Notes
J . Org. Chem., Vol. 61, No. 25, 1996 9071
Syn th esis of N-(3,6,9-Tr ioxa d ecyl)glycin e (2). To a solu-
tion of 265 mg (1.63 mmol) of aldehyde 3c and 552 mg (1.63
mmol) of glycine benzyl ester 4-toluenesulfonate in 12 mL of
methanol-acetic acid (99:1) was added 127 mg (2.02 mmol) of
sodium cyanoborohydride in 30 min. The solution was stirred
at rt for 2.5 h and then was poured into 30 mL of saturated
NaHCO3 solution. The product was extracted with ethyl acetate,
the organic phase was washed with brine and dried with
anhydrous NaSO4, and the solvent was removed in vacuo. Since
the reaction mixture consisted of an unseparable mixture of
glycine benzyl ester, the desired N-(3,6,9-trioxadecyl)glycine (2)
(ethyl acetate-methanol (9:1), Rf ) 0.40), and the dialkylated
N,N-bis(3,6,9-trioxadecyl)glycine, the residue was dissolved in
dioxane and treated with 342 mg (2.00 mmol) of benzyl chloro-
formate. The N-Cbz-N-(3,6,9-trioxadecyl)glycine benzyl ester
was then purified by column chromatography (ethyl acetate-
petroleum ether (1:1), Rf ) 0.36). Yield: 355 mg (49% from
aldehyde 3c). 1H-NMR (200 MHz): δ 7.35 (s, 5H), 7.29 (m, 5H),
5.25 (s, 2H), 5.18 (m, 2H), 4.21 and 4.16 (two s, 2H), 3.55 (m, 12
H), 3.35 (s, 3H). 13C-NMR (50 MHz): δ 169.7, 156.2, 155.8,
136.3, 136.4, 128.5, 128.4, 128.3, 128.3, 128.1, 127.9, 127.8, 127.7,
71.8, 70.4, 70.3, 67.5, 67.3, 66.7, 66.6, 58.9, 50.2, 48.5, 47.9. EI-
MS: m/z 311 (M - COOCH2Ph)+, 267, 149, 91, 68 (100). IR
(film, cm-1): 2975, 2940, 1750, 1715, 1700. N-Cbz-N-(3,6,9-
trioxadecyl)glycine (750 mg) was dissolved in methanol (40 mL),
and 50 mg of Pd/C was added. The suspension was stirred at
rt under H2 atmosphere for 18 h and then was filtered on Celite,
and the solvent evaporated. Amino acid 2 was obtained in
quantitative yield and recrystallized from methanol-ethyl ether.
Mp: >250 °C. 1H-NMR (200 MHz, CDCl3): δ 3.78 (broad t, 2H),
3.51 (m, 12H), 3.30 (s, 3H), 3.18 (broad t, 2H). 13C-NMR (50
MHz, CDCl3): δ 170.5, 71.8, 70.4, 70.4, 70.3, 66.5, 58.9, 49.9,
46.7. IR (cm-1): 3350, 1650, 1111.
Gen er a l P r oced u r e for th e Syn th esis of F u ller en e
Der iva tives 1 a n d 4a -c. To a solution of 100 mg (0.14 mmol)
of C60 in 50 mL of toluene were added 0.70 mmol of aldehyde
and 0.14 mmol of N-substituted glycine. The mixture was
heated to reflux for 2 h, brought to rt, poured on top of a silica
gel column, eluted with toluene, and then eluted with toluene-
acetate (9:1). The compounds were dissolved in dichloromethane
and precipitated by addition of methanol.
Der iva tive 1: 39% (toluene-ethyl acetate (8:2), Rf ) 0.24).
1H-NMR (250 MHz): δ 9.00 (m, 1H), 8.60 (m, 1H), 8.16 (m, 1H),
7.38 (dd, J ) 6.0 Hz, J ) 7.5 Hz, 1H), 5.02 (d, J ) 9.5 Hz, 1H),
4.99 (s, 1H), 4.32 (d, J ) 9.4 Hz, 1H), 2.83 (s, 3H). 13C NMR
(62.5 MHz): δ 155.5, 153.2, 152.2, 151.8, 150.3, 149.6, 147.0,
146.0, 145.9, 145.8, 145.4, 145.2, 145.1, 145.0, 144.9, 144.3, 142.9,
142.8, 142.4, 142.3, 142.0, 141.7, 141.6, 140.0, 139.9, 137.0, 136.2,
136.1, 135.8, 123.3, 80.8, 69.8, 68.6, 39.7. UV-vis (cyclohex-
ane): λmax nm 430, 317, 256, 212. MALDI m/z: 855 (M + H)+,
720 (C60)+. Anal. Calcd for C68H10N2: C, 95.54; H, 1.18; N, 3.28.
Found: C, 93.71; H, 0.97; N, 3.19.
F igu r e 1. UV-vis absorption spectrum for a solution of 4a
in H2O-DMSO (9:1, 1 × 10-5 M).
derivatives dissolved in polar solvents, bands are broader
and less structured, especially in the low-energy region.13
In preliminary biological tests, 4c was found to be
active against a variety of microorganisms. Different
species of bacteria and different fungal strains were killed
in a slightly modified agar diffusion test: two strains,
clinical isolates CA1 and Z11, of Candida albicans, a
fastidious pathogenic eukariote; strain ATCC 6633 of
Bacillus subtilis, a spore-forming, Gram-positive bacte-
rium; strain AB1153 of Escherichia coli, a Gram-negative
enteric bacterium; a clinical isolate, strain 261/6 of
Mycobacterium avium, an acid fast, emerging pathogen
resistant to most antimicrobial drugs. In the latter case,
70% inhibition was observed with a concentration of 26
µg/mL, whereas complete inhibition was achieved with
concentrations 10 times higher.
The nature of the activity of the fullerene derivatives
4a -c is yet to be determined. However, the rather wide
range of biological activity exhibited makes these new
water-soluble fullerene derivatives interesting candidates
for further investigations. Work along these lines is
underway.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. Details regarding instrumentation
used in this paper have been described elsewhere.14 All other
reagents were used as purchased from Fluka and Aldrich. All
solvents were distilled prior to use.
Der iva tive 4a : 37% (toluene-ethyl acetate (1:1), Rf ) 0.12).
1H-NMR (200 MHz): δ 9.01 (m, 1H), 8.58 (dd, J ) 4.8 Hz, J )
1.6 Hz, 1H), 8.19 (broad d, J ) 8.1 Hz, 1H), 7.37 (dd, J ) 8.1
Hz, J ) 4.8 Hz, 1H), 5.21 (d, J ) 9.8 Hz, 1H), 5.21 (s, 1H) 4.33
(d, J ) 9.8 Hz, 1H), 3.90-4.15 (m, 2H), 3.75 (m, 6H), 3.45 (m,
6H), 2.92 (m, 1H). 13C-NMR (50 MHz, CS2-CDCl3): δ 156.2,
153.8, 152.7, 152.3, 150.7, 150.0, 147.3, 146.3, 146.3, 16.2, 146.2,
146.2, 146.1, 146.1, 145.9, 145.7, 145.7, 145.6, 145.5, 145.5, 145.4,
145.4, 145.3, 145.3, 145.2, 144.7, 144.5, 144.4, 144.3, 143.1, 143.0,
142.7, 142.6, 142.5, 142.2, 142.1, 142.1, 142.0, 141.9, 141.8, 141.7,
141.6, 140.2, 140.1, 139.5, 137.3, 137.0, 136.3, 136.0, 135.6, 133.1,
123.6, 79.7, 76.0, 72.0, 70.8, 70.7, 70.1, 69.2, 67.6, 59.1, 52.1.
UV-vis (cyclohexane): λmax nm 701, 430, 323, 309, 255, 212.
MALDI m/z: 987 (M + H+). Anal. Calcd for C74H22N2O3: C,
90.05; H, 2.25; N, 2.84. Found: C, 88.85; H, 2.06; N, 2.76.
Der iva tive 4b: 38% (toluene-ethyl acetate (1:1), Rf ) 0.08).
1H-NMR (250 MHz): δ 8.68 (m, 2H), 7.81 (m, 2H), 5.23 (d, J )
7.8 Hz, 1H), 5.21 (s, 1H), 4.35 (d, J ) 7.8 Hz, 1H), 4.01 (2m,
2H), 3.78 (m, 6H), 3.57 (m, 2H), 3.38 (m, 4H), 2.99-2.90 (m, 1H).
13C-NMR (62.5 MHz): δ 155.9, 153.7, 152.4, 152.0, 149.5, 147.4,
147.3, 147.3, 146.3, 146.3, 146.2, 146.2, 146.2, 146.1, 146.1, 145.9,
145.9, 145.6, 145.6, 145.5, 145.4, 145.4, 145.3, 145.3, 145.3, 145.2,
145.2, 144.7, 144.5, 144.4, 144.3, 143.1, 143.0, 142.7, 142.6, 142.5,
142.2, 142.1, 142.1, 142.0, 141.9, 141.8, 141.7, 141.6, 141.5, 140.2,
139.9, 139.4, 137.1, 136.3, 136.1, 135.5, 124.5, 80.9, 75.5, 71.9,
70.7, 70.6, 70.0, 69.3, 67.4, 59.0, 52.1. UV-vis (cyclohexane):
Syn th esis of 3,6,9-Tr ioxa d eca n a ld eh yd e (3c). To a solu-
tion of oxalyl chloride (3 mL) in dichloromethane (75 mL) under
nitrogen and cooled in a dry ice-acetone bath were carefully
added 5 mL of dimethyl sulfoxide in 15 mL of CH2Cl2. The
solution was stirred for 10 min, and then a solution of 5 mL
(29.7 mmol) of triethylene glycol monomethyl ether in 30 mL of
CH2Cl2 was added dropwise. The mixture was stirred for 15
min, and then triethylamine (20 mL) was added dropwise over
a period of 20 min. The reaction mixture was left for 30 min at
-78 °C and then allowed to reach rt. After a standard workup
with a saturated aqueous NaCl solution, the crude was purified
by flash chromatography (eluant: ethyl acetate-methanol (9:
1), Rf ) 0.54) affording 2.7 g (56%) of pure aldehyde 3c. Bulb-
to-bulb distillation at 90 °C (0.01 Torr) gave a clear homogeneous
oil, which gave a single peak in GC-MS analysis. 1H-NMR (250
MHz, C6D6): δ (ppm) 9.74 (t, J ) 0.7 Hz, 1H), 4.16 (d, J ) 0.7
Hz, 2H), 3.72 (m, 2H), 3.64 (m, 2H), 3.56 (m, 2H), 3.38 (s, 3H).
13C-NMR (62.5 MHz, C6D6): δ (ppm) 200.1, 76.8, 72.2, 71.3, 71.0,
70.8, 58.6. EI-HRMS: m/z 162 (M+, <0.3%, exact mass not
measurable), 133.0899 ([M - CHO]+, 3%; C6H13O3 requires
133.0861).
(13) Diederich, F.; J onas, U.; Gramlich, V.; Herrmann, A.; Ringsdorf,
H.; Thilgen, C. Helv. Chim. Acta 1993, 76, 2445.
(14) Bianco, A.; Maggini, M.; Scorrano, G.; Toniolo, C.; Marconi, G.;
Villani, C.; Prato, M. J . Am. Chem. Soc. 1996, 118, 4072.