Peptoid atropisomers

Article abstract of DOI:10.1021/ja2028684

We report the isolation of N-aryl peptoid oligomers that adopt chiral folds, despite the absence of chiral centers. Peptoid monomers incorporating ortho-substituted N-aryl side chains are identified that exhibit axial chirality. We observe significant ene

Full text of DOI:10.1021/ja2028684

ARTICLE
pubs.acs.org/JACS
Peptoid Atropisomers
Bishwajit Paul,† Glenn L. Butterfoss,‡,§ Mikki G. Boswell,|| P. Douglas Renfrew,‡,§ Fanny G. Yeung,||
Neel H. Shah,† Christian Wolf,|| Richard Bonneau,‡,§ and Kent Kirshenbaum*,†
†Department of Chemistry, ‡Center for Genomics & Systems Biology, and Courant Institute of Mathematical Sciences, and
§Department of Computer Science, New York University, New York, New York 10003, United States
Department of Chemistry, Georgetown University, Washington, D.C. 20057, United States
S Supporting Information
b
ABSTRACT: We report the isolation of N-aryl peptoid oligomers that
adopt chiral folds, despite the absence of chiral centers. Peptoid mono-
mers incorporating ortho-substituted N-aryl side chains are identified
that exhibit axial chirality. We observe significant energy barriers to
rotation about the stereogenic carbonÀnitrogen bond, allowing chro-
matographic purification of stable atropisomeric forms. We study the
atropisomerism of N-aryl peptoid oligomers by computational modeling,
NMR, X-ray crystallography, dynamic HPLC, and circular dichroism.
The results demonstrate a new approach to promote the conformational
ordering of this important class of foldamer compounds.
’ INTRODUCTION
secondary structures: bulky N-alkyl side chains promote a
polyproline I type helix,12,21 and N-aryl side chains promote a
polyproline II type (pp II) helix.19 The peptoid backbone is
generally flexible and lacks chiral centers. The achirality ineluctably
leads to a racemic mixture of right- and left-handed helical structures.
This shortcoming can be compensated by inclusion of chiral centers
in the peptoid side chains. For example, the inclusion of R or S
homochiral bulky N-alkyl side chains can determine a right- or left-
handed peptoid helix.12,22 Control of helical pitch in N-aryl
peptoids, however, has not been demonstrated.
Itisnow possible to select peptoidsidechainsthat reliably direct
the backbone j, ψ, and ω dihedral angles.18 Side chain func-
tional groups can engender peptoid conformational stability by
means of hydrogen bonding,14,20 stereoelectronic effects,23,24 metal
coordination,4,8 or covalent bond formation via macrocyclization
reactions.25 Our attention is now focused on strategies to constrain
the side chain (χ1) dihedral angle, as these rotamers are an
important source of conformational variability in polypeptide
structures.26 Following our initial studies of N-aryl peptoids, we
were intrigued to evaluate whether the presence of bulky ortho-aryl
substituents would provide a steric influence to constrain energeti-
cally accessible χ1 angles in a predictable manner. The presence of
congested anilide groups could give rise to atropisomerism,27,28
leading to a novel structural influence for foldamer compounds.29
Atropisomerism is a stereochemical phenomenon in which
hindered single-bond rotation leads to isolable stereoisomers.30,31
For example, the restricted rotation about C(sp2)ÀC(sp2) single
bonds in ortho-substituted biphenyls can generate conformationally
Peptoids are a family of peptidomimetic oligomers composed of
N-substituted glycine monomer units. An efficient solid-phase synth-
esis protocol enables the generation of peptoid oligomers bearing a
specific sequence of highly diverse side chain groups.1,2 Peptoids can
exhibit a range of functions, such as self-assembly,3À5 enantioselective
catalysis,6 intracellular transport,7 molecular recognition,8,9 antimi-
crobial activity,10 and other biological activities.11 The search
for peptoids with new functions propels efforts to understand
how particular peptoid sequences may encode for a specific
conformation.12À14 Until recently, the development of predict-
able sequenceÀstructureÀfunction relationships has been ex-
clusively a characteristic of biological polymers.15 This paradigm
is now changing, as chemists are learning how to enforce the
folding of peptoids, beta-peptides, aromatic oligoamides, and
other “foldamer” compounds.16
Many of the critical attributes contributing to polypeptide
folding are seemingly absent from the peptoid backbone. Peptoids
feature tertiary amide linkages and therefore lack an intrinsic
capacity for hydrogen bonding. In comparison with natural poly-
peptides, the absence of chiral centers may also increase peptoid
conformational heterogeneity. Nevertheless, a judicious choice of
peptoid side chains can promote the formation of stable
secondary structures. For example, the incorporation of bulky
N-alkyl side chains can enforce an energetic preference for cis
(Z) amide bonds (ω = 0°) 17 and also constrains the other two
backbone dihedral angles j and ψ (Scheme 1).18 Previous
studies have demonstrated that N-aryl side chains could simi-
larly enforce a propensity for trans (E) omega bonds (ω =
180°).19,20 Through these complementary constraints, certain
peptoid sequences can direct the formation of stable helical
Received: March 29, 2011
Published: June 02, 2011
r
2011 American Chemical Society
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Scheme 1. Peptoid Monomer and Oligomera
Scheme 3. Chemical Structures of N-aryl Peptoid Monomers
and Dimeric and Trimeric N-aryl Peptoidsa
a (A) An ortho-substituted N-aryl glycine peptoid monomer showing
atom labels. (B) Dihedral angles for a representative peptoid oligomer
with an acetylated N-terminus.
Scheme 2. Atropisomerism in Biaryl and Nonbiaryl Systemsa
a (A) Chemical structure of N-aryl peptoid monomers. (B) Dimeric
N-aryl peptoids. (C) Trimeric N-aryl peptoid. For the purpose of this
study, the terms dimer and trimer are used to indicate the number of
anilide side chain groups.
bromide from tert-butyl bromoacetate by various aromatic amines
in refluxing conditions to obtain an ortho-substituted N-(tert-buty-
lacetate)aniline. This was followed by acetylation of the
N-terminus with acetyl chloride overnight at room temperature.
For the synthesis of peptoid oligomers, we adopted a solution-
phase ‘submonomer’ synthesis cycle consisting of a modular and
iterative two-step protocol (Scheme 4). Due to the poor nucleo-
philicity of ortho-subsituted aryl amines, the acylation step required
modifications from standard submonomer synthetic procedures1
as follows: For the first step, methyl anthranilate was coupled
with activated bromoacetyl bromide at 0 °C, followed by gradual
increase to room temperature (rt) to obtain ortho-substituted
N-(2-phenyl)bromoacetamide derivatives. Next, the displacement
of bromide by deactivated primary aromatic amines was conducted
under refluxing conditions to obtain peptoid dimers. These
two steps were repeated to obtain the sequence-specific ortho-
substituted N-aryl peptoid trimer (see Supporting Information).
The N-termini were acetylated using acetyl chloride to obtain
peptoid dimers 2 and the trimer 3 (Scheme 3B and C). Crude
peptoid compounds were purified by standard silica-gel column
chromatography. The purity and identity of the products were
confirmed by reversed-phase HPLC (RP-HPLC), NMR, and electro-
spray mass spectrometry (ESI-MS) (see Supporting Information).
Conformational Analysis of N-aryl Peptoid Monomers.
Ortho-substituted N-aryl peptoids feature a flexible backbone
and can potentially adopt a number of conformational states. Similar
to the convention for polypeptides, the backbone dihedral angles
are described as j, ψ, and the amide bond ω (Scheme 1). Our
previous report of N-aryl peptoids identified two low-energy
backbone states, resembling either a left-handed polyproline II
type (ppII) conformation with (ω, j, ψ) ≈ (180°, À75°, 160°)
or its mirror image (ω, j, ψ) ≈ (180°, 75°, À160°).19 The side
chain can exhibit two predominating rotameric states (χ1 ≈
(90°), both placing the aryl ring orthogonal to the plane of
a (A) Classic biphenyl system. (B) Benzamide system. (C) Anilide
system.
stable enantiomers that can be separated by chromatography or
other means (Scheme 2A).32 Ongoing studies of atropisomerism
have led to fascinating examples of conformational control of
organic compounds.33À36 Atropisomers have also been evaluated
as unusual enantioselective catalytic systems, establishing substantial
practical significance.37 Along with prototypical biaryl systems,
nonbiaryl compounds can also exhibit atropisomerism, including
nonplanar aromatic amides that are axially chiral due to restricted
rotation about the aryl-carbon/nitrogen bond (Scheme 2B and C).
This work seeks to extend the study of atropisomerism to control
the conformation of biomimetic oligomeric molecules. Here, we
report nuclear magnetic resonance (NMR), dynamic high-perfor-
mance liquid chromatography (DHPLC), circular dichroism (CD),
and X-ray crystallographic and computational studies of peptoid
atropisomers.
’ RESULTS AND DISCUSSION
N-aryl Peptoid Synthesis. We synthesized a series of simple
monomeric peptoids (compound series 1) incorporating various
N-aryl side chains with methyl (Me), tert-butyl (tBu), iodo (I), or
carboxy methyl ester (ester) groups as ortho-substituents as well
as the unsubstituted N-aryl peptoid monomer 1-H (Scheme 3A).
Compound series 1 was designed to feature ortho-substituents of
varying steric bulk, particularly including the iodo and tert-butyl
groups, as the corresponding anilides are known to form stable
atropisomers.27,36,38 To synthesize these peptoid monomers
with good yields and purities, we employed slight modifications
to previously reported protocols (see Supporting Information).23,39
Briefly, synthesis began with nucleophilic displacement of
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Scheme 4. Solution-Phase Synthesis of N-aryl Peptoid Oligomers
Figure 1. Low-energy conformational states of peptoid monomer 1-I.
Structure A is one atropisomer from the crystal unit cell, and B is its
enantiomer. Structure C represents an alternative rotamer minimized at
the HF/3-21G* level of theory, and D is its enantiomer.
Figure 2. Restricted rotation about the anilide NÀC bond allows separa-
tion of stable peptoid atropisomers. (A) Enantiomerization of peptoid
monomer 1-I between M and P stereochemical forms. (B) Chiral HPLC
allows enantioseparation of 1-I below 25 °C. Dynamic HPLC demon-
strates enantioconversion at elevated temperatures. (C) Enantiomeriza-
tion of peptoid dimer 2-I. (D) Enantioseparation of 2-I, along with
enantioconversion at elevated temperature.
Table 1. Dihedral Angles Observed by X-ray Crystallography
of (P)-1-ester, (P)-1-I, and Their Enantiomers (M)-1-ester
and (M)-1-I
peptoids
ω°
j°
ψ°
χ1°
anticipated by our previous computational studies of N-aryl
peptoids,19 (73.5°, À167.2°) and (76.9°, À170.2°) for 1-ester
and 1-I, respectively. These values are also in close agreement with
previously reported ortho-hydroxyl and ortho-acetamide N-aryl
peptoids.20 In addition, the χ1 dihedral angles for 1-ester and 1-I
are 118.1° and 103.7°, respectively, within the range of previously
predicted broad minima centered around (90°.19 These values
place the aryl ring of the tertiary anilide perpendicular to the plane
of the amide bond, with the side chain ortho-substituents of both
1-ester and 1-I pointing away from the following backbone
carbonyl group, as depicted in Figure 1A and B.
(P)-1-ester
(M)-1-ester
(P)-1-I
172.5
À172.5
175.8
73.5
À73.5
76.9
À167.2
167.2
118.1
À118.1
103.7
À170.2
170.2
(M)-1-I
À175.8
À76.9
À103.7
the amide bond. For each peptoid monomer unit, four pos-
sible local energy conformations can therefore be expected
(Figure 1AÀD). Our initial characterization efforts were aimed
at evaluating the relative energies and the dynamics of these
conformers.
Side Chain Rotational Barriers. For ortho-substituted N-aryl
peptoids to exhibit atropisomerism, rotation around the N-aryl
bond must be hindered (Scheme 2C). Restricted rotation around
the χ1 dihedral angle would render the backbone CH2 groups to
appear as magnetically nonequivalent CHAHB signals by NMR.
One-dimensional (1D) NMR spectra were collected in CDCl3 at
rt for all peptoid monomers (1-H, 1-Me, 1-tBu, 1-I, and 1-ester).
For these compounds, the geminal methylene protons were ob-
served to be magnetically nonequivalent at ambient temperature
We obtained crystals of 1-ester and 1-I by slow evaporation from
CHCl3 at 4 °C. Both compounds were monoclinic and crystallized
in the space group P21/c. Thus, the molecules were observed as
enantiomeric pairs with P or M stereochemistry (see Supporting
Information). The dihedral angles observed in the solid-state
structure of 1-ester and 1-I are listed in Table 1. As expected,
the N-aryl peptoid monomers 1-ester and 1-I include trans-amide
bonds with ω = 172.5° and 175.8°, respectively. In each case, the
other backbone dihedral angles (j, ψ) fall within the range
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Table 2. Optimized Torsions and Energies of Peptoid Monomers 1-ester, 1-I, and 1-tBu
energy (kcal/mol)a
peptoids
ω°
j°
ψ°
χ1°
B3LYP/LANL2DZ B3LYP/6-31G* (3-21G*)b M052X/6-31G* (3-21G*)b MP2(full)/ 6-31G* (3-21G*)b
1-ester
1-ester
1-I
179.9
170.2
76.7 À166.3
92.5
0.00
1.66
0.00
5.40
0.00
2.25
0.00
1.81
0.00
5.44
0.00
1.11
0.00
1.32
0.00
5.98
0.00
0.63
0.00
0.52
0.00
5.49
0.00
0.58
94.4 À166.8 À83.2
176.4 À76.1
178.9 À66.0
173.1 À69.8
À171.4 À66.1
173.3 À97.6
171.2 100.0
168.9 À99.6
155.4 112.3
1-I
1-tBu
1-tBu
a Geometries were freely optimized in each minimum at the HF/6-31G* level of theory, except for 1-I which was optimized at HF/3-21G*. b 1-ester and
1-tBu energies are calculated with the 6-31G* basis set, and 1-I energies are calculated with the 3-21G* basis set.
(with the exception of the unsubstituted compound 1-H due
to the symmetry around the χ1 dihedral angle, see Supporting
Information). These results are in accordance with studies of
ortho-substituted anilides by Siddall and Mislow et al. conducted
more than 40 years ago.40 To further investigate the restricted
rotational features around the N-aryl bond, we used variable
temperature NMR (VT-NMR) in which an increase of tempera-
ture might allow sufficiently rapid interchange of side chain
rotamers, resulting in coalescence of the NMR signals of the back-
bone methylene protons. However, no such coalescence was ob-
served for 1-I or 1-tBu up to 150 °C, indicating that the rotation
around the χ1 dihedral angle is slow on the NMR time scale (see
Supporting Information). Similar significant rotational barriers
have been previously observed in ortho-substituted anilides.41
Chromatographic and CD Studies of N-aryl Peptoid Mono-
mers. If the energy barriers to interconversion of peptoid atro-
pisomeric forms are significant, then it may be possible to separate
the M and P stereoisomers at ambient conditions (Figure 2A).35,42
We screened several chiral HPLC columns to separate the
enantiomers of compounds 1-Me, 1-tBu, 1-I, and 1-ester. We
found that 1-tBu and 1-I can be resolved by chiral HPLC. For
example, 1-I shows enantioseparation into (M)-1-I and (P)-1-I,
during HPLC on a Whelk-O 1 chiral stationary phase (Figure 2B).
Dynamic HPLC (DHPLC) can be performed at variable tempera-
tures, providing a means to determine interconversion barriers of
these compounds. Below 20 °C, baseline separation of 1-I enantio-
mers was observed. At higher temperatures, however, more rapid
interconversion between the enantiomers resulted in coalescence,
and a single peak was observed at 45 °C. Computational fitting of
the experimentally obtained DHPLC elution profiles gave an
activation energy (ΔG‡) of 21.5 kcal/mol at 25 °C. A van’t Hoff
plot of the DHPLC data obtained for 1-I gave ΔH‡ = 17.2 kcal/mol
and ΔS‡ = À14.4 cal/K mol, indicative of a highly organized
transition state. In addition, the enantiomers of 1-tBu were isolated
as (M)- and (P)-1-tBu by semipreparative chiral HPLC on
Chiralcel OD and showed mirror image CD spectra (see Supporting
Information). These experimental results establish that N-aryl
peptoids can form atropisomers that are stable and isolable.
Figure 1A and B. Both 1-I and 1-tBu contain bulky ortho-groups,
but 1-I is predicted to have a much larger energy difference
between the χ1 rotamers than 1-tBu (∼5 vs ∼1 kcal/mol,
respectively) using various levels of theory. A possible origin
for this difference may be repulsive interactions between the
substantial electron density of the iodo group and the C-terminal
carbonyl oxygen (alternatively, attractive interactions may also
be manifested as “halogen bonds”, vide infra). This notion is
supported by similar strong rotamer preferences predicted for
analogous electron-rich ortho-substituted N-aryl peptoids, i.e. ortho-
halogens and ortho-carboxylate (see Supporting Information).
This computational result suggests the physical origins for an
energetic preference of the rotamer depicted in Figure 1A and B.
Notably, the rotamer preference observed for the peptoids in this
study is opposite to that previously observed for ortho-hydroxyl
and ortho-acetamide N-aryl peptoids, which are capable of forming a
hydrogen bond with the following carbonyl when they are in
proximity.20
We further investigated the rotational barrier heights by
computational studies. The complete conversion between ortho-
substituted N-aryl peptoid atropisomeric states requires extensive
rotation around both j and χ1. We estimated the energetic
barriers to interconversion by calculating the individual barriers
separately, assuming that coupled j and χ1 interconversion will
have similar barriers. Using several model chemistries, we predicted
the transition states (TS) for rotation about j in 1-H to be in the
range of 7.3À8.5 kcal/mol for j ≈ 0° and 7.4À9.0 kcal/mol for
j ≈ 180° (see Supporting Information). We also calculated the
rotational barriers about χ1 for minimal models of various ortho-
substituted N-aryl peptoid side chains (Table 3). Notably, iodo
and tert-butyl ortho-aryl susbtituents create very high χ1 rotational
barriers, in excess of 20 and 30 kcal/mol, respectively. These
values are consistent with the large energy barriers required to
isolate stable atropisomers and are comparable to the values
determined by the DHPLC studies.34,35,43
Computational Studies of N-aryl Peptoid Dimers. We
conducted further computational studies of N-aryl peptoid
dimers. For the compound family 2, the C-terminal backbone
nitrogen is a secondary anilide, allowing the adjoining phenyl ring
to be coplanar with the amide bond. There are two low-energy
conformations of ψ in vicinity of 15° and 180°. This feature,
along with the two local minima for each j and χ1 angle, leads to
at least eight local energy minimum conformations (Figure 3).
Ab initio models predict the lowest energy geometries to be a compact
form (Figure 3D) and a more extended form (Figure 3A), in which
ψ is rotated (see Supporting Information). In both geometries,
the ortho group is disposed away from the following backbone
Computational Analysis of N-aryl Peptoid Monomers. To
elucidate the conformational preference of ortho-substituted N-aryl
peptoids, we conducted ab initio quantum mechanics calculations.
Table 2 shows the optimized torsions and the relative energies of
the nonequivalent local minima of 1-ester, 1-I, and 1-tBu. The
lowest energy conformations of 1-I and 1-ester agree with the
geometries observed in the crystal structures (see Supporting
Information). In both cases, the χ1 preference is for the ortho-
substituent to point away from the following carbonyl, as depicted in
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carbonyl, which is also the low-energy conformation predicted and
observed for the monomer compounds. The compact conforma-
tion is favored by over 1 kcal/mol relative to other low-energy struc-
tures at both the M052X/6-31G* (2-Me) and M052X/3-21G*
(2-Me, 2-I) levels of theory (see Supporting Information).
Crystallographic Analysis of N-aryl Peptoid Dimers. We
prepared peptoid dimers 2-Me, 2-tBu, and 2-I to evaluate the
potential for atropisomeric behavior in N-aryl peptoid oligomer
systems. Crystals of peptoid dimers 2-Me and 2-I were obtained
by slow evaporation from CHCl3 overnight at rt. X-ray diffrac-
tion studies showed that the dimer 2-I and 2-Me each form an
enantiomeric pair within the crystal unit cell. These structures
correspond to the lowest energy conformation predicted by the
ab initio modeling ((M)-2-I and the enantiomer (P)-2-I, see
Figure 3D). The N-aryl peptoid dimers 2-Me and 2-I form trans
amide bonds with ω = 179.2° and 178.6°, respectively. The other
backbone dihedral angles (j, ψ) of 2-Me and 2-I are (À85.0°,
6.43°) and (À102.3°, 47.1°), respectively (Table 4). Additionally,
the χ1 dihedral angles at the tertiary anilide positions of 2-Me and
2-I are À80.4° and À101.8°, respectively. For both dimers,
intramolecular hydrogen bonding is evident between the amide
NH group and the carbonyl oxygen of the side chain ester at the
C-terminus. The side chains exhibit distinct rotamer preferences.
For the C-terminal secondary anilide, the aryl ring is coplanar
with the amide bond (χ1 ≈ ( 180°), allowing hydrogen-bond
formation. As expected, for the N-terminal tertiary anilide, the
aryl ring is perpendicular to the amide plane (χ1 ≈ ( 90°).
Further analysis of the crystal structure of 2-I reveals that the
iodine is in close proximity (3.0 Å) to the carbonyl oxygen of an
adjacent molecule in the crystal lattice. The angle formed
between the CÀI bond and the carbonyl oxygen is 171.3° (see
Supporting Information). This constitutes a Lewis acid/base pair
interaction for compound 2-I and indicates the capability for
peptoids to form ‘halogen bonds’.44
Table 3. Calculated Transition State Energies for χ1 Rotation
in a Series of Peptoid Analoguesb
Unexpectedly, we were also able to observe in the solid state
the presence of a side chain rotameric conformation of 2-I with
low occupancies (∼2%). This minor form could be detected
due to the anomalous scattering of the heavy iodine atom. The
χ1 dihedral angle for this minor conformer was 107.9° and is
modeled in Figure 3B. Thus, the peptoid dimers may exhibit
some conformational heterogeneity of the side chain rotamers.
NMR Analysis of N-aryl Peptoid Dimers. NMR spectroscopy
was used to analyze the solution structures of all dimers (2-Me, 2-tBu,
and 2-I) in CDCl3 at rt. The 1-D 1H and 13C spectra show well-
resolved peaks along with a one-to-one correspondence between
the observed NMR peaks and the expected chemical shifts
a Calculations did not converge on a saddle point in these regions. b TS
energies are shown relative to the energy of the freely optimized
structure. Geometries are optimized at the HF/6-31G* level (except
for the iodo compound which is optimized at B3LYP/3-21G*).
Figure 3. Low-energy conformational states of peptoid dimer 2-I. The major conformational state observed in the crystal structure is depicted in D. An
additional three low-energy conformational states of 2-I can be obtained upon rotations about ψ (A), χ1 (B), or both ψ and χ1 (C). For each
conformation, an enantiomeric structure can be observed or predicted (right panel). Green structures are experimental, and gray structures are
optimized at the HF/3-21G* level of theory.
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Table 4. Dihedral Angles Observed from the X-ray Crystallo-
graphy for Peptoid Dimers (M)-2-Me, (M)-2-I, and the Enantio-
mers (P)-2-Me and (P)-2-I
peptoids
ω°
j°
ψ°
χ1°
(M)-2-Me
(P)-2-Me
(M)-2-I
179.2
À179.2
178.6
À85.0
85.0
6.43
À80.4
80.4
À6.43
47.1
À102.3
102.3
À101.8
101.8
(P)-2-I
À178.6
À47.1
(see Supporting Information). We also observed a distinct peak
for the amide hydrogen, which was significantly downfield shifted
(δ = 11.5 ppm). This result is consistent with the crystallographic
data (vide supra), suggesting that the amide proton is engaged in
intramolecular hydrogen bonding with the side chain carbonyl of
the ester group at the C-terminus. To gain further insight into the
conformational preference of the peptoid dimers in the solution
Figure 4. Key cross-peaks observed in NOESY spectra for 2-I (shown
as double-headed arrows).
1
state, we evaluated compound 2-I by 1HÀ H correlation spec-
troscopy (COSY) and nuclear Overhauser effect spectroscopy
1
(NOESY). The 1HÀ H COSY was carried out on 2-I to
unambiguously assign aromatic proton chemical shifts, as they
show readily distinguishable through-bond cross-peaks (see
Supporting Information). 2D-NOESY was used to gauge inter-
proton distances and to assess the solution-phase behavior of 2-I.
Figure 4 highlights the key cross-peaks observed in 2-I. The
presence of a strong NOE between the acetyl-methyl group and
the ortho-hydrogen of the N-terminal anilide, along with the
absence of an NOE between the acetyl-methyl and backbone
methylene protons, strongly indicates the presence of a trans
amide bond at the N-terminal anilide.19,20 Notably, a strong
cross-peak was observed between the C-terminal amide hydro-
gen and one of the magnetically nonequivalent protons (Ha/Hb),
while a slightly weaker NOE was observed with the other one
(Hb/Ha), further substantiating the diastereotopic behavior of
the methylene hydrogens in the N-aryl peptoid dimer (see
Supporting Information). An NOE cross-peak was also observed
between the ortho-hydrogen of the N-terminal anilide with the
amide proton of the C-terminal anilide. This cross-peak strongly
supports the notion that 2-I has a compact solution structure
similar to the solid state (Figure 3D) and does not adopt an
extended backbone structure (as depicted in Figure 3A) or the
alternate χ1 rotamers (as depicted in Figure 3B and C), as these
would most likely preclude observation of a strong NOE cross-
peak (see Supporting Information).
Figure 5. Chiral HPLC enantioseparation of 2-tBu. (A) Enantiomeriza-
tion of 2-tBu. (B) Enantioseparation of 2-tBu at rt. (C) CD spectra of the
first eluted enantiomer (red) and the second eluted enantiomer (blue).
DHPLC and CD Studies of N-aryl Peptoid Dimers. Chiral
HPLC studies of peptoid dimers showed that 2-tBu and 2-I could
be separated into enantiomers at low temperatures. The enan-
tiomers (M)-2-I and (P)-2-I were separated on Chiralcel OD at
0 °C. Peak coalescence was observed at 40 °C, however, due to
rapid enantiomerization at elevated temperatures (Figure 2C, D).
Computational analysis of the DHPLC elution profiles yielded
an enantiomerization barrier, ΔG‡, of 21.5 kcal/mol at 25 °C . The
corresponding enthalpy of activation (ΔH‡ = 17.8 kcal/mol) and
entropy of activation (ΔS‡ = À12.2 cal/K mol) were obtained
by van’t Hoff plot analysis. As expected, the enantiomerization barrier
of the N-aryl peptoid dimer 2-I is equivalent to the monomer 1-I,
suggesting that conformational stability is an intrinsic prop-
erty of the congested tertiary anilide groups and is determined
primarily by local interactions. As observed for 1-tBu, the dimer 2-tBu
could be separated and isolated by semipreparative HPLC on
Chiralpak AD. The enantioseparation was verified by the mirror
image CD spectra obtained for the two enantiomeric forms of (M)-2-
tBu and (P)-2-tBu (Figure 5).
Structural Analysis of an N-aryl Peptoid Trimer. The N-aryl
peptoid trimer 3 includes two side chains capable of exhibiting
atropisomerism at the tertiary anilide positions. In particular, com-
pound 3 includes axial chirality at the N-aryl side chains incorporating
an ortho-iodo and an ortho-tert-butyl substituent. The possibility for
rotational isomers at both anilide positions can give rise to two pairs of
enantiomers (Figure 6A). We evaluated the solution-state structure
of peptoid trimer 3 in CDCl3 at rt using NMR spectroscopy. The 1D
NMR spectra of 3 show at least two major conformations with a ratio
of 2:1 along with several minor conformers producing significant
numbers of overlapping NMR peaks (see Supporting Information).
Moreover, the RP-HPLC profile of recrystallized 3 shows two peaks
in the chromatogram, also supporting the presence of diastereomeric
forms of the peptoid trimer 3 (see Supporting Information).
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Table 5. Dihedral angles observed for N-aryl peptoid trimer
(P,P)-3
peptoid residues
ω°
j°
ψ°
χ1°
(P-tBu)-3
(P-I)-3
178.9
80.4
79.2
À169.0
98.6
À179.0
4.70
101.3
conformational preferences of the terminal ψ angle for the
peptoid dimers (2-I and 2-Me, Table 4). We also found that
the C-terminal secondary anilide forms an intramolecular hydro-
gen bond with the carbonyl of the side chain ester group, and the
corresponding aromatic ring is coplanar with the amide bond.
Like the peptoid dimer 2-I, the rotamer of peptoid trimer 3
also shows an intermolecular Lewis acid/base interaction (see
Supporting Information). The distance between the Lewis acid
(iodine group) and the Lewis base (carbonyl oxygen) is 2.96 Å.
The observed angle of 176.8° is also within halogen bonding
parameters. The presence of this interaction in both dimeric and
trimeric peptoids suggests that halogen bonding may be useful
for the design of higher order structure in peptoids.3
As observed for the peptoid dimer 2-I, we were also able to
detect the presence of additional side chain rotamers of peptoid
trimer 3 with low population density (∼2%). The χ1 dihedral
angles at the tert-butyl- and iodo-anilide positions are 98.6° and
À100.4°, respectively. Peptoid trimer 3 features axial chirality at
both the tert-butyl- and iodo-aryl side chains. For such oligomers
with multiple stereogenic sites, the presence of a particular
stereoisomer at one monomer position may influence the relative
energy of stereoisomers at neighboring positions.45 A peptoid
oligomer incorporating a discrete stable stereogenic center could
bias the preferential formation of a desired backbone conformation
within a population of otherwise dynamic atropisomeric forms.46
Future studies will evaluate the induction of chiral information in
hybrid oligomers comprising both N-alkyl and N-aryl peptoid units.
Conclusions. We demonstrate that a chiral folded oligomer
can be obtained by assembly of monomers lacking chiral centers.
Peptoids bearing bulky ortho-substituted N-aryl side chains
exhibit axial chirality, due to restricted rotation about the
congested tertiary anilide positions. For peptoids including
ortho-iodo or ortho-tert-butyl anilide groups, the energy barrier
for rotation is sufficiently high to permit the chromatographic
isolation of stable atropisomeric forms exhibiting mirror-image
CD spectra. At elevated temperatures, N-aryl peptoid atropi-
somers undergo enantioconversion. X-ray crystal structures
reveal details of the atropisomeric forms of ortho-substituted
N-aryl peptoid monomers, dimers, and a trimer. Atropisomeric
conformers of the peptoids are observed as enantiomeric pairs in
the solid state. The peptoid conformations feature trans amide
bonds and side chain rotamers in which the aryl groups are
orthogonal to the plane of the amide bonds. Both intramolecular
hydrogen and halogen bonding are observed in the crystal
structure. The presence of two sites of axial chirality in the
peptoid trimer yields diastereomeric conformers.
Figure 6. Conformations of N-aryl peptoid trimer 3. (A) The possible
stereoisomers and their relationships. (B) The predominant structure
in the solid state shows the enantiomeric pair (P,P)-3 and (M,M)-3
(hydrogen atoms have been removed for clarity).
Further structural characterization of 3 was conducted by X-ray
crystallography. A solution of trimer 3 in CHCl3 was allowed to
evaporate at rt overnight, forming block-shaped crystals in the
P21/c space group. Hence, the peptoid trimer 3 exists as enan-
tiomeric pairs (M,M)-3 and (P,P)-3 within the unit cell (Figure 6B).
The dihedral angles observed in the solid-state structure are listed
in Table 5. We observed that the dihedral angles (ω, j, ψ) were
(178.9°, 80.4°, À169.0°) for the tert-butyl-anilide and (À179.0°,
79.2°, 4.70°) for the iodo-anilide position. In addition, the
χ1 dihedral angles are 98.6° and 101.3° at the tert-butyl- and
iodo-anilide positions, respectively. Notably, the iodo-anilide
position includes a significant deviation of the ψ dihedral angle
from a ppII type conformation. This deviation from canonical pp
II dihedral values is presumably due to the presence of the
C-terminal secondary anilide group that similarly alters the
Our results show that the stereochemical features of folded
N-aryl peptoid oligomers can be dynamic, as opposed to the
stereochemistry of peptides and proteins, which is essentially
static. We have previously shown the ability for peptoids to undergo
backbone or side chain conformational rearrangements triggered
by changes in pH47 or by photoisomerization.48 Future studies
may yield functional peptoid structures that interconvert between
stereochemical forms in response to external stimuli.49
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’ EXPERIMENTAL SECTION
Synthesis of N-aryl Peptoid Trimer 3. The synthesis of the
trimer was performed following the same protocol as for the dimers, in which
iterative bromoacetylation and displacement steps were conducted prior
to final acetylation. The overall isolated yield of the trimer 3 was ∼10%.
Peptoid Characterization and Purification. Peptoid oligo-
mers were characterized by analytical RP-HPLC using an analytical C18
column (Peeke Scientific, 5 μm, 120 Å, 2.0 Â 50 mm) on a Beckman
Coulter Gold HPLC system. Products were detected by UV absorbance
at 214 nm during a linear gradient from 5 to 95% solvent B (0.1% of
trifluoroacetic acid in HPLC-grade acetonitrile) in solvent A (0.1% of
trifluoroacetic acid in HPLC-grade water) in 10 min with a flow rate of
0.7 mL.minÀ1. The expected molecular mass of each product was
confirmed using liquid chromatography-mass spectrometry (LC-MS)
on an Agilent 1100 series LC/MSD trap XCT with an electrospray ion
source in positive ion mode.
General Methods. All reagents and solvents were purchased from
commercial sources and used without further purification. Thin-layer
chromatography (TLC) was performed on precoated UV active silica
gel. Silica gel (40À63 μm, Sorbent Technologies) was used for column
chromatography.
Materials. Bromoacetyl bromide, aniline, 2-methylaniline, 2-tert-
butylaniline, 2-iodoaniline, methylanthranilate, dimethylaminopyridine
(DMAP), and triethylamine (TEA) were purchased from Sigma-Aldrich
(St. Louis, MO). N,N-diisopropylethylamine (DIEA) and pyridine (Py)
were purchased from Alfa-Aesar. Trifluoroacetic acid was purchased from
Acros Organics. Anhydrous solvents, such as chloroform, acetonitrile
(ACN), ethyl acetate (EtoAc), and dichloromethane (DCM) were
purchasedfromcommercial sources and used without further distillation.
Synthesis of Peptoid Monomers (1-H, 1-Me, 1-tBu, 1-I, 1-
ester). Displacement Step. To a solution of tert-butyl bromoacetate
(550 μL, 3.72 mmol) and diethyl isopropyl amine (DIEA, 6 mL, 33.84
mmol) was added the aniline or aniline derivative (900 mg, 10.7 mmol)
in acetonitrile. The reaction was then subjected to reflux for 14 h.
Subsequently, the solution was cooled to rt followed by removal of solvent
under reduced pressure in rotatory evaporator. The crude mixture was
then subjected to silica gel column chromatography in a n-hexane/EtoAc
to obtain the N-(tert-butyl acetate) aniline or aniline derivative.
Acetylation Step. The typical scale for this step was between 1 and 2
mmol. N-(tert-butyl acetate) aniline or its derivative was treated with
pyridine (1.2 mmol) along with the addition of catalytic amounts of
DMAP (∼0.5 mg) in dichloromethane (DCM) as solvent. The acetyl
chloride (2À2.5 mmol) was then added in dropwise manner at rt with
continued stirring and left to react overnight. Solvent was removed
under reduced pressure and then subjected to silica gel column
chromatography in a n-hexane/EtoAc mixture to obtain the pure
compounds. Products were analyzed and confirmed by NMR and mass
spectrometry (see Supporting Information). The desired compounds
were isolated in the following yields over two steps: 1-H (50%); 1-Me
(52%); 1-tBu (55%); 1-ester (54%); and 1-I (50%).
Peptoid products were purified to >95% purity, as assessed by NMR after
silica gel column purification, and the peptoid 1-tBu was purified by using the
same RP-HPLC apparatus described above with a preparatory C18 column.
Products were detected by UV absorbance at 230 nm during linear gradient
from 5 to 95% solvent B in solvent A in 50 min with a flow rate of 2.5 mL.
minÀ1. Compounds were then lyophilized before further characterization.
NMR Spectroscopy. Using either a Bruker 400 MHz NMR or a
Bruker 500 MHz NMR spectrometer, 1D proton spectra were obtained.
All 13C NMR were recorded at 100 MHz. Chemical shifts are reported in
parts per million (ppm, δ). Couplings are reported in Hertz. NOESY and
1
HÀ H COSY experiments were performed using a 500 MHz instrument
and were referenced to solvent. Except for the temperature-dependent 1H
NMR experiment, all NMR experiments were carried out at 25 °C.
NMR Analyses for Peptoids 2-I, 3. NOESY experiments on 2-I
in CDCl3 were performed at 25 °C using the following parameter values:
size of fid (TD) = 2048, 128; number of scans (NS) = 32; number of
dummy scans (DS) = 4; mixing time (D8) = 800 ms; acquisition time
1
(AQ) = 0.17 s; and relaxation delay = 1.5 s. 1HÀ H COSY experiments
on 2-I in CDCl3 were performed at 25 °C using the following parameters:
TD = 2048, 192; NS = 40; DS = 4; AQ = 150 ms; and relaxation delay
(D1) = 1.5 s. The concentration of the solution was 30 mM.
Synthesis of N-aryl Peptoid Dimers (2-I, 2-tBu, 2-Me). Bro-
moacetylation Step. Methyl anthranilate (1.5 g, 10 mmol) was dis-
solved in DCM followed by addition of triethyl amine (1.4 mL, 10
mmol) under nitrogen at 0 °C. The reaction was stirred for 15 min at
0 °C before the addition of bromoacetyl bromide. Bromoacetyl bromide
(1.4 mL, 15.9 mmol) was added dropwise for 10 min. An immediate
change was observed from colorless to yellow solution, and the reaction
mixture was allowed to stir overnight at rt. The solvent was removed
under reduced pressure to afford a crude oil, which was purified by
column chromatography in a n-hexane/EtoAc mixture.
Displacement Step. In a round-bottom flask, 1 mmol of N-(2-phenyl)
bromoacetamide derivatives was taken in acetonitrile followed by
addition of ortho-substituted amine (1.1 mmol) in the presence of DIEA
(5 mmol) as base. The mixture was then subjected to reflux condition for
12 h. After the removal of solvent under reduced pressure, the compound
was then subjected to silica gel column chromatography in a n-hexane/
EtoAc mixture.
Acetylation Step. The typical scale for the next step was ∼1 mmol. In
this step the compound was treated with pyridine (1.2 mmol) along with
a catalytic amount of DMAP (∼0.5 mg) followed by addition of the
DCM solvent at room temperature. The acetyl chloride (2.5 mmol) was
then added in a dropwise manner at rt, and the reaction was stirred overnight.
Upon removal of the solvent under reduced pressure, the product was
then subjected to silica gel column chromatography in a n-hexane/EtoAc
mixture to obtain the pure compound. The final compounds were analyzed
and characterized by NMR and mass spectrometry. The desired compounds
were isolated in the following yields over three steps: 2-Me (24%); 2-tBu
(20%); and 2-I (15%).
X-ray Crystallography. All software and sources of the scattering
factors are contained in the program suite SHELXL. The intensity data
collections were conducted with a Bruker SMART APEXII CCD area
detector on a D8 goniometer at 100 K. The temperature during the data
collection was controlled with an Oxford Cryosystems Series 700 plus
instrument. Preliminary lattice parameters and orientation matrices
were obtained from three sets of frames. Data were collected using
graphite-monochromated and 0.5 mm MonoCap-collimated MoÀKR
radiation (λ = 0.71073 Å) with the ω scan method. Data were processed
with the INTEGRATE program of the APEX2 software for reduction
and cell refinement. Multiscan absorption corrections were applied by
using the SCALE program for area detector. The structure was solved by
the direct method and refined on F2 (SHELXTL). Nonhydrogen atoms
were refined with anisotropic displacement parameters, and hydrogen
atoms on carbons were placed in idealized positions (CÀH = 0.93 or
0.96 Å) and included as riding with Uiso(H) = 1.2 or 1.5 Ueq(non-H).
Crystallization of 1-ester. Roughly 10 mg of purified 1-ester was
dissolved in 1 mL of CHCl3. The peptoid solution was filtered with a
0.5 μm stainless steel fritted syringe tip filter (Upchurch Scientific). The
resulting solution was then allowed to evaporate slowly at 4 °C to form a
block-shaped colorless crystal.
Crystallographic Data. C16H21NO5, colorless block crystal, monoclinic,
P21/c, a = 8.6027(7) Å, b = 10.4781(8) Å, c = 17.9484(14) Å, β =
96.0170(10)°,V= 1609.0(2) Å3,Z=4,T= 100(2) K, and Fcalc = 1.269 g/cm3.
Crystallization of 1-I. Roughly 10 mg of purified 1-I was dissolved
in 1 mL of CHCl3. The peptoid solution was filtered with a 0.5 μm stainless
steel fritted syringe tip filter. The resulting solution was then allowed to
evaporate slowly at 4 °C to form a plate-shaped colorless crystal.
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Crystallographic Data. C14H18INO3, plate-shaped colorless crystal,
monoclinic, P21/c, a = 9.0692(8) Å, b = 10.1549(9) Å, c = 17.5809(16) Å,
and RP-HPLC characterization data for all peptoids; additional
representations of the crystal structures of 1-ester, 1-I, 2-Me, 2-I,
and trimer 3; halogen bonding features (distance and angle) of 2-I
and 3; 1D and 2D NMR spectra of compounds all peptoid
monomers, dimers, and trimer; crystal and computationally
evaluated conformers of 2-I; additional computational data;
rotational barrier across ψ and χ, respectively; dynamic HPLC,
enantioconversion, and computational fitting of elution profiles
to obtain van’t Hoff plots of 1-I and 2-I; enantioseparation and
CD analysis of 1-tBu. This material is available free of charge via
the Internet at http://pubs.acs.org.
β = 101.0230(10)°, V = 1589.3(2) Å3, Z = 4, T = 100(2) K, and Fcalc
=
1.568 g/cm3.
Crystallization of 2-Me. Roughly 10 mg purified of 2-Me was
dissolved in CHCl3. The peptoid solution was filtered with a 0.5 μm
stainless steel fritted syringe tip filter. The solution was then allowed to
evaporate slowly at rt to obtain plate-shaped colorless crystals.
Crystallographic Data. C19H20N2O4, plate-shaped colorless crystal,
orthorhombic, Pbca, a = 10.5493(15) Å, b = 16.050(2) Å, c = 20.088(3) Å,
R = β = γ = 90°, V = 3401.4(8) Å3, Z = 8, T = 100(2) K, and Fcalc
=
1.329 g/cm3.
Crystallization of 2-I. The purified compound 2-I was dissolved in
chloroform to a concentration of 10 mM. The peptoid solution was filtered
with a 0.5 μm stainless steel fritted syringe tip filter. The solution was then
allowed to evaporate slowly at rt to obtain plated-shaped colorless crystals.
Crystallographic Data. C18H17IN2O4, plate-shaped colorless crystal,
triclinic, P1, a = 7.9952(2) Å, b = 16.050(2) Å, c = 20.088(3) Å, R =
93.2104(10)°, β = 94.7131(10)°, γ = 97.9838(5)°, V = 873.65(8) Å3,
Z = 2, T = 100(2) K, and Fcalc= 1.719 g/cm3.
’ AUTHOR INFORMATION
Corresponding Author
kent@nyu.edu
’ ACKNOWLEDGMENT
This work was supported by a National Science Foundation
CAREER Award (CHE-0645361). Funding from the NSF under
CHE-0910604 is also gratefully acknowledged. NYU is the recipient
of an NCRR/NIH research facilities improvement grant (C06RR-
165720). We thank the NYU Molecular Design Institute for
access to the Bruker SMART APEXII X-ray diffractometer and
Dr. Chunhua (Tony) Hu for his help with data collection and structure
determination. We thank Arjel Bautista, Chin Lin, Barney Yoo,
and James Canary for their helpful discussions and suggestions.
Crystallization of 3. The purified compound 3 was dissolved in
chloroform to a concentration of roughly 10 mM. The peptoid solution was
filtered with a 0.5 μm stainless steel fritted syringe tip filter. The solution was
then allowed to evaporate slowly at rt to obtain block-shaped colorless crystals.
Crystallization Data. C30H32IN3O5, block, colorless crystal, mono-
clinic, P21/c, a = 8.1287(3) Å, b = 20.4002(8) Å, c = 17.2759(7) Å,
β = 92.1300(10)°, V = 2862.83(19) Å3, Z = 4, T = 100(2) K, and Fcalc
=
1.488 g/cm3.
Computational Studies. All ab initio quantum mechanics calcula-
tions used Gaussian 03 (Supporting Information for full references list).
The levels of theory and basis sets are indicated in the main text. The TS
optimizations began with starting structures thought to be in the confor-
mational vicinity of the TS and used the “TS Opt=(TS,NoEigenTest,
CalcFC) nosym” options. The SCF = tight option was specified in all
calculations.
Chiral HPLC and CD analysis of N-aryl Peptoids: 1-I. The
analytical enantioseparation was conducted on a (S,S)-Whelk-O1CSPusing
hexanes/IPA (90/10 v/v) as the mobile phase at a flow rate of 1 mL/min.
The enantiomers were detected by UV absorbance at 230 nm.
1-tBu. The analytical separation was performed on a Chiralcel OD
CSP using hexanes/IPA (95/5 v/v) as the mobile phase at a flow rate of
1 mL/min. The enantiomers were detected by UV absorbance at 254 nm.
The semipreparative enantioseparation was conducted at rt using a sample
concentration of 0.96 mg/mL and an injection volume of 100 μL. After
the isolation of the two enantiomers, CD spectroscopy was conducted
with sample concentrations of 4.8 mM.
Enantioseparation of 2-I. The analytical separation was per-
formed on a Chiralcel OD CSP using hexanes/EtOH (85/15 v/v) as the
mobile phase at a flow rate of 1 mL/min. The enantiomers were detected
by UV absorbance at 230 nm.
Semipreparative Chromatography of 2-tBu. The analytical
separation was performed on Chiralpak AD using hexanes/IPA (90/10 v/v)
as the mobile phase at a flow rate of 1 mL/min. The enantiomers were
detected by UV absorbance at 254 nm. The semipreparative enantiosepara-
tion was conducted at rt using a sample concentration of 1.59 mg/mL and an
injection volume of 50 μL. After the isolation of the two enantiomers, CD
spectroscopy was conducted with sample concentrations of 4.0 mM.
’ REFERENCES
(1) Zuckermann, R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W. H.
J. Am. Chem. Soc. 1992, 114, 10646–10647.
(2) (a) Simon, R. J.; Kania, R. S.; Zuckermann, R. N.; Huebner,
V. D.; Jewell, D. A.; Banville, S.; Ng, S.; Wang, L.; Rosenberg, S.;
Marlowe, C. K. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 9367–9371.
(b) Culf, A. S.; Ouellette, R. J. Molecules 2010, 15, 5282–5335.
(3) (a) Murnen, H. K.; Rosales, A. M.; Jaworski, J. N.; Segalman,
R. A.; Zuckermann, R. N. J. Am. Chem. Soc. 2010, 132, 16112–16119.
(b) Nam, K. T.; Shelby, S. A.; Choi, P. H.; Marciel, A. B.; Chen, R.; Tan,
L.; Chu, T. K.; Mesch, R. A.; Lee, B.-C.; Connolly, M. D.; Kisielowski, C.;
Zuckermann, R. N. Nat. Mater. 2010, 9, 454–460.
(4) Lee, B.-C.; Chu, T. K.; Dill, K. A.; Zuckermann, R. N. J. Am.
Chem. Soc. 2008, 130, 8847–8855.
(5) (a) Lee, B.-C.; Zuckermann, R. N.; Dill, K. A. J. Am. Chem. Soc.
2005, 127, 10999–11009. (b) Burkoth, T. S.; Beausoleil, E.; Kaur, S.;
Tang, D.; Cohen, F. E.; Zuckermann, R. N. Chem. Biol. 2002, 9, 647–654.
(6) Maayan, G.; Ward, M. D.; Kirshenbaum, K. Proc. Natl. Acad. Sci.
U.S.A. 2009, 106, 13679–13684.
(7) (a) Murphy, J. E.; Uno, T.; Hamer, J. D.; Cohen, F. E.; Dwarki, V.;
Zuckermann, R. N. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 1517–1522. (b) Huang,
C.-Y.; Uno, T.; Murphy, J. E.; Lee, S.; Hamer, J. D.; Escobedo, J. A.; Cohen, F. E.;
Radhakrishnan, R.; Dwarki, V.; Zuckermann, R. N. Chem. Biol. 1998, 5, 345–354.
(c) Utku, Y.; Dehan, E.; Ouerfelli, O.; Piano, F.; Zuckermann, R. N.; Pagano, M.;
Kirshenbaum, K. Mol. BioSyst. 2006, 2, 312–317. (d) Wender, P. A.; Mitchell,
D. J.; Pattabiraman, K.; Pelkey, E. T.; Steinman, L.; Rothbard, J. B. Proc. Natl. Acad.
Sci. U.S.A. 2000, 97, 13003–13008. (e) Schroder, T.; Niemeier, N.; Afonin, S.;
Ulrich, A. S.; Krug, H. F.; Brase, S. J. Med. Chem. 2008, 51, 376–379.
(8) (a) Maayan, G.; Ward, M. D.; Kirshenbaum, K. Chem. Commun.
2009, 56–58. (b) Cola, C. D.; Licen, S.; Comegna, D.; Cafaro, E.; Bifulco, G.;
Izzo, I.; Tecilla, P.; De Riccardis, F. Org. Biomol. Chem. 2009, 7, 2851–2854.
(9) Maulucci, N.; Izzo, I.; Bifulco, G.; Aliberti, A.; Cola, C. D.;
Comegna, D.; Gaeta, C.; Napolitano, A.; Pizza, C.; Tedesco, C.; Flot, D.;
De Riccardis, F. Chem. Commun. 2008, 3927–3929.
’ ASSOCIATED CONTENT
S
Supporting Information. Complete reference of Gauss-
b
ian 03; NMR and mass spectrometry characterization of synthe-
sized peptoid monomers (1-H, 1-Me, 1-tBu, 1-I and 1-ester),
dimers (2-Me, 2-I and 2-tBu), and trimer 3; mass spectrometry
(10) (a) Chongsiriwatana, N. P.; Patch, J. A.; Czyzewski, A. M.;
Dohm, M. T.; Ivankin, A.; Gidalevitz, D.; Zuckermann, R. N.; Barron,
10918
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Journal of the American Chemical Society
ARTICLE
A. E. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 2794–2799. (b) Comegna,
D.; Benincasa, M.; Gennaro, R.; Izzo, I.; De Riccardis, F. Biorg. Med.
Chem. 2010, 18, 2010–2018.
(27) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am. Chem.
Soc. 1994, 116, 3131–3132.
(28) Clayden, J. Chem. Commun. 2004, 127–135.
(11) (a) Reddy, M. M.; Wilson, R.; Wilson, J.; Connell, S.; Gocke, A.;
Hynan, L.; German, D.; Kodadek, T. Cell 2011, 144, 132–142. (b) Zuckermann,
R. N.; Kodadek, T. Curr. Opin. Mol. Ther. 2009, 11, 299–307.
(12) Kirshenbaum, K.; Barron, A. E.; Goldsmith, R. A.; Armand, P.;
Bradley, E. K.; Truong, K. T. V.; Dill, K. A.; Cohen, F. E.; Zuckermann,
R. N. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 4303–4308.
(13) (a) Armand, P.; Kirshenbaum, K.; Falicov, A.; Dunbrack, R. L.;
Dill, K. A.; Zuckermann, R. N.; Cohen, F. E. Folding Des. 1997,
2, 369–375. (b) Pokorski, J. K.; Miller Jenkins, L. M.; Feng, H.; Durell,
S. R.; Bai, Y.; Appella, D. H. Org. Lett. 2007, 9, 2381–2383. (c) Shin,
S. B. Y.; Yoo, B.; Todaro, L. J.; Kirshenbaum, K. J. Am. Chem. Soc. 2007,
129, 3218–3225. (d) Fowler, S. A.; Luechapanichkul, R.; Blackwell, H. E.
J. Org. Chem. 2009, 74, 1440–1449. (e) Gorske, B. C.; Blackwell, H. E.
J. Am. Chem. Soc. 2006, 128, 14378–14387.
(29) (a) Clayden, J.; Lemiegre, L.; Morris, G. A.; Pickworth, M.;
Snape, T. J.; Jones, L. H. J. Am. Chem. Soc. 2008, 130, 15193–15202.
(b) Gaucher, A.; Dutot, L.; Barbeau, O.; Wakselman, M.; Mazaleyrat,
J.-P.; Peggion, C.; Oancea, S.; Formaggio, F.; Crisma, M.; Toniolo, C.
Tetrahedron: Asymmetry 2006, 17, 30–39. (c) Kim, I. C.; Hamilton, A. D.
Org. Lett. 2006, 8, 1751–1754. (d) Mazaleyrat, J. P.; Wright, K.; Gaucher,
A.; Toulemonde, N.; Wakselman, M.; Oancea, S.; Peggion, C.; Formaggio,
F.; Setnicka, V.; Keiderling, T. A.; Toniolo, C. J. Am. Chem. Soc. 2004, 126,
12874–12879.
(30) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley-Interscience: New York, 1994.
(31) Oki, M. The Chemistry of Rotational Isomers; Springer-Verlag:
New York, 1993.
(32) Wolf, C. (Ed.) Dynamic Stereochemistry of Chiral Compounds,
RSC Publishing: Cambridge, U.K., 2008.
(14) (a) Huang, K.; Wu, C. W.; Sanborn, T. J.; Patch, J. A.;
Kirshenbaum, K.; Zuckermann, R. N.; Barron, A. E.; Radhakrishnan, I.
J. Am. Chem. Soc. 2006, 128, 1733–1738. (b) Gorske, B. C.; Stringer,
J. R.; Bastian, B. L.; Fowler, S. A.; Blackwell, H. E. J. Am. Chem. Soc. 2009,
131, 16555–16567.
(33) (a) Adams, R.; Yuan, H. C. Chem. Rev. 1933, 12, 261–338.
(b) Clayden, J.; Westlund, N.; Frampton, C. S.; Helliwell, M. Org.
Biomol. Chem. 2006, 4, 455–461. (c) Clayden, J. Angew. Chem., Int. Ed.
1997, 36, 949–951. (d) Guthrie, D. B.; Geib, S. J.; Curran, D. P. J. Am.
Chem. Soc. 2010, 133, 115–122.
(15) Dill, K. A.; Bromberg, S.; Yue, K.; Chan, H. S.; Fiebig, K. M.;
Yee, D. P.; Thomas, P. D. Protein Sci. 1995, 4, 561–602.
(34) Clayden, J.; Moran, W.; Edwards, P.; LaPlante, S. Angew. Chem.,
(16) (a) Yoo, B.; Kirshenbaum, K. Curr. Opin. Chem. Biol. 2008,
12, 714–721. (b) Fowler, S. A.; Blackwell, H. E. Org. Biomol. Chem. 2009,
7, 1508–1524. (c) Bautista, A. D.; Craig, C. J.; Harker, E. A.; Schepartz,
A. Curr. Opin. Chem. Biol. 2007, 11, 685–692. (d) Gellman, S. H. Acc.
Chem. Res. 1998, 31, 173–180. (e) Seebach, D.; Abele, S.; Gademann, K.;
Jaun, B. Angew. Chem., Int. Ed. 1999, 38, 1595–1597. (f) Kendhale, A. M.;
Poniman, L.; Dong, Z.; Laxmi-Reddy, K.; Kauffmann, B.; Ferrand, Y.;
Huc, I. J. Org. Chem. 2010, 76, 195–200. (f) Hill, D. J.; Mio, M. J.; Prince,
R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev. 2001, 101, 3893–4012.
(g) Horne, W. S.; Gellman, S. H. Acc. Chem. Res. 2008, 41, 1399–1408.
(h) Margulies, D.; Hamilton, A. D. Curr. Opin. Chem. Biol. 2010,
14, 705–712. (i) Delsuc, N.; Massip, S.; Leger, J. M.; Kauffmann, B.;
Huc, I. J. Am. Chem. Soc. 2011, 133, 3165–3172.
(17) In order to be consistent with peptide nomenclature we use the
terms “cis” and “trans” to describe the amide dihedral angle omega (ω)
referring to the relative positions of the backbone alpha carbons. For all
N-aryl peptoids, “trans” amide conformation corresponds to the E
isomer, while the “cis” amide corresponds to the Z isomer.
(18) Butterfoss, G. L.; Renfrew, P. D.; Kuhlman, B.; Kirshenbaum,
K.; Bonneau, R. J. Am. Chem. Soc. 2009, 131, 16798–16807.
(19) Shah, N. H.; Butterfoss, G. L.; Nguyen, K.; Yoo, B.; Bonneau,
R.; Rabenstein, D. L.; Kirshenbaum, K. J. Am. Chem. Soc. 2008, 130,
16622–16632.
Int. Ed. 2009, 48, 6398–6401.
(35) Curran, D. P.; Hale, G. R.; Geib, S. J.; Balog, A.; Cass, Q. B.;
Degani, A. L. G.; Hernandes, M. Z.; Freitas, L. C. G. Tetrahedron:
Asymmetry 1997, 8, 3955–3975.
(36) Lapierre, A. J. B.; Geib, S. J.; Curran, D. P. J. Am. Chem. Soc. 2006,
129, 494–495.
(37) Gustafson, J. L.;Lim, D.;Miller, S. J. Science 2010, 328, 1251–1255.
(38) (a) Ates, A.; Curran, D. P. J. Am. Chem. Soc. 2001,
123, 5130–5131. (b) Adler, T.; Bonjoch, J.; Clayden, J.; Font-Bardia,
M.; Pickworth, M.; Solans, X.; Sole, D.; Vallverdu, L. Org. Biomol. Chem.
2005, 3, 3173–3183. (c) Kitagawa, O.; Yoshikawa, M.; Tanabe, H.;
Morita, T.; Takahashi, M.; Dobashi, Y.; Taguchi, T. J. Am. Chem. Soc.
2006, 128, 12923–12931. (d) Kitagawa, O.; Takahashi, M.; Yoshikawa,
M.; Taguchi, T. J. Am. Chem. Soc. 2005, 127, 3676–3677.
(39) Kruijtzer, J. A. W.; Liskamp, R. M. J. Tetrahedron Lett. 1995,
36, 6969–6972.
(40) (a) Siddall, T. H. J. Phys. Chem. 1966, 70, 2249–2256.
(b) Siddall, T. H. J. Org. Chem. 1966, 31, 3719–3725. (c) Siddall,
T. H.; Stewart, W. E. J. Org. Chem. 1969, 34, 2927–2933. (d) Siddall,
T. H.; Stewart, W. E. J. Phys. Chem. 1969, 73, 40–45. (e) Shvo, Y.; Taylor,
E. C.; Mislow, K.; Raban, M. J. Am. Chem. Soc. 1967, 89, 4910–4917.
(41) Kim, Y.-J.; Park, Y.; Park, K. K. J. Mol. Struct. 2006, 783, 61–65.
(42) (a) Cass, Q. B.; Degani, A. L. G.; Tiritan, M. E.; Matlin, S. A.;
Curran, D. P.; Balog, A. Chirality 1997, 9, 109–112. (b) Wolf, C. Chem.
Soc. Rev. 2005, 34, 595–608.
(20) Stringer, J. R.; Crapster, J. A.; Guzei, I. A.; Blackwell, H. E. J. Org.
Chem. 2010, 75, 6068–6078.
(21) Armand, P.; Kirshenbaum, K.; Goldsmith, R. A.; Farr-Jones, S.;
Barron, A. E.; Truong, K. T. V.; Dill, K. A.; Mierke, D. F.; Cohen, F. E.;
Zuckermann, R. N.; Bradley, E. K. Proc. Natl. Acad. Sci. U.S.A. 1998,
95, 4309–4314.
(22) Wu, C. W.; Kirshenbaum, K.; Sanborn, T. J.; Patch, J. A.;
Huang, K.; Dill, K. A.; Zuckermann, R. N.; Barron, A. E. J. Am. Chem. Soc.
2003, 125, 13525–13530.
(43) Ahmed, A.; Bragg, R. A.; Clayden, J.; Lai, L. W.; McCarthy, C.;
Pink, J. H.; Westlund, N.; Yasin, S. A. Tetrahedron 1998, 54,
13277–13294.
(44) (a) Metrangolo, P.; Neukirch, H.; Pilati, T.; Resnati, G. Acc.
Chem. Res. 2005, 38, 386–395. (b) Hardegger, L. A.; Kuhn, B.; Spinnler,
B.; Anselm, L.; Ecabert, R.; Stihle, M.; Gsell, B.; Thoma, R.; Diez, J.; Benz,
J.; Plancher, J.-M.; Hartmann, G.; Banner, D. W.; Haap, W.; Diederich, F.
Angew. Chem., Int. Ed. 2011, 50, 314–318.
(45) (a) Clayden, J. Chem. Soc. Rev. 2009, 38, 817–829. (b) Dong, Z.;
Plampin, J. N.; Yap, G. P. A.; Fox, J. M. Org. Lett. 2010, 12, 4002–4005.
(46) (a) Stone, M. T.; Fox, J. M.; Moore, J. S. Org. Lett. 2004,
6, 3317–3320. (b) Green, M. M.; Peterson, N. C.; Sato, T.; Teramoto,
A.; Cook, R.; Lifson, S. Science 1995, 268, 1860–1866.
(47) Shin, S. B. Y.; Kirshenbaum, K. Org. Lett. 2007, 9, 5003–5006.
(48) Shah, N. H.; Kirshenbaum, K. Org. Biomol. Chem. 2008,
6, 2516–2521.
(23) Gorske, B. C.; Bastian, B. L.; Geske, G. D.; Blackwell, H. E.
J. Am. Chem. Soc. 2007, 129, 8928–8929.
(24) (a) Choudhary, A.; Gandla, D.; Krow, G. R.; Raines, R. T. J. Am.
Chem. Soc. 2009, 131, 7244–7246. (b) Bartlett, G. J.; Choudhary, A.;
Raines, R. T.; Woolfson, D. N. Nat. Chem. Biol. 2010, 6, 615–620.
(c) Choudhary, A.; Kamer, K. J.; Powner, M. W.; Sutherland, J. D.;
Raines, R. T. ACS Chem. Biol. 2010, 5, 655–657. (d) Kuemin, M.; Nagel,
Y. A.; Schweizer, S.; Monnard, F. W.; Ochsenfeld, C.; Wennemers, H.
Angew. Chem., Int. Ed. 2010, 49, 6324–6327.
(49) Wang, J.; Feringa, B. L. Science 2011, 331, 1429–1432.
(25) Yoo, B.; Shin, S. B. Y.; Huang, M. L.; Kirshenbaum, K. Chem.
ÀEur. J. 2010, 16, 5528–5537.
(26) Dunbrack, R. L.; Karplus, M. J. Mol. Biol. 1993, 230, 543–574.
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