidazoles as the starting point and used this en route to
the total synthesis of members of both the oroidin and the Leucetta
families of alkaloids. Following important precedents,11 we and
others have demonstrated that 4,5-dihaloimidazoles can be func-
tionalized in a sequential and controlled manner in the order
C5?C4?C2 using Grignard reagents (for the 4- and 5-positions)
Me
N
N
H
OMe
O
O
O
O
N
H
NHMe
MeO
6: Kealiiquinone
5: (-)-Spiroleucettadine
2
Figure 1. Selected Leucetta alkaloids.
be accomplished late in a sequence, particularly the incorporation
of an amino group, has practical advantages in approaches to the
Leucetta and the oroidin alkaloids. This type of strategy has been
1
2–15
and n-BuLi (for C2).
The fact that functionalization of C2 can
1
4
used by us in a total synthesis of calcaridine A (4) and the re-
1
5
ported structure of nagelamide D. The current report describes
the extension of this strategy in the total syntheses of clathridine
A and preclathridine A.
*
Corresponding author. Tel.: +1 817 272 5446; fax: +1 817 272 3808.
E-mail address: lovely@uta.edu (C.J. Lovely).
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.088

P. B. Koswatta, C. J. Lovely / Tetrahedron Letters 50 (2009) 4998–5000
4999
OH
O
O
I
N
N
I
N
N
Et SiH, TFA
N
N
EtMgBr
CH Cl
EtMgBr
3
N
N
O
CH Cl , rt
O
2
2
then ArCHO
90%
2
2
I
then H O
72%
2
Me
Me
95%
Me
Me
7
8
9
10
n-BuLi, THF,
O
-78 °C, then
O
TsN
O
3'
3
Me
O
78%
O
N
Me 10
1'
N
N
8
NH
3
O
O
N
Pd-C, H2
N
N
N
1
OTMS
O
N3
H N
2
N
O
EtOH, 95%
O
PhMe, 80 °C,
1%
N
Me
N
6
Me
Me
1
'
2
11
Scheme 1.
Clathridine A (1) (from the sponge Clathrina clathrus) and prec-
lathridine A (2) (from the nudibranch Notodoris gardineri) were iso-
lated and reported by the Fattoruso and Crews laboratories,
respectively, almost 20 years ago.3 Little in terms of biological
activity of these natural products has been reported, although it
is mentioned that 1 is antimycotic.3a Three total syntheses of these
molecules have been described in the literature. The first report by
Ohta’s laboratory employs the sequential metalation (Br?Li) of an
imidazole derivative, but requires blocking groups (thiophenyl
groups) to prevent unwanted metalation at the 2- and 5-posi-
,4
1
6,19
17
18
tions.
Both the Molina and the van der Eycken groups have
utilized methods that involve the de novo synthesis of the amino-
imidazole system via iminophosphoranes and masked guanidine
derivatives, respectively. While strategically our approach is clo-
sely related to that reported by the Ohta’s laboratory,1 as indi-
cated above, we have developed methodology based on the
elaboration of haloimidazoles via Grignard reagents which does
not require protection (and subsequent deprotection) of the more
reactive 2- and 5-positions which is necessary using deprotonation
strategies or halogen–lithium exchange.
6
Figure 2. X-ray structure of synthetic clathridine A.
In summary, we have developed high yielding five- and six-step
syntheses of the Leucetta alkaloids preclathridine A (2) and clathri-
dine A (1), respectively. The syntheses rely on chemoselective hal-
ogen–magnesium exchange, permitting the selective installation of
the C4-benzyl group without protection of the more acidic C2-and
C5-positions. Subsequent lithiation at C2 and electrophilic trapping
lead to introduction of 2-amino moiety. This chemistry is very easy
to perform and leads to the preparation of these natural products
on the gram-scale. This chemistry can be used for the synthesis
of other members of the Leucetta family of alkaloids, and it is also
amenable for the synthesis of analogs for medicinal chemistry pro-
grams. We are actively exploring these areas.
Our synthetic studies commenced with the conversion of diio-
do-l-methylimidazole (7) to 4-iodoimidazole (8) by treatment
with EtMgBr, followed by water (Scheme 1).13 The resulting 4-
iodoimidazole was reacted with EtMgBr to effect formation of
imidazol-4-yl Grignard which was treated with piperonal to pro-
1
6
vide the alcohol 9. Removal of the doubly benzylic alcohol was
accomplished by reduction with Et SiH and TFA at room temper-
ature affording 10. Lithiation at C2 was accomplished with n-BuLi
and the resulting species was treated with TsN to install an azide
3
3
moiety. The synthesis of preclathridine A (2) was completed by
reduction of the azide to the amine on catalytic hydrogenation.
Preclathridine A was converted to clathridine A (1) using the pro-
cedure reported by Watson and co-workers with TMS-activated
methyl parabanic acid.6b The two synthetic compounds displayed
spectroscopic data generally consistent with the structures of the
Acknowledgments
We are grateful to Dr. Mohammed Yousufuddin for the deter-
mination of the X-ray structure of synthetic clathridine A. This
work was supported by the Robert A. Welch Foundation (Y-
362). We thank the NSF (CHE-9601771, CHE-0234811) for partial
funding of the purchases of the NMR spectrometers used in this
work.
1
natural product. The H NMR data were in excellent agreement,
1
3
the C NMR data were generally in good agreement but we
13
noted small differences in the C NMR spectrum to that reported
1
3
,4,19
in both the isolation papers and in synthetic material.
All
three sets of reported data were acquired in different solvents,
but there is apparently little solvent dependence on the chemical
shifts, and so we do not believe that this is the cause of the dis-
crepancies. Fortunately, our synthetic material provided a nicely
crystalline product, which was subjected to X-ray crystallography,
and this provided confirmation of the connectivity (Fig. 2). We
also observed, that in the crystalline state, (1) exists as the
N(8)H tautomer (cf 1’ in Scheme 1).
References and notes
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2
3
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.
He, Y.; Du, H.; Sivappa, R.; Lovely, C. J. Synlett 2006, 965.
(a) Ciminiello, P.; Fattorusso, E.; Magno, S.; Mangoni, A. Tetrahedron 1989, 45,
873; (b) Ciminiello, P.; Fattorusso, E.; Mangoni, A.; Di Blasio, B.; Pavone, V.
Tetrahedron 1990, 46, 4387. See also Ref. 4.
3

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000
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Alvi, K. A.; Peters, B. M.; Hunter, L. M.; Crews, P. Tetrahedron 1993, 49, 329.
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(
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