Synthesis of novel [60]fullerene-flavonoid dyads

Article abstract of DOI:10.1016/S0040-4039(02)00122-3

[60]Fullerene-chalcone and [60]fullerene-flavone dyads were obtained by 1,3-dipolar cycloaddition reactions of azomethine ylides with C₆₀.

Full text of DOI:10.1016/S0040-4039(02)00122-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1689–1691
Synthesis of novel [60]fullerene–flavonoid dyads
Maria D. L. de la Torre, Gian L. Marcorin, Giovanna Pirri, Augusto C. Tome´,* Artur M. S. Silva
and Jose´ A. S. Cavaleiro
Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
Received 7 November 2001; revised 15 January 2002; accepted 16 January 2002
Abstract—[60]Fullerene–chalcone and [60]fullerene–flavone dyads were obtained by 1,3-dipolar cycloaddition reactions of
azomethine ylides with C60. © 2002 Elsevier Science Ltd. All rights reserved.
The potential applications of fullerene derivatives
makes the study of the chemical, physical and biologi-
cal properties of these compounds an important sub-
ject.1–5 One of the most promising areas of application
of fullerenes is the medicinal chemistry, namely as free
radical scavengers6,7 for the treatment of neurodegener-
ative diseases, as inhibitors of the HIV-1 protease8–10 or
in the photodynamic therapy of neoplastic tissues.11–13
Flavonoids are an especially well-studied class of phy-
tochemicals widely distributed in higher plants; many of
them, particularly flavones, flavonols and chalcones,
are conspicuous components of flowers, fruits and
other parts of plants.14 These compounds contribute to
the quality, colour, and taste of many foods (vegeta-
bles, fruits) and drinks (tea, wine).15,16 Many diverse
functions have been attributed to them: aside from
acting as antioxidants17 and anticarcinogens,18,19 they
express beneficial effects in inflammatory and
immunomodulatory systems.15,16
In this communication we present the synthesis of
fullerene–chalcone and fullerene–flavone dyads, which
may have interesting physical and biological properties.
Since the antioxidant activity of flavonoids is highly
influenced by the presence of oxygenated groups on the
aromatic system,17 we decided to prepare several com-
Scheme 1.
* 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)00122-3

1690
M. D. L. de la Torre et al. / Tetrahedron Letters 43 (2002) 1689–1691
Scheme 2.
pounds differing in the number of oxygenated sub-
stituents. Knowing that both moieties can act as radical
scavengers, we may expect that these fullerene–
flavonoid dyads may behave as ‘radical sponges’ and,
eventually, may be useful as drugs in medicine.
C-5¦ and C-2¦ appear at ca. 70.0 and 83.0 ppm, respec-
tively, while the signals corresponding to C-4¦ and C-3¦
(C60 sp3 carbons) appear at ca. 76.5 and 68.8 ppm.
The starting compounds 1a, 2a and 2b were prepared
according to the literature procedures.24 The chalcone
1b and the flavone 2c were prepared as indicated in
Scheme 2. All products of this sequence were character-
The novel [60]fullerene–flavonoid dyads 3 and 4 were
synthesized from formylchalcones 1 and formylflavones
2 via 1,3-dipolar cycloaddition reactions of the corre-
sponding azomethine ylides (generated in situ from the
reaction of the formyl group with N-methylglycine and
then decarboxylation) to [60]fullerene (Scheme 1). All
cycloaddition reactions were carried out in refluxing
toluene, under nitrogen atmosphere, using an excess of
C60 (1.4 equiv.) and N-methylglycine (5 equiv.). The
reaction mixtures were separated by flash chromatogra-
phy using gradients of toluene:ethyl acetate as eluent.
The first fraction was the unchanged C60 and the next
one was the mono-adduct 3 or 4. Products with higher
polarity, probably bis-adducts, were discharged. The
isolated yields are in the range of 31–67%. All adducts
3 and 4 are stable compounds.
1
ized by H and 13C NMR and MS.
The study of the photophysical properties and the
biological activities of some of these new [60]fullerene–
flavonoid derivatives and the synthesis of other
fullerene–flavonoid dyads, starting with natural
flavonoids, are currently under investigation.
Acknowledgements
Thanks are due to the Fundac¸a˜o para a Cieˆncia e a
Tecnologia (FCT, Portugal) for funding the Organic
Chemistry Research Unit and to the European Com-
munity for funding the Research Network FMRX-
CT98-0192 (TMR Program).
1
The adducts 3 and 4 were characterized by H and 13C
1
NMR and MS.20,21 In the H NMR spectra of these
compounds the resonance of the N-methyl group
appears typically at l 2.82–2.84 ppm and the proton 2¦
appears as a singlet at ca. 5.0 ppm. The two non-equiv-
alent protons 5¦ appear as two doublets: one centered
at ca. 4.3 and the other at ca. 5.0 ppm. The geminal
coupling constant for these protons is in the range of
9.4 to 9.5 Hz. The resonances of the protons in the
chalcone and flavone moieties in the starting com-
pounds and in the adducts are very similar. It is inter-
esting to note that, in both compounds 3 and 4, the
signals corresponding to the protons of the phenyl
group directly attached to the pyrrolidine ring are
broadened. This indicates restricted rotation of the
phenyl substituent on the pyrrolidine ring, as previously
described for similar systems.22,23 In the 13C NMR
spectra of adducts 3 and 4 the signals corresponding to
References
1. Hirsh, A. The Chemistry of the Fullerenes; Thieme: New
York, 1994.
2. Mart´ın, N.; Sa´nchez, L.; Illescas, B.; Pe´rez, I. Chem. Rev.
1998, 98, 2527–2547.
3. Diederich, F.; Go´mez-Lo´pez, M. Chem. Soc. Rev. 1999,
28, 263–277.
4. Prato, M. Top. Curr. Chem. 1999, 199, 173–187.
5. Guldi, D. M. Chem. Commun. 2000, 321–327.
6. 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.

M. D. L. de la Torre et al. / Tetrahedron Letters 43 (2002) 1689–1691
1691
7. Bensasson, R. V.; Brettreich, M.; Frederiksen, J.; Go¨t-
tinger, H.; Hirsch, A.; Land, E. J.; Leach, S.; McGarvey,
D. J.; Scho¨nberger, H. Free Rad. Biol. Med. 2000, 29,
26–33.
8. Friedman, S. H.; DeCamp, D. L.; Sijbesma, R. P.;
Srdanov, G.; Wudl, F.; Kenyon, G. L. J. Am. Chem. Soc.
1993, 115, 6506–6509.
9. Sijbesma, R.; Srdanov, G.; Wudl, F.; Castoro, J. A.;
Wilkins, C.; Friedman, S. H.; DeCamp, D. L.; Kenyon,
G. L. J. Am. Chem. Soc. 1993, 115, 6510–6512.
10. Marcorin, G. L.; Da Ros, T.; Castellano, S.; Stefancich,
G.; Bonin, I.; Miertus, S.; Prato, M. Org. Lett. 2000, 2,
3955–3958.
11. Da Ros, T.; Prato, M. Chem. Commun. 1999, 663–669.
12. Jensen, W.; Wilson, S. R.; Schuster, D. I. Bioorg. Med.
Chem. 1996, 4, 767–779.
1.2, 1H, H-6%), 6.92 (ddd, J 8.5, 7.6 and 1.1, 1H, H-5%),
5.00 (s, 1H, H-2¦), 5.02 (d, J 9.3, 1H, H-5¦), 4.31 (d, J
9.3, 1H, H-5¦), 2.86 (s, 3H, N-CH3); 13C NMR (75.47
MHz, CDCl3/CS2) l: 192.4 (CO), 163.5 (C-2%), 152.7,
152.5, 147.1, 146.3, 146.2, 146.0, 145.9, 145.8, 145.7,
145.2, 145.1, 145.0, 144.5 (C-b), 144.4, 144.2, 142.9,
142.5, 142.4, 142.0, 141.9, 141.8, 141.7, 141.6, 141.5,
141.4, 140.1 (C-4), 140.0, 139.4, 136.8, 136.3, 136.2, 135.8,
135.5, 134.7 (C-a), 129.8, 129.4 (C-4%), 128.9, 120.2, 119.8
(C-6%), 119.7, 118.6 (C-5%), 83.0 (C-2¦), 76.9 (C-4¦), 69.9
(C-5¦), 68.8 (C-3¦), 39.9 (N-CH3). HRMS (FAB) m/z
calculated for C78H18NO2 (M+H)+ 1000.1338, found
1000.1373.
1
21. Selected data for compound 4a: H NMR [300.13 MHz,
CDCl3/CS2) l (ppm), J (Hz)]: 8.80 (dd, J 7.8 and 1.5, 1H,
H-5), 8.02 (m, 4H, H-2%, H-3%, H-5%, H-6%), 7.79 (ddd, J
8.0, 7.6 and 1.5, 1H, H-7), 7.57 (dd, J 8.0 and 0.9, 1H,
H-8), 7.45 (ddd, J 7.8, 7.6, 0.9, 1H, H-6), 6.83 (s, 1H,
H-3), 5.05 (s, 1H, H-2¦), 5.04 (d, J 9.4, 1H, H-5¦), 4.28 (d,
J 9.4, 1H, H-5¦), 2.86 (s, 3H, N-CH3); 13C NMR (75.47
MHz, CDCl3/CS2) l: 192.2 (C-4), 177.5 (C-2), 155.7
(C-9), 153.5 (C-7), 152.6, 152.3, 147.1, 146.1, 145.8, 145.6,
145.5, 145.4, 145.3, 145.1, 144.6, 144.2, 143.0, 142.9,
142.5, 142.4, 142.1, 142.0, 141.9, 141.8, 141.7, 141.5,
141.4, 140.9 (C-4%), 140.1, 139.8, 139.4, 136.8, 136.2,
135.8, 135.5, 133.5, 131.7 (C-1%), 129.7 (C-3%, C-5%), 126.5
(C-2%, C-6%), 125.7, 125.1 (C-6), 123.8 (C-10), 117.8 (C-8),
107.6 (C-3), 82.9 (C-2¦), 76.6 (C-4¦), 69.9 (C-5¦), 68.8
(C-3¦), 39.9 (N-CH3). HRMS (FAB) m/z calculated for
C78H16NO2 (M+H)+ 998.1181, found 998.1194.
13. Tabata, Y.; Ikada, Y. Pure Appl. Chem. 1999, 71, 2047–
2053.
14. The Flavonoids—Advances in Research Since 1986,
Haborne, J. B., Ed.; Chapman and Hall: London, 1996.
15. 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.
16. Flavonoids in Health and Diseases; Rice-Evans, C. A.;
Packer, L., Eds.; Marcel Dekker: New York, 1998.
17. Rice-Evans, C. A.; Miller, N. J.; Paganga, G. Free Rad.
Biol. Med. 1996, 20, 933–956.
18. Beudot, C.; De Me´o, M. P.; Dauzone, D.; Elias, R.;
Laget, M.; Guiraud, M.; Balausard, G.; Du´menil, G.
Mutat. Res. 1998, 417, 141–153.
22. Eckert, J.-F.; Nicoud, J.-F.; Nierengarten, J.-F.; Liu,
S.-G.; Echegoyen, L.; Barigelletti, F.; Armaroli, N.;
Ouali, L.; Krasnikov, V.; Hadziioannou, G. J. Am.
Chem. Soc. 2000, 122, 7467–7479.
23. De la Cruz, P.; De la Hoz, A.; Font, L. M.; Langa, F.;
Pe´rez-Rodr´ıguez, M. C. Tetrahedron Lett. 1998, 39,
6053–6056.
19. 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.
1
20. Selected data for compound 3a: H NMR [300.13 MHz,
CDCl3/CS2) l (ppm), J (Hz)]: 12.74 (s, 1H, 2%-OH), 7.92
(d, J 15.5, 1H, H-b), 7.90 (m, 3H, H-3%, H-2, H-6), 7.74
(d, J 8.4, 2H, H-3, H-5), 7.67 (d, J 15.5, 1H, H-a), 7.45
(ddd, J 7.8, 7.6 and 1.2, 1H, H-4%), 6.99 (dd, J 8.5 and
24. Patonay, T.; Cavaleiro, J. A. S.; Le´vai, A.; Silva, A. M.
S. Heterocycl. Commun. 1997, 3, 223–229.