Fullerene sugar balls

Article abstract of DOI:10.1039/c0cc00034e

Fullerene hexakis-adducts bearing 12 peripheral carbohydrate moieties have been prepared by grafting sugar derivatives onto the fullerene core through the copper mediated Huisgen 1,3-dipolar cycloaddition of azides and alkynes.

Full text of DOI:10.1039/c0cc00034e

Chemical Communications
www.rsc.org/chemcomm
Volume 46 | Number 22 | 14 June 2010 | Pages 3805–4000
ISSN 1359-7345
FEATURE ARTICLES
Adam F. Lee et al.
Surface X-ray studies of catalytic
clean technologies
Bao-Lian Su et al.
Living hybrid materials
COMMUNICATION
Jean-François Nierengarten et al.
Fullerene sugar balls
1359-7345(2010)46:22;1-K

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Fullerene sugar ballswz
a
a
a
a
Jean-Franc¸
Beatriz M. Illescas, Antonio Mun
ois Nierengarten,* Julien Iehl, Vincent Oerthel, Michel Holler,
b
b
b
c
˜
nchez-Navarro, Samy Cecioni, Se
oz, Nazario Martı
´
d
n,* Javier Rojo,*
d
c
e
Macarena Sa
´
Maxime Durka and Stephane P. Vincent*
´
´
bastien Vidal,* Kevin Buffet,
e
e
Received 19th February 2010, Accepted 25th March 2010
First published as an Advance Article on the web 23rd April 2010
DOI: 10.1039/c0cc00034e
Fullerene hexakis-adducts bearing 12 peripheral carbohydrate
moieties have been prepared by grafting sugar derivatives
onto the fullerene core through the copper mediated Huisgen
preparing fullerene hexakis-adducts, thus obtaining truly
‘‘sugar balls’’ and providing a spherical platform for a globular
multivalent presentation of ligands. Herein, we describe the
efficient preparation of fullerene sugar balls with different
sugars as potential carbohydrate multivalent systems for
biological applications.
1
,3-dipolar cycloaddition of azides and alkynes.
Carbohydrates play a key role in many natural and patho-
logical processes through interaction with their corresponding
As far as the synthesis of the sugar balls is concerned, the
direct grafting of six malonates bearing sugar residues to the
fullerene core would be quite limited. Indeed, fullerene
hexakis-adducts are generally obtained in rather low yields
1
receptors, mainly proteins. This interaction is highly selective,
2
calcium dependent in some cases, and multivalent. The
multivalent presentation of carbohydrates is a crucial point
for achieving high affinity interactions and, therefore, an
essential requirement for developing artificial tools with the
aim to understand, unravel and interfere with those processes
1
2
from structurally complicated malonates. Furthermore, this
strategy would require the preparation of new malonates for
each derivative as well as the use of protecting groups for the
hydroxyl functions of the sugars. Therefore, we have decided
to apply the approach based on click chemistry developed by
3
where carbohydrates are involved. Different synthetic
scaffolds allowing a multivalent presentation of ligands have
already been described in the literature. Among them, the
1
3
some of us for the efficient functionalization of fullerene
hexakis-adducts with sugar residues. As click reactions are
modular, tolerant to a wide range of functional groups, and
4
most popular are dendrimers, nanoparticles, polymers, and
5
6
7
liposomes. Owing to their rigid spherical shape, fullerene
1
4
hexakis-adducts with a T -symmetrical octahedral addition
h
8
pattern appear to be a very attractive core molecule for the
high yielding, no protecting groups are needed and a large
number of sugar balls should become easily available by using
this synthetic approach.
synthesis of unique globular multivalent derivatives. Until
now, some fullerene derivatives bearing sugar residues have
Fullerene hexakis-adduct 1 was prepared in three steps as
1
9
been reported in which either a monoaddition pattern on the
3b
previously described.
Treatment with an excess of tetra-
1
0,11
fullerene sphere or a ‘‘one-side’’ multiaddition
led to
butylammonium fluoride (TBAF) gave the corresponding
hexa-adduct 2 bearing 12 terminal alkyne units (Scheme 1).
The reaction conditions for the 1,3-dipolar cycloaddition of
compound 2 with sugars bearing an azide group were first
adjusted with the commercially available derivatives 3a and
amphiphilic structures, with a hydrophobic fullerene subunit
occupying a part of the outer architecture of the molecule. The
aggregation of these molecules has been documented in some
1
1
cases. Such amphiphilic character could be avoided by
3
b. In the case of the acetylated derivative 3a, the reaction
a
Laboratoire de Chimie des Mate
´riaux Mole´culaires,
Universite´ de Strasbourg et CNRS (UMR 7509),
Ecole Europe´enne de Chimie, Polyme`res et Mate´riaux (ECPM),
25 rue Becquerel, 67087 Strasbourg Cedex 2, France.
13
conditions previously developed for the grafting of azide
groups to fullerene derivative 2 were successfully applied to
give compound 4a in excellent yield. A mixture of 2 (1 equiv.),
E-mail: nierengarten@chimie.u-strasbg.fr; Fax: +33-368-85-27-74
Departamento de Quı´mica Orga´nica, Facultad de Ciencias Quı´micas,
Universidad Complutense, 28040 Madrid, Spain.
3a (13 equiv.), CuSO
0.3 equiv.) in CH Cl
ꢀ5H
O (0.1 equiv.) and sodium ascorbate
4
2
b
c
d
(
2
2
2
–H O was vigorously stirred at room
temperature for 12 h. Compound 4a was obtained in 91%
yield after work-up and purification by fast filtration on SiO2
followed by gel permeation chromatography (Biobeads SX-1,
CH Cl ). The reaction conditions used for the preparation of
E-mail: nazmar@quim.ucm.es; Fax: +34-91-394-4103
Grupo de Carbohidratos, Instituto de Investigaciones Quı´micas,
CSIC-Universidad de Sevilla, Ame´rico Vespucio, 49. Isla de la
Cartuja, 41092 Sevilla, Spain. E-mail: javier.rojo@iiq.csic.es
Institut de Chimie et Biochimie Mole´culaires et Supramole´culaires,
Laboratoire de Chimie Organique 2 – Glycochimie, UMR5246,
CNRS, Universite´ Lyon 1, 43 Boulevard du 11 Novembre 1918,
F-69622, Villeurbanne, France. E-mail: sebastien.vidal@univ-lyon1.fr
University of Namur (FUNDP), De´partement de Chimie,
Laboratoire de Chimie Bio-Organique, rue de Bruxelles 61,
B-5000 Namur, Belgium. E-mail: stephane.vincent@fundp.ac.be
2
2
4
a from 3a were then adapted to unprotected azide 3b.
Actually, in CH Cl –H O, no reaction could be observed.
2
2
2
The latter observation is most probably related to the difference
e
in solubility of the two precursors, 3b being only soluble in the
2 2
aqueous phase and 2 only in the CH Cl one. This prompted
w This article is part of the ‘Carbon Nanostructures’ web-theme issue
for ChemComm.
z Electronic supplementary information (ESI) available: Experimental
details for the preparation of the new compounds and NMR data of
compounds 4c–d and 7a–d. See DOI: 10.1039/c0cc00034e
us to attempt the reaction between 2 and 3b in different
solvents. The best results were obtained in DMSO in which
both 2 and 3b are soluble. Under optimized conditions,
a mixture of 2 (1 equiv.), 3b (13 equiv.), CuSO ꢀ5H O
4
2
3
860 | Chem. Commun., 2010, 46, 3860–3862
This journal is ꢁc The Royal Society of Chemistry 2010

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3
C atoms (d = 69.0 for the sp C atom; 141.0 and 145.8 ppm for
the sp C atoms). Indeed, these 3 signals are reminiscent of
2
those of the three non-equivalent fullerene C atoms of the
hexakis-adduct carrying achiral addends (overall T symmetry).
h
No influence of the overall symmetry of 4a which is T could be
2
deduced and the two pairs of diastereotopic sp C atoms are
pseudo-equivalent. Similar observations have been reported for
15
1
3b
mixed fullerene hexa-adducts and related C60 derivatives.
The MALDI-TOF mass spectrum further confirmed the
structure of 4a with an intense signal at m/z = 6606 corres-
+
ponding to the expected molecular ion peak ([M] , calcd. for
1
132: 6606.01). The H and C NMR spectra of
13
C
306
H
312
N
36
O
4b were also in perfect agreement with the proposed formulation.
As shown in Fig. 1, the two expected resonances of the C
atoms of the 1,2,3-triazole unit as well as the 6 signals of the 6
different C atoms of the 12 equivalent glucose residues are
1
3
clearly observed in the C NMR spectrum of 4b. To further
confirm the structure of 4b, mass spectra (MALDI-TOF,
ESMS and FAB) were recorded under different conditions.
However, in all the cases, a high level of fragmentation
prevented the observation of the expected molecular ion peak.
We thus decided to acetylate a sample of compound 4b to
generate 4a for which MS analysis has been successfully
achieved. An aliquot of 4b was treated with a large excess of
acetic anhydride in pyridine. The resulting product was identical
1
TLC and H NMR) to the original sample of 4a prepared
(
from 2 and 3a. Importantly, its MALDI-TOF mass spectrum
was also identical to the one obtained from an original sample
of 4a. The latter result clearly validates the structural
characterization of the unprotected fullerene sugar balls based
1
13
on their H and C NMR data.
The reaction conditions used for the preparation of 4b from
azide 3b were then applied to the more elaborated sugar azide
Scheme 1 Reagents and conditions: (i) TBAF, CH
from 2: CuSO O, sodium ascorbate [4a: in CH Cl
ꢀ5H
b–d: in DMSO (4b: 74%; 4c: 90%; 4d: 72%)]; (iii) from 1: TBAF,
CuSO O, sodium ascorbate [4a: in CH Cl –H O (51%); 4b: in
ꢀ5H
DMSO (4b: 58%)].
2
Cl
2
(92%); (ii)
4
2
2
2
–H
2
O (91%);
4
4
2
2
2
2
(
0.1 equiv.) and sodium ascorbate (0.3 equiv.) in DMSO was
stirred at room temperature for 60 h. At the end of the
reaction, the product was precipitated by addition of MeOH,
filtered and extensively washed with MeOH and CH Cl .
2
2
Sugar ball 4b was thus obtained in 74% yield. Interestingly,
we found that compounds 4a–b can also be directly prepared
from fullerene derivative 1. Indeed, compound 1 can be
desilylated in situ with TBAF to form 2, to which the azide
precursors 3a or 3b can be subsequently clicked. Compounds
4
a and 4b were thus obtained from 1 and the corresponding
azide in 51 and 58% yield, respectively. The chemical structure
1
of compound 4a was easily confirmed by its H and C NMR
13
1
3
spectra. In particular, the C NMR spectrum of fullerene
hexakis-adduct 4a (Fig. 1) is in full agreement with its
T-symmetrical structure and shows the expected signals
for the 6 equivalent malonate addends. Only 3 signals out of
the 5 expected ones are however observed for the fullerene
13
Fig. 1
C NMR spectra of 4a (top) recorded in CDCl (100 MHz,
6
Cl ) and of 4b (bottom) recorded in DMSO-d (100 MHz,
3
*
: residual CH
2
2
*: residual CH Cl and MeOH); unambiguous assignment was achieved
2
2
with the help of the corresponding DEPT spectra (see ESIz).
This journal is ꢁc The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 3860–3862 | 3861

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derivatives 3c–d. The clicked derivatives 4c–d were thus
obtained in 73% yield. The same conditions were then
successfully used for the preparation of 7b–d from 5 and the
corresponding sugar-alkyne derivatives 6b–d. In the case of 7c,
the moderate isolated yield is explained by the difficulties in
separating the product from unreacted 6c (used in excess)
during the successive dissolution/precipitation. The structure
obtained in excellent yields (72–90%) and their structure
1
13
confirmed by their H and C NMR spectra as well as
by IR spectroscopy. Furthermore, the UV/vis spectra of
compounds 4a–d show the characteristic features of fullerene
8
,12
hexa-adducts.
Having developed an efficient procedure for
1
13
the preparation of sugar balls from a fullerene alkyne building
block and sugar azide derivatives, we also decided to attempt
the reverse approach starting from fullerene derivative 5
of compounds 7a–d was confirmed by their H and C NMR
1
spectra. Inspection of the H NMR spectra clearly indicates
the disappearance of the CH
2
-azide signal at d 3.33 ppm. IR
data also confirmed that no azide (2092 cm ) residues remain
1
3a
ꢂ1
bearing 12 azide functional groups (Scheme 2).
1
in the final products. Importantly, the H NMR spectra of
Treatment of 5 with alkyne 6a under the reaction conditions
developed for the preparation of 4b (CuSO
4
ꢀ5H
2
O, sodium
7a–d show the typical signal of the 1,2,3-triazole unit at ca. d
7.81–8.04 ppm.
ascorbate, DMSO) gave only partially clicked derivatives.
Indeed, these intermediates precipitate during the course of
the reaction. Longer reaction time and/or higher temperatures
were not efficient strategies to complete the reaction and
another solvent had to be selected to allow the preparation
of sugar balls from 5. The best results were obtained when the
In conclusion, we have reported for the first time on the
synthesis of fullerene glycoconjugates in which the C60 core is
completely surrounded by sugar residues. The methodology
based on the Huisgen-type click chemistry allows for the easy
preparation of a large variety of sugar balls. The peculiar
spherical distribution of the sugar residues gives rise to
unprecedented globular polytopic ligands and their biological
activities are under investigation.
2 2 2
reaction was carried out in a CH Cl –H O–DMSO (1 : 1 : 1)
mixture. Hence, when the reaction between 5 and 6a was
performed in this ternary solvent system, compound 7a was
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Scheme 2 Reagents and conditions: (i) CuSO
4
ꢀ5H
2
O, sodium ascorbate,
¨
se, Chem.
CH Cl –H O–DMSO 1:1:1 (7a: 73%; 7b: 81%; 7c: 40%; 7d: 54%).
2
2
2
3
862 | Chem. Commun., 2010, 46, 3860–3862
This journal is ꢁc The Royal Society of Chemistry 2010