Synthesis of symmetric bis(imidazole-4,5-dicarboxamides) substituted with amino acids

Article abstract of DOI:10.1021/jo049045z

A series of symmetric bis(imidazole-4,5-dicarboxamides) (bis-I45DCs) were prepared with amino acid esters and a variety of linker groups. The critical pyrazine intermediates, substituted with amino acid esters, were synthesized by stoichiometric control o

Full text of DOI:10.1021/jo049045z

â-hairpin14 have all been previously used to identify
bioactive R-helix mimics for interacting with a variety
of protein-protein interactions. The combination of con-
formational and structural features along with their
synthetic accessibility makes the bis-I45DCs a useful
scaffold. A series of bis-heterocyclic compounds have been
recently synthesized from resin-bound amino acids,15-17
further illustrating the interest in such compounds for
the discovery of new chemical entities.
Synthesis of Symmetric
Bis(imidazole-4,5-dicarboxamides)
Substituted with Amino Acids
Alexander V. Wiznycia, Jeremy R. Rush, and
Paul W. Baures*,†
Department of Chemistry, Kansas State University,
Manhattan, Kansas 66506
The bis-I45DC compounds can form intramolecular
hydrogen bonds that are favored even in water.18 Hydro-
gen bonds have shallow energy potentials in comparison
with covalent bonds, and we think this represents an
advantage of the bis-I45DCs over structurally complex
and covalently bound scaffolds in the discovery of small
molecule proteomimetics, as protein-protein interactions
pbaures@bowdoin.edu
Received June 7, 2004
Abstract: A series of symmetric bis(imidazole-4,5-dicar-
boxamides) (bis-I45DCs) were prepared with amino acid
esters and a variety of linker groups. The critical pyrazine
intermediates, substituted with amino acid esters, were
synthesized by stoichiometric control of the amino acid ester,
even though primary alkanamines, in comparison, generally
offer less selectivity for this reaction. Diamines are added
to subsequently react with and open the remaining acyl
imidazole bonds in the pyrazine intermediates and thereby
yield the bis-I45DCs.
require a high degree of shape complementarity.19
A
symmetric bis-I45DC (24) was identified as an inhibitor
of the CD81 binding interaction with the hepatitis C virus
glycoprotein E2 having an EC50 of 38 µM.1
The preparation of the bis-I45DCs in this study begins
with a symmetric pyrazine derivative (1) bearing reactive
acid chloride and acyl imidazole functionalities (Scheme
1). A modified preparation of 1 has been previously
reported.20 Amino acid ester hydrochlorides or tosylate
salts are capable of reacting with both functionalities in
THF to thereby produce the symmetrically disubstituted
I45DCs (2-8) summarized in Table 1. Dissymmetrically
disubstituted I45DCs produced by two subsequent pri-
mary amine additions to 1 results in the desired product
contaminated by substantial amounts of symmetrically
disubstituted products. Thus, an alternate procedure to
produce dissymmetrically disubstituted I45DCs in high
purity was developed.20 In contrast to the reactivity and
poor selectivity of primary amines with 1, we observed
that modest yields of the symmetric amino acid ester-
substituted pyrazines 9-14 could be obtained by addition
of 2 equiv of an amino acid salt along with a base to
scavenge the acid in this reaction (Table 2). The amino
acid ester-substituted pyrazines are then readily opened
by diamines leading to the bis-I45DCs 15-25 (Table 3).
Compound 26 (Table 3) was prepared by catalytic hy-
drogenation of 25. It is also possible to open the acyl
imidazole bonds with alcohols as shown by the reaction
There is a current need for small molecules capable of
inhibiting protein-protein interactions of biological sig-
nificance to be used as both biochemical tools and as
potential clinical candidates for treating disease. We
herein report on a series of symmetrically disubstituted
bis(imidazole-4,5-dicarboxamides) (bis-I45DCs) bearing
amino acid esters as part of a continuing effort to
illustrate the utility of the imidazole-4,5-dicarboxylic acid
as a scaffold for the synthesis of new chemical entities.
These compounds were designed to present amino acid
side chains in relative 3-dimensional space in order to
yield functional mimics of the surface of an R-helix found
in the large extracellular loop of tetraspanin CD81,1 the
putative receptor of the hepatitis C virus.2 Disrupting
protein-protein interactions with small molecules is a
difficult task, yet this remains an important goal for the
discovery of new therapeutic agents.3-9
The relative presentation of substituent groups off of
a terphenyl scaffold,10-12 an oligoamide-foldamer,13 or a
† Current address: Bowdoin College, Department of Chemistry,
6600 College Station, Brunswick, ME 04011.
(1) VanCompernolle, S.; Wiznycia, A. V.; Rush, J. R.; Dhanasekaran,
M.; Baures, P. W.; Todd, S. C. Virology 2003, 314, 371-380.
(2) Pileri, P.; Uematsu, Y.; Campagnoli, S.; Galli, G.; Falugi, F.;
Petracca, R.; Weiner, A. J.; Houghton, M.; Rosa, D.; Grandi, G.;
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(13) Ernst, J. T.; Becerril, J.; Park, H. S.; Yin, H.; Hamilton, A. D.
Angew. Chem., Int. Ed. 2003, 42, 535-539.
(14) Fasan, R.; Dias, R. L.; Moehle, K.; Zerbe, O.; Vrijbloed, J. W.;
Obrecht, D.; Robinson, J. A. Angew. Chem., Int. Ed. 2004, 43, 2109-
2112.
(3) Gadek, T. R.; Nicholas, J. B. Biochem. Pharmacol. 2003, 65, 1-8.
(4) Boger, D. L. Bioorg. Med. Chem. 2003, 11, 1607-1613.
(5) Sharma, S. K.; Ramsey, T. M.; Bair, K. W. Curr. Med. Chem.
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(16) Acharya, A. N.; Ostresh, J. M.; Houghton, R. A. Tetrahedron
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(6) Loregian, A.; Marsden, H. S.; Palu, G. Rev. Med. Virol. 2002,
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(17) Nefzi, A.; Giulianotti, M. A.; Ong, N.; Houghton, R. A. Org. Lett.
2000, 2, 3349-3350.
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(9) Cochran, A. G. Chem. Biol. 2000, 7, R85-94.
(18) N,N′-Dimethylimidazole-4,5-dicarboxamide in H2O shows two
broad amide NH resonances (8.1 and 10.8 ppm) above pH ∼5.4. Below
this pH value the imidazole ring is protonated part of the time, thereby
disrupting the intramolecular hydrogen bond and leading to a coalesced
amide NH signal. A figure of these amide chemical shifts as a function
of pH is shown in the Supporting Information.
(10) Orner, B. P.; Ernst, J. T.; Hamilton, A. D. J. Am. Chem. Soc.
2001, 123, 5382-5383.
(11) Kutzki, O.; Park, H. S.; Ernst, J. T.; Orner, B. P.; Yin, H.;
Hamilton, A. D. J. Am. Chem. Soc. 2002, 124, 11838-11839.
(12) Ernst, J. T.; Kutzki, O.; Debnath, A. K.; Jiang, S.; Lu, H.;
Hamilton, A. D. Angew. Chem., Int. Ed. 2002, 41, 278-281.
(19) Cole, C.; Warwicker, J. Protein Sci. 2002, 11, 2860-2870.
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10.1021/jo049045z CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/02/2004
J. Org. Chem. 2004, 69, 8489-8491
8489

SCHEME 1
TABLE 1. Substituents and Isolated Yields of Amino
TABLE 3. Substituents and Isolated Yields of the
Acid Ester Symmetrically Disubstituted I45DCs 2-8
Bis-I45DCs 15-27
compd
substitution, R1 )
yield (%)
compd
substitution
n
R3
yield (%)
2
3
4
5
6
7
8
(S)-PheOtBu
(S)-PheOMe
(S)-LeuOMe
(S)-ValOMe
(S)-AlaOMe
GlyOEt
89
94
93
99
94
33
89
15
16
17
18
19
20
21
22
23
24
25
26
27
R2 ) (S)-ValOBzl
R2 ) (S)-ValOBzl
R2 ) (S)-ValOBzl
R2 ) (S)-ValOBzl
R2 ) (S)-PheOtBu
R2 ) (S)-ValOBzl
R2 ) (S)-ValOBzl
R2 ) (S)-ValOtBu
R2 ) (S)-ValOEt
R2 ) (S)-ValOBzl
R2 ) (S)-LeuOBzl
R2 ) (S)-LeuOH
R2 ) (S)-ValOBzl
2
3
4
6
6
6
2
2
2
2
2
2
H
47
69
71
67
73
49
49
42
28
85
59
100
49
H
H
H
H
Bu
Et
Et
Et
GlyOtBu
TABLE 2. Substituents and Isolated Yields of Amino
-(CH2)2-
Et
Et
Acid Ester Substituted Pyrazines 9-14
compd
substitution, R2 )
yield (%)
9
10
11
12
13
14
(S)-PheOtBu
(S)-IleOtBu
(S)-ValOBzl
(S)-ValOEt
(S)-ValOtBu
(S)-LeuOBzl
40
59
69
77
80
54
TABLE 4. Substituents and Isolated Yields of the
Bis-I45DCs 28-31
compd
substitution
n
yield (%)
28
29
30
31
R2 ) (S)-PheOtBu
R2 ) (S)-PheOtBu
R2 ) (S)-IleOtBu
R2 ) (S)-IleOtBu
2
3
2
4
47
69
71
67
of 9 with ethylene glycol to produce 27 (Table 3), although
this reaction is slow even at elevated temperatures. The
bis-I45DCs 15-27 contain only two amino acid side
chains. In select examples there are alkyl groups sub-
stituted off the nitrogens of the diamine that can, at least
in part, substitute for an amino acid side chain. Repre-
sentative bis-I45DCs 28-31 contain four amino acids and
were prepared by linking (S)-Boc-PheOH with alkyl-
diamines, removal of the Boc group with TFA, and
addition of the resulting diamine salts in the presence
of a base to an amino acid ester-substituted pyrazine
(Table 4).
bears an N-alkyl substituent. The conformational behav-
ior of bis-I45DCs having N-methyl imidazole rings has
been described,21 and we expect the bis-I45DCs in this
study to be similar. We note that many of the bis-I45DCs
show evidence of multiple conformations in both their 1H
and 13C NMR spectra at room temperature.
This work illustrates how readily the I45DC scaffold
is derivatized with amino acids to provide structurally
The bis-I45DCs can adopt conformations that are, at
least in part, dependent upon whether the diamine linker
(21) Bouck, K. J.; Rasmussen, P. G. Macromolecules 1993, 26, 2077-
2084.
8490 J. Org. Chem., Vol. 69, No. 24, 2004

Supporting Information Available: Experimental sec-
tion and data, 1H and 13C NMR spectra, and HPLC traces.
This material is available free of charge via the Internet at
http://pubs.acs.org.
diverse new chemical entities that are useful in discover-
ing inhibitors of protein-protein interactions.
Acknowledgment. This work was supported by a
NIH-COBRE award 1-P20-RR15563 and matching sup-
port from the state of Kansas.
JO049045Z
J. Org. Chem, Vol. 69, No. 24, 2004 8491