Total synthesis of ageladine A, an angiogenesis inhibitor from the marine sponge Agelas nakamurai

Article abstract of DOI:10.1021/ol0602304

A 12-step total synthesis of the tricyclic heteroaromatic marine metabolite ageladine A has been achieved using a 6π-azaelectrocyclization and a Suzuki-Miyaura coupling of N-Boc-pyrrole-2-boronic acid with a chloropyridine as key steps.

Full text of DOI:10.1021/ol0602304

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1443-1446
Total Synthesis of Ageladine A, an
Angiogenesis Inhibitor from the Marine
Sponge Agelas nakamurai
Matthew L. Meketa and Steven M. Weinreb*
Department of Chemistry, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
smw@chem.psu.edu
Received January 26, 2006
ABSTRACT
A 12-step total synthesis of the tricyclic heteroaromatic marine metabolite ageladine A has been achieved using a 6π-azaelectrocyclization
and a Suzuki−Miyaura coupling of N-Boc-pyrrole-2-boronic acid with a chloropyridine as key steps.
In 2003, Fusetani and co-workers described the isolation of
ageladine A (1) by bioassay-guided fractionation of the
marine sponge Agelas nakamurai Hoshino collected near
Kuchinoerabu-jima Island in southern Japan.1 The structure
of this metabolite was established primarily by 2D NMR
analysis. Ageladine A shows activity at micromolar levels
as an inhibitor of matrixmetalloproteinases (MMPs) which
are involved in regulation of angiogenesis. Such inhibitors
have promise as antimetastatic agents, and some are currently
in clinical trials.2 It is believed that ageladine A inhibits
MMP-2 via a mechanism of action different from that of
other inhibitors. This metabolite thus provides a novel
structural and biological lead in this field and spurred our
interest as a worthwhile target for total synthesis. In this
communication, we describe the first total synthesis of
ageladine A.
Scheme 1
Our basic strategy for the synthesis of ageladine A is
outlined in Scheme 1. The initial plan was to prepare a
tricyclic intermediate 2 via a 6π-azaelectrocyclization of a
(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) (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.
vinylimidazole system such as 4. This process would proceed
through a dihydropyridine 3, which would then aromatize
10.1021/ol0602304 CCC: $33.50
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by elimination of HX. Such electrocyclizations of 1-aza-
trienes have been known for a number of years, although
this reaction has not been widely utilized in natural product
synthesis.3,4 Moreover, there was good precedent for our
strategy in the nice work of Hibino et al. who used elec-
trocyclizations of 1-azatrienes for the preparation of various
imidazopyridines.5
To prepare the requisite substrates for the ageladine A
project, we chose to make use of the fact that trihaloimida-
zoles can be sequentially and predictably metalated.6 We
have explored two series of N-protected imidazoles in this
work, one involving benzyloxymethyl (BOM) protection and
the other utilizing a p-methoxybenzyl (PMB) group. Thus,
readily available BOM-protected tribromo compound 5a7 was
first metalated with n-butyllithium at C(2), and a thiomethyl
group was introduced using dimethyl disulfide (Scheme 2).
C(5), followed by introduction of DMF, leading to aldehyde
6a in 91% overall yield for the one-pot operation. Similarly,
known PMB-protected imidazole 5b8 could be transformed
to bromo aldehyde 6b in high yield. Continuing with the
BOM-protected bromo aldehyde 6a, it was possible to effect
a Stille coupling with vinyltributylstannane to generate
vinylimidazole aldehyde 7. Addition of 2-lithio-N-benzene-
sulfonylpyrrole9 to this aldehyde, followed by oxidation of
the resulting alcohol with the Dess-Martin periodinane,
yielded ketone 8. However, despite considerable effort, we
were unable to convert the ketone to the corresponding oxime
or O-methyloxime 9. Moreover, ketone 8 was unreactive
toward any substituted hydrazines or semicarbazide. In view
of these failures, it became necessary to modify the synthetic
strategy.
Using Wittig chemistry, we converted imidazole aldehydes
6a and 6b to bromo vinylimidazoles 10a and 10b, respec-
tively (Scheme 3). These bromides could then be lithiated,
Scheme 2
Scheme 3
and upon treatment with carbon dioxide, they produced
carboxylic acids 11a and 11b. Applying the methodology
of Kikugawa, we transformed BOM-protected compound 11a
directly into N-methoxy imidoyl chloride 12a in good yield.10
Similarly, the PMB-protected acid 11b was converted into
both the N-methoxy imidoyl chloride 12b and the corre-
sponding bromo compound 12c.
Inspired by the publication of Kim and co-workers,11 we
decided at this point to convert imidoyl bromide 12c directly
into oxime derivative 16 (eq 1). Unfortunately, attempts at
coupling 12c with either commercially available N-Boc-
pyrrole boronic acid 14 or the stannane 15 were uniformly
unsuccessful. In general, the only product which could be
Without workup, a second equivalent of n-butyllithium was
then added to the reaction mixture to effect metalation at
(3) For a review, see: Okamura, W. H.; de Lera, A. R. 1,3-Cyclohexa-
diene Formation Reactions. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 699-750.
(4) (a) Maynard, D. F.; Okamura, W. H. J. Org. Chem. 1995, 60, 1763.
(b) Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura, S. J. Org. Chem.
2001, 66, 3099. (c) Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J.
Org. Chem. 2004, 69, 5906.
(5) (a) Yoshioka, H.; Choshi, T.; Sugino, E.; Hibino, S. Heterocycles
1995, 41, 161. (b) Yoshioka, H.; Matsuya, Y.; Choshi, T.; Sugino, E.;
Hibino, S. Chem. Pharm. Bull. 1996, 44, 709. (c) Kumemura, T.; Choshi,
T.; Yukawa, J.; Hirose, A.; Nobuhiro, J.; Hibino, S. Heterocycles 2005,
66, 87.
(6) (a) Iddon, B.; Khan, N. J. Chem. Soc., Perkin Trans. 1 1987, 1445.
(b) Lipshutz, B. H.; Hagen, W. Tetrahedron Lett. 1992, 33, 5865. (c)
Groziak, M. P.; Wei, L. J. Org. Chem. 1991, 56, 4296. (d) Chen, Y.; Dias,
H. V. R.; Lovely, C. J. Tetrahedron Lett. 2003, 44, 1379. (e) Carver, D. S.;
Lindell, S. D.; Saville-Stones, E. A. Tetrahedron 1997, 53, 14481.
(7) Preparation of 5a from commercially available 2,4,5-tribromoimi-
dazole: Schumacher, R. W.; Davidson, B. S. Tetrahedron 1999, 55, 935.
(8) Preparation of 5b: Iddon, B.; Khan, N.; Lim, B. L. J. Chem. Soc.,
Perkin Trans. 1 1987, 1437.
(9) (a) Hasan, I.; Marinelli, E. R.; Lin, L.-C. C.; Fowler, F. W.; Levy,
A. B. J. Org. Chem. 1981, 46, 157. (b) Lautens, M.; Fillion, E. J. Org.
Chem. 1997, 62, 4418.
(10) Kikugawa, Y.; Fu, L. H.; Sakamoto, T. Synth. Commun. 1993, 23,
1061.
(11) Chang, S.; Lee, M.; Kim, S. Synlett 2001, 1557.
1444
Org. Lett., Vol. 8, No. 7, 2006

isolated from these reactions was the vinylimidazole nitrile
derived from reductive elimination of the bromide 12c.
synthesis of bromopyridine 13c were lower than that for the
chloro compound and because of the poorer coupling yields,
we concentrated on optimizing the formation of 17 from
chloropyridine 13b. It was found that, if the coupling of 13b
with boronic acid 14 is conducted at 150 °C for 40 min in
a microwave reactor,15 tricycle 17 can be produced in 91%
yield along with only 5% of recovered chloride.
To continue the synthesis, tricyclic sulfide 17 was oxidized
to the corresponding sulfoxide 18, and this functionality
could be displaced by heating with sodium azide in DMF to
afford 2-azidoimidazolopyridine 19.16 Unfortunately, we have
been unable to remove the PMB protecting group from any
of the intermediates 17-19 by either treatment with acid or
catalytic hydrogenation. Because of these difficulties, we
therefore returned to the BOM-protected series.
It was found, however, that Suzuki-Miyaura coupling of
BOM-protected chloropyridine 13a with boronic acid 14
could not be effected, once again requiring a modification
of the strategy.17 Thus, Oxone oxidation of sulfide 13a led
to the sulfoxide 20, and displacement with sodium azide at
room temperature afforded the azide 21 in good yield
(Scheme 5). Catalytic hydrogenation of this azide then
cleanly afforded 2-aminoimidazolopyridine 22.
At this stage, we returned to the N-methoxy imidoyl
halides, and 6π-electrocyclizations of these systems were
investigated based upon the results of Hibino.5b It was found
that heating a dilute solution of imidoyl chloride 12b in
o-xylene indeed afforded the desired chloro imidazopyridine
13b in 73% yield. The yield of 13b could be improved
slightly to 81% if the electrocyclization was run in a
microwave reactor, but because of scale-up problems, this
procedure was not normally used. In the case of imidoyl
bromide 12c, the electrocyclization afforded only a modest
46% yield of bromopyridine 13c, along with about 13% of
recovered starting material. With the BOM-protected imidoyl
chloride 12a, chloropyridine 13a was obtained in 84%
isolated yield upon heating in o-xylene.
We next turned to introduction of a pyrrole moiety into
these halopyridines via a transition-metal-mediated coupling,
and this transformation turned out to be surprisingly difficult
to effect. In general, standard Suzuki-Miyaura couplings
with pyrrole boronic acid 14 or Stille couplings with stannane
15 left the halopyridines unchanged. In addition, similar
problems were found with Negishi couplings using known
methodology.12 After considerable experimentation, it was
finally discovered that if Buchwald’s 2-biphenyldicyclo-
hexylphosphine ligand was used13 Suzuki-Miyaura cou-
plings of our halopyridines with boronic acid 14 could be
achieved. Thus, heating chloropyridine 13b in 1,4-dioxane
at 80 °C for 20 h in the presence of the Buchwald ligand,
Pd(dba)2, and potassium phosphate afforded tricycle 17 in
70% yield, along with 25% of recovered starting chloride
(Scheme 4). In the case of bromopyridine 13c, the yield of
Scheme 5
Scheme 4
Using the reaction conditions previously employed (cf.
Scheme 4), we could couple chloride 22 with boronic acid
coupled product 17 was somewhat lower (60%), along with
that of starting material (20%).14 Because the yields for the
(13) (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685. (b) Lakshman, M. K.; Hilmer, J. H.;
Martin, J. Q.; Keeler, J. C.; Dinh, Y. Q. V.; Ngassa, F. N.; Russon, L. M.
J. Am. Chem. Soc. 2001, 123, 7779.
(12) Dinsmore, A.; Billing, D. G.; Mandy, K.; Michael, J. P.; Mogano,
D.; Patil, S. Org. Lett. 2004, 6, 293.
Org. Lett., Vol. 8, No. 7, 2006
1445

14 to afford a ∼2:1 mixture of Boc-protected tricyclic pyrrole
23 and compound 24 where the Boc group has been lost. In
this reaction, no coupling of the amino group of 22 with
boronic acid 14 was observed.18 The crude mixture of
coupled products 23 and 24 was then hydrolyzed with 6 N
HCl in ethanol to afford deprotected tricycle 25 in 67%
overall yield from chloropyridine 22.
for the halogenation involved treating 25 with bromine in
cold acetic acid/methanol which produced ageladine A (1)
(17%), along with recovered starting material (29%), the
5-bromo compound 26 (50%), and a small amount of 3,4,5-
tribromopyrrole 27 (2%).20 These compounds were separable
by reverse-phase HPLC. Both the monobromopyrrole 26 and
the starting material could be recycled to the natural product.
Synthetic ageladine A has proton and carbon NMR spectra,
as well as UV and fluoresence maxima, identical to those
reported for the natural material.1
Bromination of pyrrole 25 proved to be problematic and
was quite difficult to control.19 The best conditions found
(14) It should be noted that, using similar reaction conditions in purine
systems, Lakshman et al. found that chlorides generally undergo Suzuki-
Miyaura couplings in higher yields than do the corresponding bromides.13b
(15) Song, Y. S.; Kim, B. T.; Heo, J.-N. Tetrahedron Lett. 2005, 46,
5987.
(16) Jarosinski, M. A.; Anderson, W. K. J. Org. Chem. 1991, 56, 4058.
(17) Only the compounds shown below could be isolated in low yields
in these reactions. It appears that the BOM group directs metalation to the
C(2) position of imidazolopyridine 13a.
Acknowledgment. We are grateful to the National
Science Foundation (CHE-0404792) for financial support of
this research. We also thank Professor Blake Peterson and
Jocelyn Edathil for assistance with reverse-phase HPLC
analysis and Dr. A. Ganesan (University of Southampton,
U.K.) for helpful discussions.
Supporting Information Available: Experimental pro-
cedures for the preparation of new compounds including
copies of 1H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) For analogous chemoselectivity, see: Thompson, A. E.; Hughes,
G.; Batsanov, A. S.; Bryce, M. R.; Parry, P. R.; Tarbit, B. J. Org. Chem.
2005, 70, 388.
(19) Although bromination of the Boc-protected pyrrole 23 was more
controllable, to our surprise, the product in this case was the undesired
3,5-dibromo compound.
OL0602304
(20) Attempts to push the bromination of 25 to completion led to
significant quantities of tribromopyrrole 27 which is difficult to separate
from ageladine A (see Supporting Information).
1446
Org. Lett., Vol. 8, No. 7, 2006