Interplay between a Foldamer Helix and a Macrocycle in a Foldarotaxane Architecture

Article abstract of DOI:10.1002/anie.202100349

The design and synthesis of a novel rotaxane/foldaxane hybrid architecture is reported. The winding of an aromatic oligoamide helix host around a dumbbell-shaped thread-like guest, or axle, already surrounded by a macrocycle was evidenced by NMR spectrosc

Full text of DOI:10.1002/anie.202100349

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 8380–8384
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Rotaxanes
Hot Paper
Interplay between a Foldamer Helix and a Macrocycle in
a Foldarotaxane Architecture
Maxime Gauthier+, Victor Koehler+, Caroline Clavel, Brice Kauffmann, Ivan Huc,
Yann Ferrand,* and Frꢀdꢀric Coutrot*
Abstract: The design and synthesis of a novel rotaxane/
foldaxane hybrid architecture is reported. The winding of an
aromatic oligoamide helix host around a dumbbell-shaped
thread-like guest, or axle, already surrounded by a macrocycle
was evidenced by NMR spectroscopy and X-ray crystallog-
raphy. The process proved to depend on the position of the
macrocycle along the axle and the associated steric hindrance.
The macrocycle thus behaves as a switchable shield that
modulates the affinity of the helix for the axle. Reciprocally, the
foldamer helix acts as a supramolecular auxiliary that com-
partmentalizes the axle. In some cases, the macrocycle is forced
to move along the axle to allow the foldamer to reach its best
recognition site.
encircled axle.[3] Within these so-called “molecular shuttles”,
motion may be triggered by external stimuli, such as solvent
effect,[4] variation of temperature,[5] photo-irradiation,[6]
molecular recognition[7] or the chemical modifications of an
interaction site at the surrounding macrocycle or at the axle.
Here, we introduce an alternative approach whereby the
position of a threaded macrocycle is controlled by a supra-
molecular auxiliary, namely a foldamer helix reversibly
wound around the same axle.
We have previously described that one or several aromatic
foldamer single or double helices may bind to complementary
alkyl-carbamate thread-like guests to form pseudo-rotaxane
architectures named foldaxanes (Figure 1b).[8] Such con-
structs have allowed for the design of molecular pistons in
which the foldamer could slide between two regions of the
thread.[9] Foldaxanes may form by threading a guest devoid of
stoppers,[10] or by winding of the helix around a dumbbell-
shaped guest.[9] We thus devised that a foldaxane may form
when the axle is already encircled by a macrocycle to produce
a three component hybrid assembly (Figure 1c). In the
following, we demonstrate the formation of such “foldaro-
taxanes”.[11] We show that the presence and localization of the
macrocycle modulates the association between the helix and
the axle. Reciprocally, we highlight the use of the foldamer as
a supramolecular auxiliary to compartmentalize[3g,12] the
macrocycle around a region of the thread for which it may
have a lesser affinity.
The axle of our first foldarotaxane target 1ꢀ2-HPF6
(Figure 1 f) possesses recognition groups for both a macro-
cycle and a foldamer single helix. An ammonium moiety
directed the synthesis of the interlocked rotaxane through
hydrogen bonding to the oxygen atoms of a dibenzo-24-
crown-8 macrocycle (DB24C8).[13] The ammonium also
behaved as a pH-responsive binding station for the DB24C8
in the final structure. In addition, the axle comprises two
carbamate moieties that bind to the 2,6-pyridinedicarboxa-
mide pinchers located at both ends of aromatic foldamer helix
1 (Figure 1d).[9] Noteworthy, a spacer of a sufficient length
between the ammonium and the nearest carbamate was
introduced, to prevent that the DB24C8 encircling the
ammonium hinders binding of the foldamer helix to the
carbamates. Within that spacer, an amide moiety may serve as
a secondary binding station for DB24C8:[14] it does not
outcompete the ammonium and plays a role only in depro-
tonated 2 or N-carbamoylated 2-Boc that were subsequently
investigated.
D
uring the past decades, interest for mechanically inter-
locked molecules has continued unabated because their
singular topologies give rise to unique physical and chemical
properties. [2]Rotaxanes consist of an end-capped molecular
axle threaded into a macrocycle (Figure 1a). The two
stoppering extremities of the axle prevent dethreading, and
thus create a mechanical bond that stabilizes the assembly.[1]
Rotaxanesꢀ popularity stems in part from their distinct
chemical reactivity with respect to their free non-interlaced
components.[2] Rotaxanes also enable the implementation of
controlled translating motions of the macrocycle along the
[*] M. Gauthier[+,++], Dr. C. Clavel, Dr. F. Coutrot
Supramolecular Machines and ARchitectures Team, Institut des
Biomolꢀcules Max Mousseron (IBMM) UMR 5247 CNRS; Universitꢀ
de Montpellier; ENSCM, case courrier 1706, Bꢁtiment Chimie (17),
3ꢂme ꢀtage, Facultꢀ des Sciences
Place Eugꢂne Bataillon, 34095 Montpellier cedex 5 (France)
E-mail: frederic.coutrot@umontpellier.fr
Homepage: http://www.glycorotaxane.fr
V. Koehler[+,++], Dr. Y. Ferrand
Institut de Chimie et Biologie des Membranes et Nano-objets CBMN
(UMR5248), Universitꢀ de Bordeaux, CNRS, IPB
2 rue Robert Escarpit, 33600 Pessac (France)
E-mail: y.ferrand@iecb.u-bordeaux.fr
Dr. B. Kauffmann
Universitꢀ de Bordeaux, CNRS, INSERM, UMS3033, IECB
2 rue Robert Escarpit, 33600 Pessac (France)
Prof. I. Huc
Department of Pharmacy and Center for Integrated Protein Science
Ludwig-Maximilians-Universitꢃt
Butenandtstr. 5–13, 81377 Mꢄnchen (Germany)
[+] These authors contributed equally to this work.
++] Co-first authors
[
Foldarotaxanes were formed via the winding of 1 around
the axle of various [2]rotaxanes. The first targeted rotaxane 2-
HPF6 was synthesized through a straightforward, ester
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202100349.
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Figure 1. Representation of: a) a rotaxane; b) a foldaxane; c) a foldarotaxane. Templating groups for the macrocycle and the helix are shown in
green and blue, respectively. d) Formula of 1 with the same color code as in the helix representation. e) Representation of the equilibria between
a double helix and a single helix followed by its winding around a rotaxane leading to the formation of a foldarotaxane. f–i) Preparation of
foldarotaxanes 1ꢀ2-HPF6, 1ꢀ2 and 1ꢀ2-Boc and of foldaxanes 1ꢀ2u-HPF6, 1ꢀ2u and 1ꢀ2u-Boc.
aminolysis-based, post-interlocking elongation of the encir-
cled axle that preserves the mechanical bond (Schemes S2,
Further characterization of foldarotaxane 1ꢀ2-HPF6 was
performed using X-ray crystallography (Figure 3b–e). Single
crystals were obtained by the slow diffusion of hexane in
a chlorobenzene solution of 1ꢀ2-HPF6. The structure vali-
dated the initial design, with the DB24C8 positioned on the
ammonium group and the foldamer helix on the dicarbamate
station. One of the DB24C8 aromatic units stacks on the
terminal xylyl stoppers. The thread was found to be kinked
with an angle of 86.18 allowing the formation of an intra-
molecular hydrogen bond between the carbonyl oxygen atom
1
S3).[15] As evidenced by H and 19F NMR (Figures 2a–d and
S9, S10), the corresponding host-guest complex 1ꢀ2-HPF6
forms readily at room temperature upon adding 2-HPF6 to
a solution of single helix 1. Yet, complex formation is slow at
298 K and competes with the dimerization of 1 into kinetically
stable double helix (1)2 (Figures 1e, 2b, 3a and S4). To
overcome this issue and reach full complexation, the mixture
was heated at 318 K,[16] allowing (1)2 to disassemble com-
pletely into 1, and affording 1ꢀ2-HPF6 as the thermodynami-
cally most stable species (Figure 2d). As with other foldax-
anes,[9] the distinct resonances of 1ꢀ2-HPF6 indicate slow
exchange with 1 and (1)2 on the NMR time scale. Worthy of
note is the splitting of the signals of the entwined helix of 1ꢀ2-
HPF6 as a typical signature of a symmetrical helix bound to
a dissymmetrical thread. The integration of the signals of each
species at thermodynamic equilibrium allowed to determine
the association constant (Ka = 207000 MÀ1, Table 1).
Table 1: Association constants[a] (Ka) relative to the formation of
foldarotaxanes and foldaxanes.
1ꢀ2-
1ꢀ2 1ꢀ2-
1ꢀ2u-
1ꢀ2u 1ꢀ2u-
HPF6
Boc
HPF6
Boc
Ka [103 MÀ1
]
207
9.1 3.8
375
397
317
[a] Association constants calculated with: Ka =([axle-helix com-
plex]2 Kdim/([(1)2][axle]2))0.5 with Kdim =[(1)2]/[1]2.
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Figure 2. Sections of 700 MHz 1H NMR spectra (298 K in CDCl3 at
0.1 mM of 1) showing the amide resonances of: a) single helix
1 obtained by precipitation in methanol; b) a mixture of single helix
1 and double helix (1)2. Titration experiments showing the winding of
the single helix 1 around protonated rotaxanes: c) 0.5 equiv. of 2-HPF6
and d) 2.5 equiv. of 2-HPF6; e) 0.5 equiv. of 2 and f) 4 equiv. of 2;
g) 0.5 equiv. of 2-Boc and h) 7 equiv. of 2-Boc. Signals of the double
helix and the single helix are marked with empty triangles and empty
diamonds, respectively. Signals of the protonated foldarotaxane 1ꢀ2-
HPF6, the deprotonated foldarotaxane 1ꢀ2 and carbamoylated foldar-
otaxane 1ꢀ2-Boc are marked with blue, green and red circles,
respectively.
Figure 3. Structures in the solid state analyzed by X-ray crystallography
of: a) the double helix (1)2 and b–e) the protonated foldarotaxane 1ꢀ2-
HPF6. In (a) (1)2 is shown with one strand in an orange tube
representation whereas the other strand is shown in a blue CPK
representation. b) Structure of the dumbbell-shaped guest equipped
with functional groups to bind to the DB24C8 macrocycle and single
helix 1. Enlargement of the dumbbell-shaped guest showing a kink due
to a hydrogen bond between the amide and the carbamate functions
of the thread. c) The rotaxane 2-HPF6 as it exists in the structure of
1ꢀ2-HPF6 and an enlargement highlighting the binding mode between
DB24C8 and its ammonium template. d,e) The protonated foldarotax-
ane 1ꢀ2-HPF6. Side views of the energy-minimized molecular models
(using Merck Molecular Force Field static, MMFFs) of: f) 1ꢀ2 and
g) 1ꢀ2-Boc. In (b), (c) and (d), the helix and the macrocycle are
shown as a tube representation whereas the dumbbell-shaped guest is
shown as a CPK representation. In (e), (f), and (g), all the components
are shown as space-filling representations. The functional groups are
color coded as in Figure 1. Hydrogen bonds are represented with
orange dashed lines. Helix side chains (OiBu groups) and included
solvent molecules have been removed for clarity.
of a carbamate and the NH of the neighboring amide group
(Figure 3b).
We next investigated the influence of the macrocycle
position along the axle on the helix association and whether
potential steric conflicts or competition for the same binding
station would occur. Deprotonated 2 and N-carbamoylated 2-
Boc [2]rotaxanes were considered for the study. For both
interlocked architectures, deprotonation or deprotonation-
carbamoylation of the ammonium station resulted in the
shuttling of the DB24C8 toward both the amide and the
neighboring carbamate moiety, with which it interacts
through hydrogen bonds (Figure 1g,h, see also Figures S6–8
for NMR evidence). Adding [2]rotaxanes 2 or 2-Boc to single
helix 1 led to the formation of foldarotaxanes 1ꢀ2 and 1ꢀ2-
Boc, respectively (Figure 2e–h). Ka values proved to be
significantly reduced as compared to that measured for 1ꢀ2-
HPF6, highlighting a protecting effect of DB24C8 with respect
to helix binding.[17] Since deprotonation and t-butyl-carba-
moylation are both invertible, these changes are in principle
switchable.
the DB24C8 that competes with the helix to hydrogen bond to
the amide and the carbamate groups. Nevertheless, binding
remains high and the formation of 1ꢀ2 remains quantitative
at submicromolar concentrations (Figure 2 f), which displaces
the macrocycle from its initial thermodynamically more
favorable carbamate-amide station (Figure 1g, left). The
helix can thus be viewed as a supramolecular auxiliary that
Specifically, 1 has a 23-fold lower affinity for 2 than for 2-
HPF6 (Table 1). This lesser affinity may be partly assigned to
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traps the DB24C8 within a compartment of the axle for which
its affinity is lower.
Conflict of interest
Quantitative foldarotaxane formation also occurs with 2-
Boc (Figure 2h). In this case, the Boc group further reduces
the space available to accommodate the DB24C8 when it is
displaced by the helix from the amide-carbamate station
(Figure 1h). Furthermore, upon winding of the helix, the
carbamoylated amine of 2-Boc cannot assist the displacement
of the DB24C8 through electronic attraction, on contrary to 2
that possesses a free amine as a very weak site of interaction
for the DB24C8.[18] It follows that helix binding is further
reduced (Ka = 3800 MÀ1, Table 1). For comparison, associa-
tion constants were also determined for the foldaxane
analogues, 1ꢀ2u-HPF6, 1ꢀ2u and 1ꢀ2u-Boc (Figure 1i).
All the foldaxanes were found to be slightly more stable than
1ꢀ2-HPF6 (Ka values from 317000 to 397000 MÀ1), corrob-
orating the fact that the DB24C8 does not significantly disturb
the wrapping of the helix around the dicarbamate region of
the axle when it sits around the ammonium station.[19]
Notwithstanding such effects, binding of 1 to 2u and 2u-Boc
is stronger than to 2 and 2-Boc, respectively, confirming the
partial protective shielding effect of the DB24C8 against the
helix both in deprotonated and N-carbamoylated states.
Energy-minimized molecular models of 1ꢀ2 and 1ꢀ2-Boc
(Figures 3 f,g, S22, S23) reveal a bulk interface between the
helix and the macrocycle, which may be responsible for some
steric hindrance. In the case of 1ꢀ2-Boc the Boc protective
group of the secondary amine requires the macrocycle to be
pressed onto the helix.
In conclusion, we have reported the design of several
foldarotaxanes through the winding of a helix around the
encircled thread of [2]rotaxanes. The recognition between the
helix and rotaxaneꢀs thread is reminiscent of an allosteric
system.[18a] Chemical reactions at one end of the encircled
thread of [2]rotaxanes trigger co-conformational changes
through the shuttling of the macrocycle, therefore inducing an
alteration of the recognition of the [2]rotaxane for the helix at
the other end. Through its controlled and switchable position,
the macrocycle may thus act as a tunable moderator of the
affinity of the encircled axle for the helix. Conversely, the
helix acts as a supramolecular auxiliary to compartmentalize
the rotaxane molecular shuttle through the induced trans-
lation of the macrocycle out from its best recognition site.
These results pave the way to the design of foldarotaxane
molecular machines that might operate through interdepend-
ent motions of both helix and macrocycle. Such studies are
currently in progress in our laboratories and will be reported
in due course.
The authors declare no conflict of interest.
Keywords: crystallography · foldamers · molecular motion ·
rotaxanes
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Acknowledgements
We thank the “Agence Nationale de la Recherche” for
funding the project ANR-17-CE07-0014-01 and the France-
Germany International Research Project “Foldamers Struc-
tures and Functions” (IRP FoldSFun). This work benefited
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Structural Chemistry platform at IECB, CNRS UMS3033,
INSERMUS001, and Bordeaux University, France.
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[19] In order to make a comparison, the association constant in
chloroform at 293 K between a similar dialkylammonium and
the DB24C8 is about 500 MÀ1. It is much lower with amide and
even lower with carbamate.
[16] This was achieved in the presence of Et3N (3 equiv.) to prevent
any adverse acidity from CDCl3 decomposition, which may
cause the protonation of the pyridyl units of the helix, hence its
unfolding. Note that this amount of Et3N does not deprotonate
the ammonium moiety of the [2]rotaxane which is stabilized
Manuscript received: January 8, 2021
Accepted manuscript online: January 21, 2021
Version of record online: March 10, 2021
8384
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