A new total synthesis of the zinc matrixmetalloproteinase inhibitor ageladine A featuring a biogenetically Patterned 6π-2-azatriene electrocyclization

Article abstract of DOI:10.1021/ol063038a

(Chemical Equation Presented) A convergent second generation total synthesis of the heterocyclic marine sponge metabolite ageladine A has been achieved by using a biomimetically inspired 6π-2-azatriene electrocyclization as the key step for formation of the imidazolopyridine moiety.

Full text of DOI:10.1021/ol063038a

ORGANIC
LETTERS
2007
Vol. 9, No. 5
853-855
A New Total Synthesis of the Zinc
Matrixmetalloproteinase Inhibitor
Ageladine A Featuring a Biogenetically
Patterned 6π-2-Azatriene
Electrocyclization
Matthew L. Meketa and Steven M. Weinreb*
Department of Chemistry, The PennsylVania State UniVersity, UniVersity Park,
PennsylVania 16802
smw@chem.psu.edu
Received December 15, 2006
ABSTRACT
A convergent second generation total synthesis of the heterocyclic marine sponge metabolite ageladine A has been achieved by using a
biomimetically inspired 6 -2-azatriene electrocyclization as the key step for formation of the imidazolopyridine moiety.
π
The Fusetani group recently described the isolation and
characterization of ageladine A (1) from the marine sponge
Agelas nakamurai Hoshino collected near Kuchinoerabu-
jima Island in southern Japan.1 Ageladine A was found to
be active at micromolar levels as an inhibitor of various zinc
matrixmetalloproteinases (MMPs) which, among other func-
tions, are involved in the regulation of angiogenesis. Such
inhibitors have shown potential as chemotherapeutic agents
for the treatment of cancer, and some are presently being
evaluated in clinical trials.2 Earlier this year we reported the
first total synthesis of this unique marine metabolite via a
route that utilized a 6π-1-azatriene electrocyclization and a
Suzuki-Miyaura coupling of N-Boc-pyrrole-2-boronic acid
with a 2-chloropyridine derivative as key steps.3 More
recently, Shengule and Karuso have described a short
synthesis of 1 using a Pictet-Spengler reaction of an imine
derived from 2-aminohistamine and N-Boc-2-formyl-4,5-
dibromopyrrole, followed by an oxidation, to generate the
pyridine ring system.4
It was proposed by Fusetani and co-workers1 that ageladine
A (1) arises in nature from pyrrole aldehyde 2 (presumably
derived from proline or arginine) and histamine (3) (Scheme
1).5 These two fragments combine, eventually leading to
N-vinylimine 4, which then undergoes a 6π-2-azatriene
electrocyclization to produce dihydropyridine 5. Subsequent
dehydrogenation of intermediate 5 affords the natural
(3) Meketa, M. L.; Weinreb, S. M. Org. Lett. 2006, 8, 1443.
(4) Shengule, S. R.; Karuso, P. Org. Lett. 2006, 8, 4083.
(5) For biosynthetic studies on pyrrole-imidazole alkaloids see: (a)
Vergne, C.; Boury-Esnault, N.; Perez, T.; Martin, M.-T.; Adeline, M.-T.;
Dau, E. T. H.; Al Mourabit, A. Org. Lett. 2006, 8, 2421 and references
cited therein. (b) Al Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237.
(1) Fujita, M.; Nakao, Y.; Matsunaga, S.; Seiki, M.; Itoh, Y.; Yamashita,
J.; van Soest, R. W. M.; Fusetani, N. J. Am. Chem. Soc. 2003, 125, 15700.
(2) For reviews see: (a) Whittaker, M.; Floyd, C. D.; Brown, P.; Gearing,
A. J. H. Chem. ReV. 1999, 99, 2735. (b) Matter, A. Drug DiscoVery Today
2001, 6, 1005.
10.1021/ol063038a CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/30/2007

protected as its N-BOM derivative 12 (Scheme 3). The nitrile
functionality was then transformed into amide 13 with basic
hydrogen peroxide,8 and bromination with NBS led to
dibromopyrrole amide 14. To ensure that the dibromination
step had occurred with the desired regiochemistry, the
structure of 14 was confirmed by X-ray crystallography.
Scheme 1
Scheme 3
product. In this letter, we describe a new synthesis of
ageladine A that features a biomimetically inspired 6π-2-
azatriene electrocyclization as the pivotal step to construct
the imidazolopyridine moiety.
The synthesis commenced with tribromoimidazole 6,3
which was selectively transmetallated at C-2 with n-
butyllithium and converted into sulfide 7 with dimethyl
disulfide (Scheme 2). In a one-pot process based upon the
By using the protocol of Buchwald and co-workers,9 it
was possible to combine vinyl iodide 10 with amide 14 to
produce (Z)-enamide 15 stereoselectively in high yield
(Scheme 4). We were pleased to find that the bromine atoms
Scheme 4
Scheme 2
methodology of Begtrup,6 dibromide 7 was first selectively
transmetallated at C-5 and the resulting carbanion was
C-silylated. Without isolation the 4-bromosilylimidazole
product was transmetallated and formylated to produce
aldehyde 8. The crude compound was then desilylated with
potassium carbonate to afford the desired imidazole aldehyde
9 in good overall yield from tribromide 6. Employing the
procedure of Stork and Zhao,7 aldehyde 9 could subsequently
be converted cleanly into the (Z)-vinyl iodide 10.
in the pyrrole ring were fully compatible with this coupling
process.10 This enamide could be converted to the thio-
enamide 16 with Lawesson’s reagent, and methyl triflate
The requisite pyrrole fragment was prepared from com-
mercially available 2-cyanopyrrole (11), which was first
(8) Zlatopolskiy, B. D.; Kroll, H.-P.; Melotto, E.; de Meijere, A. Eur. J.
Org. Chem. 2004, 4492.
(9) Jieng, L.; Job, G. E.; Klapers, A.; Buchwald, S. L. Org. Lett. 2003,
5, 3667.
(10) Cf.: Sun, C.; Camp, J. E.; Weinreb, S. M. Org. Lett. 2006, 8, 1779.
(6) Eriksen, B. L.; Vedso, P.; Begtrup, M. J. Org. Chem. 2001, 66, 8344.
(7) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
854
Org. Lett., Vol. 9, No. 5, 2007

served to produce the thiomethyl imidate 17.11,12 To effect
the key electrocyclization step,13,14 heating N-vinyl imidate
17 in a dilute solution of mesitylene at 145 °C for 16 h
afforded the desired imidazolopyridine 19 (44% isolated
yield, 51% based on recovered starting material 17). The
major byproduct detected in this process appears to be the
isomerized (E)-vinyl imidate 20 (27%).
Scheme 5
To continue the synthesis, sulfide 19 was first treated with
m-CPBA to produce mainly sulfoxide 21a (76%) along with
a smaller amount of the corresponding sulfone 21b (10%)
(Scheme 5). This mixture was subsequently treated with
sodium azide in DMSO at room temperature to afford the
2-azidoimidazole 22 in good yield. The azide was then
reduced by hydrogenation over Lindlar catalyst to afford
amine 23 in 94% yield. After some experimentation, it was
found that both BOM protecting groups can be removed by
exposure of intermediate 23 to anhydrous aluminum tri-
chloride15 in methylene chloride at room temperature,
affording ageladine A (1) identical with material that we have
previously synthesized.3
ageladine A (1) that features as the key step a thermal 6π-
2-azatriene electrocyclization for construction of the imid-
azolopyridine system. This new convergent synthesis requires
only seven steps from easily prepared (Z)-vinyl iodide
imidazole fragment 10 and dibromopyrrole amide 14, and
the approach would appear to be amenable to facile synthesis
of structural analogues of the natural product.
In conclusion, we have completed a biogenetically inspired
total synthesis of the antiangiogenic marine metabolite
(11) In some extensive studies with model enamide A we were unable
to directly form any imidate derivatives B
Acknowledgment. We are grateful to the National
Science Foundation (CHE-0404792) for financial support of
this research and Dr. H. Yennawar (Penn State Small
Molecule X-ray Crystallographic Facility) for the X-ray
structure determination of dibromopyrrole 14. We also thank
Professor Blake Peterson and Jocelyn Edathil (Penn State
University) for assistance with reverse phase HPLC analysis.
.
(12) The NMR spectra of thioimidate 17 show broad peaks (see the
Supporting Information) which might be due to rapid inversion of the imine
nitrogen.
(13) Cf.: (a) Biere, H.; Russe, R.; Seelen, W. Liebigs Ann. Chem. 1986,
1749. (b) Qiang, L. G.; Baine, N. H. Tetrahedron Lett. 1988, 29, 3517. (c)
Palacios, F.; Gil, M. J.; Martinez de Marigorta, E.; Rodriguez, M.
Tetrahedron 2000, 56, 6319. (d) Campos, P. J.; Caro, M.; Rodriguez, M.
A. Tetrahedron Lett. 2001, 42, 3575.
(14) For a general review of triene electrocyclizations see: Okamura,
W. H.; de Lera, A. R. 1,3-Cyclohexadiene Formation Reactions. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 5, pp. 699-750.
(15) Groves, J. K.; Cundasawmy, N. E.; Anderson, H. J. Can. J. Chem.
1973, 51, 1089.
Supporting Information Available: Experimental pro-
cedures for preparation of new compounds including X-ray
and spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL063038A
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