Cyclodextrin tetraplexes: First syntheses and potential as cross-linking agent

Article abstract of DOI:10.1039/b921567k

The first syntheses of two cyclic tetramers of cyclodextrins, dubbed tetraplexes, are described as well as the use of one of them to form a supramolecular assembly with a modified biopolymer.

Full text of DOI:10.1039/b921567k

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Cyclodextrin tetraplexes: first syntheses and potential as cross-linking
agentw
a
a
b
a
Thomas Lecourt, Yves Bleriot, Rachel Auzely-Velty* and Matthieu Sollogoub*
´ ´
Received (in Cambridge, UK) 15th October 2009, Accepted 15th December 2009
First published as an Advance Article on the web 20th January 2010
DOI: 10.1039/b921567k
4
–6
The first syntheses of two cyclic tetramers of cyclodextrins,
dubbed tetraplexes, are described as well as the use of one of
them to form a supramolecular assembly with a modified
biopolymer.
same context.
Two sequential cross-metatheses of an
olefinated CD monomer should provide a CD dimer then a
tetramer and a final ‘‘giant’’ ring-closing metathesis should
deliver the desired tetraplex. Once this synthetic strategy
was optimized using a-CD, which is easy to characterize by
NMR spectroscopy because it is symmetric, the same set of
reactions was applied to b-CD for which a mixture of regio-
isomers (A–D and A–E for each CD) is obtained as in the
Cyclodextrins (CDs) are unique entities able to form inclusion
complexes with hydrophobic guests in water. Hence, tuning
their inclusion ability has been thoroughly explored, mainly
through their chemical modification. For instance, linking two
CDs to generate a dimer can remarkably induce a doubling of
the binding free energy with guest molecules that can be hosted
4
,5
case of b-CD duplexes. We present here both syntheses
in parallel. The now classical per-benzylation-deprotection
sequence applied to both a- and b-CDs afforded diols 1a
16
1
2–7, 11
12
by both cavities. Doubly linked CDs, called duplexes,
and 1b respectively, which were selectively monoalkylated
8
5
constitute an interesting subclass in the vast CD dimer family,
which display higher guest affinities and shape discrimination
2
due to their restricted conformations. Therefore insertion of
towards CDs 2a/2b. Grubbs catalyst induced the first
dimerization of alkenes 2a/2b followed by saturation of the
newly formed double bond to afford dimers 3a/3b in 85% and
87% yields, respectively. Monoalkylation of diols 3a/3b
using 5-bromo-pent-1-ene in the presence of potassium
hydride and 18-crown-6 in THF afforded 4a/4b in 51 and
53% yields, respectively, as well as 20% of recovered starting
material and 20% of the doubly alkylated product in each
case, a result in sharp contrast with the selectivity observed for
the monoalkylation of diols 1a and 1b underlining their unique
reactivity. Monoalkylated dimers 4a/4b were in turn homo-
coupled through a second cross-metathesis, and subsequent
saturation of the double bond afforded the tetrameric CDs
5a/5b in 74% and 75% yields, respectively, over two steps.
Tetrameric CD diols 5a/5b were next bis-alkylated in the
presence of a large excess of bromoalkene to deliver tetra-
meric CD dienes 6a/6b in 86% and 82% yields, respectively.
A final giant ring-closing metathesis of tetrameric CD dienes
6a/6b gave the corresponding protected CD tetraplexes.
The reaction was conducted in the presence of 20 mol% of
additional cavities ought to afford supramolecular structures
with even better binding properties. However, relatively few
9
linearly or centrally linked trimers and tetramers have been
10
11
synthesized, and only one cyclic CD trimer has been reported,
but its study was somewhat limited by its low yielding
synthetic route. The main limitation in the synthesis of a cyclic
oligomer of CDs is the access to the required doubly modified
CD precursor. For some time now, we have been developing
an efficient regioselective deprotection reaction of perbenzylated
1
2
13
CDs to give access to CDs bearing two or three new
functionalities on their primary rim. Another advantage of
this strategy is the relevant use of benzyl protecting groups,
which allows the use of modern chemical reactions in apolar
solvents and standard silica-gel flash chromatography. Hence,
multistep syntheses of CD-duplexes were achieved in usable
4
,5
overall yields. Here we report on the first syntheses of cyclic
tetramers of a- and b-CDs, dubbed CD-tetraplexes, as well as
the evaluation of the b-CD tetraplex as a cross-linking agent
for a biopolymer grafted with hydrophobic guests targeting
the CD cavity.
À3
Grubbs catalyst and in dilute conditions (10 M) affording
the protected tetraplexes in 47% yield. More diluted con-
ditions to avoid possible side oligomerisation did not
improve the yield of this reaction. Final debenzylation using
sodium in a mixture of THF and liquid ammonia, and
saturation of the double bond afforded tetraplexes 7a/7b
(64% and 69%, respectively, over those two steps) in
an honourable 6% overall yield from both a- and b-CDs.
The synthetic route towards the tetraplexes was designed
relying on the easy access to difunctional CDs as well as on the
1
4
efficiency of the metathesis reaction, which proved its worth
1
in the dimerisation of CDs and ring closing reactions in the
5
a
(
Scheme 1).
UPMC Univ Paris 06, Institut Parisien de Chimie Moleculaire
(UMR CNRS 7201), FR629, 4 place Jussieu, 75005 Paris, France.
As illustrated in Fig. 1, CD-tetraplex 7a belongs to the D
2
group of symmetry, due to the presence of three axes of
1
symmetry. Its H NMR spectrum is therefore extremely
E-mail: matthieu.sollogoub@upmc.fr; Fax: +33 1 4427 5504;
Tel: +33 1 4427 6163
Centre de Recherches sur les Macromolecules Vegetales
b
(
CERMAV-CNRS), BP53, 38041 Grenoble cedex 9, France,
simplified because glucose units become equivalent eight by
eight, and only three signals are observed corresponding to the
three families of anomeric protons. Similarly, the 24 aliphatic
inter-CD chain carbons also appear as three peaks on the
affiliated with Universite Joseph Fourier, and member of the Institut
de Chimie Moleculaire de Grenoble France
w Electronic supplementary information (ESI) available: Experimental
details and spectroscopic analysis of all new products. See DOI:
1
3
1
0.1039/b921567k
C NMR spectrum. (Fig. 1)
2
238 | Chem. Commun., 2010, 46, 2238–2240
This journal is ꢀc The Royal Society of Chemistry 2010

View Article Online
Scheme 1 Synthesis of tetraplexes 7a/7b. Reagents and conditions: (i) BnCl, NaH, DMSO, rt, 18h; (ii) DIBAL-H, toluene, 50 1C, 2h;
À1
(
iii) 5-bromo-pent-1-ene (1.7 equiv.), KH (1.7 equiv.), THF, nBu
4
NI (0.1 equiv.), rt, 18 h; (iv) Cl
2
(PCy
3
)
2
RuQCHPh (5 mol%), CH
2
Cl
2
(10 M),
reflux, 6 h then Pb(OAc) , rt 18 h; (v) H
4
2
, PtO
2
, AcOEt, 3 h; (vi) 5-bromo-pent-1-ene (2.5 equiv.), KH (2.5 equiv.), THF, 18-crown-6 (0.1 equiv.), rt,
À1
1
1
8 h; (vii) Cl
2
(PCy
3
)
2
RuQCHPh (5 mol%), CH
2
Cl
2
(10 M), reflux, 6 h then Pb(OAc)
4
, rt 18 h; (viii) H
RuQCHPh (20 mol%), CH Cl
, Pd/C 10%, MeOH–H O (1 : 1), 3 h.
2 2
, PtO , AcOEt, 3 h; (ix) 5-bromo-pent-
À3
-ene (10 equiv.), KH (10 equiv.), THF, 18-crown-6, rt, 4 h; (x) Cl
/THF (1 : 1), À33 1C, 1 h; (xii) H
2
(PC y
3
)
2
2
2 4
(10 M), reflux, 48 h then Pb(OAc) ,
rt, 18 h; (xi) Na, liq NH
3
2
2
We have previously shown that two b-CD duplexes 8 and 9,
tethered with two different kinds of spacers, could significantly
displays the dependence of the zero-shear viscosity of chit-AD
À1
À1
solutions, at a concentration of 2.5 g L or 3 g L , on the
[CD]/[AD] ratio. Addition of tetraplex 7b to the solution of
chit-AD leads to a spectacular enhancement of the viscosity, in
the same range of magnitude as for duplex 8, and much higher
than with duplex 9. The highest viscosity value observed for
tetraplex 7b with respect to the [CD]/[AD] ratio is not quite as
high as that obtained with duplex 8 but it appears at a much
lower [CD]/[AD] ratio. The observed decrease of the viscosity
beyond the optimal [CD]/[AD] ratio can be attributed to an
increase of tetraplex monocomplexation to the detriment of
di- or multi-complexation.
enhance the viscosity of an adamantane-grafted chitosan
4
chit-AD 10) solution in water (Fig. 2). With this system,
(
under optimal conditions, CD duplexes form inclusion com-
plexes with hydrophobic adamantane residues of two distinct
strands of polymer forming stable supramolecular assemblies,
acting as a non-covalent cross-linking agent. As such reversible
systems may have potential applications in various fields
including drug delivery, coatings or personal care goods,
we undertook the study of the effect of the synthesized
CD-tetraplex 7b on the viscosity of biopolymer 10.
The ability of the b-CD tetraplex 7b to form stable supra-
molecular assemblies with adamantane-grafted chitosan 10
was monitored by viscosity measurements. These were performed
maintaining a constant polymer concentration, while progres-
sively increasing the concentration of CD tetraplex 7b. Fig. 2
We have synthesized for the first time two cyclic tetramers of
CDs, dubbed tetraplexes, in a usable 6% overall yield from
native CDs. Our efficient synthetic route enables reasonable
quantities of 7b tetraplex to be obtained, which was used to
form a supramolecular assembly with a modified biopolymer.
This journal is ꢀc The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 2238–2240 | 2239

View Article Online
Notes and references
1
2
3
R. Breslow, S. Halfon and B. Zhang, Tetrahedron, 1995, 51, 377
and references therein.
R. Breslow and S. Chung, J. Am. Chem. Soc., 1990, 112,
9
659.
I. Tabushi, Y. Kuroda and K. Shimokawa, J. Am. Chem. Soc.,
979, 101, 1614; D. Q. Yuan, S. Immel, K. Koga, M. Yamagushi
1
and K. Fujita, Chem.–Eur. J., 2003, 9, 3501; X. Zhang, K. Sasaki
and Y. Kuroda, J. Org. Chem., 2006, 71, 4872; D. Q. Yuan,
K. Koga, I. Kouno, T. Fujioka, M. Fukudome and K. Fujita,
Chem. Commun., 2007, 828.
4
O. Bistri, K. Mazeau, R. Auzely-Velty and M. Sollogoub,
Chem.–Eur. J., 2007, 13, 8847; T. Lecourt, P. Sinay
C. Chassenieux, M. Rinaudo and R. Auzely-Velty, Macromolecules,
004, 37, 4635.
¨
T. Lecourt, J.-M. Mallet and P. Sinay, Eur. J. Org. Chem., 2003,
¨
,
2
5
6
4
2
¨
553; T. Lecourt, J.-M. Mallet and P. Sinay, Tetrahedron Lett.,
002, 43, 5533.
¨
D. Dong, D. Baigl, Y. Cui, P. Sinay, M. Sollogoub and Y.
Zhang, Tetrahedron, 2007, 63, 2973; O. Bistri, T. Lecourt,
J.-M. Mallet, M. Sollogoub and P. Sinay, Chem. Biodiversity,
004, 1, 129.
L. Kumprecht, M. Budesı
I. Cısarova, J. Brynda, V. Herzig, P. Koutnı
T. Kraus, J. Org. Chem., 2009, 74, 1082.
For example, see: K. Fujita, S. Ejima and T. Imoto, J. Chem. Soc.,
Chem. Commun., 1984, 1277; R. Breslow, N. Greenspoon, T. Guo
and R. Zarzycki, J. Am. Chem. Soc., 1989, 111, 8296; E. van
Dienst, B. H. M. Snellink, I. von Piekartz, M. H. B. Grote Gancey,
F. Venema, M. C. Feiters, R. J. M. Nolte, J. F. J. Engbersen and
D. N. Reinhoudt, J. Org. Chem., 1995, 60, 6537; M. R. De Jong, J.
F. J. Engbersen, J. Huskens and D. N. Reinhoudt, Chem.–Eur. J.,
¨
2
7
8
´
nsku
¨
, J. Vondra
´
sek, J. Vymetal, J. Cernu
¨
,
´
´
´
k, J. Zavada and
´
Fig. 1 Symmetry of CD-tetraplex 7a.
2
000, 6, 4034; H. F. M. Nelissen, M. C. Feiters and R. J. M. Nolte,
J. Org. Chem., 2002, 67, 5901; M. Munteanu, S. Choi and
H. Ritter, J. Inclusion Phenom. Macrocyclic Chem., 2008, 62, 197.
M. M. Luo, W. H. Chen, D. Q. Yuan and R.G. Xie, Synth.
Commun., 1998, 28, 3845; T. Kikuchi, M. Narita and F. Hamada,
Tetrahedron, 2001, 57, 9317; H. Nakajima, Y. Sakabe, H. Ikeda
and A. Ueno, Bioorg. Med. Chem. Lett., 2004, 14, 1783; J. A. Faiz,
N. Spencer and Z. Pikramenou, Org. Biomol. Chem., 2005, 3, 4239;
V. H. Soto Tellini, A. Jover, J. Carrazana, L. Galantini, F. Meijide
and J. Vazquez Tato, J. Am. Chem.Soc., 2006, 128, 5728;
L. Galantini, A. Jover, C. Leggio, F. Meijide, N. Viorel Pavel,
V. H. Soto Tellini, J. Vazquez Tato and C. Tortolini, J. Phys.
Chem. B, 2008, 112, 8536; M. Mourer, F. Hapiot, S. Tilloy,
E. Monflier and S. Menuel, Eur. J. Org. Chem., 2008, 5723.
9
1
0 T. Jiang, M. Li and D. S. Lawrence, J. Org. Chem., 1995, 60, 7293;
R. Breslow, X. Zhang and Y. Huang, J. Am. Chem. Soc., 1997,
1
19, 4535.
1 K. Sasaki, M. Nagasaka and Y. Kuroda, Chem. Commun., 2001,
630.
2 T. Lecourt, A. J. Pearce, A. Herault, M. Sollogoub and P. Sinay
Chem.–Eur. J., 2004, 10, 2960.
3 O. Bistri, P. Sinay and M. Sollogoub, Tetrahedron Lett., 2005, 46,
1
1
1
2
¨
,
¨
7
1
5
4
757; O. Bistri, P. Sinay
112; O. Bistri, P. Sinay
34; O. Bistri, P. Sinay
7, 4137; O. Bistri, P. Sinay
¨
and M. Sollogoub, Chem. Commun., 2006,
and M. Sollogoub, Chem. Lett., 2006, 35,
¨
Fig. 2 Variation of the viscosity of solutions of AD-chitosan 10 at a
À1
¨
and M. Sollogoub, Tetrahedron Lett., 2006,
, J. Jimenez-Barbero and M. Sollogoub,
concentration of 2.5 or 3 g L (0.3 M CH
3
COOH/0.03 M CH COONa,
3
¨
´
2
5 1C) with the [CD]/[AD] ratio (i.e. with increasing concentration
Chem.–Eur. J., 2007, 13, 9757; S. Guieu and M. Sollogoub, J. Org.
Chem., 2008, 73, 2819; S. Guieu and M. Sollogoub, Angew. Chem.,
Int. Ed., 2008, 47, 7060; M. Sollogoub, Eur. J. Org. Chem., 2009,
À1
of CD oligomeric species).E tetraplex 7b/AD-chit 2.5 g L , J Duplex
À1
À1
.
8/AD-chit 2.5 g L , ’ Duplex 9/AD-chit 3 g L
1
295.
1
1
4 R. H. Grubbs, Tetrahedron, 2004, 60, 7117; A. H. Hoveyda and
A. R. Zhugralin, Nature, 2007, 450, 243.
5 S. Chiu, D. C. Myles, R. L. Garell and J. F. Stoddart, J. Org.
Chem., 2000, 65, 2792.
16 T. Lecourt, J.-M. Mallet and P. Sinay, C. R. Chimie, 2003, 6, 87.
¨
As for the dimeric counterpart, a large increase of viscosity of
the polymer solution was obtained but at a much lower con-
centration of tetraplex. The basis of this surprising enhanced
efficiency is currently under investigation in our laboratories.
2
240 | Chem. Commun., 2010, 46, 2238–2240
This journal is ꢀc The Royal Society of Chemistry 2010