Synthesis and water solubility of adamantyl-OEG-fullerene hybrids

Article abstract of DOI:10.1021/jo0479359

(Chemical Equation Presented) A series of new adamantyl- oligoethyleneglycol-fullerene hybrids was prepared via Bingel-Hirsch functionalization of the C₆₀ fullerene with various adamantyl-oligoethyleneglycol malonates. As NMDA-targeted antioxid

Full text of DOI:10.1021/jo0479359

Synthesis and Water Solubility of Adamantyl-OEG-fullerene
Hybrids
Amnon Bar-Shir, Yoni Engel, and Michael Gozin*
School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University,
Tel Aviv 69978, Israel
cogozin@mgchem.tau.ac.il
Received November 21, 2004
A series of new adamantyl-oligoethyleneglycol-fullerene hybrids was prepared via Bingel-Hirsch
functionalization of the C60 fullerene with various adamantyl-oligoethyleneglycol malonates. As
NMDA-targeted antioxidants, these compounds may have the potential to be developed as
therapeutic agents for the treatment of neurological disorders.
During recent years, research in the field of water-
soluble C60 fullerene derivatives has significantly in-
creased due to a broad range of biological activity that
of the well-established approaches to overcome the lack
of fullerenes’ solubility in aqueous solutions is by chemi-
cal modification of fullerenes with polar groups such as
1
polyols,8 carboxylates,9 polyethers, and dendrons.
10
11
was found for these compounds. This includes antioxi-
2
dant and neuroprotective properties, inhibitory activity
3
4
for various enzymes, antiviral and antibacterial proper-
(
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*
To whom correspondence should be addressed. Tel: +972-3-640-
878. Fax: +972-3-640-5879.
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10.1021/jo0479359 CCC: $30.25 © 2005 American Chemical Society
2660
J. Org. Chem. 2005, 70, 2660-2666
Published on Web 03/02/2005

Synthesis and Water Solubility of Adamantyl-OEG-fullerene Hybrids
16
Further development of this concept led to the construc-
tion of hybrid systems in which a variety of functional
moieties such as peptides,12 oligonucleotides, porphy-
rins,14 flavonoids,15 steroids, and DNA-binding and
17
protein-binding fragments were attached to a fullerene
core. Such dyad systems could amplify or alter biochemi-
cal characteristics of their components or even produce
compounds with new biological properties.
Recently, preparation of novel fullerene hybrids bear-
ing 1,4-dihydropyridin18 and arylpiperazine functional
groups was described by Martin and co-workers. Al-
though these materials combine components with very
promising biological activity, their best solubility in a 10%
DMSO aqueous solution was reported to be in the range
13
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19
-
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of ∼10 M and could present a challenge in further
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21
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J. Org. Chem, Vol. 70, No. 7, 2005 2661

Bar-Shir et al.
FIGURE 1. Synthesis of compound 6a. Reagents and conditions: (i) tert-butyldimethylsilyl chloride, imidazole, DMF, 0 °C; (ii)
malonic acid, DCC, acetonitrile; (iii) tetrabutylammonium fluoride, THF, 0 °C; (iv) p-nitrophenylchloroformate, triethylamine,
2
THF, 0 °C; (v) aminoadamantane, triethylamine, DMF; (vi) C60, I , DBU, toluene, rt.
movement disease, depression,28 and cocaine depen-
2
7
are very attractive, as they lay a platform for the
synthesis of other target-specific fullerene derivatives.
2
9
dence. Aminoadamantyl derivatives are especially ef-
fective in the treatment of fatigue associated with
The general synthetic strategy toward these materials
was based on initial construction of malonate oligoeth-
yleneglycol esters terminated with adamantylcarbamates
that were further coupled to a C60 fullerene, following
3
0
multiple sclerosis and Parkinson’s and Alzheimer’s
31
diseases. On the molecular level, adamantyl derivatives
were found to function as noncompetitive antagonists for
the N-methyl-D-aspartate (NMDA) receptor.32 As the
latter contributes importantly to the etiology and pro-
gression of many neurological diseases states,33 new
adamantyl-fullerene hybrids may have potential to be-
come therapeutic agents for treating these diseases.
In this work, we describe the preparation and charac-
terization of new water-soluble adamantyl-oligoethyl-
eneglycol-fullerene hybrids, in which adamantyl groups
are connected to a carboxyfullerene moiety through
oligoethyleneglycol (OEG) bridges of various lengths. In
addition to water-solubility, incorporation of biocompat-
ible and flexible OEG bridges between the two functional
moieties should provide these compounds with improved
NMDA receptor affinity characteristics since, in the
described arrangement, receptor-binding moieties are not
sterically hindered by a fullerene fragment. The described
architecture and preparation methods of new compounds
34
the Bingel-Hirsch methodology. The synthetic route for
the preparation of compound 6a is outlined in Figure 1.
To avoid a possible polymerization reaction, which
typically takes place in direct esterification of malonic
acid with diols, one hydroxyl terminal of tetraethylene-
glycol was protected by reaction with tert-butyldimeth-
ylsilyl chloride (TBDMS-Cl) at 0 °C in DMF, using
imidazole as a base. DCC-mediated coupling of mono-
35
silyl-protected tetraethyleneglycol 1 with malonic acid
in acetonitrile produced bis(TBDMS-tetraethyleneglycol)-
malonate 2 in 81% yield, which was further converted to
the corresponding diol 3 in 91% yield, by deprotection
with tetrabutylammonium fluoride (TBAF) at 0 °C in
THF. Bis-p-nitrophenyl carbonate 4 was obtained in 70%
yield by reaction of diol 3 with p-nitrophenylchloro-
formate at 0 °C in THF, using triethylamine as a base.
The synthesis of the target adamantyl-tetraethylenegly-
col-fullerene hybrid 6a was completed by coupling syn-
thon 4 with 1-aminoadamantane in DMF to produce
adamantylcarbamate-tetraethyleneglycol-malonic ester
5a and its subsequent attachment to a C60 fullerene in
(
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1
To evaluate the influence of OEG length on adamantyl-
(
fullerene hybrids solubility in aqueous solutions, we
prepared several compounds. A straightforward proce-
dure for preparing target compounds 6a-c, without the
use of protection groups, was based on the reaction of
tetraethyleneglycol, diethyleneglycol, or PEG-400 with
adamantylisocyanate under reflux conditions in THF, to
6
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68.
(
33) (a) Le, D. A.; Lipton, S. A. Drugs Aging 2001, 18 (10), 717-
24. (b) Rison, R. A.; Stanton, P. K. Neurosci. Biobehav. Rev. 1995, 19
7
(
4), 533-552.
2662 J. Org. Chem., Vol. 70, No. 7, 2005

Synthesis and Water Solubility of Adamantyl-OEG-fullerene Hybrids
FIGURE 2. Synthesis of compounds 6a-c. Reagents and conditions: (i) adamantylisocyanate, THF, reflux; (ii) malonic acid,
DCC, acetonitrile; (iii) C60, I , DBU, toluene, rt.
2
FIGURE 3. Synthesis of compound 9. Reagents and conditions: (i) tert-butyldiphenylsilyl chloride, imidazole, DMF; (ii) malonic
acid, DCC, acetonitrile.
produce a series of compounds 7a-c. These reactions
were followed by DCC-assisted coupling of 7a-c with
malonic acid in acetonitrile and by subsequently attach-
ing the product to a C60 core (Figure 2).
However, attempts to achieve higher solubility of
hybrids by incorporating PEG-1500 into their structures
were less successful. Reaction of PEG-1500 with ada-
mantylisocyanate produced an inseparable mixture of
products, under all tested reaction and separation condi-
tions. In an alternative approach, tert-butyldiphenylsilyl
chloride (TBDPS-Cl) was used to protect one hydroxyl
group of PEG-1500, utilizing DMF as a solvent and
imidazole as a base (Figure 3).
Use of the bulky silyl protection group allowed obtain-
ing purified 8 in 43% yield. A subsequent DCC-mediated
coupling of 8 with malonic acid in acetonitrile resulted
in a mixture of products, from which target bis(TBDPS-
PEG-1500)-malonate 9 was separated in 15% yield, after
several consecutive chromatographic steps. Further depro-
tection of 9, with TBAF in THF, led to an inseparable
mixture of products.
These results indicated that a more practical approach
to the solubility improvement of adamantyl-fullerene
hybrids would be the poly-substitution of a fullerene core,
with purifiable OEG-derivatives, rather than the syn-
thesis of monosubstituted fullerenes with longer OEG
fragments. The synthesis of fullerene derivative 10 was
achieved in 77% yield, by reacting 2 equiv of PEG-400-
derived 5c with a pristine C60 fullerene (Figure 4).36
Since, commercially available PEG-400 contains a
mixture of oligoethyleneglycols, electrospray ionization
mass spectrometry (ESI-MS) was found to be particularly
useful in the analysis of this starting material and all
subsequent derivatives, including 5c and target fullerene
hybrids 6c and 10, the typical ESI-MS spectra of which
are shown in Figure 5. In this figure (top) ESI-MS spectra
of 5c clearly exhibit a typical distribution of molecular
2 2
weights (44 m/z for each -CH CH O- unit) around the
average mass, due to a variability in the OEG chain
lengths.
Solubility results of hybrids 6a-c and 10 in DMSO
aqueous solutions are summarized in Table 1 and Figure
6.
The solubility of 10 in 2% DMSO aqueous solution was
found to be even higher, reaching maximum concentra-
-
4
tion of 5.15 × 10 M (1.6 mg/mL) and clearly exhibiting
an overall validity of our approach.
The present work describes the preparation of new
adamantyl-oligoethyleneglycol-fullerene hybrids and quali-
tative evaluation of the influence of the oligoethyleneg-
lycol length on the solubility of these compounds in
aqueous solutions. The developed methodology should
provide a platform for the synthesis of other well-defined
and targeted fullerene derivatives for a broad variety of
biomedical applications.
(
36) Nakamura, Y.; O-Kawa, K.; Nishimura, J. Bull. Chem. Soc.
Jpn. 2003, 76, 865-882.
J. Org. Chem, Vol. 70, No. 7, 2005 2663

Bar-Shir et al.
2
FIGURE 4. Synthesis of compound 10. Reagents and conditions: 0.46 equiv of C60, I , DBU, toluene.
FIGURE 5. ESI-MS spectra of compounds 5c (top), 6c (bottom, left), and 10 (bottom, right).
Experimental Section
mL) was cooled to 0 °C and stirred for 30 min under argon. To
this solution was added tert-butyldimethylsilyl chloride (15.5
g, 102.8 mmol) in dry DMF (50 mL) dropwise. After 2 h at 0
Compound 1. A solution of imidazole (7.0 g, 102.8 mmol)
and tetraethyleneglycol (30.0 g, 154.4 mmol) in dry DMF (70
2664 J. Org. Chem., Vol. 70, No. 7, 2005

Synthesis and Water Solubility of Adamantyl-OEG-fullerene Hybrids
3
as a light yellow oil (0.27 gr, 91%). 1H NMR (400 MHz,
CDCl
3
): δ 4.20 (t, J ) 4.8 Hz, 4 H), 3.61 (m, 4 H), 3.61 (m, 4
1
3
H), 3.56 (m, 16 H), 3.49 (t, J ) 5.2 Hz, 4 H), 3.36 (s, 2 H).
NMR (100 MHz, CDCl ): δ 167.6, 72.7, 70.7, 70.6, 70.5, 64.6,
3
C
6
1.6, 41.3. IR (neat): 940, 1104, 1283, 1340, 1458, 1636, 1743,
-
1
+
2
876, 3387 cm . MS (CI): m/z 457.1 (MH ).
Compound 4. A solution of 3 (1.10 g, 2.41 mmol) and
triethylamine (1.9 mL) in dry THF (100 mL) was cooled to 0
°
C under argon. To this solution was added p-nitrophenyl-
chloroformate (1.07 g, 5.30 mmol) in dry THF (40 mL) dropwise
during 1 h. After the end of addition, the reaction mixture was
allowed to warm to rt, stirred for 2 h, and monitored by TLC
(
SiO
and after solvent evaporation, the crude product was purified
by flash chromatography (SiO ; ethyl acetate) to yield 4 as
yellow oil (1.33 g, 70%). H NMR (400 MHz, CDCl ): δ 8.22
d, J ) 9.2 Hz, 2 H), 7.35 (d, J ) 9.2 Hz, 4 H), 4.39 (t, J ) 4.4
Hz, 4 H), 4.25 (t, J ) 4.8 Hz, 4 H), 3.77 (t, J ) 4.8 Hz, 4 H),
2
; ethyl acetate). The formed precipitate was filtered out,
2
1
3
(
13
3
.67 (m, 12 H), 3.61 (m, 8 H), 3.40 (s, 2 H). C NMR (100 MHz,
CDCl ): δ 166.7, 155.7, 152.7, 145.6, 125.5, 122.0, 70.9, 70.81,
0.76, 69.0, 68.8, 68.5, 64.7, 41.4. IR (neat): 664, 774, 860,
3
FIGURE 6. UV-vis spectra of compounds 6a-c and 10
measure in 0.1% DMSO aqueous solution.
7
1
7
8
-1
214, 1349, 1491, 1524, 1592, 1615, 1753 cm . MS (CI): m/z
+
87.0 (MH ). HRMS (MALDI-TOF): calcd for C33
42 2
H N O20Na
09.2223, found 809.2232.
TABLE 1. Maximum Concentrations Measured for 6a-c
Compound 5a (Procedure A). To a solution of 1-adamant-
and 10 Hybrids in DMSO Aqueous Solutions
ylamine (0.634 g, 4.19 mmol) in dry DMF (8 mL) were added
conc of DMSO
in water (%)
6a
6b
6c
10
triethylamine (2 mL) and 4 (1.5 g, 1.9 mmol) at rt. The reaction
progress was monitored by TLC (SiO ; CH Cl /CH OH, 95:5;
2 2 2 3
(10- M)
5
(10 M)
-5
(10 M)
-5
(10 M)
-5
R
f
) 0.6). After reaction completion, DMF was removed under
reduced pressure, and the crude product was purified by flash
chromatography (SiO ; CH Cl /CH OH, 95:5) to yield 5a as a
light yellow oil (1.14 g, 74%). H NMR (400 MHz, CDCl ): δ
.70 (broad s, 2 H), 4.23 (t, J ) 4.8 Hz, 4H), 4.08 (t, J ) 4.0
Hz, 4 H), 3.65 (t, J ) 5.2 Hz, 4 H) 3.59 (m, 20 H), 3.39 (s, 2 H),
0
0
1
.1
.5
.0
1.18
1.38
3.14
0.07
0.35
1.40
1.17
5.12
6.97
1.80
14.0
27.0
2
2
2
1
3
3
4
°
C, the reaction mixture was allowed to warm to rt. Water
2
1
6
1
.00 (m, 6 H), 1.86 (d, J ) 2.8 Hz, 12 H), 1.60 (t, J ) 2.8 Hz,
(
900 mL) was added, and the resulting solution was extracted
13
2 H). C NMR (100 MHz, CDCl
3
): δ 166.6, 154.4, 70.7, 70.6,
with ethyl acetate (4 × 400 mL). The combined organic extracts
9.9, 69.0, 64.7, 63.2, 50.8, 41.9, 41.4, 36.5, 29.6. IR (CHCl
3
):
were washed with brine. After solvent evaporation, the crude
-
1
067, 1139, 1277, 1295, 1456, 1508, 1723, 2853, 2912 cm
.
2
product was purified by flash chromatography (SiO ; ethyl
+
+
+
1
MS (FAB ): m/z 833.5 (MNa ), 849.0 (MK ).
acetate) to yield 1 as a light yellow oil (19.2 g, 61%). H NMR
400 MHz, CDCl ): δ 3.66 (m, 16 H), 0.86 (s, 9 H), 0.03 (s, 6
H). C NMR (100 MHz, CDCl ): δ 73.0, 72.8, 71.0, 70.9, 63.0,
2.0, 26.2, 18.6, -5.0. IR (neat): 778, 836, 943, 1107, 1253,
(
3
Compound 5a (Procedure B). To a solution of malonic
acid (0.25 g, 2.45 mmol) and 7a (2.0 g, 5.4 mmol) in dry
acetonitrile (20 mL) was added a solution of DCC (1.10 g, 5.4
mmol) in dry acetonitrile (7 mL) dropwise over 20 min under
argon. The reaction mixture was stirred for an additional 20
min during which time a white precipitate was formed. The
1
3
3
6
1
-1
+
355, 1467, 1648, 2860, 2930, 3445 cm . MS (CI ): m/z 309.2
+
(
MH ).
Compound 2. To a solution of malonic acid (0.31 g, 2.9
mmol) and 1 (2.0 g, 6.5 mmol) in dry acetonitrile (9 mL) was
precipitate was filtered and washed with CH
and combined organic fractions were evaporated. The crude
product was purified by flash chromatography (SiO ; CH Cl
CH OH, 95:5) to yield 5a as a light yellow oil (1.32 g, 65%).
H NMR (400 MHz, CDCl ): δ 4.70 (broad s, 2 H), 4.23 (t, J )
2
Cl
2
(3 × 20 mL),
added a solution of DCC (1.4 g, 6.5 mmol) in dry acetonitrile
(
7 mL) dropwise over 20 min under argon. The reaction
2
2
2
/
mixture was stirred for an additional 20 min during which
time a white precipitate was formed. The precipitate was
3
1
3
filtered and washed with CH
organic fractions were evaporated. The crude product was
purified by flash chromatography (SiO ; ethyl acetate/hexanes,
5:35) to yield 2 as a light yellow oil (1.61 gr, 81%). H NMR
400 MHz, CDCl ): δ 4.29 (t, J ) 4.8 Hz, 4 H), 3.76 (t, J ) 5.6
Hz, 4 H), 3.70 (t, J ) 4.8 Hz, 4 H), 3.64 (m, 16 H), 3.55 (t, J )
2
Cl
2
(3 × 20 mL), and combined
4.8 Hz, 4H), 4.08 (t, J ) 4.0 Hz, 4 H), 3.65 (t, J ) 5.2 Hz, 4 H)
3.59 (m, 20 H), 3.39 (s, 2 H), 2.00 (m, 6 H), 1.86 (d, J ) 2.8 Hz,
1
3
3
12 H), 1.60 (t, J ) 2.8 Hz, 12 H). C NMR (100 MHz, CDCl ):
2
1
6
(
δ 166.6, 154.4, 70.7, 70.6, 69.9, 69.0, 64.7, 63.2, 50.8, 41.9, 41.4,
3
36.5, 29.6. IR (CHCl ): 1067, 1139, 1277, 1295, 1456, 1508,
3
-
1
+
+
1723, 2853, 2912 cm . MS (FAB ): m/z 833.5 (MNa ), 849.0
.6 Hz, 4 H), 3.44 (s, 2 H), 0.89 (s, 9 H), 0.06 (s, 6 H). 13C NMR
100 MHz, CDCl ): δ 166.7, 72.9, 71.0, 70.9, 69.1, 64.8, 63.0,
+
5
(MK ).
(
3
Compound 6a. DBU (0.47 g, 3.08 mmol) in 30 mL of
toluene was added to a stirred solution of 5a (1.0 g, 1.23 mmol),
4
1.5, 26.2, 18.6, -5.0. IR (neat): 774, 837, 947, 1108, 1253,
+
1
466, 1744, 2860, 2933 cm-1. MS (CI): m/z 685.3 (MH ).
C60 (0.9 g, 1.23 mmol), and I (0.3 g, 1.23 mmol) in 310 mL of
2
HRMS (MALDI-TOF): calcd for C31
found 707.3821.
H
64
O
12NaSi
2
707.3829,
toluene, and the mixture was stirred for 36 h under an argon
atmosphere. The reaction mixture was loaded on top of a short
Compound 3. To a solution of 2 (6.53 g, 9.5 mmol) in THF
50 mL) was added a solution of tetrabutylammonium fluoride
2
SiO flash chromatography column and eluted with toluene
(
to remove the unreacted fullerene. Further elution with
in THF (24 mL of 1 M solution) by syringe at 0 °C. After 2 h
at 0 °C, the reaction mixture was allowed to warm to rt and
toluene/2-propanol (99:1) afforded 6a as dark brown solid (0.83
1
g, 44%). H NMR (400 MHz, CDCl
3
): δ 4.63 (broad s, 2 H),
stirred at rt for an additional 30 min. CH
added, and the resulting solution was washed with a saturated
Na SO
aqueous solution (3 × 50 mL). The aqueous solution
was extracted with CH Cl
(3 × 50 mL), combined organic
fractions were evaporated, and the crude residue was purified
by flash chromatography (SiO ; CH Cl /CH OH, 9:1) to yield
2
Cl
2
(400 mL) was
4.63 (t, J ) 4.8 Hz, 4H), 4.11 (t, J ) 4.0 Hz, 4 H), 3.85 (t, J )
4.8 Hz, 4 H) 3.62 (m, 20 H), 2.03 (m, 6 H), 1.88 (d, J ) 2.4 Hz,
1
3
2
4
3
12H), 1.62 (m, 12H). C NMR (100 MHz, CDCl ): δ 163.8,
2
2
154.5, 145.6, 145.5, 145.2, 145.0, 144.9, 144.2, 143.4, 143.3,
143.2, 142.5, 142.2, 141.2, 139.4, 71.8, 71.01, 71.00, 70.9, 70.8,
69.1, 66.6, 63.4, 51.0, 42.1, 36.6, 29.7. IR (KBr): 524, 704, 804,
2
2
2
3
J. Org. Chem, Vol. 70, No. 7, 2005 2665

Bar-Shir et al.
1
1
025, 1098, 1263, 1449, 1714, 2907, 2963 cm-1. HRMS
MALDI-TOF): calcd for C101 14Na 1551.4250, found
): 257, 326, 424, 475, 683 nm.
Compound 7a. A mixture of 1-adamantylisocyanate (2.0
characterized by their H NMR, 13C NMR, MS, and IR spectra
(
64 2
H N O
(see the Supporting Information).
1
551.4174. λmax(CHCl
3
Acknowledgment. We thank the Multiple Sclerosis
Center Foundation (Brigham & Women’s Hospital,
Massachusetts General Hospital, Boston, MA) and
Israeli Science Foundation for their generous financial
support. We thank also Dr. Ayelet Sacher from the
Maiman Institute for Proteome Research at Tel-Aviv
University for the HRMS measurements.
g, 11.3 mmol) and tetraethyleneglycol (4.4 g, 22.6 mmol) in
dry THF (30 mL) was refluxed for 20 h under argon. After the
mixture was cooled to rt, the solvent was evaporated and the
crude product was purified by flash chromatography (SiO
CH Cl /CH OH, 92:8) to yield 7a as a colorless oil (3.46 g, 82%).
H NMR (400 MHz, CDCl ): δ 4.14 (t, J ) 8.8 Hz, 2 H), 3.72
t, J ) 4.0 Hz, 2 H), 3.67 (m, 10 H), 3.61 (t, J ) 4.0 Hz, 2 H),
.06 (m, 3 H), 1.91 (d, J ) 2.8 Hz, 6 H), 1.65 (t, J ) 2.8 Hz, 6
2
;
2
2
3
1
3
(
2
1
3
H). C NMR (100 MHz, CDCl
3
): δ 154.5, 72.8, 70.7, 70.6, 70.5,
Supporting Information Available: Experimental de-
1
13
7
1
0.4, 69.9, 63.2, 61.8, 50.8, 41.9, 36.5, 29.6. IR (neat): 943,
067, 1232, 1360, 1455, 1535, 1708, 2852, 2902, 3437 cm
tails, characterization data, and H NMR, C NMR, and MS
spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
-
1
.
+
+
+
+
MS (FAB ): m/z 372.2 (MH ), 394.2 (MNa ), 410.0 (MK ).
6
HRMS (ESI): calcd for C19H33NO Na 394.2200, found 394.2077.
Compounds 5b,c, 6b,c, 7b,c, and 8-10 were prepared
following described above procedures. The products were
JO0479359
2666 J. Org. Chem., Vol. 70, No. 7, 2005