Intrastrand foldamer crosslinking by reductive amination

Article abstract of DOI:10.1002/pola.23848

A series of m-phenylene ethynylene (mPE) foldamers were crosslinked in their helical conformation using a reductive amination-based strategy. This was accomplished by placing aldehyde moieties in the backbone of the oligomer at specific residues, which al

Full text of DOI:10.1002/pola.23848

Intrastrand Foldamer Crosslinking by Reductive Amination
RONALD A. SMALDONE,1 EN-CHI LIN,1 JEFFREY S. MOORE1,2
1Department of Chemistry and The Beckman Institute for Advanced Science and Technology, University of Illinois, Urbana,
Illinois 61801
2Department of Materials Science and Engineering and The Beckman Institute for Advanced Science and Technology, University
of Illinois, Urbana, Illinois 61801
Received 19 October 2009; accepted 23 November 2009
DOI: 10.1002/pola.23848
Published online in Wiley InterScience (www.interscience.wiley.com).
ABSTRACT: A series of m-phenylene ethynylene (mPE)
foldamers were crosslinked in their helical conformation using a
reductive amination-based strategy. This was accomplished by
placing aldehyde moieties in the backbone of the oligomer at
specific residues, which allowed a diamine crosslinker to cova-
lently link the helical loops together. Three different foldamers
with crosslinks placed at different locations in the backbone
were synthesized and characterized by mass spectrometry, 1H
NMR, and gel permeation chromatography. The effect of the
crosslinking on the stability of the folded state was evaluated
through solvent denaturation studies. These studies show a
reduction in the oligomer’s ability to unfold of up to 30% relative
to an unmodified mPE oligomer of the same length in solvents
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that promote unfolding. 2010 Wiley Periodicals, Inc. J Polym
Sci Part A: Polym Chem 48: 927–935, 2010
KEYWORDS: crosslinking; oligomers; self-organization; supra-
molecular structures
INTRODUCTION In biological molecules, stabilization of the
secondary structure is critical for their ability to fold and
function correctly.1–6 This stabilization can come from the
arrangement of nonpolar functional groups to minimize
unfavorable solvent contacts and incorporation of salt
bridges, hydrogen bonds, or covalent crosslinks that are
most commonly found as cys-cys disulfide linkages.7 Syn-
thetic covalent crosslinks have also been used to stabilize
the helical structure of peptides and to improve their life-
time in vivo.8–10 Similarly, the flexibility and structural
robustness of supramolecular host molecules can affect their
molecular recognition properties and their reactive behav-
ior.11 Developing effective methods for controlling the reac-
tive and structural properties of these synthetic systems has
been a goal of supramolecular chemists for several de-
cades.12–16
backbone could affect its reactivity with bound guests. To
more rigorously test the contribution of conformational flexi-
bility to the observed behavior, it was necessary to develop
foldamers with restricted conformational freedom.
One other approach for covalently crosslinking mPE fol-
damers using UV light to promote a [2 þ 2] cycloaddition
has been reported in the literature. However, this method
results in significant decomposition of the foldamer and
poor crosslinking efficiency.27 The method was applied to
polydisperse oligomers and is unlikely to be suitable for syn-
thesizing discrete oligomers needed in reactivity or molecu-
lar recognition studies. Previously, our group used reductive
amination chemistry to form two-dimensional molecular lad-
ders with mPE oligomers.28 Because mPE foldamers can be
made using an iterative solid-phase methodology, they are
amenable to rapid, modular synthesis, and precise incorpora-
tion of crosslinking sites by sequence design.29 Using these
methods, we synthesized several crosslinkable mPE fol-
damers and tested a reductive amination-based crosslinking
strategy for its ability to restrict the unfolding of the helical
conformation.
m-Phenylene ethynylene (mPE) foldamers are a class of
amphiphilic oligomers that are capable of folding into a sol-
vophobically driven helical conformation. This group and
others have studied these molecules for their molecular rec-
ognition and reactive properties.17–26 Our group has investi-
gated one particular reactive property, known as reactive
sieving,17 in which functionalized mPE oligomers are capable
of differentiating between reactive substrates based on
subtle differences in the guest’s structure when it is
bounded in the cavity of the foldamer. Although the exact na-
ture of this selectivity is not completely understood, we
hypothesized that the flexible nature of the mPE foldamer
OLIGOMER DESIGN AND SYNTHESIS
Several strategies were considered with respect to the place-
ment of the crosslink junction (illustrated in Fig. 1). A single
crosslink can be placed into the backbone to lock only one
loop of the helix (left) or to span several turns (right).
Additional Supporting Information may be found in the online version of this article. Correspondence to: J. S. Moore (E-mail: jsmoore@illinois.edu)
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oligomers 1–3. The coupled products were purified by prep-
arative-scale GPC.
CROSSLINKING OPTIMIZATION AND CHARACTERIZATION
A deprotected oligomer (1–3) was dissolved in solution at a
concentration of ꢀ5 lM along with 0.1 mg of scandium(III)-
triflate, which acts as a catalyst for the formation of the
imine. The dilute conditions were used to prevent aggrega-
tion of the foldamer, thus reducing the opportunities for
interstrand coupling. A diamine was then added to the mix-
ture and allowed to stir for 2.5 h before the concomitant
imines were reduced using sodium cyanoborohydride in
large excess (100 equiv). The reduction was allowed to pro-
ceed overnight at room temperature. The solvents were then
removed under vacuum, and the residue was dissolved in
chloroform and washed with water to remove any aqueous
soluble material from the sample. The residue obtained from
evaporating the chloroform fraction was analyzed by matrix-
assisted laser desorption ionization mass spectrometry
(MALDI-MS) using the 2-(40-hydroxyphenylazo)benzoic acid
matrix.
FIGURE 1 Cartoon illustrations of potential mPE foldamer
crosslinking designs.
Multiple crosslinks could also be used to make the structure
even more rigid (middle). To test each of these possibilities
(Fig. 2), three sequences were synthesized and subjected to
a reductive amination crosslinking.
Monomers containing an aldehyde moiety in place of the
typical Tg-ester group were used to introduce the crosslink
junction. The oligomer sequence determines the relative
location of crosslinkable monomers, and these sequences are
constructed efficiently using our established solid-phase
methods along with a fragment coupling approach The syn-
theses of the aldehyde monomers and oligomers 1–3 are
shown in Schemes 1 and 2, respectively. The aldehyde mono-
mer synthesis was adapted from monomer syntheses that
have been previously reported by this group.28 Monomers 7
and 10 are used in the solid-phase synthesis.
Previous studies indicate that the pitch of an mPE oligomer
is ꢀ3.6 Å,31 and computational models suggested that the
optimal crosslinker to span one turn would be an ethane or
propane diamine. Therefore, a series of diamines that met
these criteria were tested under reductive amination condi-
tions (sodium cyanoborohydride). In addition to finding the
correct diamine crosslinker, a set of optimal reaction condi-
tions for the reductive amination were also needed. A series
of small-scale reactions were performed, and the crude
products were analyzed by MALDI-MS. Although mass
Hexamers 11a–c were made using solid-phase synthesis and
then coupled to difunctional monomer unit 12 through Sono-
gashira coupling.30 Deprotection of the aldehydes was
achieved using p-toluenesulfonic acid in acetone to give
FIGURE 2 Oligomer sequences containing aldehyde functionality that can be used to test each crosslinking strategy.
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SCHEME 1 Synthesis of protected aldehyde monomers.
spectrometry is not a quantitative method for determining
the absolute composition of a mixture, it was used in this
case to determine whether the given reaction conditions
were able to produce the crosslinked product.
optimal, a three carbon spacer was the correct length to
bridge a single turn of the helix. Comparable aromatic
spacers (e.g., 1,2-diaminobenzene and 1,3-diaminobenzene)
did not give any crosslinked product. Longer diamines (e.g.,
1,4-butanediamine) were not tested for the single-loop cross-
linking strategy because of the large deformations observed
in the computational models of the folded structure.
Initially, 1,2-diaminoethane and 1,3-diamino-2,2-dimethylpro-
pane were tested as crosslinkers for 1, and the results are
shown below in Figure 3.32 A number of partially aminated
but uncrosslinked products were observed using 1,2-diami-
noethane, indicating that a two carbon crosslinker may be
too short. Using 1,3-diamino-2,2-dimethylpropane, some
uncrosslinked material was observed along with starting ma-
terial, and the partially aminated product was not observed.
This indicated that when the reaction conditions were not
Once we determined that 1,3-diamino-2,2-dimethylpropane
was the ideal length crosslinker for a single helical turn, the
reaction conditions were optimized. Because some uncross-
linked material was still visible by MS, we added chloroform
(as a cosolvent that promotes the unfolded conformation of
the mPE oligomers) in an attempt to relax the conformation
SCHEME 2 Synthesis of crosslinkable oligomers 1–3.
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FIGURE 3 Spectra of 1 following
reductive amination conditions
with
ethane
and
propane
diamines.
and impart flexibility to the folded structure. The crosslink-
ing reaction was carried out on oligomer 1 using 1,3-dia-
mino-2,2-dimethylpropane using solvent mixtures of 50:50
and 90:10 acetonitrile/chloroform. Reactions that were per-
formed in 100% chloroform did not give any of the cross-
linked products. The resulting mass spectral data are shown
below in Figure 4. The 90:10 mixture showed very little
starting material and no observable amounts of partially
aminated products.
tions (Fig. 6). Although both diamines gave crosslinked prod-
uct, the five carbon spacers appear to be better suited for
crosslinking across two loops of the folded conformation.
Shown in Figure 7 are the final optimized crosslinking condi-
tions used, along with the crosslinked oligomers (13–15)
used to test if the crosslinked architecture offers resistance
toward denaturation. Larger amounts of crosslinked fol-
damers were prepared using the optimized conditions and
purified by preparative gel permeation chromatography
(GPC). Further characterization of the crosslinked oligomers
13–15 was completed using UV–vis spectrophotometry and
GPC. GPC was used to qualitatively determine the presence
of crosslinked material, and UV–vis was used to quantita-
tively determine the ability of the crosslinker to reduce the
unfolding capability of the oligomer.
Using the reaction conditions that were optimized for 1,
oligomer 2 was crosslinked at two positions. Because the
aldehyde moieties on 1 and 2 are in the same relative dis-
tance, further reaction optimization was not performed. The
crosslinked product was observed by mass spectrometry
(Fig. 5). However, some unidentified higher molecular weight
peaks were also present. The first higher molecular weight
peak has a m/z ratio that roughly corresponds to partially
crosslinked structure shown in Figure 5. The other two
peaks are impurities that could not be definitively assigned.
Solvent denaturation titrations have been used previously to
characterize the stability of the folded state of mPE oligo-
mers.21,33 Hence, these experiments were used to determine
the extent of unfolding of crosslinked oligomers compared
with uncrosslinked ones. By varying the polarity of the sol-
vent using different ratios of acetonitrile (folding solvent) to
chloroform (denaturing solvent), the helix transition of the
As crosslinking two loops of the helix in oligomer 3 would
require a longer diamine, 1,4-diaminobutane and 1,5-diami-
nopentane were tested using the optimized reaction condi-
FIGURE 4 MALDI MS spectra of
the crosslinked product for reac-
tions conducted in 50:50 acetoni-
trile/chloroform (left) and 90:10
acetonitrile/chloroform (right).
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FIGURE 5 MALDI-MS chromatogram of doubly crosslinked products of oligomer 2 using 1,3-diamino-2,2-dimethylpropane.
oligomer can be monitored. The ratio of absorbance at 305–
289 nm represents the cisoid versus transoid conformational
equilibrium (Fig. 8). A larger absorbance ratio corresponds
to the unfolded (or transoid) conformation.
the radius of gyration of the molecule, resulting in a shift in
the retention time, which can be seen in the chromatograms
in Figure 10. This shift is discussed in further detail in the
discussion section.
Shown in Figure 9 are the folding titrations for uncross-
linked oligomer 1 and crosslinked oligomers 13–15. A small
shoulder begins to appear in the UV spectrum as the concen-
tration of chloroform increases. This is representative of the
shift in conformation from predominantly cisoid to transoid.
DISCUSSION
The most useful method for quantifying the crosslinker’s
ability to maintain the folded conformation is solvent dena-
turation. Formation of a shoulder in the spectrum with
increasing concentration of chloroform is indicative of
oligomer unfolding. Upon visual analysis of the raw UV spec-
tra for the denaturation studies, crosslinked oligomers 13–
15 do appear to unfold somewhat, but the shoulder
GPC analysis of both the crosslinked and uncrosslinked ma-
terial was performed. Each chromatogram shows the uncros-
slinked starting material with its corresponding crosslinked
analog (Fig. 10). Crosslinking of the foldamer should affect
FIGURE 6 MALDI-MS spectrum
of oligomer 3 crosslinked with
1,4-diaminobutane (left) and 1,5-
diaminopentane (right).
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JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
that is typically seen and appears to be more unfolded than
the other oligomers in 100% acetonitrile. It is possible that
the extra crosslink could be destabilizing the folded confor-
mation. However, because this sample could not be com-
pletely purified because of unknown high-molecular-weight
oligomers, we are unable to draw conclusions about this.
GPC can provide a unique method of characterizing the
extent of crosslinking. As mentioned previously, the GPC
traces were collected using THF as a mobile phase, which
does not promote the folded conformation in mPE oligomers.
Because crosslinked foldamers would not have the same ra-
dius of gyration, when unfolded as their uncrosslinked ana-
logs they would appear to be smaller in molecular weight
and therefore have a longer retention time. This behavior is
in fact observed with 13 and 15. Oligomer 13 appears to
have a large amount of uncrosslinked material that overlaps
with starting material 1, followed by a shoulder of what
appears to be material of lower molecular weight, which is
likely the fully crosslinked foldamer 13. The large shoulder
overlapping with 1 indicates that the extent of crosslinking
in this case appears to be relatively poor. This is confirmed
by the presence of some residual benzyl aldehyde proton
FIGURE 7 Optimized reaction conditions for crosslinking and
the crosslinked products (13–15) of oligomers 1–3 that were
used in further analysis.
formation is not as sharp compared with uncrosslinked
oligomer 1. To further quantify this interaction, the relative
fraction of oligomer that is unfolded can be calculated using
eq 1 based on the A305/A289 ratio from the UV spectrum.
This analysis assumes that the samples consist of pure,
crosslinked oligomers. AF is the A305/A289 ratio for oligomer
1 in 100% acetonitrile, AU is the ratio in 100% chloroform,
and A is the A305/A289 ratio of the oligomer being examined
at the given concentration of chloroform in acetonitrile. The
results of this study for oligomer 1 and 13–15 are plotted in
Figure 11.
1
peak in the H NMR for all of the crosslinked oligomers (see
Experimental Section in Supporting Information). Oligomer 3
appears to have undergone a more efficient crosslinking
reaction to give 15, as the smaller molecular weight peak
appears to be larger than the preceding shoulder that corre-
sponds to uncrosslinked material. The GPC analysis of 14
shows a broad, relatively featureless peak adding further evi-
dence that a combination of products, varying in their degree
of crosslinking, were formed by the reductive amination
reaction. Unfortunately, we were unable to separate the
uncrosslinked material from the fully crosslinked using prep-
arative GPC. As these peaks could not be resolved chromato-
graphically, the degree of crosslinking could not be quanti-
fied. Although this reaction was performed under high
dilution conditions, larger molecular weight products still
formed as evidenced by the short, broad peaks with shorter
retention times than the main peaks, which are likely inter-
strand coupling products. Unfortunately, these products
could not be definitively identified, as they were not
observed by MALDI-MS. These higher molecular weight
peaks likely contribute to the lower isolated yields of the
purified oligomers, which ranged from ꢀ20–35% (See Sup-
porting Information for specific crosslinking reaction yields).
AF ꢁ A
fu ¼
:
(1)
AF ꢁ AU
In comparison with the uncrosslinked oligomer 1, the singly
crosslinked foldamers 13 and 15 appear to restrict the
oligomers ability to unfold by ꢀ30%. Surprisingly, crosslink-
ing the oligomer at its ends (15) rather than in the middle
did not provide a significant advantage in terms of reducing
the unfolding capability of the mPE foldamer. It is possible
that both of these oligomers have similar, partially unfolded
structural conformations in chloroform that cannot be distin-
guished by UV–vis.
However, doubly crosslinked oligomer 14 has a much differ-
ent denaturation profile than the other two foldamers. It
does not undergo the expected sigmoidal unfolding process
FIGURE 8 Transoid versus cisoid struc-
tures corresponding to the unfolded and
folded conformations of the mPE oligomer
backbone.
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FIGURE 9 UV–vis solvent denaturation titrations for uncrosslinked oligomer 1 and crosslinked oligomers 13–15.
These impurities could be removed to some degree, although
not completely, using preparative GPC.
i and i þ 7 positions.9 This orientation is analogous to the
placement of aldehyde groups in the backbone of oligomer
15, which are at the i and i þ 13 positions.
Based on these data, crosslinking an oligomer with two
loops (oligomer 15) reduces the unfolding to the same
degree as crosslinking a single loop (13). This behavior is
also observed for the crosslinking of helical peptides. Verdine
and coworkers found that the yield of the crosslinking reac-
tion was highest when the peptide was restricted across the
CONCLUSIONS
In conclusion, we have demonstrated a reductive amination
strategy for crosslinking the backbone of mPE oligomers.
Based on the model studies presented here, it appears that
FIGURE 10 GPC comparison of mPE foldamers 1–3 and their crosslinked analogs 13–15.
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the efficiency of the crosslinking reaction depends not only
on the length of the diamine tether but also on the place-
ment of the crosslink points (i.e., benzyl aldehyde moieties)
in the oligomer sequence. Placing a single crosslink in the
backbone across one turn of the helix provides some helix
stability, but results in a low degree of crosslinking. Adding
an additional staple using this strategy is generally ineffec-
tive both in terms of conversion and rigidifying the folded
structure. The most effective crosslinking strategy, in terms
of both conversion to product and restricting the unfolded
conformation, is to staple the foldamer across two turns of
the helix. This behavior has been observed previously in
peptide crosslinking studies,8,9 and it is interesting that it
appears to be conserved here using an entirely nonbiological
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Future applications of this methodology can include the syn-
thesis of foldamers that are incapable of unfolding entirely
where the folded conformation would remain persistent in
solvents that are known to promote the random coil confor-
mation (i.e., chloroform and methylene chloride). This would
also provide an opportunity to lock in stereochemistry to an
mPE foldamer biased with an excess of either its M or P
twist sense, creating a supramolecular host with a helically
chiral binding site. Chiral bias can be induced through the
use of either a chiral guest molecule or incorporation of chi-
ral elements into the foldamer structure itself.20,23,34,35 Addi-
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be used to systematically explore the effects of host flexibil-
ity on their reactivity with guest molecules.
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30 Since the Tg-ester sidechain that is attached to the mono-
mer in the adjacent loop would obstruct the ability of the dia-
mine crosslinker to reach to the aldehyde handle, it was
deleted from the sequence by using monomer 12b.
were later deleted from the sequence for convenience. These
end groups do not have a measurable effect on the folding
capability of the oligomer and their absence or presence does
not affect the crosslinking reaction.
33 Heemstra, J. M.; Moore, J. S. Chem Commun 2004,
31 Lee, O.; Saven, J. G. J Phys Chem B 2004, 108, 11988–11994.
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32 During the initial studies, oligomer 1 contained trimethyl-
silyl acetylene end groups as an artifact of the solid-phase syn-
thesis (see Ref. 29), resulting in the different m/z ratios
34 Prince, R. B.; Brunsveld, L.; Meijer, E. W.; Moore, J. S.
Angew Chem Int Ed 2000, 39, 228–230.
observed in Figure
3 in comparison with the crosslinked
35 Stone, M. T.; Fox, J. M.; Moore, J. S. Org Lett 2004, 6,
oligomer used in the more detailed studies later on. These
3317–3320.
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