Molecular modeling study for a novel structured oligomer subunit selection: the example of 2-aminomethyl-phenyl-acetic acid

Article abstract of DOI:10.1016/j.tetlet.2007.01.032

Oligomers derived from dipeptide mimics were selected by computational study for their suitability to fold in ordered structures. After selection of a monomeric unit, short oligomers were synthesized and analyzed by NMR and IR. Oligomers built from 2-aminomethyl-phenyl-acetic acid were shown to adopt a helical structure stabilized by 10-membered ring hydrogen bonds.

Full text of DOI:10.1016/j.tetlet.2007.01.032

Tetrahedron Letters 48 (2007) 1787–1790
Molecular modeling study for a novel structured oligomer
subunit selection: the example of 2-aminomethyl-phenyl-acetic acid
a
b
a
c
´
Nicolas Raynal, Marie-Christine Averlant-Petit, Gilbert Berge, Claude Didierjean,
Michel Marraud,b Christiane Duru,a Jean Martineza and Muriel Amblarda,*
aUMR-CNRS 5810, Universite´ de Montpellier I et II, Montpellier Cedex 05, France
bUMR CNRS-INPL 7568, ENSIC, BP 451, 54001 Nancy Cedex, France
cUMR CNRS-UHP 7036, Faculte´ des Sciences, BP 259, 54506 Vandoeuvre Cedex, France
Received 31 October 2006; revised 21 December 2006; accepted 5 January 2007
Available online 10 January 2007
Abstract—Oligomers derived from dipeptide mimics were selected by computational study for their suitability to fold in ordered
structures. After selection of a monomeric unit, short oligomers were synthesized and analyzed by NMR and IR. Oligomers built
from 2-aminomethyl-phenyl-acetic acid were shown to adopt a helical structure stabilized by 10-membered ring hydrogen bonds.
ꢀ 2007 Elsevier Ltd. All rights reserved.
a-Helices are widely involved in protein–protein,
protein–nucleic acid recognition, and binding processes.
Identification of unnatural helical oligomers, stable to-
ward enzymatic degradation, that present the structural
and biological characteristics of biopolymers has been
the focus of extensive research over the last 10 years in
several laboratories. They constitute attractive struc-
tures for understanding molecular assembly and protein
folding as well as for designing new classes of drugs and
new biomaterials. The first studies by Gellman and See-
bach groups have shown that oligomers derived from b-
amino acids (b-peptides), called ‘foldamers’, can adopt a
well-defined secondary structure.1–3 Today, several
other oligomers have been described to fold into a spe-
cific helical secondary structure.4 Our efforts were aimed
at identifying new oligomers derived from dipeptide
mimics for their suitability as ‘foldamer’ building blocks.
Our research was motivated by a molecular modeling
analysis of oligomers constructed from various dipep-
tide mimics described in the literature.5,6 This study
showed that their most stable conformers possessed a
strong helix-forming propensity.7 In order to validate
our molecular modeling protocol, it was applied to the
oligomers of (2R,3S,4R)-3-amino-4-[(1S)-1-hydroxy-
ethyl]oxetane-2-carboxylic acid and (R,R)-trans-2-
aminocyclopentanecarboxylic acid (ACPC) described
in the literature.8,9 In both cases, the 10-helical and 12-
helical conformations obtained by molecular modeling
were in agreement with the experimental results
obtained by the groups of Fleet and Gellman.
The first step of our study was to establish a selection of
rigidified motifs. For this purpose, we virtually con-
structed decamers of these motifs that we analyzed by
molecular modeling for structural prediction.10 After
selection of motifs likely to adopt helix-like structures,
we synthesized the corresponding oligomers of various
1
lengths for H NMR and IR studies.
Herein, we report NMR and IR studies of short oligo-
mers of one of the first motives that we have selected
as potential novel structured oligomer subunits, the 2-
aminomethyl-phenyl-acetic acid motif (AMPA). Molec-
ular modeling analysis showed that the predicted lowest
energy structure of the Ac-(AMPA)10-NHMe oligomer
adopts a helical structure defined by a 10-membered ring
hydrogen bond between a carbonyl at position i and an
amide proton at position i + 2 (Fig. 1).
Due to the lack of chiral center, the oligomer has no
helical handedness (the right-handed helix was pre-
sented). This dipeptide mimetic helix has approximately
3.36 residues per turn and a pitch of about 10.4 A. The
most stable helical structure is represented in Figure 1a.
Keywords: Helical oligomers; 1H NMR and IR studies; Molecular
modeling; Dipeptide mimics; Poly(AMPA).
˚
*
Corresponding author. Tel./fax: +33
muriel.amblard@univ-montp1.fr
4 67 54 86 37; e-mail:
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.032

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N. Raynal et al. / Tetrahedron Letters 48 (2007) 1787–1790
Figure 1. Computational conformation of Ac-(AMPA)10-NH-Me oligomers with trans (a) or syn (b) orientation of the amide group.
The molecular modeling prediction that oligomers of
AMPA could adopt a 10-helix secondary structure
remained to be experimentally verified. We undertook
NMR and IR studies of different AMPA oligomers.
We prepared derivatized AMPA dimers and trimers,
Boc-(AMPA)2-NH-Me (3a), Boc-(AMPA)3-NH-Me
(4a). NMR and IR analyses of the Ac-(AMPA)10-NH-
Me oligomer, that we used for molecular modeling pre-
diction, were not possible for solubility problems.
ubility in poor solvating medium (CH2Cl2, CHCl3)
required for intramolecular H-bonding.
The IR spectra of monomers 2a and 2b, and especially
the balance between the high frequency domain (3400–
3500 cmÀ1) typical of free NHs and the low frequency
domain (3250–3400 cmÀ1) typical of bonded NHs,
strongly depend on the solvent (CH2Cl2 or CCl4).
Although CH2Cl2 is considered as a very poor solvating
medium favoring intramolecular H-bonds, the small
intensity of the wide absorption at 3356 cmÀ1 (2a) or
3339 cmÀ1 (2b) indicated a small percentage of NH to
CO H-bonding. The sensitivity of this absorption is rel-
ative to the nature of the C-terminus, that is, 2a
(R = NHMe) or 2b (R = NHiPr). This indicates that
the amide proton involved in the hydrogen bond is the
C-terminal NH (vs the Boc-NH).12,13 In CCl4, the low
frequency absorptions at 3372 cmÀ1 (2a) or 3354 cmÀ1
(2b) were much more intense and indicated a higher per-
centage of folded molecules. Moreover, the Boc-CO
absorption clearly gave two components at 1716 and
1703 cmÀ1 (2a) with nearly equal intensity, confirming
the occurrence of the NHR to Boc-CO H-bond for
about half of the molecules.
The precursor monomer N-Boc-protected 2-amino-
methyl-phenyl-acetic acid (Boc-AMPA-OH, 1) was pre-
pared according to the method described by Zhilian and
Pelletier.11 Condensation of Boc-AMPA-OH with
methylamine or isopropylamine was carried out through
activation with BOP in the presence of DIEA to afford
the corresponding Boc-AMPA-NHMe (2a) and Boc-
AMPA-NHiPr (2b) in quantitative yields (Scheme 1).
Boc removal by a 4 N HCl solution in AcOEt followed
by successive coupling to Boc-AMPA-OH with BOP
reagent in the presence of DIEA afforded compounds
3a and 4a.
To determine the conformational properties induced by
the increasing number of AMPA motives, we have
examined the IR (NH and CO stretching) and proton
NMR data (NH solvent accessibility) for Boc-(AM-
PA)n-NHR (R = Me or iPr) oligomers, n = 1–3. Higher
oligomers could not be investigated due to their low sol-
X-ray crystallographic structure of the monomeric unit
Boc-AMPA-NHiPr 2b14 revealed an extended molecule
exchanging two intermolecular urethane NH to ure-
˚
thane CO (NHÁ Á ÁO = 2.93 A), and amide NH to amide
BOP, DIEA
H2N-R , DCM
BocHN
CONHR
BocHN
BocHN
CO2H
1
2a R = CH3
2b R = iPr
a) 4N HCl, AcOEt
b) Boc-AMPA-OH
BOP, DIEA, DMF
Boc HN
CO NH-Me
n = 2, 3
CONHMe
2a
3a R = CH3 n = 2
4a R = CH3 n = 3
Scheme 1. Boc(AMPA)n-NHMe synthesis.

N. Raynal et al. / Tetrahedron Letters 48 (2007) 1787–1790
1789
taining an intra-chain N-substituted amide link.15,16
This prompted us to examine the propensity of oligomer
to have the amide group into a syn orientation (Fig. 1b).
The number n of AMPA motifs in Boc-(AMPA)n-NHR
oligomers induces noticeable changes in the low fre-
quency domain of the NH stretching absorption
(Fig. 4). Its intensity increases with n, and the maximum
of the absorption is progressively shifted to lower fre-
quencies. In fact, two maxima are observed at about
3350 and 3280 cmÀ1. The former, which is observed
for 2a, is progressively embedded in the latter for 3a
and even more for 4a.
The solvent sensitivity of the NH proton resonances has
been measured in CDCl3/DMSO-d6 mixtures with
increasing DMSO-d6 content for oligomers 3a and 4a
(Fig. 5). Both N- and C-terminal NHs are solvent acces-
sible and mostly free of H-bonding, even in CDCl3. On
the contrary, the NHs between two AMPA-motifs17 are
solvent protected and engaged in intramolecular H-
bonding. The fact that one NH in 3a and two NHs in
4a share the same behavior strongly suggests that this
H-bond closes a 10-membered pseudocycle, exactly as
Figure 2. View of the crystal packing of the extended molecular
structure of 2b. NHÁ Á ÁO Hydrogen bonds, indicated by dashed lines,
join molecules into infinite chains in the [100] direction. The isopropyl
group is disordered over three sites with occupancy factors 0.48, 0.32,
and 0.20. Only one component is shown. The aliphatic and aromatic
hydrogens have been omitted for clarity.
˚
CO (NHÁ Á ÁO = 3.08 A) H-bonds with its neighbors. The
amide groups are nearly trans-planar with standard
dimensions, and are in an anti orientation with reference
to the planar aromatic group (Fig. 2).
The AMPA motif is therefore intrinsically flexible and
capable of adopting an extended conformation in the
solid state or in a solvating medium, and a folded con-
formation in an inert medium. A molecular modeling
analysis of 2a showed that the H-bond stabilizing the
putative folded conformation closes a 10-membered
pseudocycle with trans or syn orientation of the amide
group (Fig. 3). Both in the predicted lowest energy con-
former of Ac-(AMPA)10-NHMe and in the Boc-AMPA-
NHiPr crystal, even though no intramolecular H-bonds
were observed, the monomeric unit amide group, with
reference to the planar phenyl ring, adopted a trans ori-
entation. However, we have no experimental evidence
for the actual trans or syn orientation of the folded con-
formation in solution. The syn orientation is similar to
the so-called bVI-turn found in peptide sequences con-
Figure 4. Influence of the number n of AMPA motifs on the NH
stretching absorption for oligomers 2a, 3a, and 4a (n = 1, 2, and 3,
respectively) in CH2Cl2.
Figure 5. Influence of DMSO-d6 volumetric percentage in CDCl3/
DMSO-d6 mixtures (logarithmic scale) on the NH proton resonances
for the Boc-(AMPA)n-NHMe oligomers with n = 2 (red) and 3 (blue).
The left graph refers to the N-terminal Boc-NH group, the right one to
the C-terminal NHMe group, and the middle one to the NH group
between two X motifs.
Figure 3. Two putative folded conformations of 2a with an intramo-
lecular H-bond closing a 10-membered pseudocycle, in a syn (a) or an
anti (b) orientation of the amide groups with reference to the phenyl
ring (energy minimization using MOPAC program in CS Chem3D). The
aliphatic and aromatic hydrogens have been omitted for clarity.

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N. Raynal et al. / Tetrahedron Letters 48 (2007) 1787–1790
for the minor folded conformation of 2a. The low fre-
quency observed for 4a, in comparison with 2a, may
be the consequence of the double involvement, both of
its NH and CO groups in an H-bonding.18 Luppi
et al. raised such results with the oligomers of oxazolid-
inone derivatives.19 These data suggested that there is an
increase of hydrogen bonds with the oligomer size sug-
gesting that short oligomers of AMPA are able to fold
in an ordered structure. The propensity of short oligo-
mers to fold in organized structure was observed in
foldamers.1–4,19
References and notes
1. Gellman, S. H. Acc. Chem. Res. 1998, 31, 173–180.
2. Cheng, R. P.; Gellman, S. H.; Degrado, W. F. Chem. Rev.
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´
7. Amblard, M.; Martinez, J.; Berge, G. Patent 11/01/2000
However, as discussed before, in the absence of further
experimental data on the syn and anti orientations pres-
ent in the AMPA oligomer, we constructed the two pos-
sible helices (Fig. 1) and we compared their stability by
computational analysis. Among the conformations of
lowest energy, those presenting a syn orientation of
the amide group contained hydrogen bond between
the CO and NH of the same AMPA residue resulting
in an eight-membered ring. However, this computa-
tional prediction did not fit with the experimental IR
data showing a C@O–H–N hydrogen in the N- to C-ter-
minal direction forming a 10-membered ring. The helix
with a 10-membered ring hydrogen bond and a syn
amide group orientation observed in the transition state
(Fig. 1b), led after molecular modeling minimization to
an unstructured oligomer. These different results
prompted us to consider that the preferred structure
adopted a 10-helix with the amide groups in a trans
orientation.
sous le nꢁ 0000288, WO B0384.
8. Claridge, T. D. W.; Goodman, J. M.; Moreno, A.; Angus,
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L. A.; Gellman, S. H. J. Am. Chem. Soc. 1998, 120, 4891–
4892.
10. Experiments were performed on silicon graphics using
Discover Molecular Simulation program, Biosym/MSI.
We first performed a molecular dynamic at 1000 K and a
minimization of the monomer under its aldehydic form
H-AMPA-H. The conformer of the lowest energy was
selected and its corresponding Ac-AMPA-NH-Me was
subjected to a 45ꢁ variation of the four dihedral angles.
After minimization, we selected 10 conformations corre-
sponding to the predicted lower energy conformation
(34.33 kcal/mol) and those having an energy of 34.33 kcal
plus an increment equal to or less than 5 kcal/mol.
11. Zhilian, T.; Pelletier, J. C. Tetrahedron Lett. 1998, 39,
4773–4776.
12. Aubry, A.; Cung, M. T.; Marraud, M. J. Am. Chem. Soc.
1985, 107, 7640–7647.
In summary, we have shown by NMR and IR studies
that the short oligomers of 2-aminomethyl-phenyl-acetic
acid, selected by computational analysis for their possi-
bility to induce a well-defined secondary structure, could
adopt a 10-helical folding pattern. In the absence of chi-
ral center within the molecule and the difficulty of ana-
lyzing homo-oligomers, the availability of syn and anti
orientations of the amide was analyzed by molecular
modeling. The anti orientation of the amide group that
was also observed in the crystal of the AMPA derivative
seems to be the preferred conformation.
´
13. Jimenez, A. I.; Cativiela, C.; Aubry, A.; Marraud, M. J.
Am. Chem. Soc. 1998, 120, 9452–9459.
14. Crystal data 1b: C17H26N2O3, Mr = 306.40, colorless
3
˚
prism, crystal size 0.2 · 0.1 · 0.1 mm , a = 5.1411(4) A,
˚
˚
b = 11.5197(10) A, c = 15.236(2) A, a = 82.930(3)ꢁ, b =
3
˚
89.537(2)ꢁ, c = 78.520(7)ꢁ, V = 877.42(15) A , T = 293 K,
triclinic, space group P1, Z = 2, Dc = 1.160 g cmÀ3
,
ꢀ
l = 0.079 mmÀ1, k = 0.71073 A. 4323 reflections collected,
2474 independent (Rint = 0.0340) and 1394 observed
˚
reflections,
203
refined
parameters,
R = 0.064,
wR2 = 0.125. CCDC-633961 contains the supplemen-
tary crystallographic data for this paper. These data can
be obtained free of charge from the Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
This study suggested that computational analysis can al-
low us to establish a pre-selection of dipeptide mimetic
to construct new families of foldamers. The use of
AMPA oligomers as templates to design more function-
alized and soluble oligomers is under investigation in
our laboratory.
15. Aubry, A.; Vitoux, B.; Marraud, M. J. Chim. Phys., Phys.
Chim. Biol. 1985, 82, 933–939.
16. Muller, G.; Gurrath, M.; Kurz, M.; Kessler, H. Proteins
1993, 15, 235–251.
17. Due to the superposed proton resonances for the Ph–CH2
protons in 3a, and to the absence of Overhauser effects
across X motifs, the middle NHs in 3a could not be
discriminated.
18. Cung, M. T.; Marraud, M.; Neel, J.; Aubry, A. Biopoly-
mers 1978, 17, 1149–1173.
Supplementary data
Experimental procedures, NMR, HPLC, and mass spec-
trometry data, and 2b X-ray data. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2007.01.032.
`
19. Luppi, G.; Soffre, C.; Tomasini, C. Tetrahedron: Asym-
metry 2004, 15, 1645–1650.