A concise total synthesis of naamidine A

Article abstract of DOI:10.1021/ol052568o

A total synthesis of naamidine A is reported. Key benefits of the described pathway include its brevity, its synthetic ease, and its flexibility with respect to the preparation of analogues. Formation of the 2-aminoimidazole core is achieved by condensati

Full text of DOI:10.1021/ol052568o

ORGANIC
LETTERS
2006
Vol. 8, No. 3
419-421
A Concise Total Synthesis of
Naamidine A
Nicholas S. Aberle, Guillaume Lessene, and Keith G. Watson*
Medicinal Chemistry Group, The Walter and Eliza Hall Institute of Medical Research,
Biotechnology Centre, 4 Research AVenue, Bundoora 3086, Victoria, Australia
kwatson@wehi.edu.au
Received October 23, 2005
ABSTRACT
A total synthesis of naamidine A is reported. Key benefits of the described pathway include its brevity, its synthetic ease, and its flexibility
with respect to the preparation of analogues. Formation of the 2-aminoimidazole core is achieved by condensation of the appropriate
r
-aminoketone with cyanamide.
Since the late 1980s, a range of 2-aminoimidazole alkaloids
have been isolated from sponges of the genus Leucetta
(Figure 1),1 with naamidine A (1) being one of the more
prominent members of the family. After being isolated by
Carmely and Kashman in 1987,2 naamidine A received little
attention until initial reports of its biological activity were
made by Ireland over a decade later.3 Early studies showed
the unusual tetrasubstituted 2-aminoimidazole alkaloid to be
an antagonist of the epidermal growth factor receptor (EGFR)
signaling pathway, overexpression of which has been im-
plicated in a wide variety of human cancers and is typically
associated with poor prognosis.4 In vivo assays of 1, featuring
implanted tumors in athymic mice, demonstrated 85% tumor
growth inhibition at the highest tolerated dose of 25 mg/kg.
(1) (a) Ralifo, P.; Crews, P. J. Org. Chem. 2004, 69, 9025. (b) Edrada,
R. A.; Stessman, C. C.; Crews, P. J. Nat. Prod. 2003, 66, 939. (c) Crews,
P.; Clark, D. P.; Tenney, K. J. Nat. Prod. 2003, 66, 177. (d) Gross, H.;
Kehraus, S.; Konig, G. M.; Woerheide, G.; Wright, A. D. J. Nat. Prod.
2002, 65, 1190. (e) Fu, X.; Schmitz, F. J.; Tanner, R. S.; Kelly-Borges, M.
J. Nat. Prod. 1998, 61, 384. (f) Plubrukarn, A.; Smith, D. W.; Cramer, R.
E.; Davidson, B. S. J. Nat. Prod. 1997, 60, 712.
(2) Carmely, S.; Kashman, Y. Tetrahedron Lett. 1987, 28, 3003.
(3) Copp, B. R.; Fairchild, C. R.; Cornell, L.; Casazza, A. M.; Robinson,
S.; Ireland, C. M. J. Med. Chem. 1998, 41, 3909.
Figure 1. Examples of 2-aminoimidazoles from genus Leucetta.
(4) For example: (a) Laskin, J. J.; Sandler, A. B. Cancer Treat. ReV.
2004, 30, 1. (b) Nicholson, R. I.; Gee, J. M. W.; Harper, M. E. Eur. J.
Cancer 2001, 37, S9. (c) Baselga, J. Oncologist 2002, 7, 2.
Subsequent analysis revealed total abrogation of DNA
synthesis at ∼1 µM with corresponding cell cycle arrest in
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G1, thought to be induced by enhanced phosphorylation of
ERK1/2,5 which are serine/threonine protein kinases of the
MAPK signal transduction cascade and important anti-cancer
targets.6 The associated increase in phosphotransferase
activity of ERK1/2 is a phenomenon unique among small
molecules to naamidine A. This feature of its activity, along
with its potential anti-tumor properties, make it an interesting
target for further investigation.
Scheme 2. Retrosynthetic Analysis
The only previous total synthesis of naamidine A and its
precursor naamine A was reported by Ohta and co-workers
(Scheme 1).7 A partially functionalized imidazole ring 2 was
sequentially substituted at the 5- and 4-positions by a series
of lithiation and alkylation steps. Several protections and
deprotections were necessary to achieve the requisite inter-
mediate 3. Six further steps were required to eliminate the
benzylic hydroxyl groups and to convert the 2-thiophenyl
group to the primary amine. Introduction of the dehydrohy-
dantoin unit was performed by an interesting regioselective
condensation with 1-methyl-3-(trimethylsilyl)parabanic acid.8
To this end, we chose the relatively inexpensive, com-
mercially available Boc-Tyr(Bzl)-OH (6) as our starting point
(Scheme 3). Selective N-methylation of the Boc-protected
amino acid was performed using the conditions of Benoiton,9
proceeding in 96% yield (7) with no methyl ester formation
observed. Methylation of this nitrogen at any early stage of
the synthesis is essential to achieve the required regiospeci-
ficity in the formation of the imidazole ring. In situ formation
of the acid fluoride was followed by reaction with N,O-
dimethylhydroxylamine10 to provide the Weinreb amide 8
(86%), existing as a mixture of four rotamers. This was then
treated with the appropriate Grignard reagent to give the
protected R-amino ketone 9 (62%).
Scheme 1. Ohta Synthesis of Naamidine A
Scheme 3. Synthesis of R-Amino Ketone 9
Our interest in an efficient total synthesis of naamidine A
had two major goals: (i) to be able to easily produce
sufficient quantities of the natural product for a range of
biological analyses and (ii) for the synthesis to be amenable
to the rapid preparation of a diverse set of analogues as part
of our medicinal chemistry program. In assessing the
fulfillment of these criteria, we considered that several
improvements to the Ohta synthesis could be made.
From a retrosynthetic perspective (Scheme 2), we intended
to make use of the conditions developed by Ohta for the
regioselective introduction of the dehydrohydantoin moiety.
Rather than beginning with a preformed imidazole ring, we
determined to create the 2-aminoimidazole via condensation
of cyanamide with the appropriate R-amino ketone (4). This,
in turn, we envisioned, could be easily obtained in several
steps from a suitably protected tyrosine derivative (5), raising
the possibility of a correlation between our approach and a
potential biosynthetic pathway for these alkaloids.
Removal of the Boc protecting group of 9 was best
achieved using 4 M HCl in diethyl ether (Scheme 4), as an
aqueous suspension of the resulting salt provided a pH ideal
for the subsequent condensation with cyanamide,11 ultimately
affording the trisubstituted 2-aminoimidazole (86%). Cleav-
age of the benzyl group was effected in quantitative yield
by standard catalytic hydrogenolysis conditions (10% Pd/
C) to provide naamine A, 10.
(5) James, R. D.; Jones, D. A.; Aalbersberg, W.; Ireland, C. M. Mol.
Cancer Ther. 2003, 2, 747.
(6) (a) Sebolt-Leopold, J. S.; Herrera, R. Nat. ReV. Cancer 2004, 4, 937.
(b) English, J. M.; Cobb, M. H. Trends Pharmacol. Sci. 2002, 23, 40. (c)
Sebolt-Leopold, J. S. Oncogene 2000, 19, 6594.
(7) Ohta, S.; Tsuno, N.; Nakamura, S.; Taguchi, N.; Yamashita, M.;
Kawasaki, I.; Fujieda, M. Heterocycles 2000, 53, 1939.
Applying the general concept of Ohta’s introduction of
the unique dehydrohydantoin moiety, 1-methylparabanic acid
(11)12 was silylated to 12 with N,O-bis(trimethylsilyl)-
(8) The conditions used in the total synthesis were subsequently improved
and applied to the total synthesis of related imidazole alkaloids: Nakamura,
S.; Kawasaki, I.; Yamashita, M.; Ohta, S. Heterocycles 2003, 60, 583.
(9) Cheung, S. T.; Benoiton, N. L. Can. J. Chem. 1977, 55, 906.
(10) Tunoori, A. R.; White, J. M.; Georg, G. I. Org. Lett. 2000, 2, 4091.
(11) (a) Lancini, G. C.; Lazzari, E. J. Heterocycl. Chem. 1966, 3, 152.
(b) Boehm, J. C.; Gleason, J. G.; Pendrak, I.; Sarau, H. M.; Schmidt, D.
B.; Foley, J. J.; Kingsbury, W. D. J. Med. Chem. 1993, 36, 3333.
(12) Kolonko, K. J.; Shapiro, R. H.; Barkley, R. M.; Sievers, R. E. J.
Org. Chem. 1979, 44, 3769.
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Org. Lett., Vol. 8, No. 3, 2006

linear steps with an overall yield of 35%. Spectral data (1H
and 13C NMR) for the synthetic material matched that
reported in the literature for the natural sample.13 Preliminary
biological assessment has confirmed that the synthetic 1
inhibits EGF- and IL3-stimulated DNA synthesis in BaF/
ERX cells with an IC50 of 3 µM, consistent with the reported
values.
Scheme 4. Synthesis of Naamidine A
We are now in a position to conduct an in depth analysis
of naamidine A’s biological activity and to prepare a range
of analogues for structure-activity relationships in the quest
for clinically relevant anti-cancer properties.
Acknowledgment. We thank Ed Nice and Jenny Catimel
of the Ludwig Institute for Cancer Research (Melbourne)
for the biological testing. This work was supported by an
Australian Postgraduate Award from the Australian Research
Council (NA).
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL052568O
acetamide (BSA) and then reacted with 10 (80%) to complete
the second total synthesis of naamidine A, carried out in six
(13) Carmely, S.; Ilan, M.; Kashman, Y. Tetrahedron 1989, 45, 2193.
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