Directional Threading and Sliding of a Dissymmetrical Foldamer Helix on Dissymmetrical Axles

Article abstract of DOI:10.1002/anie.201813125

We have investigated the self-assembly of a dissymmetrical aromatic oligoamide helix on linear amido-carbamate rods. A dissymmetric sequence bearing two differentiated ends is able to wrap around dissymmetric dumbbell guest molecules. Structural and therm

Full text of DOI:10.1002/anie.201813125

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Accepted Article
Title: Directional Threading and Sliding of a Dissymmetrical Foldamer
Helix on Dissymmetrical Axles
Authors: Xiang Wang, Quan Gan, Barbabara Wicher, Yann Ferrand,
and Ivan Huc
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201813125
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10.1002/anie.201813125
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Directional Threading and Sliding of a Dissymmetrical Foldamer
Helix on Dissymmetrical Axles
Xiang Wang,[a] Quan Gan,[a] Barbara Wicher,[b] Yann Ferrand,*[a] and Ivan Huc*[a,c]
Abstract: We have investigated the self-assembly of
a
for the definition of a front and a rear of the shuttle, and also of
frontward and backward motions. By extension, one could
imagine chemical transformations that would occur exclusively at
the rear and favor forward motion, for example via a ratcheting
mechanism induced by processive catalysis (i.e. the installation
of stoppers on the rod), or via a self-propelling mechanism.[9] As
preliminary steps towards this goal, we herein present a
dissymmetrical helix-rod host-guest system with a very strong
thermodynamic preference for a particular relative helix/rod
orientation (Figure 1a). We also show that kinetic bias in threading
the rod into the helix cavity allows for the implementation of the
directional motion of an oriented helix along an oriented rod.
We have previously introduced multi-turn helical aromatic
oligoamide foldamers that form stable pseudo-rotaxane
complexes, also termed foldaxanes, around rod-like guests.[10,11]
Helices based on 7-amino-8-fluoro-2-quinolinecarboxylic acid
oligoamides such as 1 possess a tubular cavity that can
accommodate ,-alkanediamine-derived dicarbamate guests
and slide long them. Threading and sliding of these helices along
guests are much faster than their direct unwinding and rewinding,
allowing for the design of kinetically favored supramolecular
pathways depending on whether bulk too large to pass through
the helix cavity is on the way or not.[12] Solution and solid state
data demonstrated that helix-rod association is mainly driven by
hydrogen bonds between carbamate carbonyl groups on the rods
and 2,6-pyridinedicarboxamide protons on the helix carbamate
cleft (CC in Figure 1b). This interaction should in principle make it
possible to bind rods with other carbonyl-containing groups than
carbamates. However, oligomers such as 1 do not bind to diamide
rods or to ,-alkanediol-derived dicarbamate rods, i.e. when the
orientation of the carbamates has been reverted. A closer look at
earlier crystal structures[11a] pointed to secondary hydrogen
bonding between the terminal pivaloyl amide proton and the
carbamate sp3 oxygen atom as being responsible for this
selectivity (Figure 1c). This observation hinted at the possibility to
replace the foldamer terminal amide NH donor by a hydrogen
acceptor and change guest selectivity, eventually giving access
to dissymmetrical guest binding.
dissymmetrical aromatic oligoamide helix on linear amido-carbamate
rods. A dissymmetric sequence bearing two differentiated ends is able
to wrap around dissymmetric dumbbell guest molecules. Structural
and thermodynamic investigations allowed us to decipher the mode
of binding of the helix that can bind specifically to the amide and
carbamate groups of the rod. In parallel kinetic studies of threading
1
and sliding of the helix along linear axles were also monitored by H
NMR. Results show that threading of a dissymmetrical host can be
kinetically biased by the nature of the guest terminus allowing a
preferential sense of sliding of the helix. The study presented below
further demonstrates the valuable potential of foldaxanes to combine
designed molecular recognition patterns with fine control of self-
assembly kinetics to conceive complex supramolecular events.
Inspired by the molecular biomachinery, chemists have long
tried to reproduce the controlled directional translations observed,
for example, in the motion of DNA polymerases along DNA
templates or of kinesin proteins along microtubules. Abundant
literature thus exists on the translation of macrocycles on rod-like
molecular axles.[1] Miniature artificial walkers have also been
described.[2,3] Translation directionality can be imposed when
changing the preferred position of macrocycles on a molecular rod
by means of an external stimulus. Biased Brownian motion then
allows the system to relax to its new preferred state leading to a
net flux from one station to the other.[4] Reverting the preferred
position back to its original state leads to a reversal of translation
and shuttling is observed.[5] Besides the directionality of the
motion, the relative inherent orientation of the axle and the
component that slides along it is an intriguing aspect that has less
often been addressed.[6-8] This stems from the fact that most
macrocycles that have been used as molecular shuttles have a
symmetrical structure. In contrast dissymmetrical macrocycles,
e.g. cone-shaped calixarenes[6] cylodextrins[7] and others,[8] may
thread onto a dissymmetrical axle. The lack of symmetry allows
[a]
X. Wang, Q. Gan, Dr. Y. Ferrand, Dr. I. Huc
CBMN (UMR5248), Univ. Bordeaux – CNRS – IPB
Institut Européen de Chimie et Biologie
2 rue Escarpit, 33600 Pessac (France)
E-mail: y.ferrand@iecb.u-bordeaux.fr
The AC segment was designed for this purpose (Figure 1b).
For this, the terminal pyridine ring of CC was mutated into a
naphthyridine[13] unit with the hope to create repulsive
electrostatic interactions with the carbamate sp3 oxygen atom of
the rod (Figure 1d). By analogy with 1, sequence 2 comprising a
CC and an AC terminal segments was thus designed and
synthesized (see the supporting information). To ascertain our
hypothesis, dumbbell shaped guests 3-9 including both amide
and carbamate groups were also prepared (Figure 1e). Titrations
between single helix 2 and rods 3-9 were monitored by 1H NMR
in CDCl3 and, in some cases, revealed the emergence of a single
new species in slow exchange on the NMR time scale typical of
foldaxane formation (Figures S12-S17). As previously observed
[b]
[c]
Dr. B. Wicher
Department of Chemical Technology of Drugs, Poznan University of
Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland.
Prof. I. Huc
Department Pharmazie and Center for Integrated Protein Science
Ludwig-Maximilians-Universität
Butenandtstr. 5-13, D-81377 München (Germany)
E-mail: ivan.huc@cup.lmu.de
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Figure 1. Host-guest components and assembly. (a) Schematic representation of the complex formation between a dissymmetric single helix and a dissymmetric
dumbbell guest. (b) Formula of 1 and 2. Binding mode of a carbamate in a carbamate cleft (c) or in an amide cleft (red). The latter is destabilized by electrostatic
repulsion (green double arrow). (e) Formula of dumbbell guests 3-9 and their association constants (Ka) with 2 at 323K.
Figure 2. Excerpts of 400 MHz 1H NMR spectra (323K in CDCl3) showing the amide resonances of 2 at 1 mM (a) and in the presence of 3 equiv. of 5 after: (b) 5
min; (c) 60 min. and (d) at equilibrium. Amide signals of the free single helix 2, matching and mismatching complexes 25 are marked with empty diamond, empty
circles and black crosses, respectively. (e,f) Side views of 25 solid state structure analyzed by single crystal X-ray crystallography. In (e) the helix and the dumbbell
rod are shown in CPK representation. In (f) the helix and the rod are shown as tube representation. The latter is covered by a transparent isosurface representing
its volume. (g,h) Views from above and below showing the binding modes between AC and CC and the amide and carbamate groups of the rods shown in red and
blue colors, respectively. In (e-h) CC and AC and the central helical segment are colored in blue, red and grey, respectively. Side chains (OiBu groups) and included
solvent molecules have been removed for clarity.
for binding studies between 1 and dicarbamate rods,[14] high
foldaxane stability with 2 requires a match between the helix and
the rod lengths (Figure 1e). The highest affinity constant was
obtained for rod 5 bearing seven methylene units between its two
binding anchors (Ka = 2.8 104 M-1).
Because of the dumbbell shape of the guests, host-guest
complex formation requires the winding of the helix around the
rod and this process is slow (Figure 1a). Monitoring of the binding
of 5 by 2 at 323 K (i.e. under slight heating) revealed the
progressive disappearance of the empty host, the concomitant
emergence of the thermodynamically favored complex and also
the transient appearance of another species (Figure 2a-2d). This
is consistent with the initial formation of both a matching and a
mismatching complex followed by the progressive disappearance
of the less stable mismatching complex. At equilibrium, the minor
species has disappeared showing quantitative bias as far as NMR
can detect. Remarkably, the initial proportion of the mismatching
complex is small (less than 6 %), indicating that this species is not
only less stable, i.e. that it has a larger dissociation rate constant,
but also that it has a slower formation rate. Thus, upon winding
around the rod, the helix finds a faster pathway towards the most
stable complex.
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Figure 3. (a) Formula of rods 10-12. Schematic representations of: (b) the biased threading of a dissymmetrical single helix along a dissymmetrical rod and (c) the
threading followed by the unidirectional sliding of a dissymmetrical single helix along a double station rod. Excerpts from the 700 MHz 1H NMR spectra (CDCl3)
showing the amide resonances of 2 at 1 mM alone (d,h,l), and in the presence of: 10 (3 equiv., 273K) after 7 min. (e); 30 min (f); and at equilibrium (g); 11 (3 equiv. ,
273K) after 7 min. (i); 30 min. (j); and at equilibrium (k); 12 (3 equiv. at 283K) after 7 min (m); 120 min (n); and at equilibrium (o). Signals of the free double helix,
the matching and mismatching complexes on the single station rods are marked with empty diamonds, empty circles and black crosses, respectively. Amide signals
of the matching complex at -station and -station, are marked with empty and black circles, respectively.
Structural information on 25 and in particular its assignment to
a matching complex was gathered using X-ray crystallography.
Single crystals were obtained by slow diffusion of n-hexane into a
chloroform solution. The structure revealed that the single helix
can fully wrap around the alkyl segment of the rod whose diphenyl
groups protrude from both apertures of the foldamer cavity (Figure
2e, 2f). The structure fully validates the initial hypothesis that the
newly designed AC binds to the amide group whereas the CC
hydrogen bonds to the carbamate of the guest (Figure 2g, 2h).
These favorable interactions and the repulsions that are expected
to occur in the mismatching complex are strong enough to
achieve quantitative selectivity in solution.
Foldaxane formation was then investigated with single
station rods 10 and 11 possessing a bulky stopper at one end only
(Figure 3a). This design allows for the unhindered threading of the
other end of each axle into the helix at rates much faster than the
winding of the helix onto binding stations (Figure 3b). Threading
is actually so fast that an oligoethylene glycol chain (PEG750,
M.W. = 750 g/mol) had to be introduced and the samples cooled
to 273 K to slow it down and observe intermediates before
equilibrium is reached. Rods 10 and 11 were used to study a
possible preferred direction of threading. They both have a
methoxy-terminated PEG chain and differ mainly in the position of
amide and carbamate groups: the respective matching and
mismatching complexes on these two rods have opposite
orientations. For both rods, the two complexes are easily
distinguished by H NMR. In the case of 10, some mismatching
1
complex was detected but, even at very early stages of the
threading, its proportion remained small (< 20%). At equilibrium
the mismatching complex had disappeared (Figure 3d-3g). This
indicates that threading through the CC extremity of the helix, i.e.
threading conducive to the matching complex, has been
kinetically favored. In contrast, threading of 11 first produces a
majority of mismatching complex that eventually quantitatively
converts to the matching complex (Figure 3h-3k), confirming the
faster threading through the CC extremity, even when it is
conducive to a mismatching complex. Additional rods with various
termini were prepared (compounds 13-16 in the supporting
information). Monitoring foldaxane formation kinetics hints to
threading being inherently favored at the CC terminus regardless
of the rod functionality (Figures S22-S30). The rate limiting step
in the threading process may involve favorable conformations of
the helix, desolvation and interactions at the helix entrance.
However, there is no information on which of these parameter is
critical and why threading may be favored at the CC terminus.
We then prepared 12 to achieve a fully controlled oriented
threading. This new rod bears two identical - and -binding
stations (Figure 3a) positioned on both sides of a PEG600 spacer.
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In summary, this study demonstrates that helical foldamers
can be used to design selective molecular recognition patterns of
rod-like guests and combine them with fine control of self-
assembly kinetics to promote directional sliding processes in
which both the rod and the helix have a defined orientation. We
showed that a biased threading of a dissymmetrical helix can be
programmed by varying the structure of the axle. We also
demonstrated that the kinetic segregation of the helix threading
and unthreading from its sliding further along the axle made
possible a full control over the helix orientation on the rod. Precise
anisotropic arrangements as those shown could give access to
(poly)foldaxanes with potential use in processive catalysis or
transport. Progress in these directions are currently being made
in our laborotary and will be reported in due course.
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Acknowledgements
This work was supported by the China Scholarship Council (pre-
doctoral fellowship to X.W.), the Conseil Régional d’Aquitaine
(Q.G.) and by grant ANR-17-CE07-0014. The authors thank Brice
Kauffmann (IECB-UMS 3033) for his help during data collection
and resolution of the crystal structures. this work has benefited
from the facilities and expertises of the Biophysical and
Structural Chemistry plateform (BPCS) at IECB, CNRS
UMS3033, Inserm US001, Bordeaux University.
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Keywords: foldamer • molecular recognition • foldaxane •
directional motion • molecular shuttle
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Xiang Wang, Quan Gan, Barbara Wicher,
Yann Ferrand,* Ivan Huc*
Page No. – Page No.
Directional Threading and Sliding of a
Dissymmetrical Foldamer Helix on
Dissymmetrical Axles
A foldamer helix that can thread and slide directionally on a dissymmetrical linear
axle.
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