The click triazolium peptoid side chain: A strong cis-amide inducer enabling chemical diversity

Article abstract of DOI:10.1021/ja302342h

Access to homogeneous and discrete folded peptoid structures primarily depends on control of the cis/trans isomerism of backbone tertiary amides. This can be achieved by designing specific side chains capable of forming local interactions with the backbone. This is often undertaken at the expense of side-chain diversity, which is a key advantage of peptoids over other families of peptidomimetics. We report for the first time a positively charged triazolium-type side chain that does not compromise diversity and exhibits the best ability reported to date for inducing the cis conformation. The cis-directing effect was studied in N-acetamide dipeptoid model systems and evaluated in terms of K_cis/trans using NMR spectroscopy in aprotic and protic solvents. Computational geometry optimization and natural bond orbital analysis in combination with NOESY experiments were consistent with a model in which n → π*_Ar electronic delocalization [from carbonyl (O_i-1) to the antibonding orbital (π*) of the triazolium motif on residue i] may be operative. In the computational model (gas-phase) and experimentally in CDCl₃, H-bonding between the triazolium C-H proton and the C_i=O_i oxygen was also identified and may act cooperatively with the n → π*_Ar delocalization, resulting in the absence of the trans rotamers in CDCl ₃.

Full text of DOI:10.1021/ja302342h

Communication
pubs.acs.org/JACS
The Click Triazolium Peptoid Side Chain: A Strong cis-Amide Inducer
Enabling Chemical Diversity
Cecile Caumes, Olivier Roy, Sophie Faure, and Claude Taillefumier*
́
Clermont Universite,
France, and CNRS, UMR 6296, ICCF, BP 80026, F-63171 Aubier
́ ́
Universite Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand,
̀
e, France
S
* Supporting Information
robust conformation still remains a major challenge. The
stereoelectronic factors that may favor the cis-amide population
have been scrutinized in the recent past. Importantly, Blackwell
and co-workers have shown that n → π* donation from a
carbonyl oxygen (Oi−1) to the antibonding orbital (π*) of an
aromatic side chain on residue i (denoted as n → π*Ar)
stabilizes the cis-amide conformation in peptoids.11,12 Research
from this group culminated in a recent publication providing
firm evidence from solution and crystallographic studies that
homooligomers composed of (S)-N-(1-naphthylethyl)glycine
(Ns1npe) form homogeneous and robust PPI peptoid helices
but that steric interactions more than the n → π*Ar donation
served as the primary cause for conformational restriction in 1-
naphthylethylglycine oligomers.13 The 1npe and 4mpy side
chains (Figure 1) are the most efficient ones described to date
in promoting the cis geometry in peptoids.
ABSTRACT: Access to homogeneous and discrete folded
peptoid structures primarily depends on control of the cis/
trans isomerism of backbone tertiary amides. This can be
achieved by designing specific side chains capable of
forming local interactions with the backbone. This is often
undertaken at the expense of side-chain diversity, which is
a key advantage of peptoids over other families of
peptidomimetics. We report for the first time a positively
charged triazolium-type side chain that does not
compromise diversity and exhibits the best ability reported
to date for inducing the cis conformation. The cis-directing
effect was studied in N-acetamide dipeptoid model systems
and evaluated in terms of Kcis/trans using NMR spectros-
copy in aprotic and protic solvents. Computational
geometry optimization and natural bond orbital analysis
in combination with NOESY experiments were consistent
with a model in which n → π*Ar electronic delocalization
[from carbonyl (Oi−1) to the antibonding orbital (π*) of
the triazolium motif on residue i] may be operative. In the
computational model (gas-phase) and experimentally in
CDCl3, H-bonding between the triazolium C−H proton
and the CiOi oxygen was also identified and may act
cooperatively with the n → π*Ar delocalization, resulting in
the absence of the trans rotamers in CDCl3.
Figure 1. Literature peptoid models and corresponding cis/trans ratios
in CD3CN. Side chains: (A) phenylethyl (pe); (B) 4-methylpyridinium
(4mpy); (C) 1-naphthylethyl (1npe).
N-Substituted glycine oligoamides, termed peptoids, emerged
in the early 1990s to answer the demand for large sets of
compounds for high-throughput biological screening.1,2 They
are very attractive peptidomimetics3 because of their ease of
synthesis with huge side-chain diversity,4,5 and they possess
other desirable advantages over peptides such as proteolytic
stability and greater cell permeability.6,7 The major limitation of
peptoids is their inherent flexibility due to the absence of
internal hydrogen bonding, their achiral backbones, and above
all, the low-energy rotameric cis/trans equilibrium of backbone
tertiary amides. Interestingly, peptoids still retain a propensity
to adopt stable secondary structures, provided that the cis/trans
isomerism is optimally controlled. N-Aryl-substituted peptoids8
have been shown to fold into the naturally occurring
polyproline type-II helix conformation (PPII) with trans
amide bonds, and peptoids with α-chiral aromatic or aliphatic
side chains can adopt the PPI-like conformation featuring only
cis amide bonds.9,10 However, in the latter case, conformational
heterogeneity originating from cis/trans interconversion is very
often observed, and constructing peptoids in a discrete and
Figure 2. Structure of cis-directing triazolium-type peptoid side chains.
A desirable side chain should not only predispose a peptoid
to adopt a specific conformation but also allow the introduction
of a wide variety of substituents to facilitate foldamer
applications.14 Here we show that triazolium-type side chains
(Figure 2) provide a solution to this challenge. The triazolium
motif is easily formed using Cu-catalyzed azide−alkyne
Received: March 9, 2012
Published: May 21, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a b
,
cycloaddition (CuAAC) “click” postmodification of N-prop-
argyl side chains15 and subsequent methylation. The effect of
triazolium side chains was studied using I, an acetamide peptoid
model capped as a piperidinyl amide at the C-terminus
(Scheme 1).
Scheme 2. Post-Side-Chain Modifications of 1, 2, and 5
The model proposed by Blackwell and co-workers12 was very
well suited for predicting the proportions of cis- and trans-
amides in peptoid oligomers. Its use also ensured a direct
comparison of our results to literature data. Two versions of the
triazolium side chain were envisaged to probe the contribution
of steric and electronic factors: N-Cα-branched and unsub-
stituted at N-Cα (N-Cα-methylene).16 The cis/trans ratios
1
(Kcis/trans) were measured from H NMR spectra in various
aprotic and protic solvents. We found the electron-deficient
triazolium motif to be the most effective peptoid cis-amide
inducer reported to date. The high values of Kcis/trans even for
the noncrowded N-Cα-methylene triazolium side chains gave
strong evidence that the origin of the effect of the triazolium
side chain is not steric in nature. Here we show that an n →
π*triazolium interaction contributes to stabilization of the cis-
amide geometry. This was supported by molecular calculations
and solution conformational studies using nuclear Overhauser
effect spectroscopy (NOESY). Only aromatic groups (phenyl,
naphthyl) and carbonyl amides have been studied as acceptors
in backbone−side-chain n → π* interactions.11,12 We also
report the significant effect on the amide cis/trans equilibrium
due to a cyano-containing side chain in comparison with alkyne
and alkene side chains of comparable steric bulk.
a
Numbers inside parentheses denote unoptimized isolated yields.
Letters in italics denote side chain abbreviations: bte, 1-
b
(benzyltriazolyl)ethyl; btm, benzyltriazolylmethyl; chtm, cyclohexylme-
thyltriazolylmethyl; bte+, 1-(benzyltriazolium)ethyl; btm+, benzyltria-
zoliummethyl; chtm+, cyclohexylmethyltriazoliummethyl.
Remarkably high values of Kcis/trans (>19) were observed for
compounds 7, 9, and 13 in CDCl3, indicating complete
suppression of the trans rotamers. It is worth noting that the
population of cis-amides remained exceptionally high in
CD3CN (>90%) and protic solvents (∼90% in MeOD and
85% in D2O). The efficiency of the bte+ triazolium side chain of
7 in inducing the cis geometry is higher than that for the
previously reported positively charged Nα-chiral pyridinium
(4mpy) side chain,11 which could be considered as the best one
Compounds 1−4 were prepared by methods similar to those
of Blackwell and co-workers11 [Scheme 1a; see the Supporting
+
reported to date (bte Kcis/trans 11.7 vs
K
cis/trans
= 7.8 in
4mpy
a
CD3CN).20 Even the N-Cα-methylene btm+ side chain in 9 was
able to suppress the trans rotamer completely in CDCl3 and to
a great extent in the other solvents examined. It is particularly
important to notice that in protic solvents, Kcis/trans for 9 is
comparable to that for peptoid model 7. Kcis/trans for 13 (chtm+)
is in the same range as for 9 (btm+), suggesting that the results
are not influenced by the nature of the substituent on the
triazolium motif and in particular by aromatic groups. The
effect of the achiral triazolium side chain was also assessed using
11, the β-peptoid homologue of 9. Despite a decrease in
Scheme 1. Synthesis of α- and β-Peptoid Models
K
cis/trans (by 30% on average) relative to 9, the population of cis-
acetamide was still exceptionally high for this flexible backbone.
Relative to the triazolium peptoid models discussed above,
the triazole precursors 6, 8, 10, and 12 showed a dramatic
decrease in Kcis/trans, which was in the range 1−2 rather than
>19. This trend could be anticipated if an n → π*Ar attraction is
operative in these systems, as the efficiency of the n → π*Ar
interaction can be correlated with the electron-deficient
character of the Ar motif. Unsurprisingly, the N-Cα-branched
bte triazole side chain in 6 slightly increased the cis-amide
population relative to the achiral btm (8) and chtm (12)
analogues. The influence of the bte side chain was on the same
a
Letters in italics are side-chain abbreviations: ee, 1-(ethynyl)ethyl; em,
ethynylmethyl; ce, 1-(cyano)ethyl; ve, 1-(vinyl)ethyl.
Information (SI) for details]. The alkyne functions of the
ethynylethyl (ee) and ethynylmethyl (em) side chains in 1 and 2
were converted into triazoles by CuAAC using benzylazide or
cyclohexylmethylazide partners, affording 6, 8 and, 12;17
subsequent methylation18 gave 7, 9, and 13 with triazolium
side chains (Scheme 2). β-Peptoid19 model 5 with the pendant
N-propargyl side chain was also prepared (Scheme 1b) and
converted into the corresponding triazole and triazolium
compounds 10 and 11 (Scheme 2). 1H NMR spectra of
these peptoid models (with side chains R1−R3) were then
recorded in CDCl3, CD3CN, MeOD, and D2O at 15 mM
concentration, and Kcis/trans values for the N-terminal
acetamides were obtained by integration of characteristic
signals (Table 1).
order of magnitude as that of the pe side chain (see Figure 1) in
pe
model peptoid I (bteKcis/trans = 1.45 vs
K
cis/trans
= 1.26 in
CD3OD and bteKcis/trans = 1.99 vs peKcis/trans = 2.04 in CD3CN).12
In view of the large dipole moment of the triazole ring (∼5
D),21 this shows that dipole−dipole interactions do not have
any significant impact on Kcis/trans. The same conclusion can be
drawn a priori for the triazolium ring, which is characterized by
a small intrinsic dipole moment (∼1.2 D; see the SI).
Surprisingly, the N-Cα-chiral ee side chain in 1 slightly
promotes the cis rotamer of model peptoid I, particularly in
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a b
Communication
c
,
Table 1. Cis/Trans Ratios Kcis/trans and Corresponding Free Energy Differences ΔG for 1−13 in Various Solvents (15 mM)
CDCl3
CD3CN
Kcis/trans
MeOD
D2O
avg
cis/trans
peptoid
side chain
Kcis/trans
ΔG
ΔG
Kcis/trans
ΔG
Kcis/trans
ΔG
K
(% cis)
1
2
ee
1.55
0.54
4.34
0.56
0.63
2.06
−0.26
0.36
3.04
1.31
8.22
1.41
1.38
1.99
11.73
1.11
10.92
1.20
7.89
1.09
10.54
−0.66
−0.16
−1.24
−0.20
−0.19
−0.41
−1.46
−0.06
−1.41
−0.11
−1.22
−0.05
−1.39
1.90
0.78
3.71
0.83
0.73
1.45
11.12
1.03
8.67
1.04
6.27
1.00
−0.38
0.15
1.36
1.00
2.92
0.69
1.24
1.34
5.52
1.07
5.86
1.27
4.05
1.06
4.94
−0.18
0.00
2.51 (72)
0.96 (49)
5.37 (84)
1.06 (51)
1.01 (50)
1.76 (64)
>14.20 (93)
1.08 (52)
>12.01 (92)
1.23 (55)
8.22 (89)
1.06 (51)
>10.94 (92)
em
3
ce
−0.87
0.34
−0.77
0.11
−0.63
0.22
4
ve
5
em
0.27
0.19
−0.12
−0.17
−1.01
−0.04
−1.04
−0.14
−0.83
−0.03
−0.94
6
bte
−0.43
−0.22
−1.42
−0.02
−1.27
−0.02
−1.08
0.00
d
d
7
bte+
btm
btm+
btm
btm+
chtm
chtm+
>19
−
8
1.10
−0.06
d
d
9
>19
−
10
11
12
13
1.56
18.03
1.12
−0.26
−1.71
−0.07
d
d
>19
−
9.03
b
−1.30
a
c
1
Determined by integrating and averaging several (typically 3−4) H NMR signals. Standard deviations for Kcis/trans were ≤10%. ΔG = −RT ln
Kcis/trans. Values are given in kcal/mol. Trans-amide rotamers were not detected; ΔG not measurable.
d
CD3CN and MeOD (Kcis/trans = 3.04 and 1.90, respectively).
Steric effects undoubtedly play a critical role in this result, as
shown by a comparison with 2 (emKcis/trans = 1.31 in CD3CN
and 0.78 in MeOD), but we also suspected an n → π*CC
interaction between the acetamide carbonyl O and the alkyne
π* orbital. This was supported by a comparison of the Kcis/trans
values for alkyne ee (1) and alkene ve (4) side chains of
comparable steric bulk. The marked decrease in Kcis/trans for ee
relative to ve may be explained by the higher tendency of
alkynes to accept lone-pair electrons due to their lower LUMO
energies relative to alkenes. It was also supported by the
remarkable effect of the ce side chain in 3 containing the
electron-withdrawing nitrile group, which gave a high
proportion of cis-amide (89% in CD3CN, 79% in MeOD, and
75% in D2O). These values are in the same range as for the very
sterically hindered 1npe side chain, which recently allowed
Blackwell’s group to build homogeneous, robust PPI-type
helices.13
image near (−60°, −60°) (see the SI). The geometrical
requirements for n → π*Ar overlap22 (distance of 2.8−3.8 Å
between the carbonyl O atom and the ring centroid; dihedral
angle of ∼90° between the OCX2 and aromatic ring planes)
are respected in the lowest-energy conformations: the O−
centroid distance is 3.4 Å, and the dihedral angle is 87°.
The energy of this interaction was estimated as 1.11 kcal/mol
using second-order perturbation theory as implemented in
Natural Bond Orbital 5.9 (NBO 5.9); this value has the same
order of magnitude as those evaluated for carbonyl−carbonyl
interactions in proteins.23,24 Importantly, the conformationally
optimized model II (Figure 4) also revealed the presence of H-
To understand better the cis-directing effect of triazolium
side chains, the potential energy surface of peptoid model II
(Figure 3), with the acetamide in the cis conformation, was
determined at the B3LYP/6-31G+* level using systematic
variation of the torsion angles χ1 and χ2 by intervals of 20°. As
expected for an achiral molecule, the Ramachandran-type plots
for this peptoid model system show two centrosymmetric
minima: a deep one centered around (60°, 60°) and its mirror
Figure 4. Orbital overlaps stabilizing the preferred conformation of II:
(A) n → π*Ar delocalization; (B) H-bonding interaction (n → σ*).
bonding between the carbonyl O of the N,N-dimethylamide
and the triazolium proton (dC−H8···O4 = 2.17 Å; C4−O4−H8 =
152°). The dihedral angles (ϕ, ψ) = (117°, −175°), associated
with (χ1, χ2) = (−61°, −64°), roughly correspond to the known
cis αD conformation (ϕ and ψ clustered around 90° and 180°,
respectively).25 The slight deviation for ϕ (117° vs 90° on
average) may be due to a conformational adjustment arising
from the formation of the H-bond.
Experimentally, involvement of the triazolium proton in H-
bonding was strongly suggested by NMR downfield chemical
shifts of the triazolium proton (H8) and carbon (C8). For 7 in
CDCl3, δH8 = 10.18 ppm and δC8 = 131.4 ppm. These values
are shifted significantly downfield relative to standard values
reported in the literature for 1,2,3-triazolium motifs not
involved in H-bonding (typically δH = 9.10−9.80 and δC
=
127−129 ppm).26 Moreover, increasing the temperature did
not change δH8 in CDCl3 (see the SI). The correlations
observed in the 2D NOESY spectrum of 7 in CDCl3 were
consistent with the correct orientation of the triazolium moiety
to form the H-bond with the carbonyl of the piperidinylamide.
In this conformation (Figure 5), the geometrical criteria
Figure 3. Computational study of peptoid model II. (A) Definition of
the dihedral angles and labels of selected atoms. (B) Low-energy
conformation calculated at the B3LYP/6-31G+* level. The n → π*Ar
interaction is shown by the red arrow and the H-bond by the dotted
line; the associated distances are also shown. (C) Dihedral angles for
one of the two centrosymmetric lowest-energy conformations.
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ACKNOWLEDGMENTS
■
This work was supported by funding from the French Ministry
of Higher Education and Research (MESR). We are grateful to
L. Nauton and Dr. V. Thery for technical assistance and
contributive discussions about molecular modeling.
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= 8.57 ppm was observed, suggesting from the relevant
literature27 the absence of an intramolecular H-bond. Never-
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(acetamide) and triazolium ring to adopt the proper orientation
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effect would explain why the trans rotamers are completely
suppressed in CDCl3 regardless of the side-chain type (N-Cα-
branched or unsubstituted at N-Cα).
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chain containing a triazolium moiety capable of controlling the
amide isomerism in α- and β-peptoid model systems while
maintaining the potential for side-chain diversity. This type of
side chain should facilitate the understanding of how β-peptoids
fold. To our knowledge, the triazolium motif represents the
best cis-amide control conceived to date both in aprotic and
protic solvents. We have shown that its ability to promote the
cis-amide geometry is not steric in nature. The conformation
found in CDCl3 and CD3CN is consistent with an attractive
interaction arising from a backbone−side-chain n → π*Ar
electronic delocalization. These results are supported by DFT
and NBO analysis. It is obvious that other types of noncovalent
interactions (e.g., electrostatic dipole−dipole or charge−charge
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the nitrile group in stabilizing the cis-amide conformation in
peptoids. Work on syntheses and conformational studies of
peptoid oligomers with various sequence patterns of triazolium
side chains are underway.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and additional data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
Claude.taillefumier@univ-bpclermont.fr
(27) White, N. G.; Beer, P. D. Beilstein J. Org. Chem. 2012, 8, 246.
Notes
The authors declare no competing financial interest.
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