Unique β-Turn Peptoid Structures and Their Application as Asymmetric Catalysts

Article abstract of DOI:10.1002/chem.202000595

Peptoids, N-substituted glycine oligomers, represent an important class of peptidomimetics that can fold into three-dimensional structures in solution. Most of the folded peptoid structures, however, resemble helices, and this can limit their applications

Full text of DOI:10.1002/chem.202000595

A Journal of
Accepted Article
Title: Unique β-Turn Peptoid Structures and their Application as
Asymmetric Catalysts
Authors: Chandramohan Drapaneni, Pritam Ghosh, Totan Ghosh, and
Galia Maayan
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Unique β-Turn Peptoid Structures and their Application as
Asymmetric Catalysts
Darapaneni Chandra Mohan,‡ Pritam Ghosh,‡ Totan Ghosh, Galia Maayan*[a]
Abstract: Peptoids – N-substituted glycine oligomers – represent an
important class of peptidomimetics that can fold into three-
dimensional structures in solution. Most of the folded peptoid
structures, however, resemble helices, and this can limit their
Nevertheless, controlling the secondary or higher-order
structure of peptoids is still challenging and the few defined
structures reported to date mostly resemble the polyproline
[
7]
helix motif, with a few unique examples of a peptoid
applications, specifically in asymmetric catalysis. Herein we describe, ribbon and a peptoid square helix.[9] Although the helix is
[
8]
for the first time, unique examples of pyrrolidine-based β-turn-like
peptoids and characterize them both in the solid state by single
crystal X-ray analysis and in solution by circular dichroism
spectroscopy. Furthermore, we demonstrate their highly efficient and
enantioselective catalytic activity for the production of γ-nitro
aldehydes via asymmetric Michael reaction in water. The structural
properties and DFT-D3 calculations of the new β-turn-like peptoids,
as well as catalytic and spectroscopic studies on designed
pyrrolidine-based helical peptoids, suggest that the β-turn structure
the most abundant secondary structure in nature, it has
been evaluated, for example, that β-turns are generated
from up to 25% of all the proteins residues.[10] Indeed, great
efforts in the field of peptidomimetics had focused on the
development of β-turn mimics and of oligomers with turn-
like conformations.[11] Nevertheless, there are currently no
examples of a β-turn-like peptoid structure. This may limit
the utilization of peptoids: it was shown, for example, that
many peptide-based enantioselective catalysts adopt a β-
turn structure, which is crucial for their high efficiency and
selectivity.[12] Designing β-turn-like peptoids is therefore
essential not only for enlarging the structure versatility of
peptoids but also for their development as asymmetric
catalysts. We note here that there are currently only a few
plays a key role in the stereoselectivity of the catalytic reaction
.
Introduction
reports on catalytic peptoids,[6] and among these, even
The remarkable efficiency and selectivity of natural
biopolymers in carrying out valuable functions such as
molecular recognition and catalysis have been a source of
inspiration for the design and synthesis of functional
chemical systems. Mimicking the capabilities of
biopolymers such as enzymes requires the ability to imitate
their unique properties, including their well-defined three-
dimensional structures and the established relationship
between structure and function. This goal has led to the
development of “foldamers” – biomimetic oligomers that can
adopt three-dimensional structures in solution.[1] Among
peptidomimetic foldamers, peptoids, N-substituted glycine
oligomers,[ are especially suitable for the mimicry of
biocatalysts due to their facile synthesis and chemical
diversity. Peptoids can be efficiently generated by the “sub-
monomer” solid-phase method that employs primary
[6e-f]
fewer on asymmetric peptoid catalysts.
In addition,
these examples do not include the use of peptoids as
asymmetric catalysts in the conjugate addition reaction
(
Michael reaction), which is one of the most useful
[13]
asymmetric C-C-bond forming reactions
leading to
enantiopure synthetic intermediates for the production of
specialty chemicals and pharmaceuticals.[14] In contrast,
short peptides and peptidomimetics containing proline and
in some cases, a carboxylic acid group, were developed as
highly efficient and enantioselective catalysts for this
reaction.[12, 15, 16] Studies on the peptide catalysts reveal that
they all have a β-turn structure and that this specific motif is
a key for the high enantioselectivity obtained in the Michael-
type and other addition reactions. Thus, we thought to
2]
rationally design and develop
a small set of β-turn
pyrrolidine-based peptoids, evaluate their structural
properties, test them as catalysts for the Michael addition
reaction and investigate the effect of the catalyst structure
on its activity.
[
3]
amines rather than amino acids,
enabling the
4]
[
incorporation of various functional groups (e.g.; metal-
binding ligands[5] and catalysts ) with high sequence
specificity. Moreover, their chirality and structure can be
systematically tuned by simply altering their sequence. This
should facilitate the construction of rationally designed
functional peptoid sets, such as peptoid catalysts, aiming to
[6]
Results and Discussion
Rational design, synthesis and characterization of
pyroloidine-based β-turn peptoids.
study
sequence-structure-function
relationships
and
optimize, for example, catalytic activity and selectivity.
Currently, there is only one report on β-turn structures
containing peptoid residues.[17] In this report, Rainaldi et al.
describe the sequences, IR and NMR spectroscopies of
peptide-peptoid trimers bearing a proline residue at the N-
terminus. It was also shown that within enantioselective
peptide catalysts the proline group has the opposite chirality
[
a]
Schulich faculty of chemistry
Technion-Israel Institute of Technology
Haifa, Israel 3200008
E-mail: gm92@tx.technion.ac.il
[
18]
with respect to the peptide backbone.
Accordingly we
‡
Equal contribution.
wished to design a peptoid trimer having S- or R-pyrrolidine
group at the N-terminus and two chiral structure-directing
groups (instead of the amino acid residues). Among the
Supporting information for this article is given via a link at the end of
the document.
1
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Chemistry - A European Journal
10.1002/chem.202000595
FULL PAPER
dichloromethane layered with hexane. We were pleased to
obtain small needle-shaped white crystals suitable for
single-crystal analysis. X-ray analysis of these crystals
revealed that the two naphthylethyl groups are in the cis
conformation relative to the peptoid scaffold, and both the
pyrrolidine group and the C-terminus amide bond are facing
the other side of the scaffold, forming a β-turn-like structure
(
see SI for the ORTEP diagram). The distance between the
pyrrolidine –NH (N1) and the C-terminus amide bond
oxygen (O3) is 3.54 Å, indicating a hydrogen-bonding
interaction and supporting a β-turn-like structure.[20]
We have used the coordinates from this crystal structure
to calculate the structures of the peptoid P2, having the
same pyrrolidine and side-chain chirality like P1, and of the
control peptoids P4 and P5, by Density Functional Theory
(
DFT-D3) considering the dispersion correction (Tables S4
and S5). In each case the piperazine amide bond was
added manually to the structure of P1 and the geometry of
the structure was optimized (see SI for details). The lowest
energy optimized structures of P2 and P4 are depicted in
Fig. 1b. The calculated structures of P2 and P4 show
similar distances between the pyrrolidine–NH proton and
the C-terminus carbonyl oxygen (C=O) adjacent to
piperazine center, which are 2.45
Å
and 2.21
Å
respectively, suggesting that these also adopt β-turn-like
structures. However, a sharp difference between these two
compounds has been observed. Both the napthylethyl
groups in P2 (and also in P1) are situated at the same
plane (the z-axis), whereas in P4 these two groups are
located in different planes, one in the z-axis and the other in
the y-axis. Therefore, the structure of P4 cannot be
considered as a β-turn-like motif. The calculated structure
of P5 (Fig. S4b), on the other hand, shows that the
pyrrolidine–NH proton faces away from the oxygen of the
C-terminus amide bond and because these two groups do
not face each other at all, the distance between them is as
large as 5.15 Å, suggesting that similar to P4, the structure
Figure 1. Sequences of the designed peptoids P1-P4 (a)
and the crystal structure of the oligomer P1, as well as the
structures of P2 and P4 calculated by DFT-D3 method (b).
Bond distance between H1A to O3 is 3.53Å in P1, 2.45Å
between H50 to O37 in P2 and 2.21Å between H50 to O17
in P4. Calculations were performed using the Turbomole
software (V.7.3) with B3-LYP hybrid functional considering
the dispersion correction and def2-SVP as the basis set for
all atoms in macOS workstation (Mojave V. 10.14.5).
reports on peptoids having structure-directing side chains,7
there is only one published crystal structure of a peptoid
dimer that resembles a (helical) turn structure, a homo-
oligomer incorporating two chiral naphthylethyl (Ns1npe)
side chains.[7j] We therefore designed and synthesized the
peptoid trimer P1 having an S-pyrrolidine group at the N-
terminus and two Nr1npe side chains (Fig. 1a). To increase
the solubility of P1 in water, we have incorporated a
piperazine group at its C-terminus,[19] forming P2 (Fig. 1a)
and then modify the chirality of either the naphthylethyl or
pyrrolidine side chains to obtain peptoids P3 and P4 (Fig.
of P5 also does not represents
a β-turn-like motif.
1a). The peptoids P1-P3 were designed to have a
pyrrolidine group with the opposite chirality of the side
chains and P4 was designed as a control peptoid, in which
all the side chains have the same chirality. As an additional
control peptoid, we have synthesized peptoid P5 (Fig. S4a),
which is similar to P3, but the naphthylethyl side chains are
achiral. The peptoids were synthesized using the “sub-
monomer” solid phase method, cleaved from the solid
support and purified by RP-HPLC (>95% purity). The
molecular weight measured by electrospray mass
spectrometry was consistent with the mass expected for
their sequences (see SI). Attempts to crystalize the
peptoids led to the crystallization of P1 from
Figure 2. CD spectra of peptoids P1-P5 (100 µM) in water.
Inset: CD spectra of poly(Ala2-Gly2) (-) and of type II f
-
turn calculated by Woody[21] (- - -, right coordinate). [22]
2
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FULL PAPER
The structures of peptoids P1
-
P5 were further
The CD spectrum of P1 also show one positive and one
negative band in this region but the value of 218 is much
higher than 207.5 and this, together with the lower intensity
compare with the bands of P2 and P3 suggest that the turn
of P1 is less structured. On the contrary, these wavelengths
are different from the ones seen in the CD spectra of the
characterized by circular dichroism (CD) spectroscopy in
water (Fig. 2). The spectra of peptoids P1 P3 and P5
exhibit a band near 228 nm, while a band near 230 nm is
shown in the spectrum of P4. Each of the peptoids P1 P5
exhibits an additional band near 218, 210, 210, 205 or
19.5 nm, respectively. An additional band near 222 nm is
observed only in the spectrum of P4. The highest intensity
of the bands was obtained in the cases of P2 and P3
-
-
2
peptoids P4
,
P5, the naphthyl dimer peptoid Ac-(s1npe)
2
-
-
CONH
CONH
2
and the helical naphthyl peptoid Ac-(s1npe)
6
,
2
(Table 1). The CD spectrum of P4 exhibits three
suggesting that these peptoids are the most structured
ones, or in other words, these peptoids exhibit the most
conformational homogeneity in solution. The distinctly low
band intensity observed in the spectrum of P5 is related to
the low chiral content of this peptoid; only one monomer
bands in this region and is more similar to the spectra of
Ac-(s1npe) -CONH and Ac-(s1npe) -CONH that show four
characteristic bands in this region. This observation reflects
a structural difference between P4 and P1 P3 as already
implied based on their X-ray and calculated structures (see
Fig. 1), and suggest that P4 adopts a helical turn similar to
the structures of helical naphthyl peptoids. We therefore
2
2
6
2
-
(pyrrolidine) out of four is chiral.
As there are currently no examples of β-turn-like
peptoids, we wished to compare the CD spectra of peptoids
P1
P5 to the CD spectra of a peptidic β-turn motif, [21-23] and
to homo-oligomer peptoids bearing Ns1npe side chains
conclude that only P1
solution, with the structures of P2 and P3 being more stable
that this of P1
-P3 adopt a β-turn-like structure in
-
.
[
7j]
(naphthyl peptoids).
A search in the literature revealed
-turns, measured in water, in the
that the CD spectrum of

region between 200-230 nm is characterized by a positive
band near 207.5 or 209 nm and a negative band near 227
[
22,23]
or 228 nm (Fig. 2, inset and Table 1).
These
wavelengths are very similar to the ones found for P2 and
P3 (210 nm and 228 nm).
Table
1
.
Spectral characteristics of peptide
P5
-turns,
naphthyl peptoids and peptoids P1
-
Peptide/Peptoid

1
, nm

2
, nm
Ref.
2
Peptide -Turn (Ala -
2
2
27
207.5
209
22
Gly
2
)
n
Figure 3. 1H NMR spectra (400 MHz) of P2 measured in
CDCl . Inset: experimental CD spectrum of P2 (100 µM) in
3
Peptide -Turn (Piv-L-
water (blue), and theoretical CD spectrum of P2 calculated
directly from the optimized geometry of the peptoid with
def2-SVP and COSMO (Water) combined with BJ damping
parameters.
28
23
PTo-Aib-NHMe)
2
28,
224,
20
Ac-(s1npe)
2
-CONH
2
203
7j
Although the CD of peptoids P2-P3 is highly similar to
2
these of the two β-turn peptides presented in Table 1, we
note here that compared with peptides, peptoids exhibit
multiple conformations in solution caused by the cis/trans
isomerization of the backbone amides. Hence, the
observed CD of P2, for example, should reflect this
conformational heterogeneity, representing all the different
rotamers and other isomers/conformers of P2 that exist in
solution, rather than the one stable rotamer that was
calculated by DFT (Fig. 1b). We therefor wished to further
probe the conformational heterogeneity of P2 in solution
and understand whether its β-turn-like structure obtained by
the DFT calculation can also exist in solution. To this aim,
All-cis Polyproline type
230,
218,
208
II peptoid helix (Ac-
7j
2
25
(
5 2
s1npe) -CONH )
P1
P2
P3
228
228
228
218
210
210
This work
This work
This work
1
we characterized P2 by solution H-NMR and calculated its
230,
CD spectrum in solution, based on its calculated structure.5o
As seen in Fig. 3, the NMR spectrum of the peptoid trimer
P2 exhibits multiple overlapping signals, suggesting that
indeed in solution, P2 exists as a mixture of rotamers. A
P4
P5
205
This work
This work
2
22
228
219.5
3
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Chemistry - A European Journal
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comparison between the theoretical and experimental CD
spectra of P2, which is also shown in Fig. 3, indicates that
the intense band near 228 nm is well reproduced by the
DFT calculation. This result suggests that the β-turn-like
structure calculated for P2 (Fig. 2) is the major rotamer
present in solution. The negative band near 210 nm shown
in the experimental CD spectrum is absent in the calculated
spectrum, suggesting that there are also other rotamers
and/or isomers/conformers present in the solution, as
indicated by the 1H NMR spectrum. Additionally, variable
temperature CD measurements of P2 showed only a slight
decrease in the intensity of the bands, even when the
temperature was as high as 70C (Fig. S2), indicating that
this β-turn-like rotamer is stable in solution. Collectively, the
experimental and theoretical CD spectra, as well as the
NMR spectrum of P2, strongly suggest that it exists in
solution as an ensemble of conformational isomers
including a highly stable β-turn-like rotamer.
Figure 4. Reactions performed by using β-nitrostyrene (1a
,
From structure to function: pyroloidine-based β-turn
peptoids as asymmetric catalysts.
0
.15 mmol), pentanal (2a, 0.45 mmol) and the peptoid
a
1
catalysts (3 mol%) for 72h. Determined by H NMR of the
crude product. Determined by chiral HPLC.
Following their structural characterization, peptoids P1
-
b
P5 were tested as catalysts in the Michael reaction.
Specifically, we chose to focus on the combination between
aldehydes and nitro-olefins because it results in γ-nitro
aldehydes, which are versatile building blocks for the
production of valuable chiral compounds such as γ-amino
acids.[24] Thus, we investigated the catalytic performance of
To better understand the activity of the new peptoid
catalysts, the Michael reaction described in Fig. 3 and
catalyzed by P2 was further investigated. First, we
examined the progress of the reaction with time and found
that upon obtaining 85% conversion in 36h, the reaction
slows down significantly, as full conversion is achieved only
after 72h (Fig. S5). This can imply that the reaction kinetics
is dependent on the reactant’s concentrations. Second, we
varied the catalyst loading from 5 to 1 mol%, which
significantly slowed down the reaction from 48h to 150h for
achieving full conversion but the enantioselectivity was not
effected (Fig. S6a). This suggests that no racemization
occurs during the reaction. Finally, increasing the
temperature to 35°C resulted in a slight decrease in
enantioselectivity (Fig. S6b), consistent with the slight
decrease in the stability of the β-turn-like structure (Fig. S2).
As most structured peptoids resemble the polyproline
peptoids P1
pentanal (1a and 2a, Fig. 4) in water. The conversion of 1a
to (R)-2-((S)-2-nitro-1-phenylethyl) pentanal 3a in all
-P5 in the reaction between β-nitrostyrene and
(
)
cases was >90%, however, the enantioselectivity of the
reaction varied with the different catalysts and was highly
dependent on their structures and chirality. Remarkably,
95% enantioselective excess (ee) was observed with both
P2 and P3 but to the opposite chirality. A slight drop to 87%
ee was observed when P1, which also exhibits a β-turn-like
motif, was used as a catalyst. The lower enantioselectivity
of P1 compared with P2 is in correlation with the slightly
lower stability of its structure as observed in the CD
measurements, and might be related to the distance
between the pyrrolidine–NH proton and the C-terminus
amide bond oxygen, which is larger in P1 than this distance
in P2 (3.54 Å vs. 2.45 Å). Another, sharper decrease in the
enantioselectivity (56% ee), was observed when P4, which
its structure does not fulfill the requirements for a β-turn-like
motif, was used as a catalyst. Finally, only 41% ee was
obtained when P5 was used as a catalyst, and this can be
explained by its unstructured nature together with its achiral
non-catalytic side chains. Notably, L-proline could not
catalyze this reaction in these conditions (Fig. 4). These
results emphasize the vital role of side-chain chirality on the
type helices, we wished to investigate whether
a
pyrrolidine-based helical peptoids can also perform as
enantiosselective catalysts in the Michael reaction between
β-nitrostyrene and pentanal as described in Fig. 3. It was
previously demonstrated that helical peptoids bearing at
least five phenylethyl (Nspe) side chains and the achiral
catalyst 2,2,6,6-Tetramethyl-1-piperidinyloxy (TEMPO), can
catalyze the oxidative kinetic resolution of secondary
alcohols with high enantioselectivity, due to chiral induction
from the helical peptoid structure to the achiral catalyst.[
Based on this report, as well as on water solubility
considerations, we decided to design and synthesize three
additional control peptoids that are expected to adopt a
helical structure, namely the peptoid hexamer P6, having
five Nspe groups and S-pyrrolidine at the N-terminus, and
peptoids P7 and P8 with additional one or two piperazine
6f]
[
6f]
enantioselectivity of peptoid catalysts,
and more
importantly, reveal for the first time that pyrrolidine-based
peptoids stabilized in a β-turn-like structure, which locks the
stereogenic center of the C-terminal position, can be used
as asymmetric catalysts.
[
19]
units, respectively, to enable water solubility
(Fig. 5).
These peptoids were synthesized via the “sub-monomer”
4
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Chemistry - A European Journal
10.1002/chem.202000595
FULL PAPER
solid phase method, purified (>95%) and characterized by
MS analysis and CD spectroscopy. The CD spectra of
peptoids P6-P8 exhibit double minima near 200 and 220
nm, in which the band at 220 nm is much more intense (Fig.
S7), indicating a helical structure.[7a] All three peptoids were
tested as catalysts for the Michael reaction between β-
nitrostyrene and pentanal as described in Fig. 4, in the
same reaction conditions and substrate concentrations that
3.11 Å within P2 to 4.54 Å in the intermediate (Fig. 6). The
similarity between these distances indicates that the
intermediate maintains the turn-like structure of P2 possibly
due to the cis inducing chiral backbone of the peptoid.
Significantly, the Re-face of the intermediate is hindered by
the bulky naphthylethyl groups within the turn-like structure,
which provide a steric shielding of this face (Fig. 6).[26] Thus,
the enamine can selectively approach the Si-face of the
nitrostyrene which eventually affords the product. Indeed, in
this reaction, such a shielding effect over a specific
pyrrolidine face is biased by the pyrrolidine stereochemistry,
resulting in a specific enantiomer as the major product.
were used in the reactions with P1-P5. Using P6 as a
catalyst resulted in 99% conversion of 1a to 3a with 20%
ee. As P1 is not soluble in water, we assumed that the poor
enantioselectivity is because the reaction is taking place ‘on
water’; however, only
a
slight improvement in the
enantioselectivity was observed with the water-soluble
catalysts P7 and P8 (Fig. 5, entries 2 and 3). Moreover,
replacing the water media in organic solvents completely
diminished the activity of P6. Overall these results suggest
that the enantioselectivity in this reaction is dependent on
the structure of the peptoid catalysts and that pyrrolidine-
based helical peptoids cannot catalyze this reaction with
high enantioselectivity.
Figure 5. Sequences of the helical peptoids P6-P8 and their
catalytic performance in the Michael reaction. Reactions
Figure 6.
A schematic diagram showing the suggested
explanation for the high enantioselectivity obtained with P2 (a).
DFT-D3 energy optimized structure of (b) and the intermediate
in the reaction (c) Calculations were performed using the
Turbomole software (V.7.3) with B3-LYP hybrid functional
considering the dispersion correction and def2-SVP as the basis
set for all atoms in macOS workstation (Mojave V. 10.14.5).
were performed by using 1a (0.15mmol), 2a (0.45 mmol) and
a
1
the peptoid catalysts (3 mol%) for 72h. Determined by H-
b
NMR of the crude product. Determined by chiral HPLC.
Suggested mechanism.
To examine the effect of the
-turn structure on the
catalytic performance of P2 we looked into the mechanism
of the catalytic process. Enantio-selection in the Michael
addition reaction was previously explained by the
Seebach’s topological model, in which the anti-enamine
approaches the nitro olefin at the less hindered face
through a synclinal transition state.[25] Based on this model,
our X-ray and CD analysis, the geometry of anti enamine
intermediate was optimized by DFT-D3 calculations (Fig.
S8). Initially, P2 reacts with an aldehyde by the elimination
of water to yield the anti-enamine intermediate in the more
stable E configuration (Fig. 6). As a consequence, the
distance between the pyrrolidine nitrogen and the carbonyl
oxygen adjacent to piperazine center slightly increases from
Reaction scope.
Finally, the scope of the reaction was explored starting with
the combination between different aliphatic aldehydes and
trans β-nitrostyrene (Fig. 7). The products 3a-3d were
obtained with good to excellent isolated yields along with
high diastereo selectivity and %ee. Further on, different
substituted trans-β-nitrostyrene compounds, including
ortho-substituted ones and a heterocyclic nitro olefin, were
reacted with 2a affording the corresponding Michael
adducts 3e
-3i with good conversions and diastereo
selectivity, and excellent %ee.
5
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Chemistry - A European Journal
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FULL PAPER
(
Nsnpe) and piperazine were purchased from Acros organics, Israel;
Carbazole, N,N’-diisopropylcarbodiimide (DIC), bromoacetic acid and
chloroacetic acid were purchased from Sigma Aldrich. Other reagents
and solvents were purchased from commercial sources and used without
additional purification. Trifluoroacetic acid (TFA) was purchased from
Apollo Scientific Ltd.
Instrumentation. Peptoid oligomers were analyzed by reversed-phase
HPLC (analytical C18 column, 5 μm, 100 Å, 2.0x50 mm) on a Jasco UV-
2
075 instrument. A linear gradient of 5–95% acetonitrile (ACN) in water
0.1% TFA) over 10 min was used at a flow rate of 0.7 mL/min.
Preparative HPLC was performed using a phenomenex C18 column
15μm, 100 Å 21.20x100mm) on a Jasco UV-2075 instrument with 214
(
(
Figure 7. Substrate scope for the Michael reaction catalyzed by
P2. Reactions performed in water with 0.15 mmol nitro
compound, 0.45 mmol aldehyde and 3 mol% of P2 (5 mol% in
the cases of 3f and 3i) for 72h. The diastereoselectivity was
determined by 1H-NMR of the crude product. The %ee was
determined by chiral HPLC.
nm analytical and 230 nm for prep. Peaks were eluted with a linear
gradient of 5–95% ACN in water (0.1% TFA) over 50 min at a flow rate of
5 mL/min. Mass spectrometry was performed on an Waters LCT Premier
mass and Advion expression mass under electrospray ionization (ESI),
2
direct probe ACN: H O (70:30), flow rate 0.3 ml/min. CD measurements
were performed using an Applied Photophysics chirascan circular
dichroism spectrometer. 1H &13C NMR spectra were recorded on a
Bruker 400 MHz instrument. Coupling constants are given in Hz. The
abbreviations used to indicate the multiplicity are: s, singlet; d, doublet; m,
multiplet; bs, broad signal. X-ray crystallography was done on a Kappa
CCD diffractometer at 293K. The DFT-D3 calculations were performed
using the Turbomole software (V.7.3) in macOS Mojave (V. 10.14.5)
work station.
Conclusions
This paper describes a unique example of peptoids that
were designed to have a -turn-like structure. For the first time,
the crystal structure along with a solution CD spectrum of such
peptoid, P1, a pyrrolidine-based trimer, which incorporates two
naphthylethyl side-chains, is reported, together with the water-
soluble peptoids, P2 and P3 that adopt similar structures, as
demonstrated by DFT-D3 calculations (for P2) and CD analysis.
We showed that a –turn-like structure is formed only when the
naphthylethyl side-chains have the reverse chirality of the
pyrrolidine side-chain as suggested by the calculated structure
of two additional peptoids, P4 and P5. Peptoids P1-P5, as well
as the pyrrolidine-based helical peptoids P6-P8 that were
designed and synthesized as control peptoids in this study, were
further used as catalysts for the conjugate addition reaction
between aldehydes and β-nitro olefins in water. Our results
Preparation of peptoid oligomers: Peptoids were synthesized
manually on Rink amide resin using the submonomer approach at rt.
typically, 100 mg of resin was swollen in dichloromethane (DCM) for 40
minutes before initiating oligomer synthesis. De-protection of resin was
performed by addition of 20% piperidine solution (1.5 ml in Dimethyl
formamide (DMF)) and the reaction was allowed to shake at room
temperature for 20 min before piperidine was washed from the resin
using DMF (10 mL g-1 resin) (3 x 1 min). Bromoacetylation was
completed by adding 20 eq. bromoacetic acid (1.2 M in DMF, 8.5 mL g-1
resin) and 24 eq. of diisopropylcarbodiimide (DIC) (2 mL g-1 resin); this
reaction was allowed to shake at room temperature for 20 min. Following
the reaction, the bromoacetylation reagents were washed from the resin
suggest that the –turn motif plays
a role in the high
enantioselectivity in this reaction. Based on our spectroscopic
data and DFT-D3 calculation we were also able to understand
the probable spatial orientation of the anti-enamine intermediate
and realize the role of the –turn-like peptoid structure in the
high enantioselectivity. This work enlarges the versatility of
peptoid structures and increases the understanding of structure-
function relationships within catalytic peptoids. Thus, it
represents an important milestone in the construction of
peptoids and other peptidomimetic oligomers with diverse
structures and catalytic function towards efficient and
enantioselective asymmetric catalysts.
using DMF (10 mL g-1 resin) (3 x 1 min) and 20 eq. of submonomer
amine (1.0 M in DMF, 10 mL g-1 resin) were added. The amine
displacement reaction was allowed to shake at room temperature for 20
min and was followed by multiple washing steps (DMF, 10 mL g-1 resin).
This two-step addition cycle was modified as follows: To introduce
piperazine scaffolds, initially, chloro acylation was completed by adding
0 eq. chloroacetic acid (1.2 M in DMF, 8.5 mL g-1 resin) and 24 eq. of
2
DIC (2 mL g-1 resin); this reaction was allowed to agitate at room
temperature for 35 min. Following the reaction, the chloro acylation
reagents were washed from the resin using DMF (10 mL g-1 resin) (3 x 1
min) and 15 eq. of piperazine (105 mg , 1.23 M in DMF, 10 mL g-1 resin
after each the substitution reaction with piperazine washed with hot DMF,
1
0 mL g-1 resin [3 x 1 min]) was added. The amine displacement reaction
was allowed to shake at room temperature for 45 min and was followed
by multiple washing steps (DMF, 10 mL g-1 resin) (3
min).
Experimental Section
Materials. Rink Amide resin and knorr amide Ram resin were purchased
x
1
Bromoacylations or chloroacylation and amine displacement steps were
repeated until the desired peptoids were obtained. Finally with Proline
from Novabiochem; (S)-1-phenylethylamine (Nspe) and benzylamine
(
Npm), (S)-1-Cyclohexylethylamine (Nsch), (S)-1-(2-Naphthyl)ethylamine
6
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Chemistry - A European Journal
10.1002/chem.202000595
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in DMF, 8.5 mL g-1 resin) and
M
Zborovsky, H. Tigger-Zaborov, G. Maayan, Chem. Eur. J. 2019, 25,
9098 –9107.
take over night with (2
diisopropylcarbodiimide (DIC) (4 mL g-1 resin). To cleave the peptoid
oligomers from solid support for analysis, approximately 5 mg of resin
was treated with 95% Trifluoroacetic acid (TFA) in water (40 mL g-1 resin)
for 10 minutes. The cleavage cocktail was evaporated under nitrogen gas
and the peptoid oligomers were re-suspended in 0.5 mL HPLC solvent
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This research was funded by the Israeli Science Foundation
Huang, K. A. Dill, R. N. Zuckermann, A. E. Barron, J. Am. Chem.
Soc. 2003, 125, 13525- 13530; (e) B. C. Gorske, B. L. Bastian, G.
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Entry for the Table of Contents
COMMUNICATION
Darapaneni Chandra Mohan, Pritam
Ghosh, Totan Ghosh, Galia Maayan*
Page No. – Page No.
Unique β-Turn Peptoid Structures
and their Application as Asymmetric
Catalysts
9
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