Strengthening Peptoid Helicity through Sequence Site-Specific Positioning of Amide cis-Inducing NtBu Monomers

Article abstract of DOI:10.1021/acs.joc.9b02916

The synthesis of biomimetic helical secondary structures is sought after for the construction of innovative nanomaterials and applications in medicinal chemistry such as the development of protein-protein interaction modulators. Peptoids, a sequence-defined family of oligomers, enable a peptidomimetic strategy, especially considering the easily accessible monomer diversity and peptoid helical folding propensity. However, cis-trans isomerization of the backbone tertiary amides may impair the peptoid's adoption of stable secondary structures, notably the all-cis polyproline I-like helical conformation. Here, we show that cis-inducing NtBu achiral monomers strategically positioned within chiral sequences may reinforce the degree of peptoid helicity, although with a reduced content of chiral side chains. The design principles presented here will undoubtedly help achieve more conformationally stable helical peptoids with desired functions.

Full text of DOI:10.1021/acs.joc.9b02916

Subscriber access provided by AUT Library
Article
Strengthening Peptoid Helicity through Sequence Site-
Specific Positioning of Amide Cis-Inducing NtBu monomers
Maha Rzeigui, Mounir Traikia, Laurent Jouffret, Alexandre
Kriznik, Jameleddine Khiari, Olivier Roy, and Claude Taillefumier
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02916 • Publication Date (Web): 24 Dec 2019
Downloaded from pubs.acs.org on December 28, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
“Strengthening Peptoid Helicity through Sequence Site-Specific
Positioning of Amide Cis-Inducing NtBu monomers”
7
8
9
Maha Rzeigui,a,d Mounir Traikia,a Laurent Jouffret,a Alexandre Kriznik,b,c
Jameleddine Khiari,d Olivier Roy,a and Claude Taillefumier*,a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aUniversité Clermont Auvergne, CNRS, SIGMA Clermont, ICCF, F-63000 Clermont-Ferrand,
France
bUniversité de Lorraine, CNRS, IMoPA, F-54000 Nancy, France
cUniversité de Lorraine, CNRS, Inserm, UMS2008 IBSLor, Biophysics and Structural Biology
core facility, F-54000 Nancy, France
dUniversité de Carthage, Faculté Des Sciences de Bizerte, Laboratoire de Chimie Organique et
Analytique, ISEFC, 2000, Bardo, Tunisie
corresponding author : claude.taillefumier@uca.fr
Keywords: Peptoids; Polyproline type I helix, Cis-trans isomerization; Peptidomimetics
ABSTRACT
The synthesis of biomimetic helical secondary structures is sought after for the construction of
innovative nanomaterials and applications in medicinal chemistry such as the development of
protein-protein interactions modulators. Peptoids, a sequence-defined family of oligomers,
enable a peptidomimetic strategy, especially considering the easily accessible monomer diversity
and peptoid helical folding propensity. However, cis-trans isomerization of the backbone tertiary
amides may impair the peptoid’s adoption of stable secondary structures, notably the all-cis
polyproline I-like helical conformation. Here we show that cis-inducing NtBu achiral monomers
strategically positioned within chiral sequences may reinforce the degree of peptoid helicity,
although a reduced content of chiral side chains. The design principles presented here will
undoubtedly help to achieve more conformationally stable helical peptoids with desired
functions.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 26
1
2
3
4
INTRODUCTION
5
6
7
8
N-substituted glycine oligomers, also called “peptoids” have emerged as a very attractive class of
synthetic amide-based oligomers. There are many reasons for this, ranging from their ease of
synthesis with unique side chain diversity1 to their conformational versatility which opens up a
wide range of potential applications relevant to biomaterial science23, therapeutics development,
45 and catalysis.7,8,9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Peptoids should be regarded as biotic foldamers since their backbone closely resembles that of
peptides with the side chains attached to the amide nitrogen atoms rather than the C carbons,
and also because single-chain peptoids may exhibit biopolymer-like conformational behaviours.
The iterative “submonomer” method10 used to synthesise peptoids generates sequence-defined
oligomers with protease-resistant tertiary amide bonds,11,12 a desirable property for developing
peptidomimetic ligands and biomimetic discrete secondary structures. Peptoids have been shown
to fold in a variety of secondary structures, some of which are reminiscent those of peptides, like
helices, sheets and turns,13,14,15,16,17,18,19 and others are singular like square helices and
ribbons.20,21,22 However, cis-trans isomerisation of the peptoid tertiary amide bonds (N,N-
disubstituted amides) is a source of conformational heterogeneity23,24 which may impair the
formation of well-defined secondary structures. A number of research groups have engineered
peptoid side chains that allow a local control of the dihedral angles through a set of backbone to
side chain and side chain to side chain weak non-covalent interactions.25,26,27,28,29,30,31 Two
peptoid helical conformations have been characterized; one of them has an overall shape
resembling the naturally-occurring polyproline II, an extended all-trans helix most frequently
occurring in proline-rich sequences. The other one resembles the all-cis polyproline I helix (PPI)
which is characterised by a three-fold periodicity and a helical pitch of approximate to 6
Angstrom. The latter has been observed for proline-rich sequences in hydrophobic solvents, like
n-PrOH.32 Zuckermann was the first to uncover the role of N chiral aromatic peptoid side
chains, typically (S)- or (R)-1-phenylethyl (spe/rpe) side chain, on the folding into the PPI-like
conformation.33 (S)-N-(1-phenylethyl)glycine monomers are, for example, commonly used to
induce right-handed helices.9,34,35 Sequence requirements and chain length effects were carefully
studied which established the rules for the formation and stabilisation of chiral PPI-type helical
secondary structures from aromatic-containing monomers.36,37,38 In contrast, the control of
peptoid helicity from non-aromatic monomers has been much less investigated.14,30 Recently we
started to explore new avenues for stabilizing PPI-like peptoid helices avoiding aromatic side
chains. Two novel aliphatic side chains were added to the peptoid “toolbox”, the bulky tert-butyl
ACS Paragon Plus Environment

Page 3 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
and tert-butylethyl side chains, the monomers of which have been termed NtBu and Ns1tbe (S
configuration) (Figure 1). The very bulky tert-butyl group is the only one known to lock peptoid
amide bonds in the cis conformation.29 X-ray crystal structures of NtBu oligomers showed their
PPI-like helix folding and calculations revealed that this conformation is stabilized through weak
non-covalent interactions, notably London interactions between tBu side chains located on the
same face of the helix.30 Nonetheless, the lack of NC stereogenic center means that the 
dihedral angles may adopt + and – values (around 85°, Figure 1a) which results in
conformational heterogeneity in solution. On the other hand, the chiral aliphatic tert-butylethyl
side chain is one of the best cis-peptoid amide inducer allowing the formation of discrete PPI
helices of defined handedness.16
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Interestingly, an increase of helicity was observed by CD spectroscopy for the mixed Ac-NtBu-
(Ns1tbe)4-NtBu-OtBu and Ac-(NtBu)2-(Ns1tbe)4-(NtBu)2-OtBu oligomers, compared to their
parent homo-oligomers composed solely of Ns1tbe residues. This observation was correlated to
an increase of cis-amide bonds population for the Ns1tbe monomers, suggesting that the two
types of monomers can act synergistically to achieve extremely robust helices of defined
handedness. Proof of this is the solid state structure of the octamer Ac-(NtBu)2-(Ns1tbe)4-
(NtBu)2-OtBu, the longest linear peptoid ever solved which revealed a right-handed helix of
great regularity despite only a 50% content of chiral monomers. These fascinating results
evoking a Sergeant-and-Soldiers behaviour39 encouraged us to pursue our investigations. Here
we address the questions of the amount and site-specific placement of achiral NtBu glycine
monomers within Ns1tbe sequences with respect to peptoid helicity. 2D NMR HSQCAD
experiments were used to determine the overall backbone amide Kcis/trans in deuterated
chloroform and acetonitrile and, CD spectroscopy to evaluate variation of peptoid helicity. Two
crystal structures are also reported with backbone dihedral angles corresponding to the PPI helix.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 26
1
2
3
4
a) Achiral NtBu monomer
H
H
H
H
5
6
7
8
Me
Me
Me
Me and O=C
O
N
tBu
tBu
N
staggered
O
O
N
O

=
176.5, - 64.5,
a
9
O
O
57.2°
a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
 = -
4.7
a
100% cis
 = - 85.1°
 ~  85°
a
 = -177.4°
b) Chiral Ns1tbe monomer
tBu
Me
tBu
Me
H
H
O
C-HO=C
eclipsed
O
O
O
N
N
b

=
- 104.4°
cis
trans
b
 = -
14.3
b
 = - 68.2°
b
 = -178.8°
Figure 1.Structure and conformational characteristics of the NtBu and Ns1tbe peptoid residues
a
used in this study (drawn in blue), see table 2 for the dihedral angles definition. Measured for
the central residue of the crystal structure of H-(NtBu)5-OBn.30 bMeasured for the central residue
of the crystal structure of Ac-(Ns1tbe)5-OtBu16. The 1 angles have been measured for each tBu
NC methyl carbon in case of the representative NtBu monomer; the tBu NC has been used for
measuring the 1 angle (-104.4) in case of the representative Ns1tbe monomer.
ACS Paragon Plus Environment

Page 5 of 26
The Journal of Organic Chemistry
1
2
3
4
RESULTS AND DISCUSSION
5
6
7
8
Design and synthesis of peptoid oligomers 1-16. Recently, we have proposed two efficient
structure-inducing peptoid side chains avoiding aromatic groups: the tert-butyl (tBu) and (S)-1-
tert-butylethyl (s1tbe) side chains. The following two mixed peptoids Ac-NtBu-(Ns1tbe)4-NtBu-
OtBu (A) and Ac-(NtBu)2-(Ns1tbe)4-(NtBu)2-OtBu (B) of 6 and 8 residues in length have
revealed a remarkable level of helicity.16 In the initial design, the NtBu monomers were
positioned at the N- and C-termini of the peptoid chains, and the amount of chiral side chain was
66% for the hexamer and 50% for the octamer. The above results pose several questions: (1)
Should the all-cis inducing NtBu monomers be necessarily positioned at the extremities of the
oligomers to enhance conformational homogeneity ? (2) Is a single NtBu monomer capable of
exerting such control over the conformation, and, if so, at which position should it be placed in
the sequence? (3) Considering the initial design with the achiral monomers at the oligomer’s end,
to what extent the length of the chiral central Ns1tbe-based segment can be shortened?
Conversely how many consecutive NtBu residues can be placed at the extremities without
affecting chiral induction from the center to both ends of the oligomers. Peptoid helix folding is a
chain length-dependent process.37 For example, an increase of ellipticity was observed for Nrpe
oligomers between 4 and 12 residues in length, suggesting that the helix with cis-amide bonds
becomes the most favored conformation, only when the oligomer length of 11-13 residues is
reached. Designing medium-size peptoids displaying a strong conformational stability is still
challenging. For this reason and also because of the remarkable level of helicity of hexamer A,
we chose to synthesize a first family of peptoid hexamers (1-6) enabling us to answer points (1)
and (2) (Table 1). Peptoids 7-11 were designed to evaluate how the length of the chiral and
achiral segments impact helicity (question 3 above) and peptoids 12-16 were prepared in order to
evaluate oligomers composed of the same repeated (NtBu-Ns1tbe-Ns1tbe) pattern, thus placing
the tBu side chains on the same face of the helical structure. This design is of particular
importance since “functional versions” of the tert-butyl side chain of structure NC(CH3)2CH2R
have been proposed. They allow mimicking amino acid side chains while retaining the
conformational properties of the parent tBu group.40
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In view of the difficulties experienced by our group for the solid-phase synthesis of NtBu-based
oligomers, solution-phase synthesis was preferred in this study.41 Thus, peptoids 1-16 were
synthesized via a solution-phase submonomer method (SI, Figure S1). All final compounds were
isolated with purity greater than 95%, as determined by integration of peaks with UV detection
at 214 nm, after purification by flash silica gel column chromatography or preparative RP-HPLC
(see ESI for HPLC data). They were characterized by MS to confirm their identity (Table 1).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 26
1
2
3
4
5
6
7
Peptoids 1-16 were further analyzed by NMR experiments (1H, 13C, COSY, HSQC, HMBC and
HSQCAD, see SI for NMR data) and two crystal structures were also obtained for peptoids 12
and 14.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Sequence of the Peptoid Synthesized, Purity and Mass Spectra Data for Peptoids
1-16
%
expected
mass
Peptoid la
monomer sequence
observed mass
purityb
1
2
3
4
5
6
7
8
9
6
6
6
6
6
6
6
6
6
Ac-Ns1tbe-Ns1tbe-Ns1tbe-Ns1tbe-Ns1tbe-NtBu-OtBu
Ac-Ns1tbe-Ns1tbe-Ns1tbe-Ns1tbe-NtBu-Ns1tbe-OtBu
Ac-Ns1tbe-Ns1tbe-Ns1tbe-NtBu-Ns1tbe-Ns1tbe-OtBu
Ac-Ns1tbe-Ns1tbe-NtBu-Ns1tbe-Ns1tbe-Ns1tbe-OtBu
Ac-Ns1tbe-NtBu-Ns1tbe-Ns1tbe-Ns1tbe-Ns1tbe-OtBu
Ac-NtBu-Ns1tbe-Ns1tbe-Ns1tbe-Ns1tbe-Ns1tbe-OtBu
Ac-NtBu-Ns1tbe-NtBu-Ns1tbe-NtBu-Ns1tbe-OBn
Ac-NtBu-Ns1tbe-NtBu-Ns1tbe-NtBu-Ns1tbe-OH
Ac-NtBu-NtBu-Ns1tbe-Ns1tbe-NtBu-NtBu-OtBu
96%
>95%
97%
96%
98%
98%
98%
96%
>99%
934.74
934.74
934.74
934.74
934.74
934.74
912.66
822.62
850.65
935.75 [M+H]+
935.75 [M+H]+
935.75 [M+H]+
935.74 [M+H]+
957.73 [M+Na]+
935.75 [M+H]+
913.67 [M+H]+
823.62 [M+H]+
851.65 [M+H]+
1014.75
10
11
7
9
Ac-NtBu-NtBu-Ns1tbe-Ns1tbe-Ns1tbe-NtBu-NtBu-OtBu
>97%
95%
991.77
[M+Na]+
Ac-NtBu-NtBu-NtBu-Ns1tbe-Ns1tbe-Ns1tbe-NtBu-NtBu-NtBu-
OtBu
1217.93
1218.93 [M+H]+
12
13
14
15
3
4
5
6
Ac-NtBu-Ns1tbe-Ns1tbe -OtBu
Ac-Ns1tbe-NtBu-Ns1tbe-Ns1tbe-OtBu
>99%
99%
511.40
652.51
793.63
906.71
512.40 [M+H]+
653.52 [M+H]+
794.63 [M+H]+
907.72 [M+H]+
Ac-Ns1tbe-Ns1tbe-NtBu-Ns1tbe-Ns1tbe -OtBu
Ac-NtBu-Ns1tbe-Ns1tbe-NtBu-Ns1tbe-Ns1tbe-OtBu
98%
>98%
Ac-NtBu-Ns1tbe-Ns1tbe-NtBu-Ns1tbe-Ns1tbe-NtBu-Ns1tbe-
Ns1tbe-OtBu
16
9
>99%
1302.03
1303.03 [M+H]+
aNumber of residues
bDetermined by integration of the HPLC UV trace at 214 nm.
X-ray Studies for Peptoids 12 and 14.
Crystals of trimer 12 and pentamer 14 suitable for X-ray crystallography were obtained by slow
evaporation in ethyl acetate (Figure 2) and crystals of 12 were solved in the P1 space group and
crystals of 14 were solved in the P212121 space group. The high resolution structures of trimer 12
and pentamer 14 complement the previously reported X-ray structures for NtBu (dimer, trimer
and pentamer) and Ns1tbe (pentamer) homo-oligomers, and mixed NtBu/Ns1tbe (compound B,
Table 3) oligomers.16,29,30 The dihedral angles for 12 and 14 are characteristic of the PPI-helical
fold, primarily the ω values which are indicative of all-cis patterns. Some of the amide bonds
display a significant distortion from planarity, especially the amide bond between residues 3 and
4 of 14 (ω = -24.7). The discrepancy between the φ values of the NtBu ( -90) and Ns1tbe
ACS Paragon Plus Environment

Page 7 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
monomers ( -70) has already been noted (see Figure 1).16 The φ torsion angle at the C-terminus
of 14 is positive (+80.7), the opposite of what is expected from the S configuration. This may
due to packing considerations together with the greater flexibility of the C-termini of peptoid
chains. The difference of side-chains 1 dihedral angles between the two types of monomers, has
also been noted earlier (see Figure 1).16
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
b
a
Figure 2. High resolution structures of peptoid trimer 12 (a) and pentamer 14 (b) as determined
by X-ray crystallography.
Table 2. Observed torsion angles for peptoids 12 and 14 as determined by X-ray
crystallography
Peptoid
12
residue
NtBu


1

11.6
-2.1
-92.7
-67.1
-69.1
-69.5
-71.7
-88.5
-71.2
80.7
-165.6
174.2
-
-81.0
Ns1tbe
Ns1tbe
Ns1tbe
Ns1tbe
NtBu
-101.0
-98.3
NC
NC
C(i-1)
O
H
C
-5.3
1
N
C(CH3)3
CH3
14
-15.6
-11.3
-13.0
-24.7
-3.02
-178.9
173.4
-178.2
-161.7
-
-100.4
-100.0
-60.6


O

C
Ns1tbe
Ns1tbe
-105.1
-102.8
Dihedral angles definition: ω [Cα(i−1); C(i−1); N; Cα], φ [C(i−1); N; Cα; C], ψ [N; Cα;C;N(i+1)], 1 [C(i−1); N;
NC; NC]
Overall backbone amide Kcis/trans values. Conformational control of a peptoid chain rests first
on the individual control of its amide bonds geometry, i.e. cis or trans. The PPI-like
conformation involves a continuous succession of cis-amide bonds. It has been established that
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 26
1
2
3
4
5
6
7
8
9
NtBu monomers do form cis-amide bonds with their preceding residue, independently of the
oligomer length. We therefore focussed on the cis/trans isomerization of the Ns1tbe residues
with their preceding units. For that purpose, we have looked at the NC methyne protons of the
Nstbe residues, which display separate NMR chemical shifts in the cis and trans conformations
(determined previously by COSY and NOESY NMR experiments).16 The methyne proton of the
Ns1tbe is deshielded by approximately 1.0 ppm in the cis conformation ( 4.6 ppm) relative to
the trans ( 3.6 ppm), in accordance with reported data on both aromatic and aliphatic side-
chains.15,26,28,42 The overall Kcis/trans values were determined in deuterated chloroform,
acetonitrile, and methanol (for some representative compounds), by integration of the cis and
trans methyne proton-carbon correlations of 2D-NMR HSQCAD experiments (Table 3). From
this first series of values corresponding to the overall Kcis/trans for the amide bonds between the
Ns1tbe residues and their preceding residues, a second series of Kcis/trans values was calculated by
including the NtBu-based amide linkages. For each sequence, the weighted average Kcis/trans were
estimated taking a Kcis/trans of 32 for the NtBu monomers (97% of cis).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 9 of 26
The Journal of Organic Chemistry
1
2
3
4
Table 3. Peptoid Structure and Overall Kcis/trans Values as determined by integration of
5
6
HSQCAD NMR spectra in CDCl3 and CD3CN
weighted average of
weighted average of Kcis/trans
7
8
9
% chiral
side
chains
Kcis/trans
(Ns1tbe residues)c
Monomer
sequenceb
peptoid
la
(all residues)d
CDCl3
CD3CN
CD3OD
> 49.0e
CDCl3
CD3CN
CD3OD
> 49.0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2
6
6
6
6
6
6
6
6
6
8
6
7
9
3
4
5
6
9
83
83
83
83
83
83
50
50
66
50
33
43
33
66
75
80
66
66
c-c-c-c-c-a
> 49.0e
11.9
11.2
16.2
11.0
18.0
2.0
> 49.0e
7.7
> 49
> 15.2
> 14.6
> 18.8
> 14.5
> 20.3
> 17.0
-
> 49
> 11.7
> 10.2
> 10.5
> 11.8
> 13.4
> 16.8
-
c-c-c-c-a-c
c-c-c-a-c-c
c-c-a-c-c-c
c-a-c-c-c-c
a-c-c-c-c-c
a-c-a-c-a-c
a-c-a-c-a-c
a-c-c-c-c-a
a-a-c-c-c-c-a-a
a-a-c-c-a-a
a-a-c-c-c-a-a
a-a-a-c-c-c-a-a-a
a-c-c
3
5.9
4
6.3
5
7.8
6
9.7
29.5
33.3
32.7
43.7
7
1.7
8
-
-
A16
B16
9
> 19.0
> 19.0
23.5
> 49.0e
> 49.0e
2.4
> 19.0
> 19.0
19.5
32.8
> 49.0
-
> 23.3
> 25.5
> 29.1
> 49
> 23.3
> 25.5
> 27.8
> 42.0
> 49.0
-
10
11
12
13
14
15
16
> 49.0
> 12.2
> 9.5
c-a-c-c
2.0
-
-
c-c-a-c-c
3.6
7.7
> 9.3
> 12.5
> 15.2
> 20.6
a-c-c-a-c-c
a-c-c-a-c-c-a-c-c
12.3
4.2
6.8
19.6
15.9
> 18.8
> 13.4
29.4
26.9
15.0
aNumber of residues
bThe achiral NtBu monomers are represented by the letter “a” and the chiral Ns1tbe by “c”
cDetermined for the amide bonds between Ns1tbe residues and their preceding residues
dDetermined for all the residues, considering that the NtBu monomers form exclusively cis-amide bonds with their
preceding (i-1) residues. Calculation was made with Kcis/trans = 32 for the NtBu monomers (97% of cis)
eTrans rotamers were not detected.
Acetonitrile has been commonly used in structural studies of peptoids, notably those with -
chiral aromatic side chains which were found to adopt the all-cis PPI helix conformation.
Acetonitrile is recognized to minimize interamide n→*C=O interactions within peptoid, thereby
destabilizing the trans amide conformation.26 Furthermore, determination of the cis/trans ratio of
the N-terminal acetamide of diamide peptoid model systems, expected to reproduce the behavior
of larger peptoid oligomers, indicates that the fraction of cis isomer is generally higher in
acetonitrile than in methanol or chloroform, at least for uncharged side chains.26 This trend is not
verified for the peptoids 1-16 (Table 3). Indeed, with the exception of peptoids 14 and 16, the
fraction of cis isomer is higher in non-polar CDCl3 than in CD3CN, and is even higher in d4-
methanol, as seen from the CD ODKcis/trans determined for the representative compounds 1, 6, 9, 15
3
and 16 for which the trans rotamers are completely or largely suppressed. Also of note from the
comparison of the overall Kcis/trans for compounds 1-6 is that the positioning of a single cis-
enforcing NtBu monomer at the carboxy terminus proves exceptionally efficient to suppress the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 26
1
2
3
4
5
6
7
8
9
trans-amide rotamers. This is consistent with the finding that the carboxy terminus of the PPI
peptoid helix is structurally less stable than the amino terminus.36 Although the cis/trans
isomerization of the backbone tertiary amides is totally suppressed in the case of peptoid 1, its 1H
NMR spectrum (CDCl3) showed a very small amount of residual conformational heterogeneity,
evidenced for example on the CO2tBu resonance, which is no longer present in d4-methanol.
There is also evidence that the peptoids containing a central chiral segment of 2 to 4 Ns1tbe
consecutive residues, surrounded by NtBu residues display the higher overall Kcis/trans (A, B, 9-
11). In contrast, the incorporation of NtBu monomers every two Ns1tbe residues (12-16) does
not ensure the complete suppression of the peptoid amide cis-trans rotameric isomerism.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Circular dichroism of hexamers 1-6. The CD spectra of oligomers 1-6 are shown in Figure 3.
All the CD curves are well-defined and display the spectral features that are typically associated
to the polyproline type I helix of peptoids substituted with aliphatic side-chains, i.e., two minima
at 190 nm and 225 nm, and a positive maximum around 210 nm.14 In acetonitrile, compound 1
with the NtBu monomer positioned at the C-terminus displays the more intense ellipticity on a
per-residue molar basis (MRE = 11 741 at 208 nm, Figure 3a and Figure S2), at a high level
comparable to that of the nonamer Ac-(Ns1tbe)9-OtBu (MRE = 12 673, 210 nm).16 By contrast,
hexamers 5 and 6 with the NtBu residues located at the 2nd and first position of the sequence
(from N to C), display lower ellipticities (MRE = 4324 for 6 at 208 nm), of the same order of
magnitude as that of the homo-pentamer Ac-(Ns1tbe)5-OtBu (MRE = 4967 at 208 nm).16
Compounds 2, 3 and 4, form a homogeneous group whose ellipticity at 208 nm (in the range
6100-6900) is intermediate those of compound 1 and 5/6. On the whole, there appears to be a
trend toward ellipticity decreasing with increasing remoteness of the NtBu monomer from the
carboxy terminus. This was further verified in MeOH, in which the spectral intensity at 208 nm
consistently decreases when the NtBu unit moves away from the carboxy terminus (Figure 3b
and 4). The strongest CD intensity of hexamer 1 within the group of peptoids 1-6 is consistent
with an all cis-amide backbone (Kcis/trans > 49 in deuterated chloroform, acetonitrile and
CD3CN
methanol, Table 3). The
K
values between 10.2 and 13.4 for hexamers 2-6 are
cis/trans
indicative of a remaining backbone amide conformational heterogeneity (trans rotamers
populated at 7-9%), comparable to that of the peptoid hexamer Ac-(Ns1tbe)6-OtBu (CD CNKcis/trans
3
= 10.4).16 An increase of ellipticity (compound 2) and a decrease (compound 6) are observed by
switching the solvent from acetonitrile to methanol, but more generally, this first series of
peptoids is not much affected by solvent polarity, which is consistent with the fact that the
conformation is primarily governed by steric interactions.15This is in contrast with the CD
ACS Paragon Plus Environment

Page 11 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
spectra of the Ns1tbe homooligomers which were decreased in methanol relative to those in
acetonitrile.16 This suggests that the presence of a single bulky NtBu residue within the peptoid
sequence may already have a positive effect on the conformational stability.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
b
Figure 3. CD spectra of hexamers 1-6 and reference compound Ac-(Ns1tbe)6 in acetonitrile (a) and methanol (b).
12,352.1
14
9,973.5
7,784.9
12
10
8
6,578.0
5,785.2
4,060.0
2,547.8
6
4
2
0
compounds
Figure 4. MRE values of hexamers 1-6 and reference compound Ac-(Ns1tbe)6 at 208 nm in MeOH
Of note, is the significant difference between the intensity of the negative band at 190 nm
between the homo-oligomer Ac-(Ns1tbe)6-OtBu and the hexamers 1-6. For hexamers 1-6, the
negative band at 190 nm also tends to increase with the decrease of the positive band at 210 nm.
Interestingly, the CD curves of hexamers 1 (c-c-c-c-c-a) and A (a-c-c-c-c-a) in acetonitrile and
methanol are virtually superposable (Figure 5), which in the light of the previous results, show
that within this group of peptoids, a single NtBu monomer strategically positioned at the C-
terminus is sufficient to achieve a robust helical structure. Also of note is that, once a first NtBu
is positioned at the C-terminus, a second mutation of a chiral Ns1tbe monomer by a NtBu at the
N-terminus is not detrimental to peptoid helicity, albeit a decrease of the amount of chiral side-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 26
1
2
3
4
5
6
7
8
9
chains from 83% (1) to 66% (A). “Ends effects” have been observed previously in the study of
peptoids and retropeptoids composed of aromatic chiral and achiral monomers.36 It has been
shown, for example, that placing a bulky chiral Nrpe monomer on the carboxy terminus rather
than on the amino terminus dramatically increased CD intensity.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
b
Figure 5. CD spectra of hexamers 1 and A in acetonitrile (a) and methanol (b).
Circular dichroism of hexamers 7-11.
The CD spectra of the alternated (NtBu-Ns1tbe)3 hexamer 7 and its corresponding free carboxy
acid 8 are shown in figures S3-S5. The hexamer 7 is better structured in methanol than in
acetonitrile with a MRE value at 208 nm in methanol nearly twice that in acetonitrile. The CD
spectrum of 7 in MeOH is close to those of hexamers A and 15 in shape and intensity (Figure
S4). In contrast, a significant decrease of helical fold was observed for the free acid hexamer 8,
notably in acetonitrile and acetonitrile/aqueous buffer solutions, as compared to the ellipticity in
methanol (Figure S5).
All three compounds 9-11 are characterized by a central chiral portion (2 or 3 Ns1tbe residues),
flanked on both ends by achiral segments of same length (2 or 3 NtBu residues). Their CD
curves were compared to those of the reference compounds A and B (Figure 6). The CD curves
of peptoids 9-11 in acetonitrile show a profile similar to those of compounds A and B, albeit
with reduced intensities of the maxima. The positive band of peptoids 9 and 11 (211 nm) is blue
shifted by 3 nm relative to that of peptoid A (208 nm), which seems to be in line with their
smaller chiral content. (33% for 9 and 11 vs 66% for A, Tables 2). The decline in the ellipticity
of peptoids 9-11 relative to A in acetonitrile, as estimated in the region of the spectra at around
210 nm, is more pronounced for the nonamer 11 (- 43%), than for the heptamer 10 (- 31%) and
the hexamer 9 (- 26%). We find that in methanol; more intense CD spectra are obtained,
ACS Paragon Plus Environment

Page 13 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
indicating a more robust helical fold. The oligomers 9 and 11 display the strongest intensities
(MRE209 nm > 12 000), after the octamer B (MRE209 nm = 15 000). It is premature to establish a
relationship between the monomer composition of this sub-family of peptoids (9-11, A and B)
and their conformational properties, but some notable observations can be made. In both
solvents, the intensity of the negative band at 190 nm increases with the increase of proportion of
s1tbe chiral side-chains (SI, Table S2), suggesting a contribution from coupling interactions
between the s1tbe side chains and backbone groups. Also, the per-residue molar ellipticity of
peptoid 9 (a-a-c-c-a-a) is remarkable, considering its short length and low percentage of chiral
side chains (33%). The MRE intensity of peptoid 9 at 208 nm is at the same level as that of
hexamer 1, which has 83% of chiral side-chains (SI, Figure S6). In addition, the CD spectrum of
hexamer 9 in methanol has comparable shape and intensity to that of the nonamer 11 (a-a-a-c-c-
c-a-a-a), also composed of only 33% of chiral residues. This is the first time that peptoids
composed of just one-third -chiral side chains give a stronger CD signal than their parent
peptoid comprising only chiral side chains.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The few compounds studied here owning the generic sequence (a)x(c)y(a)x with (a) and (c)
corresponding to the achiral NtBu and chiral Ns1tbe monomers, respectively, show that this
design principle is advantageous to achieve a stable helical folding with a low content of chiral
side chains. The central segment in the oligomers studied is able to transfer its chirality with
great efficacy to both ends of the oligomers.
a
b
Figure 6. CD spectra of peptoids 9-11, A and B in acetonitrile (a) and methanol (b).
Circular dichroism of peptoids 12-16.
Characterization of peptoids 12-16 by CD shows that the minimum chain length to obtain the
characteristic helix-like profile is the pentamer length (14) (Figure 7). Indeed, trimers 12 and
tetramers 13 show no helical structure by CD (Figure 7 and 8). The CD spectra of pentamer 14
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 26
1
2
3
4
5
6
7
8
9
and hexamer 15 show that the signal intensity increases with increasing the length by one
residue. In contrast, comparison of spectra for hexamer 15 (a-c-c)2 and nonamer 16 (a-c-c)3 in
acetonitrile and methanol shows that the intensity at ≈ 210 nm does not increase with the
oligomer length. The positive band of 16 is even slightly diminished (and red-shifted by 3 nm)
relative to 15 (Figure 7), despite the fact that the overall backbone amide cis:trans ratio is higher
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
for 16 (CD CNKcis/trans = 20.6) than for 15 (CD CNKcis/trans = 15.2). These observations suggest that
the (a-c-c)n sequence design does not allow for an optimal propagation of the chiral secondary
structure.
3
3
b
a
Figure 7. CD spectra of peptoids 12, 15 and 16 corresponding to (a-c-c)n (n = 1, 2, 3), in acetonitrile (a) and
methanol (b).
b
a
Figure 8. CD spectra of peptoids 13 (c-a-c-c), 14 (c-c-a-c-c) and 15 (a-c-c-a-c-c), in acetonitrile (a) and methanol
(b).
Temperature study of compound 16
Previously, we demonstrated the thermal conformational stability of the PPI-like helix of the
homo-nonamer Ac-(Ns1tbe)9-OtBu.16 In contrast, the degree of helical fold significantly
decreased upon heating the solution of the nonamer 16, AcO-(NtBu-Ns1tbe-Ns1tbe)3-OtBu, in
ACS Paragon Plus Environment

Page 15 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
acetonitrile from 15 to 75 °C, demonstrating the lesser thermal stability of Ns1tbe-based peptoid
sequences incorporating NtBu monomers at every two residues (SI, Figure S7). Nevertheless,
when the sample was cooled back to 15 °C, reversibility took place, giving back a CD spectrum
of same shape and intensity than at start (SI, Figure S8). The helical folding sensitivity of the
nonamer 16 to an increase of temperature was also examined by NMR by measuring the average
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Kcis/trans for the Ns1tbe units within the peptoid backbone at various temperatures (CD3CN, 15-75
AVG
°C) (Table S3). We observed a gradually decrease in
K
with increasing the temperature,
cis/trans
going from a value of 18.3 at 15 °C (95% of cis rotamer) to 2.1 at 75 °C (68% of cis rotamer).
We therefore confirm that the decrease of helical folding upon elevating the temperature can be
essentially ascribed to the increase of cis/trans rotameric heterogeneity.
In summary, we investigated the effect of site-specific placement of NtBu cis-inducer monomer
on the helical secondary structure of Ns1tbe-based sequences. The synthesized oligomers 1-16
comprising exclusively aliphatic side-chains, chain lengths between 3 and 9 residues, of which
ten are hexamers, and percentages of chiral monomers ranging from 33 to 83% were analyzed by
NMR, CD spectroscopy and X-ray diffraction for two of them. The degree of helical fold was
estimated by CD at around 210 nm which corresponds to the more relevant signal for the PPI-
like helix of peptoids carrying aliphatic side-chains. Switching the solvent from acetonitrile to
methanol increased the fraction of cis isomer as seen from the NMR of the representative
peptoids 1, 6, 9, 15 and 16. This observation is commensurate with the CD spectra of the
peptoids in methanol which are either identical or greater in intensity as compared to those
observed in acetonitrile. At this time no correlation can be found between the intensity of the
negative band at 190 nm and the monomer composition of the peptoids. It is noteworthy that the
CD spectrum of the short length tetramer 13 only displays this negative band around 190 nm. A
single mutation of each of the six Ns1tbe residues of homo-oligomer (Ns1tbe)6 to NtBu residue
(hexamers 1-6) was used to probe the influence of the positioning of a single achiral tBu side
chain on the helical structure. We show that a single NtBu monomer at the carboxy terminus
enables to completely suppress the backbone trans-amide rotamers and consequently reinforce
the helical fold of peptoid hexamers. This finding is consistent with the fact that the carboxy
terminus of the peptoid helix is recognized to be less structurally stable than the amino
terminus.36 We anticipate that this favorable C-terminal stabilizing “end effect” might also
operate in longer peptoids, including oligomers carrying aromatic side chains. Of the ten
hexamer sequences studied, peptoid 9 consisting of two central Ns1tbe residues flanked at both
ends by two NtBu residues revealed a remarkable helical folding, especially in methanol, in view
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 26
1
2
3
4
5
6
7
8
9
of its rather short length and low content of chiral sides chains (33%). Overall, the sequence
design consisting of a central chiral segment flanked by achiral parts (9-11) permits an efficient
helical chirality transfer to the peptoid extremities. In contrast, the incorporation of NtBu
monomers every two residues, thus forming an achiral helix face, results in a slight decrease of
helicity. Our finding will be useful to reinforce the stability of organosoluble peptoid helices
aimed at interacting with a biological hydrophobic environment such as phospholipidic
membranes. Work is now in progress to extend the scope of our finding to peptoids
incorporating chiral aromatic monomers, hydrosoluble monomers and functional monomers.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
General methods. THF, CH2Cl2 were dried over aluminum oxide via a solvent purification
system. EtOAc, CH2Cl2, cyclohexane, and MeOH for column chromatography were obtained
from commercial sources and were used as received. All other solvents and chemicals obtained
from commercial sources were used as received. Melting points were determined on a Stuart
Scientific SMP3 microscope apparatus and are uncorrected. NMR spectra were recorded on a
400 MHz Bruker Avance III HD spectrometer or a 500 MHz Bruker AC-500 spectrometer.
Chemical shifts are referenced to the residual solvent peak and J values are given in hertz. The
following multiplicity abbreviations are used: (s) singlet, (ls) large singlet, (d) doublet, (t) triplet,
(q) quartet, (m) massif, and (br) broad. Where applicable, assignments were based on COSY,
HMBC, HSQC, and 13Cexperiments. TLC was performed on Merck TLC aluminum sheets,
silicagel 60, F254. Progression of reactions was, when applicable, followed by TLC. Visualizing
of spots was effected with UV-light and/or vanillin in EtOH/H2SO4. Flash chromatography was
performed with Merck silica gel 60, 40−63 μm. HRMS was recorded on a Micromass Q-Tof
Micro (3000 V) apparatus or a Q Exactive Quadrupole-Orbitrap Mass Spectrometer. LC−MS
was recorded a Q Exactive Quadrupole-Orbitrap mass spectrometer coupled to a UPLC Ultimate
3000 (Kinetex EVO C18; 1.7 μm; 100 mm × 2.1 mm column with a flow rate of 0.45 mL min−1
with the following gradient: a linear gradient of solvent B from 5% to 95% over 7.5 min (solvent
A = H2O + 0.1% formic acid, solvent B = acetonitrile + 0.1% formic acid) equipped with a DAD
UV/vis 3000 RS detector. HPLC analysis was performed on a Dionex instrument equipped with
an Uptisphere (ODB, 5 μm, 120 Å, 4.6 × 250 mm) and a Dionex UVD 340 detector. X-ray data
were collected at 100 K with an Oxford Diffraction Xcalibur 2 diffractometer equipped with a
copper microsource (λ = 1.5418 Å).
NMR experiments. A Bruker Avance III HD 500 spectrometer operating at 500.13 MHz for 1H
and 125.77 MHz for 13C with a 5 mm pulsed-field z-gradient TXI probe was used. For each
ACS Paragon Plus Environment

Page 17 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
sample, the probe was carefully tuned, and all normal and adiabatic pulses were well calibrated.
1
For each 2D heteronuclear H/13C HSQCAD (Bruker sequence: hsqcedetgpsisp2.3) experiments
were performed with quadrature phase detection in dimensions, using Echo-Antiecho detection
mode in the indirect one. For each 768 increments in the indirect dimension, 2K data points were
13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
collected and 8 transients were accumulated in the direct dimension. Adiabatic C decoupling
(Bruker sequence : bi_p5m4sp_4sp.2) was performed during acquisition. The spectral widths
(SW) were fixed to 8 ppm for 1H and to 165 ppm for 13C. A π/2 shifted square sine-bell function
was applied in the two dimensions before Fourier transformation. Spectra were acquired and
treated with Bruker Topspin version 3.5pl5 and referenced to solvent. All NMR spectra were
recorded at 298K.
Circular Dichroism Spectroscopy in the far-UV range. Peptoid stock solutions were prepared
by dissolving at least 2 mg of each peptoid, weighed using a high-precision balance (Sartorius),
in spectroscopic grade acetonitrile or methanol. The stock solutions then were diluted with
spectroscopic grade solvent to the concentration of 500 μM. CD experiments were carried out in
a Chirascan-plus spectropolarimeter equipped with a Peltier system (Applied Photophysics Ltd,
Surrey, UK). CD spectra were obtained in a flat quartz cell (path length 0.01 cm) at 293°K using
a scan rate of 0.5 nm/sec, in the far-UV range (180 to 260 nm) and are the average of three
successive measurements. The spectrum of a solvent blank was subtracted from the raw CD data,
and the resulting data were expressed in terms of per-amide molar ellipticity (deg.cm2.dmol-1), as
calculated per mole of amide groups present and normalized by the molar concentration of
peptoid.
General procedure for the solution-phase synthesis of peptoids 1-16 by the submonomer
protocol. tert-Butyl bromoacetate was used as starting material for all synthesized compounds
with the exception of the synthesis of hexamers 7 and 8 for which benzyl bromoacetate was
used. The commercially available primary amines tert-butylamine or the (2S)-3,3-dimethylbutan-
2-amine (s1tbe amine) were employed for the substitution steps. The bromoacetamide
compounds were purified by flash silica gel chromatography prior to their reaction with the
submonomer primary amine building blocks
General procedure A: Submonomer bromine atom substitution with primary amines. To a
solution of tert-butyl bromoacetate (or benzyl bromoacetate for the synthesis of peptoid 7) or
crude bromoacetyl amide (1.0 equiv, 0.2 M) in EtOAc or THF at rt was added Et3N (2.0 equiv.)
followed by the chosen primary amine (4.0 equiv.). After stirring overnight at room temperature,
the resulting mixture was diluted with EtOAc (10mL per mmol of starting material) and filtered,
washing the solids with EtOAc. The filtrate was then concentrated under reduced pressure.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 26
1
2
3
4
5
6
EtOAc was added to the residue which was then concentrated under reduced pressure. This was
repeated twice and the residue was dried in vacuo, yielding the desired crude secondary amine
which was used in the next step without further purification.
7
8
9
General procedure B: Submonomer bromoacetylation. To a solution of the crude secondary
amine (1.0 equiv, 0.2 M) in dry THF (or EtOAc) at -10°C under argon was added Et3N (1.2
equiv.) and then bromoacetyl bromide (1.05 equiv.). After stirring for 1 h at -10°C the resulting
mixture was diluted with EtOAc (10 mL per mmol of starting material) and the salts were
filtered, washing the solid with EtOAc. The filtrate was then concentrated in vacuo, yielding the
crude bromoacetyl amide which was purified by flash column chromatography on silica gel.
General procedure C: terminal N-acetylation. To a solution of a peptoid (1 equiv.) and Et3N
(1.4 equiv.) in dry EtOAc (0.2 M) at 0°C under Ar, was added dropwise AcCl (1.2 equiv.) and
the reaction mixture was stirred overnight at room temperature. The mixture was filtered, and the
solids washed with EtOAc. The filtrate was then concentrated in vacuo, yielding the crude N-
terminal acetylated compound which was purified by flash column chromatography on silica gel
Peptoid hexamer 1 (Ac-Ns1tbe-Ns1tbe-Ns1tbe-Ns1tbe-Ns1tbe-NtBu-OtBu). The peptoid
1 was synthesized in 12 steps from tert-butyl bromoacetate (390 mg, 2.0 mmol) according to
procedures A and B for the submonomer elongation steps and procedure C for the final N-
terminal acetylation. Peptoid 1 was isolated as a white solid after purification by flash column
chromatography on silica gel. (89 mg, 0.095 mmol); Rf = 0.54 (100% EtOAc). m.p. 227.5-228.5
°C HRMS (TOF MS ES+) m/z calcd for C52H99N6O8 [M+H]+ 935.7518; found 935.7525.
Analytical HPLC purity 96%.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H NMR (400 MHz, CDCl3)  (ppm): 0.82-1.06 (m, 60H, CH(CH3)C(CH3)3), 1.42 (s, 9H,
NtBu), 1.52 (s, 9H, CO2tBu), 2.09 (s, 3H, COCH3) 3.68-4.26 (m, 12H, NCH2CO), 4.62-4.79 (m,
5H, H methyne cis rotamer).
Peptoid hexamer 2 (Ac-Ns1tbe-Ns1tbe-Ns1tbe-Ns1tbe-NtBu-Ns1tbe-OtBu). The peptoid
2 was synthesized in 12 steps from tert-butyl bromoacetate (390 mg, 2.0 mmol) according to
procedures A and B for the submonomer elongation steps and procedure C for the final N-
terminal acetylation. Peptoid 2 was isolated as a white solid after purification by flash column
chromatography on silica gel. (350 mg, 0.374 mmol); Rf = 0.64 (100% EtOAc). m.p. 168.5-
169.5 °C HRMS (TOF MS ES+) m/z calcd for C52H99N6O8 [M+H]+: 935.7518; found: 935.7524.
Analytical HPLC purity 95%.
1H NMR (400 MHz, CDCl3)  (ppm): 0.81-1.35 (m, 60H, CH(CH3)C(CH3)3), 1.41 (s, 9H,
NtBu), 1.45 (s, 3H, CO2tBu), 1.50 (s, 6H, CO2tBu), 2.10, (s, 3H, COCH3), 3.61-4.44 (m, 12.37H,
NCH2CO and H methyne trans rotamer), 4.64-4.80 (m, 4.63H, H methyne cis rotamer).
ACS Paragon Plus Environment

Page 19 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Peptoid hexamer 3 (Ac-Ns1tbe-Ns1tbe-Ns1tbe-NtBu-Ns1tbe-Ns1tbe-OtBu). The peptoid
3 was synthesized in 12 steps from tert-butyl bromoacetate (150 mg, 0.77 mmol) according to
procedures A and B for the submonomer elongation steps and procedure C for the final N-
terminal acetylation. Peptoid 3 was isolated as a white solid after purification by flash column
chromatography on silica gel. (72 mg, 0.077mmol); Rf = 0.74 (100% EtOAc). m.p. 178.5- 179.5
°C HRMS (TOF MS ES+) m/z calcd for C52H99N6O8 [M+H]+: 935.7518; found: 935.7516.
Analytical HPLC purity 97%.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H NMR (400 MHz, CDCl3)  (ppm): 0.73-1.30 (m, 60H, CH(CH3)C(CH3)3), 1.38 (s, 9H,
NtBu), 1.42 (s, 3H, CO2tBu), 1.52 (s, 6H, CO2tBu), 2.05-2.15 (m, 3H, COCH3), 3.46-4.26 (m,
12.56H, NCH2CO and H methyne trans rotamer), 4.61 -4.81 (m, 4.44H, H methyne cis rotamer).
Peptoid hexamer 4 (Ac-Ns1tbe-Ns1tbe-NtBu-Ns1tbe-Ns1tbe-Ns1tbe-OtBu). The peptoid
4 was synthesized in 12 steps from tert-butyl bromoacetate (164 mg, 0.84 mmol) according to
procedures A and B for the submonomer elongation steps and procedure C for the final N-
terminal acetylation. Peptoid 4 was isolated as white solid after purification by flash column
chromatography on silica gel. (44 mg, 0.047mmol); Rf = 0.60 (100% EtOAc). m.p. 140.5-141.5
°C; HRMS (TOF MS ES+) m/z calcd for C52H99N6O8 [M+H]+: 935.7518; found: 935.7495.
Analytical HPLC purity 96%.
1H NMR (400 MHz, CDCl3)  (ppm): 0.81-1.10 (m, 60H, CH(CH3)C(CH3)3), 1.41 (s, 9H,
NtBu), 1.46 (s, 2.2H, CO2tBu) 1.51 (s, 6.8H, CO2tBu), 2.02 (s, 2.34H, COCH3), 2.05, (s, 0.25H,
COCH3) 2.08 (s, 0.41H, COCH3), 3.61-4.44 (m, 12.54H, NCH2CO and H methyne trans
rotamer), 4.64-4.80 (m, 4.46H, H methyne cis rotamer).
Peptoid hexamer 5 (Ac-Ns1tbe-NtBu-Ns1tbe-Ns1tbe-Ns1tbe-Ns1tbe-OtBu). The peptoid
5 was synthesized in 12 steps from tert-butyl bromoacetate (134 mg, 0.68 mmol) according to
procedures A and B for the submonomer elongation steps and procedure C for the final N-
terminal acetylation. Peptoid 5 was isolated as a white solid after purification by flash column
chromatography on silica gel. (142 mg, 0.15 mmol); Rf = 0.70 (EtOAc). m.p. 160.1-160.5 °C
HRMS (TOF MS ES+) m/z calcd for C52H98N6O8Na [M+Na]+: 957.7339; found: 957.7305.
Analytical HPLC purity 98%.
1H NMR (400 MHz, CDCl3)  (ppm): 0.81-1.08 (m, 59.2H, CH(CH3)C(CH3)3), 1.33 (d, J= 7.3
Hz, 0.8H, CH(CH3)C(CH3)3 trans rotamer), 1.39 (s, 2.5H, CO2tBu), 1.42 (s, 9H, NtBu), 1.51 (s,
6.5H, CO2tBu), 1.98-2.22 (3H, COCH3), 3.5-4.37 (m, 12.54H, NCH2CO and H methyne trans
rotamer), 4.50-4.90 (m, 4.46H, H methyne cis rotamer).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 26
1
2
3
4
5
6
7
8
9
Peptoid hexamer 6 (Ac-NtBu-Ns1tbe-Ns1tbe-Ns1tbe-Ns1tbe-Ns1tbe-OtBu). The peptoid
6 was synthesized in 12 steps from tert-butyl bromoacetate (97 mg, 0.50 mmol) according to
procedures A and B for the submonomer elongation steps and procedure C for the final N-
terminal acetylation. Peptoid 6 was isolated as a solid after purification by flash column
chromatography on silica gel. (149 mg, 0.16 mmol); Rf = 0.70 (EtOAc). m.p. 148.2-148.6 °C
HRMS (TOF MS ES+) m/z calcd for C52H99N6O8 [M+H]+: 935.7518; found: 935.7491.
Analytical HPLC purity 98%.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H NMR (400 MHz, CDCl3)  (ppm): 0.82-1.08 (m, 59.2H, CH(CH3)C(CH3)3 and
CH(CH3)C(CH3)3 cis rotamer), 1.33 (d, J= 6.8 Hz, 0.8H, CH(CH3)C(CH3)3 trans rotamer), 1.40-
1.54 (m, 18H, NtBu and CO2tBu), 1.98-2.21 (m, 3H, COCH3), 3.46-4.28 (m, 12.50H, NCH2CO
and H methyne trans rotamer), 4.62-4.79 (m, 4.50H, H methyne cis rotamer).
Peptoid hexamer 7 (Ac-NtBu-Ns1tbe-NtBu -Ns1tbe-NtBu-Ns1tbe-OBn). The peptoid 7
was synthesized in 12 steps from benzyl bromoacetate (452 mg, 1.97 mmol) according to
procedures A and B for the submonomer elongation steps and procedure C for the final N-
terminal acetylation. Peptoid 7 was isolated as a white solid after purification by flash column
chromatography on silica gel. (110 mg, 0.12 mmol); Rf = 0.85 (EtOAc). m.p. 134.7-135.2 °C.
HRMS (TOF MS ES+) m/z calcd for C51H89N6O8 [M+H]+: 913.6736; found: 913.6724
Analytical HPLC purity 98%.
1H NMR (400 MHz, CDCl3)  (ppm): 0.73-1.18 (m, 33H, CH(CH3)C(CH3)3 and
CH(CH3)C(CH3)3 cis rotamer), 1.22-1.32 (m, 3H, CH(CH3)C(CH3)3 trans rotamer), 1.33-1.53
(m, 27H, NtBu), 1.95-2.16 (m, 3H, COCH3), 3.25-4.56 (m, 13.0H, NCH2CO and H methyne
trans rotamer), 4.74 (s, 2H, OCH2Ph), 5.01-5.31 (m, 2.0H, H methyne cis rotamer), 7.28-7.45
(m, 5H, Ph).
Peptoid hexamer 8 (Ac-NtBu-Ns1tbe-NtBu -Ns1tbe-NtBu-Ns1tbe-OH). To a solution of
peptoid 7 (50 mg, 0.055 mmol) in MeOH (5 mL), carefully purged with argon was added a
catalytic amount of 10% Pd/C (5 mg). The suspension was then stirred for 30 min under an
atmosphere of hydrogen. The mixture was filtered through a plug of celite which was rinsed with
MeOH. The solvent was removed in vacuo to yield peptoid 8 as a white solid after purification
by flash column chromatography on silica gel. (45.5 mg, 0.054 mmol); Rf= 0.50 (EtOAc). m.p.
213.9-214.4 °C. HRMS (TOF MS ES+) m/z calcd for C44H83N6O8 [M+H]+: 823.6266; found:
823.6267. Analytical HPLC purity 96%.
1H NMR (400 MHz, CDCl3)  (ppm): 0.78-1.13 (m, 34.1H, CH(CH3)C(CH3)3 and
CH(CH3)C(CH3)3 cis rotamer), 1.23-1.51 (m, 28.9H, NtBu and CH(CH3)C(CH3)3 trans rotamer),
ACS Paragon Plus Environment

Page 21 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
2.01-2.34 (m, 3H, COCH3), 3.29-4.51 (m, 12.63H, NCH2CO and H methyne trans rotamer),
4.58-4.80 (m, 2.37H, H methyne cis rotamer), 11.64 (bs, 1H, CO2H).
Peptoid hexamer 9 (Ac-NtBu-NtBu-Ns1tbe-Ns1tbe-NtBu-NtBu-OtBu). The peptoid 9 was
synthesized in 12 steps from tert-butyl bromoacetate (264 mg, 1.35 mmol) according to
procedures A and B for the submonomer elongation steps and procedure C for the final N-
terminal acetylation. Peptoid 9 was isolated as a white solid after purification by flash column
chromatography on silica gel. (248 mg, 0.29 mmol); Rf = 0.84 (EtOAc). m.p. 144.3-144.7°C.
HRMS (TOF MS ES+) m/z calcd for C46H87N6O8 [M+H]+: 851.6580; found: 851.6578.
Analytical HPLC purity 99%.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H NMR (400 MHz, CDCl3)  (ppm): 0.84-0.94 (m, 18H, CH(CH3)C(CH3)3), 0.98-1.07 (m, 6H
CH(CH3)C(CH3)3 cis rotamer), 1.35-1.46 (m, 36H, NtBu), 1.50 (s, 9H, CO2tBu), 1.88- 2.04 (m,
3H, COCH3), 3.37-4.40 (m, 12H, NCH2CO), 4.57-4.79 (m, 2H, H methyne cis rotamer).
Peptoid heptamer 10 (Ac-NtBu-NtBu-Ns1tbe-Ns1tbe-Ns1tbe-NtBu-NtBu-OtBu). The
peptoid 10 was synthesized in 14 steps from tert-butyl bromoacetate (264 mg, 1.35 mmol)
according to procedures A and B for the submonomer elongation steps and procedure C for the
final N-terminal acetylation. Peptoid 1 was isolated as a white foam after purification by flash
column chromatography on silica gel. (178 mg, 0.18 mmol); Rf = 0.80 (EtOAc). HRMS (TOF
MS ES+) m/z calculated for C54H101N7O9Na [M+Na]+: 1014.7553; found: 1014.7476. Analytical
HPLC purity 97%.
1H NMR (400 MHz, CDCl3)  (ppm): 0.84-1.08 (m, 36H, CH(CH3)C(CH3)3 and
CH(CH3)C(CH3)3 cis rotamer), 1.36-1.47 (m, 36H, NtBu), 1.51 (s, 9H, CO2tBu), 1.90- 2.10 (m,
3H, COCH3), 3.70-4.37 (m, 19H, NCH2CO), 4.61-4.86 (m, 3H, H methyne cis rotamer).
Peptoid nonamer 11 (Ac-NtBu-NtBu-NtBu-Ns1tbe-Ns1tbe-Ns1tbe-NtBu-NtBu-NtBu-
OtBu). The peptoid 11 was synthesized in 17 steps from tert-butyl bromoacetate (264 mg, 1.35
mmol) according to procedures A and B for the submonomer elongation steps and procedure C
for the final N-terminal acetylation. Peptoid 11 was isolated as a white solid after purification by
flash column chromatography on silica gel. (252 mg, 0.21 mmol); Rf = 0.87 (EtOAc). m.p.
165.9-166.7°C HRMS (TOF MS ES+) m/z calcd for C66H124N9O11 [M+H]+: 1218.9342; found:
1218.9441. Analytical HPLC purity 95%.
1H NMR (400 MHz, CDCl3)  (ppm): 0.81-1.08 (m, 36H, CH(CH3)C(CH3)3 and
CH(CH3)C(CH3)3 cis rotamer), 1.32-1.49 (m, 54H, NtBu), 1.52 (s, 9H, CO2tBu), 1.89- 2.10 (m,
3H, COCH3), 3.42-4.39 (m, 14 H, NCH2CO), 4.62-4.82 (m, 3H, H methyne cis rotamer).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 26
1
2
3
4
5
6
7
8
9
Peptoid trimer 12 (Ac-NtBu-Ns1tbe-Ns1tbe-OtBu). The peptoid 12 was synthesized in 6
steps from tert-butyl bromoacetate (74 mg, 0.38 mmol) according to procedures A and B for the
submonomer elongation steps and procedure C for the final N-terminal acetylation. Peptoid 12
was isolated as a white solid after purification by flash column chromatography on silica gel. (94
mg, 0.18 mmol); Rf =0.48 (EtOAc/cyclohexane 60:40). m.p. 200-201 °C HRMS (TOF MS ES+)
m/z calcd for C28H54N3O5 [M+H]+: 512.4058; found: 512.4059. Analytical HPLC purity 99%.
1H NMR (400 MHz, CDCl3)  (ppm): 0.84-1.10 (m, 21.9H, CH(CH3)C(CH3)3 and
CH(CH3)C(CH3)3 cis rotamer), 1.21-1.28 (m, 2.1H, CH(CH3)C(CH3)3 trans rotamer), 1.39-1.52
(m, 18H, NtBu and CO2tBu), 1.93-2.06 (m, 3H, COCH3), 3.48-3.61 (m, 0.70H, H methyne trans
rotamer), 3.70-4.36 (m, 6H, NCH2CO), 4.64-4.82 (m, 1.30H, H methyne cis rotamer).
Peptoid tetramer 13 (Ac-Ns1tbe-NtBu-Ns1tbe-Ns1tbe-OtBu). The peptoid 13 was
synthesized in 8 steps from tert-butyl bromoacetate (70 mg, 0.36 mmol) according to procedures
A and B for the submonomer elongation steps and procedure C for the final N-terminal
acetylation. Peptoid 13 was isolated as a white solid after purification by flash column
chromatography on silica gel. (56 mg, 0.08 mmol); Rf =0.53 (EtOAc/cyclohexane 60:40). m.p.
118.3-118.9 °C HRMS (TOF MS ES+) m/z calcd for C36H69N4O6 [M+H]+: 653.5211; found:
653.5214. Analytical HPLC purity 99%.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H NMR (400 MHz, CDCl3)  (ppm): 0.84-1.10 (m, 33.06H, CH(CH3)C(CH3)3 and
CH(CH3)C(CH3)3 cis rotamer), 1.22-1.32 (m, 2.94H, CH(CH3)C(CH3)3 trans rotamer), 1.35-1.55
(m, 18H, NtBu and CO2tBu), 1.89-2.06 (m, 2.02H, COCH3), 2.11-2.18 (m, 0.98H, COCH3),
3.34-4.41 (m, 8.98H, NCH2CO and H methyne trans rotamer), 4.61-4.81 (m, 2.02H, H methyne
cis rotamer).
Peptoid pentamer 14 (Ac-Ns1tbe-Ns1tbe-NtBu-Ns1tbe-Ns1tbe-OtBu). The peptoid 14
was synthesized in 10 steps from tert-butyl bromoacetate (96 mg, 0.49 mmol) according to
procedures A and B for the submonomer elongation steps and procedure C for the final N-
terminal acetylation. Peptoid 14 was isolated as a white solid after purification by flash column
chromatography on silica gel. (67mg, 0.08 mmol); Rf= 0.60 (EtOAc). m.p. 224-225 °C. HRMS
(TOF MS ES+) m/z calcd for C44H84N5O7 [M+H]+: 794.6365; found: 794.6371. Analytical
HPLC purity 98%.
1H NMR (400 MHz, CDCl3)  (ppm): 0.78-1.12 (m, 45.36H, CH(CH3)C(CH3)3 and
CH(CH3)C(CH3)3 cis rotamer), 1.22-1.60 (m, 20.64H, NtBu and CO2tBu and CH(CH3)C(CH3)3
trans rotamer), 1.92-2.08 (m, 2.31H, COCH3), 2.12-2.24 (m, 0.69H, COCH3), 3.34-4.46 (m,
10.88H, NCH2CO and H methyne trans rotamer), 4.60-4.86 (m, 3.12H, H methyne cis rotamer).
ACS Paragon Plus Environment

Page 23 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Peptoid hexamer 15 (Ac-NtBu-Ns1tbe-Ns1tbe-NtBu-Ns1tbe-Ns1tbe-OtBu). The peptoid
15 was synthesized in 12 steps from tert-butyl bromoacetate (97 mg, 0.49 mmol) according to
procedures A and B for the submonomer elongation steps and procedure C for the final N-
terminal acetylation. Peptoid 15 was isolated as a white solid after purification by flash column
chromatography on silica gel. (42 mg, 0.046 mmol); Rf= 0.66 (100% EtOAc). m.p. 135.8-136.5
°C. HRMS (TOF MS ES+) m/z calcd for for C50H95N6O8 [M+H]+: 907.7205; found: 907.7216.
Analytical HPLC purity 98%.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H NMR (400 MHz,CDCl3)  (ppm): 0.79-1.26 (m, 48H, CH(CH3)C(CH3)3), 1.27-1.55 (m, 27H,
NtBu and CO2tBu), 1.93-2.14 (m, 3H, COCH3), 3.45-4.30 (m, 12.69H, NCH2CO and H methyne
trans rotamer), 4.62-4.77 (m, 3.31H, H methyne cis rotamer).
Peptoid nonamer 16 (Ac-NtBu-Ns1tbe-Ns1tbe-NtBu-Ns1tbe-Ns1tbe-NtBu-Ns1tbe-
Ns1tbe-OtBu). The peptoid 16 was synthesized in 18 steps from tert-butyl bromoacetate (292
mg, 1.50 mmol) according to procedures A and B for the submonomer elongation steps and
procedure C for the final N-terminal acetylation. Peptoid 16 was isolated as a white solid after
purification by flash column chromatography on silica gel. (22 mg, 0.017 mmol); Rf= 0.55
(100% EtOAc). m.p. 153.4-154.0 °C. HRMS (TOF MS ES+) m/z calcd for C72H136N9O11
[M+H]+: 1303.0353; found: 1303.0353. Analytical HPLC purity 99%.
1H NMR (400 MHz,CDCl3)  (ppm): 0.76-1.16 (m, 72H, CH(CH3)C(CH3)3), 1.31-1.51 (m, 36H,
NtBu and CO2tBu), 1.91-2.03(m, 3H, COCH3), 3.39-4.37 (m, 19.2H, NCH2CO and H methyne
trans rotamer), 4.60- 4.81(m, 4.8H, H methyne cis rotamer).
ASSOCIATED CONTENT
1
General synthetic scheme, HPLC traces, H NMR and HSQCAD spectra, CD of a number of
different peptoid oligomers, crystal structure report for peptoids 12 and 14.
X-ray crystallographic data for compounds 12 (CCDC 1960900) (CIF) and 14 (CCDC 1960948)
(CIF).
AUTHOR INFORMATION
ORCID
Claude Taillefumier: 0000-0003-3126-495X
ACKNOWLEDGEMENTS
We thank Aurélie Job for HPLC measurements and Martin Leremboure (UCA Partner) for
LCMS. M.R. was supported by a grant from the Ministry for Higher Education and Scientific
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 26
1
2
3
4
Research of Tunisia. We acknowledge use of the UMS2008-IBSLor Biophysics and Structural
5
6
Biology core facility at Université de Lorraine for CD measurements.
7
8
9
1
Culf, A. S.; Ouellette, R. J. Solid-Phase Synthesis of N-Substituted Glycine Oligomers (alpha-Peptoids) and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Derivatives. Molecules 2010, 15, 5282-5335.
Knight, A. S.; Zhou, E. Y.; Francis, M. B.; Zuckermann, R. N. Sequence Programmable Peptoid Polymers for
2
Diverse Materials Applications. Adv. Mater. 2015, 27, 5665-5691.
3
Gangloff, N.; Ulbricht, J.; Lorson, T.; Schlaad, H.; Luxenhofer, R. Peptoids and Polypeptoids at the Frontier of
Supra- and Macromolecular Engineering. Chem. Rev. 2016, 116, 1753-1802.
4 Zuckermann, R. N.; Kodadek, T. Peptoids as potential therapeutics. Curr. Opin. Mol. Ther. 2009, 11, 299-307.
5
Dohm, M. T.; Kapoor, R.; Barron, A. E. Peptoids: Bio-Inspired Polymers as Potential Pharmaceuticals. Curr.
Pharm. Des. 2011, 17, 2732-2747.
6 Horne, W. S. Peptide and peptoid foldamers in medicinal chemistry. Expert Opin. Drug Dis. 2011, 6, 1247-1262.
7 Maayan, G.; Ward, M. D.; Kirshenbaum, K. Metallopeptoids. Chem. Commun., 2009, 56-58.
8
Maayan, G.; Ward, M. D.; Kirshenbaum, K. Folded biomimetic oligomers for enantioselective catalysis. Proc.
Natl. Acad. Sci. USA 2009, 106, 13679-13684.
9
Zborovsky, L.; Tigger-Zaborov, H.; Maayan, G. Sequence and Structure of Peptoid Oligomers Can Tune the
Photoluminescence of an Embedded Ruthenium Dye. Chem. Eur. J. 2019, 25, 9098-9107.
10
Zuckermann, R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W. H. Efficient method for the preparation of peptoids
[oligo(N-substituted glycines)] by submonomer solid-phase synthesis. J. Am. Chem. Soc. 1992, 114, 10646-10647.
11
Miller, S. M.; Simon, R. J.; Ng, S.; Zuckermann, R. N.; Kerr, J. M.; Moos, W. H. Proteolytic Studies of
Homologous Peptide and N-Substituted Glycine Peptoid Oligomers. Bioorg. Med. Chem. Lett. 1994, 4, 2657-2662.
12 Miller, S. M.; Simon, R. J.; Ng, S.; Zuckermann, R. N.; Kerr, J. M.; Moos, W. H. Comparison of the Proteolytic
Susceptibilities of Homologous L-Amino-Acid, D-Amino-Acid, and N-Substituted Glycine Peptide and Peptoid
Oligomers. Drug Dev. Res. 1995, 35, 20-32.
13
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. NMR determination of the major solution
conformation of a peptoid pentamer with chiral side chains. Proc. Natl. Acad. Sci. USA 1998, 95, 4309-4314.
14 Wu, C. W.; Kirshenbaum, K.; Sanborn, T. J.; Patch, J. A.; Huang, K.; Dill, K. A.; Zuckermann, R. N.; Barron, A.
E. Structural and spectroscopic studies of peptoid oligomers with -chiral aliphatic side chains. J. Am. Chem. Soc.
2003, 125, 13525-13530.
15
Stringer, J. R.; Crapster, J. A.; Guzei, I. A.; Blackwell, H. E. Extraordinarily Robust Polyproline Type I Peptoid
Helices Generated via the Incorporation of alpha-Chiral Aromatic N-1-Naphthylethyl Side Chains. J. Am. Chem.
Soc. 2011, 133 (39), 15559-15567.
16
Roy, O.; Dumonteil, G.; Faure, S.; Jouffret, L.; Kriznik, A.; Taillefumier, C. Homogeneous and Robust
Polyproline Type I Helices from Peptoids with Nonaromatic -Chiral Side Chains. J. Am. Chem. Soc. 2017, 139,
13533-13540.
17 Shah, N. H.; Butterfoss, G. L.; Nguyen, K.; Yoo, B.; Bonneau, R.; Rabenstein, D. L.; Kirshenbaum, K. Oligo(N-
aryl glycines): A New Twist on Structured Peptoids. J. Am. Chem. Soc. 2008, 130, 16622-16632.
18
Crapster, J. A.; Stringer, J. R.; Guzei, I. A.; Blackwell, H. E. Design and Conformational Analysis of Peptoids
Containing N-Hydroxy Amides Reveals a Unique Sheet-Like Secondary Structure. Biopolymers 2011, 96, 604-616.
19
(a) Shin, S. B.; Yoo, B.; Todaro, L. J.; Kirshenbaum, K. Cyclic Peptoids. J. Am. Chem. Soc. 2007, 129, 3218-
3225. (b) D'Amato, A.; Pierri, G.; Tedesco, C.; Della Sala, G.; Izzo, I.; Costabile, C.; De Riccardis, F. Reverse Turn
and Loop Secondary Structures in Stereodefined Cyclic Peptoid Scaffolds. J. Org. Chem. 2019, 84, 10911-10928.
(c) Huang, K.; Wu, C. W.; Sanborn, T. J.; Patch, J. A.; Kirshenbaum, K.; Zuckermann, R. N.; Barron, A. E.;
Radhakrishnan, I. A Threaded Loop Conformation Adopted by a Family of Peptoid Nonamers. J. Am. Chem. Soc.
2006, 128, 1733-1738.
20
Gorske, B. C.; Mumford, E. M.; Gerrity, C. G.; Ko, I. A Peptoid Square Helix via Synergistic Control of
Backbone Dihedral Angles. J. Am. Chem. Soc. 2017, 139, 8070-8073.
21
Crapster, J. A.; Guzei, I. A.; Blackwell, H. E. A Peptoid Ribbon Secondary Structure. Angew. Chem. Int. Ed.
2013, 52 (19), 5079-5084.
22
Gorske, B. C.; Mumford, E. M.; Conry, R. R. Tandem Incorporation of Enantiomeric Residues Engenders
Discrete Peptoid Structures. Org. Lett. 2016, 18, 2780-2783.
23 Sui, Q.; Borchardt, D.; Rabenstein, D. L. Kinetics and Equilibria of Cis/Trans Isomerization of Backbone Amide
Bonds in Peptoids. J. Am. Chem. Soc. 2007, 129, 12042-12048.
ACS Paragon Plus Environment

Page 25 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
24
Butterfoss, G. L.; Renfrew, P. D.; Kuhlman, B.; Kirshenbaum, K.; Bonneau, R. A Preliminary Survey of the
Peptoid Folding Landscape. J. Am. Chem. Soc. 2009, 131, 16798-16807.
25
Gorske, B. C.; Bastian, B. L.; Geske, G. D.; Blackwell, H. E. Local and tunable n ->pi* interactions regulate
amide isomerism in the peptoid backbone. J. Am. Chem. Soc. 2007, 129, 8928-8929.
26
8
Gorske, B. C.; Stringer, J. R.; Bastian, B. L.; Fowler, S. A.; Blackwell, H. E. New Strategies for the Design of
9
Folded Peptoids Revealed by a Survey of Noncovalent Interactions in Model Systems. J. Am. Chem. Soc. 2009, 131,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
16555-16567.
27
Stringer, J. R.; Crapster, J. A.; Guzei, I. A.; Blackwell, H. E. Construction of Peptoids with All Trans-Amide
Backbones and Peptoid Reverse Turns via the Tactical Incorporation of N-Aryl Side Chains Capable of Hydrogen
Bonding. J. Org. Chem. 2010, 75, 6068-6078.
28
Caumes, C.; Roy, O.; Faure, S.; Taillefumier, C. The Click Triazolium Peptoid Side Chain: A Strong cis-Amide
Inducer Enabling Chemical Diversity. J. Am. Chem. Soc. 2012, 134, 9553-9556.
29 Roy, O.; Caumes, C.; Esvan, Y.; Didierjean, C.; Faure, S.; Taillefumier, C. The tert-Butyl Side Chain: A Powerful
Means to Lock Peptoid Amide Bonds in the Cis Conformation. Org. Lett. 2013, 15, 2246-2249.
30
Angelici, G.; Bhattacharjee, N.; Roy, O.; Faure, S.; Didierjean, C.; Jouffret, L.; Jolibois, F.; Perrin, L.;
Taillefumier, C. Weak backbone CH...O=C and side chain tBu...tBu London interactions help promote helix folding
of achiral NtBu peptoids. Chem. Commun. 2016, 52, 4573-4576.
31
Gimenez, D.; Aguilar, J. A.; Bromley, E. H.; Cobb, S. L. Stabilising Peptoid Helices Using Non-Chiral
Fluoroalkyl Monomers. Angew. Chem. Int. Ed. 2018, 57, 10549-10553.
32
Kuemin, M.; Engel, J.; Wennemers, H. Temperature-induced transition between polyproline I and II helices:
quantitative fitting of hysteresis effects. J. Peptide Sci. 2010, 16, 596-600.
33
Armand, P.; Kirshenbaum, K.; Falicov, A.; Dunbrack Jr, R. L.; Dill, K. A.; Zuckermann, R. N.; Cohen, F. E.
Chiral N-substituted glycines can form stable helical conformations. Fold. Des. 1997, 2, 369-375.
34
Baskin, M.; Maayan, G. A rationally designed metal-binding helical peptoid for selective recognition processes.
Chem. Sci. 2016, 7, 2809-2820.
35
Tigger-Zaborov, H.; Maayan, G. Aggregation of Ag(0) nanoparticles to unexpected stable chain-like assemblies
mediated by 2,2 '-bipyridine decorated peptoids. J. Colloid Interf. Sci. 2019, 533, 598-603.
36
Wu, C. W.; Sanborn, T. J.; Huang, K.; Zuckermann, R. N.; Barron, A. E. Peptoid oligomers with -chiral,
aromatic side chains: Sequence requirements for the formation of stable peptoid helices. J. Am. Chem. Soc. 2001,
123, 6778-6784.
37
Wu, C. W.; Sanborn, T. J.; Zuckermann, R. N.; Barron, A. E. Peptoid Oligomers with -Chiral, Aromatic Side
Chains: Effects of Chain Length on Secondary Structure. J. Am. Chem. Soc. 2001, 123, 2958-2963.
38 Shin, H. M.; Kang, C. M.; Yoon, M. H.; Seo, J. Peptoid helicity modulation: precise control of peptoid secondary
structures via position-specific placement of chiral monomers. Chem. Commun. 2014, 50 (34), 4465-4468.
39Green, M. M.; Reidy, M. P.; Johnson, R. D.; Darling, G.; O'Leary, D. J.; Willson, G. Macromolecular
stereochemistry: the out-of-proportion influence of optically active comonomers on the conformational
characteristics of polyisocyanates. The sergeants and soldiers experiment. J. Am. Chem. Soc.1989, 111, 6452-6454.
40
Shyam, R.; Nauton, L.; Angelici, G.; Roy, O.; Taillefumier, C.; Faure, S. NC-gem-dimethylated peptoid side
chains: A novel approach for structural control and peptide sequence mimetics. Biopolymers 110, 2019, e23273.
41
Hjelmgaard, T.; Faure, S.; Caumes, C.; De Santis, E.; Edwards, A. A.; Taillefumier, C. Convenient Solution-
Phase Synthesis and Conformational Studies of Novel Linear and Cyclic -Alternating Peptoids. Org. Lett. 2009,
11, 4100-4103.
42
Gorske, B. C.; Blackwell, H. E. Tuning peptoid secondary structure with pentafluoroaromatic functionality: A
new design paradigm for the construction of discretely folded peptoid structures J. Am. Chem. Soc. 2006, 128,
14378-14387.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 26
1
2
3
4
5
TOC graphic
6
7
8
9
Me
Me
97% cis
Me
O
O
N
Synergy
effect
100% cis
Chirality
transfer
Cis-amide
transmission
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
97% cis
Improved
stability
91% cis
tBu
Me
H
O
9% trans
O
N
cis > trans
ACS Paragon Plus Environment