Synthesis of fluorine-containing betulin esters

Article abstract of DOI:10.1007/s10600-012-0105-8

28-O-Fluoroacylbetulins were synthesized via acylation of betulin by fluorocarboxylic (perfluorobutyric, perfluorooctanoic, 3-fluorobenzoic, perfluorobenzoic) acid chlorides in CHCl₃ in the presence of Py. 3,28-Di-O-fluoroacylbetulins were prep

Full text of DOI:10.1007/s10600-012-0105-8

Chemistry of Natural Compounds, Vol. 47, No. 6, January, 2012 [Russian original No. 6, November-December, 2011]
SYNTHESIS OF FLUORINE-CONTAINING BETULIN ESTERS
1*
1
1
T. S. Khlebnikova, Yu. A. Pivenꢀ, V. A. Nikolaevich,
UDC 547.914.5
1
1
A. V. Baranovskii, F. A. Lakhvich,
2
and Nguen Van Tuen
28-O-Fluoroacylbetulins were synthesized via acylation of betulin by fluorocarboxylic (perfluorobutyric,
perfluorooctanoic, 3-fluorobenzoic, perfluorobenzoic) acid chlorides in CHCl in the presence of Py.
3
3,28-Di-O-fluoroacylbetulins were prepared by treatment of betulin with fluorocarboxylic (trifluoroacetic,
pentafluoropropionic) acid anhydrides in Py in the presence of 4-dimethylaminopyridine. 3,28-Di-O-
(3-fluorobenzoyl)betulin was obtained from acylation of betulin by 3-fluorobenzoic acid in CH Cl
2
2
in the presence of N,Nꢀ-dicyclohexylcarbodiimide and 4-dimethylaminopyridine whereas acylation by
perfluorobutyric acid under the same conditions gave 28-O-perfluorobutanoylbetulin.
Keywords: betulin, acylation, fluorine-containing betulin esters.
Betulin is a triterpene alcohol that is isolated from birch bark and many other plants. It possesses antiviral (in
particular, against herpes virus HSV-1), anti-inflammatory, and antituberculosis activity and other types of biological activity
[1, 2]. Therefore, the development of approaches to chemical modification of betulin and the synthesis of effective biologically
active compounds based on it are undoubtedly timely. Investigations of the pharmacological properties of betulin esters
revealed their hepatoprotective, anti-inflammatory, antitumor, and antiviral properties [3, 4].
Synthetic methods for various fluorine-containing polyfunctional compounds of interest as potential drugs and plant
protection agents are currently widely studied [5-9]. Introduction of F atoms and fluoroalkyl groups into a structure affect
considerably the physical and chemical properties, reactivity, and biological activity of the compounds [5–9].
We studied the acylation of betulin by fluorocarboxylic acids and their anhydrides and chlorides in order to prepare
new fluorine-containing betulin esters.
Betulin (1) has two secondary hydroxyls on C-3 and C-28 that can undergo acylation. Depending on the acylation
conditions, mono- or diacylated products are formed [3]. Monoacylation of 1 was observed upon treatment with fluorocarboxylic
(perfluorobutyric, perfluorooctanoic, 3-fluorobenzoic, perfluorobenzoic) acid chlorides at 18–20°C in anhydrous CHCl in
3
the presence of an equivalent amount of Py. The 28-O-acylbetulins 2a–d were obtained in 55–83% yield. Diacylation of 1
occurred by reaction with a 12-fold excess of fluorocarboxylic (trifluoroacetic, pentafluoropropionic) acid anhydrides in Py in
the presence of 4-dimethylaminopyridine at 18–20°C. 3,28-Di-O-fluoroacylbetulins 3a and 3b were isolated in 82 and 78%
yields. Treatment of 1 in CHCl with a 12-fold excess of trifluoroacetic anhydride at 18–20°C produced an inseparable
3
mixture of mono- and diacylated products. Acylation of 1 by 3-fluorobenzoic acid in CH Cl in the presence of
2
2
N,Nꢀ-dicyclohexylcarbodiimide and 4-dimethylaminopyridine at 0°C for 10 min and then for 72 h at room temperature gave
diester 3c in 85% yield whereas acylation of 1 by perfluorobutyric acid under the same conditions gave monoester 2a.
3,28-Di-O-trifluoroacetylbetulin (3a) was isolated earlier via oxidation of 1 by DMSO activated with trifluoroacetic
anhydride [10] and also by reaction of 1 with an excess of trifluoroacetic anhydride in CCl at 0–10°C [11].
4
19
13
The structures of products 2a–d and 3a–c were established and confirmed using IR, PMR, F NMR and C NMR
spectroscopy, and elemental analysis.
1) Institute of Bioorganic Chemistry, NationalAcademy of Sciences of Belarus, 220141, Minsk, ul. Akad. Kuprevicha,
5/2, e-mail: khlebnicova@iboch.bas-net.by; 2) Chemistry Institute of the Viet Nam Academy of Sciences and Technology,
Hanoi, Viet Nam. Translated from Khimiya Prirodnykh Soedinenii, No. 6, November–December, 2011, pp. 807–810. Original
article submitted April 27, 2011.
©
0009-3130/12/4706-0921 2012 Springer Science+Business Media, Inc.
921

13
TABLE 1. PMR and C NMR Spectra of 3a and 3b
ꢁÑ, ppm, JCF/Hz
ꢁÍ, ppm
C atom
H atom
3à
3b
3à
3b
1
2
3
4
5
6
7
8
9
38.37
23.41
86.39
38.22
55.40
18.23
34.17
41.04
50.36
37.20
20.93
25.22
37.91
42.90
27.08
29.50
46.76
48.93
47.82
149.65
29.50
34.36
27.93
16.38
16.28
16.14
14.91
67.04
110.44
19.24
38.42
23.42
86.85
38.23
55.48
18.25
34.22
41.10
50.43
37.25
20.98
25.30
38.01
42.95
27.08
29.50
46.83
49.03
47.84
149.62
29.53
34.31
27.87
16.30
16.26
16.16
14.95
67.43
110.43
19.28
1.02
1.75
1.70
1.75
4.67
0.81
1.54
1.43
1.42
1.31
1.43
1.25
1.08
1.68
1.65
1.10
1.68
1.33
1.83
1.65
2.43
1.46
1.98
1.16
1.77
0.890
0.895
0.88
1.05
1.00
4.14
4.57
4.63
4.71
1.69
1.01
1.74
1.72
1.72
4.71
0.81
1.54
1.42
1.42
1.31
1.42
1.25
1.06
1.66
1.65
1.10
1.66
1.32
1.79
1.65
2.42
1.46
1.98
1.15
1.75
0.88
0.88
0.88
1.05
0.99
4.15
4.60
4.62
4.71
1.69
1ꢂ
ꢃ
ꢂ
1
2
2ꢃ
3ꢂ
5ꢂ
6
6
7 (2)
ꢂ
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
CF3
CF3
2CF2
CO
CO
ꢂ
11
11ꢃ
12ꢂ
12ꢃ
13ꢃ
15
15
ꢂ
16
16ꢃ
18ꢂ
19ꢃ
21ꢂ
21ꢃ
22ꢂ
ꢃ
22
23ꢂ
24ꢃ
25ꢃ
26ꢃ
27ꢂ
28
114.83 (q, 1J 285)
117.90 (qt, J 286, 34)
=
=
114.89 (q, 1J 285)
117.97 (qt, J 286, 34)
28
=
=
ꢂ
29
–
106.12 (tq, J 264, 39)
=
157.57 (q, 2J 42)
158.33 (t, 2J 29)
29ꢃ
30
=
=
=
=
158.12 (q, 2J 42)
158.94 (t, 2J 29)
29
19
30
26
20
18
21
17
11
9
OR
25
5
1
13
28
15
1
10
3
7
27
RO
23 24
1, 2a - d, 3à - c
1: R = R = H; 2a: R = H, R = COC F ; 2b: R = H, R = COC F
7 15
1
1
3 7
1
2c: R = H, R = COC H -(3F); 2d: R = H, R = COC F
1
6
4
1
6 5
3a: R = R = COCF ; 3b: R = R = COC F ; 3c: R = R = COC H -(3F)
1
3
1
2
5
1
6 4
Taking into account the varied and contradictory data regarding the assignment of proton resonances in the NMR
spectra of betulin esters [12], we performed a series of two-dimensional experiments in order to refine the resonances and
13
assign them completely in the PMR and C NMR spectra. The experiments (HSQC, COSY, HMBC, TOCSY, NOESY) were
performed with 3a and 3b. This allowed the C and H chemical shifts and in most instances the steric position of the protons
922

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

28-O-Pentafluorobenzoylbetulin (2d). Yield 83%, mp 105–108°C (EtOH), C H F O . IR spectrum (KBr, ꢄ,
37 49
5 3
–1
cm ): 1740 (C=O), 1640 (C=C), 1230 (C–F).
3
PMR spectrum (CDCl , ꢁ, ppm, J/Hz): 0.69 (1H, d, J = 9.4, 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 ), 1.70 (3H, s, CH ), 0.87-2.05 (4H, m, CH, CH ), 2.47 (1H, m, H-19), 3.19 (1H, dd,
3
3
3
3
2
2
2
J = 11.4, 4.7, H-3), 4.15 (1H, d, J = 11.0, H-28), 4.59 (1H, d, J = 11.0, H-28), 4.61 (1H, s, H-29), 4.71 (1H, s, H-29).
19
F NMR spectrum (CDCl , ꢁ, ppm): –160.66 (2F), –148.9 (1F), –138.2 (2F).
3
Acylation of Betulin by Fluorocarboxylic Acid Anhydrides. A solution of betulin (0.1 mmol) and
4-dimethylaminopyridine (0.2 mmol) in Py (5 mL) at 18–20°C was treated with fluorocarboxylic (trifluoroacetic,
pentafluoropropionic) acid anhydride (1.2 mmol). The mixture was stirred for 1.5 h at room temperature, diluted with
EtOAc (20 mL) and washed with HCl solution (20%, 3 ꢅ 40 mL) and H O. The organic layer was dried over anhydrous
2
MgSO . The solvent was removed to isolate 3,28-di-O-acyl derivatives of betulin 3a and 3b as colorless crystalline compounds.
4
13
Table 1 presents the PMR and C NMR data for 3a and 3b.
3,28-Di-O-trifluoroacetylbetulin (3a). Yield 82%, mp 172–175°C (EtOH), C H F O . IR spectrum (KBr, ꢄ,
34 48 8
4
–1
19
cm ): 1780 (C=O), 1640 (C=C), 1220 (C–F). F NMR spectrum (CDCl , ꢁ, ppm): –75.6, –75.2.
3
3,28-Di-O-pentafluoropropanoylbetulin (3b). Yield 78%, mp 54–57°C (EtOH), C H F O . IR spectrum (KBr,
36 48 10
4
–1
19
ꢄ, cm ): 1780 (C=O), 1640 (C=C), 1220 (C–F). F NMR spectrum (CDCl , ꢁ, ppm): –121.8 (2F), –121.6 (2F), –83.1 (3F),
3
–83.0 (3F).
Acylation of Betulin by FluorocarboxylicAcids. Asolution of 1 (0.1 mmol), fluorocarboxylic acid (perfluorobutyric,
3-fluorobenzoic) (0.4 mmol), and 4-dimethylaminopyridine (catalytic amount) in CH Cl (10 mL) at 0°C was treated with
2
2
N,Nꢀ-dicyclohexylcarbodiimide (0.4 mmol), stirred at 0°C for 10 min and at 18–20°C for 72 h, and filtered to remove the
precipitate. The solvent was removed. Column chromatography isolated as colorless crystalline compounds 28-O-
perfluorobutanoylbetulin (2a) in 70% yield for perfluorobutanoic acid and the 3,28-di-O-acylderivative of betulin 3c using
3-fluorobenzoic acid.
3,28-Di-O-(3-fluorobenzoyl)betulin (3c). Yield 89%, mp 192–195°C (EtOH), C H F O . IR spectrum (KBr, ꢄ,
44 56 2
4
–1
cm ): 1720 (C=O), 1715 (C=O), 1640 (C=C), 1270 (C–F).
3
PMR spectrum (CDCl , ꢁ, ppm, J/Hz): 0.87 (1H, d, J = 7.1, H-5), 0.91 (3H, s, CH ), 0.92 (3H, s, CH ), 0.99 (3H, s,
3
3
3
CH ), 1.02 (3H, s, CH ), 1.08 (3H, s, CH ), 1.56 (3H, s, CH ), 1.0-2.07 (4H, m, CH, CH ), 2.52 (1H, m, H-19), 4.09 (1H, d,
3
3
3
3
2
2
2
J = 11.5, H-28), 4.54 (1H, d, J = 11.5, H-28), 4.62 (1H, s, H-29), 4.71 (1H, dd, J = 11, 5.4, H-3), 4.72 (1H, s, H-29), 7.26 (2H,
m, H
), 7.42 (2H, m, H
F NMR spectrum (CDCl , ꢁ, ppm): –112.8, –112.6.
), 7.71 (2H, m, H
), 7.84 (2H, m, H
).
arom
arom
arom
arom
19
3
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