Oxidation of betulin and its monoacetates by "activated" DMSO

Article abstract of DOI:10.1023/A:1024826316939

The oxidation of betulin and its 3-O- and 28-O-acetates by "activated" dimethylsulfoxide was investigated.

Full text of DOI:10.1023/A:1024826316939

Chemistry of Natural Compounds, Vol. 39, No. 2, 2003
OXIDATION OF BETULIN AND ITS MONOACETATES
BY "ACTIVATED" DMSO
O. Yu. Ashavina, O. B. Flekhter, F. Z. Galin,
UDC 547.918:547.914.4.057
N. N. Kabal′nova, L. A. Baltina, and G. A. Tolstikov
The oxidation of betulin and its 3-O- and 28-O-acetates by "activated" dimethylsulfoxide was investigated.
Key words: betulin, 3-O-acetylbetulin, 28-O-acetylbetulin, oxidation, "activated" dimethylsulfoxide.
Triterpenes of the lupane group (betulin, lupeol, betulinic acid, and their derivatives) typically have high biological
activity (anti-inflammatory, cholagogic, antiviral, antitumor, immunomodulating, etc.) [1-4]. The high content of betulin (up
to 35%) in white birch and the ease of its isolation [5] make it available for investigations of oxidative transformations of it and
its acetates in order to find new oxidants and to synthesize new biologically active compounds.
An effective reagent for preparing carbonyl compounds by oxidation of alcohols is "activated" DMSO [DMSO in the
presence of dicyclohexylcarbodiimide, (COCl) , (CH CO) O, Ac O, P O , etc.] [6]. We previously found that oxidataion of
2
3
2
2
2 5
betulin and 3-O-acetylbetulin by DMSO activated by oxalylchloride produced betulonic and 3-O-acetylbetulinic aldehydes [7].
In continuation of these studies [7-9], we investigated the oxidation of betulin (1) and its 3-O- (2) and 28-O-acetates
(3) by DMSO activated by acetic anhydride (Albright—Goldman) [10, 11]. It was found that oxidation of 1 by two and
more equivalents of oxidant produces a mixture of the 3-oxo-28-O-methylthiomethyl ether of betulin (4) and
3-O-methylthiomethylbetulin aldehyde (5). Oxidation of 2 by one and more equivalents of oxidant gives in quantitative yield
the 3-O-acetyl-28-O-methylthiomethyl ether of betulin (6). Oxidation of 3 by one and more equivalents of oxidant forms a
mixture of 3-oxo-28-O-acetylbetulin (7) and 3-O-methylthiomethyl-28-O-acetylbetulin (8). It can be seen that ether formation
occurs in addition to oxidative transformations owing to the facile alkylation of the hydroxyl of these triterpene alcohols.
Nevertheless, this reagent can be recommended for synthesizing 3-oxo derivatives owing to the facile reaction and product
separation. Furthermore, 4-6 and 8 were synthesized for the first time and are interesting as potential biologically active
29
compounds.
20
28
CH OR
R
3
2
2
DMSO/CH Cl
2
2
CH Cl
2
2
R
2
3
3
R
1
R
1
1- 3
4 - 8, 12
28
1'
2'
1: R = OH, R = H;
4: R + R = O, R = CH OCH SCH ;
1
2
1
2
3
2
2
3
2: R = AcO, R = H;
1
2
2'
1'
5: R = CH SCH O, R = H, R = CHO;
3: R = OH, R = Ac
1
3
2
2
3
1
2
6: R = OAc, R = H, R = CH OCH SCH ;
1
2
3
2
2
3
7: R + R = O, R = CH OAc;
1
2
3
2
8: R = CH SCH O, R = H, R = CH OAc;
1
3
2
2
3
2
12: R + R = O, R = CHO
1
2
3
Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, 450054, Ufa, pr. Oktyabrya, 71,
fax (3472) 35 60 66, e-mail: obf@anrb.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 156-159, March-April,
2003. Original article submitted March 28, 2003.
0009-3130/03/3902-0207$25.00 ©2003 Plenum Publishing Corporation
207

1
We also studied oxidation of by DMSO activated by (CF CO) O (according to Swern) [12]. Use of two equivalents
3
2
9
of oxidant leads exclusively to acylation of the alcohols to form a mixture of 3,28-di-O-trifluoroacetylbetulin ( ) and 28-O-
10
1
trifluoroacetylbetulin ( ). Also, the hydroxyl of could be oxidized by increasing the number of equivalents to four and
10
lengthening the reaction time to 48 h. This produced a mixture of 28-O-trifluoroacetylbetulin ( ), 3-oxo-28-O-
11 12
trifluoroacetylbetulin ( ), and betulonic aldehyde ( ).
CH OH
CH OCOCF
2 3
2
DMSO/(CF CO )O
3
2
R
2
HO
R
1
1
9 - 11
9: R = CF OCO, R = H;
1
3
2
10: R = OH, R = H;
1
2
11: R + R = O
1
2
The structures of - were established using IR and NMR spectroscopies. Thus, the presence in the 13C NMR of
4 12
signals at δ 13.7-13.9 and 73.3-75.8 ppm provided evidence that the CH SCH group was added. The SCH protons resonated
2
3
3
at δ 2.11-2.14 ppm as sharp singlets. Oxidation was confirmed bysignals for aldehyde (δ 204.9-206.1 ppm, 13C) and 9.64 ppm
13
5
12
4 7 11
12
(PMR) in and and the 3-oxo group (δ 217.6-218.1 ppm C) in , , , and . Signals for the ester bonds in spectra of
9 11
trifluoroacetates - appeared at δ 155-158 ppm. The signals for C-3 and C-28 also shifted to weak field (δ, 86.3 and 66.8-
67.0 ppm, respectively) compared with those in the starting alcohols.
1
Betulin ( ) was found to be stable to oxidation by2-20 equivalents of DMSO activated byP O (according to Onodera)
2
5
[13] with cooling or heating to 60°C.
EXPERIMENTAL
IR spectra were recorded on a Specord M80 spectrometer in mineral oil. 13C NMR and PMR spectra were recorded
on a Bruker AM-300 spectrometer (75.5 and 300 MHz, respectively) in CDCl with SiMe internal standard. Melting points
3
4
were determined on a Boetius microstage. TLC was performed on Silufol plates (Chemapol, Czech Rep.) using CHCl :CH OH
3
3
(25:1). Compounds were developed by phosphotungstic acid in ethanol (10%) with subsequent heating at 100-120°C for
1
2
2-3 min. DMSO was distilled at reduced pressure over freshly calcined CaO. Betulin ( ), 3-O-acetylbutlin ( ), and 28-O-
3
acetylbetulin ( ) were prepared by the literature methods [14, 15]. Elemental analyses of all compounds corresponded to those
calculated.
Oxidation of 1-3 According toAlbright—Goldman.
1 3
A solution of - (1 mmol) in CH Cl (40 mL) was treated with
2
2
DMSO (3 mL) in Ac O (2 mL) (1 equiv. of reagent), stirred for 24-48 h at room temperature (TLC monitoring), treated with
2
EtOH (5 mL), stirred for 1 h, diluted with water (10 mL), and treated with NH OH (5 mL, 15%). The organic layer was
4
separated and dried over MgSO . The solvent was removed in vacuum.
4
3-Oxo-28-O-methylthiomethyletherofbetulin(4)and3-O-methylthiomethylbetulinic aldehyde (5)
wereprepared
byoxidation of byoxidant (2-4 equiv.) and isolation after purification bycolumn chromatographyover Al O (benzeneeluent).
1
2
3
-1
Compound 4
: Yield 0.37 g (73%), R 0.52, mp 174-176°C. C32H52O2S. IR spectrum (ν, cm ): 1710, 1640, 1475, 1395, 1150,
f
1095, 922, 810, 765, 710.
PMR spectrum (δ, ppm, J/Hz): 0.72, 0.90, 0.93, 0.99, 1.05 (s, 5CH ), 1.70 (s, CH -30), 2.14 (s, CH -2′), 2.45-2.55 (m,
3
3
3
2
H-19), 3.50 and 3.98 (d, J = 11, 2H-28), 4.55 and 4.69 (both br. signals, 2H-29), 4.63 and 4.72 (both br. signals, 2H-1 ).
13C NMR spectrum (δ, ppm): 13.9 (C-2′), 14.8, 15.8, 16.0, 16.7, 19.2, 19.5, 21.5, 23.7, 25.7, 26.9, 27.9, 29.9, 30.7,
34.1, 34.4, 36.8, 37.1, 37.8, 38.3, 40.7, 42.5, 46.8, 47.0, 49.3, 49.6, 55.6, 66.2 (C-28), 75.8 (C-1 ), 109.7 (C-29), 150.6 (C-20),
217.9 (C-3).
Compound 5: Yield 0.07 g (14%), R 0.28, mp 194-196°C, C32H52O2S. IRspectrum (ν, cm-1): 1720, 1650, 1465, 1390,
f
1200, 1100, 930, 815, 765, 710.
208

PMR spectrum (δ, ppm): 0.72, 0.91, 0.95, 0.10, 1.04 (s, 5CH ), 1.68 (s, CH -30), 2.11 (s, CH -2 ), 2.48-2.55 (m,
3
3
3
H-19), 3.45-3.53 (m, H-3), 4.57 and 4.70 (both br. signals, 2H-29), 4.64 and 4.68 (both br. signals, 2H-1′), 9.64 (s, H-28).
13C NMR spectrum (δ, ppm): 13.7 (C-2′), 14.5, 15.9, 16.0, 16.8, 19.3, 19.5, 21.0, 25.7, 26.9, 27.9, 29.8, 30.7, 33.4,
34.5, 34.4, 37.0, 37.3, 38.0, 40.7, 42.5, 46.5, 47.2, 47.6, 49.8, 49.6, 55.9, 73.3 (C-1 ), 83.6 (C-3), 109.9 (C-29), 150.6 (C-20),
204.9 (C-28).
3-O-Acetyl-28-O-methylthiomethyl etherofbetulin(6)waspreparedbyoxidation of3-O-acetylbetulin (2) byoxidant
(1-2 equiv.) and recrystallization from ethanol. Yield 0.48 g (88%), R 0.76, mp 185-187°C. C34H56O3S. IR spectrum
f
(ν, cm-1): 1735, 1645, 1485, 1395, 1355, 1150, 1085, 1030, 890, 840, 770, 725, 710.
PMR spectrum (δ, ppm, J/Hz): 0.78, 0.88, 0.90, 0.95, 1.01 (s, 5CH ), 1.72 (s, CH -30), 2.04 (s, OAc), 2.12 (s, CH -2′),
3
3
3
2
2.40-2.50 (m, H-19), 3.52 and 4.00 (d, J = 11, 2H-28), 4.41-4.47 (m, H-3), 4.50 and 4.60 (both br. signals, 2H-29), 4.66 and
4.70 (both br. signals, 2H-1′).
13C NMR spectrum (δ, ppm): 13.9 (C-2′), 14.5, 15.8, 16.2, 16.7, 19.2, 19.5, 21.3, 21.5, 23.7, 25.7, 26.9, 27.9, 29.9,
30.7, 34.1, 34.6, 36.8, 37.1, 37.8, 38.3, 40.7, 42.5, 46.8, 47.0, 49.3, 49.6, 55.6, 66.2 (C-28), 75.7 (C-1′), 80.9 (C-3), 109.7
(C-29), 150.6 (C-20), 170.9 (CH COO).
3
3-Oxo-28-O-acetylbetulin (7) and 3-O-methylthiomethyl-28-O-acetylbetulin (8) were prepared by oxidation of 3
by oxidant (1-2 equiv.) and isolation after purification by column chromatography over Al O (benzene eluent).
2
3
Compound 7: Yield 0.33 g (69%), R 0.88, mp 117 C. Lit. [16] mp 117-119°C. C32H50O3. IR spectrum (ν, cm-1):
f
1740, 1710, 1650, 1465, 1390, 1345, 1095, 930, 815, 765, 710.
PMR spectrum (δ, ppm, J/Hz): 0.84, 0.86, 0.93, 0.97, 1.02 (s, 5CH ), 1.70 (s, CH -30), 2.00 (s, OAc), 2.35-2.45 (m,
3
3
2
H-19), 3.83 and 4.21 (d, J = 11, 2H-28), 4.54 and 4.70 (both br. signals, 2H-29).
13C NMR spectrum (δ, ppm): 14.0, 15.9, 16.2, 16.5, 19.3, 19.9, 21.0, 21.2, 25.7, 26.9, 27.0, 29.5, 29.6, 33.4, 34.1, 34.5,
37.0, 37.6, 39.5, 40.7, 42.5, 46.5, 47.2, 47.6, 48.6, 49.6, 54.9, 62.9 (C-28), 109.9 (C-29), 150.6 (C-20), 171.1 (CH COO), 218.1
3
(C-3).
Compound 8: Yield 0.10 g (18%), R 0.50, mp 180-182°C. C34H56O3S. IR spectrum (ν, cm-1): 1720, 1640, 1483,
f
1391, 1350, 1205, 1080, 1032, 895, 836, 725, 710.
PMR spectrum (δ, ppm, J/Hz): 0.72, 0.93, 0.95, 1.00, 1.01 (s, 5CH ), 1.68 (s, CH -30), 2.01 (s, OAc), 2.14 (s, CH -2′),
3
3
3
2
2.50-2.62 (m, H-19), 3.82 and 4.24 (d, J = 10.9, 2H-28), 3.48-3.55 (m, H-3), 4.63 and 4.73 (both br. signals, 2H-29), 4.65 and
4.69 (both br. signals, H-1′).
13C NMR spectrum (δ, ppm): 13.7 (C-2 ), 14.5, 16.0, 16.5, 16.8, 19.9, 20.1, 20.5, 21.0, 23.4, 25.0, 26.1, 27.8, 29.9,
30.7, 33.8, 34.9, 37.0, 37.8, 37.9, 38.0, 40.7, 41.5, 46.4, 47.2, 49.8, 49.9, 55.9, 62.9 (C-28), 73.5 (C-1′), 83.1 (C-3), 109.9
(C-29), 150.0 (C-20), 171.9 (CH COO).
3
Oxidation of 1 According to Swern. A solution of DMSO (1.98 mL) in CH Cl (14 mL) at -30°C under Ar was
2
2
treated dropwise with (CH CO) O (0.40 mL, 2 equiv.), stirred for 10 min, and treated dropwise with 1 (0.44 g, 1 mmol) in
3
2
CH Cl (50 mL). The reaction mixture was stirred at -30 C for 5 h (TLC monitoring), treated with Et N (0.93 mL), and stirred
2
2
3
for 1.5 h. The temperature was adjusted to 5°C before adding HCl (21 mL, 2 M) and extracting with CH Cl (2×15 mL). The
2
2
organic layers were combined, washed with water (2×25 mL), dried over MgSO , evaporated in vacuum, and chromatographed
4
over a column of Al O (CH Cl eluent).
2
3
2
2
3,28-Di-O-trifluoroacetylbetulin(9)and28-O-trifluoroacetylbetulin(10)wereprepared byoxidation of1byoxidant
(2 equiv.).
Compound 9: Yield 0.44 g (71%), R 0.74, mp 210-212°C. C34H48O4F6. IR spectrum (ν, cm-1): 1735, 1720, 1635,
f
1483, 1392, 1360, 1200, 1185, 1085, 1030, 1010, 890, 840, 770, 725, 715.
PMR spectrum (δ, ppm, J/Hz): 0.86, 0.89, 0.93, 0.97, 1.01 (s, 5CH ), 1.72 (s, CH -30), 2.40-2.50 (m, H-19), 4.90 and
3
3
5.10 (d, J = 11.0, 2H-28), 4.65-4.70 (m, H-3), 4.63 and 4.75 (both br. signals, 2H-29).
13C NMR spectrum (δ, ppm): 14.0, 15.9, 16.2, 16.5, 18.3, 19.1, 21.8, 23.3, 25.1, 26.9, 27.9, 29.4, 30.7, 34.0, 34.2, 37.0,
37.8, 38.0, 38.2, 40.7, 42.5, 46.5, 47.2, 48.8, 49.9, 55.9, 66.9 (C-28), 86.3 (C-3), 109.9 (C-29), 112.8 and 116.4 (CF ), 150.6
3
(C-20), 155.1 and 158.0 (CF COO).
3
Compound 10. Yield 0.13 g (24%), R 0.42, mp 192-194°C. C32H49O3F3. IR spectrum (ν, cm-1): 3480, 1720, 1643,
f
1475, 1395, 1355, 1200, 1085, 1030, 890, 840, 770, 725, 710.
PMR spectrum (δ, ppm, J/Hz): 0.90, 0.92, 0.94, 0.97, 1.04 (s, 5CH ), 1.72 (s, CH -30), 2.50-2.60 (m, H-19), 3.15-3.20
3
3
2
(m, H-3), 4.95 and 5.15 (d, J = 10.9, 2H-28), 4.64 and 4.72 (both br. signals, 2H-29).
209

13C NMR spectrum (δ, ppm): 14.3, 15.4, 16.0, 16.5, 19.1, 19.8, 21.3, 23.9, 25.3, 26.3, 27.9, 30.0, 30.7, 34.3, 34.9, 37.2,
37.3, 37.5, 38.1, 40.7, 41.4, 46.3, 47.3, 49.8, 49.9, 55.9, 67.0 (C-28), 78.3 (C-3), 109.0 (C-29), 116.8 (CF ), 150.0 (C-20), 155.5
3
(CF COO).
3
28-O-Trifluoroacetylbetulin (10), 3-oxo-28-O-trifluoroacetylbetulin (11), and betulinic aldehyde (12) were
prepared by oxidation of 1 by oxidant (4 equiv.) for 4 h.
Compound 10. Yield 0.11 g (21%).
Compound 11. Yield 0.26 g (49%), R 0.56, mp 167-169°C. C32H47O3F3. IR spectrum (ν, cm-1): 1720, 1710, 1638,
f
1472, 1400, 1352, 1202, 1092, 1028, 895, 832, 770, 725, 715.
PMR spectrum (δ, ppm, J/Hz): 0.92, 0.96, 0.97, 0.99, 1.02 (s, 5CH ), 1.70 (s, CH -30), 2.48-2.60 (m, H-19), 4.86 and
3
3
2
5.10 (d, J = 11, 2H-28), 4.65 and 4.75 (both br. signals, 2H-29).
13C NMR spectrum (δ, ppm): 14.5, 15.6, 16.2, 16.5, 19.3, 19.9, 21.2, 23.9, 25.7, 26.5, 27.7, 30.0, 30.5, 34.5, 34.9, 37.0,
37.5, 37.5, 38.0, 40.4, 41.1, 46.5, 47.2, 49.6, 49.8, 55.8, 66.8 (C-28), 109.6 (C-29), 117.0 (CF ), 151.1 (C-20), 154.8
3
(CF COO), 218.3 (C-3).
3
Compound 12. Yield 0.09 g (20%), mp 163°C, lit. [7] mp 163-164°C.
PMR and 13C NMR spectra were analogous to those reported previously [7].
Oxidation of 1 According to Onodera. A solution of 1 (0.44 g, 1 mmol) in CH Cl (50 mL) under Ar at 0°C was
2
2
treated with DMSO (0.15 mL) and P O (0.29 g, 2 equiv.), stirred for 2 h (TLC monitoring) at room temperature or with heating
2
5
with a reflux condenser at 60°C for 3 h, treated dropwise with Et N (0.50 mL), stirred for 30 min, treated with HCl (20 mL,
3
10%), and extracted with CH Cl (2×15 mL). The organic layers were combined, washed with saturated NaCl solution (25 mL)
2
2
and water (2×25 mL), dried over MgSO , and evaporated in vacuum. The reaction was also carried out with 5, 10, and 20
4
equiv. of reagent. The physicochemical properties and spectral data of the isolated product corresponded to those of starting
betulin [5, 17].
ACKNOWLEDGMENT
The work was supported by the Russian Foundation for Basic Research (project Nos. 01-03-33131 and 02-03-81007).
REFERENCES
1.
2.
T. Fujioka, Y. Kashiwada, R. E. Kilkuskie, L. M. Cosentino, L. M. Ballas, J. B. Jiang, W. P. Janzen, I. S. Chen,
and K. H. Lee, J. Nat. Prod., 57, 243 (1994).
E. Pisha, H. Chai, I. S. Lee, T. E. Chagwedera, N. R. Farnsworth, G. A. Cordell, C. W. W. Beecher, H. H. S. Fong,
A. D. Kinghorn, D. M. Brown, M. C. Wani, M. E. Wall, T. J. Hieken, T. K. Das Gupta, and J. M. Pezzuto, Nat.
Med., 1, 1046 (1985).
3.
4.
M. C. Recio, R. M. Giner, S. Manez, and J. L. Rios, Planta Med., 61, 9 (1995).
O. B. Flekhter, L. T. Karachurina, L. R. Nigmatullina, T. A. Sapozhnikova, L. A. Baltina, F. S. Zarudii, F. Z.
Galin, L. V. Spirikhin, G. A. Tolstikov, O. A. Plyasunova, and A. G. Pokrovskii, Bioorg. Khim., 28, 6, 543 (2002).
P. Jaaskelainen, Pap. Puu, 63, No. 10, 599 (1981).
5.
6.
7.
T. T. Tidwell, Synthesis, 857 (1990).
O. B. Flekhter, O. Yu. Ashavina, E. I. Boreko, L. T. Karachurina, N. I. Pavlova, N. N. Kabal′nova,
O. V. Savinova, F. Z. Galin, S. N. Nikolaeva, F. S. Zarudii, L. A. Baltina, and G. A. Tolstikov,Khim-Farm. Zh.,
36, 6, 21 (2002).
8.
O. Yu. Ashavina, O. B. Flekhter, N. N. Kabal′nova, E. V. Ivanova, F. Z. Galin, and G. A. Tolstikov, in: Materials
of the Young Scientists Scientific Educational Conference "Current Problems in Organic Chemistry," Novosibirsk,
April 2-6, 2001, 52.
9.
O. Yu. Ashavina, N. N. Kabal′nova, S. A. Grabovskii, O. B. Flekhter, F. Z. Galin, and G. A. Tolstikov, in:
Materials of the VIth International Conference "Bioantioxidant," Moscow, April 16-19, 2002, 47.
J. D. Albright and L. Goldman, J. Am. Chem. Soc., 87, 4214 (1963).
10.
210

11.
12.
13.
14.
J. D. Albright and L. Goldman, J. Am. Chem. Soc., 89, 2416 (1967).
C. M. Amon, M. G. Banwell, and G. L. Gravatt, J. Org. Chem., 52, 4851 (1987).
D. F. Taber, J. C. Amedio, and K.-Y. Jung, J. Org. Chem., 52, 24, 5621 (1987).
O. B. Flekhter, L. T. Karachurina, V. V. Poroikov, L. R. Nigmatullina, L. A. Baltina, F. S. Zarudii,
V. A. Davydova, L. V. Spirikhin, I. P. Baikova, F. Z. Galin, and G. A. Tolstikov, Bioorg. Khim., 26, 3,
215 (2000).
15.
16.
17.
L. F. Tietze, H. Heinzen, P. Moyna, M. Rischer, and H. Neunaber, Leibigs Ann. Chem. 1245 (1991).
A. V. Korovin and A. V. Tkachev, Izv. Akad. Nauk, Ser. Khim., 2, 292 (2001).
J. S. Alves, J. C. M. de Castro, M. O. Friere, E. V. Leitao da-Cunha, J. M. Baebosa-Filho, and M. S. de Silva,
Magn. Reson. Chem., 38, 201 (2000).
211