Synthesis of [60]fullerene-quercetin dyads

Article abstract of DOI:10.1016/S0040-4039(02)00867-5

Starting from quercetin, a natural flavonol with high antioxidant activity, three novel [60]fullerene-flavone derivatives were synthesized via cyclopropanation of C₆₀.

Full text of DOI:10.1016/S0040-4039(02)00867-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4617–4620
Synthesis of [60]fullerene–quercetin dyads
Maria D. L. de la Torre, Augusto C. Tome´,* Artur M. S. Silva and Jose´ A. S. Cavaleiro
Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
Received 18 April 2002; revised 30 April 2002; accepted 7 May 2002
Abstract—Starting from quercetin, a natural flavonol with high antioxidant activity, three novel [60]fullerene–flavone derivatives
were synthesized via cyclopropanation of C60. © 2002 Elsevier Science Ltd. All rights reserved.
Among the various potential applications of the
fullerene derivatives, their use in medicinal chemistry is
probably the most promising one. It has been shown
that they exhibit several types of biological activities,
both in vitro and in vivo, that can be exploited for
medicinal purposes.1,2 The ability of C60 and its deriva-
tives to scavenge a large number of radicals per
molecule3,4 makes them potentially useful drugs in the
prevention or treatment of pathologies in which oxida-
tive damage is involved, namely cardiovascular5,6 and
neurodegenerative diseases.7,8
Currently we are developing a project concerning the
synthesis of new radical scavengers with potential appli-
cation in medicine. Knowing the aptitude of fullerenes
and flavonoids to trap radicals, we have been preparing
fullerene–flavonoid dyads aiming to obtain compounds
that may behave as radical sponges. Recently we
reported15 the synthesis of novel fullerene–chalcone and
fullerene–flavone dyads, obtained by 1,3-dipolar
cycloaddition reactions of azomethine ylides to C60.
Synthetic chalcones and flavones were then used. Now
we report the synthesis of new fullerene–flavone dyads
but starting with quercetin, a natural flavonol with high
antioxidant activity. The new compounds were
obtained by cyclopropanation16 of C60 with the appro-
priate malonate derivatives. The antioxidant activity of
quercetin (3,3%,4%,5,7-pentahydroxyflavone) is higher
than other pentahydroxyflavonoids (catequin, for
Flavonoids, a widely distributed class of phytochemi-
cals, also possess important medicinal properties: they
act as antioxidants9,10 and anticarcinogens,11,12 and they
express beneficial effects in inflammatory and
immunomodulatory systems.13,14
OMe
OMe
OH
OH
OMe
OMe
MeO
O
O
HO
O
O
MeO
O
a
+
OMe
2, 38%
OH
OMe
OH
OH
OMe O
3, 56%
1
d
b
OMe
OMe
OMe
OMe
OMe
OMe
MeO
O
MeO
O
O
MeO
O
c
OH
OH
OMe
OMe O
6, 47%
OTs
OTs
O
5, 79%
4, 86%
Scheme 1. (a) CH3I (30 mmol), K2CO3 (22.5 mmol), CH3CN/CH3OH (2:1) 60°C, 10 h. (b) p-TsCl (4 equiv.), K2CO3 (8 equiv.),
CH3CN, 60°C, 1 h. (c) AlBr3 (3.1 equiv.), CH3CN, 0°C, 1 h. (d) AlBr3 (1.1 equiv.), CH3CN, 0°C, 1 h.
* Corresponding author. Tel.: +351 234 370 712; fax: +351 234 370 084; e-mail: actome@dq.ua.pt
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00867-5

4618
M. D. L. de la Torre et al. / Tetrahedron Letters 43 (2002) 4617–4620
instance). This is due to the presence of a 2,3-double
bond and to the 4-oxo function in ring C which allows
electron delocalization across the molecule and
increases the stability of the aryloxyl radical after
hydrogen donation.10 The presence of a 3%,4%-dihydroxy-
phenyl system and a 3-hydroxyl group also contributes
to the high antioxidant activity of this compound.10
methylation/demethylation process,17 we succeeded to
prepare quercetin derivatives with 5-OH (compound 2)
and 3-OH (compounds 5 and 6) free groups.
Methylation of quercetin with methyl iodide afforded a
mixture of compounds 2 and 3. These compounds were
separated by flash chromatography using mixtures of
CH2Cl2/acetone (9:1 to 7:3) as eluent and were crystal-
lized from ethanol. Demethylation of compound 3 gave
the 3-OH derivative 6 and an additional amount of 2
(26%). Compound 2 was used in the reaction with
3-iodo-1-propanol (Scheme 2) and also in the prepara-
tion of derivative 5 (Scheme 1): tosylation followed by
demethylation led exclusively to 5. All these compounds
were purified by flash chromatography using
dichloromethane/acetone 9:1 as eluent and were crystal-
lized from ethanol. Alkylation of 2 and 6 with 3-iodo-1-
propanol afforded directly the propanol derivatives 7
The synthetic steps for the formation of different C60-
quercetin derivative dyads are indicated in Schemes
1–3. It involved the alkylation of one hydroxyl group of
the quercetin with 3-iodo-1-propanol, conversion of the
resulting alcohol into a malonate derivative and, finally,
coupling the malonate to C60 via a cyclopropanation
reaction (Bingel reaction).16 Since quercetin has five
hydroxyl groups, to prevent the formation of mixtures
of isomers, it is important to protect selectively four
hydroxyl groups. As indicated in Scheme 1, by a O-
OMe
OMe
OMe
OMe
MeO
O
O
MeO
O
O
b
a
2
OMe
O
OMe
OH
O
O
O
O
OMe
8, 73%
7, 72%
OMe
OMe
OMe
OMe
MeO
O
O
MeO
O
a
b
5, 6
O
O
R
R
O
O
O
OH
c
9a, R = OTs
9b, R = OH
O
60%
10a, R = OH, 86%
10b, R = OMe, 83%
OMe
9c, R = OMe, 82%
Scheme 2. (a) 3-Iodo-1-propanol (2 equiv.), K2CO3 (4 equiv.), dimethylformamide, 60°C, 3 h. (b) Methyl malonyl chloride (4.3
equiv.), triethylamine (2 equiv.), CH2Cl2, 0°C to rt, 3 h. (c) K2CO3 (2 equiv.), methanol, reflux, 0.5 h.
Scheme 3. (a) C60 (2.5 equiv.), I2 (1.1 equiv.), DBU (3.5 equiv.), toluene, rt, 1 h.

M. D. L. de la Torre et al. / Tetrahedron Letters 43 (2002) 4617–4620
4619
and 9c in good yields (Scheme 2). In a similar process,
5 yielded the corresponding tosylated propanol deriva-
tive 9a which after treatment with K2CO3 in refluxing
methanol afforded 9b in 60% (two steps). These com-
pounds were converted into the corresponding mal-
onates 8 and 10 by esterification with methyl malonyl
chloride (Scheme 2).
5. Wang, I. C.; Tai, L. A.; Lee, D. D.; Kanakamma, P. P.;
Shen, C. K.-F.; Luh, T.-Y.; Cheng, C. H.; Hwang, K. C.
J. Med. Chem. 1999, 42, 4614–4620.
6. Hsu, H. C.; Chiang, P. Y.; Chen, W. J.; Lee, Y. T. J.
Cardiovascular Pharmacol. 2000, 36, 423–427.
7. Dugan, L. L.; Turetsky, D. M.; Du, C.; Lobner, D.;
Wheeler, M.; Almli, C. R.; Shen, C. K.-F.; Luh, T.-Y.;
Choi, D. W.; Lin, T. S. Proc. Natl. Acad. Sci. USA 1997,
94, 9434–9439.
8. Dugan, L. L.; Lovett, E. G.; Quick, K. L.; Lotharius, J.;
Lin, T. T.; O’Malley, K. L. Parkinsonism Related Disor-
ders 2001, 7, 243–246.
9. Pietta, P.-G. J. Nat. Prod. 2000, 63, 1035–1042.
10. Rice-Evans, C. A.; Miller, N. J.; Paganga, G. Free Rad.
Biol. Med. 1996, 20, 933–956.
11. Beudot, C.; De Me´o, M. P.; Dauzone, D.; Elias, R.;
Laget, M.; Guiraud, M.; Balausard, G.; Du´menil, G.
Mutation Res. 1998, 417, 141–153.
12. Akama, T.; Ishida, H.; Shida, Y.; Kimura, U.; Gomi, K.;
Saito, H.; Fuse, E.; Kobayashi, S.; Yoda, N.; Kasai, M.
J. Med. Chem. 1997, 40, 1894–1900.
13. Bors, W.; Heller, W.; Michel, C.; Stettmaier, K.
Flavonoids and Polyphenols: Chemistry and Biology, In
Handbook of Antioxidants, Cadenas, E.; Packer, L.,
Eds.; Marcel Dekker: New York, 1996; p. 409
14. Flavonoids in Health and Diseases; Rice-Evans, C. A.;
Packer, L., Eds; Marcel Dekker: New York, 1998.
15. De la Torre, M. D. L.; Marcorin, G. L.; Pirri, G.; Tome´,
A. C.; Silva, A. M. S.; Cavaleiro, J. A. S. Tetrahedron
Lett. 2002, 43, 1689–1691.
Compounds 7 and 9 were purified by flash chromato-
graphy using dichloromethane/acetone 4:1 as eluent
and were crystallized from ethanol; compounds 8 and
10 were also purified by flash chromatography but
using dichloromethane/acetone 95:5 as eluent.
Cyclopropanation reactions of C60 with malonates 8 or
10 afforded the final dyads 11 or 12 in moderate yields
(Scheme 3). Compounds 11 and 12 were separated from
the unreacted C60 by flash column chromatography
using toluene to toluene/ethyl acetate 7:3 as eluent. The
first fraction was the unchanged C60 and the next one
was the monoadduct 11 or 12. Products with higher
polarity, probably bis-adducts, were discharged. The
fullerene derivatives were fully characterized by mass
1
and H and 13C NMR spectra.18–20 In the 13C NMR
spectra the signals appearing at ca. 52 and 71.5 ppm
correspond, respectively, to the methano bridge and to
the C60-sp3 carbons. These assignments were corrobo-
rated by DEPT (135°) experiments. The signals of all
carbons from the malonyl moiety were unequivocally
assigned by HETCOR (or HSQC) and HMBC experi-
ments. When we compare the NMR spectra of a series
of derivatives (7, 8 and 11, for instance) there are no
significant variations in the signals corresponding to the
quercetin moiety.
16. Bingel, C. Chem. Ber. 1993, 126, 1957.
17. Horie, T.; Kitou, T.; Kawamura, Y.; Yamashita, K. Bull.
Chem. Soc. Jpn. 1996, 69, 1033–1041.
1
18. Selected data for compound 11: H NMR [300.13 MHz,
CDCl3, l (ppm), J (Hz)]: 7.66–7.63 (m, 2H, H-2%, H-6%),
6.98 (d, J=8.4, 1H, H-5%), 6.45 (d, J=2.2, 1H, H-8), 6.25
(d, J=2.2, 1H, H-6), 4.96 (t, J=5.7, 2H), 4.19 (t, J=5.7,
2H), 4.80 (s, 3H, CO2CH3), 3.97, 3.96, 3.86, 3.80 (4 s,
4×3H, 4×OCH3), 2.48 (qui, J=5.7, 2H); 13C NMR [75.47
MHz, CDCl3, l (ppm)]: 173.6 (C-4), 163.8 (CO2CH3),
163.7 (C-7), 163.4 (CO2R), 160.0 (C-5), 158.8 (C-9), 152.9
(C-2), 150.8 (C-4%), 148.6 (C-3%), 145.4, 145.2, 145.1,
145.0, 144.8, 144.7, 144.6, 144.5, 144.3, 144.2, 143.8,
143.0, 142.9, 142.8, 142.5, 142.1, 142.0, 141.8, 141.6,
141.2, 140.8, 140.7 (C-3), 139.5, 138.3, 129.2, 128.2, 125.3,
123.3 (C-1%), 121.6 (C-6%), 111.1 (C-2%), 110.7 (C-5%), 109.8
(C-10), 96.8 (C-6), 92.8 (C-8), 71.5 (C60-sp3), 64.9
(OCH2CH2CH2OCO), 63.9 (OCH2CH2CH2OCO), 59.9
(3-OCH3), 56.0 (7-OCH3), 55.8 (3%-OCH3 and 4%-OCH3),
54.1 (CO2CH3), 52.0 (methano bridge), 28.0
(OCH2CH2CH2OCO); HRMS (FAB) m/z calculated for
C86H27O11 (M+H)+: 1235.1553, found: 1235.1599.
The extension of this work to the synthesis of novel
fullerene derivatives having other natural antioxidant
moieties and the evaluation of the properties of the
final products is currently under way.
Acknowledgements
Thanks are due to the Fundac¸a˜o para a Cieˆncia e a
Tecnologia (Portugal) for funding the Organic Chem-
istry Research Unit and to the European Community
for funding the Research Network FMRX-CT98-0192
(TMR Program).
1
References
19. Selected data for compound 12a: H NMR [300.13 MHz,
CDCl3, l (ppm), J (Hz)]: 12.60 (s, 1H, 5-OH), 7.73 (dd,
J=8.5 and 1.9, 1H, H-6%), 7.60 (d, J=1.9, 1H, H-2%), 7.01
(d, J=8.5, 1H, H-5%), 6.43 (d, J=2.1, 1H, H-8), 6.34 (d,
J=2.1, 1H, H-6), 4.65 (t, J=6.2, 2H), 4.15 (t, J=6.2,
2H), 4.07 (s, 3H, CO2CH3), 4.04, 3.96, 3.86 (3 s, 3×3H,
3×OCH3), 2.27 (qui, J=6.2, 2H); 13C NMR [75.47 MHz,
CDCl3, l (ppm): 178.5 (C-4), 165.5 (CO2CH3), 165.5
(C-7), 164.0 (COR), 162.0 (C-5), 158.0 (C-9), 156.7 (C-2),
151.4 (C-4%), 148.7 (C-3%), 145.3, 145.2, 145.1, 145.0,
144.9, 144.8, 144.7, 144.5, 143.9, 143.8, 143.0, 142.9,
1. Da Ros, T.; Prato, M. Chem. Commun. 1999, 663–669.
2. Jensen, W.; Wilson, S. R.; Schuster, D. I. Bioorg. Med.
Chem. 1996, 4, 767–779.
3. Morton, J. R.; Negri, F.; Preston, K. F. Acc. Chem. Res.
1998, 31, 63–69.
4. Bensasson, R. V.; Brettreich, M.; Frederiksen, J.; Go¨t-
tinger, H.; Hirsch, A.; Land, E. J.; Leach, S.; McGarvey,
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26–33.

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M. D. L. de la Torre et al. / Tetrahedron Letters 43 (2002) 4617–4620
142.8, 142.2, 142.1, 141.9, 141.7, 140.9, 139.3, 138.6,
3.97, 3.95, 3.90 (3 s, 4×3H, 4×OCH3), 2.28 (qui, J=6.2,
2H); 13C NMR [75.47 MHz, CDCl3, l (ppm)]: 173.8 (C-4),
164.1 (CO2CH3), 164.0 (C-7), 163.4 (CO2R), 160.1 (C-5),
158.8 (C-9), 152.8 (C-2), 150.8 (C-4%), 148.6 (C-3%), 145.3,
145.2, 145.1, 145.0, 144.9, 144.8, 144.7, 144.6, 144.5, 143.9,
143.8, 143.0, 142.9, 142.8, 142.2, 142.1, 141.9, 141.7, 140.9,
140.2 (C-3), 139.3, 138.5, 138.0, 137.9, 129.0, 128.2, 125.3,
123.2 (C-1%), 122.0 (C-6%), 110.8 (C-5%), 111.2 (C-2%), 109.4
(C-10), 95.9 (C-6), 92.1 (C-8), 71.5 (C60-sp3), 69.0
(OCH2CH2CH2OCO), 64.7 (OCH2CH2CH2OCO), 55.8
(7-OCH3), 56.4, 55.1 (3%-OCH3, 4%-OCH3 and 5-OCH3),
54.1 (CO2CH3), 52.3 (methano bridge), 29.7 (OCH2CH2-
CH2OCO); HRMS (FAB) m/z calculated for C86H27O11
(M+H)+: 1235.1553, found: 1235.1542.
138.0, 137.9 (C-3), 129.0, 128.2, 125.3, 122.8 (C-6%), 122.5
(C-1%), 111.2 (C-2%), 110.8 (C-5%), 106.1 (C-10), 98.0 (C-6),
92.3 (C-8), 71.5 (C60-sp3), 69.3 (OCH2CH2CH2OCO),
64.3 (OCH2CH2CH2OCO), 56.1 (7-OCH3), 56.0, 55.8
(3%-OCH3 and 4%-OCH3), 54.1 (CO2CH3), 52.3 (methano
bridge), 29.5 (OCH2CH2CH2OCO); HRMS (FAB) m/z
calculated for C85H25O11 (M+H)+: 1221.1397, found:
1221.1399.
1
20. Selected data for compound 12b: H NMR [300.13 MHz,
CDCl3, l (ppm), J (Hz)]: 7.71 (dd, J=8.5 and 1.9, 1H,
H-6%), 7.64 (d, J=1.9, 1H, H-2%), 7.00 (d, J=8.5, 1H, H-5%),
6.50 (d, J=2.1, 1H, H-8), 6.35 (d, J=2.1, 1H, H-6), 4.65
(t, J=6.2, 2H), 4.17 (t, J=6.2, 2H), 4.04 (s, 3H, CO2CH3),