[60]Fullerene-flavonoid dyads

Article abstract of DOI:10.1016/j.tet.2004.03.003

A range of fullerene-chalcone, fullerene-flavone, and fullerene-chromone dyads, including a bis(flavonyl)-fullerene dyad, were prepared by 1,3-dipolar cycloaddition reactions of azomethine ylides to C₆₀ and by cyclopropanation of C₆₀ with flavonyl malonates. Synthetic and natural flavonoid derivatives were used as starting materials.

Full text of DOI:10.1016/j.tet.2004.03.003

Tetrahedron 60 (2004) 3581–3592
[60]Fullerene–flavonoid dyads
†
Maria D. L. de la Torre, Andrea G. P. Rodrigues, Augusto C. Tome, Artur M. S. Silva
´
and Jose A. S. Cavaleiro
*
´
Department of Chemistry, University of Aveiro, University Campus, 3810-193 Aveiro, Portugal
Received 15 December 2003; revised 13 February 2004; accepted 2 March 2004
Abstract—A range of fullerene–chalcone, fullerene–flavone, and fullerene–chromone dyads, including a bis(flavonyl)-fullerene dyad,
were prepared by 1,3-dipolar cycloaddition reactions of azomethine ylides to C60 and by cyclopropanation of C60 with flavonyl malonates.
Synthetic and natural flavonoid derivatives were used as starting materials.
q 2004 Elsevier Ltd. All rights reserved.
Studies with fullerene derivatives have shown that they
exhibit several types of biological activities, both in vitro
and in vivo, that can be exploited for medicinal purposes.1,2
As an example, the ability of C60 and its derivatives to
scavenge a large number of radicals per molecule3,4 makes
them potentially useful drugs in the prevention or treatment
of pathologies in which oxidative damage is involved,
namely cardiovascular5,6 and neurodegenerative diseases.7,8
The results already published are encouraging and new
optimized molecules are being designed, synthesized and
evaluated.9
chalcones and flavones, a chromone and a natural flavonol
were used as reagents.
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 corresponding
azomethine ylides (generated in situ from the reaction of the
formyl group with N-methylglycine) to [60]fullerene
(Scheme 1). These 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
chromatography using gradients of toluene/ethyl acetate as
eluent. The isolated yields are in the range of 31–67%. All
adducts 3 and 4 are stable compounds.
Recently, we reported the synthesis of new fullerene
derivatives having flavonoid moieties of synthetic and
natural origin.10,11 The idea of preparing fullerene–
flavonoid dyads arised from the fact that flavonoids, a
widely distributed class of phytochemicals, also possess
significant antioxidant activity12,13 and, eventually, the
resulting dyads could show increased radical scavenging
activities. Beyond acting as antioxidants, natural flavonoids
also act as anticarcinogens,14,15 and they express beneficial
effects in inflammatory and immunomodulatory
systems.16,17
The starting compounds 1a, 2a and 2b were prepared
according to the literature procedures.20 The chalcone 1b
and the flavone 2c0were prepared as indicated in Scheme 2.
Benzylation of 2 ,30,40-trihydroxyacetophenone 5a with
benzyl chloride in the presence of 0potassium carbonate
afforded the corresponding 20,30,4 -tribenzyloxy-aceto-
phenone 5b in 90% yield. This compound was condensed
with terephthalaldehyde mono(diethyl acetal) to give
chalcone 6. Hydrolysis of the acetal group furnished the
formylchalcone 1b. Selective debenzylation of the
2-benzyloxy group was achieved by the treatment of 1b
with a mixture of acetic acid and concentrated hydrochloric
acid (10:1) for 1 h at 40 8C. Finally, formylflavone 2c was
obtained by oxidative cyclization of 1c in refluxing
dimethylsulfoxide with a catalytic amount of iodine.21
In this paper, we give full account of our work related with
the synthesis of fullerene–flavonoid dyads. The new
compounds were obtained by 1,3-dipolar cycloaddition
reactions of azomethine ylides18 to C60 and by cyclo-
propanation19 of C60 with flavonyl malonates. Synthetic
Keywords: Fullerenes; Flavonoids.
*
Compound 8 was obtained from the commercially available
3-formylchromone 7 (Scheme 3) in a similar way as dyads 3
and 4. This new compound was also purified by flash
chromatography using toluene/ethyl acetate (9:1) as eluent.
Corresponding author. Tel.: þ351-234-370-712; fax: þ351-234-370-084;
e-mail address: actome@dq.ua.pt
Present address: Department of Inorganic and Organic Chemistry,
´ ´
University of Jaen, 23071 Jaen, Spain.
†
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.003

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M. D. L. de la Torre et al. / Tetrahedron 60 (2004) 3581–3592
Scheme 1.
Scheme 2. (a) BnCl, K2CO3, DMF, 150 8C, 3 h. (b) NaOH, (EtO)2CHC6H4CHO, MeOH, 60 8C, 2 h. (c) HCl (10%), rt, 3 h. (d) MeCO2H/HCl (10:1), 40 8C,
1 h. (e) I2 (cat.), DMSO, reflux, 20 min.
Scheme 3.
3-Formylchromone has been extensively used in the
synthesis of heterocyclic systems since their convenient
synthesis has been reported in the 1970s.22 Much of the
synthetic utility of this compound derives from the
reactivity of its electron-deficient centres at C-2, C-4 and
formyl group.
modification of Bingel’s procedure,19 to afford dyads 12
and 13 in moderate yields.
We decided then to extend our studies to the synthesis of
fullerene deriva0tives having ‘natural’ flavonoid moieties.
Quercetin (3,3 ,40,5,7-pentahydroxyflavone), a natural
flavonol, was our first choice because of its high antioxidant
activity. The antioxidant activity of quercetin is higher than
other pentahydroxyflavonoids (catechin, for instance) 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; this increases the stability of the aryloxyl
radical after hydrogen donation.13 The presence of a
Reduction of 40-formylflavone 2a with sodium borohydride
afforded alcohol 9 in 80% yield (Scheme 4). This compound
was allowed to react with methyl malonyl chloride and
malonyl dichloride, in the presence of triethylamine, to give,
respectively, the malonate derivatives 10 and 11. These two
compounds were then reacted with C60, following a

M. D. L. de la Torre et al. / Tetrahedron 60 (2004) 3581–3592
3583
Scheme 4.
30,40-dihydroxyphenyl system and a 3-hydroxyl group
also contributes to the high antioxidant activity of this
compound.13
step the desired compound having the free 5-hydroxyl
group. Demethylation of compound 16 with anhydrous
aluminum bromide,24 at 0 8C, gave the 3-OH derivative 19
and an additional amount of 15 (26%). Tosylation of
compound 15 followed by demethylation led exclusively to
the 3-OH derivative 18 (Scheme 5).
The use of quercetin as starting reagent presented to us the
interesting challenge of linking quercetin to C60 selectively
through one of the five-hydroxyl groups. As shown in
Schemes 5–7 we were able to do it in two different
positions.
The alkylation of the three mono-hydroxy quercetin
derivatives (15, 18 and 19) with 3-iodopropan-1-ol afforded
the propanol derivatives 20, 22a and 22c in good yields
(Scheme 6). Derivative 22a was then detosylated to
derivative 22b by treatment with K2CO3 in refluxing
methanol.25 Compounds 20, 22b and 22c were converted
into the corresponding malonates 21 and 23 by esterifica-
tion with methyl malonyl chloride in the presence of
triethylamine (Scheme 6). Finally, cyclopropanation
(Bingel reaction)19 of C60 with malonates 21 or 23
afforded the final dyads 24 or 25 in moderate yields
(Scheme 7).
Our initial idea was to methylate all hydroxyl groups and
then, using different reaction conditions, demethylate
selectively the 3- and 5-methoxy groups, taking advantage
of their higher reactivities.23 O-Methylation of quercetin
with methyl iodide afforded a mixture of two compounds
which, after separation by flash chromatography and
crystallization, were identified as the expected pentamethyl-
ated derivative 16 and the tetramethylated compound 15
(Scheme 5). In that way, unexpectedly, we obtained in one
Scheme 5. (a) MeI, K2CO3, MeCN/MeOH, 60 8C, 10 h. (b) p-TsCl, K2CO3, MeCN, 60 8C, 1 h. (c) AlBr3, MeCN, 0 8C, 1 h. (d) AlBr3, MeCN, 0 8C, 1 h.

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M. D. L. de la Torre et al. / Tetrahedron 60 (2004) 3581–3592
Scheme 6. (a) 3-Iodopropan-1-ol, K2CO3, DMF, 60 8C, 3 h. (b) Methyl malonyl chloride, NEt3, CH2Cl2, 0 8C to rt, 3 h. (c) K2CO3, MeOH, reflux, 0.5 h.
Scheme 7. (a) C60, I2, DBU, PhMe, rt, 1 h.
1. Characterization of the compounds
compounds 1 and 2 are very similar and were assigned by
using their 2D COSY, HSQC and HMBC spectra and also
by comparison with our previous work.20,28–30 The most
important features of these spectra are the resonances of:
(i) the proton resonance of hydroxyl groups (12–13 ppm)
involved in an intramolecular hydrogen bond with the
carbonyl group of compounds 1c and 3a; (b) the benzylic
groups (dH 5.1–5.3 ppm; dC 71–77 ppm) of the benzylated
compounds; (iii) the formyl groups (dH,10 ppm, dC 191–
192 ppm) of 1b, 1c and 2c; and (iv) the acetal group (dH
5.51 ppm, dC 101.1 ppm) of chalcone 6. The connectivities
found in the HMBC spectra of compounds 1-4 allowed the
assignment of the quaternary carbon resonances; some of
the most important ones for dyad 3a are shown in Figure 1.
All new compounds were characterized by 1H and 13C
NMR, MS and elemental analysis or high-resolution MS. In
the 1H NMR spectra of dyads 3, 4 and 8 the resonance of the
N-methyl group0appears typically at d 2.82–2.87 ppm and
the proton 200 (2 for 8) appears as a singlet at ca. 5.0 ppm
(5.6 ppm for H-20 in 8). The two non-equivalent protons 500
(50 for 8) 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 9.3–9.5 Hz. It is interesting
to note that, both in 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.26,27 In the 13C NMR spectra00of dyads 3 and 4 the
signals corresponding to C-200 and C-5 appear at ca. 83 and
70 ppm, respectively, while the signals corresponding to the
N-methyl group, C-300 (C60 sp3 carbons) and C-400 appear at
ca. 40, 69 and 77 ppm, respectively. The corresponding
carbons in compound 8 show very similar resonances,
except carbon C-20 which appears at 72 ppm.
The proton and carbon resonances of the flavone moieties of
compounds 9-13 are similar to those of 40-formylflavone
2a.20 The main features of the 1H and 13C NMR spectra of
the substituents of these flavones are the resonances of the
benzylic group (dH 4.8–5.6 ppm; dC 65–68 ppm) and the
methylenic group (dH,3.5 ppm; dC,41 ppm) of the
malonyl moieties. The assignment of the resonances of
the quaternary carbons of these malonyl moieties were
based on the connectivities found in their HMBC spectra;
some of the most important ones for compound 10 are
shown in Figure 1. The resonance of the methano bridge and
The proton and carbon resonances of the chalcone and
flavone moieties of dyads 3 and 4 and those of the starting

M. D. L. de la Torre et al. / Tetrahedron 60 (2004) 3581–3592
3585
Figure 1. Some of the most important connectivities found in the HMBC spectra of compounds 3a, 10 and 25.
of the C60-sp3 carbons of compounds 12 and 13 appear in its
13C NMR spectra at 53–54 and 71 ppm, respectively.
2.2. General procedure for the synthesis of [60]fullerene
derivatives 3, 4 and 8
The assignment of the proton and carbon resonances of the
quercetin moiety of compounds 15-25 were based in the
literature data,31,32 and on the detailed analysis of the 2D
COSY, HSQC and HMBC spectra of final products 21,
23-25. In Figure 1 it is shown the most important
connectivities for dyad 25; similar connectivities where
found in the other compounds. The proton and carbon
resonances of the malonyl moiety are similar to those of
10-13. The assignment of the proton and carbon resonances
of the remaining propyl moiety was also based on the
connectivities found in the HMBC spectra of compounds
20-25. The main NMR features of these chains are the
carbon resonance of the CH2OH group appearing at ca.
69 ppm in compounds 20 and 22 which, after esterification,
appear at ca. 62 ppm in compounds 21 and 23. These
assignments were also corroborated by DEPT experiments.
In the 13C NMR spectra of fullerene derivatives 24 and 25
the signals appearing at ca. 52 and 71.5 ppm correspond,
respectively, to the methano bridge and to the C60-sp3
carbons.
A solution of C60 (100 mg, 0.14 mmol), N-methylglycine
(45 mg, 0.5 mmol) and the appropriate formyl compound 1,
2 or 7 (0.1 mmol) in toluene (150 mL), was heated at
reflux under N2 for 6 h. Part of the solvent was removed
in vacuo and the mixture was purified by flash chromato-
graphy using a gradient of toluene to toluene/ethyl
acetate (8:2) as eluent. The first fraction was the unchanged
C60 and the next one was the mono-adduct 3, 4 or 8.
Products with higher polarity, probably bis-adducts, were
discharged.
2.2.1. 20-Hydroxy-4-(N-methyltetrahydro[60]fullero[c]-
pyrrol-2-yl)chalcone (3a). Compound 3a 0 (58 mg, 58%).
1H NMR (CDCl3/CS2) d: 12.74 (s, 1H, 2 -OH), 7.92 (d,
J¼15.5 Hz, 1H, H-b), 7.90 (m, 3H, H-30, H-2,6), 7.74 (d,
J¼8.4 Hz, 2H, H-3,5), 7.67 (d, J0¼15.5 Hz, 1H, H-a), 7.45
(ddd, J¼07.8, 7.6, 1.2 Hz, 1H, H-4 ), 6.99 (dd, J¼8.5, 1.2 Hz,
1H, H-600), 6.92 (ddd, J¼8.5, 7.6, 1.1 Hz, 1H, H-50), 5.00 (s,
1H, H-200), 5.02 (d, J¼9.3 Hz, 1H, H-500), 4.31 (d, J¼9.3 Hz,
1H, H-5 ), 2.86 (s, 3H, N-CH3); 13C NMR (CDCl3/CS2) d:
192.4 (CvO), 163.5 (C-20), 153.6, 152.8, 152.5, 147.1,
146.3, 146.2, 146.12, 146.06, 146.04, 145.98, 145.95, 145.8,
145.7, 145.5, 145.4, 145.4, 145.3, 145.22, 145.17, 145.10,
145.06, 145.0, 144.5 (C-b), 144.4, 144.24, 144.17, 143.0,
142.9, 142.56, 142.47, 142.45, 142.4, 142.1, 142.00, 141.98,
141.9, 141.88, 141.80, 141.70, 141.66, 141.5, 141.4, 140.09,
140.07 (C-4), 140.0, 139.8, 139.4, 136.8, 136.3, 1360.2
(C-40), 135.8, 135.5, 134.7, 129.8 (C-3,5), 129.4 (C-6 ),
128.9 (C-2,6), 120.2 (C-a), 119.8 (C-10), 118.6 (C-30 and
C-50), 83.0 (C-200), 76.9 (C-400), 69.9 (C-500), 68.8 (C-300),
39.9 (N-CH3). HRMS (FAB) m/z calculated for C78H18NO2
(MþH)þ 1000.1338, found 1000.1373.
2.2.2. 20,30,40-Tribenzyloxy-4-(N-methyltetrahydro[60]-
fullero[c]pyrrol-2-yl)chalcone (3b). Compound 3b
(87 mg, 67%). 1H NMR (500.13 MHz) d: 7.064 (d,
J¼15.7 Hz, 1H, H-b), 7.54 (d, J¼8.9 Hz, 1H, H-6 ), 7.55
(d, J¼15.7 Hz, 1H, H-a), 7.48–7.29 and 7.18–7.09 (2 m,
17H, H-2,3 and 3£OCH2C6H5), 6.85 (d, J¼8.9 Hz, 1H,
H-50), 5.18, 5.10, 5.05 (s, 6H, 3£OCH2C6H5), 5.01 (d,
J¼9.5 Hz, 1H, H-500), 4.97 (s, 1H, H-200), 4.28 (d, J¼9.5 Hz,
1H, H-500), 2.82 (s, 3H, N-CH3); 13C NMR0(125.77 MHz) d:
190.3 (CvO), 156.6 (C-40), 156.2 (C-2 ), 154.0, 153.3,
153.1, 153.0, 147.4, 146.7, 146.45, 146.36, 146.28, 146.25,
2. Experimental
2.1. General remarks
Melting points were measured on a Reichert Thermovar
1
apparatus fitted with a microscope and are uncorrected. H
and 13C solution NMR spectra were recorded in CDCl3
solutions (unless otherwise stated), on a Bruker DRX 300
spectrometer (except 3b, which were recorded on a Bruker
DRX 500). TMS was used as internal reference and the
solvent is indicated on each case; the chemical shifts are
expressed in d (ppm) and the coupling constants (J) in
Hertz (Hz). 13C assignments were made on the basis of
2D gHSQC and gHMBC experiments (delay for long-range
J C/H couplings were optimized for 7 Hz). Mass spectra and
HRMS were recorded on VG AutoSpec Q and M mass
spectrometers using CHCl3 as solvent and NBA as matrix.
Elemental analyses were performed in a Leco 932 CHNS
analyser. Column chromatography was carried out using
silica gel (Merck, 35-70 mesh). Analytical TLC was carried
out on precoated sheets with silica gel (Merck 60, 0.2 mm
thick).

3586
M. D. L. de la Torre et al. / Tetrahedron 60 (2004) 3581–3592
146.20, 146.17, 146.08, 146.0, 145.8, 145.6, 145.5, 145.4,
145.34, 145.29, 145.2, 144.8, 144.6, 144.5, 144.4, 143.2,
143.1, 142.8, 142.7, 142.4, 142.3, 142.22, 142.19, 142.15,
142.11, 142.03, 141.95, 141.90, 141.86, 141.76, 141.6,
140.3, 139.9 (C-4), 139.6, 139.3, 137.3, 137.0, 136.7, 136.5,
136.3, 136.0, 135.7, 135.3, 129.7, 128.9, 128.8, 128.70,
128.66, 128.40, 128.35, 128.23,0128.20, 128.1, 127.5, 127.1
(C-a), 126.2 (C-60), 109.3 (C-5 ), 83.4 (C-200), 77.6 (C-400),
76.9 (OCH2C6H5), 75.1 (OCH2C6H5), 71.0 (OCH2C6H5),
70.1 (C-500), 69.2 (C-300), 40.0 (N-CH3). HRMS (FAB) m/z
calculated for C99H36NO4 (MþH)þ 1302.2644, found
1302.2676.
N–CH3); 13C NMR d: 178.0 (C-4), 162.5 (C-2), 156.0
(C-7), 153.8, 152.9, 152.7, 150.8 (C-9), 147.3, 146.5,
146.35, 146.31, 146.2, 146.14, 146.11, 145.9, 145.8, 145.7,
145.54, 145.50, 145.37, 145.35, 145.30, 145.27, 145.21,
145.17, 144.7, 144.5, 144.4, 143.2, 143.0, 142.7, 142.6,
142.5, 142.23, 142.15, 142.12, 142.07, 142.03, 141.9, 141.8,
141.7, 141.6, 140.9, 140.2 (C-40), 139.9, 139.5, 136.99,
136.97 (C-8), 136.4, 136.3, 136.0, 131.7 (C-10), 129.8,
129.6, 129.0 (C-20,60), 128.7, 128.6, 128.40, 128.35, 128.2,
127.4, 126.6 (C-30,50), 125.3, 1210.00 (C-5), 11080 .9 (C-10),
111.6 (C-6), 106.9 (C-3), 83.1 (C-200), 76.6 (C-4 ), 070 6.1 and
71.2 (2£OCH2C6H5), 70.0 (C-5 ), 69.1 (C-3 ), 40.1
(N–CH3). HRMS (FAB) m/z calculated for C92H28NO4
(MþH)þ 1210.2018, found 1210.2071.
2.2.3. 40-(N-Methyltetrahydro[60]fullero[c]pyrrol-2-
1
yl)flavone (4a). Compound 4a (39 mg, 40%). H NMR
(CDCl3/CS2) d: 8.80 (dd, J¼7.8, 1.5 Hz, 1H, H-5), 8.03 (br
s, 4H, H-20,30,50,60), 7.79 (ddd, J¼8.0, 7.6, 1.5 Hz, 1H, H-7),
7.57 (dd, J¼8.0, 0.9 Hz, 1H, H-8), 7.45 (ddd, J¼7.8, 7.6,
2.2.6. 20,30,40-Tribenzyloxyacetophenone (5b). A mixture
of 20,30,40-trihydroxyacetophenone 5a (1.73 g, 10 mmol),
benzyl chloride (6.39 mL, 50 mmol) and anhydrous K2CO3
(5.58 g, 40 mmol) in DMF (10 mL) was refluxed under N2
for 3 h. The solution was then poured into ice and the
resulting precipitate was collected by filtration. It was then
purified by column chromatography (CHCl3/acetone 100:2)
00
0.9 Hz, 1H, H-6), 6.83 (s, 1H, H-3), 5.06 (s, 1H, H-2 ), 5.04
00
(d, J¼9.4 Hz, 1H, H-500), 4.28 (d, J¼9.4 Hz, 1H, H-5 ), 2.87
(s, 3H, N–CH3); 13C NMR (CDCl3/CS2) d: 177.5 (C-4),
162.4 (C-2), 155.9, 155.7 (C-9), 153.5, 152.6, 152.3, 147.7,
147.1, 146.2, 146.1, 146.02, 145.96, 145.8, 145.6, 145.5,
145.4, 145.3, 145.2, 145.13, 145.10, 145.04, 145.00, 144.5,
144.4, 144.2, 144.1, 143.0, 142.91, 142.86, 142.5, 142.44,
142.39, 142.04, 141.96, 141.87, 141.8, 141.6, 141.5, 141.44,
141.39, 141.2, 140.9 (C-40), 140.01, 139.8, 139.4, 136.8, 136.2,
10350.8, 135.5, 133.5, 131.7 (C-1 ), 129.7 (C-30,50), 126.5 (C-
2 ,6 ), 125.7 (C-5), 125.1 (C-6), 123.8 (C-10), 117.8 (C-8),
107.6 (C-3), 82.9 (C-200), 76.6 (C-400), 69.9 (C-500), 68.8 (C-300),
39.9 (N–CH3). HRMS (FAB) m/z calculated for C78H16NO2
(MþH)þ 998.1181, found 998.1194.
1
and crystallized from EtOH; yield: 90%, mp 70–72 8C. H
NMR d: 7.51 (d, J¼8.9 Hz, 1H, H-60), 7.043–7.30 (m, 15H,
OCH2C6H5), 6.82 (d, J¼8.9 Hz, 1H, H-5 ), 5.05, 5.15, 5.16
(3s, 6H, OCH2C6H5), 2.53 (s, 3H, H-2); 13C0NMR d: 198.4
(C-1), 156.7 (C-40), 153.2 (C-20), 141.6 (C-3 ), 137.0, 136.8
and 136.1 (C-1 of 3£OCH2C6H5), 128.7, 128.6, 128.52,
128.49, 128.3, 128.2, 128.1 and 127.5 (3£OCH2C6H5),
126.9 (C-10), 125.7 (C-6), 108.7 (C-5), 76.3 and 75.6
(2£OCH2C6H5), 70.8 (40-OCH2C6H5), 31.1 (C-2). MS (EI)
m/z (%): 438 (Mþz, 7), 347 (11), 181 (11), 91 (100), 65 (11).
Anal. Calcd for C29H26O4·1/4 H2O: C, 78.62; H, 6.02.
Found: C, 78.92; H, 6.18.
2.2.4. 5-Benzyloxy-40-(N-methyltetrahydro[60]fullero[c]-
pyrrol-2-yl)flavone (4b). Compound 4b (33 mg, 31%). 1H
NMR (CDCl3/CS2) d: 7.98 (br s, 4H, H-20,30,50,60), 7.62 (d,
J¼7.6 Hz, 1H, H-2,6 of 5-OCH2C6H5), 7.52 (t, J¼8.3 Hz,
1H, H-7) 7.41 (t, J¼7.6 Hz, 2H, H-3,5 of 5-OCH2C6H5),
7.31 (t, J¼7.6 Hz, 1H, H-4 of 5-OCH2C6H5), 7.15 (dd,
J¼8.3, 0.6 Hz, 1H, H-8), 6.85 (d, J¼8.3 Hz, 1H, H-6), 6.77
(s, 1H, H-3), 5.29 (s, 2H, 5-OCH2C6H5), 5.03 (s, 1H, H-200),
5.03 (d, J¼9.5 Hz, 1H, H-500), 4.31 (d, J¼9.5 Hz, 1H, H-500),
2.84 (s, 3H, N–CH3); 13C NMR (CDCl3/CS2) d: 178.1
(C-4), 160.6 (C-2), 158.5 (C-5), 158.2 (C-9), 153.8, 152.9,
152.7, 148.2, 147.3, 146.5, 146.4, 146.3, 146.2, 146.1,
145.9, 145.8, 145.55, 145.50, 145.4, 145.3, 145.22, 145.18,
144.7, 144.5, 144.4, 143.4, 143.0, 142.7, 142.6, 142.5,
142.2, 142.1, 142.02, 141.95, 141.8, 141.7, 141.5, 141.4,
140.8, 140.2 (C-40), 139.6, 137.0 (C-1 of 5-OCH2C6H5),
136.5, 136.4, 136.0, 135.6, 1330.7 0 (C-7), 131.5, 129.93
(C-10), 129.89, 129.8, 128.6 (C-2 ,6 ) 127.6, 126.6, 126.4,
115.1 (C-10), 110.4 (C-8), 109.2 (C-3), 108.5 (C-6), 83.1
(C-200), 76.6 (C-400), 70.8 (5-OCH2C6H5), 70.0 (C-500), 69.1
(C-300), 40.0 (N-CH3). HRMS (FAB) m/z calculated for
C85H22NO3 (MþH)þ 1104.1600, found 1104.1644.
2.2.7. 20,30,40-Tribenzylox0y-4-(diethoxymethyl)chalcone
(6). A mixture of 20,30,4 -tribenzyloxyacetophenone 5b
(0.68 g, 1.56 mmol) and terephtalaldehyde mono(diethyl
acetal) (0.5 mL, 2.43 mmol) in a methanolic solution of
NaOH (0.37 mmol/mL) was stirred at 60 8C for 2 h. A
precipitate was formed. It was collected by filtration and the
mother liquor was evaporated to dryness. It was then
purified by column chromatography (hexane/acetone, first
4:1 then 3:2) giving a pale yellow solid by addition of
acetone. Yield: 74%, mp 155–156 8C. 1H NMR d: 7.65 (d,
J¼15.5 Hz, 1H, H-b), 7.55 (d, J¼15.5 Hz, 1H, H-a), 7.50–
7.20 (m, 20H, H-60, H-2,3,5,6 and 3£OCH2C6H5), 6.89 (d,
J¼8.9 Hz, 1H, H-50), 5.51 [s, 1H, CH(OCH2CH3)2], 5.20,
5.12, 5.09 (3s, 6H, 3£OCH2C6H5), 3.57 [q, J¼7.0 Hz, 4H,
CH(OCH2CH3)2], 1.26 [t, J¼7.0 Hz, 3H, CH(OCH2CH3)2];
13C NMR d: 190.1 (CvO), 156.7 (C-40), 153.1 (C-20), 142.6
(C-4), 141.76 and 141.73 (C-30 and C-b), 137.2, 136.7,
136.5, 136.1 (C-1 and 3£C-1 of OCH2C6H5), 128.79,
128.76, 128.71, 128.6, 128.4, 128.35, 128.32, 128.23,
128.20, 128.15, 128.11, 127.6, 127.5, 127.3, 127.1 (C-2,06,
C-3,5, C-a and 3£OCH2C6H5), 126.9 (C-10), 126.3 (C-6 ),
109.2 (C-50), 101.1 [CH(OCH2CH3)2], 76.6 and 75.7
(2£OCH2C6H5), 70.9 (40-OCH2C6H5), 61.1 (OCH2CH3),
15.2 (OCH2CH3). MS (EI) m/z (%): 628 (Mþz, 19), 583 (23),
537 (31), 509 (11), 492 (31), 438 (12), 401 (100), 347 (24),
251 (25), 241 (36), 223 (13), 181 (52), 159 (26), 131 (25),
115 (15). Anal. Calcd for C41H40O6: C, 78.32; H, 6.41.
Found: C, 78.66; H, 6.25.
2.2.5. 7,8-Dibenzyloxy-40-(N-methyltetrahydro[60]ful-
lero[c]pyrrol-2-yl)flavone (4c). Compound 4c (62 mg,
1
52%). H NMR0 d: 7.92 (d, J¼8.9 Hz, 1H, H-5),) 7.92 (br
s, 4H, H-20,30,5 ,60), 7.47–7.12 (m, 10H, 2£OCH2C6H5),
7.11 (d, J¼8.9 Hz, 1H, H-6), 6.77 (s,001H, H-3), 5.27, 5.19
(2s, 4H, OCH2C6H5), 5.02 (s, 1H, H-2 ), 5.03 (d, J¼9.3 Hz,
1H, H-500), 4.31 (d, J¼9.3 Hz, 1H, H-500), 2.84 (s, 3H,

M. D. L. de la Torre et al. / Tetrahedron 60 (2004) 3581–3592
3587
2.2.8. 20,30,40-Tribenzyloxychalcone-4-carbaldehyde
(1b). HCl (10%, 2 mL) was added to a solution of 20,30,40-
tribenzyloxy-4-(diethoxymethyl)chalcone 6 (0.70 g, mmol)
in EtOH (10 mL) and the mixture was stirred for 3 h. A
precipitate was formed; it was collected by filtration and
washed with EtOH. Recrystallization from EtOH afforded
(C-40), 137.1 and 137.0 (C-1 of OCH2C6H5), 135.8 (C-10),
130.1 (C-30,50), 129.1, 128.8, 128.54, 128.47, 128.4 and
127.4 (2£OCH2C6H5), 126.8 (C-20,60), 121.1 (C-5), 118.8
(C-10), 111.8 (C-6), 108.4 (C-3), 76.6 and 71.3
(2£OCH2C6H5). MS (EI) m/z (%): 462 (Mþz, 40), 371
(100), 354 (15), 343 (30), 293 (13), 282 (30), 241 (19), 224
(38), 198 (22), 181 (79), 167 (48), 159 (14), 152 (51), 139
(55), 129 (69), 105 (67). Anal. Calcd for C29H26O4·3/2 H2O:
C, 73.61; H, 5.14. Found: C, 73.47; H, 4.92.
1
1b as a pure compound. Yield: 88%, mp 136–138 8C. H
NMR d: 10.03 (s, 1H, CHO), 7.82 (d, J¼8.3 Hz, 2H, H-2,6),
7.63 (s, 2H, H-a and H-b), 7.59 (d, J¼8.8 Hz, 1H, H-60),
7.52 (d, J¼8.3 Hz, 2H, H-3,5), 7.50–7.10 (m, 15H,
3£OCH2C6H5), 6.89 (d, J¼8.8 Hz, 1H, H-50), 5.20, 5.12
and 5.09 (3s, 6H, OCH2C6H5); 13C NMR d: 191.8 (CHO)
191.6 (CvO), 157.3 (C-40), 153.4 (C-20), 141.7 (C-b), 140.5
(C-30), 137.0, 136.7, 136.2 and 136.0 (C-1 and C-1 of
OCH2C6H5), 132.7 (C-4), 130.0, 129.8, 129.5, 128.8, 128.7,
128.66, 128.5, 128.41, 128.38, 128.33, 128.28, 128.19,
127.52, 127.50, (C-2,6, C-3,5, C-a and 3£OCH2C6H5),
126.5 (C-60), 109.0 (C-50), 76.5 and 75.6 (2£OCH2C6H5),
70.9 (40-OCH2C6H5). MS (EI) m/z (%): 554 (Mþz, 37), 463
(43), 357 (9), 241 (29), 221 (14), 181 (61), 159 (100), 131
(12), 115 (6). Anal. Calcd for C37H30O5: C, 80.12; H, 5.45.
Found: C, 80.14; H, 5.57.
2.2.11. 3-(N-Methyltetrahydro[60]fullero[c]pyrrol-2-
yl)chromone (8). Compound 8 (42 mg, 38%) was obtained
from 7 (21 mg) as described above in the general procedure.
1
Mp .300 8C. H NMR (CDCl3/CS2) d: 8.53 (s, 1H, H-2),
8.19 (dd, J¼7.9, 1.6 Hz, 1H, H-5), 7.68 (ddd, J¼8.2, 7.3,
1.6 Hz, 1H, H-7), 7.49 (d, J¼8.2 Hz, 1H, H-8),07.41 (ddd,
J¼7.9, 7.3, 1.0 Hz, 1H, H-6), 5.61 (s, 1H, H-2 ), 4.93 (d,
J¼9.5 Hz, 1H, H-50), 4.31 (d, J¼9.5 Hz, 1H, H-50), 2.85 (s,
3H, CH3); 13C NMR (CDCl3/CS2) d: 176.5 (C-4), 157.1
(C-2), 155.9 (C-9), 156.2 153.9, 153.1, 152.8, 147.13,
147.11, 146.5, 146.3, 146.1, 146.0, 145.90, 145.86, 145.8,
145.6, 145.43, 145.38, 145.36, 145.3, 145.2, 145.1, 145.0,
144.9, 144.4, 144.33, 144.27, 144.2, 142.9, 142.8, 142.52,
142.48, 142.39, 142.36, 142.19, 142.17, 142.1, 141.98,
141.95, 141.9, 141.83, 141.79, 141.7, 141.58, 141.56, 141.3,
140.1, 139.7, 139.6, 136.3, 136.1, 135.2, 133.7 (C-7), 126.2
(C-5), 125.4 (C-6), 123.7 (C-10),0120.7 (C-3), 118.1 (C-8),
75.8 (C-40), 72.0 (C-20), 69.7 (C-5 ), 68.7 (C-30), 39.7 (CH3).
HRMS (FAB) m/z calculated for C72H12NO2 (MþH)þ
922.0868, found 922.0883.
2.2.9. 30,40-Dibenzyloxy-20-hydroxychalcone-4-carbalde-
hyde (1c). A solution of 20,30,40-tribenzyloxychalcone-4-
carbaldehyde 1b (0.32 g, 0.58 mmol) in AcOH/concd HCl
(10:1, 27.5 mL) was stirred at 40 8C for 1 h. Then H2O
(25 mL) was added and a precipitate was formed. It was
collected by filtration, washed with H2O, and dried under
vacuu0m. Yield: 89%, mp 113–115 8C; 1H NMR d: 13.09 (s,
1H,0 2 0-OH), 10.06 (s, 1H, CHO), 7.95 (d, J¼8.2 Hz, 2H,
H-2 ,6 ),0 7.90 (d, J¼15.5 Hz, 1H, H-b), 7.79 (d, J¼8.2 Hz,
2H, H-3 ,50), 7.67 (d, J¼15.5 Hz, 1H, H-a), 7.65 (d, J¼9.1,
1H, H-60), 7.52–7.28 (m, 10H, 2£OCH2C6H5), 6.56 (d,
J¼9.1 Hz, 1H, H-50), 5.21 and 5.15 (2 s, 4H,
2£OCH2C6H5); 13C NMR d: 191.9 (CHO), 191.50 (CvO),
158.8 (C-40), 158.3 (C-20), 142.6 (C-b), 140.4 (C-3 ), 137.5,
137.3, 136.04 and 135.98 (C-1 and C-1 of OCH2C6H5),
130.2, 128.9 128.7, 128.6, 128.2, 128.0 and 127.2 (C-2,6,
C-3,5, and 2£OCH2C6H5), 126.1 (C-60), 123.2 (C-a), 115.5
(C-10), 104.6 (C-50), 74.8 and 70.8 (2£OCH2C6H5). MS (EI)
m/z (%): 464 (Mþz, 100), 373 (90), 241 (13), 198 (12), 181
(26), 159 (48), 149 (30), 131 (12), 115 (9), 103 (17). Anal.
Calcd for C29H26O4·1/3 H2O: C, 76.63; H, 5.28. Found: C,
76.95; H, 5.48.
2.2.12. (Flavon-40-yl)methanol (9). Flavone-40-carbalde-
hyde 2a (0.2 g, 0.8 mmol) was dissolved in dry THF
(50 mL) and NaBH4 (15 mg; 0.4 mmol) was added. The
reaction mixture was stirred for 8 h at rt under N2. H2O
(10 mL) was added to the reaction mixture and then 10%
HCl was added carefully and slowly until H2 liberation was
ceased. Flavone 9 was then extracted with CHCl3
(3£20 mL), the solvent was dried (Na2SO4), evaporated
under vacuo and the residue was recrystallized from hot
1
EtOH. Yield: 0.16 g (80%), mp 150–152 8C. H NMR d:
8.24 (dd, J¼7.7, 1.7 Hz, 1H, H-5), 7.94 (d, J¼8.4 Hz, 2H,
H-20,60), 7.72 (ddd, J¼7.7, 7.6, 1.7 Hz, 1H, H-7),07.50 9 (dd,
J¼7.7 Hz, 1H, H-8), 7.54 (d, J¼8.4 Hz, 2H, H-3 ,5 ), 7.44
(ddd, J¼7.7, 7.6, 1.1 Hz, 1H, H-6), 6.83 (s, 1H, H-3), 4.82
(d, J¼5.3 Hz, 2H, CH2OH), 1.87 (t, J¼5.3 Hz, 1H,
CH2OH); 13C NMR d: 178.5 (C-4), 163.2 (C-2), 156.2
(C-9), 144.7 (C-40), 133.8 (C-7), 131.0 (C-10), 127.2
(C-30,50), 126.5 (C-20,60), 125.7 (C-5), 125.3 (C-6), 124.0
(C-10), 118.1 (C-8), 107.5 (C-3), 64.6 (CH2OH). MS (EI)
m/z(%): 252 (Mþz, 100), 223 (35), 165 (17), 146 (10), 131
(15), 120 (52), 121 (52), 115 (15), 107 (10), 103 (22), 92
(57), 77 (26), 63 (28). Anal. Calcd for C16H12O3·1/2 H2O: C,
73.55; H, 5.02. Found: C, 73.77; H, 4.74.
2.2.10. 7,8-Dibenzyloxyflavone-40-carbaldehyde (2c).
Iodine 0 (14 mg, 0.055 mmol) was added to a solution
of
3 ,40-dibenzyloxy-20-hydroxy-4-formylchalcone
1c
(0.81 mmol) in DMSO (1.6 mL). The mixture was heated
under reflux for 20 min. After cooling to rt, the resulting
mixture was poured into ice to precipitate the product. The
solid was removed by filtration, dissolved in CHCl3 and
washed with a saturated solution of Na2S2O3. The organic
layer was dried (Na2SO4), concentrated, and purified by
column chromatography (CH2Cl2/MeOH, 100:3). After
evaporation of the solvent, the residue was recrystallized
from EtOH. Yield: 58%, mp 160–162 8C. 1H0NMR d: 10.11
(s, 1H, CHO), 7.97 (br s, 4H, H-20,30,5 ,60), 7.94 (d,
J¼9.0 Hz, 1H, H-5), 7.50–7.31 (m, 10H, 2£-OCH2C6H5),
7.15 (d, J¼9.0 Hz, 1H, H-6), 6.82 (s, 1H, H-3), 5.30 and
5.22 (2 s, 4H, 2£OCH2C6H5); 13C NMR d: 191.4 (CHO),
177.8 (C-4), 161.3 (C-2), 156.2 (C-7), 150.8 (C-9), 137.9
2.3. General procedure for the reactions with methyl
malonyl chloride
To a cold solution of the flavones 9, 20, 22b or 22c
(0.9 mmol) in CH2Cl2 (2–10 mL), triethylamine (0.26 mL,
1.86 mmol), methyl malonyl chloride (0.48 mL, 4 mmol)
was added dropwise with stirring; the mixture was allowed
to stand at 0 8C to rt until all starting material disappeared

3588
M. D. L. de la Torre et al. / Tetrahedron 60 (2004) 3581–3592
(about 2 h). Then it was poured onto ice and extracted with
CH2Cl2, the organic layer was dried (Na2SO4) and
evaporated to dryness. An oily residue was obtained,
which was purified by flash chromatography using
CH2Cl2/acetone 19:1 as eluent.
65%) which was crystallized from CHCl3/hexane. Dyad 13
was prepared in a similar way using 11 (20 mg, 0.035 mmol),
C60 (25 mg, 0.035 mmol), iodine (9 mg, 0.035 mmol) and
DBU (11 mL, 0.07 mmol) in toluene (25 mL). It was crystal-
lized from CHCl3/hexane yielding 6.6 mg (15%).
2.3.1. Methyl 40-flavonylmethyl malonate (10). Com-
pound 10 (62 mg, 89%) was obtained from flavone 9
(50 mg, 0,2 mmol). Crystallization from CHCl3/hexane, mp
106–107 8C. 1H NMR (500.13 MHz) 0d:08.24 (d, J¼7.8 Hz,
1H, H-5), 7.95 (d, J¼8.2 Hz, 2H, H-2 ,6 ), 7.73 (dd, J¼8.1,
7.3 Hz, 1H, H-7), 7.59 (d, J¼8.1 Hz, 1H, H-8), 7.53 (d,
J¼8.2 Hz, 2H, H-30,50), 7.44 (dd, J¼7.8, 7.3 Hz, 1H, H-6),
6.84 (s, 1H, H-3), 5.28 (s, 2H, CO2CH2R), 3.77 (s, 3H,
CO2CH3), 3.49 (s, 2H, malonate CH2); 13C NMR
(125.77 MHz) d: 178.4 (C-4), 166.8 (CO2CH3), 166.2
(CO2CH2R), 162.8 (C-2), 156.2 (C-9), 138.9 (C-40), 133.9
(C-7), 131.8 (C-10), 128.5 (C-30,50), 126.5 (C-20,60), 125.7
(C-5), 125.3 (C-6), 123.9 (C-10), 118.1 (C-8), 107.8 (C-3),
66.4 (OCH2Ph), 52.6 (OCH3), 41.2 (malonate CH2). MS
(EI) m/z(%): 352 (Mþz, 78), 251 (100); 235 (47), 223 (11),
207 (29), 178 (13), 121 (25), 104 (11), 92 (26), 74 (20).
Anal. Calcd for C20H16O6: C, 68.18; H, 4.58. Found: C,
68.49; H, 4.55.
2.4.1. Dyad 12. Mp .300 8C. H NMR (500.13 MHz) d:
1
8.25 (dd, J¼7.7, 1.5 Hz, 1H, H-5), 7.98 (d, J¼8.2 Hz, 2H,
H-20,60), 7.73 (ddd,0 J¼8.0, 7.5, 1.5 Hz, 1H, H-7), 7.67 (d,
J¼8.3 Hz, 2H, H-3 ,50), 7.59 (d, J¼8.0 Hz, 1H, H-8), 7.45
(dd, J¼7.7, 7.5 Hz, 1H, H-6), 6.85 (s, 1H, H-3), 5.61 (s, 2H,
CO2CH2R), 4.07 (s, 1H, OCH3); 13C NMR (125.77 MHz) d:
178.4 (C-4), 163.9 (CO2CH3), 163.4 (CO2R), 162.7 (C-2),
156.2 (C-9), 145.28, 145.27, 145.2, 145.11, 145.00, 144.97,
144.9, 144.74, 144.69, 144.58, 144.4, 143.89, 143.83, 143.1,
143.03, 142.95, 142.2, 141.9, 141.8, 141.00, 140.97, 139.4,
138.6, 138.2 (C-40), 133.9 (C-7), 132.4 (C-10), 129.5
(C-30,50), 126.7 (C-20,60), 125.8 (C-5), 125.4 (C-6), 124.0
(C-10), 118.1 (C-8), 108.0 (C-3), 71.3 (C60-sp3), 68.1
(CH2OR), 54.1 (CO2CH3), 51.6 (methano bridge). HRMS
(FAB) m/z calculated for C80H15O6 (MþH)þ 1071.0869,
found 1071.0837.
2.4.2. Dyad 13. Mp .300 8C. 1H NMR d: 8.13 (dd, J¼7.7,
1.7 Hz, 2H, H-5), 7.88 (d, J¼8.4 Hz, 4H, H-20,60), 7.66 (ddd,
J¼7.8, 7.7, 1.7 Hz, 2H, H-7), 7.58 (d, J¼8.4 Hz, 4H,
H-30,50), 7.50 (d, J¼7.8 Hz, 2H, H-8), 7.37 (dt, J¼7.7,
0.9 Hz, 2H, H-6), 6.77 (s, 2H, H-3), 5.57 (s, 4H, CH2OR);
13C NMR d: 178.2 (C-4), 163.2 (CO2R), 162.4 (C-2), 156.0
(C-9), 145.3, 145.2, 145.0, 144.9, 144.7, 144.6, 144.4,
143.8, 143.1, 143.05, 143.00, 142.2, 141.8, 141.0, 139.01,
138.0 (C-400), 0 133.9 (C-7), 132.2 (C-10), 129.1 (C-30,5 ),
126.5 (C-2 ,6 ), 125.6 (C-5), 125.3 (C-6), 123.7 (C-10),
118.0 (C-8), 107.8 (C-3), 71.2 (C60-sp3), 68.0 (CH2OR),
53.2 (methano bridge). HRMS (FAB) m/z calculated for
C95H23O8 (MþH)þ 1291.1393, found 1291.1345.
2.3.2. Bis(40-flavonylmethyl) malonate (11). Malonyl
dichloride (9.2 mL, 0.1 mmol) was added dropwise to a
cold solution of flavone 9 (50 mg, 0.2 mmol) in CH2Cl2
(10 mL) and triethylamine (52 mL, 0.4 mmol); the mixture
was stirred at 0 8C for 15 min and then 2 h at rt. Since the
TLC of the reaction mixture showed some starting flavone,
another portion of malonyl dichloride (9.2 mL, 0.1 mmol)
was added and stirring was continued for 2 h. Diluted HCl
(0.5%, 10 mL) was added to the reaction mixture and the
two phases were separated. The organic phase was washed
successively with HCl (0.5%, 10 mL), NaHCO3 (10%,
2£5 mL), and H2O (10 mL) and then it was dried (Na2SO4).
After concentration under vacuum, the reaction mixture was
purified by preparative TLC using a 4:1 mixture of CH2Cl2/
AcOEt as eluent. Yield: 13.6 mg (23%), mp 204–205 8C.
1H NMR d: 8.15 (dd, J¼7.7, 1.7 Hz, 2H, H-5), 7.86 (d,
J¼8.4 Hz, 4H, H-20,60), 7.66 (ddd, J¼8.0, 7.6, 1.7 Hz, 2H,
H-7), 7.50 (d, J¼8.0 Hz, 2H, H-8), 7.46 (d, J¼8.4 Hz, 4H,
H-30,50), 7.37 (ddd, J¼7.7, 7.6, 1.1 Hz, 2H, H-6), 6.77 (s,
2H, H-3), 5.25 (s, 4H, CH2OR), 3.55 (s, 2H, malonate CH2);
13C NMR d: 178.3 (C-4), 166.0 (CO2R), 162.6 (C-2), 156.1
(C-9), 138.8 (C-40), 133.9 (C-7), 131.8 (C-10), 128.5 (C-30,50),
126.5 (C-20,60), 125.7 (C-5), 125.3 (C-6), 123.9 (C-10), 118.0
(C-8), 107.7 (C-3), 66.4 (CH2OR), 41.5 (malonate CH2). MS
(FAB)m/z:573(MþH)þ. Anal. Calcd for C35H24O8:C, 73.42;
H, 4.22. Found: C, 73.68; H, 4.04.
2.5. Methylation of quercetin
A mixture of quercetin hydrate (1.01 g, 3 mmol), methyl
iodide (0.16 mL, 30 mmol) and anhydrous K2CO3 (3.17 g,
22.5 mmol) in MeCN/MeOH (2:1, 150 mL) was stirred at
60 8C until all starting material disappeared (about 10 h).
The TLC (in CHCl3/MeOH, 10:2) of the reaction mixture
showed two spots (Rf¼0.91 and 0.70). The two products
were separated by flash chromatography using mixtures of
CH2Cl2/acetone (9:1 to 7:3) as eluent. The first fraction was
identified as 5-hydroxy-3,30,40,7-tetramethoxyflavone 15
and the second one as 3,30,40,5,7-pentamethoxyflavone 16.
2.5.1. 5-Hydroxy-3,30,40,7-tetramethoxyflavone (15).
Yield: 0.42 g (39%), mp 148–150 8C. H NMR d: 12.65
1
2.4. General procedure for the synthesis of [60]fullerene-
flavone dyads 12 and 13
(s, 1H, 5-OH), 7.74 (dd, J¼8.6, 2.0 Hz, 1H, H-600), 6.69 (d,
J¼2.0 Hz, 1H, H-20), 7.00 (d, J¼8.6 Hz, 1H, H-5 ), 6.46 (d,
J¼2.2 Hz, 1H, H-8), 6.37 (d, J¼2.2 Hz, 1H, H-6), 3.98,
3.97, 3.89 and 3.87 (4 s, 12H, 4£OCH3). MS (EI) m/z (%):
358 (Mþz, 100), 343 (50), 329 (25), 315 (43), 270 (7), 239
(10), 211 (63), 196 (20), 149 (30), 136 (14), 107 (14), 97
(21), 83 (80). Anal. Calcd for C19H18O7: C, 63.68; H, 5.06.
Found: C, 63.39; H, 4.96.
A mixture of malonate 10 (20 mg, 0.057 mmol), C60
(41 mg, 0.057 mmol), iodine (14.4 mg, 0.057 mmol) and
DBU (17 mL, 0.11 mmol) in toluene (25 mL) was stirred at
rt under N2 until the starting malonate disappeared (about
1 h). Then the crude mixture was concentrated and
separated by flash chromatography using toluene and
toluene/AcOEt (7:3) as eluent. The first fraction was the
unchanged C60 and the second one the dyad 12 (39.5 mg,
2.5.2. 3,30,40,5,7-Pentamethoxyflavone (16). Yield: 0.63 g
1
(60%), mp 137–139 8C. H NMR d: 7.73–7.69 (m, 2H,

M. D. L. de la Torre et al. / Tetrahedron 60 (2004) 3581–3592
3589
H-20, H-60), 6.98 (d, J¼9.2 Hz, 1H, H-50), 6.50 (d, J¼2.2 Hz,
1H, H-8), 6.34 (d, J¼2.2 Hz, 1H, H-6), 3.97, 3.96, 3.91 and
3.87 (4 s, 15H, 5£OCH3). MS (EI) m/z (%): 372 (Mþz, 100),
357 (60), 341 (18), 329 (14), 311 (14), 283 (7), 181 (7), 172
(14), 165 (8), 149 (10), 137 (5), 119 (5), 106 (4). Anal. Calcd
for C20H20O7·1/2 H2O: C, 62.99; H, 5.55. Found: C, 62.65;
H, 5.36.
9H, 3£O–CH3), 2.46 (s, 3H, 5-OTs); 13C NMR d: 170.4
(C-4), 162.9 (C-7),0157.6 (C-9), 150.5 (C-2 and C-5), 148.8
(C-40), 147.5 (C-3 ), 145.5 (C-4 of 5-OTs), 137.8 (C-3),
132.7 (C-1 of 5-OTs), 129.6 and 128.9 (C-2,6 and C-3,5 of
5-OTs), 123.3 (C-10), 120.9 (C-60), 112.4 (C-10), 110.9
(C-20), 110.4 (C-50), 108.9 (C-6), 99.6 (C-8), 56.1, 56.0 and
55.9 (3£OCH3), 21.8 (CH3 of 5-OTs). MS (EI) m/z (%): 498
(Mþz, 20), 358 (9), 344 (100), 329 (12), 315 (57), 301 (7),
165 (7), 91 (14), 65 (7). Anal. Calcd for C25H22O9S: C,
60.23; H, 4.45. Found: C, 60.40; H, 4.52.
2.5.3. 3,30,40,7-Tetramethoxy-5-(4-methylbenzenesul-
fonyloxy)flavone (17). A mixture of 5-hydroxy-3,30,40,7-
tetramethoxyflavone 15 (0.81 g, 2.3 mmol), 4-MeC6H4SO2-
Cl (1.77 g, 9.1 mmol), and anhydrous K2CO3 (2.56 g,
18 mmol) in MeCN (15 mL) was heated at 60 8C, with
stirring, until the starting flavone disappeared (about 3 h).
The remaining K2CO3 was filtered off and the filtrate was
evaporated until dryness. The solid residue was dissolved in
hot mixture of CH2Cl2 (2 mL) and MeOH (4 mL), the
mixture was cooled in an ice bath, and the resulting solid
2.6.2. 3-Hydroxy-30,40,5,7-tetramethoxyflavone (19).
Crystallized from EtOH, mp 184–186 8C. 1H NMR d:
7.83–7.80 (m, 2H, H-20 and H-60), 7.42 (br s, 1H, 3-OH),
7.00 (d, J¼9.1 Hz, 1H, H-50), 6.56 (d, J¼1.8 Hz, 1H, H-8),
6.36 (d, J¼1.8 Hz, 1H, H-6), 3.99, 3.97 and 3.93 (3 s, 12H,
5£OCH3); 13C NMR d: 171.9 (C-4), 1604.3 (C-7), 160.5
(C-5), 158.1 (C-9), 150.2 (C-2), 148.8 (C-3 and C-40), 1370.5
(C-3), 123.7 (C-10), 120.6 (C-60), 110.8 (C-20), 110.3 (C-5 ),
106.2 (C-10), 95.6 (C-6), 92.4 (C-8), 56.4, 56.0, 55.9 and
55.8 (4£OCH3). MS (EI) m/z (%): 358 (Mþz, 100), 343 (8),
329 (10), 312 (37), 179 (8), 165 (6), 136 (4). Anal. Calcd for
C19H18O7·1/2H2O: C, 62.12; H, 5.21. Found: C, 62.07; H,
4.91.
1
was filtered off; yield: 1.00 g (86%), mp 158–160 8C. H
NMR d: 8.00 (d, J¼8.3 Hz, 2H, H-2,6 of 5-OTs), 7.70–7.67
(m, 2H, H-20, H-60), 7.34 (d,0J¼8.3 Hz, 2H, H-3,5 of 5-OTs),
7.97 (d, J¼9.0 Hz, 1H, H-5 ), 6.85 (d, J¼2.5 Hz, 1H, H-8),
6.86 (d, J¼2.5 Hz, 2H, H-6), 3.98, 3.96, 3.90 and 3.77 (4 s,
12H, 4£OCH3), 2.43 (s, 3H, CH3 of 5-OTs); 13C NMR d:
172.1 (C-4), 162.6 (C-7), 157.60(C-9), 153.6 (C-5), 151.0
(C-2), 148.6 (C-40), 147.7 (C-3 ), 145.0 (C-4 of 5-OTs),
141.0 (C-3), 132.7 (C-1 of 5-OTs), 0129.6 and 129.1 (C-2,6
and C-3,5 of 5-OTs), 122.9 (C-1 ), 121.8 (C-60), 112.3
(C-10), 111.1 (C-20), 110.7 (C-50), 108.8 (C-6), 99.8 (C-8),
59.9 (3-OCH3), 56.1, 56.02 and 55.95 (3£OCH3), 21.7 (CH3
of 5-OTs). MS (EI) m/z (%): 512 (Mþz, 20), 371 (100), 357
(70), 343 (15), 329 (19), 165 (12), 91 (38), 65 (14). Anal.
Calcd for C26H24O9S: C, 60.93; H, 4.72. Found: C, 60.66;
H, 4.91.
2.7. General procedure for the reactions with
3-iodopropan-1-ol
A mixture of flavones 15, 18 or 19 (1.3 mmol), 3-iodo-
propan-1-ol (0.26 mL, 2.6 mmol), and anhydrous K2CO3
(0.73 g, 5.2 mmol) in DMF (4 mL) was heated with stirring
at 60 8C until all starting material disappeared (about 2 h).
Then H2O (20 mL) was added and the resulting mixture was
extracted with AcOEt/Et2O (3:2, 4£25 mL). The organic
layer was dried (Na2SO4), evaporated to dryness, and the
resulting residue was purified by flash chromatography
using CH2Cl2/acetone (8:2) as eluent.
2.6. General procedure for the demethylation reactions
AlBr3 (0.29 g, 1.1 mmol) was added to a stirred ice-cold
solution of 3,30,40,5,7-pentamethoxyflavone 16 (0.37 g,
1 mmol) in MeCN (4 mL). The mixture was kept at that
temperature for 90 min, then it was diluted with 10% HCl
and warmed at 75 8C for 30 min. The mixture was
concentrated until a solid has started to appear. The solid
was filtered off and washed with H2O and MeOH. The TLC
(CH2Cl2/acetone 9:1) showed two spots (Rf¼0.64 and 0.35)
corresponding, respectively, to 5-hydroxy-3,30,40,7-tetra-
methoxyflavone 15 and 3-hydroxy-30,40,5,7-tetramethoxy-
flavone 19. The two isomers were separated by flash
chromatography using mixtures of CH2Cl2/acetone (95:5 to
80:20) as eluent. Yields: 15, 93 mg (26%); 19, 170 mg
(47%). In a similar way, 3,30,40,7-tetramethoxy-5-(4-
methylbenzenesulfonyloxy)flavone 17 (0,51 g, 1 mmol) in
MeCN (22 mL) was reacted with AlBr3 (0,83 g, 3.1 mmol)
to give 3-hydroxy-30,40,7-trimethoxy-5-(4-methylbenzene-
sulfonyloxy)flavone 18 (0.39 g, 79%).
2.7.1. 3-(3,30,40,7-Tetramethoxyflavonyl-5-oxy)propan-1-
ol (20). Compound 20 (0.39 g, 72%) was obtained from 15
(0.47 g); crystallization from EtOH; mp 92–94 8C. 1H NMR
d: 7.73–7.70 (m, 2H, H-20 and H-60), 6.83 (d, J¼8.4 Hz, 1H,
H-50), 6.52 (d, J¼2.1 Hz, 1H, H-8), 6.33 (d, J¼2.1 Hz, 1H,
H-6), 5.42 (t, J¼6.4 Hz, 1H, OH), 4.21 (t, J¼5.6 Hz, 2H,
CH2O), 3.97, 3.91 and 3.85 (3 s, 14H, 3£OCH3 and CH2OH
overlapped with the first singlet), 2.18 (qui, J¼5.5 Hz, 2H,
CH2); 13C NMR d: 174.1 (C-4), 1640.0 (C-7), 159.7 (C-5),
158.6 (C-9), 153.9 (C-2), 150.8 (C-4 ), 148.6 (C-30), 1410.0
(C-3), 123.3 (C-10), 121.3 (C-60), 111.1 (C-20), 110.7 (C-5 ),
109.0 (C-10), 96.8 (C-6), 92.5 (C-8), 69.6 (HOCH2), 61.8
(OCH2), 59.9 (3-OCH3), 56.0, 55.9 and 55.8 (3£OCH3),
31.8 (CH2). MS (EI) m/z (%): 416 (Mþz, 100), 401 (30), 371
(53), 358 (21), 341 (14), 315 (14), 299 (10), 269 (6), 255 (5),
165 (10), 149 (6). Anal. Calcd for C22H24O8·H2O: C, 60.82;
H, 6.03. Found: C, 60.62; H, 6.07.
2.6.1. 3-Hydroxy-30,40,7-trimethoxy-5-(4-methyl-
benzenesulfonyloxy)flavone (18). Crystallized from
2.7.2. 3-(5-Hydroxy-30,40,7-trimethoxyflavonyl-3-oxy)-
pro0pan-1-ol (22b). 3-[5-(4-Methylbenzenesulfonyloxy)-
30,4 ,7-trimethoxyflavonyl-3-oxy)propan-1-ol 22a was
obtained as an oily residue from 18 (0.65 g). It was
dissolved in MeOH (30 mL), K2CO3 (0.36 g, 2.6 mmol)
was added, and the mixture was heated at 60 8C for 30 min.
The reaction mixture was acidified with 10% HCl,
1
EtOH, mp 176–178 8C. H NMR d: 7.95 (d, 0J¼8.35 Hz,
2H, H-2,6 of 5-OTs), 7.81–7.77 (m, 2H, H-2 and H-60),
7.35 (d, J¼9.0 Hz, 2H, H-3,5 of 05-OTs), 7.18 (br s, 1H,
3-OH), 6.99 (d, J¼9.0 Hz, 1H, H-5 ), 6.87 (d, J¼2.3 Hz, 1H,
H-8), 6.75 (d, J¼2.3 Hz, 1H, H-6), 3.98, 3.96 and 3.91 (3 s,

3590
M. D. L. de la Torre et al. / Tetrahedron 60 (2004) 3581–3592
concentrated under reduced pressure, and then cooled. The
resulting solid was filtered off and recrystallized from EtOH
to afford 22b (0.32 g, 60%), mp 135–137 8C. H NMR d:
2.7.6. Methyl 3-(5-hydroxy-30,40,7-trimethoxyflavonyl-3-
oxy)propyl malonate (23a). Compound 23a (0.39 g, 86%)
was obtained as an oil from 22b (0.36 g). 1H NM0R d: 12.64
(s, 1H, 5-OH), 7.69 (dd, J¼8.5, 2.1 Hz, 1H, H-60), 7.60 (d,
J¼2.1 Hz, 1H, H-20), 7.50 (d, J¼8.5 Hz, 1H, H-5 ), 6.45 (d,
J¼2.2 Hz, 1H, H-8), 6.37 (d, J¼2.2 Hz, 1H, H-6), 4.30 (t,
J¼6.3 Hz, 2H, OCH2CH2CH2OCO), 4.07 (t, J¼6.3 Hz, 2H,
OCH2CH2CH2OCO), 3.98, 3.97 and 3.88 (3s, 9H,
3£OCH3), 3.71 (s, 3H, CO2CH3), 3.36 (s, 2H, malonate
CH2), 2.08 (qui, J¼6.3 Hz, 2H, CH2); 13C NMR d: 178.6
(C-4), 166.9 (CO2CH3), 166.4 (COCH2CO2CH3), 165.4
(C-7), 162.0 (C-5), 156.7 (C-9), 156.03 (C-2), 151.3 (C-40),
148.7 (C-30), 137.8 (C-3), 122.8 (C-1 ), 122.4 (C-60), 111.2
(C-20), 110.8 (C-50), 106.0 (C-10), 97.9 (C-6), 92.2 (C-8),
69.1 (OCH2CH2CH2OCO), 62.3 (OCH2CH2CH2OCO),
56.1, 56.0 and 55.8 (3£OCH3), 52.5 (CO2CH3), 41.2
(malonate CH2), 29.2 (OCH2CH2CH2OCO). HRMS
(FAB) m/z calculated for C25H27O11 (MþH)þ 503.1553,
found 503.1562.
1
12.35 (s, 1H, 5-OH), 7.078–7.74 (m, 2H, H-20 and H-60), 7.00
(d, J¼8.3 Hz, 1H, H-5 ), 6.48 (d, J¼2.2 Hz, 1H, H-8), 6.38
(d, J¼2.2 Hz, 1H, H-6), 4.32 (br s, 1H, OH), 4.05 (t,
J¼5.6 Hz, 2H, CH2O), 3.98, 3.97 and 3.89 (3 s, 11H,
3£OCH3 and CH2OH overlapped with the first two
singlets), 1.93 (qui, J¼5.6 Hz, 2H, CH2); 13C NMR d:
178.9 (C-4), 165.7 (C-7), 161.9 (C-5), 156.8 (C-9), 1560.5
(C-2), 151.5 (C-40), 148.08 (C-30), 137.8 (C-3), 122.7 (C-1 ),
122.1 (C-60), 111.1 (C-2 ), 110.9 (C-50), 105.9 (C-10), 98.0
(C-6), 92.4 (C-8), 69.2 (CH2OH), 59.1 (OCH2), 56.0
and 55.9 (3£OCH3), 32.2 (CH2). MS (EI) m/z (%): 402
(Mþz, 93), 371 (15), 357 (22), 344 (100), 329 (15), 315 (63),
301 (10), 285 (7), 167 (15), 149 (7). Anal. Calcd for
C21H22O8· 1/2 H2O: C, 61.31; H, 5.64. Found: C, 61.21; H,
5.59.
2.7.3. 3-(30,40,5,7-Tetramethoxyflavonyl-3-oxy)propan-1-
ol (22c). Compound 22c (0.44 g, 82%) was obtained from
19 (0.47 g); crystallization from 0EtOH, mp 130–132 8C. 1H
NMR d: 7.77 (d, J¼2.1 Hz, H-2 ), 7.75 (dd, J¼8.5, 2.1 Hz,
1H, H-60), 6.99 (d, J¼8.5 Hz, 1H, H-50), 6.53 (d, J¼2.3 Hz,
1H, H-8), 6.37 (d, J¼2.3 Hz, 1H, H-6), 4.67 (br s, 1H, OH),
4.02 (t, J¼5.5 Hz, 2H, CH2O), 3.97 and 3.92 (2 s, 14H,
4£OCH3 and CH2OH overlapped with the first singlet), 1.91
(qui, J¼5.5 Hz, 2H, CH2); 13C NMR d: 174.7 (C-4), 1640.2
(C-7), 161.0 (C-5), 158.9 (C-9), 153.05 (C-2), 151.0 (C-4 ),
148.7 (C-30), 139.9 (C-3), 123.1 (C-1 ), 121.6 (C-60), 111.0
(C-20), 110.8 (C-50), 109.1 (C-10), 95.9 (C-6), 92.5 (C-8),
69.1 (HOCH2), 59.6 (CH2O), 56.5, 56.04, 55.98 and 55.8
(4£OCH3), 32.3 (CH2). MS (EI) m/z (%): 416 (Mþz, 100),
401 (20), 385 (31), 371 (75), 358 (23), 341 (31), 329 (15),
312 (12), 269 (23), 234 (23), 181 (70), 165 (60), 149 (27).
Anal. Calcd for C22H24O8·1/2 H2O: C, 62.11; H, 5.92.
Found: C, 61.99; H, 5.89.
2.7.7. Methyl 3-(30,40,5,7-tetramethoxyflavonyl-3-oxy)-
propyl malonate (23b). Compound 23b (0.38 g, 83%)
1
was obtained as an oil from 22c (0.37 g). H NMR d: 7.67
(dd, J¼8.5, 1.9 Hz, 1H, H-600), 7.63 (d, J¼1.9 Hz, 1H, H-20),
6.98 (d, J¼8.5 Hz, 1H, H-5 ), 6.50 (d, J¼1.7 Hz, 1H, H-8),
6.33 (d, J¼1.7 Hz, 1H, H-6), 4.31 (t, J¼6.4 Hz, 2H,
OCH2CH2CH2OCO), 4.08 (t, J¼6.4 Hz, 2H, OCH2CH2-
CH2OCO), 3.97, 3.95 and 3.90 (3s, 12H, 4£OCH3), 3.71 (s,
3H, CO2CH3), 3.35 (s, 2H, malonate CH2), 2.10 (q, 2H); 13
C
NMR d: 173.7 (C-4), 166.8 (CO2CH3), 166.2 (COCH2CO2-
CH3), 163.7 (C-7), 160.7 (C-5), 158.6 (C-9), 152.7 (C-2),
150.6 (C-40), 148.4 (C-30), 139.8 (C-3), 123.0 (C-10), 121.7
(C-60), 111.0 (C-20), 110.5 (C-50), 109.1 (C-10), 95.6 (C-6),
92.2 (C-8), 68.4 (OCH2CH2CH2OCO), 62.6 (OCH2CH2-
CH2OCO), 56.2, 55.9, 55.8 and 55.6 (4£OCH3), 52.3
(COOCH3), 41.1 (malonate CH2), 29.7 (OCH2CH2CH2O).
HRMS (FAB) m/z calculated for C26H29O11 (MþH)þ
517.1710, found 517.1721.
2.7.4. Malonate derivatives of quercetin. Compounds 21
and 23 were prepared as indicated above in the general
procedure for the reactions with methyl malonyl chloride.
2.8. General procedure for the synthesis of [60]fullerene-
quercetin derivatives
2.7.5. Methyl 3-(3,30,40,7-tetramethoxyflavonyl-5-oxy)-
propyl malonate (21). Compound 21 (0.34 g, 73%) was
obtained as an oil from 20 (0.37 g). 1H NMR d: 7.73–7.69
(m, 2H, H-20 and H-60), 6.98 (d, J¼9.8 Hz, 1H, H-50), 6.51
(d, J¼2.2 Hz, 1H, H-8), 6.34 (d, J¼2.2 Hz, 1H, H-6), 4.53
(t, J¼6.1 Hz, 2H, OCH2CH2CH2OCO), 4.15 (t, J¼6.1 Hz,
2H, OCH2CH2CH2OCO), 3.97, 3.90 and 3.84 (3s, 12H,
4£OCH3), 3.73 (s, 3H, CO2CH3), 3.41 (s, 2H, malonate
CH2), 2.29 (qui, J¼6.1 Hz, 2H, CH2); 13C NMR d: 173.8
(C-4), 167.0 (CO2CH3), 166.4 (COCH2CO2CH3), 163.7
(C-7), 160.0 (C-5), 158.7 (C-9), 152.06 (C-2), 150.7 (C-40),
148.6 (C-30), 141.1 (C-3), 123.3 (C-1 ), 121.6 (C-60), 111.1
(C-20), 110.7 (C-50), 109.6 (C-10), 96.7 (C-6), 92.6 (C-8),
65.5 (OCH2CH2CH2OCO), 62.4 (OCH2CH2CH2OCO),
59.9 (3-OCH3), 56.0, 55.9 and 55.7 (3£OCH3), 52.5
(CO2CH3), 41.3 (malonate CH2), 28.3 (OCH2CH2CH2O).
MS (EI) m/z (%): 516 (Mþz, 100), 501 (12), 486 (11), 415
(15), 397 (17), 385 (33), 371 (65), 357 (23), 341 (19), 315
(15), 159 (27), 101 (41), 91 (40), 69 (23). Anal. Calcd for
C26H28O11·1/2 H2O: C, 59.43; H, 5.56. Found: C, 59.69; H,
5.45.
A mixture of flavone 21, 23a or 23b (0.16 mmol), C60
(280 mg, 0.39 mmol), iodine (40 mg, 0.16 mmol) and DBU
(84 mL, 0.55 mmol) in toluene (100 mL) was stirred at rt
under N2 until the starting flavone disappeared (about 1 h).
Then the crude mixture was concentrated, and separated by
flash chromatography using toluene and toluene/AcOEt
(6:4) as eluent. The first fraction was the unchanged C60 and
the second one the dyads 24, 25a or 25b.
2.8.1. Dyad 24. Compound 24 (80 mg, 49%) was obtained
0
1
from 21 (82 mg). H NMR d: 7.607–7.64 (m, 2H, H-2 and
H-60), 6.98 (d, J¼8.4 Hz, 1H, H-5 ), 6.45 (d, J¼2.2 Hz, 1H,
H-8), 6.25 (d, J¼2.2 Hz, 1H, H-6), 4.96 (t, J¼5.7 Hz, 2H,
OCH2CH2CH2OCO), 4.19 (t, J¼5.7 Hz, 2H, OCH2CH2-
CH2OCO), 4.08 (s, 3H, CO2CH3), 3.97 and 3.96 (2 s, 6H, 30-
and 40-OCH3), 3.86 (s, 3H, 7-OCH3), and 3.81 (s, 3H,
3-OCH3), 2.48 (qui, J¼5.7 Hz, 2H, CH2); 13C NMR d:
173.7 (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-40), 148.6
(C-30), 145.4, 145.2, 145.14, 145.12, 145.06, 145.02,
144.83, 144.80, 144.7, 144.60, 144.55, 144.3, 144.2,

M. D. L. de la Torre et al. / Tetrahedron 60 (2004) 3581–3592
3591
143.8, 143.6, 143.0, 142.93, 142.90, 142.8, 142.5, 142.13,
References and notes
142.07, 141.8, 141.6, 141.2, 140.8,0 140.7 (C-3), 139.5,
138.3, 129.0, 128.2, 125.3, 123.2 (C-1 ), 121.6 (C-60), 111.1
(C-20), 110.7 (C-50), 109.8 (C-10), 96.8 (C-6), 92.8 (C-8),
71.5 (C60-sp3), 64.9 (OCH2CH2CH2OCO), 63.9 (OCH2-
CH2CH2OCO), 60.0 (3-OCH3), 56.1, 55.9 and 55.8
(3£OCH3), 54.1 (CO2CH3), 52.3 (methano bridge), 28.0
(OCH2CH2CH2O). HRMS (FAB) m/z calculated for
C86H27O11 (MþH)þ 1235.1553, found 1235.1599.
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¨ttinger,
H.; Hirsch, A.; Land, E. J.; Leach, S.; McGarvey, D. J.;
¨
Schonberger, H. Free Radical Biol. Med. 2000, 29, 26–33.
2.8.2. Dyad 25a. Compound 25a (64 mg, 33%) was
obtained from 23a (80 mg). 1H NMR d: 12.60 (s, 1H,
5-OH), 7.73 (dd, J¼8.5, 1.9 Hz, 1H, H-60), 7.60 (d,
J¼1.9 Hz, 1H, H-20), 7.01 (d, J¼8.5 Hz, 1H, H-50), 6.43
(d, J¼2.1 Hz, 1H, H-8), 6.34 (d, J¼2.1 Hz, 1H, H-6), 4.65
(t, J¼6.2 Hz, 2H, OCH2CH2CH2OCO), 4.16 (t, J¼6.2 Hz,
2H, OCH2CH2CH2OCO), 4.07 (s, 3H, CO2CH3), 3.97 and
3.96 (2 s, 6H, 30- and 40-OCH3), 3.86 (s, 3H, 7-OCH3), 2.27
(qui, J¼6.2 Hz, 2H, CH2); 13C NMR d: 178.5 (C-4), 165.5
(C-7), 164.0 (CO2CH3), 163.5 (COR), 162.0 (C-5), 156.7
(C-9), 156.1 (C-2), 151.4 (C-40), 148.7 (C-30), 145.3, 145.18,
145.16, 145.1, 144.99, 144.96, 144.9, 144.67, 144.65, 144.6,
144.54, 144.47, 143.9, 143.8, 143.1, 143.0, 142.93, 142.89,
142.2, 142.1, 141.9, 141.7, 140.91, 140.87, 139.2, 138.6,
138.0 (C-3), 129.0, 128.2, 125.3, 122.8 (C-10), 122.5 (C-
60), 111.2 (C-20), 110.8 (C-50), 106.1 (C-10), 98.0 (C-6),
92.3 (C-8), 71.4 (C60-sp3), 69.5 (OCH2CH2CH2OCO),
64.3 (OCH2CH2CH2OCO), 56.1 (7-OCH3), 56.0 and 55.9
(30- and 40-OCH3), 54.1 (CO2CH3), 52.0 (methano
bridge), 29.5 (OCH2CH2CH2O). HRMS (FAB) m/z
calculated for C85H25O11 (MþH)þ 1221.1397, found
1221.1399.
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10. De la Torre, M. D. L.; Marcorin, G. L.; Pirri, G.; Tome, A. C.;
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11. De la Torre, M. D. L.; Tome, A. C.; Silva, A. M. S.; Cavaleiro,
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2.8.3. Dyad 25b. Compound 25b (102 mg, 52%) was
1
obtained from 23b (80 mg). H NMR d: 7.71 (dd, J¼8.5,
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1.9 Hz, 1H, H-60), 07.64 (d, J¼1.9 Hz, 1H, H-20), 7.00 (d,
J¼8.5 Hz, 1H, H-5 ), 6.50 (d, J¼2.1 Hz, 1H, H-8), 6.35 (d,
J¼2.1 Hz, 1H, H-6), 4.65 (t, J¼6.2 Hz, 2H, OCH2CH2-
CH2OCO), 4.17 (t, J¼6.2 Hz, 2H, OCH2CH2CH2OCO),
4.04 (s, 3H, CO2CH3), 3.98, 3.96 and 3.90 (3 s, 4£3H,
4£OCH3), 2.28 (qui, J¼6.2 Hz, 2H, CH2); 13C NMR d:
173.8 (C-4), 164.01 (CO2CH3), 163.96 (C-7), 163.4
(CO2R), 161.0 (C-5), 158.8 (C-9), 152.9 (C-2), 150.9
(C-40), 148.6 (C-30), 145.4, 145.22, 145.15, 145.13, 144.99,
144.97, 144.9, 144.63, 144.58, 144.5, 143.9, 143.8, 143.02,
142.96, 142.87, 142.2, 142.1, 141.9, 141.7, 140.9, 1400.2
(C-3), 139.3, 138.5, 137.9, 125.3, 123.2 (C-10), 122.0 (C-6 ),
111.2 (C-20), 110.8 (C-50), 109.5 (C-10), 95.9 (C-6), 92.5
(C-8), 71.5 (C60-sp3), 69.0 (OCH2CH2CH2OCO), 64.7
(OCH2CH2CH2OCO), 56.4, 56.1, 56.0 and 55.8
(4£OCH3), 54.0 (CO2CH3), 52.1 (methano bridge), 29.6
(OCH2CH2CH2O). HRMS (FAB) m/z calculated for
C86H27O11 (MþH)þ 1235.1553, found 1235.1542
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