Hydrophobic side-chain interactions in a family of dimeric amide foldamers-potential alpha-helix mimetics

Article abstract of DOI:10.1016/j.tetlet.2011.05.004

A series of new alpha-helix mimetics based on a benzamide scaffold and potentially able to disrupt protein-protein interactions have been synthesized and characterized by X-ray analysis. Inspection of the solid state structures of aromatic amide dimers co

Full text of DOI:10.1016/j.tetlet.2011.05.004

Tetrahedron Letters 52 (2011) 3705–3709
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Hydrophobic side-chain interactions in a family of dimeric amide
foldamers-potential alpha-helix mimetics
Oleg V. Kulikov a, Christopher Incarvito a, Andrew D. Hamilton a,b,
⇑
a Department of Chemistry, Yale University, New Haven, CT 06511, USA
b Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new alpha-helix mimetics based on a benzamide scaffold and potentially able to disrupt pro-
tein-protein interactions have been synthesized and characterized by X-ray analysis. Inspection of the
solid state structures of aromatic amide dimers confirmed that the molecules adopt a curved conforma-
tion with intramolecular H-bonding between the amide NH and the alkoxy oxygen of the neighboring
aromatic fragment (dNH. . .O ꢀ 2 Å). Adjacent dimer molecules are prone to form supramolecular assem-
blies due to both hydrophobic alkyl side-chain/side-chain interactions and intermolecular H-bonding.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 22 February 2011
Revised 29 April 2011
Accepted 2 May 2011
Available online 8 May 2011
Keywords:
Aromatic oligoamides
Self-assembly
Hydrophobic interactions
Helical arrangement
1. Introduction
The branched side chains should provide better interdigitation of
the alkyl groups of adjacent foldamer molecules relative to linear
The development of novel foldamers1 that mimic residues along
one face of an a-helix and that could successfully disrupt protein–
protein interactions (PPI’s) represents a challenging goal in contem-
porary medicinal chemistry. So far, a large variety of preorganized
scaffolds2–7 (indanes, terphenyls, pyridyl-pyridones, pyridazines,
and polycyclic ethers etc.) where the substituents of the scaffold mi-
mic the distance and angular orientation of amino-acid side-chains
alkyl groups (such as ethyl, propyl, etc.). A key purpose of this work
was to study the effect of alterations in substituents on hydropho-
bic side-chain/side-chain contacts between adjacent oligomer
molecules.
2. Results and discussion
on an a-helix have been explored. We have particularly been inter-
The synthesis of the molecules of interest has been accom-
plished through a simple (n + 1) elongation approach8 that involves
reduction (Pd/C, H2) of the nitro-component followed by amide
coupling with the corresponding aryl acid using Mukaiyama’s re-
agent (2-chloro-1-methylpyridinium iodide) (Scheme 1).
ested in scaffolds based on aryl amino acid oligomers in which intra-
molecular H-bonding maintains the integrity of the structure. We
have previously shown that the nature of the hydrogen bonding
and the monomer subunit (benzamide vs. pyridylamide) can con-
trol the degree of curvature3 in the scaffold allowing mimicry of
the curvature of helices often found in Nature. We have further re-
ported a trispyridylamide scaffold that uses a bifurcated H-bond
from the amide proton to the pyridine nitrogen and the ortho alkoxy
side chains on the pyridine ring to control its conformation.4
Hydrophobic forces play an important role in the structure of
proteins. A clearer understanding of how those interactions direct
and control helix binding to a target protein might be gained from
corresponding contacts between helix mimetics. In this work we
describe the synthesis and structural characterization of a series
of dimeric arylcarboxamides bearing branched alkyl side chains.
This methodology was used to synthesize a series of oligomers
incorporating various alkyl fragments from aryl acids 4–6 and cor-
responding arylamines 7–9 to give amide dimers 10–15 in reason-
able yields. Attempted amide coupling with aromatic acid acyl
chlorides (using oxalyl chloride) did not improve the yields substan-
tially. In certain cases, condensation was accompanied by the for-
mation of minor reaction products, such as compounds 13–15, as
a result of re-esterification of the COOMe during the course of the
coupling reaction. In order to assess the effect of variations of func-
tional groups on hydrophobic side-chain/side-chain interactions we
also prepared NH2-dimer 16 and acid dimer 17. All the intermedi-
ates and final products listed in Scheme 1 were purified by either
crystallization or column chromatography.
⇑
Corresponding author. Tel.: +44 01865 270242.
E-mail addresses: andrew.hamilton@admin.ox.ac.uk, Andrew.hamilton@chem.
X-ray studies of the parent dimers (Scheme S1, ESI) revealed
that they adopt a curved conformation with the side chains
ox.ac.uk, andrew.hamilton@yale.edu (A.D. Hamilton).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.004

3706
O. V. Kulikov et al. / Tetrahedron Letters 52 (2011) 3705–3709
NH2
O
NO2
O
R
H
O
N
N
Cl
NO2
NO2
O
COOH
4-6
O
O
Me
Mukaiyama`s
reagent
I
NO2
NO2
LiOH,
THF
R
R
OH
O
R-Br, K2CO3
79-85%
R
Pd/C, H2
16
COOMe
97%
º
70 C, DMF
COOMe 74-97%
Et3N, reflux for
2 days in DCM
H
H
O
O
N
N
11
Pd/C, H2
COOMe
O
O
NO2
O
NH2
O
LiOH,
THF
R
R
1-3
R
46%
COOMe
COOR
COOMe
7-9
70-94%
10-12
79-87%
13-15
3-5%
H
N
O
O
R = isopropyl (1, 4, 7, 10, 13); isobutyl (2, 5, 8, 11, 14, 16, 17); CH2-3-pentyl (3, 6, 9, 12, 15)
COOH
17
Scheme 1. Synthesis of amide oligomers: formation of aryl dimers.
projected on one face. The expected intramolecular H-bond be-
tween the amide NH and the oxygen of the alkoxy group
(dNH. . .O ꢀ 2.1–2.3 Å) was seen in every case to stabilize the con-
strained scaffold. The solid state structures of dimers 10–14, 16,
and 17 are illustrated in Figure 1 (CCDC806304-806310).
The curvature of the scaffolds was reflected in the angles of
inclination (defined as the angle formed by the line drawn from
the 1,4-aryl carbons linked to the amide carbonyl to the amide-N
linked carbons) and showed almost the same values (ranging from
157.9° for 16 to 160.7° for 12) as those reported earlier for analo-
gous dimers (159.9° for structure CCDC 6968733, CSD refcode LO-
KYIU; 160.5° for structure CCDC 1585779, CSD refcode ACALAR;
158.8° for structure SAQKEA10). As expected, they are slightly lar-
ger rather than values found for dimeric pyridylamide (152.0° for
structure CCDC 6970873, CSD refcode LOKYOA). We presume this
is due to the absence of an additional H-bond between the amide
NH-group and pyridine nitrogen that decreases the backbone
curvature. Details of the molecular structures of dimers are given
Figure 1. Molecular structures of dimers studied showing the angles of inclination and intramolecular H-bonding between alkoxy oxygen and amide nitrogen proton.

O. V. Kulikov et al. / Tetrahedron Letters 52 (2011) 3705–3709
3707
in Figures S1–7, ESI. Figure 2 shows partial crystal packing of dimer
11 (ball-and-stick and CPK format).
According to the X-ray analysis11,12, molecules of dimer 11 in
the crystal are arranged into infinite ‘zigzag’-shaped supramolecu-
lar chains. Crystal packing diagrams of structural analogues (10,
12–14, 16, and 17) are similar, suggesting a common controlling
influence in the solid state structure (Fig. S8–13, 16, ESI) from
the alkyl–alkyl interactions. The shortest distance between con-
tacting alkyl fragments of 11 (Fig. 3) and 16 was found to be
3.8 Å; 3.4 Å for acid 17; 3.9 Å for both isopropyl-dimer 10 and for
a dimer 12.
Since dimer 14 contains both ether and ester isobutyl substitu-
ents, the role of alkyl chain contact in the molecular packing will
likely be enhanced. Measured values for interdimer separation in
14 are: 4.3 Å for isobutyl ether/ether and 4.0 Å for isobutyl ether/
ester contact. We measured the interdimer spacing as the shortest
distance between the terminal carbon atoms of alkyl chains of the
neighboring dimers.
Figure 3. Dimer 11 alkyl fragments oriented toward each other.
In the crystal lattice dimers tend to form layered structures with
a distance of 3.7 Å between layers for compounds 10, 11, 17; 3.4 Å
for 14 and 16; 3.5 Å for 12. Notably, the expansion of the asymmet-
ric unit showed that dimer 16 assembles into a helical arrangement
(Fig. 4) via hydrogen bonding between adjacent aromatic amino and
amide C@O groups (dCO . . .NH = 2.1 Å). In each chain molecules are
tilted at ꢀ 80° with respect to an axis normal (Figs. S14 and 15,
ESI). This feature makes 16 distinct among the other dimers in this
paper since 10–14 and 17 are packed into linear layered supramo-
lecular arrangements as shown in Figures S17 and 18, ESI.
These results indicate that neither the length nor the shape of
the alkyl substituents affected dramatically the hydrophobic inter-
actions between dimer molecules. Although there is no evidence
that alkyl chains of the neighboring dimers are interlacing, it seems
likely that this kind of hydrophobic contact organizes the mole-
cules into supramolecular arrangements (chains and layers) at
least in the solid state.
One possibility for strengthening the alkyl chain interactions
would be through the introduction of an appropriate spacer be-
Figure 2. Partial crystal packing diagram of dimer 11 (ball-and-stick and CPK format).

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O. V. Kulikov et al. / Tetrahedron Letters 52 (2011) 3705–3709
Figure 4. Assembly of dimer 16 into the infinite helical superstructures via H-bonding (ball-and-stick format and the same helix with central part shown in CPK).
tween oligoamide residues to enforce intramolecular alkyl–alkyl
contact. For that purpose, a model bis-monomer 18 was prepared
from 2-methoxyisophthalic acid and aryl amine 8 (Scheme 2).
X-ray analysis of bis-monomer 18 (CCDC806311; Figs. S19–23,
ESI) showed that the molecule adopts a conformation where the
Me-groups of the isobutyl residues are projected toward each
other with the distance between them falling in the range of
4.99–6.65 Å. The amide protons of 18 are involved in two types
of intramolecular H-bonding: with the methoxy oxygen
(dNH. . .OMe = 1.79 Å) and the O-isobutyl fragment (dNH. . .O-isobutyl
= 2.21 Å).
In summary, we have described the synthesis of a series of di-
meric arylcarboxamides as potential alpha-helix mimetics,
through amide coupling catalyzed by Mukaiyama’s reagent and
subsequent reduction of the nitro-group. The dimer molecules
adopt a curved backbone conformation in analogy with our previ-
O
O
N
Cl
MeI
OMe
HN
Mukaiyama`s
reagent
NH
O
O
+
8
HOOC
COOH
Et3N, reflux for
2 days in DCM
OMe
COOMe
COOMe
52%
18
Scheme 2. Synthesis and molecular structure of bis-monomer 18.

O. V. Kulikov et al. / Tetrahedron Letters 52 (2011) 3705–3709
3709
1616; (e) Tew, G. N.; Scott, R. W.; Klein, M. L.; Degrado, W. F. Acc. Chem. Res.
2010, 43, 30–39.
ous results on similar oligoarylamides. Our initial goal in this study
was to understand the effect of the branched alkyl chains on the
properties and organization of dimer molecules. Those side chains
project from one face of the dimer in a way that potentially mimics
2. (a) Cummings, C. G.; Hamilton, A. D. Curr. Opin. Chem. Biol. 2010, 14, 341–346; (b)
Restorp, P.; Rebek, J., Jr. Bioorg. Med. Chem. Lett. 18 2008, 5909–5911; (c) Plante,
J. P.; Burnley, T.; Malkova, B.; Webb, M. E.; Warriner, S. L.; Edwards, T. A.; Wilson,
A. J. Chem. Commun. 2009, 5091–5093; (d) Moisan, L.; Odermatt, S.;
Gombosuren, N.; Carella, A.; Rebek, J. Eur. J. Org. Chem. 2008, 1673–1676; (e)
Marimganti, S.; Cheemala, M. N.; Ahn, J.-M. Org. Lett. 2009, 11, 4418–4421; (f)
Tosovska, P.; Arora, P. S. Org. Lett. 2010, 12, 1588–1591; (g) Haridas, V. Eur. J. Org.
Chem. 2009, 5112–5128; (h) Wilson, A. J. Chem. Soc. Rev. 2009, 38, 3289–3300; (i)
Shaginian, A.; Whitby, L. R.; Hong, S.; Hwang, I.; Farooqi, B.; Searcey, M.; Chen, J.;
Vogt, P. K.; Boger, D. L. J. Am. Chem. Soc. 2009, 131, 5564–5572; (j) Lee, J. H.;
Zhang, Q.; Jo, S.; Chai, S. C.; Oh, M.; Im, W.; Lu, H.; Lim, H.-S. J. Am. Chem. Soc.
2011, 133, 676–679.
the recognition surface of an
a-helix. Molecular structures and
hydrophobic side chain interactions of several dimers containing
branched alkyl substituents have been studied by X-ray analysis
showing that those interactions influence packing in the crystal.
Acknowledgment
3. Saraogi, I.; Incarvito, C. D.; Hamilton, A. D. Angew. Chem. Int. Ed. 2008, 47, 9691–
9694.
4. Saraogi, I.; Hebda, J. A.; Becerril, J.; Estroff, L. A.; Miranker, A. D.; Hamilton, A. D.
Angew. Chem. Int. Ed. 2010, 49, 736–739.
We thank the NSF (CHE-0750357) and NIH (CA67771) for par-
tial financial support of this work.
5. Fletcher, S.; Hamilton, A. D. Curr. Opin. Chem. Biol. 2005, 9, 632–638.
6. Saraogi, I.; Hamilton, A. D. Biochem. Soc. Trans. 2008, 36, 1414–1417.
7. Saraogi, I.; Hamilton, A. D. Chem. Soc. Rev. 2009, 38, 1726–1743.
8. Plante, J.; Campbell, F.; Malkova, B.; Kilner, C.; Warriner, S. L.; Wilson, A. J. Org.
Biomol. Chem. 2008, 6, 138–146.
9. Adams, H.; Bernad Junior, P. L.; Eggleston, D. S.; Haltiwanger, R. C.; Harris, K. D.
M.; Hembury, G. A.; Hunter, C. A.; Livingstone, D. J.; Kariuki, B. M.; McCabe, J. F.
Chem. Commun. 2001, 1500–1501.
10. Hibbert, F.; Mills, J. F.; Nyburg, S. C.; Parkins, A. W. J. Chem. Soc., Perkin Trans. 2
1998, 629–634.
11. CrystalStructure 4.0: Crystal Structure Analysis Package, Rigaku and Rigaku
Americas (2000–2010). 9009 New Trails Dr. The Woodlands TX 77381
USA.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.004.
References and notes
1. (a)Foldamers: Structure, Properties and Applications; Hecht, S., Huc, I., Eds.;
Wiley-VCH: Weinheim, 2007; (b) Iriondo-Alberdi, J.; Laxmi-Reddy, K.;
Bouguerne, B.; Staedel, C.; Huc, I. Chem. Biochem. 2010, 11, 1679–1685; (c)
Baptiste, B.; Douat-Casassus, C.; Laxmi-Reddy, K.; Godde, F.; Huc, I. J. Org. Chem.
2010, 75, 7175–7185; (d) Zhao, X.; Li, Zh.-T. Chem. Commun. 2010, 46, 1601–
12. SHELX97: Sheldrick, G.M. 1997.