Novel approach for synthesis of 2:1 permethylated β-cyclodextrin-C60 conjugate

Article abstract of DOI:10.1016/j.tet.2008.12.001

Amphiphilic cyclodextrin-fullerene conjugates have potential biological activity, due to their water solubility. In order to study the influence of the linker of these conjugates on solubility and aggregation, a permethylated β-cyclodextrin-C₆₀

Full text of DOI:10.1016/j.tet.2008.12.001

Tetrahedron 65 (2009) 1125–1129
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel approach for synthesis of 2:1 permethylated b-cyclodextrin–C60 conjugate
,
,
,c,
Zhu Guan a b, Yali Wang a, Yong Chen a y, Lihe Zhang b, Yongmin Zhang a
*
a Laboratoire de Chimie Organique, UMR CNRS 7611, Tour 44/45, Universite´ Pierre et Marie Curie, 4 Place Jussieu, 75005 Paris, France
b Peking University Health Science Center, State Key Laboratory of Natural and Biomimetic Drugs, 38 Xueyuan Rd, Haidian District, Beijing 100083, China
c ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang University, Hangzhou 310058, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 October 2008
Received in revised form 26 November 2008
Accepted 1 December 2008
Available online 6 December 2008
Amphiphilic cyclodextrin–fullerene conjugates have potential biological activity, due to their water
solubility. In order to study the influence of the linker of these conjugates on solubility and aggregation,
a permethylated
the secondary face of
CH2Cl2 and water were investigated.
b
-cyclodextrin–C60 conjugate with a short linker –(CH2)2NHCO–, which is attached to
b
-cyclodextrin was synthesized. Its solubility in water and its UV spectrum in
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Synthesis
b
-Cyclodextrin
Fullerene
C60
Amphiphilic
Conjugate
1. Introduction
primary face
6
OH
O
4
C60, the most representative among fullerenes, is currently
considered as a powerful building block in material science and
biological chemistry due to its unique photo-, electro-physical, and
chemical properties. However, lack of solubility in polar solvents
and formation of aggregates in aqueous solution limit its applica-
tion in biological field.1 There have been several attempts to over-
come the natural repulsion of fullerenes for water. Generally the
water-soluble fullerenes could be obtained either by covalent ad-
dition of hydrophilic appendages or by complex formation with
host molecules.2
HO
1
2
3
OH
O
n
secondary face
Figure 1. Structures of the cyclodextrin (CD) cavities.
n¼8.
a
-CD: n¼6;
b
-CD: n¼7;
g-CD:
However, in the case of 2:1
equilibria, such as (1) and (2) may take place in solution (Scheme 1),
so that if some other substrates with sufficient affinity for -CD
were present, C60 could be displaced and possibly precipitate. A
g-CD–C60 complexation, different
g
Cyclodextrins (CDs) are naturally occurring oligomers of
a-1,4-
linked -glucose units, with a unique hollow-truncated-cone ge-
D
ometry (Fig. 1).3 They are known to function as host molecules
making inclusion complexes with hydrophobic guest molecules in
aqueous solution.4 By formation of complex with CD, water-soluble
C60 was first obtained in 1992 by Andersson and co-workers.5 In
1994 Yoshida and co-workers reported6 first preparation of the
covalent binding between C60 and
g-CD would probably impede
this displacement.2
So far, few works have been reported on the CD–C60 conjugates.
The first water-soluble CD–C60 conjugate was described by Samal
and Geckeler in 2000.7 Liu and co-workers reported in 2005 that
the CD–C60 conjugates with DNA-cleaving properties exhibited
a moderate water solubility (2.5 mg/mL).8
stable, water-soluble
ster-fullerene’), they used the complex in a spectral investigation for
elucidation of the molecular recognition of C60 by -CD.
g-CD–C60 (2:1) complex (‘bicapped buckmin-
We recently prepared a new type of 2:1 permethylated
dextrin–C60 conjugate (Fig. 2) 1, which showed a high water
b-cyclo-
g
(C60,CD)
(1)
(2)
C60 + CD
* Corresponding author. Tel.: þ33 1 44276153; fax: þ33 1 44275504.
E-mail address: yongmin.zhang@upmc.fr (Y. Zhang).
Present address: State Key Laboratory of Elemento-Organic Chemistry,
(CD,C60,CD)
(C60,CD) + CD
y
Scheme 1. Equilibria between g-CD and C60 in water.
Department of Chemistry, Nankai University, Tianjin 300071, China.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.001

1126
Z. Guan et al. / Tetrahedron 65 (2009) 1125–1129
O
O
O(CH2)11NHCO(CH2)11
(OMe)20
O
O(CH2)11COHN(CH2)11
O
β
(MeO)20
Figure 2. Highly water-soluble CD–C60 conjugate 1.
solubility up to 320 mg/mL.9 However, UV and NMR spectra showed
the presence of aggregates. Although this high water solubility is
convenient for application to biological systems, micellar aggrega-
tion may induce chemical,10 electrochemical,11 or photophysical12
properties differing from those of the isolated fullerene molecule.
It was postulated that this kind of conjugate could be present in
water equilibria between conformers such as A, B, and C (Fig. 3).
Conformers A and B could form micelle-like aggregates, while C
could exist as a non-associated species by forming an internal
complexation.13
2. Results and discussion
Methylated -cyclodextrin was chosen to be appendage of C60
because methylated CD derivatives are thought to be able to en-
hance the solubility in an aqueous medium.14 Moreover, inclusion
complexes of methylated CDs are usually more stable than the
correspondent complexes of unmodified CDs.15 The secondary face
of CD was chosen to be a linkage connecting point due to its larger
diameter than that of primary face, which is important for C60
inclusion.
b
A
B
C
Figure 3. Postulated equilibria of the CD–C60 conjugate in water.
In molecule 1, the longer linkers between two CDs and C60 gave
a higher freedom for C60 molecule, which favors the formation of
the conformers A and B, we supposed that a shorter linker should
force the CDs and C60 to form an inclusion complex (conformer B).
In order to study the influence of the linker on solubility and ag-
gregation, we have prepared a new CD–C60 conjugate 2 in which
the two linkers are much shorter than their analogues (Fig. 4).
Herein, we describe the synthesis of this conjugate.
The key intermediate of this synthesis is a permethylated b-CD
A2,B3-diol, which was regioselectively prepared according to our
previously reported procedure9 from the commercially available
permethylated b-CD in 56% yield (Scheme 2).
Instead of preparing an azidoalkyltosylate for conjugate 1, we
used commercially available bromoacetonitrile to react with the
A2,B3-diol, giving monoalkylated derivative 3 in 91% yield via a se-
lective alkylation. Here KOH was selected instead of NaOH as basic
reagent since the reaction gave a better yield with KOH. In this step,
the hydroxyl group at 2-position is more acidic than that at 3-po-
sition, it could be first deprotonated in the presence of strong base16
to react with bromoacetonitrile, giving regioselectively the 2-alkyl
CD. The regioselectivity of this reaction was demonstrated by
analysing the structure of compound 3 based on NMR and MS data.
This structure was further confirmed from the 1H NMR spectrum of
derivative 4, obtained from 3 by acetylation (90% yield); which
displayed a deshielded signal for H3 of the glucose unit B at
5.41 ppm, indicating that alkylation of the A2,B3-diol took place at
O
O
O(CH2)2NH
(OMe)20
HN(CH2)2O
(MeO)20
β
Figure 4. CD–C60 conjugate 2.
OMe
OMe
O
B3
O
O
MeO
O
O
O
O
O
MeO
O
O
O
O
O
OMe
O
O
Me
O
O
Me
O
O
OMe
O
Me
Me
Me Me
O
OH
OH
O
Me
(OMe)19
O
Me
Me
Me
Me
O
Me
i
A2
O
β
Me
Me
O
MeO
O
O
Me
Me
MeO
Me
Me
Me
O
O
O
O
O
O
O
OMe
2
3
Me
Me
Me
O
Me
OMe
Me
Me
O
O
Me
O
O
O
O
O
O
O
O
O
O
O
HO
OH
O
O
O
MeO
MeO
O
OMe
Permethylated β-CD
O
OMe
Scheme 2. Reagents and conditions: (i) DIBAL-H, (9 equiv), 0 ꢀC, 18 h (56%).
A2, B3-diol

Z. Guan et al. / Tetrahedron 65 (2009) 1125–1129
1127
4
3.5
3
(OMe)19
(OMe)19
(OMe)19
water
DCM
β
β
β
iii
NH2CH2CH2O
i
2
3
2
3
2
3
OH
HO
NCCH2O
OH
OH
3
5
2.5
2
A2,B3-diol
ii
(OMe)19
1.5
1
β
2
3
NCCH2O OAc
4
0.5
0
Scheme 3. Reagents and conditions: (i) KOH, THF, BrCH2CN; 1 h (91%); (ii) Ac2O,
pyridine, 40 ꢀC, 24 h (90%); (iii) H2, Pd–C, 1 N HCl, CH3OH, 4 h (64%).
280
330
380
wavelength (nm)
430
480
in DCM (2.0ꢁ10ꢂ4 mmol) and water
position 2 to afford compound 3. In order to reduce the cyano group
of 3, LiAlH4 and BH3–THF were first used, but neither of them gave
desired amino product. We then found that hydrogen in the pres-
ence of Pd–C could reduce cyano group of 3 to give the amino
derivative 5 in a satisfactory yield (Scheme 3).
Figure 5. UV–vis spectra of conjugate
(3.0ꢁ10ꢂ4 mmol).
2
The structure of conjugate 2 was fully characterized by 1H NMR,
13C NMR, MS, and UV–vis techniques. The UV–vis absorption
spectra in dichloromethane (DCM) and water of 2 are reported in
Figure 5. In DCM, the typical absorption features of fullerene[60]
mono-adduct could be observed: an absorption at w330 nm,
a weak peak at w430 nm, and a broad weak band at w480 nm. The
weak absorption at w430 nm indicates conjugate 2 can exist as
a non-associated species in DCM without aggregate formation. But
in water, no absorption could be observed around 430 nm, in-
dicating the existence of aggregates in water.
The free hydroxyl group of compound 3 was then methylated to
provide cyanoalkyl permethylated
the cyano group of 6, as described for 3, gave aminoalkyl per-
methylated -CD 7 in good yield, which was condensed with
b-CD 6 in 87% yield. Reduction of
b
malonyl dichloride to afford CD dimer 8 (Scheme 4).
(OMe)19
(OMe)19
(OMe)20
β
β
ii
i
β
Conjugate 2 cannot be rapidly dissolved in water. A mixture of 2
2
3
(3 mg) in water (100 m
L) stored at 4 ꢀC for more than 24 h gave
NCCH2O
OCH2CH2NH2
7
OCH3
6
NCCH2O
OH
3
a clear brown solution.
O
O
3. Conclusion
iii
O(CH2)2NH
(OMe)20
HN(CH2)2O
(MeO)20
β
We have described the synthesis of a novel CD–C60 conjugate
(Fig. 4) in which two shorter linkers [–(CH2)2NHCO–] were used to
connect CD and C60, with two amide groups being linked directly to
the carbon atom of the methanofullerene instead of two ester
groups as in our former conjugates. For the preparation of alkyl CD,
a selective alkylation was realized in a more convenient way than
preparing conjugate 1 and its analogues, and a two-step reaction
was used for achieving the synthesis of methanofullerene.
8
Scheme 4. Reagents and conditions: (i) CH3I, NaH, DMF, rt, 2 h (87%); (ii) H2, Pd–C, 1 N
HCl, CH3OH, 4 h (80%); (iii) malonyl dichloride, Et3N, CH2Cl2, rt, 10 h (34%).
With 8 in hand, we logically used Hirsch–Bingle reaction to
perform the condensation with C60, the reaction we used for
preparation of conjugate 1.9 Surprisingly, the reaction failed to
produce the methanofullerene derivative. A two-step reaction was
then tested and proved to be successful. The first step consisted in
a mono bromination of dimer 8 to provide 9. In this step, dibromide
10 was also formed. After optimization, we found that when
1.2 equiv of bromine was used and the reaction was carefully
monitored by TLC and timely quenched, monobromide 9 could be
isolated in 40% yield and dibromide 10 in 20% yield. The starting
material was recovered in about 40% yield, which could be reused
Compared with other conjugates we prepared previously,9,17,18
conjugate 2 displays a lower solubility (30 mg/mL), and the shorter
linker (–CH2CH2–) does not reduce the formation of aggregates.
Since it is possible that the affinity of b-CD for C60 is not strong
enough, the distance between C60 and CD could play an important
role in formation of internal complexation, a conjugate with me-
dium size of linker is being synthesized. Due to their interesting
water-soluble property, these amphiphilic fullerene derivatives,
which can be transported in biological systems, are particularly
desirable for biological testing.
for the same bromination. Finally monobromo b-CD 9 was treated
with C60 in the presence DBU to afford target compound 2, as
shown in Scheme 5.
4. Experimental
4.1. General
O
O
ii
HN(CH2)2O
(MeO)20
O(CH2)2NH
(OMe)20
i
Br
2
β
8
Optical rotations were measured at room temperature with
a Perkin Elmer Model 241 digital polarimeter, using a 10 cm, 1 mL
cell. Microanalyses were performed by Service de Microanalyse de
9
+
O
O
´
l’Universite Pierre et Marie Curie, 4 Place Jussieu, 75005 Paris,
HN(CH2)2O
O(CH2)2NH
Br
France. Fast Atom Bombardment Mass Spectra FABMS were
obtained with a JMS-700 spectrometer, and ESI-MS were obtained
with Bruker DALTONTICS DataAnalysis 3.3. NMR spectra were
recorded on a Bruker DRX 400 spectrometer at ambient tempera-
ture. 1H NMR chemical shifts are referenced to residual protic
β
Br
(OMe)20
(MeO)20
10
Scheme 5. Reagents and conditions: (i) Br2, Et3N, CH2Cl2 (60%, 9/10¼2:1); (ii) C60, DBU,
toluene, rt, 1 h (33%).

1128
Z. Guan et al. / Tetrahedron 65 (2009) 1125–1129
solvent (CDCl3, dH¼7.30). 13C NMR chemical shifts are referenced to
the solvent signal (dC¼77.0 for the central line of CDCl3). Reactions
were monitored by thin-layer chromatography (TLC) on a pre-
coated silica gel 60 F245 plate (layer thickness 0.2 mm; E. Merck,
Darmstadt, Germany) and detection by charring with sulfuric acid.
Flash column chromatography was performed on silica gel 60
(230–400 mesh, E. Merck).
0.4 mmol). The reaction mixture was stirred at room temperature
for 4 h under hydrogen. After filtration, the filtrate was concen-
trated by evaporation under reduced pressure, the residue was
purified by flash chromatography, eluting with CH2Cl2/CH3OH/
NH4OH 10:1:0.05 to provide compound 5 as a white amorphous
solid (248 mg, 64%). Rf¼0.25 (CH2Cl2/CH3OH 6:1); [
CHCl3); 1H NMR (400 MHz, CDCl3):
5.16–5.09 (m, 6H, 4ꢁH1, NH2),
5.08 (d, 1H, J¼3.4 Hz, H1), 5.03 (d, 1H, J¼3.6 Hz, H1), 2.93 (m, 2H,
CH2N); 13C NMR (100 MHz, CDCl3):
100.56, 99.72, 99.30, 99.09,
a
]D þ150 (c 1.05,
d
4.2. Synthesis of 2-O-cyanomethyl-3-hydroxyl-permethylated
d
b
-cyclodextrin (3)
98.72, 98.62, 98.48 (7C, 7ꢁC1), 82.83, 82.55, 82.08, 81.97.81.84,
81.77, 81.50, 81.43, 81.42, 81.26, 81.02, 80.97, 80.53, 79.99, 79.88,
79.79, 79.27 (21C, 7ꢁC2, C3, C4), 74.57 (1C, OCH2), 71.23, 71.18, 71.05,
70.81 (7C, 7ꢁC6), 71.43, 70.72, 70.67, 70.58 (7C, 7ꢁC5), 61.65, 61.26,
61.21, 61.17, 61.11, 61.07, 58.76. 58.70, 58.66, 58.38, 58.24, 58.23,
58.19, 58.17, 58.13 (19C, 19ꢁOCH3), 41.48 (1C, CH2NH2); FABMS: m/z
1466.8 (MþNaþ). Anal. Calcd for C63H113O35N$3H2O: C, 50.49; H,
8.00; N, 0.93. Found: C, 50.56; H, 8.00; N, 0.93.
To a solution of A2,B3-diol (420 mg, 0.3 mmol) in anhydrous THF
(40 mL) was added KOH (50 mg, 0.9 mmol) under argon, the re-
action mixture was stirred at room temperature for 24 h. Diluted
BrCH2CN (31 mL, 0.45 mmol) by THF (1 mL) was dropped into the
solution and stirred for 30 min. Then the reaction was stopped with
acetic acid. After removing the solvent by evaporation under re-
duced pressure, the residue was dissolved in CH2Cl2, washed with
saturated brine, and dried over MgSO4. After evaporation of the
solvent, the residue was purified by flash chromatography, eluting
with 25:1 CH2Cl2/CH3OH to give compound 3 as a white amorphous
4.5. Synthesis of 2-O-cyanomethyl-permethylated
b-cyclodextrin (6)
solid (395 mg, 91%). Rf¼0.42 (CH2Cl2/CH3OH 10:1); [
a
]
D þ141 (c 1.1,
To a mixture of 3 (380 mg, 0.26 mmol) and NaH (60%, 54 mg,
1.34 mmol) in anhydrous DMF (4 mL) was added CH3I (80 mL,
CHCl3); 1H NMR (400 MHz, CDCl3):
d
5.18 (d, 2H, J¼3.6 Hz, 2ꢁH1),
5.10 (d, 1H, J¼3.5 Hz, H1), 5.15–5.12 (m, 4H, 4ꢁH1), 4.60 (2d, 2H,
1.34 mmol), the reaction mixture was stirred at room temperature
for 10 h. CH3OH (1 mL) was added to quench the reaction. After
removal of solvent by evaporation, the residue was purified by flash
chromatography, eluted with cyclohexane/acetone 2:1 to give
compound 6 (330 mg, 87%) as a white foam. Rf¼0.32 (cyclohexane/
J¼16.2 Hz, CH2–CN); 13C NMR (100 MHz, CDCl3):
d 115.47 (1C, CN),
100.41, 99.69, 99.46, 99.43, 98.90, 98.87, 98.61 (7C, 7ꢁC1), 83.43,
82.38, 82.16, 82.13, 82.04, 81.99, 81.88, 81.74, 81.65, 81.58, 81.39,
81.36, 81.31, 81.09, 80.95, 80.80, 80.30, 80.10, 79.82 (21C, 7ꢁC2, C3,
C4), 71.67, 71.02, 70.93, 70.89, 70.86, 70.72, 69.83 (7C, 7ꢁC5), 71.29,
71.23, 71.17, 70.82, 70.65 (7C, 7ꢁC6), 62.07, 61.44, 61.40, 61.19, 58.98,
58.91, 58.89, 58.87, 58.85, 58.76, 58.48, 58.40, 58.35, 58.33, 58.30
(19C, 19ꢁOCH3), 57.26 (1C CH2–CN); FABMS: m/z 1462.7 (MþNaþ).
Anal. Calcd for C63H109NO35$3H2O: C, 50.63; H, 7.76; N, 0.94. Found:
C, 50.61; H, 7.79; N, 1.14.
acetone 1:1); [
a
]
D þ135.2 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
d
5.15–5.10 (m, 6H, 6ꢁH1), 5.06 (d, 1H, J1,2¼3.6 Hz, H1), 4.50 (2d, 2H,
J¼15.9 Hz, CH2CN); 13C (100 MHz, CDCl3):
d 116.15 (1C, CN), 98.97,
98.91, 98.88, 98.86, 98.85 (7C, 7ꢁC1), 81.97, 81.95, 81.93, 81.90,
81.89, 81.80, 81.75, 81.70, 81.69, 81.63, 81.58, 80.54, 80.34, 80.27,
80.24, 80.18, 79.97 (21C, 7ꢁC2, C3, C4), 71.01, 70.91, 70.87, 70.82,
70.74, 70.61 (7C, 7ꢁC5), 71.38, 71.32, 71.29, 71.26 (7C, 7ꢁC6), 61.71,
61.42, 61.39, 61.37, 61.32, 61.27, 61.21, 58.92, 58.89, 58.87, 58.85,
58.74, 58.62, 58.56, 58.53, 58.49, 58.47, 58.39, 58.35, 58.32 (20C,
20ꢁOCH3), 56.35 (1C, CHCN); HRMS (FAB): calcd for: 1476.6834
(MþNaþ), found: m/z 1476.6898.
4.3. Synthesis of 2-O-cyanomethyl-3-O-acetyl-permethylated
b-cyclodextrin (4)
A mixture of 3 (460 mg, 0.31 mmol), Ac2O (5.5 mL) in anhydrous
pyridine (11 mL) was stirred at room temperature for 24 h under
argon. After removing the solvent by evaporation under reduced
pressure, the residue was dissolved in CH2Cl2, washed with brine,
and dried over MgSO4. The solvent was evaporated, and the residue
was isolated by flash chromatography, eluting with ethyl acetate/
isopropanol/H2O 10:1:0.3 to give compound 4 as a white amor-
4.6. Synthesis of 2-O-aminoethyl-permethylated-
cyclodextrin (7)
To a mixture of 6 (300 mg, 0.23 mmol), Pd–C (10%, 125 mg) in
CH3OH (10 mL) was added 1 N HCl aqueous solution (0.3 mL,
0.3 mmol). The mixture was stirred at room temperature for 2 h
under hydrogen. After filtration and removal of the solvent, the
residue was purified by flash chromatography, eluted with CH2Cl2/
CH3OH/NH3$H2O 10:1:0.05 to give 7 (269 mg, 80%) as a white foam.
phous solid (417 mg, 90%). Rf¼0.5 (CH3CN/CH3OH 16:1); [
a
]
D þ113
(c 0.75, CHCl3); 1H NMR (400 MHz, CDCl3):
d
5.41 (m, 1H, H3), 5.33
(d, 1H, J¼3.6 Hz, H1), 5.16–5.12 (m, 4H, 4ꢁH1), 5.08 (d, 1H, J¼3.5 Hz,
H1), 5.02 (d, 1H, J¼3.4 Hz, H1), 4.50 (2d, 2H, J¼16.1 Hz, CH2–CN),
3.31 (2d, 1H, J1,2¼3.6 Hz, J2,3¼10.3 Hz, H2); 13C NMR (100 MHz,
Rf¼0.14 (CH2Cl2/CH3OH 8:1); [
a
]
þ113.1 (c 1.0, CHCl3); 1H NMR
D
CDCl3):
d
170.24 (1C, C]O), 116.27 (1C, CN), 99.60, 99.59, 99.45,
(400 MHz, CDCl3):
d
5.17–5.09 (m, 6H, 6ꢁH1), 5.05 (d, 1H,
98.88, 98.78, 98.76, 98.68 (7C, 7ꢁC1), 82.42, 82.24, 82.20, 82.10,
81.86, 81.72, 81.63, 81.61, 81.59, 81.57, 81.50, 81.47, 81.39, 80.73,
80.68, 80.65, 80.58 (21C, 7ꢁC2, C3, C4), 71.77, 71.50, 71.08, 70.98,
70.94, 70.77, 70.43 (7C, 7ꢁC5), 71.95, 71.54, 71.30, 71.12, 70.89, 70.47
(7C, 7ꢁC6), 61.98, 61.76, 61.67, 61.41, 60.85, 59.36, 59.09, 59.07,
58.93, 58.88, 58.69, 58.33, 58.26, 58.00 (19C, 19ꢁOCH3), 57.19 (1C,
CH2CN), 21.48 (1C, O]CCH3); FABMS: m/z 1504.7 (MþNaþ). Anal.
Calcd for C65H111O36N: C, 52.66; H, 7.55; N, 0.94. Found: C, 52.44; H,
7.60; N, 1.12.
J1,2¼3.2 Hz, H1), 3.27–3.23 (m, 2H, CH2NH2); 13C (100 MHz, CDCl3):
d
99.38, 99.24, 99.09, 99.01, 98.98, 98.76, 98.63 (7C, 7ꢁC1), 82.45,
82.22, 82.15, 82.03, 81.94, 81.80, 81.77, 81.68, 81.63, 81.59, 81.50,
81.26, 81.21, 81.04, 80.60, 80.36, 80.22, 80.16, 79.99, 79.87, 79.79
(21C, 7ꢁC2, C3, C4), 71.61, 71.52, 71.46, 71.20, 71.11 (7C, 7ꢁC6), 71.39,
71.27, 70.92, 70.83, 70.76, 70.68 (7C, 7ꢁC5), 67.73 (1C, OCH2), 61.78,
61.75, 61.60, 61.51, 61.44, 61.28, 61.25, 61.19, 61.11, 59.14, 58.90,
58.87, 58.84, 58.77, 58.51, 58.39, 58.37, 58.26, 58.23, 58.18 (20C,
20ꢁOCH3), 40.83 (1C, CH2NH2); HRMS (FAB): calcd for: 1458.7328
(MþHþ), found: m/z 1458.7313.
4.4. Synthesis of 2-O-aminoethyl-3-hydroxyl-permethylated
b-cyclodextrin (5)
4.7. Synthesis of permethylated b-CD dimer (8)
To a mixture of 3 (390 mg, 0.28 mmol), Pd/C (10%, 160 mg) in
CH3OH (10 mL) was added 1 N HCl aqueous solution (0.4 mL,
A solution of 7 (770 mg, 0.52 mmol) in anhydrous CH2Cl2
(65 mL) in ice-bath was added Et3N (183 L, 1.32 mmol) and
m

Z. Guan et al. / Tetrahedron 65 (2009) 1125–1129
1129
malonyl dichloride (26
m
L, 0.27 mmol) under argon. The mixture
4.9. Synthesis of 2:1
conjugate (2)
b-cyclodextrin/fullerene[60]
was stirred at room temperature for 10 h. After removal of sol-
vent, the residue was purified by flash chromatography, eluted
with EtOAc/CH3OH 8:1 to provide 8 (270 mg, 34%) as colorless
To a solution of 9 (10 mg, 3.27ꢁ10ꢂ3 mmol) and C60 (4 mg,
syrup. Rf¼0.29 (EtOAc/CH3OH 6:1); [
a
]
þ133.5 (c 1.0, CHCl3); 1H
5.5ꢁ10ꢂ3 mmol) in anhydrous toluene, DBU (2
mL, 0.013 mmol) was
D
NMR (400 MHz, CDCl3):
d
7.94 (t, 2H, 2ꢁNH), 5.19 (d, 4H,
added and the mixture was stirred at room temperature for 2 h. The
reaction mixture was directly chromatographed, eluting first with
cyclohexane to remove excess C60, then cyclohexane/acetone 3:2 to
provide compound 2 (4 mg, 33%) as brown solid. Rf¼0.29 (cyclo-
J1,2¼3.6 Hz, 4ꢁH1), 5.17–5.13 (m, 8H, 8ꢁH1), 5.03 (d, 2H,
J1,2¼3.6 Hz, 2ꢁH1); 13C (100 MHz, CDCl3):
d
127.24 (2C, 2ꢁC]O),
99.26, 99.13, 99.05, 99.04, 98.84, 98.83, 98.80 (14C, 14ꢁC1), 82.15,
82.03, 81.90, 81.85, 81.80, 81.74, 81.68, 81.66, 81.62, 81.56, 81.45,
80.60, 80.58, 80.49, 80.45, 80.41, 80.39, 82.23, 79.99, 79.89, 71.03,
70.95, 70.83, 70.68 (56C, 14ꢁC2, C3, C4, C5), 71.58, 71.52, 71.49,
71.38, 71.18, 70.79 (14C, 14ꢁC6), 69.91 (2C, 2ꢁOCH2), 61.86, 61.68,
61.59, 61.56, 61.34, 61.25, 61.21, 58.99, 58.96, 58.93, 58.91, 58.81,
58.47, 58.42, 58.24 (40C, 40ꢁOCH3), 42.56, 39.74 (3C, COCH2CO,
2ꢁCH2NHCO); HRMS (ESI): calcd for: 2984.4471 (MþHþ), found:
m/z 2984.4449.
hexane/acetone 1:1); [
a
]
D þ16.5 (c 0.1, CHCl3); 1H NMR (500 MHz,
CDCl3):
d
7.95 (t, 2H, J¼5.5 Hz, 2ꢁNH), 5.15–5.11 (m, 12H, 12ꢁH1),
5.02 (d, 2H, J1,2¼3.5 Hz, 2ꢁH1); 13C NMR (125 MHz, CDCl3):
d 162.48
(2ꢁCONH), 146.69, 145.92, 145.71, 145.38, 145.16, 144.67, 144.50,
144.28, 143.74, 142.99, 142.32, 142.14, 140.87, 140.75, 137.95, 137.83
(C60-sp2C), 99.44, 98.93, 98.80 (14C, 14ꢁC1), 81.93, 81.78, 81.17,
80.35, 80.09, 79.85, 77.26, 77.00, 76.75, 71.46, 71.35, 71.09, 70.97,
70.84, 69.99 (70C, 14ꢁC2, C3, C4, C5, C6, 2ꢁOCH2, C60-sp3C), 62.06,
61.90, 61.51, 61.32, 58.96, 58.72, 58.61, 58.46 (40C, 40ꢁMe), 41.09,
29.68 (3C, 2ꢁCH2NH, bridgehead C); HRMS (ESI): calcd for:
3724.4134 (MþNaþ), found: m/z 3724.4115.
4.8. Synthesis of bromo permethylated
and dibromo permethylated -CD dimer (10)
b-CD dimer (9)
b
Acknowledgements
A solution of 8 (50 mg, 0.016 mmol) in anhydrous CH2Cl2 (1 mL)
in ice-bath under argon was added Et3N (12 L, 0.086 mmol) and
Br2 (1 L, 0.018 mmol). The reaction solution was stirred at room
m
We thank the French Embassy in China for a Ph.D. fellowship to
Z.G. Financial support from the French Agence Nationale de la
Recherche (Nꢀ ANR-05-JCJC-0211-03), the French CNRS and the
Peking University Health Science Center is gratefully
acknowledged.
m
temperature and monitored by TLC. The reaction should be
stopped when the dibromide product appear. After removal of
solvent, the residue was purified by flash chromatography, eluted
with EtOAc/CH3OH 15:1 to give 9 (20 mg, 40%) and 10 (10 mg, 20%)
both as white foam. Compound 9: Rf¼0.29 (EtOAc/CH3OH 5:1);
[
a
]
þ48.2 (c 0.4, CHCl3); 1H NMR (500 MHz, CDCl3):
d
7.93 (t, 2H,
References and notes
D
J¼5.5 Hz, 2ꢁNH), 5.17–5.11 (m, 12H, 12ꢁH1), 5.06 (d, J1,2¼3.5 Hz,
2H, 2ꢁH1); 13C NMR (125 NMR, CDCl3):
d
166.17 (2ꢁCONH), 99.26,
1. Bosi, S.; Da Ros, T.; Spalluto, G.; Prato, M. Eur. J. Med. Chem. 2003, 38, 913–923.
2. Filippone, S.; Heimann, F.; Rassat, A. Chem. Commun. 2002, 1508–1509.
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5. Andersson, T.; Nilsson, K.; Sundahl, M.; Westman, G.; Wennerstrom, O. J. Chem.
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99.25, 99.23 (14C, 14ꢁC1), 82.64, 82.50, 82.38, 82.22, 82.12, 82.08,
82.05, 80.91, 77.75, 77.43, 77.19, 77.18, 77.15, 77.13, 77.10, 77.06,
77.03, 77.02, 77.01, 71.99, 71.97, 71.32, 71.31, 71.19 (70C, 14ꢁC2, C3,
C4, C5, C6, OCH2), 61.71, 59.41, 51.36, 58.98, 58.94, 8.72 (40C,
40ꢁMe); HRMS (ESI): calcd for: 3062.3576 (MþHþ), found: m/z
3062.3196.
Compound 10: Rf¼0.33 (EtOAc/CH3OH 5:1); [
a
]
þ185.8 (c 1.0,
D
CHCl3); 1H NMR (400 MHz, CDCl3):
d
7.97 (t, 2H, J¼5.6 Hz, 2ꢁNH),
5.21–5.12 (m, 12H, 12ꢁH1), 5.04 (d, 2H, J¼3.5 Hz, 2ꢁH1); 13C NMR
10. Bhattacharyya, K. Acc. Chem. Res. 2003, 36, 95–101.
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165–169.
15. Casu, B.; Reggiani, M.; Sanderson, G. R. Carbohydr. Res. 1979, 76, 59–66.
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(100 MHz, CDCl3):
d
164.17 (2C, 2ꢁCONH), 99.55, 99.26, 99.15,
99.02, 99.00, 98.81, 98.76 (14C, 14ꢁC1), 82.26, 82.14, 82.05, 81.97,
81.91, 81.82, 81.75, 81.69, 81.21, 80.87, 80.70, 80.42, 80.24, 80.17,
80.11, 80.07, 80.03, 79.91, 71.16, 71.10, 70.96, 70.85, 70.76, 70.74
(56C, 14ꢁC2, C3, C4, C5), 71.52, 71.48, 71.37, 71.29, 71.23, 69.91 (16C,
14ꢁC6, 2ꢁOCH2), 61.80, 61.57, 61.51, 61.36, 61.30, 61.28, 58.97,
58.93, 58.81, 58.75, 58.51, 58.31 (40C, 40ꢁMe), 57.00, 41.85 (CH2NH,
CBr2); HRMS (ESI): calcd for: 3157.2946 (MþNHþ4 ), found: m/z
3157.2945.