Peptidic molecular brushes with enhanced chirality

Article abstract of DOI:10.1002/pola.26208

Tethering oligopeptides through one end densely packed onto a linear polymer main chain will greatly reduce freedom of the peptide chains, which affords an easy access to investigate the secondary structure of peptides under constrained condition. Herein,

Full text of DOI:10.1002/pola.26208

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Peptidic Molecular Brushes with Enhanced Chirality
Wen Li, Xiuqiang Zhang, Jue Wang, Xiao Qiao, Kun Liu, Afang Zhang
Department of Polymer Materials, College of Materials Science and Engineering, Shanghai University,
Chengzhong Street 20, Shanghai 201800, China
Correspondence to: W. Li (E-mail: wli@shu.edu.cn) or A. Zhang (E-mail: azhang@shu.edu.cn)
Received 30 January 2012; accepted 6 June 2012; published online
DOI: 10.1002/pola.26208
ABSTRACT: Tethering oligopeptides through one end densely
packed onto a linear polymer main chain will greatly reduce
freedom of the peptide chains, which affords an easy access
to investigate the secondary structure of peptides under con-
strained condition. Herein, molecular brushes with densely
grafted monodispersed Cbz-protected oligolysine were effi-
ciently synthesized via free radical polymerization of the mac-
romonomer-bearing lysine octamer, and the secondary
structures of the oligopeptide side chains in solutions were
investigated. To examine the architecture effects on helical
conformation, circular dichroism spectra from the polymer
were compared with that from the corresponding macromono-
mer. To check the chemical structural effects on conformation
of the oligopeptide, Cbz groups from the molecular brushes
were deprotected, and the secondary structures of the poly-
mers were compared before and after the deprotection. Con-
formation of the deprotected polymer was further explored by
varying solution pH values. Complexation of the positively
charged, deprotected polymer with anionic surfactant provides
an alternative route to mediate the secondary structures of the
short peptides in the constrained environment. It has been
found that oligolysine side chains within the molecular
brushes can adopt enhanced a-helical conformation through
the crowding structures or can form b-sheet by hydrophobic
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interactions between the complexed surfactants.
2012 Wiley
Periodicals, Inc. J Polym Sci Part A: Polym Chem 000: 000–000,
2012
KEYWORDS: branched; free radical polymerization; macromono-
mers; peptides; secondary structures
INTRODUCTION Ordered secondary structures of peptides in
nature, such as a-helices and b-sheets, play crucial role in
forming organized tertiary structures of proteins, which
dominate their functions and properties as well as their bio-
logical activities. On one hand, the stabilization of these sec-
ondary conformations will not only guarantee the proper
activities of the proteins but also prevent them from forming
abnormal amyloid fiber aggregates, which is the key issue to
cause the fatal diseases like Alzheimer’s and Parkinson’s dis-
eases.1 On the other hand, enhancement of the chirality may
also promote the ordered structural formation, which facili-
tates the biological functions of the proteins. By mimicking
these peptides in nature, to synthesize (poly)peptides with
ordered secondary structures will be interesting for both
fundamental researches and for applications ranging from
biomaterials to biotechnology. Up to date, synthetic polypep-
tides of different architectures have been reported, including
linear,2 cyclic,3 branched,4 star-like,5 dendritic,6 and comblike
ones,7 and the stability of their secondary conformation has
been widely explored. Much effort have been devoted to
investigate the secondary structures of synthetic polypep-
tides in free forms, and less attention was paid to the archi-
tecture effect on their chirality enhancement.8,9 In general,
a-helical conformation is stabilized mainly by the intramolec-
ular amide hydrogen bonds, whereas the stability of b-sheet
is dependent mostly on hydrophobic interactions between
amino acid residues.10 One specific parameter showing
strong influence on the secondary structures of a peptide is
its chain length. It is well known that a-helix is stabilized by
increasing peptide chain length,11 whereas parallel12 and
antiparallel b-sheets13 show different dependence on their
peptide lengths or the intrinsic strand lengths. In nature,
about 30% of proteins contain peptide sequences of less
than 15–25 amino acids, which often mediate biological
processes through their ordered secondary structures to
interact with proteins, DNA, or RNA.14 In contrast, short syn-
thetic peptides corresponding to these recognition motifs
generally adopt random coil structures or low populations of
ordered conformations in water. Therefore, to mimic and sta-
bilize the ordered secondary structures of short peptides15
are valuable to understand their roles in protein folding and
in mediating their interactions with biomacromolecules and
may lead to the development of novel pharmaceuticals, vac-
cines, and diagnostics.
Molecular brushes are a novel class of cylindrical polymers
with linear side chains densely pendent onto a linear poly-
mer main chain.16 The structural characteristics of these
Additional Supporting Information may be found in the online version of this article.
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polymers include high rigidity and large persistent length,
versatile chemical structure variability, and the nanosized
dimension of individual molecule. The steric repulsion
between the densely packed side chains enhances stiffness
of the backbone and, at the same time, may mediate differ-
ent behavior of the side chains. Based on these factors, mo-
lecular brushes have gathered intense research attention and
been applied in many areas.17 This kind of polymers can be
synthesized mainly through macromonomer ‘‘grafting from’’
and ‘‘grafting onto’’ routes.16(c),18 Among them, macromono-
mer route often provides the targeted polymers with rela-
tively defined chemical structures. Up to now, most of the
reported molecular brushes contain polydispersed side
chains, which to certain degree destroy the regularity of the
polymer structures. One intriguing class of molecular
brushes is that polypeptides are combined, which will not
only afford the polymer biorelated functions but also may
combine the possible secondary structures from polypep-
tides into the bulky polymers. One way is to use polypeptide
as the main chain and other polymers as the side chains,
and it was found that the secondary structures of polypep-
tide main chain are dependent on the size of the side
chain.7(f) Another way is to use polypeptide as side chains
but the other polymers as the main chain. For example,
Emrick and coworkers reported the synthesis of polyolefin-
graft-oligolysine polyelectrolytes by the combination of solid-
phase peptide synthesis and ring-opening metathesis poly-
merization and that found the polyelectrolytes could be tai-
lored to form extended, pearl-like, or multimolecular struc-
tures, depending on the composition and density of the
peptide grafts.19 Schmidt and coworkers reported cylindrical
molecular brushes with densely grafted poly(L-lysine) or
poly(L-glutamate) side chains, and both macromonomer and
grafting from routes were applied and compared. The latter
route was shown to be more successful for the synthesis of
cylindrical brushes with high molar mass main and long side
chains.20 Interestingly, these positively charged peptidic mo-
lecular brushes after deprotection can form large pitch heli-
ces by complexation with anionic surfactants.21 Improved
technique for polymerization of amino acid N-carboxyanhy-
dride (NCA) was used by Cheng and coworkers to prepare
peptidic molecular brushes with better defined structures.22
By one-pot synthesis of side-chain peptide brushes via the
combination of ring-opening metathesis polymerization and
ring-opening polymerization of NCA, the polymers with con-
trolled molecular weight were achieved, and their molecular
weight distribution (MWD) is relatively low. These peptidic
brushes alone can form ordered helices at neutral condition
through aggregation.23 Because of the synthetic challenges,
the architecture effects on the conformational structures of
grafted polypeptides have not been systematically studied in
the brush-like (co)polymers. Recently, Cheng and coworkers
reported on a class of brush-like polymers grafted with poly-
lysines and interestingly found that grafted architecture
showed positive effects on stabilizing the ordered secondary
structures of the polylysine side chains when the polymer-
ization degree of the side chains is less than 100; however,
this positive effect vanished for the case with the longer
polypeptide side chains because of the strong interchain
hydrogen bonding disruption.24
One common feature of most peptidic molecular brushes is
that the peptide side chains are polydispersed. No matter
how big or small their MWDs are, this polydispersity leads
to irregular structures to certain degree and often causes the
solubility20 or aggregation23 problems. To avoid this, we
recently reported on peptidic molecular brushes with mono-
dispersed proline octamer as the side chains through macro-
monomer route.25 Oligoproline was selected because of the
consideration that polyprolines can adopt two different heli-
cal conformations: compact polyproline I (PPI) and stretched
polyproline II (PPII). The former is favored in less polar sol-
vents such as alcohols, whereas the latter is favored in polar
solvents such as water. These two distinguished conforma-
tions are interexchangeable by cis–trans isomerization of the
peptide bonds. Because of the dense packing of rigid proline
octamer along the polymer main chain within the molecular
brush, the oligoproline side chains can only adopt the more
stretched PPII conformation no matter what solvents were
used, and the helical conformation transition from PPII to
PPI was completely hindered. In this work, a novel class of
molecular brush with well-defined oligopeptide side chains
is also prepared via macromonomer route. It is constructed
by a polymethacrylate main chain and monodispersed lysine
octamer side chains (Fig. 1). Oligolysine is selected here
because polylysines can adopt three different conformations
at certain conditions: a-helix, b-sheet, and random coil. This
system is designed to investigate whether such short lysine
peptides may show ordered conformation under this con-
strained condition, and how these conformations will be
influenced by external condition changes.
RESULTS AND DISCUSSION
Synthesis and Characterization
Oligolysines were prepared via typical solution amidation
conditions as shown in Scheme 1. Boc and Cbz are selected
as orthogonal protection groups for easy synthesis manipula-
tion, and Cbz protecting group along the oligopeptide chain
is selected for the purpose to examine possible influence of
p–p interaction on the peptide secondary conformation
within the molecular brushes. Starting from commercially
available H-Lys(Cbz)-OMe and Boc-Lys(Cbz)-OSu, the amide
coupling was readily performed in the presence of diisopro-
pylethylamine (DiPEA) at ꢀ15ꢁC, providing dipeptide ester
1a with a yield of 96%. Hydrolysis of 1a formed the acid 1b,
which was reacted with 4-nitrophenol to form the active
ester 1c. It was found that the purification of 1c with silica
gel column chromatography did not work. Most probably
because of the high reactivity of the dipeptide active ester,
majority of the products reacted with the silicon gel and
stayed inside the column. Instead, 1c was purified just by
precipitation into hexane/ethyl acetate. Deprotection of the
dipeptide ester with trifluoroacetic acid (TFA) afforded quan-
titatively the ammonium salt 1d. Amide coupling of 1c with
1d furnished the tetrapeptide ester 2a. During the reaction,
a gel-like solution was formed, which indicates the lower
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FIGURE 1 Chemical structures of the molecular brushes with monodispersed oligolysine side chains reported in this work.
solubility of 2a in dichloromethane (DCM) due to the strong
hydrogen bonding.26 Therefore, small amount of MeOH was
mixed with DCM to improve the solubility during the work
up. Through column chromatography, 2a was obtained in a
yield of 92%. By similar procedures, 2a was converted into
the active ester 2c and the corresponding ammonium salt
2d. Finally, the octamer ester 3a was achieved in 85% yield
by the amide coupling of 2c with 2d. Saponification with
SCHEME 1 Synthesis procedure of oligolysines and the macromonomer. Reagents and conditions: (a) DiPEA, DCM, DMF, ꢀ15ꢁC -
room temperature, overnight (96, 92, or 85%); (b) LiOHꢂH2O, THF, MeOH, H2O, 0ꢁC - room temperature, 6–8 h (98 or 99%); (c) EDC,
NpAOH, DCM, ꢀ10ꢁC - room temperature, overnight (93 or 94%); (d) TFA, DCM, 0ꢁC - room temperature, overnight (100%); (e)
HEMA, EDC, DMAP, DCM, 0ꢁC - room temperature, overnight (74%); (f) HBr, TFA, room temperature, 1 h (93%). Abbreviations:
AIBN, azobis(isobutyronitrile); DCM, dichloromethane; DMAP, 4-N, N-dimethylaminopyridine; DiPEA, diisopropylethylamine; DMF,
N, N-dimethylformamide; EDC, 1-(3-dimethylaminopropyl)-3-ethylcarbo-diimide hydrochloride; HEMA, 2-hydroxyethyl methacry-
late; NpAOH, para-nitrophenol; TEA, triethylamine; TFA, trifluoroacetic acid.
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1
FIGURE 2 H NMR spectra of compound 3a (at 60ꢁC for better resolution), macromonomer 3c, and the corresponding polymers
PLLy(Z) and PLLy in [d]6-DMSO. *The signal from solvent [d]6-DMSO. The dot lines are a guide for the eyes.
LiOH formed the octamer acid 3b, which was reacted with
2-hydroxyethyl methacrylate (HEMA) in the presence of 1-
(3-dimethylaminopropyl)-3-ethylcarbo-diimide hydrochloride
(EDC) to afford the macromonomer 3c. EDC was selected
here for the esterification as it produced water-soluble
byproduct, which can be easily washed away to guarantee
the high purity of the macromonomer. It is worthwhile to
note that when compared with the tetramers, all the
octamers formed higher viscous solutions in DCM. Once
evaporating 3c in DCM to dryness, the macromonomer
became gel and was not able to be dissolved anymore in var-
ious solvents even like MeOH or N, N-dimethylformamide
(DMF). To avoid this, a mixture of MeOH with DCM was used
for dissolving 3c at the beginning to achieve a dilute solu-
tion. Evaporation to dryness from this mixed solvent 3c was
obtained as a white powder, which was soluble and can be
used for polymerization. All new compounds except the
active esters were characterized as analytically pure materi-
as initiator at 65ꢁC afforded the molecular brush PLLy(Z).
This polymer is soluble in DMF, DMSO, or the mixed solution
like THF/MeOH, but cannot be dissolved even at elevated tem-
perature in other single solvent including DCM, MeOH, and
THF. The molar mass (Mn) of the polymer was determined by
gel permeation chromatography (GPC) with DMF as the elu-
ent. Surprisingly, the Mn is 2.0 ꢃ 104 (relative to PMMA stand-
ards), which is not as high as expected, and the PDI is
extremely small (1.2). Such narrow PDI is unusual for poly-
mers synthesized via conventional free radical polymerization.
The possible reason for these results is that densely packed
architecture within the molecular brush affords the polymer
with high rigidity, which leads to the underestimation of Mn
and the abnormal PDI by GPC measurements. Similar observa-
tion has also been reported for other bulky polymers.27
Dynamic light scattering (DLS) measurements of the polymer
in MeOH/THF (v/v ¼ 1:1) show that Rh of the polymer is
around 23 nm (Supporting Information Fig. S2), which also
suggests that the polymer possesses high molecular weight.
To achieve the water-soluble peptidic molecular brushes, the
Cbz-protected polymer PLLy(Z) was dissolved in TFA and
deprotected by HBr (33% in acetic acid) to afford the polymer
1
als by H and 13C NMR spectroscopy, as well as high-resolu-
1
tion mass spectroscopy. Typical H NMR spectra of the octa-
mer ester 3a and macromonomer 3c in [d6]-DMSO are
shown in Figure 2. The chemical shift assignments of 3a
1
were based on the H-1H COSY spectrum from Supporting In-
1
PLLy. The H NMR spectra of both polymers are shown in Fig-
formation Figure S17.
ure 2. In comparison of the spectra for these protected and
deprotected polymers, the disappearance of the signals at d ¼
7.3–7.4 and d ¼ 4.9–5.1 from the Cbz groups illustrates the
Conventional free radical polymerization of macromonomer
3c in DMF in the presence of azobis(isobutyronitrile) (AIBN)
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nomer and the polymer proves that the ordered secondary
structure within the molecular brush should be caused by the
densely packing of the side peptide chains, and this architec-
ture may enhance carbamate hydrogen bonding between ly-
sine side chains and the p–p stacking between the aromatic
rings from the Cbz groups, which induce the side chains to
adopt more ordered structures. Similar observation has also
been reported by Cheng and coworkers24 in brush-like poly-
mers when polymerization degree of the side-chain polyly-
sines is less than 100. The influence of the temperature on
the helical conformation stability of PLLy(Z) was also exam-
ined [Fig. 3(b)]. When the temperature increased from room
temperature to 40ꢁC, the helicity decreased slightly (ellipticity
at 221 nm decreases from 17,300ꢁ to 14,700ꢁ). However,
when solution temperature further increased to 50ꢁC, the CD
curve changed its shape and that the minimum peak blue-
shifted from 216 to the normal position (210 nm). The change
of curve shape suggests that the oligopeptides show tendency
to transfer from a-helix into b-sheet with temperature.
To examine the architecture effects on the ordered secondary
structure of peptide side chains, PLLy(Z) is deprotected into
PLLy, and its conformation in aqueous solution was thus
investigated with CD spectroscopy, and the spectra are
shown in Figure 4(a). At pH 7 when peptides are positively
FIGURE 3 CD spectra of macromonomer 3c and PLLy(Z) in
THF/MeOH (v/v ¼ 1:1.4) at 20ꢁC (a) and of PLLy(Z) at different
temperature (b).
successful deprotection of Cbz groups. Interestingly, the spec-
trum of the monomer is reminiscence very much of that of
the polymers regarding the peak broadness, most probably
due to the weak solubility of the monomer.
Secondary Structure Analysis
Optical rotation spectroscopy (OR) and circular dichroism
spectroscopy (CD) were applied to examine the secondary
structure of the polymers in solution. For comparison, the
macromonomer was also measured. Because of the solubility
reason, MeOH/THF mixed solvent was chosen for the meas-
urements. The OR from the polymer PLLy(Z) is þ122ꢁ, which
is quite different from that of the macromonomer (OR ¼
ꢀ3ꢁ). This big difference indicates that the polymer possesses
much higher order structures than the corresponding macro-
monomer. The CD spectra for both the macromonomer and
PLLy(Z) are shown in Figure 3(a). As expected for a short
peptide, the CD spectrum from the macromonomer indicates
that it adopts minimal ordered secondary structure in solu-
tion. In contrast, polymer PLLy(Z) exhibits strong Cotton
effects with two negative peaks in the wavelength of 221 and
216 nm, which resembles the characteristics of the a-helical
conformation of peptides. The red shift from 209 to 216 nm
for one of the two minima should be mainly related to the sol-
vent effects.28 The different Cotton effect from the macromo-
FIGURE 4 CD spectra of PLLy in water without (a) and with
SDS (b). [SDS]/[Lys] represents the molar ratio of SDS to lysine
unit within the deprotected polymer.
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charged, typical Cotton effect of random coil conformation
was obtained as expected. Even when solution pH was
increased to strong basic conditions such as 10 or 11 when
lysine units are not protonated, the CD spectra of the molecu-
lar brush are again reminiscent mainly of random coil with
very low population of ordered structures (a-helix and b-
sheet).10 This is in contrast to that deprotonated polylysines
of long chains can adopt a-helical conformation with intramo-
lecular hydrogen bonding interaction between repeating units
of i and i þ 3. The above results suggest that the closely
packed architecture of short peptides cannot guarantee the
formation of the well-ordered secondary structure and that
the structural effects in polymer PLLy(Z) should come from
carbamate hydrogen bonding between lysine side chains and
the p–p stacking between the aromatic rings from the Cbz
groups within the proximately packed peptide chains.
by a polymethacrylate main chain and monodispersed lysine-
based oligopeptide side chains. Their secondary structures
were investigated with OR and CD spectroscopy. This molec-
ular brush architecture affords the short peptide side chains
a constrained environment to adopt enhanced chirality.
When Cbz protection group is present, carbamate hydrogen
bonding and p–p stacking between the aromatic rings within
the proximately packed peptide chains promoted the a-heli-
cal conformation of oligopeptides in solutions at various
temperatures. After deprotection, the helical conformation of
the peptides was mostly lost even at basic conditions; how-
ever, the ordered b-sheet conformation of these short pep-
tide side chains can be easily formed by complexation with
surfactants such as SDS. With increased amount of SDS, the
propensity to form this ordered structure was enhanced.
This work demonstrates that the molecular brush architec-
ture offers a constrained environment that can stabilize and
enhance the ordered secondary structures of oligopeptides.
It is well known that free polypeptide chains can vary their
conformation at neutral condition in the presence of ionic or
amphiphilic species. For example, the conformation of high
molar mass polylysines can be transformed from random coil
into a-helix by sodium octyl sulfate or into b-sheet by sodium
dodecyl sulfate (SDS) because of the hydrophobic interaction
between the bounded surfactants that dominates over the
electrostatic interaction among the lysine units.29 In the case
of molecular brushes, oligopeptide chains are end-tethered on
the main chain with less freedom, and therefore, we are curi-
ous to see whether the very short peptide chains within the
molecular brush would adopt ordered secondary structures
on complexation with ionic surfactants. Herein, SDS salt was
complexed with PLLy in different ratios in aqueous solutions
at pH 7, and the conformation was investigated by CD spec-
troscopy. From CD spectra in Figure 4(b), it is observed that
the peptide chains changed their conformation gradually with
the increase of SDS ratio at room temperature. When the
molar ratio of SDS/lysine unit reached 0.8/1, the CD spectrum
exhibits a minimum at 217 nm and one maximum below 200
nm, which suggests that the short peptide chains adopt b-
sheet conformation. From the ellipticity at 217 nm, the con-
tent of peptide chains adopting b-sheet conformation is esti-
mated to be 70–80% according to method proposed by David-
son Fasman.10 Further increase of the ratio to 1.0 led to the
precipitation of the polymers from aqueous solution. This b-
sheet conformation is thermally unstable, and the content
decreases with the increase of solution temperature. When
the solution temperature increased to 60ꢁC, the ordered struc-
ture was mostly lost. For comparison, the CD spectra from
deprotected octamer 3d and its complexation with SDS were
also recorded (Supporting Information Fig. S1). The depro-
tected octamer itself in aqueous solution adopts random coil
structure, and this random conformation retains even with the
addition of SDS. This control experiment further supports that
the brush architecture shows positive effect on stabilization of
ordered structures from oligopeptides.
EXPERIMENTAL
Materials
AIBN was recrystallized twice from methanol. DCM was dis-
tilled from CaH2 for drying. Other reagents and solvents
were purchased at reagent grade and used without further
purification. All reactions were run under a nitrogen atmos-
phere. Macherey-Nagel precoated thin-layer chromatography
(TLC) plates (silica gel 60 G/UV254, 0.25 mm) were used for
TLC analysis. Silica gel 60M (Macherey-Nagel, 0.04–0.063
mm, 200–300 mesh) was used as the stationary phase for
column chromatography.
Instrumentation and Measurements
Proton and carbon NMR spectra were recorded on Bruker
AV 500 (1H: 500 MHz, 13C: 125 MHz) spectrometers at room
temperature (unless indicated), and chemical shifts are
reported as d values (ppm) relative to internal Me4Si. High-
resolution ESI-MS analyses were performed on IonSpec Ultra
instruments. GPC measurements were carried out on a
Waters GPC e2695 instrument with three-column set (Styra-
gel HR3þHR4þHR5) equipped with refractive index detector
(Waters 2414) and DMF (containing 1 g Lꢀ1 LiBr) as eluent
at 45ꢁC. The calibration was performed with poly(methyl
methacrylate) standards in the range of Mp ¼ 2580–981,000
(Polymer Standards Service USA). DLS measurements were
performed on an ALV/DLS/SLS-5022F spectrometer
equipped with a multi-s digital time correlation (ALV5000)
and a cylindrical 22-mW He–Ne laser (k0 ¼ 632 nm, UNI-
PHASE) as the light source, and the sample concentration is
0.66 mgmLꢀ1 in THF/MeOH (v/v ¼ 1:1). CD measurements
were performed on a JASCO J-815 spectropolarimeter with a
thermocontrolled 1-mm quartz cell (five accumulations, con-
tinues scanning mode, scanning speed: 50 nmminꢀ1, data
pitch: 1 nm, response: 1 s, band width: 5.0 nm). Monomer
and protected polymer samples were dissolved in mixed sol-
vents from THF and methanol (volume ratio ¼ 1:1.4),
whereas the deprotected polymer samples were dissolved in
buffer with different pH value. The concentrations used are
in the range of 1ꢀ2 ꢃ 10ꢀ6 dmol mLꢀ1. OR measurements
CONCLUSIONS
We present here the efficient synthesis and conformation
characterization of molecular brushes that were constructed
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were also performed on the JASCO J-815 spectropolarimeter
(wavelength ¼ 589 nm) at 20ꢁC with sample concentrations
in the range of 1.00–1.20 mgmLꢀ1. The complexation of
PLLy with SDS was conducted by adding desired amount of
SDS aqueous solution (1 mgmLꢀ1) dropwise into the PLLy
aqueous solution (0.24 mgmLꢀ1) under vigorous stirring at
pH 7.
water and extracted with DCM three times. The combined or-
ganic phases were dried over MgSO4 and concentrated in
vacuo. The residue was then precipitated into hexane/ethyl ac-
etate (2:1, v/v), and then the solid was collected. Further dry-
ing of the solid in vacuo afforded 1c (9.10 g, 93%) as a slight
yellow foam, which was used directly for the next reaction.
1H NMR (CDCl3): d ¼ 1.41–1.66 (m, 17H, CH2þCH3), 1.81–
2.00 (m, 4H, CH2), 3.15–3.26 (m, 4H, CH2), 4.11–4.17 (m, 1H,
CH), 4.68–4.72 (m, 1H, CH), 4.94 (br, 1H, NH), 5.06–5.18 (m,
4H, CH2), 7.02–7.14 (d, 1H, NH), 7.26–7.34 (m, 12H, CH),
8.21–8.24 (m, 2H, CH). 13C NMR (CDCl3): d ¼ 22.76, 28.68,
28.72, 29.74, 29.90, 31.26, 31.46, 32.07, 40.44, 40.60, 40.69,
52.76, 52.87, 54.45, 67.05, 67.11, 67.24, 80.75, 122.68,
122.72, 125.66, 125.68, 128.46, 128.53, 128.58, 128.93,
136.83, 136.94, 136.96, 145.97, 155.48, 156.26, 157.04,
157.15, 157.27, 170.36, 170.42, 172.96, 173.19. HRMS (ESI):
m/z calcd. for C39H50N5O11 [H]þ 764.3501; found: 764.3478.
Synthesis
Compound 1a
A solution of Boc-Lys(Z)-OSu (10.00 g, 20.94 mmol) in dry
DCM (50 mL) was dropped into a mixture of H-Lys(Z)-
OMeꢂHCl (7.62 g, 23.03 mmol) and DiPEA (10.82 g, 83.76
mmol) in DMF (30 mL) at ꢀ15ꢁC in 30 min. The solution
was allowed to warm at room temperature and stirred for
another 12 h. The mixture was washed with brine, and then
the aqueous phase was extracted with DCM three times. The
combined organic phases were dried over MgSO4. Purifica-
tion with column chromatography using ethyl acetate/hexane
(1:2 and 1:1, v/v) afforded 1a (13.20 g, 96%) as white foam.
Compound 1d
TFA (8.50 g, 74.50 mmol) was added into a solution of 1a
(4.70 g, 7.08 mmol) in DCM (40 mL) at 0ꢁC, and the mixture
was stirred overnight at room temperature. MeOH was
added to quench the reaction. Evaporation of all the solvents
afforded 1d as a slightly yellow oil (4.80 g, 100%).
1H NMR (CDCl3): d ¼ 1.32–1.85 (m, 21H, CH2þCH3), 3.10–
3.18 (m, 4H, CH2), 3.66 (s, 3H, CH3), 4.13–4.14 (m, 1H, CH),
4.51–4.52 (m, 1H, CH), 5.07 (s, 4H, CH2), 5.40 (br, 1H, NH),
6.85 (br, 1H, NH), 7.17–7.49 (m, 10H, CH). 13C NMR (CDCl3):
d ¼ 22.62, 22.67, 28.72, 29.52, 29.76, 31.96, 31.98, 32.22,
32.24, 40.75, 52.26, 52.80, 54.57, 54.60, 67.03, 67.11, 80.45,
80.48, 128.48, 128.54, 128.58, 128.90, 128.99, 136.95,
137.03, 157.00, 157.02, 172.61, 173.00. HRMS (ESI): m/z
1H NMR (CD3OD): d ¼ 1.51–1.58 (m, 8H, CH2), 1.70–1.76
(m, 2H, CH2), 1.86–1.90 (m, 2H, CH2), 3.09–3.17 (m, 4H,
CH2), 3.66 (s, 3H, CH3), 3.85–3.88 (m, 1H, CH), 4.40–4.43 (m,
1H, CH), 5.05 (s, 4H, CH2), 7.28–7.33 (m, 10H, CH). 13C NMR
(CD3OD): d ¼ 21.66, 23.00, 29.40, 29.47, 30.84, 31.23, 40.24,
40.40, 51.83, 52.08, 53.20, 53.26, 53.44, 53.62, 66.37, 66.45,
111.65, 113.92, 116.18, 118.44, 127.73, 127.80, 127.98,
128.01, 128.48, 137.35, 137.42, 157.80, 158.01, 158.13,
158.46, 169.33, 172.67. HRMS (ESI): m/z calcd. for
calcd. for
679.3323.
C
34H48N4O9Na [MþNa]þ 679.3314; found:
Compound 1b
1a (8.50 g, 12.93 mmol) was dissolved in a solution of THF
(120 mL), MeOH (100 mL), and water (30 mL). LiOHꢂH2O
(2.72 g, 64.65 mmol) was then added in one portion at 0ꢁC.
The reaction was stirred at room temperature for another 7 h.
The solvents were evaporated in vacuo at room temperature,
and the residue was dissolved with DCM. The pH value of the
solution was adjusted carefully to around 3–5 with 10%
KHSO4 aqueous solution. The aqueous phase was extracted
with DCM three times. The combined organic phase was
washed with brine and dried over MgSO4. After filtration,
evaporation of solvents in vacuo afforded 2a (8.2 g, 98%) as
white foam, which was used directly for the next reaction.
C
29H41N4O7 [MþH]þ 557.2970; found: 557.2985.
Compound 2a
Compound 1c (1.75 g, 2.29 mmol) in DCM (80 mL) was
slowly dropped into a solution of 1d (1.70 g, 2.53 mmol)
and DiPEA (1.31 g, 10.12 mmol) in DMF (15 mL) at ꢀ15ꢁC.
The solution was allowed to warm at room temperature and
stirred overnight. The mixture was washed with brine, and
then the aqueous phase was extracted with DCM three times.
The combined organic phases were dried over MgSO4. Purifi-
cation by column chromatography with DCM/MeOH (40/1
then 30/1, v/v) afforded 2a (2.50 g, 92%) as white foam.
1H NMR (CDCl3): d ¼ 1.39–1.86 (m, 21H, CH2þCH3), 3.10–
3.12 (m, 4H, CH2), 3.97–4.17 (m, 1H, CH), 4.52–4.4.61 (m,
1H, CH), 5.06–5.54 (m, 5H, CH2þNH), 5.99–6.23 (m, 1H, NH),
7.18–7.32 (m, 10H, CH). 13C NMR (CDCl3): d ¼ 22.39, 28.45,
29.29, 29.47, 31.05, 31.42, 32.12, 40.60, 40.71, 52.18, 54.31,
66.83, 67.26, 80.24, 128.04, 128.24, 128.64, 136.72, 156.09,
156.92, 172.82. HRMS (ESI): m/z calcd. for C33H46N4O9Na
[MþNa]þ 665.3157; found: 665.3174.
1H NMR (CDCl3): d ¼ 1.30–1.80 (m, 33H, CH2þCH3), 3.10–
3.11 (m, 8H, CH2), 3.64 (s, 3H, CH3), 4.05–4.62 (m, 4H, CH),
5.05–5.11 (m, 8H, CH2), 5.28–5.59 (br, 4H, NH), 7.31–7.44
(m, 20H, CH). 13C NMR (CDCl3): d ¼ 22.56, 28.21, 28.50,
29.35, 31.36, 31.50, 31.81, 40.38, 40.67, 41.30, 52.16, 52.27,
52.48, 53.45, 66.48, 66.72, 80.30, 127.95, 128.18, 128.63,
128.66, 136.81, 156.89, 157.23, 171.70, 172.09, 172.74,
172.93, 173.14. HRMS (ESI): m/z calcd. for C62H84N8O15Na
[MþNa]þ 1203.5948; found: 1203.5950.
Compound 1c
EDC (3.67 g, 19.18 mmol) was added into a solution of 1b
(8.22 g, 12.79 mmol) and para-nitrophenol (NpAOH; 2.67 g,
19.18 mmol) in DCM (150 mL) at ꢀ10ꢁC. After stirring over-
night at room temperature, the mixture was washed with
Compound 2b
LiOHꢂH2O (0.36 g, 8.50 mmol) was added into a solution of
2a (1.00 g, 0.85 mmol) in THF (15 mL), MeOH (20 mL), and
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water (5 mL) at 0ꢁC, and then the mixture was stirred for
another 6 h at room temperature. After acidifying with 10%
KHSO4 to pH 3–4, the organic phase was extracted with
DCM and washed with water, then dried over MgSO4. Evapo-
ration of all the solvents afforded 2b (0.98 g, 99%) as white
foam, which was used directly for next reaction.
then 20:1, v/v) afforded 3a as a colorless solid gel (0.97 g,
85%).
1H NMR (DMSO-d6): d ¼ 1.14–1.63 (m, 57H, CH2 þ CH3), 2.96
(s, 16H, CH2), 3.58 (s, 3H, CH3), 3.89 (s, 1H, CH), 4.17–4.24 (m,
7H, CH), 5.00–5.05 (m, 16H, CH2), 6.81–6.89 (m, 1H, NH), 7.19–
7.21 (m, 8H, NH), 7.25–7.33 (m, 40H, CH), 7.79–8.22 (m, 7H,
NH). 13C NMR (DMSO-d6): d ¼ 22.86, 23.02, 23.12, 23.26,
28.61, 29.15, 29.45, 30.82, 30.90, 31.91, 32.12, 32.31, 40.06–
40.68, 52.19, 52.55, 52.82, 54.88, 65.59, 78.59, 127.76, 128.18,
128.62, 128.78, 130.11, 137.71, 155.79,155.89, 156.52, 171.72,
171.93, 172.02, 172.19, 172.26, 172.64, 172.87. HRMS (ESI):
m/z calcd. for C118H156N16O27Na [MþNa]þ 2252.1224; found:
2252.7509.
1H NMR (DMSO-d6): d ¼ 1.16–1.37 (m, 25H, CH2 þ CH3),
1.48–1.63 (m, 8H, CH2), 2.96 (s, 8H, CH2), 3.88 (s, 1H, CH),
4.11–4.26 (m, 3H, CH), 5.00–5.04 (m, 8H, CH2), 6.81–6.90
(dd, 1H, NH), 7.19–7.24 (m, 4H, NH), 7.29–7.37 (m, 20H,
CH), 7.77–7.86 (dd, 1H, NH), 7.89–7.98 (dd, 1H, NH), 8.03–
8.12 (dd, 1H, NH). 13C NMR (DMSO-d6): d ¼ 22.84, 22.96,
23.10, 23.24, 28.61, 29.35, 29.55, 29.63, 30.99, 31.11, 31.89,
32.24, 40.18–40.70, 52.26, 52.44, 52.65, 54.85, 54.95, 65.58,
67.49, 78.58, 127.77, 128.18, 128.63, 128.80, 137.71, 155.81,
155.86, 156.52, 156.56, 171.83, 172.02, 172.08, 172.59,
173.93. HRMS (ESI): m/z calcd. for C61H83N8O15Na [MþH]þ
1167.5972; found: 1167.5929.
Compound 3b
LiOHꢂH2O (0.13 g, 3.09 mmol) was added into a solution of
3a (0.69 g, 0.31 mmol) in THF (15 mL), MeOH (25 mL), and
water (5 mL) at 0ꢁC, and the mixture was stirred for another
8 h at room temperature. After acidifying with 10% KHSO4
to pH 3–4, the organic phase was extracted with DCM and
washed with water, then dried over MgSO4. Evaporation of
all the solvents afforded the product as white solid (0.68 g,
99%), which was used directly for next reaction.
Compound 2c
EDC (0.54 g, 2.84 mmol) was added into a solution of 2b
(1.66 g, 1.42 mmol) and NpAOH (0.30 g, 2.13 mmol) in
DCM (120 mL) at ꢀ10ꢁC. After stirring overnight at room
temperature, the mixture was washed with water and
extracted with DCM three times. The combined organic
phases were dried over MgSO4 and concentrated in vacuo.
The residue was precipitated into hexane/ethyl acetate (1:2,
v/v), and the solid was collected after filtration. Further dry-
ing of the solid in vacuo afforded 2c (1.72 g, 94%) as a yel-
low foam, which was used directly for the next reaction.
1H NMR (DMSO-d6): d ¼ 1.14–1.63 (m, 57H, CH2 þ CH3), 2.95–
2.96 (m, 16H, CH2), 3.89 (s, 1H, CH), 4.12–4.22 (m, 7H, CH),
4.99–5.04 (m, 16H, CH2), 6.80–6.88 (m, 1H, NH), 7.18–7.23 (m,
8H, NH), 7.29–7.35 (m, 40H, CH), 7.77–8.13 (m, 7H, NH). 13C
NMR (DMSO-d6): d ¼ 22.91, 22.99, 23.24, 28.60, 29.04, 29.18,
29.49, 29.55, 31.12, 32.08, 40.03–40.66, 52.88, 54.88, 65.59,
70.36, 78.60, 127.79, 128.18, 128.62, 128.78, 137.70, 156.52,
156.55, 172.03, 173.92. HRMS (ESI): m/z calcd. for
HRMS (ESI): m/z calcd. for C67H86N9O17 [MþH]þ 1288.6136;
found: 1288.6126.
C
117H154N16O27Na [MþNa]þ 2238.1067; found:2239.2667.
Compound 2d
Compound 3c
TFA (2.30 g, 20.17 mmol) was added into a solution of 2a
(1.56 g, 1.32 mmol) in DCM (10 mL) at 0ꢁC, and the mixture
was stirred overnight at room temperature. Excess amount of
MeOH was added to quench the reaction. Evaporation of sol-
vents afforded 2d as a slightly yellow foam (1.58 g, 100%).
EDC (0.28 g, 1.47 mmol) was added dropwise to a mixture
of 3b (0.65 g, 0.29 mmol), HEMA (0.08 g, 0.59 mmol), and
4-N, N-dimethylaminopyridine (DMAP; 0.05 g) in dry DCM
(100 mL) at 0ꢁC. The mixture was stirred overnight at room
temperature. After washing with water, the organic phase
was dried over MgSO4. Purification by column chromatogra-
phy with DCM/MeOH (30/1 then 20:1, v/v) afforded the
product as white solid (0.50 g, 74%).
1H NMR (CD3OD): d ¼ 1.39–1.50 (m, 16H, CH2), 1.66–1.82
(m, 8H, CH2), 3.10 (s, 8H, CH2), 3.65–3.67 (m, 3H, CH3), 3.85
(s, 1H, CH), 4.32–4.37 (m, 3H, CH), 5.04–5.10 (m, 8H, CH2),
7.28–7.31 (m, 20H, CH). 13C NMR (CD3OD): d ¼ 21.93,
22.74, 29.21, 30.78, 31.00, 31.28, 39.99, 40.21, 51.47, 51.52,
52.31, 52.96, 53.20, 66.14, 127.50, 127.54, 127.73, 128.23,
137.14, 157.70, 172.93. HRMS (ESI): m/z calcd. for
1H NMR (DMSO-d6): d ¼ 1.24–1.63 (m, 57H, CH2 þ CH3), 1.86
(s, 3H, CH3), 2.96 (s, 16H, CH2), 3.50–3.60 (m, 2H, CH2), 3.89
(s, 1H, CH), 4.23–4.26 (m, 9H, CH þ CH2), 5.00–5.04 (m, 16H,
CH2), 5.67 (s, 1H, CH2), 6.02 (s, 1H, CH2), 6.83–6.89 (m, 1H,
NH), 7.19–7.20 (m, 8H, NH), 7.29–7.41 (m, 40H, CH), 7.78–
8.30 (m, 7H, NH). 13C NMR (DMSO-d6): d ¼ 18.36, 22.92,
23.28, 28.61, 29.56, 31.11, 31.91, 32.12, 32.25, 40.22–41.21,
52.16, 52.39, 52.90, 54.88, 54.95, 62.68, 62.79, 65.59, 70.36,
78.59, 126.62, 127.78, 128.18, 128.61, 128.78, 135.98, 137.71,
155.89, 156.52, 166.78, 171.94, 172.04, 172.30, 172.66,
C
57H77N8O13 [MþH]þ 1081.5605; found: 1081.5614.
Compound 3a
Compound 2d (0.73 g, 0.61 mmol) and DiPEA (0.53 g, 4.10
mmol) in DMF (3 mL) were added into a solution of 2c
(0.66 g, 0.51 mmol) in DCM (30 mL) at ꢀ15ꢁC. The solution
was allowed to warm at room temperature and stirred over-
night. After washing with water, the organic phase was dried
over MgSO4 and concentrated in vacuo. The residue was pre-
cipitated into hexane/ethyl acetate (1:1, v/v). After filtration,
the solid was collected. Further purification of the crude
product by column chromatography with DCM/MeOH (30:1
172.86. HRMS (ESI): m/z calcd. for
[MþNa]þ 2350.1591; found: 2351.3609.
C123H162N16O29Na
Compound 3d
Compound 3a (70.00 mg, 0.03 mmol) was dissolved in TFA
(2 mL), and then HBr (33% in acetic acid; 148.00 mg, 0.6
8
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202, 75–11; (c) Li, J.; Wang, T.; Wu, D.; Zhang, X.; Yan, J.; Du,
S.; Guo, Y.; Wang, J.; Zhang, A. Biomacromolecules 2008, 9,
2670–2676; (d) Shu, J. S.; Tan, C.; DeGrado, W. F.; Xu, T. Bio-
macromolecules 2008, 9, 2111–2117; (e) Marsden, H. R.; Kros,
A. Macromol. Biosci. 2009, 9, 939–951; (f) Jain, A.; Ashbaugh,
H. S. Biomacromolecules 2011, 12, 2729–2734; (g) Zhang, Y.;
Lu, H.; Lin, Y.; Cheng, J. Macromolecules 2011, 44, 6641–6644;
(h) Lu, H.; Wang, J.; Bai, Y.; Lang, J. W.; Liu, S.; Lin, Y.; Cheng,
J. Nat. Commun. 2011, 2, 1209/1–1209/9.
mmol) was added. After stirring for 1 h, the mixture was
precipitated into ethyl ether, which was then collected by
ultracentrifugation. The product was dissolved in water and
freeze dried under high vacuum to afford 3d as slightly yel-
low foam (60 mg, 93%).
1H NMR (D2O): d ¼ 1.36–1.37 (m, 16H, CH2), 1.59–1.85 (m,
32H, CH2), 2.91–2.92 (m, 16H, CH2), 3.64–3.65 (m, 3H, CH3),
3.98–4.01 (m, 1H, CH), 4.19–4.32 (m, 7H, CH).
3 (a) Shepherd, N. E.; Hoang, H. N.; Abbenante, G.; Fairlie, D.
P. J. Am. Chem. Soc. 2005, 127, 2974–2983; (b) Harrisona, R.
PLLy(Z)
ꢀ
S.; Shepherda, N. E.; Hoanga, H. N.; Ruiz-Gomeza, G.; Hilla, T.
Monomer 3c (0.37 g, 0.16 mmol) and AIBN (1.8 mg, 0.5 wt
% to the monomer) were dissolved in DMF (0.4 mL) in a
Schlenk tube. The solution was thoroughly deoxygenated by
several freeze-pump-thaw cycles and then stirred at 65ꢁC for
24 h. After cooling to room temperature, the mixture was
precipitated into ethyl acetate. After ultracentrifugation, the
polymer was collected. Further drying under vacuum
afforded white solid (210 mg, 57%).
A.; Drivera, R. W.; Desaib, V. S.; Youngb, P. R.; Abbenantea, G.;
Fairlie, D. P. Proc. Natl. Acad. Sci. USA 2010, 107, 11686–11691.
ꢀ
4 (a) Klok, H.-A.; Rodr´ıguez-Hernandez, J. Macromolecules
2002, 35, 8718–8723; (b) Scholl, M.; Nguyen, T. Q.; Bruchmann,
B.; Klok, H.-A. Macromolecules 2007, 40, 5726–5734.
5 (a) Vlasov, G. P.; Illarionova, N. G.; Izvarina, N. L.; Denisov, I.
G. Makromol. Chem. 1985, 9, 239–249; (b) Ghoorchian, A.;
Cole, J. T.; Holland, N. B. Macromolecules 2010, 43, 4340–4345;
(c) Ghoorchian, A.; Holland, N. B. Biomacromolecules 2011, 12,
4022–4029.
1H NMR (DMSO-d6): d ¼ 1.24–1.61 (m, 57H, CH2 þ CH3),
2.94 (s, 16H, CH2), 3.88–4.22 (m, 12H, CH þ CH2), 4.98–4.99
(m, 16H, CH2), 6.88 (br, 1H, NH), 7.19–7.21 (m, 8H, NH),
7.31–7.33 (m, 40H, CH), 7.78–8.01 (m, 7H, NH). 13C NMR
(DMSO-d6): d ¼ 22.99, 23.24, 28.60, 29.55, 32.14, 39.46,
40.22–40.67, 52.93, 54.96, 65.59, 78.58, 127.76, 128.16,
128.75, 128.78, 137.69, 155.88, 156.51, 171.93, 172.01,
172.64. Some signals from the backbone were not resolved.
6 (a) Kinberger, G. A.; Cai, W.; Goodman, M. J. Am. Chem.
ꢀ
Soc. 2002, 124, 15162–15163; (b) Lee, C. C.; Frechet, J. M. J.
Macromolecules 2006, 39, 476–481; (c) Javor, S.; Natalello, A.;
Doglia, S. M.; Reymond, J.-L. J. Am. Chem. Soc. 2008, 130,
17248–17249; (d) Zhang, A. Macromol. Rapid Commun. 2008,
29, 839–845; (e) Zhang, A.; Rodr´ıguez-Ropero, F.; Zanuy, D.;
ꢀ
Aleman, C.; Meijer, E. W.; Schluter, A. D. Chem. Eur. J. 2008,
¨
14, 6924–6934; (f) Filipe, L. C. S.; Machuqueiro, M.; Baptista, A.
M. J. Am. Chem. Soc. 2011, 133, 5042–5052.
PLLy
ꢀ
7 See, for example, (a) Kopecˇek, J.; Kopecˇkova, P.; Minko, T.;
Polymer PLLy(Z) (0.03 g, 0.013 mmol) was dissolved in TFA
(1.5 mL), and then HBr (33% in acetic acid; 16.00 mg, 0.065
mmol) was added. After stirring for 1 h, the mixture was
precipitated into ethyl ether, which was then collected by
ultracentrifugation. The product was dissolved in water and
freeze dried under high vacuum to afford PLLy (23 mg,
95%).
Lu, Z.-R. Eur. J. Pharm. Biopharm. 2000, 50, 61–81; (b) Murata,
H.; Sanda, F.; Endo, T. Macromol. Chem. Phys. 2001, 202,
€
759–764; (c) Ayres, L.; Adams, P. H. H. M.; Lowik, D. W. P. M.;
van Hest, J. C. M. Biomacromolecules 2005, 6, 825–831; (d)
Couet, J.; Samuel, J. D. J. S.; Kopyshev, A.; Santer, S.; Biesal-
ski, M. Angew. Chem. Int. Ed. Engl. 2005, 44, 3297–3301; (e)
Wang, Y.; Chang, Y.-C. Macromolecules 2003, 36, 6511–6518;
(f) Tang, H.; Li, Y.; Lahasky, S. H.; Sheiko, S. S.; Zhang, D. Mac-
romolecules 2011, 44, 1491–1499; (g) Singha, N. K.; Gibson, M.
I.; Koiry, B. P.; Danial, M.; Klok, H.-A. Biomacromolecules 2011,
12, 2908–2913.
1H NMR (DMSO-d6): d ¼ 1.24–1.66 (m, 53H, CH2 þ CH3),
2.78 (s, 16H, CH2), 3.91–4.27 (m, 12H, CH þ CH2), 7.44–8.63
(m, 34H, NH þ NH3þ). 13C NMR (DMSO-d6): d ¼ 21.53,
22.72, 26.76, 26.93, 29.58, 30.92, 31.80, 40.23–40.57, 52.76,
54.96, 168.85, 171.98. Some signals from the backbone were
not resolved.
8
Higashi, N.; Koga, T.; Niwa, M. Adv. Mater. 2000, 12,
1373–1375.
9 For amplifications of chirality through dynamic supramolecu-
lar aggregation, see, for example, Palmans, A. R. A.; Meijer, E.
W. Angew. Chem. Int. Ed. Engl. 2007, 46, 8948–8968.
ACKNOWLEDGMENTS
10 Davidson, B.; Fasman, G. D. Biochemistry 1967, 6,
1616–1629.
The authors thank Dr. Hongmei Deng from the Instrumental
Analysis of Research Center (Shanghai University) for her assis-
tance in NMR measurements. This work is financially sup-
ported by the National Natural Science Foundation of China
(Nos.: 21034004, 21104043, and 20974020) and by the Sci-
ence and Technology Commission of Shanghai (Nos.:
10520500300 and 11PJ1404100).
11 (a) Zimm, B. H.; Doty, P.; Iso, K. Proc. Natl. Acad. Sci. USA
1959, 45, 1601–1607; (b) Goodman, M.; Verdini, A. S.; Toniolo,
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J. M.; Baldwin, R. L. Biochemistry 1992, 31, 1263–1269.
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Muir, T.; Gellman, S. H. Proc. Natl. Acad. Sci. USA 2001, 98,
12015–12020; (b) Nowick, J. S. Acc. Chem. Res. 2008, 41,
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