High stability of the polyproline II helix in polypeptide bottlebrushes

Article abstract of DOI:10.1002/chem.200801191

Polymer bottlebrushes with monodisperse oligoproline side chains were efficiently synthesized, and the conformation of the peptide side chains in different solvents was investigated. Polymers with number-average degrees of polymerization (DP_n)

Full text of DOI:10.1002/chem.200801191

FULL PAPER
DOI: 10.1002/chem.200801191
High Stability of the Polyproline II Helix in Polypeptide Bottlebrushes
Afang Zhang* and Yifei Guo[a]
Abstract: Polymer bottlebrushes with
monodisperse oligoproline side chains
were efficiently synthesized, and the
conformation of the peptide side
chains in different solvents was investi-
gated. Polymers with number-average
degrees of polymerization (DPn) of 89
and 366 were obtained by polymeri-
zation of the macromonomer in
iPrOH/MeCN (1:1) and hexafluoroiso-
propanol, respectively. Circular dichro-
ism (CD) spectra of the bottlebrush
polymers in the neutral and charged
states reveal that the oligoproline side
chains attain stable polyproline II
(PPII) helical conformations not only
in aqueous solution, but also in aliphat-
ic alcohol solutions. Dense attachment
of oligopeptides onto a linear polymer
chain did not lead to an increase in
helix content. The possible effects of
the main-chain length on the confor-
mational stability were examined. The
switching between the polyproline I
(PPI) and PPII helical conformations
for the oligoproline side chains in ali-
phatic alcohol solutions is believed to
be inhibited by the overcrowded struc-
ture in the polymer bottlebrushes.
Keywords: conformation analysis ·
helical structures
·
peptides
·
polymerization · proline
Introduction
trans conformation. PPII is found to be a common secon-
dary structure in natural proteins, which plays important
roles in many biological processes,[8] such as protein–protein
recognition and cell penetration.[9] These two distinguished
conformations are interchangable by cis–trans isomerization
of the peptide bonds.[10] They can be differentiated by opti-
cal rotation,[10b,11] NMR spectroscopy,[12] and circular dichro-
ism (CD) spectropolarimetry.[13] The stability of these helical
conformations is not only based on the solvent polarity but
is also related to the concrete chemical structure of the pro-
line repeat units. 4-Substituted prolines, such as 4-fluoropro-
line[14] or 4-azidoproline,[15] have a strong propensity to form
the more stable PPII. In addition, the longer the oligopro-
lines, the greater the stability of the PPI helix in n-propa-
nol.[16] Depending on the nature of the N and C termini, the
threshold for oligoprolines to adopt the PPI conformation is
between three and five residues.[13a,17] Conformational transi-
tions between PPI and PPII have also been observed in oli-
goproline-based dendrimers.[18]
Synthetic macromolecules with tunable helical structures are
increasingly interesting for the design of molecular devices
and chiral materials.[1] Helical structures can be formed
through either covalent bonds[2] or noncovalent interac-
tions[3] and can be divided into dynamic[4] and static[5] types.
Recently, the conformational stability of helices in peptides
has drawn considerable attention due to its crucial influence
on the functions and bioactivities of these biomacromole-
cules.[6]
An intriguing class of helical polymers are oligoprolines,
which are well known to adopt predominately two different
helical conformations: polyproline I (PPI) and polyproline II
(PPII).[7] The former, which is favored in aliphatic alcohols,
is a compact, right-handed helix with 3.3 repeat units per
turn (5.6 ꢀ) and all amide bonds in the cis conformation.
The latter, favored in aqueous solution, fluorinated solvents,
or organic acids, is a stretched, left-handed helix with 3
repeat units per turn (9.4 ꢀ) and all amide bonds in the
Given the considerable steric congestion encountered by
pendent substituents in bottlebrush polymers,[19] we won-
[a] Prof. Dr. A. Zhang, Y. Guo
School of Materials Science and Engineering
Zhengzhou University
Daxue Beilu 75, Zhengzhou 450052 (China)
Fax : (+86)371-6776-6821
E-mail: azhang@zzu.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801191.
Chem. Eur. J. 2008, 14, 8939 – 8946
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8939

dered whether placing linear
oligoproline units in close
proximity by attaching them to
each repeat unit of a linear po-
lymer could be a way to force
them into the less tight PPII
conformation.
Herein,
we
report on the synthesis and
conformational peculiarities of
a novel type of polypeptide
bottlebrush[20] with monodis-
perse l-proline octamers as
side chains and polymethacry-
late as the backbone. We in-
vestigate how the conforma-
tional stability of the helices,
as well as the transition be-
tween PPI and PPII, is influ-
enced by the macromolecular
architecture. To our knowl-
edge, this is the first example
of an investigation into the ef-
fects of architecture, rather
than chemical modification, on
the stability of oligoproline
helices.
Scheme 1. Synthesis procedures for macromonomer 1: a) EDC, HOBt, Pro-OMe·HCl, TEA, CH2Cl2/DMF,
À30 to 258C, 14 h, 80%; b) TFA, CH2Cl2, MeOH, À0 to 258C, 6 h, 100%; c) LiOH·H2O, MeOH/H2O, À5 to
258C, 14 h, 90%; d) Pfp-OH, EDC, CH2Cl2, 258C, overnight, 92%; e) 3b, 3d, TEA, DMF, 258C, overnight,
70%; f) TFA, CH2Cl2, MeOH, À0 to 258C, 6 h, 100%; g) LiOH·H2O, MeOH/H2O, À5 to 258C, 14 h, 70%;
h) Pfp-OH, EDC, CH2Cl2, 258C, overnight, 86%; i) 4b, 4d, DiPEA, DMF, 258C, overnight, 74%; j) NaBH4,
LiCl, THF, À5 to 258C, 24 h, 80%; k) trimethylacetyl chloride, THF, TEA, À0 to 258C, 4 h, 86%; l) TFA,
CH2Cl2, MeOH, 258C, 5 h, 100%; m) MAC, TEA, DMAP, THF, À0 to 258C, 4 h (80%). Boc: tert-butoxycar-
bonyl; DiPEA: diisopropylethylamine; DMAP: 4-dimethylaminopyridine; EDC: N-(3-dimethylaminopropyl)-
N’-ethylcarbodiimide hydrochloride; HOBt: N-hydroxybenzotriazole; MAC: methacryloyl chloride; Pfp: pen-
tafluorophenyl; TEA: triethylamine; TFA: trifluoroacetic acid.
Results and Discussion
Synthesis: Oligoprolines and
the corresponding macromo-
nomer 1 were synthesized on
multigram scales by solution
peptide synthesis, in analogy to previous procedures
(Scheme 1).[21] Coupling of the commercially available com-
pound Boc-l-proline (2) with l-proline methyl ester in the
presence of EDC and HOBt afforded Boc-protected dimer
3a. Deprotection with TFA yielded the salt 3b. Saponifica-
tion with LiOH formed the dimer acid 3c, which was then
treated with pentafluorophenol and converted into the
active ester 3d. The tetramer ester 4a was prepared by di-
rectly coupling 3b with 3d. By similar procedures to those
mentioned above, this ester was converted into the salt 4b
and the active ester 4d. Finally, the octamer ester 5 was ob-
tained from 4b and 4d in yields of 72–78% on a multigram
scale. Reduction of 5 with NaBH4 and LiCl afforded alcohol
6 with a yield of 80%. The reaction of 6 with methacryloyl
chloride afforded macromonomer 1 in a yield of 80%. For
conformation comparisons, model compounds 7 and 8 were
also prepared. All compounds were characterized as analyti-
cally pure materials by 1H and 13C NMR spectroscopy, as
well as by high-resolution mass spectrometry.
Abstract in Chinese:
Polymerization: Conventional radical polymerization of 1
initiated with AIBN was conducted in either iPrOH/MeCN
(1:1) or hexafluoroisopropanol (HFIP) at 608C and provid-
ed the polypeptide bottlebrush poly(1). These two solvents
were initially chosen because it was expected that the oligo-
proline unit would attain different conformations in these
8940
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8939 – 8946

Helical Conformations
FULL PAPER
solvents, which could impact on the polymerization behavior
in different ways.[22] In macromonomer polymerization, a
high concentration of the reactive species is a prerequisite
for achieving high-molar-mass polymers[23] and we, there-
fore, decided to use 0.53m solutions. Typical polymerization
results are compiled in Table 1. The molar masses of the po-
Table 1. Conditions for and results of the radical polymerization of 1.
Entry
Polymerization
conditions[a]
Yield [%]
GPC[b]
[e]
[1]
A
Mn (ꢂ10À4
)
PDI DPn
A
]
A
]
1[c]
2[d]
527
527
15.2
15.2
87
82
8.4
34.7
2.14 89
2.53 366
[a] In DMF at 608C with AIBN as the initiator, 12 h. [b] DMF as the
eluent at 408C. [c] Isopropanol/acetonitrile 1:1 as the polymerization sol-
vent mixture. [d] HFIP as the polymerization solvent. [e] DPn represents
the number-average degree of polymerization of the main chain.
lypeptide bottlebrushes were determined by GPC with
DMF as the eluent and universal calibration. Poly(1) was
obtained from iPrOH/MeCN and HFIP with main-chain
number-average degrees of polymerization (DPn) of approx-
imately 89 and 366, respectively. The considerable difference
in the DPn values for the resultant bottlebrush polymers
may be explained by assuming the presence of different con-
formations for the same macromonomer in the different
polymerization media. Both bottlebrush polymers showed
excellent solubility in different solvents, such as water,
MeOH, CH2Cl2, iPrOH, and nPrOH. To check the possible
effects of charges on the conformational stability of the
oligopeptide side chains, the Boc groups in poly(1) were re-
moved with TFA to furnish the positively charged bottle-
1
brush polymer de-poly(1). H NMR spectra of poly(1) and
de-poly(1) were recorded at 808C in [D6]-dimethylsulfoxide
([D6]DMSO) to achieve better resolution and, thus, a basis
for the assessment of the backbone tacticity. Based on these
spectra, the polymers contain around 63% syndiotactic
triads, irrespective which solvent was used for the polymeri-
zation (see Figure S2 in the Supporting Information).[24] This
tacticity is close to that of poly(methyl methacrylate) syn-
thesized by conventional free-radical polymerization in
DMF at 608C (containing ꢀ62% syndiotactic triads).[25]
Therefore, the chiral substituent of the macromonomer and
the polymerization solvents did not show any obvious influ-
ence on the stereochemical course of monomer addition.
Conformation: The conformation of the oligoproline side
chains in poly(1) at different temperatures and in different
solvents was investigated with circular dichroism (CD) spec-
troscopy (Figure 1). Typical CD spectra for PPII helices (a
weak positive band at 228 nm and a strong negative band at
Figure 1. CD spectra of poly(1) (DPn =366) in aqueous solution in the
temperature range 10–808C (a), in nPrOH at 258C (b), and in nPrOH at
708C (c), as well as the CD spectra of poly(1) (DPn =89) in water in the
temperature range 10–808C (d) and in nPrOH at 258C (e).
Chem. Eur. J. 2008, 14, 8939 – 8946
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8941

A. Zhang and Y. Guo
204 nm)[13] were obtained from an aqueous solution of the
long poly(1) (DPn =366). This conformation was retained at
up to 808C without significant change (Figure 1a). In con-
trast to free linear oligoprolines, the proline octamers in
poly(1) also adopted the PPII conformation in nPrOH at
258C, and the spectral characteristics stayed unchanged for
20 days (Figure 1b). In addition, this conformation was even
retained at 708C for four days without obvious spectral
changes (Figure 1c). The temperature-dependent CD spec-
tra of the short poly(1) (DPn =89) in aqueous solution were
also recorded, and the PPII conformation was found to be
retained up to 808C (Figure 1d). The short poly(1) also
yielded CD spectra with the characteristics of 100% PPII in
nPrOH; like those of the long poly(1), these spectra re-
mained unchanged for 20 days (Figure 1e). All of the above
results suggest that the main-chain length does not have a
significant influence on the surprising stability of the PPII
conformation, at least within the range of main-chain
lengths investigated.[26]
The conformation of the oligoproline side chains in de-
protected polymer bottlebrush de-poly(1) was also exam-
ined with CD spectroscopy. As expected, the oligoproline
side chains in the long de-poly(1) (DPn =366) adopted the
PPII conformation in aqueous solution; this conformation
was stable within a temperature range of 25–758C (Fig-
ure 2a). This behavior very much resembles that for the pro-
line octamer 8 (inset in Figure 2a). In a comparison of the
intensities of the CD signals for de-poly(1) with those for 8,
no increase in helix content is observed for oligopeptides at-
tached densely onto a linear polymer chain, which suggests
that there is no cooperative interaction between the neigh-
boring oligoproline chains. The conformation of the oligo-
proline side chains in the de-poly(1) in aliphatic alcohols,
such as nPrOH and MeOH, was also examined. CD spectra
with the characteristics of 100% PPII helix were retained
after the nPrOH or MeOH solution was kept at room tem-
perature for 20 or 40 days, respectively (Figure 2b); this
proves that the oligoproline side chains in the long de-
poly(1) also adopted the stable PPII conformation in these
solvents. For comparison, CD spectra for the model com-
pound 8 in nPrOH were recorded under the same conditions
(inset in Figure 2b). This oligoproline started to adopt the
PPI conformation in less than 1 h, and showed the charac-
teristics of 100% PPI helix (a weak negative band at
232 nm, a medium positive band at 214 nm, and a medium
negative band at 202 nm) after 24 h. CD spectra of the short
de-poly(1) (DPn =89) in water (Figure 2c) and nPrOH (Fig-
ure 2d) were recorded to check the effect of the main-chain
length on the PPII-conformation stability. These spectra
very much resemble the corresponding spectra for the long
de-poly(1) (DPn =366), a result that suggests negligible ef-
fects of the main-chain length. Therefore, attachment of the
oligoprolines densely on a linear polymer chain forces the
peptide side chains to adopt only the PPII helical conforma-
tion in different solvents and over a broad temperature
range.
Figure 2. CD spectra of de-poly(1) (DPn =366) in aqueous solution in the
temperature range 25–758C (a; inset: spectra of 8 in water) and in ali-
phatic alcohol solvents at 258C (b; inset: spectra of 8 in nPrOH), as well
as the CD spectra of de-poly(1) (DPn =89) in water in the temperature
range 10–808C (c) and in nPrOH at 258C (d).
Conclusion and Outlook
We have presented the efficient synthesis of polypeptide
bottlebrushes with monodisperse oligoprolines as the side
8942
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8939 – 8946

Helical Conformations
FULL PAPER
was added at À308C, and the reaction mixture was stirred until the EDC
was completely dissolved. A solution of TEA (6.06 g, 60.00 mmol) and
Pro-OMe·HCl (6.00 g, 36.35 mmol) in DMF/CH2Cl2 (1:1, 120 mL) was
then added dropwise at À308C. The resulting mixture was warmed to
room temperature and stirred for 14 h. After successive washing of the
mixture with aqueous NaHCO3 and brine, the separated organic phase
was dried over MgSO4. After evaporation of the solvent in vacuo, the
product was purified by column chromatography (ethyl acetate/hexane
1:2 to 1:1) to afford a colorless solid product (7.98 g, 80%). 1H NMR
(CDCl3): d=1.36, 1.42 (ds, 9H; Boc), 1.79–2.13 (m, 8H; CH2), 3.35–3.75
(m, 7H; CH2, CH3), 4.35–4.57 ppm (m, 2H; CH); 13C NMR (CDCl3): d=
23.54, 24.05, 24.98, 25.03, 28.36, 28.50, 28.71, 28.81, 29.05, 29.99, 46.47,
46.66, 46.85, 52.05, 52.15, 57.69, 57.75, 58.68, 79.43, 154.48, 171.15,
172.91 ppm; HRMS: m/z: calcd: 327.18 [M+H]+; found: 349.1730
[M+Na]+.
chains and polymethacrylate as the main chain through radi-
cal polymerization of the corresponding macromonomer.
CD investigations revealed that the oligoproline side chains
in the cylindrical bottlebrush polymers attained a stable
PPII helical conformation not only in aqueous solution but
also in aliphatic alcohol solutions over a broad temperature
range. The helical-conformation switching between PPII and
PPI in aliphatic alcohol solutions is not observed. We attri-
bute this to the dense packing of the proline oligomers
along the polymer backbone, which forces them to adopt
only the stretched PPII conformation. The main-chain
length and removal of Boc groups from the periphery show
negligible effects on the PPII-conformation stability. This
enforced stretching could, in future, possibly be used in the
opposite way, namely to stretch the main chain of a related
bottlebrush polymer into a more extended conformation by
finding out how to fold the peptidic substituents from PPII
into PPI conformations. Further investigation could also in-
clude raising the threshold of side-chain length for stability
of helical conformations. The successful construction of mac-
romolecules with unprecedentedly stable helical conforma-
tions of their peptidic side chains could help to shine a new
light on the relationship between the structure and bioactiv-
ity of biomacromolecules, such as collagen. Such stable heli-
ces could also be useful as chiral scaffolds for supramolec-
ular helical-structure formation.
Compound 3b: TFA (7.00 g, 61.39 mmol) was added to a solution of 3a
(4.00 g, 12.26 mmol) in CH2Cl2 (30 mL) at 08C, and the mixture was
stirred for 6 h before being quenched with an excess of methanol. Evapo-
ration of the solvents in vacuo yielded the salt as a colorless solid (2.03 g,
100%). 1H NMR (D2O): d=1.92–2.52 (m, 8H; CH2), 3.31–3.72 (m, 7H;
CH2, OCH3), 4.45–4.59 ppm (m, 2H; CH); 13C NMR (75.5 MHz, D2O):
d=23.81, 24.48, 28.36, 28.64, 30.43, 46.76, 47.25, 47.40, 53.06, 59.01, 59.61,
107.11, 113.38, 119.17, 124.96, 162.36, 163.07, 168.19, 174.15 ppm; HRMS:
m/z: calcd: 227.13 [M+H]+; found: 227.1387 [M+H]+.
Compound 3c: LiOH·H2O (1.30 g, 31.00 mmol) was added to a solution
of 3a (5.00 g, 15.30 mmol) in methanol (50 mL) and water (20 mL) at
À58C with stirring, and the reaction mixture was allowed to warm to
room temperature. After the mixture had been stirred for 3 h, the sol-
vents were evaporated in vacuo at room temperature. The residue was
dissolved with ethyl acetate, and the pH value of the solution was adjust-
ed carefully to around pH 5–6 with 10% KHSO4 aqueous solution. After
the organic phase had been washed with brine and dried over MgSO4,
the crude product was purified by column chromatography (ethyl ace-
tate/hexane 2:1) to afford colorless crystals (4.30 g, 90%). 1H NMR
(CDCl3): d=1.34, 1.40 (ds, 9H; Boc), 1.68–2.20 (m, 8H; CH2), 3.33–3.75
(m, 4H; CH2), 4.33–4.57 ppm (m, 2H; CH); 13C NMR (CDCl3): d=
23.76, 24.29, 25.08, 28.05, 28.26, 28.47, 28.53, 28.55, 28.60, 29.30, 30.13,
46.82, 47.07, 47.10, 57.79, 57.89, 59.45, 59.55, 79.89, 79.98, 153.83, 154.82,
172.99, 173.31, 173.80, 174.16 ppm; HRMS: m/z: calcd: 313.17 [M+H]+;
found: 313.1760 [M+H]+, 335.1580 [M+Na]+, 351.1319 [M+K]+.
Experimental Section
Materials: AIBN was recrystallized twice from methanol. TEA and
DiPEA were dried over NaOH pellets. THF and dioxane were dried by
refluxing over sodium. CH2Cl2 was dried over CaH2. MAC was freshly
distilled before use. Other reagents and solvents were purchased from
Acros or Aldrich and used as received unless otherwise stated.
Compound 3d: The acid 3c (2.00 g, 6.40 mmol) and pentafluorophenol
(1.80 g, 9.80 mmol) were dissolved in CH2Cl2 (30 mL) and stirred for
10 min. EDC (1.20 g, 6.40 mmol) was then added. The mixture was
stirred overnight at room temperature before being washed with saturat-
ed NaHCO3 and brine, successively. After the organic phase had been
dried over MgSO4, purification by column chromatography (ethyl ace-
tate/hexane 2:1) afforded the product as colorless crystals (2.82 g, 92%).
1H NMR (CDCl3): d=1.39, 1.43 (ds, 9H; Boc), 1.80–2.39 (m, 8H; CH2),
3.35–3.86 (m, 4H; CH2), 4.38–4.51 (m, 1H; CH), 4.48–4.90 ppm (m, 1H;
CH); 13C NMR (CDCl3): d=23.65, 24.19, 25.23, 25.32, 28.53, 28.63, 29.03,
29.11, 29.26, 30.20, 46.63, 46.80, 47.01, 57.72, 57.83, 58.54, 79.71, 79.78,
136.97, 138.98, 140.18, 140.25, 142.19, 142.26, 153.73, 154.73, 168.37,
168.64, 171.65, 172.06 ppm; HRMS: m/z: calcd: 478.15 [M+H]+; found:
379.1077 [MÀBoc+H]+, 479.1604 [M+H]+, 501.1428 [M+Na]+, 517.1170
[M+K]+.
Instrumentation: 1H and 13C NMR spectra were recorded on a Bruker
300 MHz (1H: 300; 13C: 75 MHz) spectrometer in either CDCl3 or
[D6]DMSO solution at room temperature. High-resolution ESI mass
measurements were carried out on a Waters a-Tof Micro spectrometer
with an electrospray-ionization source. GPC measurements were carried
out at 408C by using a PL-GPC 50 instrument equipped with two PL-gel
5 mm Mixed-C columns (300ꢂ7.5 mm), a differential refractive index,
and viscosity (Viscotek) detectors. The system was operated with DMF
(containing 1 gLÀ1 LiBr) as the eluent at a flow rate of 1 mLminÀ1. Uni-
versal calibration was performed with poly(methyl methacrylate) stand-
ards in the molar-mass range of Mp =2.93ꢂ103–7.50ꢂ106 Da (Polymer
Laboratories Ltd, UK). Column chromatography was performed by using
300–400 mesh silica gel. CD measurements were performed on a JASCO
J-715 spectropolarimeter (continuous scanning mode; scanning speed:
20 nmminÀ1; data pitch: 1 nm; response: 1 s; band width: 5.0 nm). A ther-
mocontrolled quartz cell with a pathlength of 1 mm was used with pep-
tide solutions containing approximately 3–5ꢂ10À6 dmolmLÀ1 per octamer
residue. CD data are given as mean molar ellipticities based on octamer
residuals (q in degdmolÀ1 cm2). All samples were equilibrated for at least
12 h before measurement, except for the time-dependent measurements
in nPrOH. The spectra are the result of five accumulations for the meas-
urements in aqueous and nPrOH solutions or of one scan for the time-
dependent measurements in nPrOH. The blank spectrum of the solution
was always subtracted.
Compound 4a: A solution of 3b (4.50 g, 13.25 mmol) and TEA (7.00 g,
69.15 mmol) in dry DMF (30 mL) was added dropwise to a solution of
3d (4.35 g, 9.10 mmol) in dry DMF (30 mL) at room temperature. The
mixture was stirred overnight and then washed with saturated NaHCO3
and brine, successively. After the organic phase had been dried over
MgSO4, purification by column chromatography (CH2Cl2/methanol 20:1)
afforded the product as colorless crystals (3.30 g, 70%). 1H NMR
(CDCl3): d=1.39, 1.44 (ds, 9H; Boc), 1.78–2.16 (m, 16H; CH2), 3.36–3.82
(m, 11H; CH2, OCH3), 4.37–4.54 (m, 2H; CH), 4.69–4.75 ppm (m, 2H;
CH); 13C NMR (CDCl3): d=23.80, 24.33, 24.80, 24.84, 24.97, 25.06, 28.02,
28.06, 28.18, 28.57, 28.68, 28.90, 29.22, 30.10, 46.64, 46.67, 46.84, 47.08,
47.11, 52.31, 57.89, 57.94, 58.00, 58.03, 58.10, 58.74, 79.52, 79.57, 153.98,
154.78, 170.32, 170.65, 170.76, 171.09, 171.66, 172.93, 172.97 ppm; HRMS:
Compound 3a: HOBt in N-methylpyrrolidine (31 mL, 31.00 mmol) was
added to a solution of Boc-Pro-OH (6.6 g, 30.60 mmol) in dry CH2Cl2
(80 mL) at room temperature. After 10 min, EDC (6.30 g, 30.60 mmol)
Chem. Eur. J. 2008, 14, 8939 – 8946
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8943

A. Zhang and Y. Guo
m/z: calcd: 521.29 [M+H]+; found: 421.2441 [MÀBoc+H]+, 521.2980
[M+H]+, 543.2794 [M+Na]+, 559.2539 [M+K]+.
CH, CH2), 4.00–4.42 (m, 2H; CH), 4.64 (brs, 6H; CH), 4.88–4.98 ppm
(m, 1H; OH); 13C NMR (CDCl3): d=22.16, 23.58, 24.12, 24.42, 24.58,
24.63, 24.75, 24.90, 25.06, 27.43, 27.58, 27.75, 27.86, 28.03, 28.37, 28.49,
28.59, 28.70, 29.01, 29.28, 29.91, 45.70, 46.66, 46.84, 47.37, 47.45, 57.68,
57.75, 57.84, 57.91, 58.45, 59.69, 60.70, 66.34, 66.70, 79.20, 79.26, 153.72,
154.54, 170.10, 170.19, 170.35, 170.73, 170.98, 171.13, 171.31, 172.98 ppm;
HRMS: m/z: calcd: 880.51 [M+H]+; found: 881.5103 [M+H]+, 903.4967
[M+Na]+, 919.4731 [M+K]+.
Compound 4b: TFA (2.50 g, 20.00 mmol) was added to a solution of 4a
(2.5 g, 4.80 mmol) in CH2Cl2 (50 mL) at 08C, and the mixture was stirred
for 6 h before an excess amount of methanol was added to quench the re-
action. Evaporation of the solvents in vacuo yielded the deprotected
1
product as a colorless solid (2.56 g, 100%). H NMR (D2O): d=1.77–2.49
(m, 16H; CH2), 3.31–3.65 (m, 11H; CH2, OCH3), 4.31–4.53 ppm (m, 4H;
CH); 13C NMR (D2O): d=23.92, 24.64, 24.67, 27.87, 28.01, 28.34, 28.70,
46.74, 47.45, 47.72, 47.80, 53.01, 58.75, 59.09, 59.19, 59.57, 115.26, 117.58,
162.90, 163.18, 167.72, 171.22, 172.10, 174.80 ppm; HRMS: m/z: calcd:
421.24 [M+H]+; found: 421.2442 [M+H]+, 443.2259 [M+Na]+.
Compound 7: A solution of trimethylacetyl chloride (0.16 g, 1.35 mmol)
in dry THF (5 mL) was added dropwise into a mixture of 6 (0.40 g,
0.45 mmol), TEA (0.23 g, 2.25 mmol), and DMAP (0.1 g) in dry THF
(20 mL) at 08C over a period of 15 min. After the reaction mixture had
been stirred for 4 h at room temperature, it was washed with saturated
NaHCO3 and brine, successively. The organic phase was dried over
MgSO4. Evaporation of the solvents under vacuum, followed by chroma-
tographic separation (CH2Cl2/CH3OH 20:1), yielded 7 as a colorless solid
(0.37 g, 86%). 1H NMR (CDCl3): d=1.28 (s, 9H; CH3), 1.38, 1.42 (ds,
9H; Boc), 1.78–2.08 (m, 32H; CH2), 3.35–3.81 (m, 16H; CH2), 4.11–
4.72 ppm (m, 10H; CH); 13C NMR (CDCl3): d=23.77, 24.31, 24.53, 24.61,
24.78, 24.80, 24.86, 25.11, 27.16, 27.40, 27.41, 27.96, 28.01, 28.06, 28.22,
28.57, 28.70, 28.86, 29.23, 30.11, 31.59, 46.81, 46.89, 47.05, 47.10, 47.16,
55.79, 57.84, 57.92, 58.02, 58.06, 62.14, 79.40, 79.49, 153.91, 154.70, 170.24,
170.26, 170.55, 170.83, 170.90, 171.50, 177.71 ppm; HRMS: m/z: calcd:
965.56 [M+H]+; found: 965.5460 [M+H]+, 987.5321 [M+Na]+.
Compound 4c: LiOH·H2O (1.00 g, 23.00 mmol) was added to a solution
of 4a (6.00 g, 11.50 mmol) in methanol (100 mL) and water (30 mL) at
À58C with stirring, and the reaction mixture was allowed to warm to
room temperature. After the mixture had been stirred for 3 h, the sol-
vents were evaporated in vacuo at room temperature. The residue was
dissolved in CH2Cl2, and the pH value of the solution was adjusted care-
fully to around pH 5–6 with 10% KHSO4 aqueous solution. After the or-
ganic phase had been washed with brine and dried over MgSO4, purifica-
tion by column chromatography (CH2Cl2/methanol 5:1) afforded the
product as colorless crystals (4.09 g, 70%). 1H NMR (CDCl3): d=1.34,
1.39 (ds, 9H; Boc), 1.77–2.08 (m, 16H; CH2), 3.36–3.78 (m, 8H; CH2),
4.24–4.45 (m, 2H; CH), 4.65–4.70 ppm (m, 2H; CH); 13C NMR (CDCl3):
d=23.48, 23.80, 24.34, 24.91, 25.03, 27.83, 27.98, 28.14, 28.57, 28.66, 29.23,
29.78, 30.79, 45.37, 47.09, 49.65, 57.86, 58.01, 58.09, 79.54, 79.60, 153.91,
154.76, 170.87, 171.13 ppm; HRMS: m/z: calcd: 507.27 [M+H]+; found:
407.2620 [MÀBoc+H]+, 507.2822 [M+H]+, 529.2624 [M+Na]+.
Compound 4d: The acid 4c (3.40 g, 6.71 mmol) and pentafluorophenol
(1.60 g, 8.69 mmol) were dissolved in CH2Cl2 (100 mL) and stirred for
10 min. EDC (1.50 g, 7.29 mmol) was then added. The reaction mixture
was stirred overnight at room temperature before being washed with sa-
turated NaHCO3 and brine, successively. After the organic phase had
been dried over MgSO4, purification by column chromatography
(CH2Cl2/methanol 10:1) afforded the product as colorless crystals (3.88 g,
86%). 1H NMR (CDCl3): d=1.36, 1.41 (ds, 9H; Boc), 1.79–2.33 (m,
16H; CH2), 3.35–3.79 (m, 8H; CH2), 4.36–4.82 ppm (m, 4H; CH);
13C NMR (CDCl3): d=23.78, 24.32, 24.73, 24.77, 24.93, 25.08, 28.07,
28.24, 28.54, 28.64, 28.86, 29.06, 29.22, 30.10, 46.63, 46.66, 46.80, 47.01,
47.07, 57.76, 57.85, 57.91, 58.02, 58.46, 58.68, 79.44, 79.50, 136.96, 138.95,
140.14, 142.12, 153.89, 154.72, 168.50, 170.40, 170.70, 171.00, 171.60 ppm;
HRMS: m/z: calcd: 673.26 [M+H]+; found: 573.2121 [MÀBoc+H]+,
673.2683 [M+H]+, 695.2460 [M+Na]+, 711.2235 [M+K]+.
Compound 8: Compound 7 (0.20 g) in TFA (8 mL) was stirred at room
temperature for 5 h, and then MeOH (20 mL) was added to quench the
reaction. After evaporation of the solvents, the deprotected sample was
dialyzed against pure water for 3 days. This was followed by freeze
drying, which afforded compound 8 as a colorless solid (0.21 g, 100%).
1H NMR (D2O): d=1.29 (s, 9H; CH3), 1.79–2.10 (m, 32H; CH2), 3.36–
3.83 (m, 16H; CH2), 4.12–4.74 ppm (m, 10H; CH); 13C NMR (D2O): d=
23.79, 24.32, 24.53, 24.65, 24.76, 24.82, 24.84, 25.13, 27.42, 27.94, 29.26,
30.15, 31.56, 44.71, 44.73, 44.75, 46.78, 46.87, 55.76, 57.87, 57.96, 58.04,
58.11, 62.15, 79.43, 79.48, 153.94, 154.73, 170.20, 170.28, 170.56, 170.83,
170.95, 171.50, 176.42, 176.45, 177.73 ppm; HRMS: m/z: calcd: 865.52
[M+H]+; found: 865.5180 [M+H]+, 887.5112 [M+Na]+.
Compound 1: A solution of MAC (0.53 g, 5.11 mmol) in THF (20 mL)
was added dropwise into a mixture of 6 (1.50 g, 1.70 mmol), triethylamine
(TEA; 1.03 g, 10.21 mmol), and dimethylaminopyridine (DMAP; 0.02 g)
in dry THF (30 mL) at 08C over a period of 30 min. After the reaction
mixture had been stirred for 4 h at room temperature, it was washed with
saturated NaHCO3 and brine, successively. The organic phase was dried
over MgSO4. Evaporation of the solvents under vacuum at room temper-
ature, followed by chromatographic separation (CH2Cl2/CH3OH 20:1)
yielded 1 as a colorless solid (1.29 g, 80%). 1H NMR (CDCl3): d=1.38,
1.42 (ds, 9H; Boc), 1.77–2.08 (m, 35H; CH2, CH3), 3.35–3.80 (m, 16H;
CH2), 4.10–4.74 (m, 10H; CH, CH2), 5.57 (s, 1H; CH), 6.07 ppm (s, 1H;
CH); 13C NMR (CDCl3): d=18.49, 23.79, 24.32, 24.52, 24.60, 24.76, 24.82,
24.86, 25.10, 27.15, 27.96, 28.00, 28.06, 28.22, 28.57, 28.68, 28.84, 29.21,
30.12, 31.58, 46.78, 46.89, 47.02, 47.08, 47.18, 55.79, 57.87, 57.94, 58.02,
58.08, 64.04, 79.41, 79.48, 125.78, 136.29, 153.92, 154.76, 167.24, 170.22,
170.28, 170.54, 170.81, 170.92, 171.51 ppm; HRMS: m/z: calcd: 948.53
[M+H]+; found: 949.5420 [M+H]+, 971.5217 [M+Na]+.
Compound 5: A solution of 4b (3.05 g, 5.71 mmol) and DiPEA (5.20 g,
40.14 mmol) in dry DMF (20 mL) was added dropwise to a solution of
4d (3.20 g, 4.76 mmol) in dry DMF (30 mL) at room temperature. After
the reaction mixture had been stirred overnight, it was washed succes-
sively with saturated NaHCO3 and brine. The organic phase was dried
with MgSO4. Purification by column chromatography (CH2Cl2/MeOH
20:1) afforded 5 as colorless crystals (3.20 g, 74%). 1H NMR (CDCl3):
d=1.36, 1.41 (ds, 9H; Boc), 1.78–2.08 (m, 32H; CH2), 3.35–3.77 (m,
19H; CH2, CH3), 4.35–4.47 (m, 2H; CH), 4.68 ppm (brs, 6H; CH);
13C NMR (CDCl3): d=23.78, 24.31, 24.65, 24.72, 24.77, 24.81, 24.85,
24.90, 25.09, 27.94, 27.99, 28.05, 28.21, 28.56, 28.67, 28.84, 29.20, 30.11,
46.55, 46.80, 46.86, 46.97, 47.01, 47.07, 47.16, 52.29, 57.86, 57.92, 58.01,
58.65, 79.38, 79.45, 153.90, 154.74, 170.19, 170.26, 170.51, 170.60, 170.88,
171.48, 172.90 ppm; HRMS: m/z: calcd: 908.50 [M+H]+; found: 931.4917
[M+Na]+, 947.4630 [M+K]+.
Poly(1): Macromonomer 1 (0.3–0.5 g) and AIBN (0.5 wt% based on the
macromonomer) in the appropriate solvent (0.8 mL) inside a Schlenk
tube were degassed by several freeze–pump–thaw cycles and were then
kept at 608C with stirring for a predetermined time. The polymerization
was stopped by cooling, and the polymer was dissolved in CH2Cl2 and pu-
rified by column chromatography (silica gel with CH2Cl2 as the eluent).
GPC results are shown in Table 1; 1H NMR ([D6]DMSO, 808C): d=0.85
(brs; CH3), 0.92 (brs; CH3), 1.21 (brs; CH3), 1.34 (brs; CH3), 1.86 (brs;
CH2), 2.12 (brs; CH2), 3.25–3.63 (m; CH, CH2), 4.38 (brs; CH), 4.58 ppm
(brs; CH); 13C NMR ([D6]DMSO, 808C): d=9.25, 24.89, 27.98, 28.79,
46.92, 47.13, 58.10, 67.06, 70.58, 73.02, 78.89, 170.07 ppm.
Compound 6: NaBH4 (0.29 g, 7.66 mmol) and LiCl (0.48 g, 11.48 mmol)
were added to a solution of 5 (2.32 g, 2.55 mmol) in dry THF (50 mL) at
À58C. After the reaction mixture had been stirred for 3 h, it was allowed
to warm to room temperature and was stirred for another 24 h. Water
was added to quench the reaction, and the solvents were evaporated in
vacuo. The residue was dissolved in CH2Cl2 and washed with saturated
NaHCO3 and brine, successively. After the organic phase had been dried
over MgSO4, purification by column chromatography (CH2Cl2/MeOH
De-poly(1): Poly(1) (0.20 g) in TFA (5 mL) was stirred overnight at room
temperature, and then MeOH (10 mL) was added to quench the reaction.
After evaporation of the solvents, the deprotected polymer was dialyzed
against pure water for 10 days. This was followed by freeze drying, which
1
10:1) afforded 6 as a colorless solid (1.80 g, 80%). H NMR (CDCl3): d=
1.31, 1.36 (ds, 9H; Boc), 1.49–2.04 (m, 32H; CH2), 3.31–3.65 (m, 19H;
8944
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8939 – 8946

Helical Conformations
FULL PAPER
afforded the de-poly(1) as a colorless solid foam. 1H NMR ([D6]DMSO,
808C): d=0.85 (brs; CH3), 0.95 (brs; CH3), 0.98 (brs; CH3), 1.26–1.29
(m; CH3), 1.88 (brs; CH2), 2.12 (brs; CH2), 3.44–3.70 (m; CH, CH2), 4.14
(brs; CH), 4.49–4.66 ppm (m; CH); no resolved carbon NMR spectrum
was achieved.
Angew. Chem. 1970, 82, 468–479; Angew. Chem. Int. Ed. Engl.
1970, 9, 389–400; d) M. Mutter, T. Wçhr, S. Gioria, M. Kellar, Bio-
polymers 1999, 51, 121–128.
[11] a) A. R. Downie, A. A. Randall, Trans. Faraday Soc. 1959, 55, 2132–
2140; b) F. Gornick, L. Mandelkern, A. F. Diorio, D. E. Roberts, J.
Am. Chem. Soc. 1964, 86, 2549–2555; c) J. Engel, Biopolymers 1966,
4, 945–948.
[12] a) C. M. Deber, F. A. Bovey, J. P. Carver, E. R. Blout, J. Am. Chem.
Soc. 1970, 92, 6191–6198; b) D. A. Torchia, F. A. Bovey, Macromo-
lecules 1971, 4, 246–251; c) D. E. Dorman, F. A. Bovey, J. Org.
Chem. 1973, 38, 2379–2383; d) Y.-Y. Chao, R. Bersohn, Biopolymers
1978, 17, 2761–2767.
[13] a) H. Okabayashi, T. Isemura, S. Sakakibara, Biopolymers 1968, 6,
323–330; b) N. Helbecque, M. H. Loucheux-Lefebvre, Int. J. Pept.
Protein Res. 1982, 19, 94–101; c) F. Rabanal, M. D. Ludevid, M.
Pons, E. Giralt, Biopolymers 1993, 33, 1019–1028; d) R. K. Dukor,
T. A. Keiderling, Biospectroscopy 1996, 2, 83–100.
Acknowledgements
We cordially thank Prof. A. D. Schlꢃter (ETH Zurich) for his continuous
support and help with the manuscript. We also gratefully thank one of
the reviewers for helpful comments. This work was supported by the Na-
tional Natural Science Foundation of China (grant nos.: 20374047 and
20574062).
[14] J.-C. Horng, R. T. Raines, Protein Sci. 2006, 15, 74–83.
[15] M. Kꢃmin, L.-S. Sonntag, H. Wennemers, J. Am. Chem. Soc. 2007,
129, 466–467.
[1] a) Y. Okamoto, E. Yashima, C. Yamamoto in Materials-Chirality
(Eds.: M. M. Green, R. J. M. Nolte, E. W. Meijer), Wiley, New York,
2003, pp. 157–208; b) J. W. Lockman, N. M. Paul, J. R. Parquette,
Prog. Polym. Sci. 2005, 30, 423–452; c) D. B. Amabilino, J. Veciana,
Top. Curr. Chem. 2006, 265, 253–302; d) D. A. Leigh, E. M. Pꢄrez,
Top. Curr. Chem. 2006, 265, 185–208.
[2] a) Y. Okamoto, T. Nakano, Chem. Rev. 1994, 94, 349–372; b) T.
Nakano, Y. Okamoto, Chem. Rev. 2001, 101, 4013–4038;
c) J. J. L. M. Cornelissen, A. E. Rowan, R. J. M. Nolte, N. A. J. M.
Sommerdijk, Chem. Rev. 2001, 101, 4039–4070; d) M. M. Green, K.-
S. Cheon, S.-Y. Yang, J.-W. Park, S. Swansburg, W. Liu, Acc. Chem.
Res. 2001, 34, 672–680; e) E. Yashima, K. Maeda, T. Nishimura,
Chem. Eur. J. 2004, 10, 42–51; f) J. G. Rudick, V. Percec, New J.
Chem. 2007, 31, 1083–1096.
[3] a) A. R. A. Palmans, E. W. Meijer, Angew. Chem. 2007, 119, 9106–
9126; Angew. Chem. Int. Ed. 2007, 46, 8948–8968; b) H.-J. Kim, Y.-
B. Lim, M. Lee, J. Polym. Sci. Part A Polym. Chem. 2008, 46, 1925–
1935; c) G. A. Hembury, V. V. Borovkov, Y. Inoue, Chem. Rev. 2008,
108, 1–73.
[4] E. Yashima, K. Maeda, Macromolecules 2008, 41, 3–12.
[5] T. Nakano, Y. Okamoto, Macromol. Rapid Commun. 2000, 21, 603–
612.
[16] S. Kakinoki, Y. Hirano, M. Oka, Polym. Bull. 2005, 53, 109–115.
[17] a) M. Y. Ogawa, J. F. Wishart, Z. Young, J. R. Miller, S. S. Isied, J.
Phys. Chem. 1993, 97, 11456–11463; b) D. G. McCaffery, C. A. Slate,
B. M. Nakhle, Tetrahedron 1995, 51, 9859–9872; c) D. G. McCaffery,
D. A. Friesen, E. Danielson, Proc. Natl. Acad. Sci. USA 1996, 93,
8200–8204; d) C. A. Slate, R. A. Binstead, T. J. Meyer, B. W. Erick-
son, Lett. Pept. Sci. 1999, 6, 61–69; e) D. R. Striplin, S. Y. Reece,
D. G. McCaffery, C. G. Wall, D. A. Friesen, B. W. Erickson, T. J.
Meyer, J. Am. Chem. Soc. 2004, 126, 5282–5291; f) S. A. Serron, W.
Aldridge, C. N. Fleming, R. M. Danell, M. Sykora, M. Baik, D. M.
Dattelbaum, T. J. Meyer, J. Am. Chem. Soc. 2004, 126, 14506–
14514; g) W. S. Aldridge, B. J. Hornstein, S. Serron, D. M. Dattel-
baum, J. R. Schoonover, T. J. Meyer, J. Org. Chem. 2006, 71, 5186–
5190.
[18] a) L. Crespo, G. Sanclimens, B. Montaner, R. Pꢄrez-Tomꢆs, M.
Royo, M. Pons, F. Albericio, E. Giralt, J. Am. Chem. Soc. 2002, 124,
8876–8883; b) G. Sanclimens, L. Crespo, E. Giralt, F. Albericio, M.
Royo, J. Org. Chem. 2005, 70, 6274–6281.
[19] M. Zhang, A. H. E. Mꢃller, J. Polym. Sci. Part A Polym. Chem.
2005, 43, 3461–3481.
[6] a) J. Bella, M. Eaton, B. Brodsky, H. M. Berman, Science 1994, 266,
75–81; b) S. K. Holmgren, K. M. Taylor, L. E. Bretscher, R. T.
Raines, Nature 1998, 392, 666–667; c) A. V. Persikov, J. A. Ram-
shaw, A. Kirkpatrick, B. Brodsky, Biochemistry 2000, 39, 14960–
14967; d) A. V. Persikov, J. A. M. Ramshaw, A. Kirkpatrick, B.
Brodsky, J. Am. Chem. Soc. 2003, 125, 11500–11501; e) M. Kohtani,
T. C. Jones, J. E. Schneider, M. F. Jarrold, J. Am. Chem. Soc. 2004,
126, 7420–7421; f) M. D. Shoulders, J. A. Hodges, R. T. Raines, J.
Am. Chem. Soc. 2006, 128, 8112–8113; g) S. Rele, Y. Song, R. P. Ap-
karian, Z. Qu, V. P. Conticello, E. L. Chaikof, J. Am. Chem. Soc.
2007, 129, 14780–14787; h) V. Gauba, J. D. Hartgerink, J. Am.
Chem. Soc. 2007, 129, 15034–15041; i) F. W. Kotch, I. A. Guzei,
R. T. Raines, J. Am. Chem. Soc. 2008, 130, 2952–2953; j) N. Dai,
X. J. Wang, F. A. Etzkorn, J. Am. Chem. Soc. 2008, 130, 5396–5397;
k) D. Diana, B. Ziaco, G. Colombo, G. Scarabelli, A. Romanelli, C.
Pedone, R. Fattorusso, L. D. DꢅAndrea, Chem. Eur. J. 2008, 14,
4164–4166.
[20] For polymer bottlebrushes with polydispersed peptide side chains,
see, for example: a) B. Zhang, K. Fischer, M. Schmidt, Macromol.
Chem. Phys. 2005, 206, 157–162; b) L. Zhang, W. Li, A. Zhang,
Prog. Chem. 2006, 18, 939–949; c) T. Waku, M. Matsusaki, T.
Kaneko, M. Akashi, Macromolecules 2007, 40, 6385–6392; d) N.
Gunari, Y. Cong, B. Zhang, K. Fischer, A. Janshoff, M. Schmidt,
Macromol. Rapid Commun. 2008, 29, 821–825.
[21] a) A. Zhang, A. D. Schlꢃter, Chem. Asian J. 2007, 2, 1540–1548;
b) A. Zhang, F. Rodrꢇguez-Ropero, D. Zanuy, C. Alemꢆn, E. W.
Meijer, A. D. Schlꢃter, Chem. Eur. J. 2008, 14, 6924–6934.
[22] Macromonomer 1 adopts different helical conformations in isopro-
panol/acetonitrile (1:1) and HFIP, and this difference was expected
to indicate different steric effects in the polymerization process. For
the corresponding CD spectra of macromonomer 1, see Figure S1 in
the Supporting Information.
[23] A. Zhang, B. Zhang, E. Wꢈchtersbach, M. Schmidt, A. D. Schlꢃter,
Chem. Eur. J. 2003, 9, 6083–6092.
[7] a) P. M. Cowan, S. Mcgavin, Nature 1955, 176, 501–503; b) W.
Traub, U. Shmueli, Nature 1963, 198, 1165–1166.
[24] HFIP was reported to show effects on polymer-backbone tacticity in
radical polymerizations, see, for example: a) Y. Isobe, K. Yamada, T.
Nakano, Y. Okamoto, Macromolecules 1999, 32, 5979–5981; b) Y.
Isobe, K. Yamada, T. Nakano, Y. Okamoto, J. Polym. Sci. Part A
Polym. Chem. 2000, 38, 4693–4703; c) Y. Miura, T. Satoh, A.
Narumi, O. Nishizawa, Y. Okamoto, T. Kakuchi, Macromolecules
2005, 38, 1041–1043; d) Y. Miura, T. Satoh, A. Narumi, O. Nishiza-
wa, Y. Okamoto, T. Kakuchi, J. Polym. Sci. Part A Polym. Chem.
2006, 44, 1436–1446.
[8] a) R. Z. Dramer, L. Vitagliano, J. Bella, R. Berisio, L. Mazzarella,
B. Brodsky, A. Zagari, H. M. Berman, J. Mol. Biol. 1998, 280, 623–
638; b) J. T. Nguyen, C. W. Turck, F. E. Cohen, R. N. Zuckermann,
W. A. Lim, Science 1998, 282, 2088–2092; c) Z. Shi, K. Chen, Z.
Liu, N. R. Kallenbach, Chem. Rev. 2006, 106, 1877–1897.
[9] a) M. P. Williamson, Biochem. J. 1994, 297, 249–260; b) D. S. Dan-
iels, A. Schepartz, J. Am. Chem. Soc. 2007, 129, 14578–14579.
[10] a) J. Kurtz, A. Berger, E. Katchalski, Nature 1956, 178, 1066–1067;
b) I. Z. Steinberg, W. F. Harriugton, A. Berger, M. Sela, E. Katchal-
ski, J. Am. Chem. Soc. 1960, 82, 5263–5279; c) J. Engel, G. Schwarz,
[25] K. Hatada, T. Kitayama, K. Ute, Prog. Polym. Sci. 1988, 13, 189–
276.
Chem. Eur. J. 2008, 14, 8939 – 8946
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8945

A. Zhang and Y. Guo
[26] Polymer bottlebrushes can adopt either a cylindrical shape when the
main-chain length (Lm) is much longer than the side-chain length
(Ls) or a spherical shape when the ratio of Lm/Ls is relatively small.
We propose that the stable PPII conformation in the present case
would only remain for the cylindrical bottlebrushes, in which all of
the side chains are aligned in parallel to form the overcrowded
structures. For reports regarding bottlebrush shapes, see, for exam-
ple: a) Y. Tsukahara, K. Tsutsumi, Y. Yamashita, S. Shimada, Mac-
romolecules 1990, 23, 5201–5208; b) M. Wintermantel, M. Gerle, K.
Fischer, M. Schmidt, I. Wataoka, H. Urakawa, K. Kajiwara, Y. Tsu-
kahara, Macromolecules 1996, 29, 978–983; c) P. Dziezok, K. Fisch-
er, M. Schmidt, S. S. Sheiko, M. Mçller, Angew. Chem. 1997, 109,
2894–2897; Angew. Chem. Int. Ed. Engl. 1997, 36, 2812–2815; d) K.
Fischer, M. Schmidt, Macromol. Rapid Commun. 2001, 22, 787–791;
e) S. Rathgeber, T. Pakula, A. Wilk, K. Matyjaszewski, K. L. Beers,
J. Chem. Phys. 2005, 122, 124904/1–124904/13.
Received: June 17, 2008
Published online: August 11, 2008
8946
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8939 – 8946