Total synthesis of the putative structure of nagelamide D

Article abstract of DOI:10.1021/ol9001762

A total synthesis of the putative structure of nagelamide D from imidazole is described. A Stille cross-coupling is used to construct the bis imidazole skeleton, and the pyrrolecarboxamides are introduced via a double Mitsunobu reaction using a pyrrolehyd

Full text of DOI:10.1021/ol9001762

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1535-1538
Total Synthesis of the Putative Structure
of Nagelamide D
Manojkumar R. Bhandari, Rasapalli Sivappa,† and Carl J. Lovely*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Arlington,
Arlington, Texas 76019
loVely@uta.edu
Received January 27, 2009
ABSTRACT
A total synthesis of the putative structure of nagelamide D from imidazole is described. A Stille cross-coupling is used to construct the bis
imidazole skeleton, and the pyrrolecarboxamides are introduced via a double Mitsunobu reaction using a pyrrolehydantoin derivative.
Discrepancies between the published spectroscopic data and that reported in the literature cast doubts either on the assigned structure or
the reported data.
The oriodin alkaloids are a growing family of pyrrole-
imidazole alkaloids produced by members of the Agelisida,
Axinellida, and Halichondrida orders of marine sponges
(Figure 1).1 These natural products range in complexity from
the simple monomeric parent system oroidin (1)2 to the most
complex member reported to date, the tetrameric styllisadine
A.3 Formally, these natural products arise from a variety of
oxidation and oligomerization pathways of the basic building
block oroidin (1) and congeners, but little is known about
the details of their biosynthesis.4,5 In large part due to the
challenging structural problems presented by the dimeric
members of this group, we and others have become interested
in developing general synthetic approaches to the pyrrole-
imidazole alkaloids including ageliferin (2),6 axinellamine
A,7 palau’amine,8 and the nagelamides (3-6).9-11 The
original group of nagelamides is a collection of eight oroidin
dimers, which were isolated from an Okinawan marine
sponge, Agelas sp., by Kobayashi and co-workers.9 Subse-
quently, additional members of this subfamily have emerged
which reinforce the structural diversity found in the oroidin
(6) For isolation, see: (a) Kobayashi, J.; Tsuda, M.; Murayama, T.;
Nakamura, H.; Ohizumi, Y.; Ishibashi, M.; Iwamura, M.; Ohta, T.; Nozoe,
S. Tetrahedron 1990, 46, 5579. For synthetic studies, see: (b) O’Malley,
D. P.; Li, K.; Maue, M.; Zografos, A. L.; Baran, P. S. J. Am. Chem. Soc.
2007, 129, 4762. (c) Northrop, B. H.; O’Malley, D. P.; Zografos, A. L.;
Baran, P. S.; Houk, K. N. Angew. Chem., Int. Ed. 2006, 45, 4126. (d) Baran,
P. S.; Li, K.; O’Malley, D. P.; Mitsos, C. Angew. Chem., Int. Ed. 2006, 45,
249. (e) Baran, P. S.; O’Malley, D. P.; Zografos, A. L. Angew. Chem., Int.
Ed. 2004, 43, 2674. (f) Kawasaki, I.; Sakaguchi, N.; Fukushima, N.; Fujioka,
N.; Nikaido, F.; Yamashita, M.; Ohta, S. Tetrahedron Lett. 2002, 43, 4377.
(g) Kawasaki, I.; Sakaguchi, N.; Khadeer, A.; Yamashita, M.; Ohta, S.
Tetrahedron 2006, 62, 10182.
† Current address: Department of Chemistry and Biochemistry, University
of Massachusetts Dartmouth, North Dartmouth, MA 02747–2300.
(1) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753.
(7) For isolation, see: (a) Urban, S.; Leone, P. d. A.; Carroll, A. R.;
Fechner, G. A.; Smith, J.; Hooper, J. N. A.; Quinn, R. J. J. Org. Chem.
1999, 64, 731. For total synthesis, see: (b) Yamaguchi, J.; Seiple, I. B.;
Young, I. S.; O’Malley, D. P.; Maue, M.; Baran, P. S. Angew. Chem., Int.
Ed. 2008, 47, 3578. (c) O’Malley, D. P.; Yamaguchi, J.; Young, I. S.; Seiple,
I. B.; Baran, P. S. Angew. Chem., Int. Ed. 2008, 47, 3581. For recent
synthetic work, see: (d) Sivappa, R.; Hernandez, N. M.; He, Y.; Lovely,
C. J. Org. Lett. 2007, 9, 3861. (e) Zancanella, M. A.; Romo, D. Org. Lett.
2008, 10, 3685. Also see refs 8 and 10.
(2) Forenza, S.; Minale, L.; Riccio, R.; Fattorusso, E. J. Chem. Soc.,
Chem. Commun. 1971, 1129.
(3) (a) Grube, A.; Koeck, M. Org. Lett. 2006, 8, 4675. (b) Buchanan,
M. S.; Carroll, A. R.; Addepalli, R.; Avery, V. M.; Hooper, J. N. A.; Quinn,
R. J. J. Org. Chem. 2007, 72, 2309.
(4) Mourabit, A. A.; Potier, P. Eur. J. Org. Chem. 2001, 237
.
(5) Andrade, P.; Willoughby, R.; Pomponi, S. A.; Kerr, R. G. Tetra-
hedron Lett. 1999, 40, 4775
.
10.1021/ol9001762 CCC: $40.75
Published on Web 03/11/2009
2009 American Chemical Society

Figure 2. Retrosynthetic analysis of nagelamide D.
reduction would provide the same intermediate 7 suitable
for elaboration to 6. Both cross-coupling fragments can be
traced back to the protected diiodoimidazole 12.15 Elabora-
tion of the diimidazole core 7 through double C2-amination
(Figure 2, 7f8)16 and double amidation of the diol would
provide the complete skeleton of nagelamide D. Reduction
of the azides and deprotection would then furnish the natural
product 6.
Figure 1. Selected oroidin alkaloids.
natural products.9b-d Of the initial collection of natural
products, two broad groups of compounds were described
reflecting differences in one C-C bond (between C9 and
C9′) leading to a polysubstituted tetrahydrobenzimidazole
type of system (e.g., ageliferin (2) and nagelamide G (4))
and the seco systems (e.g., nagelamides A (5), C (3) and D
(6)). The examples lacking the additional ring exhibited
different levels of oxidation and may in fact serve as
biosynthetic precursors to other members of this family. To
date, only one total synthesis of a nagelamide, nagelamide
E (10-epi-2) has appeared in the literature, and this was as
a byproduct in an approach to ageliferin (2).12 Generally our
approaches to the various members of this family of natural
products have relied on the elaboration of simple imidazole
derivatives as a means to construct highly functionalized
imidazole-containing synthons.11,13 In this manuscript, we
describe an application of this strategy in a total synthesis
of the reported structure of nagelamide D (6).14
Scheme 1. Preparation of the Imidazolyl Iodide
Retrosynthetically it was envisioned that the core bis
imidazole skeleton 7 found in nagelamide D (6) would be
constructed through an appropriate cross-coupling reaction
between an imidazolyl fragment 10 and vinyl fragment 11
(Figure 2). Experience gained in earlier endeavors suggested
that (Z)-11 (X ) SnBu3) and 10 (Y ) I) would serve these
roles.15 Unfortunately, initial attempts to access the (Z)-
vinylstannane 11 were not successful, and therefore we
investigated the preparation of the corresponding and more
accessible (E)-vinylstannane which upon cross-coupling and
The imidazolyl iodide component 17 (Scheme 1) was
assembled in rapid order from the DMAS-protected 4,5-
diiodoimidazole 12 (DMAS ) dimethylaminosulfonyl),
which can be formylated by metalation at C5 with EtMgBr
and treatment with N-(2-pyridyl)-N-methylformamide form-
ing 13.17,18 A Horner-Wadsworth-Emmons reaction provides
the acrylate derivative 15, which can be reduced to the allylic
alcohol 16 on treatment with DIBAL. Reaction of allylic
(8) For recent reviews, see: (a) Koeck, M.; Grube, A.; Seiple, I. B.;
Baran, P. S. Angew. Chem., Int. Ed. 2007, 46, 6586. (b) Jacquot, D. E. N.;
Lindel, T. Curr. Org. Chem. 2005, 9, 1551. See also ref 10.
1536
Org. Lett., Vol. 11, No. 7, 2009

alcohol 16 with TBSCl affords the silyl ether 17 and the
first fragment needed for cross-coupling. The (E)-vinylstan-
nane 20 was prepared via the hydrostannylation of TBS-
protected propargyl alcohol 19 (Scheme 2). Despite extensive
Scheme 3. Fragment Assembly and Reduction
Scheme 2. Preparation of the Vinylstannane
was then protected as the bis silyl ether 24 (Scheme 4).
Double deprotonation of the imidazole C2 positions with
n-BuLi and trapping with TsN3 provides the bis azide 25 in
71% yield (Scheme 4).16 Deprotection of the silyl ethers
occurred on treatment with TBAF leading to the formation
of the expected diol 26. At this stage the introduction of the
remaining nitrogen and the two dibromopyrrole moieties was
all that remained to complete the synthesis. Strategically,
one might envision accomplishing this task by conversion
of the primary alcohols to the primary amines via the azide
or phthalimide, followed by acylation. However, we had
previously demonstrated that the pyrrolecarboxamide moiety
could be introduced directly as a pyrrolehydantoin via a Pd-
catalyzed allylic substitution reaction.21,22 Therefore, it was
not difficult to envision using a similar type of substrate as
a nucleophile in a Mitsunobu reaction. Diol 26 was subjected
to a double Mitsunobu reaction with the dibromopyrrolehy-
dantoin derivative 27 leading to 28 (Scheme 4).23 In order
to prevent competitive formation of the iminophosphorane
by reaction of the triphenylphosphine with the azide moieties,
triphenylphosphine was reacted with DIAD prior to intro-
duction of the diol.24 In this way the full carbon skeleton of
nagelamide D was accessed, all that remained to complete
the synthesis was deprotection and azide reduction. Exposure
of 28 to aqueous sodium hydroxide led to hydrolysis of the
ureas, providing the pyrrolecarboxamide 29. Initial attempts
were made to complete the sequence by reduction of the
azides with NaBH4, which proceeded uneventfully; however
experimentation with conditions and protecting groups,
mixtures of the R- and ꢀ-isomers (∼3:2) were always
obtained, and unfortunately the regioselectivity of the hy-
drostannylation reaction could not be improved. The regio-
chemistry and the stereochemistry of this reaction were
determined by the magnitudes of the vicinal coupling
constants and Sn/H coupling constants. The imidazole-
substituted propargyl alcohol 19 in turn was prepared via a
Sonogashira reaction between 4-iodoimidazole 18 and TBS-
protected propargyl alcohol.16
With the requisite two fragments in hand we began to
investigate the cross-coupling reaction, and ultimately de-
termined that the fluoride-mediated Stille cross-coupling
conditions reported quite recently by Baldwin and co-workers
provided the bis vinylimidazole 22 in good yield after
treatment with TBAF to complete the partial desilylation.19
At this point, catalytic hydrogenation led to saturation of
both double bonds to give the diol 23 (Scheme 3),20 which
(9) (a) Endo, T.; Tsuda, M.; Okada, T.; Mitsuhashi, S.; Shima, H.;
Kikuchi, K.; Mikami, Y.; Fromont, J.; Kobayashi, J. J. Nat. Prod. 2004,
67, 1262. (b) Araki, A.; Tsuda, M.; Kubota, T.; Mikami, Y.; Fromont, J.;
Kobayashi, J. Org. Lett. 2007, 9, 2369. (c) Araki, A.; Kubota, T.; Tsuda,
M.; Mikami, Y.; Fromont, J.; Kobayashi, J. Org. Lett. 2008, 10, 2099. (d)
Kubota, T.; Araki, A.; Ito, J.; Mikami, Y.; Fromont, J.; Kobayashi, J. i.
Tetrahedron 2008, 64, 10810.
(10) Arndt, H.-D.; Riedrich, M. Angew. Chem., Int. Ed. 2008, 47, 4785.
(11) He, Y.; Du, H.; Sivappa, R.; Lovely, C. J. Synlett 2006, 965.
(12) O’Malley, D. P.; Li, K.; Maue, M.; Zografos, A. L.; Baran, P. S.
J. Am. Chem. Soc. 2007, 129, 4762.
(20) Attempts to perform the reduction on the TBS-protected diol only
resulted in saturation of the more substituted double bond. Although not
useful in the present context, this chemoselectivity will be useful en route
to the related nagelamide A (5).
(21) Krishnamoorthy, P.; Sivappa, R.; Du, H.; Lovely, C. J. Tetrahedron
2006, 62, 10555. We have also investigated the use of the parent
pyrrolehydantoin in the Mitsunobu reaction and will describe these results
elsewhere. For related systems employing the Pd-catalyzed substitution of
(13) Koswatta, P. B.; Sivappa, R.; Dias, H. V. R.; Lovely, C. J. Org.
Lett. 2008, 10, 5055.
(14) Tonsiengsom, S. PhD Dissertation, Oregon State University
(Corvallis), 2006.
(15) Lovely, C. J.; Du, H.; Sivappa, R.; Bhandari, M. K.; He, Y.; Dias,
H. V. R. J. Org. Chem. 2007, 72, 3741.
allylic systems, see: Trost, B. M.; Dong, G. Org. Lett. 2007, 9, 2357
(22) Papadopoulos, E. P. J. Org. Chem. 1972, 37, 351
(23) For the preparation of compound 27, see: Spoering, R. M. PhD
Dissertation, Harvard University (Boston), 2005.
(24) Sakairi, N.; Hayashida, M.; Kuzuhara, H. Tetrahedron Lett. 1987,
28, 2871.
.
(16) Lindel, T.; Hochguertel, M. J. Org. Chem. 2000, 65, 2806.
(17) Chen, Y.; Ekanayake, V.; Lovely, C. J. Heterocycles 2007, 74, 873.
(18) Comins, D.; Meyers, A. I. Synthesis 1978, 403.
(19) Mee, S. P. H.; Lee, V.; Baldwin, J. E. Chem.-Eur. J. 2005, 11,
3294.
.
Org. Lett., Vol. 11, No. 7, 2009
1537

data for nagelamide D, natural and synthetic, in addition to
the corresponding data for the related systems archerine
nagelamide A (5), nagelamide J and dihydrooroidin are
provided in the Supporting Information.9,26,27
Scheme 4. Completion of the Synthesis
An obvious possible cause of the spectrosopic discrepancy
may be a consequence of the concentration differences
between the samples used, as Kobayashi and co-workers
report isolation of ∼2 mg of nagelamide D (6). However,
we found essentially no differences in the 1H NMR spectra
on serial dilutions down to approximately the same estimated
concentration. Addition of a couple of drops of TFA to the
final dilution sample exhibited no substantial differences in
the 1H NMR spectrum. Prior to conversion of synthetic 6 to
the TFA salt, we checked the 1H NMR spectrum of the free
base in MeOH-d4, which exhibited essentially identical
chemical shifts to the salt in DMSO-d6. It appears that neither
concentration nor pH make a major difference in the
1
appearance of the H NMR spectra.
Similarly, there are discrepancies in the 13C NMR spectra
between synthetic and natural nagelamide D, in particular a
CH2 signal is reported at δc 16.6 (t), whereas for synthetic
material the highest field signal is observed at δc 21.1. Based
on the same set of comparative molecules, our data appears
to be completely consistent with the assigned structure of
nagelamide D (see Supporting Information). Unfortunately,
we have been unable to obtain a sample or copies of the
original NMR data of the genuine natural product from the
Kobayashi laboratory to compare the chromatographic and
spectroscopic properties of the synthetic and natural material,
and therefore we cannot establish the source of this incon-
sistency at this time. While our work was in progress, we
became aware of a biomimetic total synthesis of nagelamide
D by the Horne laboratory. It is significant that both the 1H
and 13C NMR data reported matches very well with that
obtained by us, in spite of there being no common intermedi-
ates in either of the two routes until the final compound,
indicating that the structural identity of the synthetic material
is secure.14 Therefore, pending additional information we
must conclude that either the assigned structure or the
reported NMR data is in error, unraveling this may require
reisolation and characterization of the natural material.
removal of the DMAS-protecting groups at this stage was
unsuccessful. Ultimately it was determined that deprotection
could be accomplished with azide 29 upon treatment with
methanolic HCl providing 30.25 Exposure of the bis azide
30 to hydrogen in the presence of the Lindlar catalyst resulted
in reduction to the amines and provided nagelamide D (6),16
which was converted to the TFA salt by treatment with TFA.
Somewhat to our surprise, we found on comparison of
the spectroscopic data for the synthetic and naturally occur-
ring material that they were not completely identical. In
Acknowledgment. This work was supported by the Robert
A. Welch Foundation (Y-1362) and the NIH (GM065503).
The NSF (CHE-9601771 and CHE-0234811) is thanked for
partial funding of the purchase of the NMR spectrometers
used in this study.
1
particular in the H NMR spectra, there are several notable
Supporting Information Available: Detailed experimen-
discrepancies in the signals due to the aliphatic protons, and
to a lesser extent in the 13C NMR spectrum for the
corresponding carbon atoms. Notably, two of the reported
shifts δH 2.14/2.72 (nat.) vs 1.68 (syn.) for H9′ and δH
3.20-3.30 (nat.) vs 2.40 for H10′ (syn.) are substantially
different, whereas our data are very similar to that obtained
for dihydrooroidin. A full comparison of the spectroscopic
1
tal procedures and copies of H and 13C NMR spectra for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL9001762
(26) Olofson, A.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 1998,
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J. Org. Chem. 2001, 55
(25) Feldman, K. S.; Fodor, M. D. J. Am. Chem. Soc. 2008, 130, 14964.
.
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