Sugar balls: Synthesis and supramolecular assembly of [60]fullerene glycoconjugates

Article abstract of DOI:10.1002/ejoc.200700179

The synthesis and characterization of fully deprotected C₆₀ glycoconjugates 4 and 17 is reported. Bis(α-D-mannopyranosyl)malonamide 4 was obtained by using nucleophilic cyclopropanation chemistry, which in general is a very versatile method for

Full text of DOI:10.1002/ejoc.200700179

FULL PAPER
DOI: 10.1002/ejoc.200700179
Sugar Balls: Synthesis and Supramolecular Assembly of [60]Fullerene
Glycoconjugates
Haruhito Kato,[a] Christoph Böttcher,[b] and Andreas Hirsch*[a]
Keywords: Sugars / Mannose / Dendrimers / Fullerenes / Self-assembly / Micelles
The synthesis and characterization of fully deprotected C60
glycoconjugates 4 and 17 is reported. Bis(α- -mannopyrano- dritic glycoconjugate 17 containing six deprotected sugar
syl)malonamide 4 was obtained by using nucleophilic cyclo- building blocks is very soluble in water. The amphiphilic na-
struction of the core structure of the fullerene sugar. Den-
D
propanation chemistry, which in general is a very versatile
method for fullerene functionalization. Fullerene sugar 17
contains two dendritic α-D-mannopyranosides that are con-
nected through two adjacent imino bridges to the all-carbon
framework. In this adduct-type of C60, which represents a
1,9-dihydro-1a-aza-1(2)a-homo(C60-Ih)[5,6]fullerene deriva-
tive, the entire 60-π-electron system of the fullerene core is
retained. This architecture allows the basic cleavage of the
acetyl protection groups of precursor adduct 16 without de-
ture of 17 with its cone-shaped structure forces the formation
of small supramolecular aggregates in aqueous solutions to
shield the hydrophobic fullerene units from the water sub-
phase. DOSY NMR spectroscopy and TEM investigation re-
veal micellar sugar balls with an extremely narrow size dis-
tribution of around 4 nm.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Apart from monosaccharide binding, a synthetic route for
the attachment of oligosaccharides to C60 by the cyclo-
addition of azido sugars to the fullerene core, followed by
deacetylation, was reported.[6] All fullerene sugars reported
so far show, if at all, only very limited solubility in water.
We have now developed the fullerene glycoconjugate 17
where two dendritic branches terminated by six deprotected
α--mannopyranosyl building blocks are connected
through two adjacent imino bridges to the all-carbon
framework. In this bis(imino)homofullerene, the entire 60-
π-electron system of the fullerene core is retained (Fig-
ure 1). Fullerene sugar 17 represents the first very water sol-
uble glycoconjugate of C60. To also exploit nucleophilic cy-
clopropanation chemistry,[7] which represents one of most
versatile functionalization methods of fullerenes, we also
synthesized and characterized bis(α--mannopyranosyl)ful-
lerene 4 (Scheme 1).
Introduction
Since the synthesis of the first fullerene sugars in both
the fully protected and deprotected forms by Vasella and
Diederich,[1] various families of fullerene glycoconjugates
have been designed and characterized.[2] Fullerene sugars
have potential in biomedical and materials applications. For
example, amphiphilic [60]fullerene-sugar-conjugates with
one and two fully protected glycodendron headgroups, form
stable, ordered monomolecular Langmuir layers at the air–
water interface.[3] The monolayers were transferred success-
fully as X-type Langmuir–Blodgett films onto quartz slides.
In contrast, mono- and bis(α--mannopyranosyl)[60]fuller-
ene adducts displayed marked activity in blocking lectin-
induced hemagglutination by concanavaline A.[4] The corre-
sponding bis(α--mannopyranosyl)[60]fullerene was found
to form large aggregates during sugar deprotection as deter-
mined by dynamic light scattering (DLS) and atomic force
microscopy (AFM).[5] Thiolate/alkyl halide coupling in
aqueous media provided a facile one-step synthesis of ful-
lerene glycoconjugates bearing five carbohydrate groups.[2f]
[a] Institut für Organische Chemie and Interdisciplinary Center for
Molecular Materials (ICMM) der Friedrich-Alexander-Uni-
versität Erlangen-Nürnberg
Henkestrasse 42, 91054 Erlangen
E-mail: andreas.hirsch@chemie.uni-erlangen.de
[b] Forschungszentrum für Elektronenmikroskopie, Institut für
Chemie und Biochemie, Freie Universität Berlin,
Fabeckstrasse 36a, 14195 Berlin, Germany
Fax: +49-30-838-56589
Figure 1. Schematical representation of a diazabishomo[60]fuller-
ene.
E-mail: christoph.boettcher@fzem.fu-berlin.de
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H. Kato, C. Böttcher, A. Hirsch
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times as high as the remaining 26 lines and attributed to
two magnetically equivalent carbon atoms.
Treatment of 3 with MeONa in a mixture of CH2Cl2 and
MeOH led to the quantitative removal of all acetyl protect-
ing groups and the deposition of a brown precipitate of 4.
Unprotected sugar 4 is soluble in DMSO, DMF and mix-
tures of water and DMSO. However, it is insoluble in pure
water, MeOH, EtOH, acetone, THF, CH2Cl2 and CHCl3.
1
The H NMR spectrum of 4 in [D6]DMSO revealed very
broadened signals, which suggests that 4 forms aggregates
in DMSO. The poor solubility of 4 in most solvents is prob-
ably due to its pronounced propensity to form large aggre-
gates. It was observed before that many deprotected sugar
conjugates of C60 are only sparingly soluble in DMF,
DMSO and mixtures of DMSO and water and give very
broad signals in their NMR spectra.[1a,2c,4–6]
For the synthesis of target compound 17, the dendritic
mannosyl building blocks first needed to be assembled. For
this purpose, Newkome dendron 5[10] was protected with
benzyl chloroformate (CbzCl) prior to the coupling reaction
Scheme 1. Synthesis of bis(α--mannopyranosyl)malonamide-
[60]fullerene-conjugate 4: i) PPh3, H2O, THF; ii) malonic acid,
HBTU, DIPEA, DMF; iii) C60, CBr4, DBU, toluene.
with
2-aminoethyl-2,3,4,6-tetra-O-acetyl-α--mannopyr-
Results and Discussion
anoside[2b] (Scheme 2). Treatment of tris(ester) 6 with for-
mic acid led to quantitative deprotection and the formation
of corresponding tris(acid) 7. The subsequent coupling re-
Syntheses
For the synthesis of fullerene sugar 4, fully acetyl- action of tris(acid) 7 with 2-aminoethyl-2,3,4,6-tetra-O-ace-
protected bis(α--mannopyranose)malonamide 2 was first tyl-α--mannopyranoside was carried out in the presence
synthesized (Scheme 1). This was achieved by the reduction of DCC/HOBT as the coupling reagent in a mixture of
of 2-azidoethyl-2,3,4,6-tetra-O-acetyl-α--mannopyrano- dichloromethane and DMF (2:1) to give mannosyl glyco-
side (1)[2b] to the corresponding amine. Upon hydrogena- dendron 8 in 83% yield.
tion [H2/Pd or Pd(OH)2],[8] significant amounts of the di-
meric secondary amines were formed, as confirmed by 13C
NMR spectroscopy and FAB mass spectrometry. However,
clean and quantitative reduction of 1 was obtained with the
use of triphenylphosphane (Staudinger reduction)[9] in
THF. The chromatographically purified amine was then al-
lowed to undergo a coupling reaction with malonic acid in
the presence of O-(benzotriazole-1-yl)-N,N,NЈ,NЈ-tetra-
methyluronium hexafluorophosphate (HBTU) and diiso-
propylethylamine (DIPEA) in DMF. After purification, de-
sired malonamide 2 was isolated in 56% yield. The subse-
quent nucleophilic cyclopropanation of C60 with malonam-
ide 2 was carried out in toluene with CBr4 as the bromine
transfer reagent and DBU as the base. Unreacted C60 was
removed from the crude mixture by flash chromatography
(SiO2, toluene to 10% MeOH in toluene) upon which also
a fraction containing a mixture of fullerene glycoconjugates
eluted. Mono adduct 3 was isolated from higher adducts by
an additional chromatographic separation (SiO2, 1%
MeOH in CHCl3). The overall isolated yield of 3 was 6%.
The UV/Vis spectrum of 3 gives a sharp absorption at
Scheme 2. Syntheses of glycosyl dendron 8: i) ZCl, NaHCO3, ace-
426 nm, which corresponds to the typical spectrum of a
tone/water, 9:1; ii) formic acid; iii) 2-aminoethyl-2,3,4,6-tetra-O-
1
[6,6]-monoadduct of C60. The H NMR spectrum of 3 re-
vealed two equivalent 2-aminoethyl-2,3,4,6-tetra-O-acetyl-
α--mannopyranoside units. The 13C NMR spectrum of 3
acetyl-α--mannopyranoside, DCC, HOBT, DMF, CH2Cl2.
We decided to couple dendritic building 8 with C60 by
clearly reveals the expected C2-symmetry and shows the ful- using the very regioselective bisaddition of azides to give
lerene sp3 carbon atom at δ = 73.61 ppm and 27 signals for a twofold cluster-opened diazabishomofullerene adduct,[11]
the fullerene sp2 carbon atoms, where one signal, which is whose general structure is schematically depicted in Fig-
attributed to three closely overlapping resonances, is three ure 1. For this purpose, a suitable linker molecule bearing
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Sugar Balls: [60]Fullerene Glycoconjugates
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a terminal azide group was required. The best results were sion to fluoride 14, which was used for the subsequent
obtained with the hitherto unknown 2-[2-(2-azidoethoxy)- coupling reactions without further work up. For the coup-
ethoxy]acetyl fluoride (14). It was obtained by the oxidation ling reaction, the Cbz protecting group of 8 was first re-
of commercially available glycol derivative 9, followed by moved by hydrogenolysis (10% of Pd on C) in a mixture of
conversion into ester 11 and introduction of the azide group EtOH and ethyl acetate (1:2) to give the corresponding
to give compound 12 (Scheme 3). The final steps of the syn- amine in quantitative yield. The obtained amine was treated
thetic sequence were the hydrolysis to acid 13 and conver- without further work up with an excess amount of 14 in
Scheme 3. Syntheses of water-soluble dendritic fullerene sugar 17: i) TEMPO, trichlorocyanuric acid, NaHCO3, water/acetone; ii) NaOMe,
methanol, MeI, DMF; iii) NaN3, DMF, 60 °C; iv) NaOH, H2O, MeOH; v) HFPDA, CH2Cl2; vi) Pd/C, aqueous HCl, H2, ethyl acetate/
ethanol, 2:1; vii) 14, DMAP, CH2Cl2; viii) C60, toluene, reflux; ix) NaOMe, MeOH.
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the presence of DMAP as the base in CH2Cl2 to provide termined with molecular precision by using transmission
azido oligo(ethylene glycol)-terminated glycodendron 15 in electron microscopy (TEM).[15] To corroborate the observa-
94% yield. The thermal coupling reaction between 15 and tions on the aggregation of 17 described above, we also car-
C60 in toluene afforded a mixture of mono- and bisglyco- ried out TEM investigations with aqueous solutions of ful-
dendron adducts (silica gel TLC, Rf = 0.67 and Rf = 0.61, lerene sugar 17. We were very pleased to see that indeed
CHCl3/MeOH, 10:1). After removal of C60 by column very uniform micelles were formed whose diameter is below
chromatography, an additional chromatographic separation 5 nm (Figure 2). These supramolecular structures represent
step (SiO2, 10% MeOH in CHCl3) allowed the separation a new arrangement of sugars and can be considered as mi-
of the product from the monoadduct to give targeted bisgly- cellar sugar balls.
codendron 16 in 8% overall yield. The UV/Vis spectrum of
16 shows broad absorptions at 256 nm and 324 nm, which
are characteristic for a diazabishomofullerene possessing
two opened and adjacent [5,6]-bonds.[11] The 1H NMR
spectrum of 16 reveals two equivalent glycodendron ad-
dends. The 13C NMR spectrum displays 31 lines for the
fullerene sp2 C atoms, 1 with fourfold intensity, 26 with two-
fold intensity and 3 with single intensity, which implies a
C2-symmetric structure. This finding is surprising at first
glance because, owing to the chirality of the mannosyl
groups, the overall symmetry of 17 is lowered to C1 relative
to a corresponding bisadduct containing two achiral sub-
stituents.[2b,6] Obviously, the conformationally very flexible
and long spacer linking of the fullerene part with the sugar
subunits causes a high amount of flexibility. As a conse-
quence, the fullerene core experiences a local Cs symmetry
Figure 2. Transmission electron micrograph of the micellar sugar
on the NMR timescale. The most characteristic signal in
the 13C NMR spectrum is that of the bridgehead atom
C1 (Figure 1), which appears as expected[11] at about
163 ppm.
balls composed of amphiphiles 17. Thin layers of the aqueous solu-
tion of 17 were created on the surface of carbon-coated grids by
blotting droplets with a filter paper. After subsequent addition of
a contrasting solution (phosphotungstic acid at pH 7) and blotting,
the grids were dried in air. Microscopy was carried out by using a
Philips CM12 TEM (FEI Company, Oregon, USA) at an accelerat-
The quantitative deprotection of 16 to generate desired
fullerene sugar 17 was accomplished by treatment with ing voltage of 100 kV and a defocus of 600 nm corresponding to a
first zero of the contrast transfer function at 1.5 nm. The micro-
scope’s low dose protocol was used to avoid unnecessary radiation
damage in the sample. The image shows a monodisperse popula-
tion of spherical particles with a diameter in the order of
MeONa in methanol. Significantly, sugar 17 very easily dis-
solves in water; the water solubility is higher than
1
40 mgmL–1. The H NMR spectrum of 17 in D2O displays
rather broad signals, which implies that aggregates are
formed from this new sugar amphiphile. The aggregation of
amphiphilic fullerene derivatives to micelles, liposomes and
nanorods[12] as well as to Langmuir–Blodgett films,[3,13] was
documented for a variety of cases. It can be expected that
the corresponding aggregates of 17 are very small micelles
because the aqueous solutions are clear to the eye even
when they are fairly concentrated. Indeed, determination of
4Ϯ0.5 nm. Very rarely larger agglomerates were found. The con-
trast of the negative was not inverted for better visibility of the
small objects.
Conclusions
We synthesized fullerene glycoconjugate 17 where two
the particle size by using DOSY NMR spectroscopy re- dendritic α--mannopyranosides are connected through
vealed a diameter of the micelles of 4.2 nm. Considering two adjacent imino bridges to the all-carbon framework. In
that amphiphilic fullerene sugar 17 exhibits a rather cone this adduct-type of C60, which represents a 1,9-dihydro-1a-
shaped architecture in which the hydrophilic part is much aza-1(2)a-homo(C60-Ih)[5,6]fullerene derivative, the entire
larger than the hydrophobic fullerene subunit, it is unlikely 60-π-electron system of the fullerene core is retained, which
that large liposomal aggregates are easily generated.[14] The allows the basic cleavage of the acetyl protection groups of
conical shape of 17 obviously favours the formation of precursor adduct 16 without destruction of the core struc-
highly curved micelles in water where the smaller fullerene ture of the fullerene sugar. In general, nucleophilic cyclo-
moieties are located in the centre of the aggregates, whereas propanation chemistry is a very versatile method for the
the more extended hydrophilic sugar parts are exposed to functionalization of fullerenes. However, it turned out that
the water subphase. Only in this way can close-packing of basic deprotection of acetylated glycosides terminating ma-
the amphiphiles within the aggregated be achieved. Along lonates attached to C60 is accompanied by the cleavage of
the same lines, we have recently demonstrated that amphi- the malonate anchor points. However, to overcome this
philic fullerenes and calixarenes that exhibit a compara- problem, we introduced for the first time a nucleophilic cy-
tively rigid cone- or T-shape form small shape-persistent clopropanation of C60 for the synthesis of deprotected ful-
micelles, whose supramolecular arrangement could be de- lerene sugars by using a bis(α--mannopyranosyl)malon-
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UV/Vis spectroscopy was performed by using a Shimadzu UV-3102
spectrophotometer. Elementary analysis succeeded by combustion
and gas chromatographical analysis with an EA 1110 CHNS ana-
lyser (CEInstruments). Products were isolated by flash column
chromatography (FC) (silica gel 60, particle size 0.04–0.063 nm,
Merck).
amide as a precursor addend. The amide linkages tolerate
the basic deprotection conditions as demonstrated with the
synthesis of glycoconjugate 4. In contrast to 4, which con-
tains two α--mannopyranosyl moieties only, dendritic gly-
coconjugate 17 containing six deprotected sugar building
blocks is very soluble in water. To the best of our knowl-
edge, 17 is by far the most water-soluble fullerene sugar
known to date. The amphiphilic nature of 17 with its cone-
shaped structure forces the formation of small supramolec-
ular aggregates in aqueous solutions to shield the hydro-
phobic fullerene units from the water subphase. DOSY
NMR spectroscopy reveals a very small particle size of
about 4 nm. This was corroborated by TEM investigations,
Bis[2-(2,3,4,6-tetra-O-acetyl α-D-mannopyranosyl)ethyl] Malon-
amide (2): Ph3P (1.38 g, 5.5 g) and water (1.8 mL, 100 mmol) were
added to a THF solution (35 mL) of 2-azidoethyl-2,3,4,6-tetra-O-
acetyl-α--mannopyranoside (2.09 g, 5.0 mmol). The mixture was
stirred at room temperature for 16 h. The reaction mixture was
concentrated in vacuo, and the residue was separated by FC
(CHCl3/MeOH, 100:1–5:1) to give 2-aminoethyl-2,3,4,6-tetra-O-
acetyl-α--mannopyranoside (1.66 g). The obtained amine was
which showed that spherical micelles with an extremely nar- used for the next step. A DMF solution (2.0 mL) of malonic acid
(0.208 g, 2.00 mmol), HBTU (1.70 g, 4.40 mmol), HOBt (hydroxy-
benzotriazole) (674 mg, 4.40 mmol) and DIPEA (0.568 g,
4.40 mmol) was stirred for 20 min at 0 °C under a N2 stream. A
DMF solution (2.0 mL) of 2-aminoethyl-2,3,4,6-tetra-O-acetyl-α-
-mannopyranoside (1.66 g, 4.22 mmol) was added to the solution,
and the mixture was stirred for 13 h at room temp. under a N2
stream. The solvent was removed in vacuo, and the residue was
dissolved in CHCl3 (200 mL) and washed with 1  HCl, a saturated
solution of NaHCO3 and a saturated solution of NaCl. The or-
ganic layer was dried with MgSO4. After evaporation of the sol-
row size distribution are formed. These small micelles repre-
sent supramolecular sugar balls, which have potential for
biomedical applications such as neuroprotection due to su-
peroxide-dismutation.[16] So far, water-soluble fullerene de-
rivatives that were successfully studied in this regard con-
tain ionic groups such as carboxylates for the promotion of
water solubility. Fullerene sugars like 17 have neutral com-
ponents only. This may improve the bioavailability and
pharmacokinetic properties of such bioactive fullerenes
considerably. Investigations along these lines are currently vent, the resulting crude product was separated by FC (CHCl3/
MeOH, 100:2)to give 12 as a colourless solid. Yield: 946 mg (56%)
based on malonic acid. H NMR (300 MHz, CDCl3, 300 K) 2.00
underway in our laboratory.
1
(s, 6 H, Ac), 2.06 (s, 6 H, Ac), 2.11 (s, 6 H, Ac), 2.16 (s, 6 H, Ac),
3.25 (s, 2 H, COCH2CO), 3.45–3.63 (m, 4 H, OCH2CH2N), 3.50–
3.63 (m, 2 H, OCH2CH2N), 3.76–3.82 (m, 2 H, OCH2CH2N), 4.01
(ddd, J = 2.5, 5.5, 9.5 Hz, 2 H, 5-H), 4.12 (dd, J = 2.4, 12.2 Hz, 2
H, 6-H), 4.28 (dd, J = 5.4, 12.2 Hz, 2 H, 6Ј-H), 4.84 (d, J = 1.2 Hz,
2 H, 1-H), 5.26 (dd, J = 1.7, 3.1 Hz, 2 H, 2-H), 5.27 (dd, J = 10.0,
9.7 Hz, 2 H, 4-H), 5.34 (dd, J = 3.2, 10.0 Hz, 2 H, 3-H), 7.25 (t, J
= 5.2 Hz, 2 H, NH) ppm. 13C NMR (75 MHz, CDCl3, 300 K): δ
= 20.29 (2 C), 20.31 (2 C), 20.35 (2 C), 20.46 (2 C), 38.57 (2 C),
42.05 (1 C), 62.02 (2 C), 65.62 (2 C), 66.46 (2 C), 68.16 (2 C), 68.65
(2 C), 68.93 (2 C), 97.23 (2 C), 167.32 (2 C), 169.32 (2 C), 169.54
Experimental Section
General: All chemicals were obtained from Sigma–Aldrich, Acros
Organics or Merck, or they were prepared according to known
literature procedures. All reactions were performed by using stan-
dard glassware under a nitrogen atmosphere. The solvents were
purified by distillation. Dry solvents were prepared by using cus-
tomary literature procedures. Reactions were monitored by thin-
layer chromatography (TLC) using Riedel-de-Haën silica gel 60
F254 aluminium foils, detection by UV lamp. 1H and 13C NMR
spectra were recorded with Bruker Avance 300 or JEOL JNM EX
400 instruments. The chemical shifts are given in ppm relative to
TMS or the solvent peak as a standard reference. The 1H NMR
and 13C NMR of 17 in D2O were calibrated with HOD as 4.75 ppm
at 300 K, and with C=O of 17 as 175.78 ppm that was determined
with C=O of added [D6]acetone as 215.94 ppm, respectively. The
resonance multiplicities are indicated as s (singlet), d (doublet), t
(triplet), q (quartet) and m (multiplet), unresolved signals as br.
The atoms of the sugar moieties are numbered according to stan-
dard numbering for sugars. Mass spectra were measured with a
Micromass Lab Spec (FAB) with the use of a Finnigan MAT 900
spectrometer with 3-nitrobenzylalcohol as the matrix. MALDI-
TOF (Matrix-assisted laser desorption/ionisation time-of-flight)
mass spectra were acquired with an AXIMA-CFR plus instrument
(Kratos Analytical, Manchester, UK) equipped with a 1.2-m drift
tube. MALDI was produced by pulses of UV light (337 nm, 3-ns
pulse width) generated by a nitrogen laser with a maximum pulse
rate of 10 Hz. The laser was operated between 5.0 and 17 µJ. The
ion source was held at 1ϫ10–4 Pa. For the reflectron mode, the
delayed extraction was optimized according to the molecular mass
of the analyte. IR spectra were recorded with a React IR-1000 ASI
Applied Systems (ATR-DiComp-Detector) on a diamond crystal.
(2 C), 169.58 (2 C), 170.30 (2 C) ppm. IR (ATR): ν = 2945, 1741,
˜
1671, 1532, 1432, 1370, 1216, 1135, 1081, 1042, 977, 899, 687 cm–1.
MS (FAB, NBA): m/z = 850 [M]+, 808 [M – Ac]+. C35H50N2O22·
1/3CH2Cl2 (850.29): calcd. C 48.28, H 5.81, N 3.19; found C 48.29,
H 5.80, N 3.20.
1,2-{Bis[2-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyloxy)ethyl-
aminocarbonyl]methano}-1,2-dihydro(C60-Ih)[5,6]fullerene (3): C60
(72 mg, 0.10 mmol) was dissolved in dry toluene (50 mL) under an
atmosphere of N2. Subsequently, malonamide 2 (85 mg,
0.10 mmol) and CBr4 (33 mg, 0.11 mmol) were added, followed by
the dropwise addition of a solution of DBU (16 mg, 0.11 mmol) in
toluene (20 mL) over a period of 20 min. The solution was stirred
at room temperature for 1 d. The crude reaction mixture was sepa-
rated by FC. The remaining C60 and other impurities were eluted
with toluene, and then the eluent was changed to a mixture of
CHCl3/MeOH = 100:1 to give 3 as a brown solid. Yield: 10 mg
1
(6%). H NMR (300 MHz, CDCl3, 300 K): δ = 1.97 (s, 6 H, Ac),
2.04 (s, 6 H, Ac), 2.12 (s, 6 H, Ac), 2.14 (s, 6 H, Ac), 3.69–3.96 (m,
8 H, OCH2CH2N), 4.03 (ddd, J = 2.4, 5.5, 9.1 Hz, 2 H, 5-H), 4.13
(dd, J = 2.4, 12.2 Hz, 2 H, 6-H), 4.29 (dd, J = 5.5, 12.2 Hz, 2 H,
6Ј-H), 4.82 (d, J = 1.4 Hz, 2 H, 1-H), 5.23 (dd, J = 1.7, 3.0 Hz, 2
H, 2-H), 5.26 (dd, J = 9.5, 9.5 Hz, 2 H, 4-H), 5.27 (dd, J = 3.2,
9.8 Hz, 2 H, 3-H), 8.00 (t, J = 5.5 Hz, 2 H, NH) ppm. 13C NMR
(75 MHz, CDCl3, 300 K): δ = 20.68 (2 C), 20.74 (2 C), 20.82 (2 C),
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20.90 (2 C), 40.23 (2 C), 58.25 (1 C), 62.55 (2 C), 66.00 (2 C), 67.47 Benzyl N-(Tris{2-[2-(2,3,4,6-tetra-O-acetyl-α-
D-mannopyranosyl-
(2 C), 68.82 (2 C), 69.10 (2 C), 69.32 (2 C), 73.61 (2 C), 98.03 (2 oxy)ethylcarbamoyl]ethyl}methyl)carbamate (8): A solution of 2-
C), 137.80 (2 C), 137.90 (2 C), 141.00 (2 C), 141.01 (2 C), 141.97
(2 C), 142.12 (6 C), 142.88 (2 C), 142.92 (2 C), 143.00 (2 C), 143.02
(2 C), 143.06 (2 C), 143.69 (2 C), 143.74 (2 C), 144.45 (2 C), 144.52
(2 C), 144.65 (2 C), 144.67 (2 C), 144.69 (2 C), 144.74 (2 C), 145.17
(2 C), 145.20 (2 C), 145.22 (2 C), 145.26 (2 C), 145.28 (2 C), 145.38
(2 C), 145.81 (2 C), 146.23 (2 C), 163.12 (2 C), 169.66 (2 C), 169.89
aminoethyl-2,3,4,6-tetra-O-acetyl-α--mannopyranoside (1.25 g,
3.20 mmol) in dry dichloromethane (10 mL) was added to a stirred
solution of benzyl N-[tris(3-propanoic acid) methyl]carbamate
(339 mg, 0.89 mmol), N,NЈ-dicyclohexylcarboxydiimide (DCC)
(766 mg, 3.74 mmol) and 1-hydroxybenzotriazole (HOBT)
(407 mg, 2.55 mmol) in dry DMF at 0 °C. The solution was stirred
at ambient temperature for 16 h. After removal of the solvent under
reduced pressure, the residue was dissolved in CHCl3 and washed
(2 C), 170.08 (2 C), 170.80 (2 C) ppm. IR (ATR): ν = 2945, 1741,
˜
1687, 1529, 1428, 1366, 1216, 1135, 1081, 1042, 977, 896, 799,
687 cm–1. UV/Vis (CH2Cl2): λ = 257, 323, 425 nm. MS (FAB, with 1  HCl, NaHCO3 and brine. The CHCl3 layer was then dried
NBA): m/z = 3139 [2M + H]+, 1569 [M]+, 720 [C60]+. C95H48N2O22 (MgSO4), the solvent was removed in vacuo, and the residue was
(1569.40): calcd. C 72.70, H 3.08, N 1.78; found C 70.92, H 3.36,
N 1.66.
purified by FC (CHCl3/MeOH, 100:2) to give 8 as a colourless
solid. Yield: 1.10 g (83%) based on 7. 1H NMR: δ = (300 MHz,
CDCl3, 300 K) 1.97 (s, 9 H, Ac), 1.95–2.05 (m, 6 H, CH2-dendron),
2.04 (s, 9 H, Ac), 2.10 (s, 9 H, Ac), 2.15 (s, 9 H, Ac), 2.22 (t, J =
7.5 Hz, 6 H, CH2-dendron), 3.33–3.43 (m, 3 H, OCH2CH2N),
3.48–3.56 (m, 6 H, OCH2CH2N), 3.70–3.80 (m, 3 H, OCH2CH2N),
3.95–4.02 (m, 3 H, 5-H), 4.13 (dd, J = 2.3, 12.2 Hz, 3 H, 6-H), 4.26
(dd, J = 5.4, 12.2 Hz, 3 H, 6Ј-H), 4.83 (d, J = 1.3 Hz, 3 H, 3 H, 1-
H), 5.04 (s, 2 H, CH2Ph), 5.25 (dd, J = 1.8, 3.1 Hz, 3 H, 2-H), 5.26
(dd, J = 9.9, 9.9 Hz, 3 H, 4-H), 5.25 (dd, J = 3.1, 9.6 Hz, 3 H, 3-
H), 5.74 (br. s, 1 H, NH), 6.47 (br. s, 3 H, NH), 7.24–7.38 (m, 5
H, Ph) ppm. 13C NMR (75 MHz, CDCl3, 300 K): δ = 20.51 (3 C),
20.55 (3 C), 20.62 (3 C), 20.73 (3 C), 30.51 (3 C), 31.05 (3 C), 38.78
(3 C), 57.04 (1 C), 62.33 (3 C), 65.91 (3 C), 66.83 (3 C), 68.54 (3
C), 69.00 (3 C), 69.23 (3 C), 97.47 (3 C), 127.79 (2 C), 128.31 (1
C), 136.85 (2 C), 154.60 (1 C), 169.59 (3 C), 170.00 (6 C), 170.61
1,2-{Bis[2-(α-D-mannopyranosyloxy)ethylaminocarbonyl]methano}-
1,2-dihydro(C60-Ih)[5,6]fullerene (4): Sugar deprotection of 3 was
carried out under Zemplén conditions.[17] To a solution of 3 (8 mg,
5.1 µmol) in dry dichloromethane (10 mL) was added MeOH
(1.0 mL) containing a catalytic amount of MeONa (1.0 mg,
19 µmol), and this mixture was stirred for 1 h. The resulting pre-
cipitate was collected and washed with MeOH to give 4 as a brown
solid. Yield: 6 mg (95 %). 1H NMR (300 MHz, [D6]DMSO,
300 K): δ = 2.5–4.8 (br) ppm. 13C NMR (75 MHz, [D6]DMSO,
300 K) no signal. IR (ATR): ν = 3350, 2930, 1710, 1544, 1417,
˜
1131, 1058, 977, 810, 679 cm–1. MS (FAB, NBA): m/z = 1255 [M
+ Na]+.
Benzyl N-[Tris(2-tert-butoxycarbonylethyl)methyl]carbamate (6): A
solution of benzyl chloroformate (CbzCl) (8.63 g, 50.6 mol) in ace-
tone (40 mL) was added dropwise to a cooled solution (0 °C) of
amino dendron 5 (10.5 g, 25.3 mol) and NaHCO3 (4.25 g,
50.6 mmol) in 90% aqueous acetone (400 mL). The mixture was
stirred for 18 h at room temperature. The precipitates were removed
by filtration, and the filtrates were then concentrated in vacuo. The
residue was diluted with CHCl3 and washed with 1  HCl, satd.
NaHCO3, satd. NaCl and dried with MgSO4. After evaporation of
the solvents, the resulting crude product was separated by FC (hex-
ane/ethyl acetate, 4:1) to give 6 as a colourless solid. Yield: 12.0 g
(91%). 1H NMR (300 MHz, CDCl3, 300 K): δ = 1.43 (s, 9 H, tBu),
1.93 (t, J = 8.7 Hz, 6 H, CH2CH2), 2.21 (t, J = 8.7 Hz, 2 H,
CH2CH2), 4.83 (br. s, 1 H, NH), 5.04 (s, 2 H, CH2Ph), 7.45–7.25
(m, 5 H, Ph) ppm. 13C NMR (75 MHz, CDCl3, 300 K): δ = 28.00
(9 C), 29.62 (3 C), 30.04 (3 C), 56.52 (1 C), 66.15 (1 C), 80.53 (9
C), 127.92 (2 C), 127.99 (1 C), 128.44 (2 C), 136.52 (1 C), 154.11
(3 C), 173.14 (3 C) ppm. IR (ATR): ν = 1745, 1652, 1536, 1436,
˜
1370, 1220, 1135, 1081, 1046, 977, 896, 741, 691 cm–1. MS (FAB,
NBA): m/z = 6005 [4M]+, 4503 [3M]+, 3002 [2M]+, 1501 [M]+.
C66H92N4O35 (1501.44): calcd. C 52.80, H 6.18, N 3.73; found C
51.66, H 6.08, N 3.71.
2-[2-(2-Chloroethoxy)ethoxy]acetic Acid (10): An aqueous 15 wt.-%
solution of NaHCO3 (80 mL) was added to a stirred solution of
alcohol 9 (4.4 g, 26.1 mmol) in acetone (260 mL) and maintained
at 0 °C. Subsequently, solid KBr (0.626 g, 5.25 mmol) and TEMPO
(2,2,6,6-tetramethylpiperidine-N-oxide) (0.080 g, 0.8 mmol) were
added. Trichlorocyanuric acid (12.20 g, 52.5 mmol) was then slowly
added to the mixture within 20 min at 0 °C. After the addition, the
mixture was warmed to room temperature and stirred for the re-
quired time until completion and then 2-propanol (50 mL) was
added. The mixture was filtered through Celite, concentrated under
vacuum and treated with a saturated solution of Na2CO3. The
aqueous phase was washed with portions of ethyl acetate, treated
with 1  HCl and extracted twice with ethyl acetate. The organic
layer was dried (MgSO4), and the solvent was evaporated to yield
10 as a colourless liquid without further purification. Yield: 3.94 g
(83%). 1H NMR (300 MHz, CDCl3, 300 K): δ = 3.65 (t, J = 5.7 Hz,
2 H, CH2), 3.71–3.75 (m, 2 H, CH2), 3.76–3.80 (m, 2 H, CH2), 3.76
(t, J = 5.7 Hz, 2 H, CH2), 4.14 (s, 2 H, CH2), 10.77 (s, 1 H, COOH)
ppm. 13C NMR (75 MHz, CDCl3, 300 K): δ = 42.44, 68.09, 70.29,
70.79, 71.14, 174.63 ppm. MS (FAB, glycerol): m/z = 365 [2M]+,
183 [M]+.
(1 C), 172.46 (3 C) ppm. IR (KBr): ν = 3333, 2979, 2942, 2885,
˜
1726, 1535, 1461, 1417, 1393, 1368, 1330, 1258, 1226, 1154, 1086,
1043, 951, 847, 773, 773, 699 cm–1. MS (FAB, NBA): m/z = 550
[M]+, 494 [M – isobutene]+, 438 [M – 2ϫisobutene]+, 382 [M –
3 ϫisobutene]+, 416 [M – Cbz]+. C30H47NO8 (549.70): calcd. C
65.55, H 8.62, N 2.55; found C 65.52, H 8.60, N 2.57.
Benzyl N-[Tris(2-carboxyethyl)methyl]carbamate (7): Formic acid
(30 mL) was added to 6 (8.15 g, 14.8 mmol). The mixture was then
stirred for 24 h at room temperature. Evaporation of formic acid
gave tricarboxylic acid 7 as a colourless solid. Yield: 5.18 g (92%).
1H NMR (300 MHz, CD3OD, 300 K): δ = 1.43 (s, 9 H, tBu), 1.93 Methyl 2-[2-(2-Chloroethoxy)ethoxy]acetate (11): To a methanol
(m, 6 H, CH2CH2), 2.21 (m, 6 H, CH2CH2), 5.02 (s, 2 H, CH2Ph),
7.34–7.21 (m, 5 H, Ph) ppm. 13C NMR (75 MHz, CD3OD, 300 K):
δ = 29.17 (3 C), 30.66 (3 C), 57.52 (1 C), 66.89 (1 C), 128.70 (1 C),
128.89 (1 C), 129.46 (3 C), 136.62 (1 C), 156.66 (1 C), 177.11 (3 C)
(20 mL) solution of carboxylic acid 10 (3.94 g, 21.6 mmol) was
added sodium methoxide (1.19 g, 22.0 mmol) while stirring. After
stirring for 20 min, the solvent was removed from the reaction mix-
ture in vacuo. To the residue, MeI (6.13 g, 43.2 mmol) was added
and the mixture was stirred for 24 h. The resulting reaction mixture
was concentrated in vacuo. The residue was dissolved in CHCl3,
washed with 1  HCl, saturated NaHCO3 and saturated NaCl. The
organic phase was dried with MgSO4, concentrated, and the resi-
ppm. IR (KBr): ν = 3063, 2958, 1710, 1531, 1457, 1417, 1256, 1075,
˜
915, 740, 698 cm–1. MS (FAB, NBA): m/z = 1144 [3M + H]+, 763
[2M + H]+, 382 [M + H]+. C18H23NO8 (381.38): calcd. C 56.69, H
6.08, N 3.67; found C 56.10, H 5.71, N 3.72.
2664
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2659–2666

Sugar Balls: [60]Fullerene Glycoconjugates
FULL PAPER
due was purified by FC (CHCl3/MeOH, 1:0–5:1) to give 11 as a
colourless liquid. Yield: 3.73 g, (63 %). 1H NMR (300 MHz,
CDCl3, 300 K): δ = 3.65 (t, J = 5.4 Hz, 2 H, CH2), 3.60–3.72 (m,
6 H, CH2), 3.65 (s, 3 H, CH3), 4.09 (s, 2 H, CH2) ppm. 13C NMR
OCH2CO), 3.98–4.02 (m, 3 H, 5-H), 4.13 (dd, J = 2.1, 12.1 Hz, 3
H, 6-H), 4.27 (dd, J = 5.4, 12.3 Hz, 3 H, 6Ј-H), 4.84 (d, 3J = 1.3 Hz,
3 H, 1-H), 5.23–5.30 (m, 3 H, 2-H), 5.27 (dd, J = 10.0, 10.0 Hz, 3
H, 4-H), 5.34 (dd, J = 3.3, 10.4 Hz, 3 H, 3-H), 6.57 (t, J = 5.1 Hz,
(75 MHz, CDCl3, 300 K): δ = 42.44, 51.43, 68.28, 70.37, 70.57, 3 H, NH), 6.68 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3,
71.01, 170.49 ppm. MS (FAB, glycerol): m/z = 297 [M]+.
300 K): δ = 20.53 (6 C), 20.58 (3 C), (3 C), 20.70 (3 C), 30.42 (3
C), 31.14 (3 C), 38.80 (3 C), 50.29 (1 C), 58.01 (1 C), 62.29 (3 C),
65.92 (3 C), 66.97 (3 C), 68.48 (3 C), 68.93 (3 C), 69.20 (3 C), 69.86
(1 C), 69.96 (1 C), 70.0 (1 C), 70.44 (1 C), 70.83 (1 C), 97.52 (3 C),
169.20 (1 C), 169.56 (3 C), 169.83 (3 C), 169.89 (3 C), 170.53 (3
Methyl 2-[2-(2-Azidoethoxy)ethoxy]acetate (12): To a DMF
(70 mL) solution of 11 (3.73 g, 18.9 mmol) was added NaN3
(6.15 g, 94.6 mmol), and the mixture was stirred at 70 °C for 22 h.
The reaction mixture was filtered and concentrated in vacuo. The
residue was dissolved in CHCl3, washed with 1  HCl, saturated
NaHCO3 and saturated NaCl. The organic layer was dried
(MgSO4), and the solvent was evaporated to yield 12 as a liquid
without further purification. Yield: 3.28 g (85 %). 1H NMR
(300 MHz, CDCl3, 300 K): δ = 3.40 (t, J = 5.0 Hz, 2 H, CH2), 3.69
(t, J = 5.2 Hz, 2 H, CH2), 3.69–3.73 (m, 2 H, CH2), 3.74–3.78 (m,
2 H, CH2), 3.76 (s, 3 H, CH3), 4.19 (s, 2 H, CH2) ppm. 13C NMR
(75 MHz, CDCl3, 300 K): δ = 50.55, 51.74, 68.58, 69.98, 70.64,
70.90, 170.78 ppm. MS (FAB, glycerol): m/z = 204 [M + H]+.
C), 172.76 (3 C) ppm. IR (ATR): ν = 2104, 1741, 1656, 1532, 1432,
˜
1370, 1370, 1220, 1135, 1081, 1042, 977, 907, 971 cm–1. MS (FAB,
NBA): m/z = 1538 [M]+. C64H95N7O36 (1538.46): calcd. C 49.96,
H 6.22, N 6.37; found C 49.38, H 6.24, N 6.53.
1aH-1,9-[(2-{2-[(Tris{2-[2-(2,3,4,6-tetra-O-acetyl-α-
pyranosyloxy)ethylcarbamoyl]ethyl}methyl)carbamoylmethoxy]-
ethyl}ethyl)imino]-1a-(2-{2-[(tris{2-[2-(2,3,4,6-tetra-O-acetyl-α-
D-manno-
D
-
mannopyranosyloxy)ethylcarbamoyl]ethyl}methyl)carbamoyl-
methoxy]ethyl}ethyl)-1,9-dihydro-1a-aza-1(2)a-homo(C60-Ih)[5,6]-
fullerene (16): A solution of C60 (96 mg, 0.13 mmol) and azide 15
(245 mg, 0.16 mmol) in dry toluene (100 mL) was heated at reflux
for 24 h under a N2 stream. The crude reaction mixture was sepa-
rated by FC. Unreacted C60 and other impurities were eluted with
toluene. After evaporation of the solvent, the remaining solid was
dissolved in CHCl3/MeOH (100:5) and purified by FC (toluene/
MeOH, 100:10). Bisadduct 15 eluted as the second fraction. After
evaporation of the solvent and recrystallization from CH2Cl2, 16
was isolated in 8% yield (38 mg). 1H NMR (300 MHz, CDCl3,
300 K): δ = 1.99 (s, 18 H, Ac), 2.05 (s, 18 H, Ac), 2.05–2.11 (m, 12
H, CH2-dendron), 2.10 (s, 18 H, Ac), 2.15 (s, 18 H, Ac), 2.18–2.26
(m, 12 H, CH2-dendron), 3.33–3.43 (m, 6 H, OCH2CH2N), 3.45–
3.58 (m, 12 H, OCH2CH2N), 3.72–3.80 (m, 10 H, OCH2CH2N +
CH2-EG), 3.83–3.88 (m, 4 H, CH2-EG), 3.97 (s, 4 H, OCH2CO),
3.95–4.03 (m, 6 H, 5-H), 4.06–4.15 (m, 4 H, CH2-EG), 4.12 (dd, J
= 2.1, 12.1 Hz, 6 H, 6-H), 4.27 (dd, J = 5.3, 12.2 Hz, 6 H, 6Ј-H),
4.35–4.38 (m, 4 H, CH2-EG), 4.83 (d, J = 1.0 Hz, 6 H, 1-H), 5.25
(dd, J = 1.5, 2.8 Hz, 6 H, 2-H), 5.27 (dd, J = 10.0, 10.0 Hz, 6 H,
2-[2-(2-Azidoethoxy)ethoxy]acetic Acid (13): NaOH (0.520 g,
13.0 mmol) was added to a 50 % aqueous methanol solution
(40 mL) of 12 (2.20 g, 10.8 mmol), and the mixture was stirred at
room temperature for 18 h. The mixture was then neutralized with
1  HCl, and the neutralized solution was concentrated in vacuo.
The residue was dissolved in CHCl3, and washed with 1  HCl,
saturated NaHCO3, and saturated aqueous NaCl. The organic lay-
ers were dried with MgSO4, and the solvent was evaporated to yield
1
13 as a liquid. Yield: 0.828 g (41%). H NMR (300 MHz, CDCl3,
300 K): δ = 3.42 (t, J = 5.0 Hz, 2 H, CH2), 3.70 (t, J = 5.0 Hz, 2
H, CH2), 3.71–3.73 (m, 2 H, CH2), 3.77–3.80 (m, 2 H, CH2), 4.22
(s, 2 H, CH2), 10.16 (br. s, 1 H, COOH) ppm. 13C NMR (75 MHz,
CDCl3, 300 K): δ = 50.07, 67.74, 69.52, 70.01, 70.50, 174.29 ppm.
MS (FAB, glycerol): m/z = 379 [2M + H]+, 190 [M + H]+.
2-[2-(2-Azidoethoxy)ethoxy]acetyl Fluoride (14): Hexafluoropro-
pene diethylamine (3.6 g, 8.4 mmol) was added to a solution of [2-
(2-azidoethoxy)ethoxy]acetic acid (529 mg, 2.8 mmol) in dry
dichloromethane (8 mL). After the mixture was stirred at room
temperature for 4 h, triethylamine (1.13 g, 11.2 mmol) was added.
The mixture was used for the coupling reaction with the depro-
tected amine of 8 without further treatment.
3
4-H), 5.31 (dd, J = 3.0, 10.2 Hz, 6 H, 3-H), 6.75 (t, J = 5.4 Hz, 6
H, NH), 6.78 (s, 2 H, NH) ppm. 13C NMR (75 MHz, CDCl3,
300 K): δ = 20.67 (12 C), 20.72 (6 C), 20.84 (6 C), 30.59 (6 C),
31.35 (6 C), 38.93 (6 C), 51.26 (2 C), 58.11 (2 C), 62.39 (6 C), 66.00
(6 C), 67.00 (6 C), 68.60 (6 C), 69.11 (6 C), 69.31 (6 C), 70.20 (2
C), 70.27 (2 C), 70.74 (2 C), 71.09 (2 C), 97.60 (6 C), 130.56 (2 C),
131.31 (1 C), 132.70 (2 C), 134.55 (2 C), 135.15 (2 C), 137.15 (2
C), 138.86 (2 C), 139.02 (2 C), 139.34 (2 C), 139.53 (2 C), 141.03
(2 C), 141.50 (2 C), 141.58 (2 C), 141.99 (2 C), 142.61 (2 C), 143.33
(2 C), 143.49 (2 C), 143.73 (2 C), 143.89 (2 C), 144.03 (1 C), 144.11
(4 C), 144.19 (2 C), 144.57 (2 C), 144.60 (2 C), 144.85 (2 C), 144.97
(2 C), 145.12 (2 C), 145.48 (1 C), 146.78 (2 C), 147.53 (2 C), 163.04
(1 C), 169.42 (2 C), 169.67 (6 C), 170.03 (6 C), 170.04 (6 C), 170.67
2-[2-(2-Azidoethoxy)ethoxy]-N-(tris{2-[2-(2,3,4,6-tetra-O-acetyl-α-
D-mannopyranosyloxy)ethylcarbamoyl]ethyl}methyl)acetamide (15):
A mixture of palladium and carbon (400 mg) and conc. HCl
(5 drops) was added to a solution of 8 (1.05 g, 0.70 mmol) in ethyl
acetate/EtOH (1:1; 120 mL). The mixture was stirred under a hy-
drogen atmosphere at room temperature for 2.5 h. Pd/C was re-
moved by filtration through Celite. The filtrate was concentrated
in vacuo and used in the next step without further purification. A
solution of 14 (8.4 mmol) in dichloromethane was added to a solu-
tion of the deprotected glycosyl dendron and DMAP (171 mg,
1.4 mmol) in dry dichloromethane (10 mL). The solution was
stirred at ambient temperature for 48 h. Subsequently, the solution
was diluted with CHCl3 and washed twice with 1  HCl, NaHCO3
and brine. The CHCl3 layer was then dried (MgSO4), the solvent
was removed in vacuo, and the residue was purified by FC (CHCl3/
MeOH, 100:0–100:3)to give a colourless solid. Yield: 1.01 g (94%).
1H NMR (300 MHz, CDCl3, 300 K): δ = 2.00 (s, 9 H, Ac), 2.06 (s,
9 H, Ac), 2.05–2.11 (m, 6 H, CH2-dendron), 2.11 (s, 9 H, Ac), 2.16
(6 C), 172.97 (6 C) ppm. IR (ATR): ν = 2937, 1745, 1660, 1532,
˜
1432, 1370, 1220, 1135, 1081, 1042, 977, 896, 753, 687 cm–1
.
UV/Vis (CH2 Cl2 ): λ = 256, 324 nm. MS (FAB, NBA):
m/z = 3740 [M + H]+, 1512 [M – 1ϫadduct-C60]+, 720 [C60]+.
C188H190N10O72·2.5CH2Cl2 (3739.15): calcd. C 57.87, H 4.97, N.
3.54; found C 57.42, H 5.09, N 3.65.
1aH-1,9-[(2-{2-[(Tris{2-[2-(α-
carbamoyl]ethyl}methyl)carbamomethoxy]ethoxy}ethyl)imino]-1a-
(2-{2-[(tris{2-[2-(α- -mannopyranosyloxy)ethylcarbamoyl]ethyl}-
D-mannopyranosyloxy)ethyl-
D
(s, 9 H, Ac), 2.05–2.12 (m, 6 H, CH2-dendron), 3.36–3.44 (m, 3 H, methyl)carbamoylmethoxy]ethoxy}ethyl)-1,9-dihydro-1a-aza-1(2)a-
OCH2CH2N), 3.45 (t, J = 5.0 Hz, 2 H, CH2-EG), 3.49–3.57 (m, 6
homo(C60-Ih)[5,6]fullerene (17): Sugar deprotection of 16 was car-
H, OCH2CH2N), 3.66–3.72 (m, 4 H, CH2-EG), 3.72 (t, J = 4.8 Hz, ried out under Zemplén conditions.[17] To a solution of 16 (33 mg
2 H, CH2-EG), 3.74–3.80 (m, 3 H, OCH2CH2N), 3.91 (s, 2 H, 14.8 µmol) in MeOH (7 mL) was added MeOH (1.0 mL) contain-
Eur. J. Org. Chem. 2007, 2659–2666
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2665

H. Kato, C. Böttcher, A. Hirsch
FULL PAPER
[7] a) C. Bingel, Chem. Ber. 1993, 126, 1957–1959; b) X. Camps,
A. Hirsch, J. Chem. Soc., Perkin Trans. 1 1997, 1595–1596.
[8] T. Akasaka, K. Matsuura, K. Kobayashi, Bioconjugate Chem.
2001, 12, 776–785.
[9] a) L. Lebeau, P. Oudet, C. Mioskowski, Helv. Chim. Acta 1991,
74, 1697–1706; b) A. W. Schwabacher, J. W. Lane, M. W.
Schiesher, K. M. Leigh, C. W. Johnson, J. Org. Chem. 1998, 63,
1727–1729; c) S. Svedhem, C.-A. Hollander, J. Shi, P. Konrads-
son, B. Liedberg, S. C. T. Svensson, J. Org. Chem. 2001, 66,
4494–4503.
ing a catalytic amount of MeONa (1.0 mg, 19 µmol), and this mix-
ture was stirred for 2 h. The resulting precipitate was collected and
washed with MeOH to give 11 as a brown solid. Yield: 20 mg
1
(quant). H NMR (300 MHz, D2O, 300 K): δ = 1.70–2.30 (br., 24
H, CH2-dendron), 3.2–3.9 (br., 80 H, mannose + CH2-EG +
NHCH2CH2O) ppm. 13C NMR (75 MHz, D2O, 300 K): δ = 30.3
(br., 12 C), 39.4 (br., 6 C), 61.3 (br., 6 C), 66.1 (br., 6 C), 66.4 (br.,
6 C), 70.4 (br., 6 C), 70.9 (br., 6 C), 73.2 (br., 6 C), 100.0 (br., 6
C), 127–153 (br., 59 C), 171.3 (br., 2 C), 175.8 (br., 6 C) ppm. IR
[10] a) G. R. Newkome, R. K. Behera, C. N. Moorefield, G. R.
Backer, J. Org. Chem. 1991, 56, 7162–7167; b) M. Brettreich,
A. Hirsch, Synlett 1998, 12, 1396–1399.
[11] T. Groesser, M. Prato, V. Lucchini, A. Hirsch, F. Wudl, Angew.
Chem. 1995, 107, 1462–1464; Angew. Chem. Int. Ed. Engl. 1995,
34, 1343–1345.
(ATR): ν = 3358, 2934, 1640, 1544, 1455, 1420, 1135, 1092, 1058,
˜
969, 807, 730, 683 cm–1. UV/Vis (CH2Cl2): λ = 217, 256 nm. MS
(MALDI, CHCA): m/z = 2758 [M + 4Li]+. C140H142N10O48·11H2O
(2930.83): calcd. C 57.37, H 5.64, N 4.78; found C 57.20, H 5.64,
N 4.78.
[12] a) C. Burger, J. Hao, Q. Ying, H. Isobe, M. Sawamura, E. Nak-
amura, B. Chu, J. Colloid Interface Sci. 2004, 275, 632–641; b)
M. Sawamura, N. Nagahama, M. Toganoh, U. E. Hackler, H.
Isobe, E. Nakamura, S. Q. Zhou, C. Burger, B. Chu, Chem.
Lett. 2000, 1098–3776; c) S. Zhou, C. Burger, B. Chu, M. Sawa-
mura, N. Nagahama, M. Toganoh, U. E. Hackler, H. Isobe, E.
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Acknowledgments
This work was supported by the Alexander-von-Humboldt founda-
tion and the Deutsche Forschungsgemeinschaft (DFG). We thank
Prof. W. Bauer from the University of Erlangen for recording the
DOSY NMR spectra.
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Received: February 27, 2007
Published Online: April 19, 2007
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