Studies toward the total synthesis of nagelamide K

Article abstract of DOI:10.1021/ol3005886

A stereocontrolled strategy toward the synthesis of nagelamide K has been developed. The dimeric imidazole acrylate, diimidazolidenesuccinate, was constructed as a synthetic precursor by a Ni-catalyzed coupling reaction; the microwave-promoted intramolecular aza-Michael addition afforded the imidazo[1,5-a]pyridine core structure of nagelamide K in high stereoselectivity. A detaurine-dediamino analogue of nagelamide K has been prepared.

Full text of DOI:10.1021/ol3005886

ORGANIC
LETTERS
2
012
Vol. 14, No. 8
070–2073
Studies toward the Total Synthesis
of Nagelamide K
2
,
†,‡
†
Biao Jiang,* Jue Wang, and Zuo-gang Huang
‡
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China, and Shanghai Advanced Research Institute,
Chinese Academy of Sciences, 99 Haike Road, Shanghai 201210, China
jiangb@sioc.ac.cn
Received March 7, 2012
ABSTRACT
A stereocontrolled strategy toward the synthesis of nagelamide K has been developed. The dimeric imidazole acrylate, diimidazolidenesuccinate,
was constructed as a synthetic precursor by a Ni-catalyzed coupling reaction; the microwave-promoted intramolecular aza-Michael addition
afforded the imidazo[1,5-a]pyridine core structure of nagelamide K in high stereoselectivity. A detaurineÀdediamino analogue of nagelamide K
has been prepared.
1
0
BromopyrroleÀimidazole alkaloids are common sec-
or the condensation of a halomethyl ketone with guanidine
11
1
ondary metabolites from marine sponge families and have
used in Baran’s work. Although significant progress has
been made in the development of strategies for the synthesis
2
,3
attracted great attention from the synthetic community.
The pyrrole portions could be introduced by acylation
4
with 2-(trichloroacetyl)pyrroles in a chloroform reaction
(3) For examples, see: (a) Overman, L. E.; Rogers, B. N.; Tellew,
J. E.; Trenkle, W. C. J. Am. Chem. Soc. 1997, 119, 7159–7160. (b) Lovely,
C. J.; Du, H.; He, Y.; Dias, H. V. R. Org. Lett. 2004, 6, 735–738. (c)
Feldman, K. S.; Fodor, M. D. J. Am. Chem. Soc. 2008, 130, 14964–
5
or the Mitsunobu reaction with pyrrolecarboxamides.
Various strategies had been developed to introduce the
1
4965. (d) Mukherjee, S.; Sivappa, R.; Yousufuddin, M.; Lovely, C. J.
2
-aminoimidazole portion, for example, an elaboration
on the imidazole moiety by 2-lithiation and installation
Org. Lett. 2010, 12, 4940–4943. (e) Namba, K.; Inai, M.; Sundermeier,
U.; Greshock, T. J.; Williams, R. M. Tetrahedron Lett. 2010, 51, 6557–
6559. (f) Garrido-Hernandez, H.; Nakadai, M.; Vimolratana, M.; Li, Q.;
Doundoulakis, T.; Harran, P. G. Angew. Chem., Int. Ed. 2005, 44, 765–
6
of an azide (ÀN ) or methylthiol (MeSÀ) group, or via
3
7
8
imidazolone, hydantoin, or 2-thiohydantoin precursors
9
7
69. (g) Hudon, J.; Cernak, T. A.; Ashenhurst, J. A.; Gleason, J. L.
Angew. Chem., Int. Ed. 2008, 47, 8885–8888. (h) Poverlein, C.; Brekle,
G.; Lindel, T. Org. Lett. 2006, 8, 819–821. (i) Lu, J.; Tan, X.; Chen, C.
J. Am. Chem. Soc. 2007, 129, 7768–7769.
(4) (a) Berree, F.; Girard-Le Bleis, P.; Carboni, B. Tetrahedron Lett.
2002, 43, 4935. (b) Jiang, B.; Liu, J.-F.; Zhao, S.-Y. Org. Lett. 2002, 4,
3951. (c) Kawasaki, I.; Sakaguchi, N.; Fukushima, N.; Fujioka, N.;
Nikaido., F.; Yamashita., M.; Ohta, S. Tetrahedron Lett. 2002, 43, 4377–
†
Shanghai Institute of Organic Chemistry.
‡
Shanghai Advanced Research Institute.
1) Aiello, A.; Fattorusso, E.; Menna, M.; Taglialatela-Scafati, O. In
(
Modern Alkaloids: Structure, Isolation, Synthesis and Biology; Fattorusso,
E., Taglialatela-Scafati, O., Eds.; Wiley-VCH Verlag GmbH & Co. KgaA:
Weinheim, 2008; pp 271À304.
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380.
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1535–1538.
(6) (a) Kawasaki, I.; Sakaguchi, N.; Khadeer, A.; Yamashita, M.;
(
2) For recent reviews on the structural diversity of pyrroleÀ
imidazole alkaloids and synthetic approaches toward some of the family
members, see: (a) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753–1783.
(
c) Forte, B.; Malgesini, B.; Piutti, C.; Papeo, G. Mar. Drugs 2009, 7,
7
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05–753. (d) Olofson, A.; Yakushijin, K; Horne, D. A. J. Org. Chem.
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Ohta, S. Tetrahedron 2006, 62, 10182–10192. (b) Wang, X.; Ma, Z.; Lu,
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Prod. Rep. 2011, 28, 1229–1260.
1
0.1021/ol3005886 r 2012 American Chemical Society
Published on Web 04/12/2012

of such compounds, there remains a need for alternative
approaches.
imidazole acrylate intermediate B for intramolecular aza-
Michael additions to both nagelamide K (route a) and Q
(route b); in addition, the skeleton of ageliferin might also
be accessible (route c).
For this family of pyrroleÀimidazole alkaloids, it is not
hard to conceive that all these closely related structures
could arise, in a biosynthetic pathway, from one common
1
2
precursor, oroidin, which was first identified in 1971. The
hypotheses of biosynthesis have not only helped in eluci-
dation and chemical rationalization of their structures but
also facilitated the design and execution of total synthesis
Scheme 1. Proposed Synthetic Strategy for Nagelamides K and
Q and Ageliferin
1
3
endeavors. Recently, Kobayashi et al. reported the iso-
lation of four dimeric bromopyrrole alkaloids, nagela-
1
4
mides K, L, Q, and R from Okinawan marine sponges.
Interestingly, nagelamides K/Q are new dimeric bromo-
pyrrole alkaloids possessing a rare piperidine/pyrolindine
central ring and two aminoimidazole moieties with one
being tethered with a taurine unit. A plausible biogenetic
path to nagelamides K (1) and Q (2) has been proposed in
intramolecular cyclizations from a common intermediate
1
4b
A (Figure 1).
As shown in Figure 2, we chose 3, a detaurineÀ
dediamino analogue of nagelamide K, as a simplified target
for nagelamide K (1). In a retrosynthetic analysis, the
pyrrolecarboxamides could be introduced via Mitsunobu
reactions using pyrrolecarboxamide 5. The diol 4 was
postulated to diester 6, which servers as the key intemediate,
and may arise in an intramolecular aza-Michael addition as
designed in Scheme 1 from diimidazolidenesuccinate (7),
and 7 could be synthesized via dimerization of bromoacry-
late 8. Herein, we report our synthetic work on the basis of
this analysis.
Figure 1. Presumed biogenetic synthesis of nagelamide K, Q.
Since the presumed intermediate A with a variable
-aminoimidazole fragment was highly dependent on po-
larity of solvents and pH conditions, we proposed an
alternative strategy as shown in Scheme 1, with a dimeric
2
1
5
(
8) (a) Lindel, T.; Hoffmann, H. Tetrahedron Lett. 1997, 38, 8935.
b) Zancanella, M. A.; Romo, D. Org. Lett. 2008, 10, 3685–3688.
9) (a) Meanwell, N. A.; Roth, H. R.; Smith, E. C. R.; Wedding,
(
(
D. L.; Wright, J. J. K. J. Org. Chem. 1991, 56, 6897. (b) Lanman, B. A.;
Overman, L. E.; Paulini, R.; White, N. S. J. Am. Chem. Soc. 2007, 129,
1
2896–12900.
10) (a) Little, T. L.; Webber, S. E. J. Org. Chem. 1994, 59, 7299.
b) Birman, V. B.; Jiang, X.-T. Org. Lett. 2004, 6, 2369–2371.
11) For Baran’s work, see: (a) Baran, P. S.; Zografos, A. L.;
Figure 2. Retrosynthetic analysis.
(
(
(
O’Malley, D. P. J. Am. Chem. Soc. 2004, 126, 3726–3727. (b) Northrop,
B. H.; O’Malley, D. P.; Zografos, A. L.; Baran, P. S.; Houk, K. N.
Angew. Chem., Int. Ed. 2006, 45, 4126–4130. (c) O’Malley, D. P.; Li, K.;
Maue, M.; Zografos, A. L.; Baran, P. S. J. Am. Chem. Soc. 2007, 129,
(13) For hypotheses for the biosynthesis of the family members, see:
(a) Al Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237–243. (b)
Andrade, P.; Willoughby, R.; Pomponi, S. A.; Kerr, R. G. Tetrahedron
Lett. 1999, 40, 4775. (c) Baran, P. S.; O’Malley, D. P.; Zografos, A. L.
Angew. Chem., Int. Ed. 2004, 43, 2674–2677. (d) K o€ ck, M.; Grube, A.;
Seiple, I. B.; Baran, P. S. Angew. Chem., Int. Ed. 2007, 46, 6586–6594.
(14) (a) Araki, A.; Kubota, T.; Tsuda, M.; Mikami, Y.; Fromont, J.;
Kobayashi, J. Org. Lett. 2008, 10, 2099–2102. (b) Araki, A.; Kubota, T.;
Aoyama, K.; Mikami, Y.; Fromont, J.; Kobayashi, J. Org. Lett. 2009,
11, 1785–1788.
4762–4775. (d) O’Malley, D. P.; Yamaguchi, J.; Young, I. S.; Seiple,
I. B.; Baran, P. S. Angew. Chem., Int. Ed. 2008, 47, 3581–3583. (e) Su, S.;
Seiple, I. B.; Young, I. S.; Baran, P. S. J. Am. Chem. Soc. 2008, 130,
1
6490–16491. (f) Seiple, I. B.; Su, S.; Young, I. S.; Lewis, C. A.;
Yamaguchi, J.; Baran, P. S. Angew. Chem., Int. Ed. 2010, 49, 1095–1098.
12) Forenza, S.; Minale, L.; Riccio, R.; Fattorusso, E. J. Chem. Soc.
(
D 1971, 1129–1130.
(15) Al Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237.
Org. Lett., Vol. 14, No. 8, 2012
2071

First, the bromination ofmethyl urocanote to 8 (R = H)
with Br /Et N was attempted, but poor selectivities and
2
3
16
Table 1. Optimization of the Cyclization of 12 to 13
low yields were obtained. Then, as shown in Scheme 2, the
-DMAS-protected imidazole carbaldehyde 10, prepared
4
from 9 in four steps, was reacted with Ph PdCHCO Me
17
3
2
and bromodimethylsulfonium bromide (BDMS) by a
1
8
method developed in our group to afford the (Z)-
-(dimethylsulfamoyl-1H-imidazol-4-yl)bromoacrylate 11
in high yield and selectivity. The zerovalent nickel complexes
1
a
yield
trans/
Ni(cod) -mediated dimeric coupling of 11 produced the
2
b
entry solvent
condition temp/°C time
(%)
cis
19
product 12 in high yield (97%).
1
2
3
4
5
6
toluene normal heating 140
DMSO normal heating 130
DMSO normal heating 150
96 h
95
71
53
8/1
18 h
12 h
>95/1
>95/1
>95/1
>95/1
9/1
Scheme 2. Synthesis of Diimidazolidenesuccinate 12
DMSO microwave
DMSO microwave
toluene microwave
130
150
140
15 min 43
15 min 96
30 min 30
a
b
1
Yield of isolated product. Determined by H NMR.
Scheme 3. Synthesis of DetaurineÀDediaminonagelamide K (3)
Having the dimeric 12 in hand, we turned to the study of
intramolecular aza-Michael additions, and the results are
summarized in Table 1. To our delight, the cyclization to
compound 13 took place upon simply heating a toluene
solution of 12 in the presence of 2 equiv of water at 140 °C,
9
5% yield and 8/1 selectivity were obtained after 96 h
(
entry 1), and the trans-substituted isomer was determined
to predominate. Apparently, the deprotection of one
DMAS group occurred during the aza-Michael addition
in this transformation. Switching to more polar solvent
DMSO, much better trans/cis selectivity (>95/1) was
achieved with 53À71% yield after heating at 130 °C for
1
2À18 h (entries 2 and 3). Using microwave heating, 43%
yield was obtained after 15-min irradiation in DMSO at
30 °C, and a remarkable yield of 96% was achived when
1
irradiated at 150 °C without decreasing the stereoselectiv-
ity (entries 4 and 5), while microwaveheating intoluene did
not improve the reaction outcome (entry 6).
As shown in Scheme 3, reduction of 13 with LiAlH4
afforded 14 in 92% yield, and catalytic hydrogenation on
Pd/C provided 15 in excellent yield and stereoselectivity.
The diol 15 was subjected to a double Mitsunobu reac-
5
tion with dibromopyrrolehydantoin (16, DBPH) and
2
gave intermediate 17. Exposure of 17 to aqueous NaOH
0
resulted in the hydrolysis of the ureas and liberated the
(
16) Direct bromination of methyl urocanote affording (E)-bromo-
acrylate 8 in moderate yield (42%) and (Z)-bromoacrylate 8 in 16% yield.
17) (a) Matsunaga, N.; Kaku, T. Tetrahedron: Asymmetry 2004, 15,
021. (b) Carver, D. S.; Lindell, S. D. Tetrahedron 1997, 53, 14481.
c) Lovely, C. J.; Du, H.; Dias, H. V. R. Org. Lett. 2001, 3, 1319–1322.
Figure 3. Molecular structrue of the pyrrolecarboxamide 18.
pyrrolecarboxamide 18 in 73% yield over two steps, and the
structure has been confirmed by X-ray analysis (Figure 3).
Removal of the DMAS protecting group with methanolic
(
2
(
(18) Jiang, B.; Dou, Y.; Xu, X. Y. Org. Lett. 2008, 10, 593–596.
21
(19) Semmelhack, M. F.; Helquist, P.; Jones, L. D.; Keller, L.;
Mendelson, L.; Ryono, L. S.; Smith, J. G.; Stauffer, R. D. J. Am. Chem.
Soc. 1981, 103, 6460–6471.
(
20) The bishydantoin 17 was easy to hydrolyze so we could not get its
1 13
perfect H NMR and C NMR. After primary purification of 17, we
exposed the mixture to aqueous sodium hydroxide, affording 18 in 73%
yield (two steps combined).
(21) For X-ray crystal structures of compounds 11À15 and 18, see the
Supporting Information.
2
072
Org. Lett., Vol. 14, No. 8, 2012

HCl afforded compound 3 in 98% yield. In this way, the
basic skeleton of nagelamide K has been accessed, with two
amino and taurine moieties to be introduced.
high selectivities. Studies toward the total synthesis of
nagelamide K/Q and ageliferin are now in progress in
our laboratory.
In summary, a novel method toward the synthesis of
nagelamide K has been developed, and the detaurineÀ
dediamino analogue of nagelamide 3 has been prepared
efficiently. Noteworthy features of this concise synthesis
include (a) a dimeric imidazole acrylate intermediate B via
a Ni-catalyzed coupling of R-bromomethyl urocanote,
which may serve as a common precursor for nagelamide
Q/K and ageliferin; (b) an efficient intramolecular aza-
Michael addition to synthesize the rare imidazoleÀ
piperidine ring; and (c) generally excellent yields and
Acknowledgment. Financial support was provided by
the National Natural Science Foundation of China.
Supporting Information Available. Experimental pro-
cedures, characterization data, and CIF files for 11À15
and 18. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
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