Chiral poly(ureidophthalimide) foldamers in water

Article abstract of DOI:10.1002/chem.200600476

Poly(ureidophthalimide)s decorated with hydrophilic side chains, that ensure solubility in aqueous media, have been synthesized and characterized by UV/Vis and circular dichroism (CD) spectroscopy. Temperature and concentration dependent CD measurements i

Full text of DOI:10.1002/chem.200600476

FULL PAPER
DOI: 10.1002/chem.200600476
Chiral Poly(ureidophthalimide) Foldamersin Water
RenatusW. Sinkeldam, [a, b] Michel H. C. J. van Houtem,[a] Koen Pieterse,[a]
Jef A. J. M. Vekemans,[a] and E. W. Meijer*[a]
Abstract:
Poly(ureidophthalimide)s
tive for a strong intramolecular organi-
zation. Similar studies in THF demon-
strate the dynamic nature of the secon-
dary architecture, a characteristic of
foldamers. In addition, the bisignated
Cotton effect in water is opposite in
sign to that in THF, suggestive for a
solvent-dependent preference for one
helical handedness. Mixing experiments
prove the dominance of water in deter-
mining the handedness of the helical
architecture. The solvent allows for
control over the helical architecture
and thus governs the supramolecular
synthesis.
decorated with hydrophilic side chains,
that ensure solubility in aqueous
media, have been synthesized and char-
acterized by UV/Vis and circular di-
chroism (CD) spectroscopy. Tempera-
ture and concentration dependent CD
measurements in water have revealed
an almost temperature and concentra-
tion independent Cotton effect, indica-
Keywords: chirality · foldamers ·
helicity · supramolecular chemistry
Introduction
aging for a entirely synthetic approach. Besides the peptides
or peptidomimetics also the folding of other synthetic poly-
mers or oligomers into helical architectures are consid-
ered.[6] All of these structures belong to the class of foldam-
ers, according to Moore, being structures reversibly folding
into a conformationally ordered state in solution.[6e] Most
frequently, the folding is directed by intramolecular hydro-
gen bonding. In several cases folding relies on solvophobici-
ty while additional p–p stacking may stabilize the secondary
architecture. Numerous strategies have been reported to
arrive at non-natural foldamers. Prominent architectures are
based on aromatic electron donor–acceptor couples,[7] m-
phenylene–ethynylenes[8] and their backbone rigidified ana-
logues,[9] aromatic oligoamides,[10–12] aromatic oligoureas,[6b,13]
aromatic oligohydrazides[14] and aromatic iminodicarbon-
yls[15] and foldamers based on supramolecular polymers.[16]
Depending on their design they may possess an inner void
of sufficient size to host ions or small molecules. Obviously,
mimicking nature with abiotic foldamers demands solubility
in water. Natural helices constructed from a-peptides can
rely on their intrinsic bipolar zwitterionic state to ensure sol-
ubility in water. However, synthetic foldamers often contain
structural elements hampering solubility in an aqueous envi-
ronment. The use of ionic groups in non-natural foldamers
is not without consequence since it will probably also affect
folding. m-Phenylene–ethynylenes (mPEs) are known for
their helical secondary architectures.[8] However, it is still
ambiguous whether their amphiphilic ionic counterparts
adopt a helical conformation or an extended all trans con-
The intriguing helical shape of biomolecules, with the a-
helix as one of the most abundant secondary architectures
in Nature, has always fascinated chemists. Native peptides
are, therefore, an attractive source of inspiration to disclose
the interactions reversibly inducing helicity. The numerous
interactions that govern folding in natural systems have
prompted chemists to design synthetic analogues to give
more insight into the structural requirements for folding.[1]
Closest to naturally occurring a-helices are the helical sec-
ondary structures based on b-peptides.[2] Investigations of
Gellman and Seebach illustrate that modification of the b-
amino acid building blocks give more control over the sec-
ondary architecture.[3,4] Even more fascinating is the finding
that helical architectures comprising b-peptides are more
stable than their a-peptide counterparts,[5] which is encour-
[a] Dr. R. W. Sinkeldam, M. H. C. J. van Houtem, Dr. K. Pieterse,
Dr. J. A. J. M. Vekemans, Prof. Dr. E. W. Meijer
Laboratory of Macromolecular and Organic Chemistry
Eindhoven University of Technology, P. O. Box 513
5600 MB Eindhoven (The Netherlands)
Fax : (+31)40-245-1036
E-mail: E.W.Meijer@tue.nl
[b] Dr. R. W. Sinkeldam
Current address:
Department of Chemistry and Biochemistry, University of California
San Diego, 9500 Gilman Drive, MC0358
La Jolla, CA 92093-0358 (USA)
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6129

formation in aqueous solutions.[17,18] The best strategy is
probably the use of non-ionic functionalities such as ethyl-
ene oxides to guarantee solubility in water. To our knowl-
edge only Moore and co-workers have reported on a strat-
egy to solubilize mPE foldamers in water/acetonitrile solu-
tion by decoration of the backbone with chiral[19] and achi-
ral[20] ethylene oxide chains and in water by longer achiral[21]
ethylene oxide chains. In the latter case, preference of one
handedness over the other is realized by addition of a chiral
guest, a small organic molecule, which fits in the inner void
of the foldamer. This beautiful example demonstrates the
potential of synthetic foldamers as candidates for mimicking
biological functions. Besides the use of mPEs as a host, simi-
lar experiments albeit not in water, with aromatic oligo-
amides have been reported.[22] With the use of oligo(ureido–
meta-phenylene)s even mimicking of transmembrane ion
channels is anticipated.[6b,23] In that case the urea functions
adopt a cisoid conformation due to intramolecular hydrogen
bonding between the urea hydrogens and the carbonyl of an
adjacent ester functionality.
Previously we have reported on a poly(ureido-para–
phthalimidyl) foldamer in which the urea N-H groups adopt
a cisoid conformation.[24] In that case the consecutive mono-
meric units introduce a curvature in the ureidophthalimide
backbone due to intramolecular hydrogen bonding of urea
protons with the adjacent imide carbonyls. This interaction
induces a bend of somewhat larger than 1208, and thus nu-
cleates folding (Figure 1). Due to the para substitution in
the phthalimide unit a larger inner void is created upon
folding than in the oligo(ureido–meta-phenylene) system.
CD studies of the polymer in THF indicate folding into a
helical architecture. Moreover, studies in heptane indicate
the stacking of shorter oligomers to larger chiral aggregates.
However, the same compound dissolved in CHCl3 proves to
be CD silent and is regarded as residing in the non-folded
state.
Figure 1. Folding in poly(ureidophthalimide) induced by intramolecular
hydrogen bonding.
an array of 3,6-diaminophthalimides,[25] the building blocks
for the foldamers. In this way chiral oligo(ethylene oxide)
side chains have been incorporated in the foldameric struc-
ture enabling a CD study—after isolation of the high molec-
ular weight fraction—of the polymer in aqueous solution.
Results and Discussion
The ureidophthalimide based polymer 3 was obtained by re-
action of diamine 1 with diisocyanate 2 in refluxing dioxane
in the presence of one equivalent of 4-dimethylaminopyri-
dine (DMAP) (Scheme 1).
Previously, an efficient synthetic approach to tosylated
(2S)-2-methyl-3,6,9,12,15-pentaoxahexadecanol (4) and its
coupling to methyl gallate
5
have been described
(Scheme 2).[26] Subsequently, methyl ester 6 was hydrolyzed
and the acid converted to the acid chloride,[26] which was
treated with sodium azide to acyl azide 7. Curtius rearrange-
ment in dioxane at elevated temperatures rendered isocya-
nate 8, which in turn was hydrolysed to the corresponding
amine 9 by slow addition to aqueous potassium hydroxide in
dioxane at 908C.
Similar to the work of Moore, the oligo(ureidophthal-
imide) foldamer presented in this paper also relies on oligo-
(ethylene oxide) functionalities to ensure solubility in water.
Recently, we reported a general synthetic strategy towards
Scheme 1. Polymerization of diamine 1 with diisocyanate 2. i) DMAP (1 equiv), dioxane, reflux, 17 h.
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Foldamers
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Scheme 2. Synthesis of amine 9. i) 4 (3.05 equiv), 5, K2CO3 (6.2 equiv), Bu4NBr (0.05 equiv), MIBK, reflux, 6 h; KOH (3.3 equiv), EtOH/H2O 1:1, reflux,
17 h; 0.1m HCl until pH ~3, 95%; (COCl)2 (1.2 equiv), DMF (5 drops), CH2Cl2, RT, 17 h, 99%;[26] ii) NaN3 (18 equiv), THF/H2O 1:1, 58C, 1 h, 99%;
iii) dioxane, reflux, 4 h, ~100%; iv) KOH (160 equiv), H2O, 90 8C, 30 min, 97%. MIBK = methylisobutylketone.
The chirality in oligo(ethylene oxide) 4 was introduced by
starting from ethyl (S)-(ꢀ)-lactate (purity of 98%) of which
the ee value was determined by gas chromatography (GC)
on a capillary column with a permethylated b-cyclodextrin
stationary phase yielding an ee > 99.5%.[27] Part of the
routes is based on earlier work that also showed the fidelity
of keeping the enantiomeric excess as high as the starting
materials.[28]
Amine 9 was converted into the phthalimide synthon 11
by reaction with 3,6-bis(acetylamino)phthalic anhydride 10
(Scheme 3).[29,25] Removal of the acetyl functions to afford
the corresponding diamine 1 was achieved by exposure of
diamide 11 to 1.5m aqueous HCl in refluxing dioxane fol-
lowed by neutralization. Subsequent treatment of diamine 1
with 20 wt% phosgene in toluene afforded diisocyanate 2.
The conversion was monitored by IR spectroscopy and
proved to be complete and quantitative after 30 minutes at
room temperature.
Polymerization of diamine 1 with diisocyanate 2 according
to Scheme 1 furnished ureidophthalimide polymer 3. Moni-
toring the polymerization by IR spectroscopy indicated that
the reaction was finished after 17 h in refluxing dioxane
when all diisocyanate was consumed. The non-migrating
DMAP was removed by filtration over silica gel upon elu-
tion with a solvent mixture of 10% methanol in 1,2-dime-
thoxyethane. A separation of shorter and longer oligomers
was effectuated by column chromatography over silica gel
with a solvent mixture gradient from 1 to 10% methanol in
1,2-dimethoxyethane. Due to the polar nature of the oligo-
(ethylene oxide) tails, the first fraction (3a) was a mixture
of predominantly short oligomers with a small amount of
longer oligomers. The second fraction (3b) contained only
oligomers longer than eight units. The difference in poly-
meric distribution has been established on GPC (CHCl3,
mixed-E column, detection at 310 nm). Fraction 3a had a
longer elution time (max. 5.69 min) than fraction 3b (max.
4.37 min). Furthermore, from 1H NMR endgroup analysis
Scheme 3. Syntheses of polymer building blocks 1 and 2. i) Dioxane, reflux, 17 h, 90%; ii) dioxane/water/HCl (12m) 6:1.5:1, 908C, 45 min, 95%;
iii) COCl2 (40 equiv), PhCH3, RT, 2.5 h, ~100%.
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E. W. Meijer et al.
on the latter an average degree
of polymerization has been de-
duced of 20 units, that is, an Mn
of 21450 gmolꢀ1 has been esti-
mated.
Previous studies on ureidoph-
thalimide based polymers have
been restricted to organic sol-
vents such as heptane, chloro-
form and THF due to the
apolar periphery. For such sys-
tems the largest Cotton effect
was observed in THF.[24] How-
ever, the polar nature of the
oligo(ethylene oxide) tails pres-
ent in 3b ensured solubility in
water. Thus, a dilute aqueous
solution of the high molecular
weight fraction 3b was subject-
ed to a UV/Vis and CD study.
The transparency of water al-
lowed to investigate a spectral
ranging from 190 to 500 nm.
Figure 2. Temperature dependent UV/Vis and CD spectra of 3b in water (4.7”10ꢀ5 m), 158C(black line), 90 8C
(dashed line), and intermediate temperatures (grey lines), and absorption spectrum of amine 12 (closed cir-
The UV/Vis spectrum shows cles).
three distinct absorption
maxima located at 209 (with a
shoulder at 230 nm), at 312 and 398 nm (Figure 2).
The absorptions located at 310 and 398 nm can be attrib-
uted to the phthalimide part of the structure by comparison
with the absorption spectrum of amine 12. In CD spectros-
copy two bisignate Cotton effects were observed. The first
bisignate effect displayed maxima of De=ꢀ53mꢀ1 cmꢀ1
(gabs =ꢀ0.0012) at 205 nm and De=+21mꢀ1 cmꢀ1 (gabs
=
0.0009) at 222 nm (Figure 2). The zero-crossing at 213 nm
coincides with the absorption maximum in the UV/Vis spec-
trum. The second bisignate Cotton effect displays maxima
with De=ꢀ69mꢀ1 cmꢀ1 (gabs =ꢀ0.0040) at 304 nm and De=
+56mꢀ1 cmꢀ1 (gabs =0.0045) at 330 nm. The zero-crossing at
318 nm coincides with the absorption maximum of the
phthalimide unit in UV/Vis spectrometry. Additionally a
small negative CD effect was observed that relates to the
absorption at 398 nm and is presumably to be attributed to
the terminal amino end capped phthalimide. It must be
noted that 3,6-diaminophthalimide 1 as well as its precursor
3,6-bis(acetylamino)phthalimide 11 proved to be CD silent
in water.
The appearance of a Cotton effect in water is remarkable
since the folding is designed to be directed by intramolecu-
lar hydrogen bonding of the urea protons with the imide
carbonyl oxygens. Preliminary molecular modelling studies
in vacuo of a section of a poly(ureidophthalimide) helix (n
= 30) showed a cone-like structure (Figure 3). It indicates
that seven units per turn create an inner part of approxi-
mately 14 Š. The cisoid conformation is apparent, while p–
p stacking was observed reminiscent to that of helicenes. It
is safe to state that initial folding is driven by shielding the
apolar core from the polar solvent. This solvophobic effect
Figure 3. Top and side view of a section of a poly(ureidophthalimide)
helix after a 1 ns molecular dynamics simulation in vacuo at 300 K. Tails
and C-H protons are omitted for clarity.
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Foldamers
FULL PAPER
creates a hydrophobic microdomain which allows the ex-
pression of subtle hydrogen-bonding interactions. Once initi-
ated the system is templated towards folding since the favor-
able hydrophobic pocket, secured by p–p stacking, is al-
ready there. In addition, although variations were observed,
the intensity of the Cotton effect was hardly affected by
raising the temperature. The remarkable stability of this
folded structure in water contrasts to many native helix-
forming proteins which are only marginally stable in
water.[30,31] The extreme stability in water is easily explained
by the strong hydrophobic forces and p–p interaction ham-
pering the structure to be water-soluble in its unfolded form.
The significant CD effects are attributed to supramolecular
chirality and strongly support the presence of a helical archi-
tecture.
The oligo(ethylene oxide)-rich periphery of 3b does not
restrict the solubility of 3b to water alone. Thus, a dilute sol-
ution of 3b in freshly distilled THF has been subjected to a
UV/Vis and CD spectroscopy study. The width of the spec-
tral window was reduced to approximately 250 nm. The UV/
Vis spectrum revealed two absorption maxima located at
315 and 394 nm (Figure 4).
and De=ꢀ17mꢀ1 cmꢀ1 (gabs =0.0017) at 331 nm, respectively,
with a zero-crossing at 323 nm. In contrast to the tempera-
ture dependent CD measurements in water, the Cotton
effect in THF decreased upon raising the temperature and
completely vanished at 558C. The original value was re-
claimed upon cooling to room temperature illustrating the
dynamics of the system in THF. The loss of the Cotton
effect at elevated temperatures may be attributed to the un-
folding of the helical architecture into a random coil confor-
mation or mark the attained equilibrium between P and M
helices. The latter seems to be in agreement with the spec-
tral behavior at different temperatures. Elevation of the
temperature does not result in a shift of the absorption max-
imum, which implies that there is no evidence for a change
in the aromatic packing.[32] Moreover, the presence of an
isodichroic point throughout the temperature dependent
measurements in THF indicates that the structure does not
adopt other conformations or aggregation states.[19a] A melt-
ing curve (Figure 4, right) could be constructed from the
temperature dependent CD data. An exponential function
represented by a grey line adequately fits the data points.
The slope of the curve, denoted by the black line, enables
estimation of the change in enthalpy involved in this pro-
cess. Applying the formula DH = slope·T2 gives DH =
ꢀ5.5 kJmolꢀ1.
The CD spectrum of the same solution shows a Cotton
effect with a De of +24mꢀ1 cmꢀ1 (gabs =0.0009) at 313 nm
The comparison of 3b in THF and in water shows that the
Cotton effect in THF is smaller and of opposite sign com-
pared to the measurement in water. The lower intensity of
the CD effect in THF can point to a less tight packing of
the chromophores and/or less intermolecular aggregation of
the helical architectures. The latter possibility is addressed
with concentration dependent CD studies in water and THF,
which does not reveal a strong correlation between concen-
tration and CD intensity over a 100 fold concentration
range (10ꢀ4 to 10ꢀ6 m), implying that in THF and in water
only monomolecular species are present (Figure 5).
This is supported by temperature dependent gel permea-
tion chromatography experiments in THF (Figure 6). Mea-
surements at 558Cshow even a shift to shorter retention
times compared with measurements at 258C, strongly sug-
gesting the absence of aggregation.
Hence, the less intense Cotton effect in THF can most
likely be attributed to looser packing of the aromatic
system. This is supported by a 23% higher molar extinction
coefficient of 3b at 314 nm in THF compared with the over-
all optical density in water. Hypochromicity is a convincing
indication of a tighter packing of the chromophores and is
also observed in DNA, RNA and other polymers.[33] The ob-
served hypochromic effect can be rationalized by the prop-
erties of the solvent. THF is a good solvent for both the
apolar core and the polar oligo(ethylene oxide) periphery.
However, water can only dissolve the polar oligo(ethylene
oxide) periphery and will force the apolar core to minimize
exposure to water by tight folding and as a consequence in-
duces tight packing of the aromatic units.
Figure 4. Top: Temperature dependent CD (upper) and UV/Vis (lower)
spectra of 3b in THF (5.0”10ꢀ5 m) from 158C(black line) to 55 8C
(dashed line) with steps of 58C(grey lines). Bottom: melting curve con-
structed from the CD intensity at 320 nm (black circles), a fitted expo-
nential curve (dashed line) and a straight line representing the slope
(black line).
The opposite sign of the Cotton effect in THF compared
with water hints towards inversion of the helical handedness.
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E. W. Meijer et al.
Figure 5. Concentration dependent CD measurements of 3b at 208C
from 5.0”10ꢀ4 m (thick black line) to 5.0”10ꢀ6 m (dashed line) in 5 steps
(black lines) in water (top) and in THF (bottom).
Solvent induced inversion of helicity in macromolecular sys-
tems has been reported previously.[34] In this case the effect
might be attributed to differences in hydrogen-bonding in-
teractions with the two solvents and a different conforma-
tion of the chiral oligo(ethylene oxide) side chains. There is
a preference for a gauche conformation along the C–C axis
and for a trans conformation along the C–O axis of the oli-
go(ethylene oxide) tails in water, as has been established by
Matsuura et al. with detailed IR spectroscopy studies on
poly(ethylene oxide).[35] Recently a similar effect was report-
ed in dendrons decorated with chiral oligo(ethylene oxide)
tails that show an opposite Cotton effect in water compared
with THF.[36] Therein, this effect is explained as a helical M
! P transition upon going from THF to water. To investi-
gate the relative influence of the solvent on the helical ar-
chitecture, 3b is studied in THF/water mixtures, keeping the
concentration constant. From the UV/Vis spectra it becomes
clear that the optical density in pure water is increased upon
addition of the THF solution (Figure 7). This suggests loos-
ening of the intramolecular packing, which eventually might
permit helix inversion.
Figure 6. GPCchromatograms at 25 8C(solid line) and 55 8C(dashed
line) of 3b uncorrected (top); PSMP (polystyrene) standard, Mw: 30300,
10150, 5000 and 1600 (middle); 3b with correction of PSMP Mw 10150
(uncorrected curve of 3b + 0.235 minutes; bottom).
The accompanying CD spectra show that upon increasing
the THF/water ratio the Cotton effect gradually decreases.
It is quite remarkable that over 99 vol% of THF in water is
required to reach inversion of the Cotton effect. These find-
ings demonstrate the dominant influence of water on the
Figure 7. CD (top) and UV/Vis (bottom) spectra of mixing of 3b in THF
(dashed line) with a solution of 3b in water (thick black line) in 10%
steps (intermediate lines) keeping the concentration constant at 4.2”
10ꢀ5 m. Every curve represents a new mixture of 3b in THF with 3b in
water and hence does not equal a titration.
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Foldamers
FULL PAPER
conformation of the secondary architecture. This is in line
with the insensitivity of the Cotton effect in water to tem-
perature changes (Figure 2).
Conclusion
the temperature below 58C. After addition, the mixture was stirred for
1 h and THF was evaporated in vacuo at RT. The aqueous residue was
extracted with dichloromethane (4”100 mL), the combined organic
layers were dried over MgSO4 and filtered followed by concentration of
the filtrate in vacuo, yielding 7 (4.354 g, 4.621 mmol, 99%) as a light
A novel hydrophilic ureidophthalimide polymer has been
synthesized that establishes a folding dynamics in THF and
that reveals outstanding stability of the putative helical ar-
chitectures in water. Circular dichroism studies at different
concentrations show a concentration independent Cotton
effect, indicative for intramolecular folding. Temperature
dependent GPCmeasurements in THF suggest the absence
of intermolecular aggregation. The opposite Cotton effect
observed in water compared with THF indicates a solvent
induced preference for helical handedness. Titration experi-
ments with water/THF mixtures denote the dominant influ-
ence of water on the handedness. Furthermore, the assumed
helical inversion allows control over the diastereomeric
excess. The dimensions of the hollow core created by fold-
ing, may allow the hosting of ions and may even be suitable
for accommodation of small molecules. Our future research
will focus on the potential exploitation of the inner void.
1
brown thick oil that was used as such. H NMR (400 MHz, CDCl3, 258C):
d=7.31 (s, 2H, a), 4.14–4.04 (3H, b), 3.96–3.85 (5H, c), 3.81–3.69 (7H,
d), 3.68–3.58 (36H, e), 3.56–3.53 (6H, f), 3.37 (s, 9H, g), 1.31–1.27 ppm
(9H, h); FT-IR (ATR): n˜ = 2870, 2143, 1686, 1584/1498, 1453/1429, 1331,
1298, 1236, 1194, 1098, 1036, 935, 853, 808, 743, 666 cmꢀ1
.
5-Isocyanato-1,2,3-tris[(2S)-2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-
ethoxy)propoxy]benzene (8): Under argon, gallic acyl azide 7 (2.368 g,
2.513 mmol) was dissolved in dioxane (50 mL) and heated under reflux
for 4 h. Analysis by IR spectroscopy proved full conversion to the isocya-
nate 8. The solution was used as such in the next step. FT-IR (ATR): n˜ =
2870, 2263, 1591/1514, 1452/1425, 1374, 1350, 1301, 1228, 1200, 1099,
1022, 942, 848, 677 cmꢀ1
.
3,4,5-Tris[(2S)-2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)pro-
poxy]aniline (9): Under argon, isocyanate 8 (2.292 g, 2.513 mmol) in di-
oxane (50 mL) was slowly added through a cannula to a hot (608C), well-
stirred solution of KOH (22.44 g, 0.40 mol, an excess is used to minimize
Experimental Section
General experimental: All solvents used were provided by Biosolve and
of AR quality. Dry tetrahydrofuran was obtained by distillation from
Merck 4 Š molecular sieves. 1,2-Dimethoxyethane was purchased from
Acros and purified by distillation. 4-Dimethylaminopyridine was ob-
tained from Aldrich and was used as stock solution in distilled dioxane
containing molecular sieves (4) Š). Phosgene was purchased from Fluka
urea formation) in water (200 mL), which was purged with nitrogen gas
for 0.5 h prior to use. After addition of the isocyanate the mixture was
stirred at 908Cunder argon for 0.5 h and then concentrated in vacuo to
remove the dioxane. The aqueous residue was extracted with CH2Cl2 (3”
75 mL). The combined organic layers were dried over MgSO4, filtered
and concentrated in vacuo. Under argon the residue was mixed with a
solution of NaOH (8.0 g, 0.20 mol) in water (100 mL) and dioxane
(40 mL), which was purged with nitrogen for 30 minutes before use. The
stirred reaction mixture was heated under reflux for 3 d to hydrolyze the
small amount of urea present in the mixture. Then, the mixture was al-
lowed to reach room temperature and brine (10 mL) was added. Subse-
quently, the mixture was extracted with CH2Cl2 (3”75 mL), the com-
bined organic layers dried over MgSO4 and the suspension filtered. Con-
centration of the filtrate in vacuo gave 9 (2.169 g, 2.447 mmol, 97%) as a
thick brownish oil that was used as such. Rf =0.41 (silica gel, 1,2-dime-
1
as a 20 wt% solution in toluene. H and 13CNMR spectra were recorded
on a Varian Mercury, 400 MHz for 1H NMR and 100 MHz for 13CNMR,
1
or on a Varian Gemini, 300 MHz for H NMR and 75 MHz for 13CNMR.
Proton chemical shifts are reported in ppm downfield from tetramethylsi-
lane (TMS) and carbon chemical shifts in ppm downfield from TMS
using the resonance of the deuterated solvent as internal standard. IR
spectra were obtained using a Perkin–Elmer Spectrum One ATR-FTIR
machine. UV/vis spectra were measured on a Perkin–Elmer Lambda 40
spectrometer, using (HELMA) quartz cuvettes (path length 1 cm). Circu-
lar dichroism spectra were recorded on a Jasco J600 equipped with a
Jasco PTC-348WI temperature controller. All e and De values were cal-
culated per mole monomeric phthalimide units. Matrix assisted laser de-
sorption/ionization mass spectra were obtained using a-cyano-4-hydroxy-
cinnamic acid as the matrix on a PerSeptive Biosystems Voyager-DE
PRO spectrometer. Elemental analyses were carried out using a Perkin–
Elmer 2400. All moisture sensitive reactions were performed under an at-
mosphere of dry argon. Analytical thin layer chromatography was per-
formed on Kieselgel F-254 precoated silica gel plates. Visualization was
accomplished with UV light. Column chromatography was carried out on
Merck silica gel 60 (70–230 mesh or 230–400 mesh ASTM). GPCmeas-
urements on the oligomeric mixtures were performed on a mixed D
thoxyethane); HPLC(PDA detector):
tR =2.33 min, purity ~97%.
1H NMR (400 MHz, CDCl3, 258C): d=5.93 (s, 2H, a), 3.99 (m, 2H, b),
3.92 (m, 1H, c), 3.85–3.69 (12H, d), 3.67–3.61 (36H, e), 3.58–3.53 (6H, f),
3.38 (s, 9H, g), 1.28–1.26 ppm (9H, h); 13CNMR (50 MHz, CDCl
,
3
258C): d=153.4 (C1), 143.2 (C2), 130.7 (C3), 94.8 (C4), 76.8 (C5), 75.2
(C6), 74.6 (C7), 72.8 (C8), 72.1 (C9), 71.1–70.7 (C10), 69.0 (C11), 68.7
(C12), 59.3 (C13), 18.0–17.8 ppm (C14); FT-IR (ATR): n˜ = 3362, 2870,
2160, 1608, 1507, 1453, 1374, 1350, 1294, 1237, 1200, 1096, 1025, 945, 849,
737 cmꢀ1; MALDI-TOF MS: m/z (%): calcd for: 885.53; found: 885.73
(100) [M]+, 908.72 (55) [M+Na]+, 924.74 (10) [M+K]+; Elemental analy-
sis calcd (%) for C42H79NO18: C56.93, H 8.99, N 1.58; found: C56.61, H
9.00, N 1.53.
column (PL gel 5 mm, 200–400000 gmolꢀ1), with a flow of 1 mLminꢀ1
,
and chloroform as the eluting solvent. The injection volume was 50 mL
and UV detection (254 or 310 nm) was applied. Molecular weights and
polydispersity indices were calculated from a polystyrene standard.
3,4,5-Tris[(2S)-2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)pro-
poxy]benzoyl azide (7): Under argon, gallic acid chloride 6[26] (7.88 g,
8.441 mmol) was dissolved in THF (23 mL) and slowly added to an ice-
cold suspension of NaN3 (10.09 g, 0.155 mol) in water (23 mL) keeping
3,6-Bis(acetylamino)-N-{3,4,5-tris[(2S)-2-(2-{2-[2-(2-methoxyethoxy)-
ethoxy]ethoxy}ethoxy)propoxy]phenyl}phthalimide (11): Under argon,
Chem. Eur. J. 2006, 12, 6129 – 6137
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6135

E. W. Meijer et al.
125.5 (C6), 108.3 (C7), 105.8 (C8), 76.3 (C9), 75.0 (C10), 74.3 (C11), 72.6
(C12), 71.9 (C13), 70.8–70.4 (C14), 68.8 (C15), 68.5 (C16), 59.0 (C17),
17.7–17.5 ppm (C18); FT-IR (ATR): n˜ = 3465, 3355, 2871, 2179, 1732,
1688, 1656, 1619, 1595, 1494, 1434, 1374, 1350, 1292, 1242, 1190, 1094,
1025, 941, 829, 767, 730, 706 cmꢀ1; UV/Vis (H2O, 4.21”10ꢀ5 molLꢀ1): lmax
(e) = 260 (13100), 448 nm (7400 molꢀ1 dmꢀ3 cmꢀ1); MALDI-TOF MS:
m/z (%): calcd for: 1045.56, found 1045.47 (8) [M]+, 1068.47 (100)
[M+Na]+, 1084.45 (13) [M+K]+; elemental analysis calcd (%) for
C50H83N3O20: C57.40, H 8.00, N 4.02; found: C57.48, H 8.14, N 4.02.
3,6-Diisocyanato-N-{3,4,5-tris[(2S)-2-(2-{2-[2-(2-methoxyethoxy)ethoxy]-
ethoxy}ethoxy)propoxy]phenyl}phthalimide (2): Under argon, 3,6-diami-
3,6-bis(acetylamino)phthalic anhydride 10[25] (0.377 g, 1.438 mmol) and
amine 9 (1.333 g, 1.504 mmol) were mixed in dioxane (7.2 mL). After
17 h reflux the mixture was concentrated in vacuo and the remaining resi-
due was purified by column chromatography (silica gel, 25 vol% heptane
in 1,2-dimethoxyethane) yielding 11 (1.457 g, 1.289 mmol, 90%) as a
yellow thick oil. Rf =0.31 (silica gel, 20 vol% heptane in 1,2-dimethoxy-
ethane). tR =8.38 min (GPC, mixed D, 254 nm, CHCl3). 1H NMR
(400 MHz, CDCl3, 258C): d=9.38 (s, 2H, a), 8.81 (s, 2H, b), 6.62 (s, 2H,
c), 4.10–4.02 (3H, d), 3.90–3.81 (6H, e), 3.77–3.69 (6H, f), 3.68–3.62
(36H, g), 3.56–3.52 (6H, h), 3.39–3.37 (s, 9H, i), 2.26 (s, 6H, j), 1.32–
1.29 ppm (9H, k); 13CNMR (50 MHz, CDCl 3, 258C): d=169.0 (C1),
168.3 (C2), 152.9 (C3), 138.0 (C4), 133.3 (C5), 127.5 (C6), 126.0 (C7),
113.8 (C8), 105.6 (C9), 76.4 (C10), 75.1 (C11), 74.4 (C12), 72.8 (C13),
72.0 (C14), 70.9–70.5 (C15), 68.9 (C16), 68.6 (C17), 59.1 (C18), 24.9
(C19), 17.7–17.5 ppm (C20); FT-IR (ATR): n˜ = 3363, 2871, 2184, 1754,
1699, 1637, 1616, 1548, 1598, 1491, 1438, 1393, 1369, 1297, 1239, 1200,
1099, 1016, 978, 906, 845, 762, 688, 665 cmꢀ1; UV/Vis (H2O, 4.87”
nophthalimide
1 (0.157 g, 0.150 mmol) was dissolved in dry toluene
(2.0 mL). A phosgene solution (3.75 mL, 7.09 mmol of a 20 w% solution
in PhCH3) was slowly added to the reaction mixture under continuous
stirring. After addition the reaction mixture was stirred for 2.5 h at room
temperature. Subsequent concentration in vacuo gave 2 (0.165 g, ~100%)
as a thick dark-yellow oil that was used as such. 1H NMR (400 MHz,
CDCl3, 258C): d=7.29 (s, 2H, a), 6.62 (s, 2H, b), 4.08–4.02 (3H, c), 3.89–
3.69 (12H, d), 3.69–3.59 (36H, e), 3.58–3.52 (6H, f), 3.38–3.37 (9H, g),
1.31–1.28 ppm (9H, h); FT-IR (ATR): n˜ = 2872, 2246, 1769, 1717, 1597,
10ꢀ5 molLꢀ1): lmax (e)
=
259 (24000), 367 nm (4500 molꢀ1 dmꢀ3 cmꢀ1);
MALDI-TOF MS: m/z (%): calcd for: 1152.57, found: 1152.65 (100)
[M+Na]+, 1169.61 (22) [M+K]+; elemental analysis calcd (%) for
C54H87N3O22: C57.38, H 7.76, N 3.72; found: C57.41, H 7.78, N 3.61.
1505, 1539, 1437, 1370, 1299, 1239, 1181, 1111, 902, 847, 759, 704 cmꢀ1
.
3,6-Diamino-N-{3,4,5-tris[(2S)-2-(2-{2-[2-(2-methoxyethoxy)ethoxy]-
ethoxy}ethoxy)propoxy]phenyl}phthalimide (1): Under argon, 3,6-bis-
(acetylamino)phthalimide 11 (1.247 g, 1.104 mmol) was dissolved in a
Amino terminated oligo(3-ureido-N-{3,4,5-tris[(2S)-2-(2-{2-[2-(2-methoxy-
ethoxy)ethoxy]ethoxy}ethoxy)propoxy]phenyl}phthalimide-N’,6-diyl) (3):
Under argon,
a
solution of 3,6-diaminophthalimide
1
(0.157 g,
0.152 mmol) and dry 4-dimethylaminopyridine (DMAP) (18.3 mg,
0.15 mmol) in dioxane (0.5 mL) was added to 3,6-diisocyanatophthali-
mide 2 (0.165 g, 0.150 mmol). The reaction mixture was heated to reflux
overnight under continuous stirring followed by evaporation of the sol-
vent in vacuo. The DMAP was removed by column chromatography
(silica gel, 10 vol% MeOH in 1,2-dimethoxyethane) yielding a yellow-
orange sticky solid (0.316 g, 95%). A second separation by column chro-
matography (silica gel, gradient from 1 to 10 vol% MeOH in 1,2-dime-
thoxyethane) afforded 3a (0.153 g) containing the shorter oligomers,
GPC(HCCl
, mixed-E, 310 nm), tR (min)=max. 5.69 min; and 3b
3
mixture of dioxane, water and HCl (12m) (4.2 mL/1.1 mL/0.7 mL). The
stirred reaction mixture was heated at 908Cfor 45 min, and then poured
into ice-water. Subsequently, satd aq NaHCO3 solution and brine were
added, adjusting the pH to 8. The
(0.140 g) containing the long oligomers as dark yellow sticky solids. 3b;
GPC (CHCl3, mixed-E, 310 nm), tR (min)=max. 4.73 and max. 4.35, tail-
ing. 1H NMR (400 MHz, CDCl3, 258C): d=9.03–8.70 ((4n+2)H, a and b),
aqueous mixture was then extracted
with CH2Cl2 (4”75 mL), the com-
bined organic layers were dried over
MgSO4 and the filtrate concentrated
in vacuo. The residue was purified by
column chromatography (silica gel,
10 vol% heptane in 1,2-dimethoxy-
ethane, Rf =0.3) yielding 1 (1.150 g,
1.099 mmol, 95%) as an orange thick
oil. tR =8.58 min (GPC, mixed D,
254 nm,
(HPLC, PDA), purity
CHCl3);
tR =8.93 min
97%;
>
1H NMR (400 MHz, CDCl3, 258C):
d=6.81 (s, 2H, a), 6.65 (s, 2H, b),
5.00 (s, 4H, c), 4.08–4.02 (3H, d),
3.90–3.78 (6H, e), 3.78–3.68 (6H, f),
3.68–3.59 (36H, g), 3.56–3.53 (6H, h),
3.38–3.36 (s, 9H, i), 1.31–1.27 ppm (d,
9H, j); 13CNMR (50 MHz, CDCl
,
3
258C): d=168.4 (C1), 152.5 (C2),
138.8 (C3), 137.1 (C4), 127.5 (C5),
6136
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 6129 – 6137

Foldamers
FULL PAPER
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A
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Received: April 4, 2006
Published online: June 23, 2006
Chem. Eur. J. 2006, 12, 6129 – 6137
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6137