Functionalized Helical β-Peptoids

Article abstract of DOI:10.1021/acs.joc.9b00218

Peptidomimetic foldamers adopting well-defined three-dimensional structures while being stable toward proteolysis are of interest in biomedical research, chemical biology, and biomimetic materials science. Despite their backbone flexibility, β-peptoids containing N-(S)-1-(1-naphthyl)ethyl (Ns1npe) side chains can fold into unique triangular prism-shaped helices. We report herein the successful introduction of amino groups onto robustly folded β-peptoid helices by construction and incorporation of novel chiral building blocks. This is the first example of an X-ray crystal structure of a linear β-peptoid containing more than one type of side chain. We thus present a unique foldamer design comprising a robustly folded core with functionalized side chains protruding perpendicular to the helical axis to provide a highly predictable display of functional groups. This work paves the way for development of β-peptoid foldamers with a desired function, such as catalytic properties or as scaffolds enabling polyvalent display.

Full text of DOI:10.1021/acs.joc.9b00218

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Featured Article
Functionalized Helical #-Peptoids
Isabelle Wellhofer, Karla Frydenvang, Simona Kotesova, Andreas
Moesgaard Christiansen, Jonas S Laursen, and Christian A. Olsen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00218 • Publication Date (Web): 13 Mar 2019
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Functionalized Helical -Peptoids
#
Isabelle Wellhöfer, Karla Frydenvang, Simona Kotesova, Andreas M. Christiansen, Jonas S. Laursen, and
Christian A. Olsen*
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Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of
Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark
Abstract: Peptidomimetic foldamers adopting well-defined three dimensional structures while being stable
towards proteolysis are of interest in biomedical research, chemical biology, and biomimetic materials science.
Despite their backbone flexibility, -peptoids containing N-(S)-1-(1-naphthyl)ethyl (Ns1npe) side chains can
fold into unique triangular prism-shaped helices. We report herein the successful introduction of amino groups
onto robustly folded -peptoid helices by construction and incorporation of novel chiral building blocks. This
is the first example of an X-ray crystal structure of a linear -peptoid, containing more than one type of side
chain. We thus present a unique foldamer design comprising a robustly folded core with functionalized side
chains protruding perpendicular to the helical axis, to provide a highly predictable display of functional groups.
This work paves the way for development of -peptoid foldamers with a desired function, such as catalytic
properties or as scaffolds enabling polyvalent display.
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INTRODUCTION
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Peptoids, N-substituted peptidomimetics, feature desirable characteristics such as increased protease stability2
3
and cell permeability compared to peptides as well as ready access to sequence-defined oligomers containing
a wide range of side chain functionalities. Peptoids have further been shown to adopt distinct three-dimensional
structures such as turn mimetics,4-6 ribbons, sheets, helices, loops,16-17 bundles, and nanosheets
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may thus be characterized as foldamers according to the definition coined by Gellman.23 Foldamers are
molecules able to adopt well-defined secondary structures that either mimic or complement those exhibited by
biopolymers.24-30 Peptoid secondary structures may further be combined to mimic tertiary structures18, 31 and
may be decorated with functional groups to achieve metal-binding32-39 and catalysis,40-46 multivalent display47-
51, recognition52-55 or biologically active ligands.56-64 However, each desired application may require an
individual fold, rendering it important to develop structures with novel folding properties as well as means to
achieve control of the folding.25, 29, 65-70 We have been interested in a more sparsely investigated subcategory
of the peptoids called -peptoids (N-alkyl--alanine oligomers),71-80 first described by Hamper et al. These
peptidomimetics carry traits of both -peptoids and -peptides. Like in α-peptoids, their side chains are
attached to the backbone amide bond nitrogen atom, resulting in a backbone without the capability to engage
in hydrogen bonding. Due to the tertiary nature of these backbone amide bonds, they isomerize readily between
the transoid and the cisoid conformation, which may be affected by the choice of side chain82-89 or introduction
of thioamide bonds in the backbone.87, 90 These features are combined with an additional methylene group in
the backbone as in -peptides.91-93 Although the -amino acids have additional degrees of freedom compared
to -amino acids, they have been shown to complement peptide oligomers to form new secondary structures
with strong folding propensities.91-97 Despite the challenges related to the lack of hydrogen bonding combined
with the increased flexibility of the backbone, we have identified the N-(S)-1-(1-naphthyl)ethyl (Ns1npe) side
chain to promote formation of triangular prism-shaped -peptoid helices.13, 80 However, these helices comprise
exclusively hydrophobic side chains and the introduction of functional groups is necessary to improve
solubility and enable applicability.98 Preliminary experiments in our laboratory indicated that various
substitutions to the aromatic part of the side chains were detrimental to helical folding propensity. Instead, we
here present the successful introduction of functional groups by elaborating the methyl group of the side chain,
which results in retention of the helical folding while allowing for further functionalization of the foldamer
surface.
81
RESULTS
Role of Ns1npe side chains. Initially, we designed various hexamers containing side chains that had been
structurally manipulated. We then relied on circular dichroism (CD) spectroscopy to evaluate folding
propensity (see Figure 1, Scheme S1 and Figure S1 for details). In brief, introduction of side chains with an R-
configured chiral center (2) furnished a mirror image CD spectrum as expected, while a stereochemically
scrambled analog (3) gave rise to an entirely different CD spectrum (Figure S1). Furthermore, the positive
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maximum at 231 nm, which is believed to be indicative of helical folding, was significantly decreased when
perturbing the structure by loss of a chiral center (4) or substitution of a single naphthyl for a phenyl group (5).
Noteworthy, hexamer 4 exhibited a stronger helical signal than hexamer 5. Taken together, this might suggest
that “insulation”/packing of the helical backbone from the environment is more important than having an all-
chiral oligomer. However, the potential importance of the strongly cis-amide inducing nature of Ns1npe is not
addressed by these compounds. We therefore synthesized compounds 6–9 as outlined vide infra (Figure 2 and
Scheme S2).
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Figure 1. Structures of hexamers 1–5.
As a first attempt to integrate new functionalities into the helix design, we chose the highly cis-amide inducing
triazolium group introduced by Taillefumier, Faure, and coworkers.85, 88 We found this strategy appealing due
to the possibility of introducing a wide variety of side chains by Cu(I)-catalyzed azide–alkyne cycloaddition
“click” chemistry.99-100 Applying this click reaction provided both chiral and achiral triazole-containing groups,
incorporated at the peptoid trimer stage, which were coupled with an unmodified trimer to give compounds 6
and 7 (Figure 2A). Then, these oligomers were converted to their triazolium analogs (compounds 8 and 9) by
alkylation using methyl iodide (Scheme S2). Unfortunately, the CD spectra of all the compounds, including 9,
which contains both an -chiral and cis-inducing functionality, exhibited a lack of maximum at 231 nm (Figure
2B). Taken together with the loss of helicity for compounds 4 and 5, the results indicate, that packing of the
naphthyl groups may be crucial for the robust helical folding previously reported. However, without high-
resolution structural information for compounds 5–9, it cannot be ruled out that the backbone remains folded
while the CD signature changes due to loss of side chain interactions. Instead of attempting additional side
chains recently shown to be cis-inducing,14, 101 we decided to focus on a strategy where the entire triangular
prism-shaped helical core is kept intact and the protruding methyl groups are extended.
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Figure 2. Triazole- and triazolium-modified hexamers. (A) Structures of achiral (6, 8) and chiral (7, 9) triazole- or
triazolium-containing oligomers. (B) CD spectra of compounds 6–9 compared to parent hexamer 1. Spectra were
measured in MeCN (2060 M) at room temperature. The mean residue molar ellipticity [] is normalized with regards
to number of residues and peptoid concentration.
Extension of side chains through the methyl group. To test the hypothesis that folding integrity might by
retained by modifying the side chain methyl group, we first extended the side chain to (S)-1-(1-
naphthyl)pentylamine (12). We envisioned that hexamers containing the N-(S)-1-(1-naphthyl)pentyl (Ns1npp)
side chain would form a helix with the alkyl chain protruding perpendicular to the helical axis. The amine
building block 12 was previously prepared in racemic form102 from the corresponding ketone,103 and it was
instead decided to apply the Ellman type Mannich reaction104-106 to achieve stereoselective synthesis of the S-
enantiomer (Scheme 1A). 1-Naphthaldehyde and tert-butanesulfinamide were condensed to give the tert-
butanesulfinimine 10, which was then subjected to nBuLi to provide sulfinamide 11 with 90% d.r. determined
1
by NMR of the crude material. After complete separation of the diastereoisomers as judged by H NMR, the
auxiliary was cleaved with HCl to furnish building block 12 as the hydrochloride salt after precipitation from
diethylether (65% yield over 3 steps). Enantiomeric purity was confirmed using Marfey’s reagent (Figure
S2A). This building block was then introduced into trimer segments (14–17, Scheme 1B) by alternating aza-
Michael addition and acryloylation reactions as previously reported for homomers (13 and 18, Scheme 1B)13
(see Scheme S3 for details). Combination of trimer segments by HATU-mediated amide bond coupling
furnished hexamers 19–22, presenting the extended hydrocarbon side chain at different positions along the
helical axis (Figure 1C).
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The hexamers 19–22 were subjected to CD spectroscopy and compared to the parental structure 1.
Gratifyingly, a spectrum similar to the parental helix was observed for all four variants including a strong
maximum around 231 nm, suggesting helical folding (Figure 3). In addition, the cis–trans-amide bond ratios
were determined using HSQC NMR experiments to provide equilibrium constants for the isomerization
(
Figure 3). The equilibrium constants exceeded 12 for all hexamers 19–22 containing the butyl side chain.
These findings support the results from CD analysis, indicating helical folding comparable to that of the
parental hexamer 1 (Kcis/trans = 11). Thus, the introduction of a longer alkyl side chain does not appear to affect
the folding propensity of the -peptoid hexamers and we therefore chose this strategy to add functional groups
at this position as well.
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Scheme 1. Synthesis of -Peptoid Hexamers with Extended Side Chains. (A) Synthesis of (S)-1-(1-Naphthyl)pentyl-
1-amine. (B) Structures and Combinations of Trimers. (C) Structures of Hexamers 19–22.a
aReagents and conditions: (a) t-butanesulfinamide (1 equiv), 1-naphthaldehyde (1.1 equiv), Ti(OEt)
, rt, 6 h; (b) n-BuLi (2 equiv), THF, N , –78 °C, 2 h; (c) 2 M HCl in Et O–MeOH 1:1, rt, 1 h.
(2 equiv), THF,
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Figure 3. CD spectra of compounds 1 and 19–22 measured in MeCN (3070 M) at room temperature. The mean residue
molar ellipticity [] is normalized with regards to number of residues and peptoid concentration. Overall Kcis/trans values
a
for amide bond rotamers were measured by HSQC NMR in benzene-d
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. The signals from the methine protons of side
chains adopting the trans-amide conformation were below the detection limit.
X-ray diffraction crystallography. Gratifyingly, we were able to crystallize compound 21 by vapor diffusion
from a mixture of toluene and acetonitrile to provide diffraction quality crystals. The X-ray diffraction crystal
structure was solved to provide atomic scale insight into the three-dimensional structure (Figure S3 and Table
S1). In agreement with the results from CD spectroscopy, the solid state structure of compound 21 is helical
and closely resembles the crystal structure of parental compound 1 (Figure 4A). The torsion angles have similar
values as the parental structure (Table 1), which is also reflected in the low RMSD = 0.228 obtained when
pair-fitting all backbone atoms using the PyMol software (Figure S4).
Thus, the new helix features three residues per turn and a helical pitch of 9.9 Å. The naphthyl residues align
along the helical axis, covering the backbone with three highly regular faces that give rise to an overall
triangular prism-shaped structure. The butyl side chain in residue 3 protrudes from the surface (Figure 4B).
The top view of the helix shows an equilateral triangle with all naphthyl groups aligned along each helical face
(Figure 4C). Interestingly, the crystal packing differs from the parental structure. In order to accommodate the
butyl side chains, two helices face each other at an angle of approximately 110 °C (Figure 4D). Overall, this
structure provides evidence supporting the conclusions drawn from the CD spectroscopy data. Together, the
data shows that the elaboration of the methyl side chain does not affect the helical folding. Judging from the
X-ray diffraction crystal structure, this strategy can accommodate even more sterically demanding
functionalities without perturbing the folding.
Table 1. Torsion Angles of Compounds 1 and 21
angle




1b
2c
1a
97.4° 166.0° –173.9°
91.2° 163.4° –176.2°
–13.4°
–4.0°
56.3°
54.1°
–73.8°
–74.8°
2
1d
a
b
c
Values were reported in reference 13. Measured by the naphthyl substituent. Measured by the methyl substituent.
dMeasured at residue 5 in the structure to give representative values for a residue within the helix.
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Figure 4. Single crystal X-ray diffraction structure of compound 21. (A) View perpendicular to the helical axis. (B) Side
view in space filling representation, showing the packing of the naphthyl groups along the faces of the helix. The methyl
groups are shown in tan and the protruding butyl group in green. (C) Top view down along the helical axis, showing
packing of the helices. (D) Crystal packing shown perpendicular to the helical axis, demonstrating how the butyl side
chains are accommodated in the solid state.
Functionalization of -peptoid helices. Encouraged by these results, we investigated the possibility of
introducing functional groups into the alkyl side chain. An amino group was chosen and the respective Alloc
protected building block 27 was synthesized as outlined in Scheme 2A. First, 3-bromopropylamine
hydrobromide was protected to give 1-(3-bromopropyl)-2,5-dimethyl-pyrrole (23), which is stable in presence
of nBuLi. Compound 23 was subjected to a lithium–halogen exchange and reacted with sulfinimine 10 in situ
to give compound 24. Attempts to directly remove the auxiliary under acidic conditions at this stage led to side
reactions of the pyrrole ring. In addition, the harsh conditions for pyrrole deprotection – reflux in presence of
hydroxylamine – were anticipated to be problematic at a late stage in the synthesis. Therefore, we decided to
change the protecting group to allyloxycarbonyl (Alloc), which can be readily removed under mild conditions.
Acidic cleavage of the chiral auxiliary provided the chiral building block 27 after column chromatography in
an overall yield of 20% over 6 steps.
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Scheme 2. Amino-Functionalized -Peptoid Oligomers. (A) Synthesis of Protected Chiral Diamine Building Block.
(B) Synthesis of Oligomers 32 and 33. (C) Piperazine Modified Compound 34.
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aReagents and conditions: (a) (i) 23 (2 equiv), nBuLi (2 equiv), THF, N
78 °C, 45 min. (b) H NOH•HCl (15 equiv), Et N (10 equiv), 2-propanol–H
equiv), iPr NEt (2 equiv), CH Cl , N , 0 °C → rt, 1.5 h. (d) 2 M HCl in Et O–MeOH 1:1, rt, 1 h. (e) HATU (1.2 equiv),
iPr NEt (3 equiv), CH Cl , rt, 18 h. (f) Pd(PPh (10 mol%), Me NH•BH (15 equiv), CH Cl , rt, 3 h.
, –78 °C, 45 min; then (ii) 10 (1 equiv), THF, N
O 4:1, N , reflux, 18 h. (c) Alloc-Cl (1.2
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No epimerization was observed judged by conjugation of the amine with Marfey’s reagent (Figure S2B). Using
the same approach as described vide supra, the building block 27 was introduced into trimers (28 and 29,
Scheme S4). Peptide coupling of 13 or 28 with 29 followed by Alloc removal using Pd(PPh ) provided
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hexamers 32 and 33, respectively (Scheme 2B). We envisioned that the introduction of amino groups would
enhance solubility in more polar solvents than benzene and toluene significantly. However, they could be used
as chemical handles in order to attach other functionalities and in this case, their contribution to the
hydrophilicity of the helix would be lost. Therefore, it was also decided to test a recently reported strategy for
enhancement of aqueous solubility of peptoids without affecting secondary structure by conjugation of
piperazine residues107 (Scheme 2C and Scheme S5). This moiety could be attached to any peptoid and increase
hydrophilicity regardless of other functional groups incorporated on the helix.
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Figure 5. CD spectra of functionalized peptoids 30 and 32–34. (A) CD spectra of 30 and 32 with and without Et
3
N
addition (10 equiv). (B) CD spectra of 33 with and without Et N addition (20 equiv). (C) CD spectrum of 34. The spectra
3
were measured in MeCN (35–95 M) at room temperature. The mean residue molar ellipticity [] is normalized with
regards to number of residues and peptoid concentration.
Table 2. Overall Kcis/trans Values for Amide Bond Rotamers Measured by HSQC NMR in Benzene-d
6
compound
1
30
32
32+Et N 33
33+Et N 34
3
3
all cisa
Kcis/trans
11.07e 12.8
9.9
7.3
11.0
15.5
aThe signals from the methine protons of side chains on trans–amides were below the detection limit.
The folding propensity was again investigated by CD spectroscopy (Figure 5) and determination of overall
Kcis/trans values (Table 2). When measured in pure MeCN, a significant decrease in the band intensity at 231
nm was observed for the functionalized hexamer 32 (Figure 5A). Conversely, the Alloc protected hexamer 30
exhibited a similar maximum as the parental helix (1). We therefore speculated whether protonation of the
amino group could affect folding propensity in MeCN. An effect of pH on folding is not unprecedented, as
Shin and Kirshenbaum have described pH responsive folding of -peptoids containing carboxylic acid side
chains.108 Thus, to rule out protonation of the amine as the cause of this difference in CD signature, a second
CD measurement was carried out in MeCN with triethylamine (10 equiv) added. This gave rise to full recovery
of the CD maximum at 231 nm of 32 (Figure 5A) and the same effect was observed for the bis-functionalized
hexamer 33, which contains butylamine side chains at the 2nd and 5 position (Figure 5B). Piperazine-
containing hexamer 34 also gave rise to a CD spectrum similar to the parental hexamer (Figure 5C). The
methodology of attaching piperazine residues to the termini therefore appears to be a valuable tool to increase
th
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hydrophilicity of these -peptoids without affecting the secondary structure as reported previously for -
3
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peptoids. Analysis of the Alloc protected -peptoid 30 and piperazine-modified 34 showed K
values
cis/trans
similar or higher than the parental hexamer, while the deprotected amine-containing peptoids 32 and 33
exhibited a slight decrease in Kcis/trans. Similar to the trends observed by CD spectroscopy, this could be caused
by interference of the protonated amines and we therefore performed the HSQC NMR experiments in the
presence of triethylamine as well. This led to an increase of the Kcis/trans, exhibiting similar or higher values
then the parental hexamer (Table 2).
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We also tested the stability of the helical conformation of oligomer 33 towards external perturbation by heat
1
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or addition of MeOH, previously shown to denature the parent oligomer (1). The CD spectra showed a
decrease of the signal at 231 nm when increasing temperatures (Figure 6A) and a heated sample, which was
cooled down to room temperature, furnished a spectrogram similar to the original sample (Figure 6B).
Changing the solvent composition by addition of varying amounts of MeOH also affected the intensity of the
signal at 231 nm (Figure 6C). Taken together, these results indicate the presence of a both temperature- and
solvent-dependent secondary structure of compound 33 in solution, in addition to the pH dependency discussed
vide supra. Interestingly, the perturbing effect of MeOH appeared to be less pronounced than previously
observed for the parent compound (1), which could simply be related to increased solubility. However, if the
functionalized helices are in fact less prone to denaturing, this would be a useful feature with regard to potential
future applications. Furthermore, it will be interesting to investigate the dynamics involved in the folding–
unfolding processes caused by external stimuli.
Figure 6. CD spectra of functionalized peptoid 33. (A) CD spectra of 33 recorded at varying temperatures. (B) CD
spectrum of 33 after cooling. (C) CD spectra of 33 in the presence of Et
3
N and varying amounts of MeOH. The spectra
are measured in MeCN (50 M) and 20 equiv Et N at room temperature unless otherwise noted. The mean residue
3
molar ellipticity [] is normalized with regards to number of residues and peptoid concentration.
Finally, we analyzed hexamer 33 by CD spectroscopy in the near UV region (270–400 nm) together with a
series of monomer model compounds, to investigate potential effects of folding on the CD signals arising from
the naphthyl groups (Figure S5). Interestingly, the acetylated monomer gave rise to a negative maximum while
the presumed folded oligomer 33 exhibited both negative and positive maxima (Figure S5B). Upon
triethylamine addition, the negative maxima between 270 nm and 280 nm became more pronounced.
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In addition to achieving functionalization of the helical face as well as the N-terminus of our parent helix,
without affecting its folding propensity significantly, we substantially improved upon the hydrophilicity as
judged by HPLC. Thus, significant shifts in retention time were recorded when comparing to parent helix 1
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32 (5.1 min), 133 (11.0 min), and 134 (6.7 min) (Figure S6).
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DISCUSSION
Our collective findings from CD spectroscopy, HSQC NMR spectroscopy, and X-ray diffraction
crystallography provide strong evidence that preparation of the first functionalized -peptoid helices has been
achieved. We report a strategy to introduce functional groups into a -peptoid helix without disrupting its
three-dimensional structure. This design leaves previously discovered, helix-promoting, naphthyl groups in
place while introducing functional side chains that protrude from the robustly folded triangular prism-shaped
helix. Circular dichroism spectroscopy and measurement of overall Kcis/trans amide bond isomerism by HSQC
NMR experiments provided preliminary evidence that extended hydrocarbon side chains would result in
retained folding (compounds 19–22). In addition, single crystal X-ray diffraction crystallography provided
high-resolution evidence for the envisioned helical conformation, which was in strong agreement with
1
3
previously solved structures. Interestingly, this third X-ray diffraction crystal structure solved for a linear -
peptoid also revealed an alternative packing in the solid state compared to the previous two. Together with the
trends observed by CD spectroscopy under various conditions in solution, this result provides further evidence
that the observed structures arise from bona fide folding propensity and not merely crystal packing effects.
The segment coupling strategy applied for the synthesis of the -peptoid oligomers allowed for the
incorporation of variable building blocks on the desired positions in a convergent manner. To achieve the
introduction of these custom synthesized side chains, we adopted the diastereoselective Mannich-type reaction
developed by Ellman and co-workers.104-106 This method could also be extended beyond hydrocarbon side
chains to give protected diamine building block 27. Thus, a robust strategy for introduction of further
functional groups has been established for future studies.
Introduction of building block 27 into hexamers furnished mono- and bis-functionalized hexamers (32 and
33), which, gratifyingly, exhibited the attributes of helical folding according to CD and HSQC NMR
spectroscopy. Interestingly however, the extend of helical content as judged by these means were pH
dependent, which is not unprecedented for peptoids containing side chains that engage in acid–base
equilibria.108 The helical content of compounds 32 and 33 was decreased in acetonitrile (CD) and benzene-d6
(NMR) compared to parent compound (1), but the signals were rescued by addition of triethylamine. We
hypothesize that this attribute could be utilized for the development of pH responsive materials; however, it
will require further experiments to test this possibility.
The aqueous solubility of these foldamers was also improved substantially by the N-terminal attachment of a
piperazine moiety (compound 34), which did not affect the folding propensity. Potentially, this may be
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combined with functionalized side chains in the future to provide additive increase in the hydrophilicity of the
compounds. Importantly, increased solubility achieved by either introduction of side chain functional groups
and/or piperazine moieties will also enable construction of longer oligomers, as poor solubility has been the
major obstacle for elongation beyond the hexamer length for Ns1npe-containing -peptoids. This may be
important for designing functional molecules, although, there is also precedence for applications of shorter
foldamers of 4–7 residues in length in catalysis,41-45, 109 protein surface binding ligands,110-111 or very recently
as a molecular spring torsion balance.112
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In summary, we have developed a strategy for preparation of functionalized -peptoid foldamers. Our design
is unique among peptoids with the closest related oligomers being -peptoids containing Phe residues as side
chains.108 Conversely, the aromatic part of structure-promoting side chains has mainly been the subject of
functionalization previously.98, 113 The challenge associated with our strategy is that custom synthesized
building blocks are necessary to introduce the side chain functionalities. However, we provide robust synthetic
methods to achieve this and envision future introduction of azide or alkyne “click” chemistry handles which
will enable divergent, post-oligomerization functionalization. On the other hand, the present work provides
evidence that exquisite predictability in display of functional groups can be achieved because the core
surrounding the helix is untouched when applying this design. These findings are in contrast to most peptoid
or -, -, and -peptide designs where mutation of residues to substitute functional groups is highly likely to
affect folding. Furthermore, this is the first example of a high-resolution X-ray crystal structure solved for a
linear oligomeric -peptoid, containing more than one type of side chain. The presented system is significant
as it paves the way for development of -peptoid foldamers with a desired function. Efforts to introduce metal-
binding groups into -peptoid helices for preparation of higher order structures such as helix bundles are
currently ongoing in our laboratories, the results of which will be reported in due course.
EXPERIMENTAL SECTION
General methods and materials. All chemicals and solvents were analytical grade and used without further
purification. All reactions under a nitrogen atmosphere were performed in dry solvents. Dichloromethane, N,N-
dimethylformamide (DMF) and tetrahydrofuran (THF) were retrieved from a solvent purification system. All
reactions were monitored by thin-layer chromatography (TLC) using silica gel coated plates (analytical SiO2-
6
0, F-254). Liquid column chromatography was performed on silica gel (particle size 40–63 m, or in case of
vacuum liquid chromotography (VLC) 15–40 m). Ultra high-performance liquid chromatography (UPLC)-
mass spectrometry (MS) analyses were performed on an HPLC-system equipped with a C18 column (50 mm
× 2.1 mm, 1.7 m, 100 Å) using a gradient of eluent I (0.1% HCOOH in water) and eluent II (0.1% HCOOH
in acetonitrile) rising linearly from 0% to 95% of eluent II during t = 0.00–5.00 at a flow rate of 0.6 mL/min.
Analytical reversed-phase HPLC was performed on a system equipped with a C8 column (250 × 4.6 mm,
5
m, 100 Å) and a diode array UV detector, using a gradient of eluent III (wateracetonitrileTFA, 95:5:0.1)
and eluent IV (0.1% TFA in acetonitrile) rising linearly from 5% to 95% of eluent IV during t = 5–35 min
gradient A), from 50% to 95% of eluent IV during t = 5–40 min (gradient B) or from 50% to 95% of eluent
(
IV during t = 5–25 min (gradient C) with a flow rate of 1.0 ml/min. Preparative HPLC purification was
performed on a system equipped with a C8 column (250 × 21.2 mm, 5 m, 100 Å), a diode array UV detector
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and an evaporative light-scattering detector (ELSD) at a flow rate of 20 mL/min. The applied gradients using
eluent III (wateracetonitrileTFA, 95:5:0.1) and IV (0.1% TFA in acetonitrile) are specified for each
individual compound. Fractions containing the target compound were identified using UPLC-MS and
analytical HPLC. Selected fractions were pooled and lyophilized. H NMR and 13C NMR spectra were
recorded at 298 K with a cryogenically cooled probe, at 600 MHz and 151 MHz, respectively. Chemical shifts
are reported in ppm, relative to deuterated solvent as internal standard ( = CDCl 7.26 ppm, CD OD
1
H
3
3
3
.31 ppm, CD CN 1.94, C D 7.16;  = CDCl 77.16, CD OD 49.00, CD CN 1.32, C D 128.06). Coupling
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C
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constants (J) are reported in Hz. Multiplicities of NMR signals are reported as follows: s, singlet; br, broad
singlet; d, doublet; t, triplet; q, quartet; m, multiplet. Assignments of peak identities are based on 2D NMR
experiments (COSY, HSQC, HMBC). The following abbreviations are used for assignments: CH , aromatic
ar
proton/carbon; C , quaternary carbon. High-resolution mass spectra (HRMS) were recorded using quadrupole
q
time-of-flight (TOF) mass spectrometer equipped with an electrospray (ESI) source. Alternatively, they were
recorded on an UHPLC equipped with a diode array detector and coupled to a QTOF mass spectrometer
operated in positive electrospray or by either MALDI or ESI.
Crystallization – vapor diffusion. The peptoid hexamer (5 mg) was placed in a 1.5 mL vial and dissolved in
a minimum amount of toluene. The small vial was placed in a 20 mL vial and the space around it was filled
with 2 mL acetonitrile. The large vial was closed tightly and left for vapour diffusion at room temperature. The
crystals were formed within 23 weeks but were left in the solvent until X-ray diffraction experiments were
carried out.
X-ray crystallographic analysis of compound 21. Single crystals suitable for X-ray diffraction studies
were grown from a solution in toluene and acetonitrile. A single crystal was mounted and immersed in a
stream of nitrogen gas [T = 123(1) K]. Data were collected, using graphite-monochromated MoK radiation
(
 = 0.71073 Å) on a diffractometer. Data collection and cell refinement were performed using the Bruker
114
115
Apex2 Suite software. Data reduction using SAINT and multi-scan correction for absorption using
SADABS-2016-2116 were performed within the Apex2 Suite. The crystal data, data collection and the
refinement data are given in Table S1.
Structure solution and refinement of compound 21. Positions of all non-hydrogen atoms were found by
direct methods (SHELXS97).117 Full-matrix least-squares refinements (SHELXL97)117 were performed on
2
2
2 2
F , minimizing w(F – kF ) , with anisotropic displacement parameters of the non-hydrogen atoms, except
o
c
for acetonitrile. Acetonitrile was refined with isotropic displacement parameters due to partial occupancy and
observed disorder. Toluene was refined with fixed geometry as a regular aromatic ring. The positions of
hydrogen atoms were located in subsequent difference electron density maps and were included in calculated
position with fixed isotropic displacement parameters (U = 1.2U for CH and CH and U = 1.5U for
iso
eq
2
iso
eq
CH ). Refinement (space group P2 : 1139 parameters, 16109 unique reflections) converged at R = 0.061,
3
1
F
2
-1
2
2
2
2
wR = 0.129 [11758 reflections with Fo > 4(F ); w = ( (F ) + (0.0562P) + 0.5983P), where P = (F +
F
o
o
o
2
-3
2
F )/3; S = 1.020]. The residual electron density varied between –0.27 and 0.32 eÅ . Non-centrosymmetric
c
space group is assigned. The absolute configuration could not be determined (Flack = 0(2)).118 However, the
configuration was known from stereoselective synthesis of compound 21.
Complex scattering factors for neutral atoms were taken from International Tables for Crystallography as
incorporated in SHELXL97.117, 119
Supplementary CIF, which includes fractional atomic coordinates, a list of anisotropic displacement
parameters, and a complete list of geometrical data is available free of charge from the Cambridge
Crystallographic Data Centre (CCDC) via www.ccdc.cam.ac.uk/data_request/cif (Compound 21: CCDC
1
857129).
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Circular dichroism (CD) spectroscopy. Spectra were acquired with a spectrophotometer equipped with a
water circulating bath and a nitrogen gas flowmeter with sensor. Measurements were carried out in 1 mm
quartz cuvettes and compound solutions in acetonitrile were prepared using dry weight of the lyophilized
material followed by dilution to give the desired concentrations. Concentrations were verified using a
NanoDrop to measure the absorbance at  = 280 nm (A280 = ·c·l). The CD data were obtained at 298 K with
a bandwidth of 1.00 nm, a scanning speed of 20 nm/min, 3 accumulations and a data integration time of 4 s.
The measurements were performed in triplicates. Spectra were recorded in millidegree units (m°), corrected
for solvent contributions and normalized to mean residue ellipticity [] = 100·m°/l·c·n, with c being the
concentration in mM, l being the path length (0.1 cm) and n being the number of peptoid amide bonds.
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(
S)-2-Methyl-N-(naphthalen-1-ylmethylene)propane-2-sulfinamide (10). To a 0.5 M solution of Ti(OEt)4
(10.4 mL, 11.3 g, 49.5 mmol, 2.00 equiv) in anhydrous THF under nitrogen atmosphere, 1-naphthaldehyde
(3.70 mL, 4.25 g, 27.2 mmol, 1.10 equiv) and (S)-t-butanesulfineamide (3.00 g, 24.8 mmol, 1.00 equiv) were
added. The reaction mixture was stirred at room temperature for 6 h. It was then poured into a flask with brine
(100 mL) upon rapid stirring. The suspension was filtered through a pad of Celite, and the filter cake was
washed well with EtOAc. The filtrate was washed with brine (2 × 100 mL) and the aqueous layer was extracted
with EtOAc (1 × 50 mL). The combined organic phases were dried over MgSO and concentrated in vacuo.
4
The residue was purified using column chromatography (short flash column as product is labile on silica,
0
→1.5% MeOH in CH Cl ) to give the sulfinimide 10 as a yellow oil that solidified upon storage at 4 °C (5.40
2 2
1
g, 84%). R = 0.18 (CH Cl ). H NMR (600 MHz, CD CN):  = 1.27 (s, 9 H, 3 × CH ), 7.59 – 7.65 (m, 2 H,
f
2
2
3
3
2
× CH ), 7.66 – 7.71 (m, 1 H, CH ), 8.00 (d, J = 8.2 Hz, 1 H, CH ), 8.08 (d, J = 7.2 Hz, 1 H, CH ), 8.10 (d,
ar ar ar ar
13
1
J = 8.2 Hz, 1 H, CH ), 9.03 (d, J = 8.6 Hz, 1 H, CH ), 9.08 (s, 1 H, N=CH). C{ H} NMR (151 MHz,
ar
ar
CD CN):  = 22.7 (3 × CCH ), 58.1 (C(CH ) ), 125.3 (CH ), 126.4 (CH ), 127.6 (CH ), 129.2 (CH ), 129.9
3
3
3 3
ar
ar
ar
ar
(
CH ), 130.4 (naphthyl-C ), 131.9 (naphthyl-C ), 133.4 (CH ), 134.3 (CH ), 135.0 (naphthyl-C ), 163.6
ar q q ar ar q
+
+
(N=CH). HRMS (MALDI-TOF) m/z: calcd for [M + H] , C H NOS , 260.1104; found 260.1110.
15 18
(S)-2-Methyl-N-((S)-1-(naphthalen-1-yl)pentyl)propane-2-sulfinamide (11). A solution of sulfinimide 10
1.00 g, 3.86 mmol, 1.00 equiv) in anhydrous THF (100 mL) was cooled to –78°C and subsequently treated
(
with dropwise addition of n-BuLi (2.30 M in hexane) (3.35 mL, 0.49 g, 7.71 mmol, 2.00 equiv). The reaction
mixture was stirred at –78°C for 2 h and then quenched by addition of sat. aq. NH Cl (15 mL). The mixture
4
was diluted with EtOAc (20 mL), the phases were separated and the organic phase was washed with water
(
50 mL). Then it was dried over MgSO and concentrated in vacuo. The residue was purified by VLC
4
(5→12.5% EtOAc in heptane) to give sulfinamide 11 as a yellow oil (781 mg, 63%). R = 0.35 (heptane–
f
1
EtOAc, 2:1). H NMR (600 MHz, CD CN):  = 0.85 (t, J = 7.1 Hz, 3 H, CH CH ), 1.13 (s, 9 H, 3 × CCH ),
3
2
3
3
1
4
8
.26 – 1.35 (m, 3 H, CH CH CH /CH CH ), 1.36 – 1.43 (m, 1 H, CH CH CH ), 1.96 – 2.03 (m, 2 H, NCHCH ),
2 2 2 2 3 2 2 2 2
.32 (d, J = 6.8 Hz, 1 H, NH), 5.10 (q, J = 6.8 Hz, 1 H, NCH), 7.49 – 7.53 (m, 2 H, 2 × CH ), 7.56 (ddd, J =
ar
.5, 6.8, 1.5 Hz, 1 H, CH ), 7.64 (d, J = 6.7 Hz, 1 H, CH ), 7.82 (d, J = 8.2 Hz, 1 H, CH ), 7.91 – 7.93 (m, 1
ar
ar
ar
1
3
1
H, CH ), 8.21 (d, J = 8.5 Hz, 1 H, CH ). C{ H} NMR (151 MHz, CD CN):  = 14.3 (CH ), 23.0 (3 × CCH ),
ar
ar
3
3
3
23.2 (CH CH ), 29.3 (CH CH CH ), 38.0 (NHCHCH ), 56.2 (NCH), 56.5 (C(CH ) ), 124.1 (CH ), 125.4
2
3
2
2
2
2
3 3
ar
(CH ), 126.4 (CH ), 126.6 (CH ), 127.1 (CH ), 128.7 (CH ), 129.8 (CH ), 131.8 (naphthyl-C ), 134.9
ar
ar
ar
ar
ar
ar
q
+
+
(
naphthyl-C ), 140.5 (naphthyl-C ). UPLC-MS t = 2.20 min, m/z: calcd for [M + H] , C H NOS , 318.19;
q q R 19 28
found 318.53.
(S)-1-(1-Naphthyl)pentyl-1-amine·HCl (12). The sulfinamide 11 (120 mg, 0.378 mmol, 1.00 equiv) was
dissolved in a 1:1 mixture of MeOH and 2.0 M HCl in diethyl ether (6.00 mL) and stirred at room temperature
for 1 h. The mixture was concentrated and precipitated with diethyl ether. After cooling to 5 °C for 1 h, the
precipitate was collected by filtration and washed with diethyl ether to give the amine hydrochloride 12 as a
1
white solid (81.3 mg, 86%). R = 0.68 (10% MeOH, 0.25% NH in EtOAc). H NMR (600 MHz, CD OD):
f
3
3

= 0.87 (t, J = 7.2 Hz, 3 H, CH ), 1.18 – 1.27 (m, 1 H, CH CH CH ), 1.31 – 1.42 (m, 3 H,
3 2 2 2
CH CH CH /CH CH ), 2.08 – 2.20 (m, 2 H, NCHCH ), 5.25 (t, J = 7.3 Hz, 1 H, NCH), 7.57 – 7.62 (m, 2 H,
2
2
2
2
3
2
2
8
× CH ), 7.65 (ddd, J = 8.5, 6.8, 1.4 Hz, 1 H, CH ), 7.68 (dd, J = 7.3, 1.1 Hz, 1 H, CH ), 7.97 (m, 2 H, CH ),
ar ar ar ar
1
3
1
.17 (d, J = 8.5 Hz, 1 H, CH ). C{ H} NMR (151 MHz, CD OD):  = 14.1 (CH ), 23.4 (CH CH ), 28.9
ar
3
3
2
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(CH CH CH ), 36.0 (NCHCH ), 51.2 (NCH), 123.1 (CH ), 124.5 (CH ), 126.5 (CH ), 127.4 (CH ), 128.3
2 2 2 2 ar ar ar ar
(
CH ), 130.3 (CH ), 130.7 (CH ), 132.3 (naphthyl-C ), 134.7 (naphthyl-C ), 135.5 (naphthyl-C ). HRMS
ar ar ar q q q
+
+
(MALDI-TOF) m/z: calcd for [M + H] , C H N , 214.1590; found 214.1597.
1
5
20
1
-(3-Bromopropyl)-2,5-dimethyl-1H-pyrrole (23). A solution of KOH (0.51 g, 9.14 mmol, 1.00 equiv) in
MeOH (4.00 ml) and water (0.20 ml) was added over 1 h to a mixture of 3-bromopropylamine hydrobromide
2.00 g, 9.14 mmol, 1.00 equiv), hexane-2,5-dione (1.29 ml, 1.25 g, 10.9 mmol, 1.20 equiv) and MeOH (5.00
(
ml) which was boiling under reflux. The reaction mixture was refluxed for 2 h more, cooled and diluted with
Et O (10 mL). It was washed with brine, 2 M aq. HCl, sat. aq. NaHCO , and brine (10 mL each). The organic
0
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9
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9
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9
0
2
3
phase was dried over Na SO and the solvent was evaporated. The bromide 23 was obtained as a yellow oil
2
4
1
that turned brown upon storage at 4 °C. R = 0.65 (heptane–EtOAc, 3:1). H NMR (600 MHz, CD CN):  =
f
3
2.09 – 2.12 (m, 2 H, CH CH CH ), 2.18 (s, 6 H, 2 × CH ), 3.47 (t, J = 6.4 Hz, 2 H, CH Br), 3.86 – 3.91 (m, 2
H, NCH CH ), 5.65 (s, 2 H, pyrrole-CH). C{ H} NMR (151 MHz, CD CN):  = 12.6 (2 × CH ), 31.8
(CH Br), 34.6, (CH CH CH ), 42.6 (NCH ), 106.3 (2 × pyrrole-CH), 128.0 (2 × CCH ). UPLC-MS t = 2.13
2
2
2
3
2
1
3
1
2
2
3
3
2
2
2
2
+
2
3
R
+
min, m/z: calcd for [M + H] , C H BrN , 216.04; found 216.05.
9
15
(
(
S)-N-((S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(naphthalen-1-yl)butyl)-2-methylpropane-2-sulfinamide
24). Bromide 23 (2.66 g, 12.3 mmol, 2.00 equiv) was dissolved in dry THF (130 mL) and cooled to –78 °C
under nitrogen atmosphere. Then, n-BuLi (4.94 mL, 0.79 g, 12.3 mmol, 2.00 equiv) was added over 30 min
and the mixture was stirred at –78 °C for 1 h. A solution of the aldimine 10 (1.60 g, 6.17 mmol, 1.00 equiv) in
dry THF (30.0 mL) was added dropwise and the reaction mixture was stirred at –78 °C for 1.5 h. The reaction
was quenched by addition of sat. aq. NH Cl (40 mL). The mixture was diluted with EtOAc (50 mL) and the
4
organic phase was washed with water (100 mL). The aqueous phase was extracted with EtOAc (2  100 mL)
and the combined organic phases were dried with MgSO . The solvent was evaporated and the crude residue
4
was purified by column chromatography (heptane–EtOAc, 3:1→2:1) to give the product 24 as a yellow oil
1
(1.27 g, 52%). R = 0.26 (heptane–EtOAc, 2:1). H NMR (600 MHz, CD OD):  = 1.14 (s, 9 H, 3 × CH ),
f
3
3
1.58 – 1.68 (m, 1 H, CH CH CH ), 1.73 – 1.82 (m, 1 H, CH CH CH ), 2.02 – 2.06 (m, 2 H, CHCH CH ), 2.07
2
2
2
2
2
2
2
2
(s, 6 H, 2 × pyrrole-CH ), 3.74 (t, J = 7.5 Hz, 2 H, CH CH CH N), 5.15 (t, J = 7.0 Hz, 1 H, NCH), 5.60 (s, 2
3
2
2
2
H, pyrrole-CH), 7.45 – 7.50 (m, 2 H, 2 × CH ), 7.54 (ddd, J = 8.4, 6.7, 1.5 Hz, 1 H, CH ), 7.60 (d, J = 7.1 Hz,
ar
ar
1 H, CH ), 7.80 (d, J = 8.2 Hz, 1 H, CH ), 7.88 (dd, J = 8.1, 1.4 Hz, 1 H, CH ), 8.14 (d, J = 8.5 Hz, 1 H,
ar
ar
ar
13
1
CH ). C{ H} NMR (151 MHz, CD OD):  = 12.6 (2 × pyrrole-CH ), 23.1 (3 × C(CH ) ), 29.1 (CH CH CH ),
ar
3
3
3 3
2
2
2
3
1
1
5.3 (CHCH CH ), 44.0 (CH CH CH N), 56.2 (NCH), 57.3 (C(CH ) ), 106.0 (2 × pyrrole-CH), 124.0 (CH ),
25.6 (CH ), 126.3 (CH ), 126.6 (CH ), 127.3(CH ), 128.1 (2 × pyrrole-C ), 129.1 (CH ), 130.0 (CH ),
32.3 (naphthyl-C ), 135.5 (naphthyl-C ), 139.4 (naphthyl-C ). HRMS (ESI-TOF) m/z: calcd for [M + H] ,
2 2 2 2 2 3 3 ar
ar
ar
ar
ar
q
ar
ar
+
q
q
q
+
C H OSN , 397.2308; found 397.2308.
2
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2
(
S)-N-((S)-4-amino-1-(naphthalen-1-yl)butyl)-2-methylpropane-2-sulfinamide (25). Under nitrogen
atmosphere, the sulfinamide 24 (2.65 g, 6.68 mmol, 1.00 equiv) was dissolved in 80.0 mL 2-propanol–water
:1. Triethylamine (9.26 mL, 6.76 g, 66.8 mmol, 10.0 equiv) and hydroxylamine hydrochloride (6.96 g, 100
4
mmol, 15.0 equiv) were added. The reaction mixture was stirred under reflux for 18 h. After total consumption
of the starting material occurred, the mixture was cooled down to room temperature and diluted with EtOAc
(50 mL). The phases were seperated and the organic phases were washed with 2 M aq. NaOH (3 × 30 mL).
The aqueous phases were combined and extracted with EtOAc (3  100 mL).The combined organic phases
were dried over MgSO and evaporated to dryness. The crude residue was purified by column chromatography
4
(5% MeOH, 1% NH in CH Cl ) to give the sulfinamide 25 as a yellow oil (1.30 g, 61%). R = 0.11 (5%
3
2
2
f
1
MeOH, 1% NH in CH Cl ). H NMR (600 MHz, CD OD):  = 1.20 (s, 9 H, 3 × CH ), 1.48 – 1.59 (m, 1 H,
3
2
2
3
3
CH CH CH ), 1.64 – 1.72 (m, 1 H, CH CH CH ), 2.06 – 2.14 (m, 2 H, CHCH CH ), 2.64 – 2.74 (m, 2 H,
2
2
2
2
2
2
2
2
CH CH CH N), 5.21 (t, J = 7.0 Hz, 1 H, NCH), 7.50 – 7.55 (m, 2 H, 2 × CH ), 7.56 – 7.60 (m, 1 H, CH ),
2
2
2
ar
ar
7
1
4
1
.71 (d, J = 6.9 Hz, 1 H, CH ), 7.84 (d, J = 8.2 Hz, 1 H, CH ), 7.91 – 7.93 (m, 1 H, CH ), 8.21 (d, J = 8.5 Hz,
ar ar ar
1
3
1
H, CH ). C{ H} NMR (151 MHz, CD OD):  = 23.1 (3 × CH ), 30.7 (CH CH CH ), 35.8 (CHCH CH ),
ar
3
3
2
2
2
2
2
2.4 (CH CH CH N), 56.4 (NCH), 57.4 (C(CH ) ), 124.0 (CH ), 125.7 (CH ), 126.4 (CH ), 126.6 (CH ),
2
2
2
3 3
ar
ar
ar
ar
27.3 (CH ), 129.0 (CH ), 130.0 (CH ), 132.3 (naphthyl-C ), 135.5 (naphthyl-C ), 139.8 (naphthyl-C ).
ar
ar
ar
q
q
q
+
+
HRMS (ESI-TOF) m/z: calcd for [M + H] , C H OSN , 319.1839; found 319.1836.
1
8
27
2
Allyl ((S)-4-(((S)-tert-butylsulfinyl)amino)-4-(naphthalen-1-yl)butyl)carbamate (26).Under nitrogen
atmosphere, the sulfinamide 25 (1.26 g, 3.95 mmol, 1.00 equiv) was dissolved in 30.0 mL anhydrous CH Cl .
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After cooling to 0 °C, iPr NEt (1.38 mL, 1.02 g, 7.91 mmol, 2.00 equiv) and allyl chloroformate (0.51 mL,
2
572 mg, 4.74 mmol, 1.20 equiv) were added and the reaction mixture was stirred for 1 h at this temperature.
After total consumption of the starting material occurred, the mixture was diluted with CH Cl (10 mL) and
2
2
washed with 0.1 M HCl (3 × 30 mL). The combined organic phases were dried over MgSO and the solvent
4
was evaporated. The sulfinamide 26 was obtained as an orange foam (1.51 g, 92%). R = 0.20 (heptane–EtOAc,
f
1
1
(
:3). H NMR (600 MHz, CD OD):  = 1.17 (s, 9 H, 3 × CH ), 1.50 – 1.62 (m, 1 H, CH CH CH ), 1.63 – 1.74
3
3
2
2
2
m, 1 H, CH CH CH ), 2.03 (q, J = 7.6 Hz, 2 H, CHCH CH ), 3.13 (td, J = 6.9, 2.4 Hz, 2 H, CH CH CH N),
2 2 2 2 2 2 2 2
4
.49 (dt, J = 5.4, 1.6 Hz, 2 H, OCH CH), 5.14 (dd, J =10.5, 1.5 Hz, 1 H, CH=CH ), 5.19 (t, J = 7.0 Hz, 1 H,
2 2
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NCHCH ), 5.26 (dd, J = 17.3, 1.9 Hz, 1 H, CH=CH ), 5.81 – 5.98 (m, 1 H, CH=CH ), 7.45 – 7.51 (m, 2 H, 2
2
2
2
×
CH ), 7.51 – 7.56 (m, 1 H, CH ), 7.66 (dd, J = 7.3, 1.2 Hz, 1 H, CH ), 7.80 (d, J = 8.2 Hz, 1 H, CH ), 7.88
ar ar ar ar
1
3
1
(dd, J = 8.1, 1.6 Hz, 1 H, CH ), 8.16 (d, J = 8.5 Hz, 1 H, CH ). C{ H} NMR (151 MHz, CD OD):   23.2
ar
ar
3
(3 × CH ), 28.0 (CH CH CH ), 35.6 (CHCH CH ), 41.5 (CH CH CH N), 56.3 (NCHCH ), 57.5 (C(CH ) ),
3 2 2 2 2 2 2 2 2 2 3 3
6
6.2 (OCH CH), 117.3 (CH=CH ), 124.0 (CH ), 125.6 (CH ), 126.4 (CH ), 126.6 (CH ), 127.3 (CH ), 129.0
2 2 ar ar ar ar ar
(
CH ), 130.0 (CH ), 132.2 (naphthyl-C ), 134.5 (CH=CH ), 135.4 (naphthyl-C ), 139.9 (naphthyl-C ), 158.8
ar ar q 2 q q
+
+
(NCOO). UPLC-MS t = 2.29 min, m/z: calcd for [M + H] , C H O SN , 403.20; found 403.19.
R
22 31
3
2
Allyl (S)-(4-amino-4-(naphthalen-1-yl)butyl)carbamate (27). The sulfinamide 26 (1.49 g, 3.69 mmol, 1.00
equiv) was dissolved in 20.0 mL of a 1:1 mixture of MeOH and 2 M HCl in diethyl ether and stirred at room
temperature for 1 h. The mixture was concentrated and the crude residue was purified by column
chromatography (8% MeOH, 1% NH in EtOAc) to give the amine 27 as a yellow oil (1.02 g, 93%). R = 0.23
3
f
1
(
–
8% MeOH, 1% NH in EtOAc). H NMR (600 MHz, CD CN):  = 1.47 – 1.55 (m, 1 H, CH CH CH ), 1.57
3
3
2
2
2
1.63 (m, 1 H, CH CH CH ), 1.63 – 1.72 (m, 1 H, CH CH CH ), 1.79 – 1.88 (m, 1 H, CH CH CH ), 3.09 (q,
2 2 2 2 2 2 2 2 2
J = 6.8 Hz, 2 H, CH CH N), 4.46 (d, J = 5.3 Hz, 2 H, OCH CH), 4.73 (dd, J = 7.9, 5.2 Hz, 1 H, H NCH), 5.14
2
2
2
2
(
dd, J = 10.5, 1.6 Hz, 1 H, CH=CH ), 5.24 (dd, J = 17.2, 1.8 Hz, 1 H, CH=CH ), 5.63 (s, 1 H, NHCO), 5.85 –
2
2
5
.93 (m, 1 H, CH=CH ), 7.47 – 7.51 (m, 2 H, 2 × CH ), 7.51 – 7.54 (m, 1 H, CH ), 7.66 (d, J = 6.8 Hz, 1 H,
2 ar ar
1
3
1
CH ), 7.77 (d, J = 8.2 Hz, 1 H, CH ), 7.88 – 7.91 (m, 1 H, CH ), 8.20 (d, J = 8.4 Hz, 1 H, CH ). C{ H}
ar
ar
ar
ar
NMR (151 MHz, CD CN):  = 27.9 (CH CH CH ), 37.2 (CH CH CH ), 41.6 (CH CH CH ), 51.7 (H NCH),
3
2
2
2
2
2
2
2
2
2
2
6
5.5 (OCH CH), 117.2 (CH =CH), 123.6 (CH ), 124.3 (CH ), 126.4 (CH ), 126.6 (CH ), 126.8 (CH ), 127.8
2 2 ar ar ar ar ar
(
CH ), 129.7 (CH ), 131.9 (naphthyl-C ), 134.8 (CH =CH), 134.9 (naphthyl-C ), 144.2 (naphthyl-C ), 157.2
ar ar q 2 q q
+
+
(NCOO). HRMS (ESI-TOF) m/z: calcd for [M + H] , C H O SN , 299.1754; found 299.1754.
18 23
2
2
(Azidomethyl)benzene (S15). Benzyl bromide (500 mg, 2.90 mmol, 1.00 equiv) was dissolved in a 4:1
mixture of acetone and water (30.0 ml). Sodium azide (235 mg 3.60 mmol, 1.50 equiv) was added, and the
reaction was stirred for 18 h at room temperature. The mixture was washed with water (100 ml) and
extracted with diethyl ether (3 × 100 ml), then concentrated in vacuo. The azide S15 was obtained as a clear
1
oil (233 mg 60%). H NMR (600 MHz, CDCl ):  = 4.35 (s, 2 H, NCH ), 7.31 – 7.37 (m, 3 H, 3 × CH ),
3
2
ar
1
3
1
7
.38 – 7.42 (m, 2 H, 2 × CH ). C{ H} NMR (151 MHz, CDCl ):  = 55.0 (CH N), 128.4 (2 × CH ), 128.5
(CH ), 129.0 (2 × CH ), 135.6 (C ). The data is in agreement with the literature.
ar
3
2
1
ar
20
ar
ar
q
(1-Benzyl-1H-1,2,3-triazol-4-yl)methanamine (S16). Azide S15 (65.8 mg, 0.48 mmol, 1.20 equiv) and
propargylamine (22.0 mg, 0.40 mmol, 1.00 equiv) were dissolved in tert-butanol (1.00 ml) and water (1.00
ml). Then CuSO (4.84 mg, 0.02 mmol, 0.05 equiv), sodium ascorbate (56.1 mg, 0.27 mmol, 0.68 equiv) and
4
TBTA (10.6 mg, 0.02 mmol, 0.05 equiv) were added. After stirring for 18 h, the reaction was quenched with
water (100 ml) and extracted with CH Cl (3 × 100 ml), dried with MgSO and concentrated in vacuo. The
2
2
4
crude residue was purified via VLC (0→10% MeOH, 1% NH in CH Cl ) yielding a white solid (42.0 mg,
3
2
2
1
56%). H NMR (400 MHz, CDCl ):  = 1.26 (s, 2 H, NH ), 3.96 (s, 2 H, CH NH ), 5.50 (s, 2 H, PhCH ), 7.26
3
2
2
2
2
+
–
7.30 (m, 2 H, 2 × CH ), 7.33 – 7.40 (m, 4 H, 4 × CH ). UPLC-MS t = 0.52 min, m/z: calcd for [M + H] ,
C H N , 189.1; found 189.1. The data is in agreement with the literature.
ar ar R
+
121
1
0
13
4
tert-Butyl (S)-but-3-yn-2-ylcarbamate (S17). Boc-L-alanine (946 mg, 5.00 mmol, 1.00 equiv), N,O-
dimethylhydroxylamine·HCl (537 mg, 5.50 mmol, 1.10 equiv) and HOBt (84.0 mg, 5.50 mmol, 1.10 equiv)
were dissolved in dry CH Cl (20.0 mL) under nitrogen atmosphere and cooled to 0 °C. Then, iPr NEt (1.74
2
2
2
mL, 10.0 mmol, 2.00 equiv) and EDC·HCl (1.43 g, 7.50 mmol, 1.50 equiv) were added and the mixture was
stirred for 2 h. The mixture was diluted with EtOAc (10 mL) and washed with 5% aq. KHSO (2 × 100 mL),
4
5
% aq. NaHCO (2 × 100 mL), and brine (2 × 100 mL). The organic phase was dried over MgSO and
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concentrated in vacuo yielding the crude Weinreb amide as a colorless oil. Under nitrogen atmosphere, LiAlH4
(228 mg, 6.00 mmol, 1.20 equiv) was added at 0°C to a solution of the Weinreb amide in dry THF (25.0 mL).
After stirring for 1 h, the reaction was quenched by slow addition of 5% aq. KHSO (50 ml). The mixture was
4
diluted with EtOAc (60 mL), and washed with 5% aq. KHSO (2 × 100ml), 5% aq. NaHCO (2 × 100 ml) and
4
3
brine (2 × 100 ml). The organic phase was dried with MgSO and concentrated in vacuo yielding the crude
4
aldehyde. K CO (2.07 g, 15.0 mmol, 3.00 equiv) and p-toluenesulfonylazide (1.18 g, 6.00 mmol, 1.20 equiv)
2
3
were suspended in dry MeCN (14.0 mL) under nitrogen atmosphere. Dimethyl-(2-oxopropyl)-phosphonate
(1.00 g, 6.00 mmol, 1.20 equiv) was added and the mixture was stirred for 2 h at room temperature. The
aldehyde was dissolved in dry MeOH (4.00 mL) and added to the reaction mixture, which was left stirring 18
h before being concentrated in vacuo. The resulting residue was redissolved in EtOAc (30 mL), washed with
0
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9
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3
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7
8
9
0
water (2 × 100 ml) and brine (2 × 100 ml). The organic phase was dried over MgSO and concentrated in
4
vacuo. The crude residue was purified via VLC (0→2% MeOH in CH Cl ) yielding alkyne S17 as a white
2
2
1
solid (113 mg, 13% over three steps). H NMR (600 MHz, CDCl ):  = 1.39 (d, J = 6.9 Hz, 3 H, CHCH ),
3
3
1.45 (s, 9 H, 3 × CCH ), 2.25 (d, J = 2.3 Hz, 1 H, CHCCHNH), 4.48 (br, 1 H, CHCCHNH), 4.70 (br, 1 H,
3
1
3
1
NH). C{ H} NMR (151 MHz, CDCl ):  = 22.7 (CH ), 28.5 (3 × CCH ), 38.5 (CHNH), 70.3 (CHCCHNH),
3
3
3
122
8
0.1 (C(CH ) ), 84.7 (CHCCHNH), 154.8 (COO). The data is in agreement with the literature.
3 3
(S)-1-(1-Benzyl-1H-1,2,3-triazol-4-yl)ethan-1-amine (S18). Azide S15 (32.9 mg, 0.24 mmol, 1.20 equiv)
and alkyne S17 (33.0 mg, 0.20 mmol, 1.00 equiv) were dissolved in tert-butanol (1.00 ml) and water (1.00
ml). Subsequently, CuSO (1.60 mg, 0.01 mmol, 0.05 equiv), sodium ascorbate (19.8 mg, 0.10 mmol,
4
0
.50 equiv) and TBTA (5.30 mg, 0.01 mmol, 0.05 equiv) were added. After stirring for 18 h the reaction was
quenched with water (100 ml), extracted with CH Cl (3 × 100 ml), dried over MgSO and concentrated in
2
2
4
vacuo. The crude residue was purified via VLC (0→2% MeOH, 0.5% NH in CH Cl ) yielding the Boc-
3
2
2
protected product as a white solid (51.0 mg, 84%). The carbamate (51.0 mg, 0.17 mmol, 1.00 equiv) was
dissolved in CH Cl (4.00 ml). TFA (1.00 ml) was added and the mixture was stirred for 2 h at room
2
2
temperature. The mixture was concentrated in vacuo (coevaporation with toluene and CH Cl ). The amine S18
2
2
1
was obtained as the TFA salt in form of a yellow solid (45.0 mg, 84%). H NMR (600 MHz, CD CN):  =
3
1.62 (d, J = 6.7 Hz, 3 H, CH ), 4.67 (q, J = 6.9 Hz, 1 H, CHCH ), 5.53 (s, 2 H, CH ), 7.27 – 7.31 (m, 2 H, 2 ×
CH ), 7.32 – 7.39 (m, 3 H, 3 × CH ), 7.93 (s, 1 H, triazole-CH), 8.17 (br, 2 H, NH ). C{ H} NMR (151
3
3
2
13
1
ar
ar
2
MHz, CD CN):  = 19.2 (CH ), 44.8 (CHCH ), 54.7 (CH ), 123.9 (triazole-CH), 129.0 (2 × CH ), 129.4
3
3
3
2
ar
(
CH ), 129.9 (2 × CH ), 136.5 (C ), 146.4 (triazole-C ). HRMS (ESI-TOF) m/z: calcd for [M +
ar ar ar ar
+
+
H] , C H N , 203.1291; found 203.1290.
1
1
15
4
tert-Butyl 4-(3-methoxy-3-oxopropyl)piperazine-1-carboxylate (S30). Methyl-3-bromopropionate (2.69 g,
6.1 mmol, 1.50 equiv) was dissolved in 100 mL MeCN. Then, iPr NEt (2.81 mL, 2.08 g, 16.1 mmol, 1.50
1
2
equiv) and Boc-piperazine (2.00 g, 10.7 mmol, 1.00 equiv) were added and the reaction mixture was stirred at
0 °C for 18 h. The solvent was removed in vacuo and the residue resuspended in acetone. The remaining
insoluble solids were filtered off and the filtrate was concentrated. The crude was purified via column
chromatography (5% MeOH in CH Cl ) to give the piperazine derivative S30 as a yellow oil (2.47 g, 85%).
5
2
2
1
R = 0.45 (5% MeOH in CH Cl ). H NMR (600 MHz, CDCl ):  = 1.44 (s, 9 H, 3 × CCH ), 2.59 (br, 4 H, 2
f
2
2
3
3
× OOCNCH CH N), 2.68 (br, 2 H, CH COOCH ), 2.87 (br, 2 H, NCH CH COO), 3.55 (br, 4 H, 2 ×
2
2
2
3
2
2
1
3
1
OOCNCH CH N), 3.67 (s, 3 H, OCH ). C{ H} NMR (151 MHz, CDCl ):  = 28.5 (3 × CCH ), 31.4
2
2
3
3
3
(
CH COOCH ), 42.4 (OOCNCH CH N), 43.3 (OOCNCH CH N), 52.0 (OCH ), 52.7 (2 × OOCNCH CH N),
2 3 2 2 2 2 3 2 2
5
3.4 (NCH CH COO), 80.2 (C(CH ) ), 154.6 (COOCH ), 172.4 (COOC(CH ) ). UPLC-MS t = 0.68 min,
2
2
3 3
+
3
3 3
R
+
123
m/z: calcd for [M + H] , C H O N , 273.18; found 273.18. The data is in agreement with the literature.
1
3
25
4
2
Allyl 4-(3-methoxy-3-oxopropyl)piperazine-1-carboxylate (S31). The Boc-protected building block S30
2.45 g, 9.00 mmol, 1.00 equiv) was dissolved in 25% TFA in CH Cl (20.0 mL) and stirred at room
(
2
2
temperature for 2 h. After reaction completion the solvent was removed in vacuo. The residual brown liquid
crystallized during solvent-removal. The crystals were washed with CH Cl to give the crude product as TFA-
2
2
salt, which was used for the next reaction without further purification. Under nitrogen atmosphere, the crude
2.55 g, 8.90 mmol, 1.00 equiv) was dissolved in 70.0 mL anhydrous THF. At 0 °C, iPr NEt (6.22 mL, 4.60
(
2
g, 35.6 mmol, 2.00 equiv) and allyl chloroformate (1.42 mL, 1.61 g, 13.4 mmol, 1.50 equiv) were added and
the reaction mixture was stirred for 1 h while it was allowed to reach room temperature. After total
consumption of the starting material occurred, the mixture was diluted with EtOAc (30 mL) and washed with
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water (50 mL), 0.1 M aq. HCl (50 mL) and sat. aq. NaHCO . The organic phase was dried over MgSO and
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4
the solvent was removed in vacuo. The crude residue was purified by column chromatography (2% MeOH in
CH Cl ) to give the piperazine derivative S31 as a white oil (1.87 g, 81%). R = 0.58 (2% MeOH in CH Cl ).
2
2
f
2
2
1
H NMR (600 MHz, CDCl ): δ = 2.42 (t, J = 5.1 Hz, 4 H, 2 × OOCNCH CH N), 2.50 (t, J = 7.3 Hz, 2 H,
3
2
2
NCH CH COO), 2.70 (t, J = 7.3 Hz, 2 H, NCH CH COO), 3.48 (t, J = 5.1 Hz, 4 H, 2 × OOCNCH CH N),
2
2
2
2
2
2
3
.67 (s, 3 H, OCH ), 4.58 (dt, J = 5.6, 1.5 Hz, 2 H, OCH CH), 5.19 (dq, J = 10.5, 1.5 Hz, 1 H, CH=CH ), 5.28
3
2
2
13
1
(dq, J = 17.2, 1.5 Hz, 1 H, CH=CH ), 5.87 – 5.97 (m, 1 H, CH=CH ). C{ H} NMR (151 MHz, CDCl ): δ =
2
2
3
3
2.2 (NCH CH COO), 43.8 (2 × OOCNCH CH N), 51.8 (OCH ), 52.7 (2 × OOCNCH CH N), 53.6
2 2 2 2 3 2 2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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7
8
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9
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(
NCH CH COO), 66.2 (OCH CH), 117.5 (CH=CH ), 133.2 (CH=CH ), 155.1 (NCOO), 172.8 (CH COO).
2 2 2 2 2 2
+
+
HRMS (ESI-TOF) m/z: calcd for [M + H] , C H O N , 257.1496; found 257.1494.
1
2
21
4
2
3
-(4-((Allyloxy)carbonyl)piperazin-1-yl)propanoic acid (S32). The protected piperazine building block S31
(1.80 g, 7.02 mmol, 1.00 equiv) was dissolved in MeOH (100 mL) and 1 M aq. LiOH (100 mL) was added.
The solution was stirred at room temperature for 2 h. After dilution with water (20 mL) the aqueous solution
was acidified to pH 1 using aq. conc. HCl. It was then extracted with EtOAc (10 × 100 mL), whereas some
product stayed in the aqueous phase. The organic phase was dried over Na SO and the solvent was evaporated,
2
4
yielding crude product. The solid was washed with EtOAc to give the product S32 as a white solid (837 mg,
3.47 mmol). The remaining aqueous phase was lyophilized and the resulting mixture of product and salt was
resuspended in pyridine. The suspension was filtered and the solvent removed in vacuo to give the second
1
batch of product S32 as a white pyridine salt (814 mg, 2.53 mmol, 86% overall). H NMR (600 MHz, CD OD):
3

2
= 2.83 (t, J = 7.2 Hz, 2 H, CH COOH), 3.16 (t, J = 5.3 Hz, 4 H, 2 × OOCNCH CH N), 3.29 (t, J = 7.2 Hz,
H, NCH CH COO), 3.79 (br, 4 H, 2 × OOCNCH CH N), 4.64 (dt, J = 5.6, 1.5 Hz, 2 H, OCH CH), 5.25 (dq,
2 2 2 2 2
2
2
2
J = 10.5, 1.5 Hz, 1 H, CH=CH ), 5.35 (dq, J = 17.2, 1.5 Hz, 1 H, CH=CH ), 5.95 – 6.05 (m, 1 H, CH=CH ),
2
2
2
[
7.44 – 7.50 (m, 2 H, 2 × pyridine-NCHCH), 7.90 (tt, J = 7.7, 1.8 Hz, 1 H, pyridine-NCHCHCH), 8.54 – 8.57
1
3
1
(m, 2 H, 2 × pyridine-NCH)]. C{ H} NMR (151 MHz, CD OD):  = 30.1 (CH COOH), 42.5 (2 ×
3
2
OOCNCH CH N), 52.9 (2 × OOCNCH CH N), 54.2 (NCH CH COO), 67.8 (OCH CH), 118.3 (CH=CH ),
2
2
2
2
2
2
2
2
[
1
2
125.8 (2 × pyridine-NCHCH)], 133.9 (CH=CH ), [139.0 (pyridine-NCHCHCH), 149.7 (2 × pyridine-NCH),]
56.2 (COO), 174.2 (COO). HRMS (ESI-TOF) m/z: calcd for [M + H] , C H O N , 243.1339; found
11 19 4 2
43.1338.
2
+
+
General procedure for synthesis of -peptoid oligomers
General procedure A: Aza-Michael addition. The respective amine (2.00 equiv) was added to a solution of
the acrylated -peptoid (0.1 M) in MeOH. When amine·HCl-salts were used, iPr NEt (2.00 equiv) was added
2
to the reaction mixture additionally. The reaction mixture was stirred at 50 °C for 18 h. After completion, the
solvent was evaporated. In case of the dimeric and trimeric peptoids, the residue was redissolved in EtOAc
(
10 mL) and washed with 2 M aq. HCl (2 × 10 mL) and sat. aq. NaHCO (10 mL). The organic phase was
3
dried over MgSO , filtered and concentrated in vacuo. The residue was purified by column chromatography
4
(1→2% MeOH, 0.25% NH in CH Cl ).
3
2
2
General procedure B: Acryloylation reaction. Under nitrogen atmosphere, the peptoid (1.00 equiv) and
Et N (1.20 equiv) were dissolved in anhydrous THF (0.05 M) and the mixture was cooled to 0 °C. Acryloyl
3
chloride (1.40 equiv) was added and the solution was stirred for 1 h at this temperature. The reaction mixture
was filtered and the filter cake was washed with cold EtOAc. The combined filtrates were concentrated in
vacuo to give the crude acrylamide, which was used without further purification.
General procedure C: N-terminal acylation. To a solution of the peptoid (1.00 equiv) in anhydrous CH Cl
2
2
(
0.02 M) at 0 °C, Et N (1.40 equiv) and acetyl chloride (1.20 equiv) were added. The reaction mixture was
3
slowly allowed to reach room temperature and stirred for 1 h. The solvent was evaporated and the crude
product was used without further purification.
General procedure D: C-terminal deprotection. A solution of the peptoid (6.00 mM) in 1 M aq. LiOH–
MeOH 1:1 was stirred at room temperature for 25 h (methylester deprotection) or 48 h (t-butylester
a
deprotection) , respectively. After dilution with water (1), the solution was acidified (pH 1) with aq. conc.
HCl. This caused precipitation and the suspension was extracted with EtOAc (3). The combined organic
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layers were dried over MgSO , filtered, and concentrated. The resulting crude product was purified by column
4
chromatography (1→2% MeOH, 0.25% AcOH in CH Cl ).
2
2
a
t-butylester deprotection can also be achieved by conventional acidic deprotection (15% TFA in CH Cl ).
2
2
However, the reaction has to be monitored closely, as cleavage of a naphthylethyl group was be observed after
2
h under these conditions.

-Peptoid trimer 13. The peptoid trimer was synthesized from trimer S6 (1.91 g, 2.69 mmol, 1.00 equiv)
according to procedures C and D. The peptoid trimer 13 was obtained as a white foam after column
chromatography (1.47 g, 74%). R = 0.13 (3% MeOH, 0.25% AcOH in CH Cl ). HRMS (MALDI-TOF) m/z:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
f
2
2
+
+
calcd for [M + H] ,C H N O , 736.3765; found 736.3740. Purity according to analytical HPLC (gradient
4
7
50
3
5
A): 90%.
-Peptoid trimer 14. The peptoid trimer was synthesized from trimer S26 (600 mg, 0.80 mmol, 1.00 equiv)
according to general procedures C and D. The peptoid trimer 14 was obtained as a white foam after column
chromatography (597 mg, 97%). R = 0.26 (3% MeOH in CH Cl ). HRMS (MALDI-TOF) m/z: calcd for [M
f
2
2
+
+
+
H] , C H N O , 778.4214; found 778.4207. Purity according to analytical HPLC (gradient A): 84%.
50 56 3 5
-Peptoid trimer 15. The peptoid trimer was synthesized from trimer S23 (130 mg, 1.70 mmol, 1.00 equiv)
according to general procedures C and D. The peptoid trimer 15 was obtained as a white foam after column
chromatography (102 mg, 77%). R = 0.25 (3% MeOH in CH Cl ). HRMS (MALDI-TOF) m/z: calcd for [M +
f
2
2
+
+
H] , C H N O , 778.4214; found 778.4203. Purity according to analytical HPLC (gradient A): 92%.
5
0
56
3
5
-Peptoid trimer 16. The peptoid trimer was synthesized from dimer S21 (0.24 g, 0.38 mmol, 1.00 equiv)
according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (0.12
mL, 0.13 g, 0.76 mmol, 2.00 equiv). The peptoid trimer 16 was obtained as a white foam after column
chromatography (183 mg, 61%). R = 0.22 (3% MeOH in CH Cl ). HRMS (MALDI-TOF) m/z: calcd for [M
f
2
2
+
+
+ H] , C H N O , 792.4735; found 792.4751. Purity according to analytical HPLC (gradient A): 86%.
5
2
62
3
4
-Peptoid trimer 17. The peptoid trimer was synthesized from dimer S4 (535 mg, 1.02 mmol, 3.20 equiv)
according to general procedure B, followed by general procedure A using the (S)-1-(1-
naphthyl)pentylamine·HCl (12) (80 mg, 0.32 mmol, 1.00 equiv). The peptoid trimer 17 was obtained as a
white foam after column chromatography (117 mg, 46%). R = 0.21 (3% MeOH in CH Cl ). HRMS (MALDI-
f
2
2
+
+
TOF) m/z: calcd for [M + H] , C H N O , 792.4735; found 792.4730. Purity according to analytical HPLC
5
2
62
3
4
(gradient A): 79%.
-Peptoid trimer 18. The peptoid trimer was synthesized from dimer S4 (5.30 g, 9.16 mmol, 1.00 equiv)
according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (2.94
mL, 3.14 g, 18.3 mmol, 2.00 equiv). The peptoid trimer 18 was obtained as light yellow foam after column
chromatography (4.74 g, 69%). R = 0.20 (3% MeOH in CH Cl ). HRMS (MALDI-TOF) m/z: calcd for [M +
f
2
2
+
+
H] , C H N O , 750.4265; found 750.4279. Purity according to analytical HPLC (gradient A): 91%.
4
9
56
3
4
-Peptoid trimer 28. The peptoid trimer was synthesized from trimer S29 (225 mg, 0.27 mmol, 1.00 equiv)
according to general procedures C and D. The peptoid trimer 28 was obtained as a white foam after column
chromatography (154 mg, 66%). R = 0.27 (2% MeOH, 0.2% AcOH in CH Cl ). HRMS (ESI-TOF) m/z: calcd
f
2
2
+
+
for [M + H] , C H N O , 863.4378; found 863.4364. Purity according to analytical HPLC (gradient A):
5
3
59
4
7
9
0%.
-Peptoid trimer 29. The peptoid trimer was synthesized from dimer S27 (250 mg, 0.38 mmol, 1.00 equiv)
according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (0.10
mL, 0.10 g, 0.60 mmol, 2.00 equiv). The peptoid trimer 29 was obtained as a white foam after column
+
chromatography (174 mg, 52%). R = 0.20 (3% MeOH in CH Cl ). HRMS (ESI-TOF) m/z: calcd for [M + H] ,
f
2
2
+
C H N O , 877.4899; found 877.4927. Purity according to analytical HPLC (gradient A): 86%.
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5
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-Peptoid monomer S1. The peptoid monomer was synthesized according to general procedure A from t-
butyl acrylate (2.62 g, 20.4 mmol, 1.00 equiv) and (S)-1-(1-naphthyl)ethylamine (6.56 mL, 7.00 g, 40.8 mmol,
2
9
=
.00 equiv). The peptoid monomer S1 was obtained as a yellow oil after column chromatography (5.70 g,
1
3%). R = 0.26 (heptane–EtOAc, 3:1). H NMR (600 MHz, CDCl ):  = 1.45 (s, 9 H, 3 × CCH ), 1.53 (d, J
f
3
3
6.6 Hz, 3 H, CH ), 2.43 – 2.52 (m, 2 H, COCH ), 2.77 – 2.87 (m, 2 H, NCH ), 4.69 (q, J = 6.6 Hz, 1 H,
3
2
2
NCH), 7.53 – 7.46 (m, 3 H, 3 × CH ), 7.71 (d, J = 7.2 Hz, 1 H, CH ), 7.75 (d, J = 8.2 Hz, 1 H, CH ), 7.87
ar
ar
ar
1
3
1
(dd, J = 8.3, 1.3 Hz, 1 H, CH ), 8.18 (d, J = 8.4 Hz, 1 H, CH ). C{ H} NMR (151 MHz, CDCl ):  = 23.7
ar
ar
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
CH ), 28.3 (3 × CCH ), 36.0 (COCH ), 43.4 (NCH ), 53.7 (NCH), 80.7 (C(CH ) ), 122.9 (CH ), 123.1 (CH ),
3 3 2 2 3 3 ar ar
1
25.5 (CH ), 125.9 (CH ), 126.1 (CH ), 127.6 (CH ), 129.1 (CH ), 131.4 (naphthyl-C ), 134.1 (naphthyl-
ar ar ar ar ar q
+
+
C ), 140.5 (naphthyl-C ), 172.2 (COO). HRMS (MALDI-TOF) m/z: calcd for [M + H] , C H NO ,
q
q
19 26
2
7
6
3
00.1958; found 300.1961. The data is in agreement with literature.
-Peptoid monomer S2. The peptoid monomer was synthesized according to general procedure A from
methyl acrylate (1.32 mL, 1.26 g, 14.6 mmol, 1.00 equiv) and (S)-1-(1-naphthyl)ethylamine (4.69 mL, 5.00 g,
2
9.2 mmol, 2.00 equiv). The peptoid monomer S2 was obtained as a yellow oil after column chromatography
1
(3.55 g, 95%). R = 0.34 (3% MeOH in CH Cl ). H NMR (600 MHz, CDCl ):  = 1.52 (d, J = 6.7 Hz, 3 H,
f
2
2
3
CH ), 2.48 – 2.60 (m, 2 H, CH CH ), 2.79 – 2.91 (m, 2 H, NHCH ), 3.68 (s, 3 H, OCH ), 4.63 – 4.75 (m, 1 H,
3
2
2
2
3
NCH), 7.46 – 7.53 (m, 3 H, 3 × CH ), 7.69 (d, J = 7.1 Hz, 1 H, CH ), 7.76 (d, J = 8.0 Hz, 1 H, CH ), 7.88
ar
ar
ar
1
3
1
(dd, J = 8.0, 1.5 Hz, 1 H, CH ), 8.19 (d, J = 8.4 Hz, 1 H, CH ). C{ H} NMR (151 MHz, CDCl ):  = 23.8
ar
ar
3
(
CHCH ), 34.8 (CH CH ), 43.1 (NHCH ), 51.7 (OCH ), 53.8 (NCH), 122.9 (CH), 123.0 (CH), 125.5 (CH ),
3 2 2 2 3 ar
1
25.9 (CH ), 125.9 (CH ), 127.4 (CH ), 129.1 (CH ), 131.4 (naphthyl-C ), 134.1 (naphthyl-C ), 140.7
ar
ar
ar
ar
q
+
q
+
(naphthyl-C ), 173.4 (COOMe). HRMS (MALDI-TOF) m/z: calcd for [M + H] , C H NO , 258.1489; found
q
16 20
2
2
58.1484.
-Peptoid monomer S3. The peptoid monomer was synthesized according to general procedure A from t-
butyl acrylate (2.25 g, 17.5 mmol, 1.00 equiv) and (R)-1-(1-naphthyl)ethylamine (5.62 mL, 6.00 g, 35.0 mmol,
2
8
=
.00 equiv). The peptoid monomer S3 was obtained as a yellow oil after column chromatography (4.60 g,
1
8%). R = 0.53 (3% MeOH in CH Cl ). H NMR (600 MHz, CDCl ): δ = 1.44 (s, 9 H, 3 × CCH ), 1.56 (d, J
f
2
2
3
3
6.4 Hz ,3 H, CH ), 2.46  2.51 (m, 2 H, COCH ), 2.79 – 2.87 (m, 2 H, NCH ), 4.73 (q, J = 6.5 Hz, 1 H,
3
2
2
NCH), 7.47 – 7.53 (m, 3 H, 3 × CH ), 7.73 (d, J = 7.1 Hz , 1 H, CH ), 7.76 (d, J = 8.2 Hz, 1 H, CH ), 7.88
ar
ar
ar
1
3
1
(dd, J = 8.0, 1.3 Hz , 1 H, CH ), 8.17 (d, J = 8.4, 1 H, CH ). C{ H} NMR (151 MHz, CDCl ): δ = 23.6
ar
ar
3
(CH ), 28.3 (3 × CCH ), 35.6 (COCH ), 43.3 (NCH ), 53.8 (NCH), 80.9 (C(CH ) ), 122.9 (CH ), 123.1 (CH ),
3
3
2
2
3 3
ar
ar
1
25.6 (CH ), 125.9 (CH ), 126.1 (CH ), 127.6 (CH ), 129.1 (CH ), 131.4 (naphthyl-C ), 134.1 (naphthyl-
ar ar ar ar ar q
+
+
C ), 140.5 (naphthyl-C ), 172.2 (COO). UPLC-MS t = 1.62 min, m/z: calcd for [M + H] , C H NO ,
q
q
R
19 26
2
3
00.20; found 300.86.
-Peptoid dimer S4. The peptoid dimer was synthesized from monomer S1 (6.73 g, 19.0 mmol, 1.00 equiv)
according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (6.11
mL, 6.52 g, 38.1 mmol, 2.00 equiv). The peptoid dimer S4 was obtained as a yellow foam after column
chromatography (7.84 g, 99%). R = 0.28 (3 % MeOH in CH Cl ). HRMS (MALDI-TOF) m/z: calcd for [M
f
2
2
+
+
+
H] , C H N O , 525.3112; found 525.3119.
34 41 2 3
-Peptoid dimer S5. The peptoid dimer was synthesized from monomer S2 (2.00 g, 6.42 mmol, 1.00 equiv)
according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (2.06
mL, 2.20 g, 12.8 mmol, 2.00 equiv). The peptoid dimer S5 was obtained as a light yellow foam after column
chromatography (2.08 g, 67%). R = 0.17 (3% MeOH in CH Cl ). HRMS (MALDI-TOF) m/z: calcd for [M +
f
2
2
+
+
H] , C H N O , 483.2642; found 483.2631.
3
1
35
2
3
-Peptoid trimer S6. The peptoid trimer was synthesized from dimer S5 (2.25 g, 4.19 mmol, 1.00 equiv)
according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (1.35
mL, 1.44 g, 8.39 mmol, 2.00 equiv). The peptoid trimer S6 was obtained as a light yellow foam after column
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3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
chromatography (2.14 g, 72%). R = 0.27 (3% MeOH in CH Cl ). UPLC-MS t = 2.27 min, m/z: calcd for [M
f 2 2 R
+
+
+
H] , C H N O , 708.38; found 708.51.
46 50 3 4
-Peptoid trimer S7. The peptoid trimer was synthesized from dimer S4 (273 mg, 0.52 mmol, 1.00 equiv)
according to general procedure B, followed by general procedure A using 1-naphthylmethylamine (0.15 mL,
.16 g, 1.04 mmol, 2.00 equiv). The peptoid trimer S7 was obtained as a white foam after column
chromatography (212 mg, 55%). R = 0.15 (3% MeOH in CH Cl ). HRMS (MALDI-TOF) m/z: calcd for [M
0
f
2
2
+
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
H] , C H N O , 736.4109; found 763.4105. Purity according to analytical HPLC (gradient A): 82%.
48 54 3 4
-Peptoid trimer S8. The peptoid trimer was synthesized from peptoid dimer S4 (116 mg, 0.20 mmol, 1.00
equiv) and (S)-1-phenylethylamine (29.0 mg, 0.24 mmol, 1.20 equiv) according to general procedure A. The
peptoid trimer S8 was obtained as a white solid after column chromatography (106 mg, 68%). UPLC-MS t =
R
+
+
2.90 min, m/z: calcd for [M + H] , C H N O , 700.4; found 700.3.
4
5
54
3
4
-Peptoid dimer S9. The peptoid dimer was synthesized from monomer S3 (4.60 g, 15.4 mmol, 1.00 equiv)
according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (4.79
mL, 5.11 g, 29.9 mmol, 2.00 equiv). The peptoid dimer S9 was obtained as a white foam after column
chromatography (7.18 g, 92%). R = 0.42 (3% MeOH in CH Cl ). UPLC-MS t = 2.20 min, m/z: calcd for
f
2
2
R
+
+
[
M + H] , C H N O , 525.31; found 525.29.
34 41 2 3
-Peptoid dimer S10. The peptoid dimer was synthesized from monomer S3 (424 mg, 1.41 mmol, 1.00 equiv)
according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (0.45
mL, 0.48 mg, 2.83 mmol, 2.00 equiv). The peptoid dimer S10 was obtained as a dark yellow oil after column
chromatography (553 mg, 74%). R = 0.32 (3% MeOH in CH Cl ). UPLC-MS t = 2.42 min, m/z: calcd for
f
2
2
R
+
+
[
M + H] , C H N O , 525.31; found 525.34.
34 41 2 3
-Peptoid trimer S11. The peptoid trimer was synthesized from dimer S10 (0.55 g, 1.05 mmol, 1.00 equiv)
according to general procedure B, followed by general procedure A using (R)-1-(1-naphthyl)ethylamine (0.23
mL, 0.24 g, 1.43 mmol, 2.00 equiv). The peptoid trimer S11 was obtained as a white foam after column
chromatography (363 mg, 68%). R = 0.21 (3% MeOH in CH Cl ). HRMS (MALDI-TOF) m/z: calcd for
f
2
2
+
+
[
M + H] , C H N O , 750.4265; found 750.4276. Purity according to analytical HPLC (gradient C): 95%.
49 56 3 4
-Peptoid trimer S12. The peptoid trimer was synthesized from trimer S11 (182 mg, 0.24 mmol, 1.00 equiv)
according to procedures C and D. The peptoid trimer S12 was obtained as a white foam after column
chromatography (109 mg, 72%). R = 0.67 (3% MeOH, 0.25% AcOH in CH Cl ). HRMS (MALDI-TOF) m/z:
f
2
2
+
+
calcd for [M + H] , C H N O , 736.3745; found 736.3737. – Purity according to analytical HPLC (gradient
4
7
50
3
5
C): 61%.
-Peptoid dimer S13. The peptoid dimer was synthesized from dimer S9 (2.33 g, 4.45 mmol, 1.00 equiv)
according to general procedures C and D. The product S13 was obtained as a light yellow foam after column
chromatography (1.81 g, 80%). R = 0.41 (3% MeOH in CH Cl ). UPLC-MS t = 2.38 min, m/z: calcd for
f
2
2
R
+
+
[
M + H] , C H N O , 511.26; found 511.26.
32 35 2 4
-Peptoid tetramer S14. Under nitrogen atmosphere, the peptoid dimers S9 (514 mg, 0.980 mmol,
1
.00 equiv), S13 (500 mg, 0.98 mmol, 1.00 equiv) and HATU (447 mg, 1.18 mmol, 1.20 equiv) were dissolved
in anhydrous CH Cl (2.00 mL). Subsequently, iPr NEt (0.41 mL, 0.30 mg, 2.35 mmol, 2.00 equiv) was added.
2
2
2
The reaction was stirred for 18 h at room temperature. After completion, the solution was washed with 2 M
aq. HCl (2 × 10 mL) and sat. aq. NaHCO (10 mL). The organic phase was dried over MgSO , filtered and
3
4
concentrated in vacuo. The crude was purified by column chromatography (1.5→3.0% MeOH in CH Cl )
2
2
yielding peptoid tetramer S14 as a white foam (470 mg, 47%). R = 0.44 (3% MeOH in CH Cl ). HRMS
f
2
2
+
+
(
MALDI-TOF) m/z: calcd for [M + H] , C H N O , 1017.5525; found 1017.5523. Purity according to
66 73 4 6
analytical HPLC (gradient C): 59%.
2
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2
2
2
2
2
2
2
2
2
3
3
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
-Peptoid trimer S19. The peptoid trimer was synthesized from peptoid dimer S4 (180 mg, 0.31 mmol, 1.20
equiv) according to general procedure B, followed by general procedure A using amine S16 (48.2 mg, 0.26
mmol, 1.00 equiv). The peptoid trimer S19 was obtained as a white solid after column chromatography (97.0
mg, 41%). HRMS (MALDI-TOF) m/z: calcd for [M + H] , C H N O , 767.4279; found 767.4291.
+
+
4
7
55
6
4
-Peptoid trimer S20. The peptoid trimer was synthesized from peptoid dimer S4 (231 mg, 0.90 mmol, 2.00
equiv) according to general procedure B, followed by general procedure A using amine S18 (26.0 mg, 0.20
mmol, 1.00 equiv). The peptoid trimer S20 was obtained as a white solid after column chromatography (91.0
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
mg, 83%). UPLC-MS t = 2.05 min, m/z: calcd for [M + H] , C H N O , 781.4; found 781.4.
R
48 57
6
4
-Peptoid dimer S21. The peptoid dimer was synthesized from monomer S1 (706 mg, 2.00 mmol, 2.00 equiv)
according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)pentylamine·HCl
(12) (250 mg, 1.00 mmol, 1.00 equiv). The peptoid dimer S21 was obtained as a yellow oil after column
chromatography (403 mg, 71%). R = 0.27 (3% MeOH in CH Cl ). HRMS (MALDI-TOF) m/z: calcd for
f
2
2
+
+
[M + H] , C H N O , 567.3581; found 567.3594.
37 47 2 3
-Peptoid dimer S22. The peptoid dimer was synthesized from monomer S2 (412 mg, 1.60 mmol, 2.00 equiv)
according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)pentylamine·HCl
(12) (200 mg, 0.80 mmol, 1.00 equiv). The peptoid dimer S22 was obtained as a yellow oil after column
chromatography (157 mg, 37%). R = 0.32 (3% MeOH in CH Cl ). UPLC-MS t = 2.35 min, m/z: calcd for
f
2
2
R
+
+
[M + H] , C H N O , 525.31; found 525.45.
34 41 2 3

-Peptoid trimer S23. The peptoid trimer was synthesized from dimer S22 (150 mg, 0.29 mmol, 1.00 equiv)
according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (0.09
mL, 0.09 g, 0.55 mmol, 2.00 equiv). The peptoid trimer S23 was obtained as a light yellow foam after column
chromatography (131 mg, 31%). R = 0.14 (3% MeOH in CH Cl ). UPLC-MS t = 2.72 min, m/z: calcd for
f
2
2
R
+
+
[M + H] , C H N O , 750.43; found 750.68.
49 56 3 4
-Peptoid monomer S24. The peptoid monomer was synthesized according to general procedure A from
methyl acrylate (0.32 mL, 304 mg, 3.54 mmol, 2.00 equiv) and (S)-1-(1-naphthyl)-pentylamine·HCl (12) (441
mg, 1.77 mmol, 1.00 equiv). The peptoid monomer S24 was obtained as a clear oil after column
chromatography (457 mg, 86%). R = 0.27 (heptane–EtOAc, 3:1). H NMR (600 MHz, CDCl ):  = 0.84 (t, J
=
1
f
3
7.1 Hz, 3 H, CH ), 1.19 – 1.41 (m, 4 H, CH CH /CH CH CH ), 1.77 – 1.92 (m, 2 H, NCHCH ), 2.44 – 2.57
3 2 3 2 2 2 2
(m, 2 H, COCH ), 2.71 – 2.84 (m, 2 H, NCH CH ), 3.66 (s, 3 H, OCH ), 4.51 (t, J = 6.6 Hz, 1 H, NCH), 7.45
2 2 2 3
– 7.53 (m, 3 H, 3 × CH ), 7.65 (d, J = 7.1 Hz, 1 H, CH ), 7.76 (d, J = 8.1 Hz, 1 H, CH ), 7.85 – 7.91 (m, 1
H, CH ), 8.23 (d, J = 8.4 Hz, 1 H, CH ). C{ H} NMR (151 MHz, CDCl ):  = 14.0 (CH ), 22.8 (CH CH ),
ar
ar
ar
1
3
1
ar
ar
3
3
2
3
2
8.7 (CH CH CH ), 34.6 (COCH ), 37.5 (NCHCH ), 43.0 (NCH CH ), 51.6 (OCH ), 58.7 (NCH), 123.1
2 2 2 2 2 2 2 3
(CH ), 123.8 (CH ), 125.3 (CH ), 125.6 (CH ), 125.7 (CH ), 127.3 (CH ), 129.0 (CH ), 131.9 (naphthyl-
ar ar ar ar ar ar ar
C ), 134.0 (naphthyl-C ), 139.6 (naphthyl-C ), 173.3 (COO). UPLC-MS t = 1.22 min, m/z: calcd for [M +
H] , C H NO , 300.20; found 300.29.
q
q
q
R
+
+
1
9
26
2
-Peptoid dimer S25. The peptoid dimer was synthesized from monomer S24 (440 mg, 1.46 mmol,
1.00 equiv) according to general procedure B, followed by general procedure A using (S)-1-(1-
naphthyl)ethylamine (0.47 mL, 500 mg, 2.92 mmol, 2.00 equiv). The peptoid dimer S25 was obtained as a
yellow oil after column chromatography (631 mg, 82%). R = 0.28 (3% MeOH in CH Cl ). UPLC-MS t =
f
2
2
R
+
+
1
.84 min, m/z: calcd for [M + H] , C H N O , 525.31; found 525.34.
34 41 2 3

-Peptoid trimer S26. The peptoid trimer was synthesized from dimer S25 (620 mg, 1.18 mmol, 1.00 equiv)
according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (0.38
mL, 404 mg, 2.36 mmol, 2.00 equiv) The peptoid trimer S26 was obtained as a white foam after column
chromatography (626 mg, 71%). R = 0.29 (3% MeOH in CH Cl ). UPLC-MS t = 2.06 min, m/z: calcd for
f
2
2
R
+
+
[M + H] , C H N O , 750.43; found 750.57.
49 56 3 4
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
-Peptoid dimer S27. The peptoid dimer was synthesized from S1 (325 mg, 0.92 mmol, 2.00 equiv) according
to general procedure B, followed by general procedure A using the amine 27 (155 mg, 0.46 mmol, 1.00 equiv)
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and iPr NEt (0.16 mL, 120 mg, 0.92 mmol, 2.00 equiv). The peptoid dimer S27 was obtained as a yellow oil
2
after column chromatography (265 mg, 66%). R = 0.15 (3% MeOH in CH Cl ). UPLC-MS t = 2.03 min,
f
2
2
R
+
+
m/z: calcd for [M + H] , C H N O , 652.37; 652.32 found.
40 50
3
5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0

-Peptoid dimer S28. The peptoid dimer was synthesized from monomer S2 (345 mg, 1.34 mmol, 2.00 equiv)
according to general procedure B, followed by general procedure A using the amine 27 (200 mg, 0.67 mmol,
.00 equiv) and iPr NEt (0.23 mL, 173 mg, 1.34 mmol, 2.00 equiv). The peptoid dimer S28 was obtained as a
1
2
white foam after column chromatography (269 mg, 66%). R = 0.09 (3% MeOH in CH Cl ). UPLC-MS t =
f
2
2
R
+
+
1
.81 min, m/z: calcd for [M + H] , C H N O , 610.33; 610.29 found.
37 44 3 5

-Peptoid trimer S29. The peptoid trimer was synthesized from dimer S28 (250 mg, 0.41 mmol, 1.00 equiv)
according to general procedure B, followed by general procedure A using (S)-1-(1-naphthyl)ethylamine (0.12
mL, 0.13 g, 0.75 mmol, 2.00 equiv). The peptoid trimer S29 was obtained as a white foam after column
chromatography (230 mg, 66%). R = 0.23 (3% MeOH in CH Cl ). UPLC-MS t = 1.89 min, m/z: calcd for
f
2
2
R
+
+
[
M + H] , C H N O , 835.44; 835.48 found.
52 54 4 6
-Peptoid trimer S33. 3-(4-((Allyloxy)carbonyl)piperazin-1-yl)propanoic acid (S32) (171 mg, 0.71 mmol,
2
.50 equiv) was placed in a vial and dissolved in anhydrous DMF (2.00 mL). Subsequently, HATU (161 mg,
0
.42 mmol, 1.50 equiv) and iPr NEt (0.15 mL, 110 mg, 0.85 mmol, 3.00 equiv) were added. After shaking at
2
room temperature for 10 min, the peptoid trimer S6 (200 mg, 0.28 mmol, 1.00 equiv) was added to the vial
and the reaction was left on a shaker for 2 h. The crude was purified by column chromatography (2→2.5%
MeOH, 0.25% NH in CH Cl ) to give the peptoid trimer S33 as a white foam (133 mg, 51%). R = 0.28 (3%
3
2
2
f
+
+
MeOH in CH Cl ). UPLC-MS t = 2.65 min, m/z: calcd for [M + H] , C H N O , 932.50; 932.36 found.
2
2
R
57 66
5
7

-Peptoid trimer S34. The peptoid trimer was synthesized from peptoid S33 (133 mg, 0.17 mmol, 1.00 equiv)
according to general procedure D. Due to the zwitterionic character, the crude was not purified by column
chromatography and instead used without any further purification. The product S34 was obtained as a white
+
foam (crude 120 mg, 93%). R = 0.06 (3% MeOH in CH Cl ). HRMS (ESI-TOF) m/z: calcd for [M + H] ,
f
2
2
+
C H N O , 918.4800; found 918.4869. Purity according to analytical HPLC (gradient A): 65%.
5
6
64
4
7
-Peptoid hexamer 1. The peptoid trimers 13 (20.0 mg, 270 mol, 1.00 equiv) and 18 (19.6 mg, 270 mol,
1
.00 equiv) were placed in a vial and dissolved in anhydrous CH Cl (120 L). Subsequently, iPr NEt (13.9
2
2
2
L, 10.3 mg, 0.08 mmol, 3.00 equiv) and HATU (12.2 mg, 320 mol, 1.20 equiv) were added. The reaction
was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf
tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50 mL). The
resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the
residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from 50→95%
in eluent III over 30 min, t = 41.3–45.5). The peptoid hexamer 1 was obtained as a white solid (17.0 mg,
R
+
+
9
6%). UPLC-MS, t = 3.30 min, m/z: calcd for [M + H] , C H N O , 1467.78; found 1467.73. Purity
R 96 103 6 8
according to analytical HPLC (gradient C): 99%. The data is in agreement with the previously described
1
3
synthesis by sequential addition of monomers.

-Peptoid hexamer 2. Under nitrogen atmosphere, the peptoid trimers S11 (98.0 mg, 0.13 mmol, 1.00 equiv)
and S12 (80.0 mg, 0.01 mmol, 1.00 equiv) and HATU (24.3 mg, 0.06 mmol, 1.20 equiv) were dissolved in
anhydrous CH Cl (200 L). Subsequently, iPr NEt (26.0 L, 19.0 mg, 0.33 mmol, 3.00 equiv) was added.
2
2
2
The reaction was left to stir for 18 h at room temperature. The reaction mixture was then transferred to an
eppendorf tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (2.00
mL). The resulting suspension was centrifuged and the supernatant was removed. This was repeated twice
before the residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from
5
0→95% in eluent III over 20 min, t = 31.8–33.5). The peptoid hexamer 2 was obtained as a white solid (21.6
R
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2
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2
2
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
mg, 13%). HRMS (MALDI-TOF) m/z: calcd for [M + H] , C H N O , 1467.7832; found 1467.7843. Purity
according to analytical HPLC (gradient C): 99%.
9
6
103
6
8

-Peptoid hexamer 3. Peptoid tetramer S14 (470 mg, 0.46 mmol, 1.00 equiv) was subjected to C-terminal
deprotection according to general procedure D. The crude was purified by column chromatography to give the
deprotected peptoid tetramer as a white solid (368 mg, 84 %). Under nitrogen atmosphere, the tetramer (80.0
mg, 0.08 mmol, 1.00 equiv), dimer S9 (44.0 mg, 0.08 mmol, 1.00 equiv) and HATU (38.0 mg, 0.10 mmol,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
.20 equiv) were dissolved in anhydrous CH Cl (170 L). Subsequently, iPr NEt (30.0 L, 22.0 mg, 0.17
2
2
2
mmol, 2.00 equiv) was added. The reaction was stirred for 18 h at room temperature. After completion, the
reaction mixture was transferred to an eppendorf tube. The solvent was removed by a nitrogen stream and the
residue was redissolved in MeOH (2.00 mL). The resulting suspension was centrifuged and the supernatant
was removed. This was repeated twice before the residual crude product was purified by preparative HPLC
(gradient of eluent IV rising linearly from 50→95% in eluent III over 20 min, t = 31.2–32.5). The peptoid
hexamer 3 was obtained as a white solid (56.0 mg, 46%). HRMS (MALDI-TOF) m/z: calcd for [M +
R
+
+
H] , C H N O , 1467.7832; found 1467.7786. Purity according to analytical HPLC (gradient C): 99%.
9
6
103
6
8

-Peptoid hexamer 4. The peptoid trimers S7 (80.0 mg, 0.11 mmol, 1.00 equiv) and 13 (96.0 mg, 0.13 mmol,
.20 equiv) were placed in a vial and dissolved in anhydrous CH Cl (500 L). Subsequently, iPr NEt (56.8
L, 42.2 mg, 0.33 mmol, 3.00 equiv) and HATU (49.6 mg, 0.13 mmol, 1.20 equiv) were added. The reaction
was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf
tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50 mL). The
resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the
residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from 50→95%
in eluent III over 25 min, t = 30.6–32.5 min). The peptoid hexamer 4 was obtained as a white solid (73.5 mg,
7%). HRMS (MALDI-TOF) m/z: calcd for [M + H] , C H N O , 1453.7675; found 1453.7618. Purity
1
2
2
2

R
+
+
4
95 101 6 8
according to analytical HPLC (gradient B): 99%.

1
-Peptoid hexamer 5. The peptoid trimers 13 (52.2 mg, 0.07 mmol, 1.00 equiv) and S8 (50.0 mg, 0.07 mmol,
.00 equiv) were dissolved in DMF (0.1 M). Subsequently, HATU (32.3 mg, 0.09 mmol, 1.20 equiv) and
iPr NEt (10.9 mg, 0.19 mmol, 2.00 equiv) were added and the reaction was stirred for 18 h at room
temperature. The reaction was then washed with 2 M aq. HCl and extracted with CH Cl (3×). The resulting
organic phase was then washed with water before being concentrated in vacuo. The crude residue was purified
by preparative HPLC (gradient of eluent IV rising linearly from 45→95% in eluent III over 35 min, t = 52.7–
4.7 min). The peptoid hexamer 5 was obtained as a white solid (40.0 mg, 39%). HRMS (MALDI-TOF)
m/z: calcd for [M + H] , C H N O , 1417.7675; found 1417.7631. Purity according to analytical HPLC
2
2
2
R
5
+
+
9
2
101
6
8
(gradient C): 90%.
-Peptoid hexamer 6. The peptoid trimers 13 (19.0 mg, 0.03 mmol,1.00 equiv) and S19 (20.0 mg, 0.03 mmol,
.00 equiv) were dissolved in DMF (0.1 M). Subsequently, HATU (11.9 mg, 0.03 mmol, 1.20 equiv) and
iPr NEt (6.74 mg, 0.05 mmol, 2.00 equiv) were added and the reaction was stirred for 18 h at room temperature.
The reaction was then washed with 2 M aq. HCl and extracted with CH Cl (3×). The resulting organic phase
was then washed with water before being concentrated in vacuo. The crude residue was purified via VLC
0→2% MeOH in CH Cl ) yielding peptoid hexamer 6 as a white solid (5.40 mg, 5%). HRMS (MALDI-TOF)
1
2
2
2
(
2
2
+
+
m/z: calcd for [M + Na] , C H N O Na , 1507.7699; found 1507.7769. Purity according to analytical HPLC
94 101
9
8
(gradient C): 98%.

1
-Peptoid hexamer 7. The peptoid trimers 13 (110 mg, 0.13 mmol, 1.20 equiv) and S20 (81.0 mg, 0.12 mmol,
.00 equiv) were dissolved in DMF (0.1 M). Subsequently, HATU (45.0 mg, 0.19 mmol, 1.20 equiv) and
iPr NEt (28.0 mg, 0.24 mmol, 2.00 equiv) were added and the reaction was stirred for 18 h at room temperature.
The mixture was then washed with 2 M aq. HCl and extracted with CH Cl (3×). The resulting organic phase
was washed with water before being concentrated in vacuo. The crude residue was purified via VLC (0→3%
MeOH in CH Cl ). The crude residue was further purified by preparative HPLC (gradient of eluent IV rising
2
2
2
2
2
linearly from 45→95% in eluent III over 25 min, t = 47.9–50.3 min). The peptoid hexamer 7 was obtained as
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
3
3
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4
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5
5
6
a white solid (13.0 mg, 48%). HRMS (MALDI-TOF) m/z: calcd for [M + Na] , C H N O Na , 1520.7822;
95 103 9 8
found 1520.7759. Purity according to analytical HPLC (gradient C): 96%.

-Peptoid hexamer 8. The peptoid hexamer 6 (27.1 mg, 0.02 mmol, 1.00 equiv) was dissolved in MeCN (0.1
M). Subsequently, methyl iodide (38.9 mg, 0.27 mmol, 15.0 equiv) was added and the mixture was stirred at
0 °C for 18 h. The crude residue was purified by preparative HPLC (gradient of eluent IV rising linearly from
45→95% in eluent III over 35 min, t = 34.9–36.4). The peptoid hexamer 8 was obtained as a white solid (7.00
7
R
+
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mg, 25%). HRMS (MALDI-TOF) m/z: calcd for [M + H] , C H N O , 1498.8002; found 1498.7958. Purity
9
5
104
9
8
according to analytical HPLC (gradient C): 94%.
-Peptoid hexamer 9. The peptoid hexamer 7 (55.0 mg, 0.04 mmol, 1.00 equiv) was dissolved in MeCN (0.1
M). Subsequently, methyl iodide (85.0 mg, 0.60 mmol, 15.0 equiv) was added and the mixture was stirred at
70 °C for 18 h. The crude residue was purified by preparative HPLC (gradient of eluent IV rising linearly from
45→95% in eluent III over 35 min, t = 34.737.3). The peptoid hexamer 9 was obtained as a white solid (21.0
R
+
+
mg, 38%). HRMS (MALDI-TOF) m/z: calcd for [M + H] , C H N O , 1512.8159; found 1512.8098. Purity
9
6
106
9
8
according to analytical HPLC (gradient C): 90%.

-Peptoid hexamer 19. The peptoid trimers 16 (50.0 mg, 0.06 mmol, 1.00 equiv) and 13 (46.5 mg, 0.06 mmol,
1
.00 equiv) were placed in a vial and dissolved in anhydrous CH Cl (300 L). Subsequently, iPr NEt
2
2
2
(33.0 L, 24.5 mg, 0.19 mmol, 3.00 equiv) and HATU (28.8 mg, 0.08 mmol, 1.20 equiv) were added. The
reaction was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an
eppendorf tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50
mL). The resulting suspension was centrifuged and the supernatant was removed. This was repeated twice
before the residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from
5
0→95% in eluent III over 20 min, t = 41.6–47.5 min). The peptoid hexamer 19 was obtained as a white solid
R
+
+
(24.5 mg, 26%). HRMS (MALDI-TOF) m/z: calcd for [M + Na] , C H N O Na , 1532.8154; found
99 108 6 8
1
532.8152. Purity according to analytical HPLC (gradient C): 95%.
-Peptoid hexamer 20. The peptoid trimers 17 (63.0 mg, 0.08 mmol, 1.00 equiv) and 13 (58.5 mg, 0.08 mmol,
1
.00 equiv) were placed in a vial and dissolved in anhydrous CH Cl (500 L). Subsequently, iPr NEt (41.6
2
2
2
L, 30.8 mg, 0.24 mmol, 3.00 equiv) and HATU (36.3 mg, 0.10 mmol, 1.20 equiv) were added. The reaction
was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf
tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50 mL). The
resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the
residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from 50→95%
in eluent III over 35 min, t = 43.1–48.5 min). The peptoid hexamer 20 was obtained as a white solid (23.7
R
+
+
mg, 28%). HRMS (MALDI-TOF) m/z: calcd for [M + H] , C H N O , 1509.8301; found 1509.8237. Purity
99 108
6
8
according to analytical HPLC (gradient B): 99%.
-Peptoid hexamer 21. The peptoid trimers 18 (40.0 mg, 0.05 mmol, 1.00 equiv) and 14 (41.5 mg, 0.05 mmol,
1
.00 equiv) were placed in a vial and dissolved in anhydrous CH Cl (300 L). Subsequently, iPr NEt (28.0
2
2
2

L, 20.7 mg, 0.16 mmol, 3.00 equiv) and HATU (24.3 mg, 0.06 mmol, 1.20 equiv) were added. The reaction
was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf
tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50 mL). The
resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the
residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from 70→95%
in eluent III over 30 min, t = 38.2–40.5 min). The peptoid hexamer 21 was obtained as a white solid (10.4
R
+
+
mg, 13%). HRMS (MALDI-TOF) m/z: calcd for [M + H] , C H N O , 1509.8301; found 1509.8294. Purity
9
9
108
6
8
according to analytical HPLC (gradient C): 99%.
-Peptoid hexamer 22. The peptoid trimers 18 (29.0 mg, 0.04 mmol, 1.00 equiv) and 15 (30.1 mg, 0.04 mmol,
1.00 equiv) were placed in a vial and dissolved in anhydrous CH Cl (300 L). Subsequently, iPr NEt (20.2
2
2
2

L, 15.0 mg, 0.12 mmol, 3.00 equiv) and HATU (17.6 mg, 0.05 mmol, 1.20 equiv) were added. The reaction
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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4
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5
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5
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was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf
tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50 mL). The
resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the
residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from 70→95%
in eluent III over 25 min, t = 33.2–39.0 min). The peptoid hexamer 22 was obtained as a white solid (9.00
R
+
+
mg, 15%). HRMS (MALDI-TOF) m/z: calcd for [M + H] , C H N O , 1509.8301; found 1509.8309. Purity
9
9
108
6
8
according to analytical HPLC (gradient C): 73%.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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4
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9
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0
-Peptoid hexamer 30. The peptoid trimers 29 (50.0 mg, 0.06 mmol, 1.00 equiv) and 13 (45.0 mg, 0.07 mmol,
1
.10 equiv) were placed in a vial and dissolved in anhydrous CH Cl (500 L). Subsequently, iPr NEt (30.0
2
2
2
L, 22.1 mg, 0.17 mmol, 3.00 equiv) and HATU (26.0 mg, 0.068 mmol, 1.20 equiv) were added. The reaction
was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf
tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50 mL). The
resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the
residual crude product was purified by preparative HPLC (gradient of eluent IV rising linearly from 50→95%
in eluent III over 30 min, t = 40.6–42.5 min). The peptoid hexamer 30 was obtained as a white solid (36.2
R
+
+
mg, 40%). HRMS (ESI-TOF) m/z: calcd for [M + H] , C H N O , 1594.8465; found 1594.8414. Purity
102 112
7
10
according to analytical HPLC (gradient C): 99%.
-Peptoid hexamer 32. Under nitrogen atmosphere, the peptoid hexamer 30 (20.0 mg, 13.0 mol, 1.00 equiv)
was dissolved in 600 L anhydrous CH Cl . Dimethylamine borane complex (11.7 mg, 200 mol, 15.0 equiv)
2
2
and tetrakis palladium (1.53 mg, 1.30 mol, 10 mol%) were added and the mixture was stirred for 3 h at room
temperature. The solvent was removed in vacuo and the crude residue was purified by preparative HPLC
(gradient of eluent IV rising linearly from 50→95% in eluent III over 25 min, t = 25.3–26.2 min). The peptoid
R
+
hexamer 32 was obtained as a white solid (9.40 mg, 48%). HRMS (ESI-TOF) m/z: calcd for [M + H] ,
+
C H N O , 1510.8254; found 1510.8243. Purity according to analytical HPLC (gradient C): 95%.
9
8
108
7
8
-Peptoid hexamer 33. The peptoid trimers 28 (50.0 mg, 0.06 mmol, 1.00 equiv) and 29 (60.9 mg, 0.07 mmol,
1
.20 equiv) were placed in a vial and dissolved in anhydrous CH Cl (500 L). Subsequently, iPr NEt (30.3
2
2
2
L, 22.5 mg, 0.17 mmol, 3.00 equiv) and HATU (26.4 mg, 0.07 mmol, 1.20 equiv) were added. The reaction
was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an eppendorf
tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50 mL). The
resulting suspension was centrifuged and the supernatant was removed. This was repeated twice before the
residual crude product (36.0 mg, 21.0 mol, 1.00 equiv) was redissolved in anhydrous CH Cl (1.00 mL) under
2
2
nitrogen atmosphere. Dimethylamine borane complex (25.0 mg, 0.42 mmol, 20.0 equiv) and subsequently
tetrakis palladium (4.83 mg, 4.20 mol, 20 mol%) were added and the mixture was stirred for 2 h at room
temperature. The solvent was removed in vacuo and the crude residue was purified by preparative HPLC
(
gradient of eluent IV rising linearly from 50→95% in eluent III over 25 min, t = 16.1–17.8 min). The peptoid
R
+
hexamer 33 was obtained as a white solid (15.7 mg, 24%). HRMS (ESI-TOF) m/z: calcd for [M + H] ,
C H N O , 1553.8676; found 1553.8657. Purity according to analytical HPLC (gradient C): 99%.
+
1
00 113
8
8
-Peptoid hexamer 34. The peptoid trimers S34 (36.7 mg, 0.04 mmol, 1.00 equiv) and 18 (36.0 mg, 0.05
mmol, 1.20 equiv) were placed in a vial and dissolved in anhydrous CH Cl (300 L). Subsequently, iPr NEt
2
2
2
(20.9 L, 15.5 mg, 0.12 mmol, 3.00 equiv) and HATU (18.2 mg, 0.05 mmol, 1.20 equiv) were added. The
reaction was left on a shaker for 18 h at room temperature. The reaction mixture was then transferred to an
eppendorf tube. The solvent was removed by a nitrogen stream and the residue was redissolved in MeOH (1.50
mL). The resulting suspension was centrifuged and the supernatant was removed. This was repeated twice
before the residual crude product (33.0 mg, 0.02 mmol, 1.00 equiv) was redissolved in anhydrous CH Cl (1.00
2
2
mL) under nitrogen atmosphere. Dimethylamine borane complex (17.7 mg, 0.30 mmol, 15.0 equiv) and
subsequently tetrakis palladium (2.31 mg, 2.00 mol, 10 mol%) were added and the mixture was stirred for 2
h at room temperature. The solvent was removed in vacuo and the crude residue was purified by preparative
HPLC (gradient of eluent IV rising linearly from 50→95% in eluent III over 25 min, t = 21.9–23.5 min). The
R
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peptoid hexamer 34 was obtained as a white solid (16.4 mg, 30%). HRMS (ESI-TOF) m/z: calcd for [M + H] ,
C H N O , 1565.8676; found 1565.8644. Purity according to analytical HPLC (gradient C): 98%.
+
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ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS Publications website.
Supporting schemes, figures, and tables, experimental procedures, HPLC traces, and copies of UV and NMR
spectra (PDF).
0
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Data for compound 21 (CCDC 1857129) (CIF)
AUTHOR INFORMATION
Corresponding Author
*Email: cao@sund.ku.dk
ORCID
Christian A. Olsen: 0000-0002-2953-8942
Isabelle Wellhöfer: 0000-0002-3311-2856
Present address
#J.S.L. is research and development chemist at NCK A/S, Rugmarken 28, DK-3520, Farum, Denmark
Notes
The authors declare no competing financial interests
ACKNOWLEDGMENT
This work was supported by the Carlsberg Foundation (2013-01-0333; C.A.O.), the Danish Independent
Research Council  Technical and Production Sciences (Grant No. 6111-00170), and The University of
Copenhagen (Center for Biopharmaceuticals grant). Mr. Niels Vissing Holst (Department of Chemistry,
University of Copenhagen) is gratefully acknowledged for technical assistance with X-ray diffraction data
collecting and reduction.
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and Robust Polyproline Type I Helices from Peptoids with Nonaromatic α-Chiral Side Chains. J. Am. Chem.
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Barron, A. E.; Radhakrishnan, I., A Threaded Loop Conformation Adopted by a Family of Peptoid Nonamers.
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Multihelical Structure. J. Am. Chem. Soc. 2005, 127 (31), 10999-11009.
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R. A.; Lee, B.-C.; Connolly, M. D.; Kisielowski, C.; Zuckermann, R. N., Free-Floating Ultrathin Two-
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