Straightforward synthesis of a double-lasso macrocycle from a nonsymmetrical [c2]daisy chain

Article abstract of DOI:10.1021/ol303186j

The straightforward synthesis of a double-lasso macrocycle from a nonsymmetrical [c2]daisy chain, using the copper(I)-catalyzed Huisgen alkyne-azide 1,3-dipolar cycloaddition, is described. The preparation of the nonsymmetrical alkyne azide [c2]daisy chain precursor was realized in situ via the exchange of the monomers contained in both symmetrical alkyne and azide [c2]daisy chains and was followed by mass spectrometry.

Full text of DOI:10.1021/ol303186j

ORGANIC
LETTERS
2013
Vol. 15, No. 1
184–187
Straightforward Synthesis of a
Double-Lasso Macrocycle from a
Nonsymmetrical [c2]Daisy Chain
†
‡
‡
,†
ꢀ ꢀ
Camille Romuald, Guillaume Cazals, Christine Enjalbal, and Frederic Coutrot*
ꢀ
Supramolecular Machines and Architecture Team, Institut des Biomolecules Max
ꢀ
Mousseron, IBMM, UMR 5247 CNRS ꢀ UM1-UM2, Universite Montpellier 2,
ꢁ
Place Eugene Bataillon, case courrier 1706, F-34095 Montpellier Cedex 5, France
frederic.coutrot@univ-montp2.fr
Received November 26, 2012
ABSTRACT
The straightforward synthesis of a double-lasso macrocycle from a nonsymmetrical [c2]daisy chain, using the copper(I)-catalyzed Huisgen
alkyneꢀazide 1,3-dipolar cycloaddition, is described. The preparation of the nonsymmetrical alkyne azide [c2]daisy chain precursor was realized
in situ via the exchange of the monomers contained in both symmetrical alkyne and azide [c2]daisy chains and was followed by mass
spectrometry.
Interlocked and interwoven molecules constitute a class
of fascinating compounds which have been intensively
studied in the past decades. Whereas some potential
applications in the material1 or biological field2 shed light
on the interest of such molecules, chemical access to new
molecular interlocked architectures still represents a syn-
thetic challenge. Therefore, several interlocked molecules
such as rotaxanes,3 catenanes,4 foldaxanes,5 [c2]daisy
chains,6 “molecular muscles”,7 “molecular jump rope”,8
and knots9 have been synthesized up to date. On the
contrary, very few molecular lassos have been the subject
of targeted molecules. However, their chemical synthetic
access is of high interest, especially because such inter-
locked compounds can be found in nature. This is the case
of lasso peptides,10 which exhibit biological activities as
receptor antagonist or enzymatic inhibitor. It is suggested
that their biological role and their resistance against
protease degradation would be essentially due to their
constrained bent conformation. We recently reported the
† Supramolecular Machine and Architectures Team (http://www.glycor-
otaxane.fr).
(7) (a) Coutrot, F.; Romuald, C.; Busseron, E. Org. Lett. 2008, 10,
3741–3744. (b) Romuald, C.; Busseron, E.; Coutrot, F. J. Org. Chem.
2010, 75, 6516–6531. (c) Bonnet, S.; Collin, J. P.; Koizumi, M.; Mobian,
P.; Sauvage, J. P. Adv. Mater. 2006, 18, 1239–1250. (d) Jimenez-Molero,
M. C.; Dietrich-Buchecker, C.; Sauvage, J. P. Chem.;Eur. J. 2002, 8,
1456–1466. (e) Collin, J. P.; Dietrich-Buchecker, C.; Gavina, P.;
Jimenez-Molero, M. C.; Sauvage, J. P. Acc. Chem. Res. 2001, 34, 477–
487. (f) Consuelo Jimenez, M.; Dietrich-Buchecker, C.; Sauvage, J. P.
Angew. Chem., Int. Ed. 2000, 39, 3284–3287. (g) Wu, J.; Leung, K. C. F.;
Benitez, D.; Han, J. Y.; Cantrill, S. J.; Fang, L.; Stoddart, J. F. Angew.
Chem., Int. Ed. 2008, 47, 7470–7474. (h) Dawson, R. E.; Lincoln, S. F.;
Easton, C. J. Chem. Commun. 2008, 3980–3982.
‡
ꢀ
ꢀ
ꢀ
Sciences Analytiques des Biomolecules & Modelisation moleculaire.
(1) Kay, E. R.; Leigh, D. A.; Zerbetto, F. Angew. Chem., Int. Ed.
2007, 46, 72–191.
(2) Fernandes, A.; Viterisi, A.; Coutrot, F.; Potok, S.; Leigh, D. A.;
Aucagne, V.; Papot, S. Angew. Chem., Int. Ed. 2009, 48, 6443–6447.
(3) For a recent example, see: Barnes, J. C.; Fahrenbach, A. C.; Dyar,
S. M.; Frasconi, M.; Giesener, M. A.; Zhu, Z.; Liu, Z.; Hartlieb, K. J.;
Carmieli, R.; Wasielewski, M. R.; Stoddart, J. F. Proc. Natl. Acad. Sci.
U.S.A. 2012, 109, 11446–11551.
(4) For a recent example, see: Ayme, J.-F.; Lux, J.; Sauvage, J.-P.;
Sour, A. Chem.;Eur. J. 2012, 18, 5565–5573.
(8) Romuald, C.; Arda, A.; Clavel, C.; Jimenez-Barbero, J.; Coutrot,
F. Chem. Sci. 2012, 3, 1851–1857.
(9) For a recent review, see: Forgan, R. S.; Sauvage, J.-P.; Stoddart,
J. F. Chem. Rev. 2011, 111, 5434–5464.
(5) (a) Ferrand, Y.; Gan, Q.; Kauffmann, B.; Jiang, H.; Huc, I.
Angew. Chem., Int. Ed. 2011, 50, 7572–7575. (b) Gan, Q.; Ferrand, Y.;
Bao, C.; Kauffmann, B.; Grelard, A.; Jiang, H.; Huc, I. Science 2011,
331, 1172–1175.
ꢀ
(6) For a recent review, see: Rotzler, J.; Mayor, M. Chem. Soc. Rev.
2013, 42, 44–62.
(10) Maksimov, M. O.; Pan, S. J.; Link, A. J. Nat. Prod. Rep. 2012,
29, 996–1006.
r
10.1021/ol303186j
Published on Web 12/20/2012
2012 American Chemical Society

preparation, tightening, and loosening of a double-lasso
molecule from a symmetrical ends-activated [c2]daisy
chain.8 Here, we report on a novel straightforward syn-
thetic route to a double-lasso molecular architecture from
a nonsymmetrical [c2]daisy chain. The chosen synthetic
strategy to yield the targeted molecular double lasso is
based on the pseudocyclization of a nonsymmetrical al-
kyne azide [c2]daisy chain, using the copper(I)-catalyzed
Huisgen alkyneꢀazide 1,3-dipolar cycloaddition,11 also
called “CuAAC click chemistry”.12 The two needed sym-
metrical diazide and dialkyne[c2]daisy chain precursors 3
and 5 were both synthesized from the already reported13
dibenzo-24-crown-8(DB24C8)-based macrocycle 1 hold-
ing an aldehyde moiety (Scheme 1). Reductive amination
by, first, refluxing the aldehyde 1 with, respectively, the
12-azidododecan-1-amine or the tridec-12-yn-1-amine
and, second, reducing the intermediate imine using sodium
borohydride afforded the secondary amines 2 and 4. These
latter were then submitted to a protonation using a hydro-
chloride solution in ether and then to an anion exchange
with hexafluorophosphate to yield “hermaphrodite”
monomers which interwove in the less polar hydrogen-
bond promoting solvent like CD2Cl2 or CD3CN to
form “meso” supramolecular S2-symmetric pseudo
rotaxane dimers 3 and 5 in, respectively, 70 and 87%
overall yield.
Figure 1. 1H NMR spectra (400 MHz, 298 K) of (a) the
uncomplexed alkyne compound 5u in DMSO-d6, (b) the di-
alkyne pseudo rotaxane dimer 5 in CD3CN, (c) the stoichio-
metric mixture of pseudorotaxane dimers 3 and 5 in CD3CN, (d)
the diazido pseudo rotaxane dimer 3 in CD3CN, and (e) the
uncomplexed azido compound 3 in DMSO-d6. The coloring,
lettering, and numbering correspond to the proton assignments
indicated in Scheme 1.
The interwoven molecular architectures of the pseudo
1
rotaxane dimers 3 and 5 were elucidated by H NMR
spectroscopy and mass spectrometry (Figures 1 and 2, a
and b).
In the polar solvent DMSO-d6, simple 1H NMR signals
were observed for the DB24C8 moieties, indicating the
presenceof the uncomplexed “hermaphrodite”monomers,
hence the absence of any [c2]daisy chain self-assembling
(Figure 1, a and e). In the hydrogen-bond-promoting
solvent like CD3CN, the 1H NMR spectra become much
more complicated (Figure 1, b and d). In particular, the
hydrogen signals of the methylenic hydrogens of the
DB24C8 parts are split, indicating their nonmagnetic
equivalence, which is directly due to the interwoven struc-
ture. Indeed, when the macrocycles surrounds the mole-
cular axles, the methylenic hydrogens of the DB24C8 are
facing the two nonsymmetrical ends of the pseudo daisy
chain. Concerning the hydrogens of the aromatic rings of
the DB24C8, the highfield chemical shift of hydrogen HE
should be noted, which experiences the shielding effect of
thearomaticringsofthe[c2]daisy arrangement. Moreover,
0
trend is observed for hydrogens H1, H1 , H3, and H3 for
0
identical reasons.
The equilibrium between the pseudorotaxanes 3 and 5
and the nonsymmetrical enantiomers 6/60 was then inves-
tigated (Scheme 1). It is noteworthy that 6 and 60 exist as a
pair of enantiomers. Indeed, contrary to compounds 3 and
5, pseudo rotaxane dimers 6 and 60 do not have any S2
symmetry because of the two different alkyne and azide
ends of the [c2]daisy chain.
In a first instance, we compared the 1H NMR spectra in
CD3CN of the isolated pseudo rotaxanes 3 and 5 with the
1H NMR spectrum of a stoichiometric mixture of 3 and 5
(Figure 1, bꢀd). Unfortunately, the ratio between the four
possible exchangeable pseudo rotaxanes were impossible
to determine, since the spectrum of the mixture matches
exactly with the superimposition of the spectra of the two
isolated symmetrical diazido and dialkyne pseudo rotax-
anes 3 and 5. No other 1H NMR signal corresponding to
the nonsymmetrical pseudo rotaxane enantiomers 6/60 was
detected. Nevertheless, this observation does not mean
that no exchange is possible between pseudo rotaxane
dimers. It rather results from the fact that an alkyne or
an azide moiety located at one extremity of the pseudo
rotaxane dimer has no influence on the chemical shift
of hydrogen atoms located at the other extremity. This
assumption was corroborated by a kinetic study of
0
the hydrogens H2 and H2 are detected at high chemical
shift because they interact by hydrogen bonds with the
oxygen atoms of the dibenzo-24-crown-8 parts. The same
(11) (a) Huisgen, R. Pure. Appl. Chem. 1989, 61, 613–628. (b) Huisgen,
€
R.; Szeimies, G.; Mobius, L. Chem. Ber. 1967, 100, 2494–2507. (c) Huisgen,
R. Angew. Chem. 1963, 75, 604–637. Angew. Chem., Int. Ed. Engl. 1963, 2,
565–598. (d) Huisgen, R. Angew. Chem. 1963, 75, 742–754. Angew. Chem.,
Int. Ed. Engl. 1963, 2, 633–645.
(12) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004–2021. (b) Tornoe, C. W.; Christensen, C.; Meldal, M.
J. Org. Chem. 2002, 67, 3057–3064.
(13) Cantrill, S. J.; Youn, G. J.; Stoddart, J. F. J. Org. Chem. 2001, 66,
6857–6872.
Org. Lett., Vol. 15, No. 1, 2013
185

Scheme 1. Synthesis of the Two Symmetrical Diazide and Dialkyne [c2]Daisy Chains 3 and 5, Equilibrium between Pseudorotaxanes 3,
5, and 6/60, and Synthesis of the Double-Lasso Rotamacrocycle Enantiomers 7/70
exchange using matrix-assisted laser desorption/ionization
time-of-flight (MALDI-TOF) mass spectrometry (MS) on
a stoichiometric mixture of compounds 3 and 5 (Figure 2 c).
This way, it was easy to detect each pseudo rotaxane dimer
3, 5 and 6/60, since each compound has a different molecular
weight.
Over time, the variation observed in the peak intensity
gave a good tendency of the rate of the chemical exchange
between the pseudo rotaxane dimers. After 1 min, the
appearance of a peak corresponding to the enantiomers
6/60 was observed. At the same time, the peak intensities
corresponding to the relative abundance of the two sym-
metrical pseudo rotaxane dimers 3 and 5 decreased, which
is consistent with a chemical exchange between the dimer
precursors. The concentration of the pseudo rotaxane
dimers 6/60 increased until the equilibrium was reached
after about 60 min. After that, no significant variation was
noticed. By making the assumption that the difference of
MS peak intensities of 3 and 5 is due to their different
ionization yields (in favor of 5), one may reasonably
suppose that the proportion at the equilibrium exactly
matches with a statistical distribution of monomers (i.e.,
3:5:6/60 25:25:50). Indeed, if the azide or alkyne extremities
do not play any role in the interlocking of the structure,
which looks to be reasonable to think in the present case,
there is twice more chance to yield the two enantiomers 6
186
Org. Lett., Vol. 15, No. 1, 2013

Figure 3. 1H NMR spectra (400 MHz, CD3CN, 298 K) of (a) the
uncomplexed compound 7u and (b) the lasso rotamacrocycle 7.
The coloring, lettering and numbering correspond to the proton
assignments indicated in Scheme 1.
The hydrogens H1 and H29, on one hand, and H3 and
H27, on the other hand, are all shifted downfield in the
rotamacrocycle 7 because of their hydrogen bonding with
the oxygen atoms of the crown ethers. Moreover, the
hydrogen HE belonging to one aromatic ring of a crown
ether is shielded by the presenceof the aromatic rings of the
other crown ether, demonstrating the “sandwich”-type
conformation of the [c2]daisy arrangement. The signals
of the methylenic hydrogens of the DB24C8 parts are
simple in the uncomplexed compound 7u, whereas they
are all split in the rotamacrocycle 7, indicating their
nonmagnetic equivalence due to the nonsymmetrical pseu-
do macrocycle thread. No other chemical shift variation is
observed for the other hydrogens, indicating the localiza-
tion of the DB24C8 around the ammonium sites.
Inconclusion, we havedescribedastraightforwardroute
to a double-lasso rotamacrocycle, based on the cyclization
of a nonsymmetrical alkynazide pseudo rotaxane dimer,
which was generated by a chemical exchange between two
symmetrical dialkyne and diazide pseudo rotaxane dimers.
The use of nonsymmetrical [c2]daisy chain precursors
could be of real interest for polymerization at high con-
centration, whereas double-lasso rotamacrocycles could
be appealing targets due to their tailorable bent molecular
architecture.
Figure 2. MALDI-TOF mass spectra of (a) the diazido pseu-
dorotaxane dimer 3, (b) the dialkyne pseudorotaxane dimer 5,
(c) a stoichiometric mixture of pseudorotaxane dimers 3 and 5
over time, and (d) after protonation of a stoichiometric mixture
of monomers 2 and 4.
and 60 than respectively the compounds 3 and 5. As it
looks rational that the ionization potentials of the non-
symmetrical azidoalkyne pseudo rotaxane dimers 6 and 60
are comprised between respectively those of the symmet-
rical diazido and dialkyne pseudo rotaxanes 3 and 5, the
relative abundance of 50% observed by mass spectrometry
for 6/60 at the equilibrium should fit with the molar ratio,
accordingly to a statistical distribution. By comparison,
the protonation and the subsequent counteranion ex-
change of a stoichiometric mixture of deprotonated mono-
mers 2 and 4 was realized and gave very similar results
(Figure 2 d).
The pseudo cyclization using “click chemistry” between
the azide and alkyne extremities of the nonsymetrical
rotaxane dimers 6/60 was envisaged. It was carried out at
a concentration of 5 ꢁ 10ꢀ4 M to minimize the side
polymerization reactions and afforded the racemic double-
lasso compound 7/70 in a 51% yield after silica gel chro-
matographic purification, accompanied by traces of the
dimeric tetra-lasso 8 which were only detected by MALDI-
TOF MS (Scheme 1). No other compound was isolated
from the silica gel chromatography, suggesting the side
Acknowledgment. We are grateful to the Ligue Nationale
Contre le Cancer for Ph.D. financial support.
Supporting Information Available. Characterization
data and full experimental procedures for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
formation of polymers. The comparison between the H
NMR spectra of the lasso compound 7 and its uncom-
plexed analogue 7u revealed the interlocked double-lasso
structure (Figure 3).
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 1, 2013
187