Solid-phase synthesis and circular dichroism study of β-abpeptoids

Article abstract of DOI:10.3390/molecules24010178

The development of peptidomimetic foldamers that can form well-defined folded structures is highly desirable yet challenging. We previously reported on α-ABpeptoids, oligomers of N-alkylated β²-homoalanines and found that due to the presence of chiral methyl groups at α-positions, α-ABpeptoids were shown to adopt folding conformations. Here, we report β-ABpeptoids having chiral methyl group at β-positions rather than α-positions as a different class of peptoids with backbone chirality. We developed a facile solid-phase synthetic route that enables the synthesis of β-ABpeptoid oligomers ranging from 2-mer to 8-mer in excellent yields. These oligomers were shown to adopt ordered folding conformations based on circular dichroism (CD) and NMR studies. Overall, these results suggest that β-ABpeptoids represent a novel class of peptidomimetic foldamers that will find a wide range of applications in biomedical and material sciences.

Full text of DOI:10.3390/molecules24010178

molecules
Article
Solid-Phase Synthesis and Circular Dichroism Study
of β-ABpeptoids
Ganesh A. Sable , Kang Ju Lee and Hyun-Suk Lim *
Department of Chemistry and Division of Advanced Material Science, Pohang University of Science and
Technology (POSTECH), Pohang 37673, Korea; sganesh105@postech.ac.kr (G.A.S.);
dlrkdwn2tlfd@postech.ac.kr (K.J.L.)
* Correspondence: hslim@postech.ac.kr; Tel. +82-54-279-2131; Fax: 054-279-3399
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 3 December 2018; Accepted: 4 January 2019; Published: 5 January 2019
Abstract: The development of peptidomimetic foldamers that can form well-defined folded
structures is highly desirable yet challenging. We previously reported on -ABpeptoids, oligomers
2-homoalanines and found that due to the presence of chiral methyl groups
α
of N-alkylated
at -positions,
β
α
α
-ABpeptoids were shown to adopt folding conformations. Here, we report
-positions rather than -positions as a different class of
peptoids with backbone chirality. We developed a facile solid-phase synthetic route that enables the
synthesis of -ABpeptoid oligomers ranging from 2-mer to 8-mer in excellent yields. These oligomers
were shown to adopt ordered folding conformations based on circular dichroism (CD) and NMR
studies. Overall, these results suggest that -ABpeptoids represent a novel class of peptidomimetic
β-ABpeptoids having chiral methyl group at
β
α
β
β
foldamers that will find a wide range of applications in biomedical and material sciences.
Keywords: solid-phase synthesis; peptidomimetics; foldamers; peptoids; β-ABpeptoids
1. Introduction
Peptidomimetic foldamers are a class of artificial oligomers that can form defined and predictable
structures that are capable of mimicking the three-dimensional structure and function of natural
peptides and proteins [
compared to native peptides, synthetic peptidomimetic foldamers that adopt well-defined protein
secondary structures can be highly useful in biological applications and material sciences [ ].
1,2]. Given their improved proteolytic stability and structural diversity
3
As such, the development of such synthetic foldamers is of great interest and a number of
different classes of peptidomimetic foldamers have been described over the last two decades,
including
β- and
γ
-peptides [
4–
8
], oligoureas [
9
,10], oligopyrrolidines [11],
γ-AApeptides [12,13],
oligotriazoles [14], azapeptides [15
and peptoids [19–21].
,
16], oligocarbamates [17], α
-aminoxy acid containing oligomers [18],
Peptoids are oligomers of N-alkylated glycines [22]. They are efficiently synthesized by
submonomer solid-phase synthesis [23]. Like other unnatural peptidomimetic foldamers, peptoids are
resistant to proteolysis [24
to penetrate cell membranes, presumably due to the presence of amide protons, peptoids are relatively
cell permeable [26 28]. Although peptoids possess many of the desirable features of peptidomimetics,
,25]. While native peptides and most peptidomimetics are generally unable
–
they are structurally flexible and generally do not form folding structures because of the lack of amide
protons and chirality in their backbones. To overcome the intrinsic limitation of peptoids associated
with their flexible nature, various strategies have been developed. For instance, the development of
macrocyclic peptoids has been of significant interest to restrict the conformational flexibility of linear
peptoids [29
–35]. Alternatively, it has been proven that the introduction of chiral centers to peptoid
frameworks enables them to have ordered folding structures, which is in contrast to regular peptoids
Molecules 2019, 24, 178; doi:10.3390/molecules24010178
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Molecules 2019, 24, 178
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lacking chirality. For example, peptoid oligomers substituted with
α
-chiral side chains are found to
adopt well-defined folding conformations like polyproline-type helical structures (Figure 1) [36–41].
Figure 1. General structures of
chains, α-ABpeptoids and β-ABpeptoids.
β α- and β-peptoids, α- and β-peptoids with α-chiral side
3-peptides,
Recently, our group reported
peptoids [42,43]. They are oligomers of N-alkylated
α
-ABpeptoids (
α
-alkyl beta-peptoids) as a new class of
2-homoalanines and structurally similar to
-peptoids, except that they have chiral methyl groups at -positions (Figure 1). As a result, and in
-ABpeptoids contain backbone chirality. -ABpeptoid oligomers were
β
β
α
contrast to general peptoids,
α
α
shown to adopt folding conformations based on circular dichroism (CD) and NMR studies. This finding
demonstrates that chiral methyl groups in the peptoid backbone act like those in peptoid with -chiral
side chains. Here we report the design, solid-phase synthesis, and preliminary structural studies of
-ABpeptoids having chiral methyl group at -positions rather than -positions as a different class of
α
β
β
α
peptoids with backbone chirality.
2. Results and Discussion
2.1. Synthesis of Monomer Building Blocks
As demonstrated in
the backbone -positions would also influence the structural conformation of peptoids. To explore this,
we synthesized a series of -ABpeptoid oligomers using a facile solid-phase synthetic method. Initially,
we prepared
3-homoalanines substituted with benzyl or naphthyl group as monomer building blocks
because it is known that aromatic side chains such as N-benzyl and N-naphthyl groups in peptoids
with chiral side chains play a critical role in forming ordered structures (Scheme 1) [41 45]. (R)-methyl
α-ABpeptoids, we envisioned that the introduction of chiral methyl groups at
β
β
β
–
3-hydroxy-3-methylpropanoate, a commercially available and inexpensive starting material, was
tosylated to give (R)-1 in 84% yield. The tosyl group of (R)-1 was then replaced with the azide group
by treatment with sodium azide to produce azide (S)-2 with an inversion of configuration. The resulting
azide (S)-2 was reduced to obtain (S)-3, which was then nosylated to afford (S)-4. N-Alkylation was
performed by treatment with benzyl bromide or naphthyl bromide in the presence of cesium carbonate
and N,N-dimethylformamide (DMF) at room temperature (rt), providing (S)-5 in 92–95% yields. Finally,
hydrolysis with lithium hydroxide gave N-alkylated nosyl-protected (S)-6. N-Benzylated monomer
with opposite chirality (R)-6a was also prepared using the same procedure starting with (S)-methyl
3-hydroxy-3-methylpropanoate (Scheme 1). This synthetic route was highly efficient, yielding the
desired monomer building blocks in enantiomerically pure forms without significant racemization as
determined by comparing their optical rotation (Table S1). In addition, the enantiomeric purity was
further confirmed by using chiral HPLC (Supplementary Information Figure S1). The enantiomeric
excess (ee) for (R)-6 and (S)-6 was 94% and 85%, respectively, showing the synthetic efficiency.

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Scheme 1. Synthesis of N-Alkyl
temperature).
β
3-Homoalanine (S)-6 building block monomers (rt = room
2.2. Solid-Phase Synthesis of β-ABpeptoid Oligomers
For solid-phase synthesis of N-benzyl substituted
β-ABpeptoid oligomers, (S)-6a was first
loaded on Rink amide MBHA resin in the presence of hexafluorophosphate azabenzotriazole
tetramethyl uronium (HATU)/1-hydroxy-7-azabenzotriazole (HOAt)/N,N-diisopropylethylamine
(DIPEA) in DMF at rt for 2 hr (Scheme 2). The nosyl group of (S)-7 was then deprotected by
treating it with 2-mercaptoethanol and 1,8-diazabicycloundec-7-ene in DMF, giving resin bound
secondary amine (S)-8. In our previous method to synthesize
N,N -diisopropylcarbodiimide (DIC) as a coupling reagent. In the present work, we initially employed
α-ABpeptoid oligomers, we used
0
the same DIC condition, but the reaction was not successful. After testing several different coupling
conditions, we found that the use of HATU/HOAt/DIPEA [46
(S)-9a-Ns with excellent yield (Supplementary Information Figure S2). Iterative deprotection and
coupling reactions allowed for the generation of N-benzylated -ABpeptoid oligomers ranging from
2- to 8-mers (S)-9a (Table 1 and Supplementary Information Figure S3). After the completion
of solid phase synthesis, the resulting -ABpeptoids were cleaved from resin by using cleavage
,47] provided the desired dimer
β
–
g
β
cocktail containing 95% trifluoroacetic acid (TFA), 2.5% water, and 2.5% triisopropylsilane (TIPS).
The resulting crude products were purified by HPLC, and their identity was determined by mass
spectrometry (Table 1 and Supplementary Information Figure S4, Table S2–S4). To examine the
efficiency of our solid-phase method, we synthesized
N-naphthyl groups (S)-10a using N-napthylated monomer (S)-6b. Using the same solid-phase
synthetic route, N-naphthylated -ABpeptoids ranging from 2- to 8-mers (S)-10a were prepared
β-ABpeptoid oligomers substituted with
–
g
β
–g
in high yield (Table 1 and Supplementary Information Table S2). As shown in Figure 2, the crude
purity of the 8-mer oligomers substituted with benzyl or naphthyl group was excellent, demonstrating
the robustness of our solid-phase method. Although the synthetic method developed by Sando and
co-workers is elegant and convenient, the synthetic route was not sufficiently efficient for generating
longer oligomers (20–30% for pentamers) [48]. On the contrary, our solid-phase method is able to
synthesize longer
β-ABpeptoid oligomers with remarkable efficiency (71–81% for 8-mer β-ABpeptoids
as determined by analytical HPLC of the crude products, Figure 2 and Table 1).

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Scheme 2. Solid-phase synthesis of oligomers of N-Alkyl β3-Homoalanine.
Table 1. Structures and analytical data of synthesized (S) form of β-ABpeptoid oligomers.
Obsd Mass b
368.2 [M + H]+
543.3 [M + H]+
718.4 [M + H]+
893.4 [M + H]+
1068.5 [M + H]+
1243.6 [M + H]+
1440.9 [M + H]+c
1132.5 [M + H]+
468.2 [M + H]+
693.4 [M + H]+
918.4 [M + H]+
1144.5 [M + H]+
1368.6 [M + H]+
1614.8 [M + Na]+c
1839.9 [M + Na]+c
Compd No.
(S)-9a
Chain Length
% Purity a
Calcd Mass
367.23
2
3
4
5
6
7
8
6
2
3
4
5
6
7
8
65
68
77
78
79
73
71
70
94
82
94
92
87
85
81
(S)-9b
(S)-9c
(S)-9d
(S)-9e
(S)-9f
(S)-9g
542.33
717.43
892.53
1067.62
1242.72
1417.82
1109.64
467.26
692.37
917.49
1142.60
1367.72
1592.83
1817.95
(S)-9e-Ac d
(S)-10a
(S)-10b
(S)-10c
(S)-10d
(S)-10e
(S)-10f
(S)-10g
a
b
Determined by analytical reversed-phase HPLC of crude products. Mass spectrometry data were acquired using
c
d
ESI techniques. Mass spectrometry data were acquired using MALDI technique. N-terminal was acetylated.

Molecules 2019, 24, 178
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Figure 2. HPLC chromatograms of crude β-ABpeptoid oligomers 9g and 10g.
2.3. Structural Studies
Next, we measured circular dichroism (CD) spectra to explore the folding propensity of the
synthesized -ABpeptoid oligomers. The CD spectra of (R) form of N-benzylated -ABpeptoids
(R)-9a
were first recorded in acetonitrile (ACN) at 20 ◦C (Figure 3a). While dimer (R)-9a did not
β
β
–
g
display an apparent CD signal, trimer (R)-9b showed a distinct CD signature. The CD intensity
was gradually increased as the residues were added, and oligomers with more than four residues
exhibited nearly identical CD spectra with an intense minimum at near 196 nm and a shallow
minimum near 218 nm. Notably, the CD spectra of
from those of -ABpeptoids [42 43]. Their spectral shapes resemble the previously reported CD
spectra for -peptoids [49] and -peptoids [37] bearing -chiral, aromatic side chains, suggesting
that N-benzylated -ABpeptoid oligomers might adopt a similarly ordered structure. This result was
further supported by the nuclear Overhauser effect (NOE) experiments using short oligomers (R)-9a
β-ABpeptoid oligomers are quite different
α
,
β
α
α
β
–
c
(Supplementary Information Figure S10). We found that the number of NOEs for trimer (R)-9b and
tetramer (R)-9c was markedly increased compared to that of dimer (R)-9a. Because these additional
NOEs are normally observed in ordered structures and unfolded structures do not produce such NOEs,
this observation, in agreement with the CD results, demonstrates that β-ABpeptoids with more than
three residues can adopt ordered structures. However, we cannot rule out the possibility that the
increased NOE signals could result from the presence of multiple conformational states, and further
structural studies are necessary.
We then investigated the CD spectra of N-benzylated
chirality (S)-9a (Figure 3b). (S)-Form oligomers ranging in size from 2-mer to 8-mer were synthesized
using N-benzylated monomer with opposite chirality (R)-6a through the same solid-phase synthetic
method (Scheme 2). As anticipated, (S)-form -ABpeptoid oligomers revealed mirror image CD spectra
compared to (R)-form oligomers (Figure 3b), demonstrating that -ABpeptoids possessing opposite
β-ABpeptoid oligomers with opposite
–
g
β
β
backbone chirality adopt identical structures consisting of opposite handedness. These results are in
good agreement with the findings by Wu et. al. where they showed that the peptoid with aromatic,
α
-chiral (S or R) side chains show mirror image helical CD spectra [37]. This also indicates that the
ordered conformation of -ABpeptoid oligomers is due to the presence of chiral methyl groups on
β
their backbone. We then tested whether the N-terminus amine could affect the conformation of these
oligomers through terminal intramolecular hydrogen bonding. We synthesized (R)- and (S)-forms
of N-acylated hexamers (S)-9e-Ac and (R)-9e-Ac by reacting with acetic anhydride/DIPEA/DMF
(Supplementary Information Table S2 and S3). The CD spectra of the acetylated hexamers (S)-9e-Ac

Molecules 2019, 24, 178
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and (R)-9e-Ac were almost identical in shape and intensity to those of (S)-9e and (R)-9e (Figure 3c),
showing that N-terminal amine had no effect on the formation of the ordered structure.
a
b
c
d
e
f
Figure 3. CD data; (
a
) CD spectra of (R)-form of N-benzylated
b
β
-ABpeptoid oligomers (
-ABpeptoid oligomers (
R
S
)
)
-9a
-9a
–
–g
g
in
in
acetonitrile (60
µM), (
) CD spectra of (S)-form of N-benzylated
) CD spectra of (S)- and (R)-forms of N-benzylated
M). ( ) CD spectra of (R)-9e at 5
) CD spectra of (S)-form of N-napthylmethyl -ABpeptoid oligomers (
) CD spectra of (S)-form of N-napthylmethyl -ABpeptoid ( -10g at 5–70 C in acetonitrile (60
β
acetonitrile (60
and without N-acetyl in acetonitrile (60
µ
M), (
c
β
-ABpeptoid hexamers with
◦
µ
d
−
70 C in acetonitrile (60
µ
M),
M),
M).
(e
β
S)-10a–g in acetonitrile (60
µ
◦
(f
β
S)
µ
To assess the solvent effects on the conformations of oligomers, CD spectra were recorded of
oligomers of (S)-9a in various polar solvents such as phosphate-buffered saline (PBS) buffer-ACN
–g
(1:3), MeOH, and trifluoroethanol (TFE) (Supplementary Information Figures S5 and S6). The oligomers
maintain similar CD spectral shapes in PBS buffer-ACN (1:3) solvents, however, in MeOH and TFE
solvents, the peaks are intensified and the overall spectral shapes are broadened, suggesting that
the formation of conformation could be a result of steric interactions between side chains that may
alter in a solvent dependent manner, as demonstrated in N-benzylated peptoids with
chains [39 50]. Next, we investigated the temperature dependence of the ordered structure. The CD
spectrum of hexamer (R)-9e was measured at different fixed temperatures ranging from 5 to 70 ◦C
α-chiral side
,

Molecules 2019, 24, 178
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(Figure 3d). We found that signal intensity was gradually decreased upon heating, indicating the
temperature-dependent denaturation of the folded structure. The thermal denaturation behavior was
similarly observed for previously reported β-peptoids, which had stable helical conformations [41].
In addition to N-benzylated
β-ABpeptoids, we also obtained the CD spectra of N-naphthylated
β
-ABpeptoid oligomers (S)-10a-g at 20 ◦C in acetonitrile (Figure 3e). The spectrum of dimer (S)-10a
displayed no apparent signal, while trimer (S)-10b exhibited characteristic spectral features with a
minimum at near 212 nm and an intense maximum at near 228 nm. For tetramer (S)-10c and longer
oligomers (S)-10d
indicates that tetramer or longer oligomers of N-napthyl-
dependent stable ordered structures. Interestingly, the spectral shape differs considerably from
those of N-benzylated -ABpeptoids and is somewhat similar to the CD spectra of -peptoids
bearing a similar -chiral napthyl ethyl side chain [41]. As demonstrated in the previous study
by Laursen et al. [41], the notable differences in the CD shapes between the N-benzylated oligomers
(S)-9a and N-naphthylated ones (S)-10a could be attributed to the different side chains, rather
–
g
, CD intensities were significantly increased and nearly identical. This result
β
3-homoalanine form oligomeric length
β
β
α
–
g
–g
than to the formation of different secondary structures. Further studies are needed to determine their
three-dimensional structures.
Next, we examined the thermal stability of the ordered structure of N-napthyl β-ABpeptoid.
The CD spectrum of octamer (S)-10g was recorded at various temperatures ranging from 5 to
70 ◦C (Figure 3f). The intensity of both peaks at 212 nm and 228 nm was gradually decreased
upon heating, but the CD spectra returned to the original shape when the temperature decreased to
◦
20 C (Figure S8). This finding showed that the observed temperature-dependent changes in the
CD spectra was due to the thermal denaturation of the folded structure on heating, as observed in
N-naphthylated
recording the CD spectra of oligomers of (S)-10a
MeOH and trifluoroethanol (TFE) (Supplementary Information Figure S7). Like N-benzyl substituted
oligomers, N-naphthylated -ABpeptoid oligomers exhibited nearly identical CD spectral shapes in
polar protic solvents compared to those observed in acetonitrile. Overall, CD spectroscopic data for
-ABpeptoid oligomers indicate that they form ordered three-dimensional structures, while further
β-peptoids with chiral side chains [37,41]. We then examined the solvent effect by
–
g
in polar protic solvents such as PBS-ACN (1:3),
β
β
structural studies such as high-resolution X-ray studies are needed to fully ascertain their structures.
3. Materials and Methods
3.1. General
All chemicals and reagents were purchased from commercial suppliers (Sigma-Aldrich,
Saint Louis, MO, USA; TCI, Tokyo, Japan) and used without further purification, unless
specified. In particular, chiral starting materials (methyl (R)-3-hydroxybutanoate and methyl
(S)-3-hydroxybutanoate) were purchased from Alfa Aesar (Haverhill, MA, USA). Rink amide MBHA
resin (0.45 mmol/g) was purchased from BeadTech (Seoul, South Korea). Analytical HPLC and LC/MS
were performed on Agilent systems (Santa Clara, CA, USA) with a C18 reversed phase HPLC column
(Eclipse XDB, 3.5
µ
m, 4.6 mm
×
150 mm). Linear gradients of A/B solvents (solvent A: 100% H2O,
0.1% TFA; B: 100% acetonitrile, 0.1% TFA) were used with the flow rate of 0.7 mL/min (10–60 to
100% B gradient over 7 min followed by 100% B until 13–15 min). Preparative HPLC purification was
performed on an Agilent 1120 Compact LC system (Agilent Technology) with a C18 reversed-phase
column (Agilent Technology, 5
B by changing solvent composition over 50 min with the flow rate of 5 mL/min. Chiral HPLC was
performed on AQUITY UPLC system Waters with CHIRALPAK IG 5 m (4.6 250 mm ID) column
and UV detection at 230 nm. For analysis 0.5 L sample (1 mg/mL) was injected with the flow rate
µm, 21.2 mm
×
150 mm) using a linear gradient from 20% B to 90%
µ
×
µ
of 1.0 mL/min of isocratic mobile phase (n-hexane/EtOH/DEA 80:20:0.1 or n-hexane/EtOH/TFA
80:20:0.1) over 25 to 30 min. CD spectra were recorded on a Jasco J-815 spectropolarimeter (Jasco
Corporation, Tokyo, Japan). The CD spectra were measured in the quartz cuvette with a 2 mm path

Molecules 2019, 24, 178
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length. The spectra were averages of 5 successive accumulations, employing 100 nm/min scan rate.
Data were expressed in terms of per-residue molar ellipticity (deg cm2/dmol), as calculated per mole
of amide groups present and normalized by the molar concentration of peptoids. Smoothing and
correction of the background spectra was performed afterwards. 1H- and 13C-NMR spectra were
collected at resonance frequencies of 300, 500 or 600 MHz and 125.7 MHz, respectively using Bruker
AVANCE 600 spectrometer (Bruker, Billerica, MA, USA). Proton 2D NOESY experiments were carried
out on a Bruker AVANCE 600 spectrometer equipped with a xyz gradient triple-resonance probe.
The samples were dissolved in CD3CN and the NOESY spectra were recorded with a mixing time of
300 ms.
3.2. Chemistry
3.2.1. Solution-Phase Synthesis Building Block Monomers and Intermediates
Methyl (R)-3-(tosyloxy)butanoate [(R)-1]. A solution of p-toluenesulfonyl chloride (35.1 g, 184 mmol,
1.15 equiv) in toluene (50 mL) was added in a dropwise manner to a stirred solution of methyl
(R)-3-hydroxybutanoate (20 g, 160 mmol) in anhydrous pyridine (50 mL) under N2. The reaction
mixture was stirred overnight after warming to room temperature and quenched with 1N aqueous
HCl (100 mL). The resulting mixture was then extracted with EtOAc (3
×
200 mL) and the combined
organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in
vacuo. The crude residue was purified by SiO2 flash chromatography to give the title compound
(R)-1 (38.7 g, 84%) as a white solid. [
α
]20D −8.3 (c 3.0, CH3CN); 1H-NMR (500 MHz, CDCl3):
δ 7.79
(d, J = 8 Hz, 2H), 7.35 (d, J = 8 Hz, 2H), 4.97 (sextet, J = 6.5 Hz, 1H), 3.6 (s, 1H), 2.73 (dd, J = 6.5 and
15.5 Hz, 1H), 2.52 (dd, J = 6.5 and 16 Hz, 1H), 2.45 (s, 3H), 1.35 (d, J = 6.5 Hz, 3H). 13C-NMR (500 MHz,
CDCl3):
δ
179.69, 144.71, 134.01, 129.77 (
×
2), 127.78 ( 2), 75.74, 51.81, 41.29, 21.60, 20.94. Mass m/z
×
calcd. for [M + H]+ 273.8, found [M + H]+ 273.8.
Methyl (S)-3-((4-nitrophenyl)sulfonamido)butanoate [(S)-4]. NaN3 (5.26 g, 80.8 mmol, 1.1 equiv) was
◦
added to a mixture of (R)-1 (20 g, 73.5 mmol) in DMF (70 mL). The mixture was stirred at 48 C for 14 h.
The mixture was cooled down to room temperature and filtered to remove insoluble solid. The filtrate
was diluted with water (150 mL) and the product was extracted with 5% EtOAc in diethyl ether
(2 × 200 mL). The organics were washed with brine (200 mL), dried over Na2SO4 and concentrated
under reduced pressure to afford the crude intermediate methyl (S)-3-azidobutanoate [(S)-2], 8.2 g],
which was used for the next step without further purification (caution: product is volatile). The crude
material (S)-2 (8.2 g) was dissolved in MeOH/CH2Cl2 (9:1, 120 mL) and then hydrogenated with
catalytic Pd/C 10% (0.82 g) at 30 psi for 4 h. The catalyst was removed by filtration through Celite®,
and the filtrates were evaporated to afford crude methyl (S)-3-aminobutanoate [(S)-3, 6.7 g], which was
used for the next step without further purification. (caution: product is volatile). The concentrated
product (S)-3 (6.7 g) was dissolved in CH2Cl2 (130 mL), and Et3N (15.9 mL, 114.6 mmol, 2 equiv) was
added. To the solution, cooled to 0 ◦C, was slowly added p-nitrobenzenesulfonyl chloride (12.6 g,
57.3 mmol, 1 equiv). The mixture was stirred for 30 min to complete the reaction. Then, the reaction
mixture was washed with water (3
×
150 mL) and the combined organic phase was dried over
Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash column
chromatography to afford a title compound (S)-4 (8.5 g, 38% overall yield for 3 steps) as yellowish
powder. [α]20D +14.8 (c 3.13, ACN) for the (R)-enantiomer [α]20D −16.3 (c 3.0, ACN); TLC Rf = 0.40
(EtOAc/hexane 2:3); 1H-NMR (300 MHz, CDCl3):
δ 8.35 (d, J = 7.8 Hz, 2H), 8.06 (d, J = 7.8 Hz, 2H),
5.56 (d, J = 8.4 Hz, 2H), 3.77 (m, 1H), 3.63 (s, 3H), 2.48 (d, J = 5.4 Hz, 2H), 1.18 (d, J = 6.9 Hz, 3H).
13C-NMR (300 MHz, CDCl3):
171.69, 150.18, 147.12, 128.44 ( 2), 124.58 ( 2), 52.12, 47.21, 40.55, 21.35.
Mass m/z calcd. for [M + Na]+ 325.05, found [M + Na]+ 325.0.
δ
×
×
Methyl (S)-3-((N-benzyl-4-nitrophenyl)sulfonamido)butanoate [(S)-5a]. To a solution of (S)-4 (3.0 g,
9.9 mmol) in DMF (40 mL) was added Cs2CO3 (5.8 g, 17.8 mmol, 1.8 equiv) and benzyl bromide
(2.36 mL, 19.8 mmol, 2 equiv). The mixture was stirred for 2 h at room temperature. After completion

Molecules 2019, 24, 178
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of reaction, the mixture was diluted with water (100 mL), extracted with EtOAc (2
with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was
×
100 mL), washed
purified by flash column chromatography to afford title compound (S)-5a (3.7 g, 95%) as yellowish
powder. [
α
]20
D
+5.4 (c 3.0, ACN) for the (R)-enantiomer [
α
]20D −5.8 (c 3.25, ACN); TLC Rf = 0.4
(EtOAc/hexane 1:3); 1H-NMR (500 MHz, CDCl3):
δ
8.30 (d, J = 9.0 Hz, 2H), 7.94 (d, J = 9.0 Hz, 2H),
7.33–7.26 (m, 5H), 4.55 (d, J = 15.5 Hz, 1H), 4.46–4.40 (m, 1H), 4.33 (d, J = 15.0 Hz, 1H), 3.56 (s, 3H), 2.53
(dd, J = 6.5, 16.0 Hz, 1H), 2.26 (dd, J = 8.0, 16.0 Hz, 1H), 1.13 (d, J = 7.0 Hz, 3H). 13C-NMR (500 MHz,
CDCl3):
δ
171.01, 149.93, 146.92, 136.73, 128.84 (
×
2), 128.53 ( 2), 128.41 (x2), 128.22, 124.38 (x2), 52.02,
×
51.96, 48.52, 40.66, 19.51. Mass m/z calcd. for [M + H]+ 393.1, found [M + H]+ 393.1.
Methyl (S)-3-((N-(naphthalen-1-ylmethyl)-2-nitrophenyl)sulfonamido)butanoate [(S)-5b]. Cs2CO3
(8.14 g, 25.0 mmol, 1.8 equiv) and 2-(Bromomethyl)naphthalene (4.61 gm, 20.8 mmol, 2 equiv) was
added to a solution of (S)-4 (4.2 g, 13.9 mmol) in DMF (45 mL). The mixture was stirred for 2 h at room
temperature. After completion of the reaction, the mixture was diluted with water (100 mL), extracted
with EtOAc (2
reduced pressure. The residue was purified by flash column chromatography to afford title compound
(S)-5b (5.6 g, 92%) as a yellowish powder. [ ]20 +7 (c 2.5, ACN); TLC Rf = 0.42 (EtOAc/hexane 2:3);
1H-NMR (500 MHz, CDCl3):
8.17 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H),
×
100 mL), washed with brine (100 mL), dried over Na2SO4 and concentrated under
α
D
δ
7.75 (d, J = 8.1 Hz, 1H), 7.63 (m, 2H), 7.58–7.46 (m, 4H), 7.40–7.34 (m, 1H), 5.06 (q, J =10.2 Hz, 2H),
4.64–4.53 (m, 1H), 3.55 (s, 3H), 2.58 (dd, J = 15.6, 5.1 Hz, 1H), 2.20 (dd, J = 15.6, 9.3 Hz, 1H), 1.18 (d,
J = 6.6 Hz, 3H). 13C-NMR (500 MHz, CDCl3):
δ 171.12, 147.90, 133.82, 133.72, 133.68, 132.38, 131.92,
131.79, 131.28, 129.01, 128.75, 127.12, 126.74, 126.09, 125.34, 124.38, 123.03, 51.97, 51.65, 46.21, 40.24,
18.95. Mass m/z calcd. for [M + Na]+ 465.11, found [M + Na]+ 465.1.
(S)-3-((N-benzyl-4-nitrophenyl)sulfonamido)butanoic acid [(S)-6a] and [(R)-6a]. The compound (S)-5a
◦
(3.5 g, 8.93 mmol) was dissolved in THF/water (20 mL/10 mL), cooled to 0 C, and a solution of LiOH
(0.24 g, 9.82 mmol, 1.1 equiv) in water (10 mL) was subsequently added. The mixture was stirred at
room temperature for 2 h. After complete consumption of the starting material, volatiles were removed
from the reaction mixture using a rotary evaporator and the remaining aqueous layer was washed
with diethyl ether (2
solution reached ~2–3. The precipitated compound was extracted by EtOAc (3
layer was dried over Na2SO4 and concentrated. The remaining residue was dried in vacuo to afford
title compound (S)-6a (2.05 g, 60%) as a white powder. [ ]20 +8.3 (c 3.0, ACN/CHCl3 2:1); TLC
Rf = 0.25 (EtOAc/hexane/AcOH 1:2:0.1); 1H-NMR (500 MHz, CDCl3):
8.27 (d, J = 9.0 Hz, 2H), 7.93
(d, J = 9.0 Hz, 2H), 7.37–7.30 (m, 5H), 4.52–4.33 (m, 3H), 2.58 (dd, J = 7.2, 16.2 Hz, 1H), 2.27 (dd, J = 7.2
16.2 Hz, 1H), 1.12 (d, J = 6.9 Hz, 3H). 13C-NMR (500 MHz, CDCl3):
176.84, 149.99, 146.80, 136.71,
2), 51.78, 48.54, 40.23, 20.15. Mass m/z calcd.
×
60 mL). The aqueous phase was acidified with 1N HCl solution until the pH of
×
40 mL). The organic
α
D
δ
,
δ
128.97 (
×
2), 128.62 (
×
2), 128.45 (
×
2), 128.39, 124.39 (
×
for [M + Na]+ 401.08, found [M + Na]+ 401.1. HRMS (HR-FAB-MS) m/z: calcd for C17H18N2O6S [M
+ H]+ 379.0964; found 379.0964. (R)-Enantiomer (R)-6a was synthesized by the same procedure as
described above. [
α
]20D −8.7 (c 3.0, ACN/CHCl3 2:1); 1H-NMR (600 MHz, CDCl3):
δ 8.31 (dd, J = 7.2
Hz, 1.8 Hz, 2H), 7.96 (dd, J = 7.2 Hz, 1.8 Hz, 2H), 7.39–7.33 (m, 5H), 4.54–4.4 (m, 3H), 2.61 (dd, J = 6.6,
16.2 Hz, 1H), 2.30 (dd, J = 7.8, 16.2 Hz, 1H), 1.16 (d, J = 6.6 Hz, 3H). 13C-NMR (600 MHz, CDCl3):
δ
175.58, 149.86, 146.70, 136.51, 128.76 (
×
2), 128.44 (
×
2), 128.27 (
×
2), 128.18, 124.16 ( 2), 51.66, 48.44,
×
40.00, 19.84. Mass m/z calcd, for [M + Na]+ 401.08, found [M + Na]+ 401.1. HRMS (HR-FAB-MS) m/z:
calcd for C17H18N2O6S [M + H]+ 379.0964; found 379.0961.
(S)-3-((N-(naphthalen-1-ylmethyl)-2-nitrophenyl)sulfonamido)butanoic acid [(S)-6b]. The compound
(S)-5b (4.6 g, 10.4 mmol) was dissolved in THF/water (24 mL/12 mL), cooled to 0 ◦C, and a solution
of LiOH (0.28 g, 11.44 mmol, 1.1 equiv) in water (12 mL) was subsequently added. The mixture
was stirred at room temperature for 2 h. After the complete consumption of the starting material,
volatiles were removed from the reaction mixture using a rotary evaporator and the remaining aqueous
layer was washed with diethyl ether (2
solution until the pH of solution reached ~2–3. The precipitated compound was extracted by EtOAc
×
60 mL). The aqueous phase was acidified with 1 N HCl

Molecules 2019, 24, 178
10 of 13
(
3 × 50 mL). The organic layer was dried over Na2SO4 and concentrated. The crude was dried in vacuo
to afford title compound (S)-6b (2.49 g, 56%) as an off-white solid. [ ]20 +8.1 (c 3.0, ACN/CHCl3
2:1); TLC Rf = 0.25 (EtOAc/hexane/AcOH 1:2:0.1); 1H-NMR (500 MHz, CDCl3):
8.17 (d, J = 8.5 Hz,
α
D
δ
1H), 7.92 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.63 (m, 2H), 7.58–7.48 (m,
4H), 7.39–7.36 (m, 1H), 5.06 (q, J = 16 Hz, 2H), 4.59–4.54 (m, 1H), 2.62 (dd, J = 15.5, 4.5 Hz, 1H), 2.22
(dd, J = 16.0, 9.0 Hz, 1H), 1.20 (d, J = 6.5 Hz, 3H). 13C-NMR (300 MHz, CDCl3):
δ 176.09, 147.89, 133.85,
133.81, 133.59, 132.24, 131.87, 131.30, 129.07, 128.87, 127.21, 126.82, 126.15, 125.37, 123.02, 51.37, 46.28,
40.11, 31.17, 19.05. Mass m/z calcd. for [M + Na]+ 451.09 found [M + Na]+ 451.1. HRMS (HR-FAB-MS)
m/z: calcd for C21H20N2O6S [M + H]+ 429.1120; found 429.1116.
Note: Para-nosyl group was used for all nosyl protected compounds except for (S)-5b and (S)-6b
where ortho-nosyl group was used. No notable difference was observed throughout the syntheses
(solution/solid-phase) between ortho- and para-nosyl protecting group.
3.2.2. General Solid-Phase Synthesis Method for Oligomers Synthesis
Solid-phase synthesis was conducted in a 3 to 5 mL fritted syringe (Torviq, Tucson, AZ, USA).
Rink amide MBHA resin (100 mg, 0.045 mmol) was swelled with DMF (1 mL) for 2 h. Fmoc protecting
group of resin (100 mg, 0.045 mmol) was removed by 20% piperidine in DMF (2
For sub-monomer coupling, resins were treated with the solution of synthesized monomer
×
10 min).
(3.0 equiv),
6
HATU (3.0 equiv), HOAt (3.0 equiv), and DIPEA (4.5 equiv) in DMF (1.0 mL) at room temperature.
After shaking for 3 h, the reaction mixture was drained, and the resin was washed with DMF ( 5)
and CH2Cl2 ( 5). Then, the nosyl protecting group was removed by treating with 2-mercaptoethanol
(2% in DMF, 0.6 mL) and 1,8-diazabicycloundec-7-ene (2.1% in DMF, 0.6 mL) for 45 min ( 2) at room
×
×
×
temperature. After a thorough washing cycle, the next monomer conjugation and nosyl deprotection
steps were repeated to provide oligomers with the desired chain length. For N-terminal acetylation,
oligomers on solid support were treated with acetic anhydride (10 equiv) and DIPEA (10 equiv) in
DMF (1 mL) for 2 h at room temperature. Final products were cleaved from the resin using a cleavage
cocktail (95% TFA, 2.5% triisopropylsilane, and 2.5% water) for 2 h (1 h
purified by reverse-phase HPLC.
×
2) at room temperature and
4. Conclusions
In summary, we have developed a facile and efficient solid-phase method for the synthesis of
-ABpeptoids, which consists of oligomers of N-substituted
3-alanines. Iterative on-resin coupling
reactions of N-alkylated
3-homoalanines as monomer building blocks allow for the preparation
of -ABpeptoid oligomers ranging from 2- to 8-mers in excellent yields. Although our solid-phase
β
β
β
β
method is highly efficient, each monomer building blocks should be synthesized individually via a
somewhat cumbersome solution-phase synthesis and purification process. We are currently developing
a submonomer solid-phase synthetic method that does not require the preparation of each monomers,
and the results will be reported in due course. Notably,
contrast to regular peptoids, and thus, are anticipated to form ordered structures. Indeed, these
-ABpeptoids with longer than 4-mer exhibited characteristic CD spectra and increased NOE signals,
β-ABpeptoids have backbone chirality in
β
suggesting that they adopt well-defined folding structures. Further structural studies including X-ray
study are needed to determine their detailed 3-dimensional structure. Given their potential to form
folding conformation, along with advantages as peptoids such as good cell permeability and stability,
β-ABpeptoids represent a novel class of peptidomimetic foldamers and will find a wide range of
applications in biomedical and material sciences.
Supplementary Materials: The following are available online: supplemental figures and tables regarding
characterization data including HPLC chromatograms, mass spectrometry data, CD spectra, and NMR data.

Molecules 2019, 24, 178
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Author Contributions: Conceptualization, G.A.S., K.J.L. and H.S.L.; methodology, G.A.S.; software, G.A.S. and
K.J.L; validation, G.A.S.; formal analysis, G.A.S.; investigation, G.A.S. and H.S.L.; resources, G.A.S. and K.J.L.;
data curation, G.A.S.; writing—original draft preparation, G.A.S. and H.S.L.; writing—review and editing, H.S.L.;
visualization, G.A.S. and H.S.L. supervision, H.S.L.; project administration, H.S.L.; funding acquisition, H.S.L.
Funding: This work was supported by the National Research Foundation of Korea (NRF-2017M3A9F6029753 and
NRF-2017M3A9E4077447).
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
Hill, D.J.; Mio, M.J.; Prince, R.B.; Hughes, T.S.; Moore, J.S. A Field Guide to Foldamers. Chem. Rev. 2001, 101,
3893–4012. [CrossRef] [PubMed]
Goodman, C.M.; Choi, S.; Shandler, S.; DeGrado, W.F. Foldamers as versatile frameworks for the design and
evolution of function. Nat. chem. biol. 2007, 3, 10–1038. [CrossRef] [PubMed]
Martinek, T.A.; Fulop, F. Peptidic foldamers: Ramping up diversity. Chem. Soc. Rev. 2012, 41, 687–702.
[CrossRef] [PubMed]
Cheng, R.P.; Gellman, S.H.; DeGrado, W.F.
3219–3232. [CrossRef] [PubMed]
β-Peptides: From Structure to Function. Chem. Rev. 2001, 101,
Seebach, D.; Gardiner, J.
[PubMed]
β-Peptidic Peptidomimetics. Acc. Chem. Res. 2008, 41, 1366–1375. [CrossRef]
Kritzer, J.A.; Lear, J.D.; Hodsdon, M.E.; Schepartz, A. Helical
Interaction. J. Am. Chem. Soc. 2004, 126, 9468–9469. [CrossRef] [PubMed]
Fisher, B.F.; Gellman, S.H. Impact of -Amino Acid Residue Preorganization on
Helicity in Aqueous Solution. J. Am. Chem. Soc. 2016, 138, 10766–10769. [CrossRef]
β-Peptide Inhibitors of the p53-hDM2
γ
α/γ-Peptide Foldamer
Shin, Y.-H.; Gellman, S.H. Impact of Backbone Pattern and Residue Substitution on Helicity in
α/β/γ-Peptides. J. Am. Chem. Soc. 2018, 140, 1394–1400. [CrossRef]
Violette, A.; Averlant-Petit, M.C.; Semetey, V.; Hemmerlin, C.; Casimir, R.; Graff, R.; Marraud, M.; Briand, J.-P.;
Rognan, D.; Guichard, G. N,N0-Linked Oligoureas as Foldamers: Chain Length Requirements for Helix
Formation in Protic Solvent Investigated by Circular Dichroism, NMR Spectroscopy, and Molecular
Dynamics. J. Am. Chem. Soc. 2005, 127, 2156–2164. [CrossRef]
10. Collie, G.W.; Pulka-Ziach, K.; Lombardo, C.M.; Fremaux, J.; Rosu, F.; Decossas, M.; Mauran, L.; Lambert, O.;
Gabelica, V.; Mackereth, C.D.; et al. Shaping quaternary assemblies of water-soluble non-peptide helical
foldamers by sequence manipulation. Nat. Chem. 2015, 7, 871. [CrossRef]
11. Kudryavtsev, K.V.; Ivantcova, P.M.; Churakov, A.V.; Wiedmann, S.; Luy, B.; Muhle-Goll, C.; Zefirov, N.S.;
Bräse, S. Alternating Asymmetric Self-Induction in Functionalized Pyrrolidine Oligomers. Angew. Chem.
Int. Ed. 2013, 52, 12736–12740. [CrossRef] [PubMed]
12. Shi, Y.; Teng, P.; Sang, P.; She, F.; Wei, L.; Cai, J.
γ-AApeptides: Design, Structure, and Applications.
Acc. Chem. Res. 2016, 49, 428–441. [CrossRef] [PubMed]
13. Teng, P.; Ma, N.; Cerrato, D.C.; She, F.; Odom, T.; Wang, X.; Ming, L.-J.; van der Vaart, A.; Wojtas, L.; Xu, H.;
et al. Right-Handed Helical Foldamers Consisting of De Novo d-AApeptides. J. Am. Chem. Soc. 2017, 139,
7363–7369. [CrossRef] [PubMed]
14. Angelo, N.G.; Arora, P.S. Nonpeptidic Foldamers from Amino Acids: Synthesis and Characterization of
1,3-Substituted Triazole Oligomers. J. Am. Chem. Soc. 2005, 127, 17134–17135. [CrossRef] [PubMed]
15. Günther, R.; Hofmann, H.-J. Hydrazino Peptides as Foldamers: An Extension of the β-Peptide Concept.
J. Am. Chem. Soc. 2001, 123, 247–255. [CrossRef] [PubMed]
16. Proulx, C.; Sabatino, D.; Hopewell, R.; Spiegel, J.; García Ramos, Y.; Lubell, W.D. Azapeptides and their
therapeutic potential. Future Med. Chem. 2011, 3, 1139–1164. [CrossRef] [PubMed]
17. Cho, C.Y.; Moran, E.J.; Cherry, S.R.; Stephans, J.C.; Fodor, S.P.; Adams, C.L.; Sundaram, A.; Jacobs, J.W.;
Schultz, P.G. An unnatural biopolymer. Science 1993, 261, 1303–1305. [CrossRef]
18. Li, X.; Wu, Y.-D.; Yang, D. α-Aminoxy Acids: New Possibilities from Foldamers to Anion Receptors and
Channels. Acc. Chem. Res. 2008, 41, 1428–1438. [CrossRef]
19. Yoo, B.; Kirshenbaum, K. Peptoid architectures: Elaboration, actuation, and application. Curr. Opin.
Chem. Biol. 2008, 12, 714–721. [CrossRef]

Molecules 2019, 24, 178
12 of 13
20. Fowler, S.A.; Blackwell, H.E. Structure-function relationships in peptoids: Recent advances toward
deciphering the structural requirements for biological function. Org. Biomol. Chem. 2009, 7, 1508–1524.
[CrossRef]
21. Laursen, J.S.; Engel-Andreasen, J.; Olsen, C.A.
2696–2704. [CrossRef]
β-Peptoid Foldamers at Last. Acc. Chem. Res. 2015, 48,
22. Simon, R.J.; Kania, R.S.; Zuckermann, R.N.; Huebner, V.D.; Jewell, D.A.; Banville, S.; Ng, S.; Wang, L.;
Rosenberg, S.; Marlowe, C.K. Peptoids: A modular approach to drug discovery. Proc. Natl. Acad. Sci. USA
1992, 89, 9367–9371. [CrossRef] [PubMed]
23. Zuckermann, R.N.; Kerr, J.M.; Kent, S.B.H.; Moos, W.H. Efficient method for the preparation of peptoids
[oligo(N-substituted glycines)] by submonomer solid-phase synthesis. J. Am. Chem. Soc. 1992, 114,
10646–10647. [CrossRef]
24. Miller, S.M.; Simon, R.J.; Ng, S.; Zuckermann, R.N.; Kerr, J.M.; Moos, W.H. Proteolytic studies of homologous
peptide and N-substituted glycine peptoid oligomers. Bioorg. Med. Chem. Lett. 1994, 4, 2657–2662. [CrossRef]
25. Wang, Y.; Lin, H.; Tullman, R.; Jewell, C.F., Jr.; Weetall, M.L.; Tse, F.L. Absorption and disposition of a
tripeptoid and a tetrapeptide in the rat. Biopharm. Drug Dispos. 1999, 20, 69–75. [CrossRef]
26. Yu, P.; Liu, B.; Kodadek, T. A high-throughput assay for assessing the cell permeability of combinatorial
libraries. Nat. Biotechnol. 2005, 23, 746. [CrossRef]
27. Tan, N.C.; Yu, P.; Kwon, Y.U.; Kodadek, T. High-throughput evaluation of relative cell permeability between
peptoids and peptides. Bioorg. Med. Chem. 2008, 16, 5853–5861. [CrossRef]
28. Shin, M.-K.; Hyun, Y.-J.; Lee, J.H.; Lim, H.-S. Comparison of Cell Permeability of Cyclic Peptoids and Linear
Peptoids. ACS Comb. Sci. 2018, 20, 237–242. [CrossRef]
29. Webster, A.M.; Cobb, S.L. Recent Advances in the Synthesis of Peptoid Macrocycles. Chemistry 2018, 24,
7560–7573. [CrossRef]
30. Shin, S.B.Y.; Yoo, B.; Todaro, L.J.; Kirshenbaum, K. Cyclic Peptoids. J. Am. Chem. Soc. 2007, 129, 3218–3225.
[CrossRef]
31. Lee, J.H.; Meyer, A.M.; Lim, H.-S. A simple strategy for the construction of combinatorial cyclic peptoid
libraries. Chem. Commun. 2010, 46, 8615–8617. [CrossRef] [PubMed]
32. Lee, J.H.; Kim, H.-S.; Lim, H.-S. Design and Facile Solid-Phase Synthesis of Conformationally Constrained
Bicyclic Peptoids. Org. Lett. 2011, 13, 5012–5015. [CrossRef] [PubMed]
33. Lee, K.J.; Lim, H.-S. Facile Method To Sequence Cyclic Peptides/Peptoids via One-Pot
Ring-Opening/Cleavage Reaction. Org. Lett. 2014, 16, 5710–5713. [CrossRef] [PubMed]
34. Kaniraj, P.J.; Maayan, G. A Facile Strategy for the Construction of Cyclic Peptoids under Microwave
Irradiation through a Simple Substitution Reaction. Org. Lett. 2015, 17, 2110–2113. [CrossRef] [PubMed]
35. Oh, M.; Lee, J.H.; Moon, H.; Hyun, Y.-J.; Lim, H.-S. A Chemical Inhibitor of the Skp2/p300 Interaction that
Promotes p53-Mediated Apoptosis. Angew. Chem. Int. Ed. 2016, 55, 602–606. [CrossRef] [PubMed]
36. Armand, P.; Kirshenbaum, K.; Goldsmith, R.A.; Farr-Jones, S.; Barron, A.E.; Truong, K.T.V.; Dill, K.A.;
Mierke, D.F.; Cohen, F.E.; Zuckermann, R.N.; et al. NMR determination of the major solution conformation
of a peptoid pentamer with chiral side chains. Proc. Natl. Acad. Sci. USA 1998, 95, 4309–4314. [CrossRef]
[PubMed]
37. Wu, C.W.; Sanborn, T.J.; Zuckermann, R.N.; Barron, A.E. Peptoid Oligomers with α-Chiral, Aromatic Side
Chains: Effects of Chain Length on Secondary Structure. J. Am. Chem. Soc. 2001, 123, 2958–2963. [CrossRef]
38. Wu, C.W.; Kirshenbaum, K.; Sanborn, T.J.; Patch, J.A.; Huang, K.; Dill, K.A.; Zuckermann, R.N.; Barron, A.E.
Structural and Spectroscopic Studies of Peptoid Oligomers with α-Chiral Aliphatic Side Chains. J. Am.
Chem. Soc. 2003, 125, 13525–13530. [CrossRef]
39. Stringer, J.R.; Crapster, J.A.; Guzei, I.A.; Blackwell, H.E. Extraordinarily Robust Polyproline Type I Peptoid
Helices Generated via the Incorporation of -Chiral Aromatic N-1-Naphthylethyl Side Chains. J. Am.
Chem. Soc. 2011, 133, 15559–15567. [CrossRef]
40. Roy, O.; Dumonteil, G.; Faure, S.; Jouffret, L.; Kriznik, A.; Taillefumier, C. Homogeneous and Robust
α
Polyproline Type I Helices from Peptoids with Nonaromatic α-Chiral Side Chains. J. Am. Chem. Soc. 2017,
139, 13533–13540. [CrossRef]
41. Laursen, J.S.; Harris, P.; Fristrup, P.; Olsen, C.A. Triangular prism-shaped β-peptoid helices as unique
biomimetic scaffolds. Nat. Commun. 2015, 6, 7013. [CrossRef] [PubMed]

Molecules 2019, 24, 178
13 of 13
42. Lee, K.J.; Lee, W.S.; Yun, H.; Hyun, Y.-J.; Seo, C.D.; Lee, C.W.; Lim, H.-S. Oligomers of N-Substituted
β2-Homoalanines: Peptoids with Backbone Chirality. Org. Lett. 2016, 18, 3678–3681. [CrossRef] [PubMed]
43. Sable, G.A.; Lee, K.J.; Shin, M.-K.; Lim, H.-S. Submonomer Strategy toward Divergent Solid-Phase Synthesis
of α-ABpeptoids. Org. Lett. 2018, 20, 2526–2529. [CrossRef] [PubMed]
44. Kirshenbaum, K.; Barron, A.E.; Goldsmith, R.A.; Armand, P.; Bradley, E.K.; Truong, K.T.V.; Dill, K.A.;
Cohen, F.E.; Zuckermann, R.N. Sequence-specific polypeptoids: A diverse family of heteropolymers with
stable secondary structure. Proc. Natl. Acad. Sci. USA 1998, 95, 4303–4308. [CrossRef] [PubMed]
45. Wu, C.W.; Sanborn, T.J.; Huang, K.; Zuckermann, R.N.; Barron, A.E. Peptoid Oligomers with α-Chiral,
Aromatic Side Chains: Sequence Requirements for the Formation of Stable Peptoid Helices. J. Am. Chem. Soc.
2001, 123, 6778–6784. [CrossRef] [PubMed]
46. Sable, G.A.; Park, J.; Kim, H.; Lim, S.-J.; Jang, S.; Lim, D. Solid-Phase Total Synthesis of the Proposed Structure
of Coibamide A and Its Derivative: Highly Methylated Cyclic Depsipeptides. Eur. J. Org. Chem. 2015, 2015,
7043–7052. [CrossRef]
47. Sable, G.A.; Park, J.; Lim, S.-J.; Lim, D. Solid-phase Total Synthesis of Amide Analogues of Coibamide A:
Azacoibamide A and O-Desmethyl Azacoibamide A. Bull. Korean Chem. Soc. 2016, 37, 330–334. [CrossRef]
48. Morimoto, J.; Fukuda, Y.; Sando, S. Solid-Phase Synthesis of beta-Peptoids with Chiral Backbone Substituents
Using Reductive Amination. Org. Lett. 2017, 19, 5912–5915. [CrossRef]
49. Norgren, A.S.; Zhang, S.; Arvidsson, P.I. Synthesis and Circular Dichroism Spectroscopic Investigations of
Oligomeric β-Peptoids with α-Chiral Side Chains. Org. Lett. 2006, 8, 4533–4536. [CrossRef]
50. Gorske, B.C.; Stringer, J.R.; Bastian, B.L.; Fowler, S.A.; Blackwell, H.E. New Strategies for the Design of
Folded Peptoids Revealed by a Survey of Noncovalent Interactions in Model Systems. J. Am. Chem. Soc.
2009, 131, 16555–16567. [CrossRef]
Sample Availability: Samples of the compounds (S)-6a, (R)-6a, (S)-6b, 9a–g, (S)-10a–g, 9e-Ac and, (S)-10e-Ac
are available from the authors.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).