to be determined. The configurations of the C-6 and C-15 protons could not be established because of overlap of the cross
peaks. Table 1 presents the analysis of the spectra.
As expected, differences in the structures of the carboxylic acids had a minimal effect on the chemical shifts of nuclei
near the hydroxyls. The substituents did have an effect on the C-3, C-19, C-24, C-26, and C-28 protons in PMR spectra of
13
betulin itself and its acetate [13]. The resonances for C-2, C-3, and C-28 differed by greater than 1 ppm in C NMR spectra
of betulin and esters 3a and 3b and by about 1 ppm for C-17, C-18, C-19, and C-24.
Thus, we synthesized fluorine-containing esters of betulin. Acylation of betulin by fluorocarboxylic (perfluorobutyric,
perfluorooctanoic, 3-fluorobenzoic, perfluorobenzoic) acid chlorides in CHCl in the presence of Py
formed
3
28-O-fluoroacylbetulins whereas acylation of betulin by fluorocarboxylic (trifluooracetic, pentafluoropropionic) acid anhydrides
in Py in the presence of 4-dimethylaminopyridine gave 3,28-di-O-fluoroacylbetulins. Use of 3-fluorobenzoic acid in the
presence of N,Nꢀ-dicyclohexylcarbodiimide and 4-dimethylaminopyridine in CH Cl as the acylating agent formed 3,28-di-
2
2
O-(3-fluorobenzoyl)betulin whereas use of perfluorobutyric acid under the same conditions gave 28-O-perfluorobutanoylbetulin.
EXPERIMENTAL
NMR spectra were recorded in CDCl (if not otherwise specified) with TMS internal standard for PMR spectra
3
13
19
(500 MHz) and C NMR spectra (125 MHz) and ꢂ,ꢂ,ꢂ-trifluorotoluene with a conversion to CCl F for F NMR (470 MHz)
3
on a Bruker Avance-500 spectrometer. All NMR experimental data were obtained and processed using XWIN-NMR 3.5
programs. IR spectra were recorded in KBr pellets on a Bomem Michelson 100 instrument. Mass spectra were measured in an
HPLCAccela system with an LCQ-Fleet mass detector (three-dimensional ion trap) in chemical ionization mode at atmospheric
pressure (APCI). Melting points were determined on a Boetius stage. The course of reactions and purity of products were
monitored by TLC on Silufol UV-254 plates (EtOAc:hexane). Column chromatography was carried out over silica gel
(EtOAc:hexane). Solvents were evaporated in vacuo. Elemental analyses of all compounds agreed with those calculated.
Acylation of Betulin by Fluorocarboxylic Acid Chlorides. A solution of 1 (0.1 mmol) in anhydrous CHCl (7 mL)
3
was stirred at 18–20°C; treated with Py (0.1 mmol) and dropwise with fluorocarboxylic acid chloride (0.1 mmol) in anhydrous
CHCl (5 mL); and stirred for 1 h for perfluorobutyric and perfluorooctanoic acid chlorides, 48 h for 3-fluorobenzoic acid
3
chloride, and 8 h for perfluorobenzoic acid chloride. The solvent was removed. Column chromatography isolated 28-O-acyl
betulin derivatives 2a–d.
–1
28-O-Perfluorobutanoylbetulin (2a). Yield 70%, mp 79–83°C (EtOH), C H F O . IR spectrum (KBr, ꢄ, cm ):
34 49 7
3
1780 (C=O), 1640 (C=C), 1220 (C–F).
PMR spectrum (CDCl , ꢁ, ppm, J/Hz): 0.68 (1H, d, J = 9.4, H-5), 0.76 (3H, s, CH ), 0.83 (3H, s, CH ), 0.97 (3H, s,
3
3
3
3
CH ), 0.99 (3H, s, CH ), 1.04 (3H, s, CH ), 1.69 (3H, s, CH ), 0.87-2.00 (4H, m, CH, CH ), 2.41 (1H, m, H-19), 3.19 (1H, dd,
3
3
3
3
2
2
2
J = 11.3, 4.7, H-3), 4.13 (1H, d, J = 11.0, H-28), 4.59 (1H, d, J = 11.0, H-28), 4.61 (1H, s, H-29), 4.70 (1H, s, H-29).
19
F NMR spectrum (CDCl , ꢁ, ppm): –127.13 (2F), –119.4 (2F), –81.0 (3F).
Mass spectrum (APCI): 621 [M – 18] .
3
+
–1
28-O-Perfluorooctanoylbetulin (2b). Yield 73%, mp 69–72°C (EtOH), C H F O . IR spectrum (KBr, ꢄ, cm ):
38 49 15
3
1780 C=O), 1640 (C=C), 1220 (C–F).
3
PMR spectrum (CDCl , ꢁ, ppm, J/Hz): 0.68 (1H, d, J = 9.4, H-5), 0.76 (3H, s, CH ), 0.83 (3H, s, CH ), 0.97 (3H, s,
3
3
3
CH ), 0.99 (3H, s, CH ), 1.04 (3H, s, CH ), 1.69 (3H, s, CH ), 0.87-2.00 (4H, m, CH, CH ), 2.41 (1H, m, H-19), 3.19 (1H, dd,
3
3
3
3
2
2
2
J = 11.3, 4.7, H-3), 4.13 (1H, d, J = 11.0, H-28), 4.58 (1H, d, J = 11.0, H-28), 4.61 (1H, s, H-29), 4.70 (1H, d, H-29).
19
F NMR spectrum (CDCl , ꢁ, ppm): –126.4 (2F), –122.0 (2F), –122.8 (2F), –122.3 (2F), –121.9 (2F), –118.5 (2F),
3
–80.0 (3F).
+
Mass spectrum (APCI): 821 [M – 18] .
–1
28-O-(3-Fluorobenzoyl)betulin (2c). Yield 55%, mp 190–192°C (EtOH), C H FO . IR spectrum (KBr, ꢄ, cm ):
37 53
3
1725 (C=O), 1640 (C=C), 1270 (C–F).
3
PMR spectrum (CDCl , ꢁ, ppm, J/Hz): 0.69 (1H, d, J = 9.7, H-5), 0.76 (3H, s, CH ), 0.84 (3H, s, CH ), 0.97 (3H, s,
3
3
3
CH ), 1.00 (3H, s, CH ), 1.06 (3H, s, CH ), 1.71 (3H, s, CH ), 0.88-2.07 (4H, m, CH, CH ), 2.51 (1H, m, H-19), 3.19 (1H, dd,
3
3
3
3
2
2
2
J = 11.4, 4.7, H-3), 4.01 (1H, d, J = 11.0, H-28), 4.53 (1H, d, J = 11.0, H-28), 4.61 (1H, s, H-29), 4.72 (1H, s, H-29), 7.43 (1H,
m, H
3
3
), 7.72 (1H, d, J = 9.2, H
F NMR spectrum (CDCl , ꢁ, ppm): –112.6.
), 7.76 (1H, m, H
), 7.84 (1H, d, J = 7.7, H
).
arom
arom
arom
arom
19
3
923