One-step synthesis of chiral cages

Article abstract of DOI:10.1039/b816628e

A novel type of hemispherical cage was synthesized in a one-pot procedure, which displayed good binding properties towards nickel(II). The Royal Society of Chemistry.

Full text of DOI:10.1039/b816628e

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COMMUNICATION
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One-step synthesis of chiral cagesw
Vincent Steinmetz, Franc¸ ois Couty and Olivier R. P. David*
Received (in Cambridge, UK) 23rd September 2008, Accepted 7th November 2008
First published as an Advance Article on the web 26th November 2008
DOI: 10.1039/b816628e
A novel type of hemispherical cage was synthesized in a one-pot
procedure, which displayed good binding properties towards
nickel(II).
Due to the poor solubility of the produced di-, tetra- and
hexa-aldehydes, a DMSO–water mixture had to be employed
to avoid premature precipitation of partially ‘‘clicked’’ com-
pounds; tris-triazole 9 could then be isolated in fair yield.
Formation of a cyclic hexa-imine was next attempted by reac-
ting compound 9 with three equivalents of ethylenediamine
(I module) in dichloromethane. Hexa-aldehyde 9 being only
very slightly soluble in dichloromethane, completion of the
reaction required full solubilization of the starting material
and was observed only after three weeks. Gratifyingly, upon
evaporation of the solution, a unique product was obtained that
In order to mimic enzymes, chemists have created various
molecular architectures aimed at reproducing the major
characteristics of those biological entities, namely the binding
of specific guests followed by their chemical transformation in
a regio, stereo and enantioselective manner.1 To that end,
rather simple molecules have been prepared which possess a
three-dimensional arrangement defining a pocket able to
accommodate cationic or anionic species, as well as neutral
molecules, depending on the moieties present within the cage.
Among the numerous architectures prepared to date, calix[6]trens
of type 1 developed by Reinaud and Jabin2 attracted our
attention due to their ability to complex all three kinds of
guests mentioned above. They are represented as their
topological skeleton in Scheme 1 (I and V or Y symbolize
bi- and tri-functional modules, respectively). This synthesis
relied on the closing of a desymmetrized calix[6]arene 2 in
which three of the six phenols are linked together with a ‘‘cap’’
of type 3 (route a in Scheme 1). We report herein an alternative
approach to this type of topology, in which the macrocyclic
crown in 1 is constructed around a preexistent cap 4 after
ring-closure with three linkers 5 (route b).3
1
exhibited a set of signals in its H NMR spectrum fitting the
expected tricyclic hexa-imine structure 10 (Scheme 2).
Similar polycondensation gave 11, when (1R,2R)-1,2-diamino-
cyclohexane was used as the linking diamine. All spectroscopic
data (1H, 13C, HRMS, IR) supported the depicted structures.
Eventually, we found that a mixture of dichloromethane and
methanol (9 : 1) readily dissolved compound 9, and thus reduced
the macro-imination reaction time to 12 h. Noteworthy is that
dilute conditions were not necessary, and half-gram scale experi-
ments could be run in 6 ml of the above mixture of solvents. Cage
11 proved stable indefinitely at room temperature, either in the
solid state or in solution; furthermore the imines were resistant
enough to allow purification over silica-gel.
Interestingly, the product 11 exhibited a set of signals in its
1H NMR spectrum fitting with a chiral structure possessing
a C3 symmetry axis. In particular, the whole architecture
appeared to be twisted in a propeller-like shape as shown by
NMR spectroscopy. The proton NMR spectrum reproduced
in Fig. 1 exhibits two signals for the iminic protons (noted Hj
and Hj0), suggesting that three are pointing inward and three
outward. The same differentiation was observed for the
aromatic protons ortho to the oxygen substituent (Hg and
Hg0), and for the diastereotopic methylene protons Ha and
Ha0 remote from the chiral centers but strongly differentiated
by the twisted shape.
In order to prepare a bowl-shaped cage presenting topo-
logical structure 1, synthesis of tripodal module 4 was
envisioned using copper catalyzed Huisgen cycloaddition
(CuAAC) since this would also introduce a tris-triazole motif
that could serve as complexing entity.4 As a bridging reaction
(4 + 3 ꢀ 5), imine formation has already demonstrated its
efficiency for building complex architectures5 and we planned
to take advantage of the chemistry of ‘‘trianglimines’’ deve-
loped by Gawronski and Kuhnert.6 In addition, through this
cyclocondensation, a chiral cage can be prepared by using a
chiral linker for 5. The combination of these two linking
reactions (CuAAC and imine condensation) led us to the
design of the star-like compound 9 bearing six aldehyde
groups. This synthesis thus began with the preparation of
azido-aldehyde 8 (V module) in four steps from dimethyl
5-hydroxyisophthalate. This compound was then reacted with
tripropargylamine (Y module) in a threefold cycloaddition
reaction using the standard CuSO4–sodium ascorbate system.7
With the aim of running the cycloaddition as well as the
imine formation processes in a one-pot procedure, we sought
UniverSud Paris, Institut Lavoisier, Universite´ de Versailles St
Quentin-en-Yvelines, UMR 8180, 45 avenue des Etats-Unis, 78035
Versailles, France. E-mail: odavid@chimie.uvsq.fr;
Fax: +33 (0)1 3925 4452; Tel: +33 (0)1 3925 4455
w Electronic supplementary information (ESI) available: Detailed
experimental
10.1039/b816628e/
procedures,
spectroscopic
data.
See
DOI:
Scheme 1 Topological representation of the targeted cage.
Chem. Commun., 2009, 343–345 | 343
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Fig. 2 Relative K values versus cation.
In order to evaluate the complexation abilities of the
synthesized cage 11, it was titrated with an array of metallic
ions (Mn2+, Fe3+, Co2+, Ni2+, Cu2+, Zn2+, Cs+, Hg2+
,
Ag+) (Fig. 2); quantification was accomplished by mass-
spectrometry measurements.8
Scheme 2 Assembly of tripod 9 and cages 10–11.
Nickel(II) was the most efficiently complexed cation, while
other metals belonging to the same period are also recognized by
11 but with lower complexation constants. Importantly this
binding takes place without observable degradation of the poly-
imine structure. Caesium also showed a non-negligible affinity,
but, quite surprisingly, heavy metals like Hg(II) or Ag(I) and
iron(III) were not at all complexed and promoted hydrolysis of
the imines at high concentration. Finally, competition experi-
ments employing equimolar quantities of all the cations tested
above showed exclusive complexation of nickel(II).
Having demonstrated the ability of cage 11 to complex
cations, we next wanted to gather some information on the
nature of the complexation site. In fact, in cage 11, no fewer
than nineteen heteroatoms are potential binding sites. In
particular, we wanted to know if the cation was complexed
by the large macroimine crown or by the tris-triazole tripod.
As attempts at crystallization of cage 11 with nickel(II) and
other cations proved unsuccessful, we decided to use NMR
techniques to ascertain the location of the complexation site.
Zinc(II) was chosen as the cation because of its ease of
manipulation and compatibility with the NMR method.
Compound 11 is only sparingly soluble in acetone-d6 but
upon addition of one equivalent of zinc(II) triflate, complete
solubilization occurred and a new set of signals was displayed
Fig. 1 Proton NMR spectrum of cage 11.
for experimental conditions that would intersect the require-
ments for both reactions, hence allowing a direct assembly of
the cage. This was realized by dissolving the three partners,
trialkyne, diamine and azide 8, in a dichloromethane–methanol
mixture and by employing CuI as catalyst (Scheme 3).
Pleasingly, after 12 h, cage 11 was produced, although partially
complexed with copper ions. Decomplexation by treat-
ment with sodium diethyl-dithiocarbamate, followed by flash
chromatography, gave 11 in 70% yield.
1
in the H NMR spectrum. Since the NMR data demonstrate
The superposition of two reactions, one reversible and one
irreversible, allowed the complete conversion of the different
fragments into a unique and defined architecture. The con-
stant equilibration of the imine functions allows the autorepair
of an eventual ‘‘mistake’’ and drives the reaction to the
thermodynamically stable compound.
that C3 symmetry was retained, the cation is expected to be
located along this axis. This observation excludes coordination
by the imines as the interatomic distances are too great to
allow complexation at the center of the macrocyclic crown.
Secondly, comparison with the initial chemical shifts revealed
the zinc(II) ion to be most probably located in the triazole
region, as depicted in Scheme 4. In fact, if the oxygen atoms
participate in coordination, important shifts should be
observed for the He and Hg protons, which is not the case.
Therefore, a tetradentate complexation with the three N3
atoms of the triazoles and with the apical nitrogen atom
was assumed,9,10 although this preliminary study does not
unambiguously answer the question.
Having demonstrated the ease of preparation of chiral cages
of type 11 and verified that complexation was effective with
Scheme 3 Direct assembly of Y, V and I modules into cage 11.
344 | Chem. Commun., 2009, 343–345
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4 T. R. Chan, R. Hilgraf, K. B. Sharpless and V. V. Fokin, Org.
Lett., 2004, 6, 2853–2855.
5 Striking examples are found in: (a) X. Liu, Y. Liu, G. Li and
R. Warmuth, Angew. Chem., Int. Ed., 2006, 45, 901–904;
(b) Y. Liu, X. Liu and R. Warmuth, Chem.–Eur. J., 2007, 13,
8953–8959; (c) O. Francesconi, A. Ienco, G. Moneti, C. Nativi and
S. Roelens, Angew. Chem., Int. Ed., 2006, 45, 6693–6696;
(d) P. Mal, D. Schultz, K. Beyeh, K. Rissanen and
J. R. Nitschke, Angew. Chem., Int. Ed., 2008, 47, 8297–8301;
(e) K. S. Chichak, S. J. Cantrill, A. R. Pease, S.-H. Chiu, G. W.
V. Cave, J. L. Atwood and J. F. Stoddart, Science, 2004, 304,
1308–1312.
Scheme 4 Proton shifts upon complexation of Zn(II), Dd values in
ppm.
6 (a) J. Gawronski, H. Ko"bon, M. Kwit and A. Katrusiak, J. Org.
Chem., 2000, 65, 5768–5773; (b) M. Chadim, M. Budesınsky,
J. Hodacova, J. Zavada and P. C. Junk, Tetra-
hedron: Asymmetry, 2001, 12, 127–133; (c) N. Kuhnert,
G. M. Rossignolo and A. Lopez-Periago, Org. Biomol. Chem.,
2003, 1, 1157–1170; (d) N. Kuhnert, A. Lopez-Periago and
G. M. Rossignolo, Org. Biomol. Chem., 2005, 3, 524–537;
(e) J. Gawronski, K. Gawronska, J. Grajewski, M. Kwit,
A. Plutecka and U. Rychlewska, Chem.–Eur. J., 2006, 12,
1807–1817.
this entity, we now plan to design related architectures fitted
with chemical moieties able to act as organocatalyst, thus
opening new perspectives for pseudo-enzymatic catalysis.
Currently, the host–guest studies of these new cages with
cations, as well as small organic molecules, are underway in
our laboratory.
7 For reviews on alkyne-azide cycloaddition see: (a) M. Meldal and
C. W. Tornøe, Chem. Rev., 2008, 108, 2952–3015; (b) V. D. Bock,
H. Hiemstra and J. H. van Maarseveen, Eur. J. Org. Chem., 2006,
51–68.
8 For an example of quantification of binding constants by mass-
spectrometry see: M. Desage-El Murr, S. Nowaczyk, T. Le Gall,
C. Mioskowski, B. Amekraz and C. Moulin, Angew. Chem., Int.
Ed., 2003, 42, 1289–1293.
9 For comparison of coordination behaviors of tripodal ligands see:
C.-Y. Su, B.-S. Kang, T.-B. Wen, Y.-X. Tong, X.-P. Yang,
C. Zhang, H.-Q. Liu and J. Sun, Polyhedron, 1999, 18, 1577–1585.
10 For a discussion on the binding of tristriazole ligands with Cu(I)
and (II) see: V. O. Rodionov, S. I. Presolski, D. Diaz Diaz,
V. V. Fokin and M. G. Finn, J. Am. Chem. Soc., 2007, 129,
12705–12712.
Notes and references
1 (a) W. B. Motherwell, M. J. Bingham and Y. Six, Tetrahedron,
2001, 57, 4663–4686; (b) Y. Murakami, J.-I. Kikuchi, Y. Hisaeda
and O. Hayashida, Chem. Rev., 1996, 96, 721–758.
2 (a) X. Zeng, N. Hucher, O. Reinaud and I. Jabin, J. Org. Chem.,
2004, 69, 6886–6889; (b) U. Darbost, M.-N. Rager, S. Petit,
I. Jabin and O. Reinaud, J. Am. Chem. Soc., 2005, 127,
8517–8525; (c) I. Jabin and O. Reinaud, J. Org. Chem., 2003, 68,
3416–3419; (d) O. Seneque, M.-N. Rager, M. Giorgi and
O. Reinaud, J. Am. Chem. Soc., 2000, 122, 6183–6189.
3 For a similar strategy with C2v symmetrical calix[4]pyrroles:
C.-H. Lee, H. Miyaji, D.-W. Yoon and J. L. Sessler, Chem.
Commun., 2008, 24–34.
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