Selective oxidation of betulin by Cr(VI) reagents

Article abstract of DOI:10.1023/A:1015733832373

Oxidation of betulin by pyridinium dichromate, pyridinium chlorochromate, and K₂Cr₂O₇ - H₂SO₄ in the presence of tetrabutylammonium bromide was studied. Products of regioselective C-3, C-28-, and exha

Full text of DOI:10.1023/A:1015733832373

Chemistry of Natural Compounds, Vol. 38, No. 1, 2002
SELECTIVE OXIDATION OF BETULIN BY Cr(VI) REAGENTS
UDC 547.992+547.943:543.766
N. G. Komissarova, N. G. Belenkova, L. V. Spirikhin,
O. V. Shitikova, and M. S. Yunusov
Oxidation of betulin by pyridinium dichromate, pyridinium chlorochromate, and K Cr O —H SO in the
2
2
7
2
4
presence of tetrabutylammonium bromide was studied. Products of regioselective C-3, C-28-, and exhaustive
β
oxidation, 28-hydroxylup-20(29)-3-one, 3 -hydroxy- and 3-oxolup-20(29)-en-28-al were obtained.
betulin, selective oxidation, pyridinium chlorochromate, pyridinium dichromate, potassium bichromate,
Key words:
synthesis, 28-hydroxylup-20(29)-3-one, 3
β-hydroxylup-20(29)-en-28-one, 3-oxolup-20(29)-en-28-al.
The high content of betulin (1) in birch bark (up to 40%) and its exceedingly simple extraction [1] have stimulated
research on its use as starting material for synthesizing biologically active compounds.
We studied the selective oxidation and developed convenient methods for synthesizing functionalized derivatives of
1 that are difficultly accessible because of their low content in the plant material.
Betulin contains primary and secondary hydroxyls that are situated in different steric environments and should have
fundamentally different reactivities. However, until now data on their different behavior toward oxidants have not appeared
[2, 3]. It has only been stated [4] that oxidation of 1 by pyridinium dichromate (PDC) in aqueous DMF and in CH Cl leads
2
2
to a complicated mixture of hydroxyaldehyde 2, ketoaldehyde 3, betulinic and betulonic acids in the first instance and to
ketoaldehyde 3 in 85% yield in the second. Either the traditional approach of manipulation by hydroxyl protecting groups [5]
or exhaustive oxidation to betulonic acid by Jones reagent [3] or CrO in AcOH [2] with subsequent reduction of the 3-ketone
3
by NaBH are used to prepare betulinic acid from 1.
4
O
2
3
+
+
O
H
4
2
OH
O
H
2
3
+
O
HO
1
3
We tested several reagents based on Cr(VI), i.e., pyridinium dichromate (PDC) [6], pyridinium chlorochromate (PCC)
[7], and K Cr O in H SO (9 M) in the presence of tetrabutylammonium bromide (TBAB) [8]. We noted the effect of the type
2
2
7
2
4
of oxidant, solvent, and mole ratio of reactants on the selectivity of the process. It has been found that the reaction of 1 and PDC
(2 equivalents) in benzene occurs regioselectively with oxidation of the primary C-28 OH.
Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, 450054, Ufa, pr. Oktyabrya 71,
fax (3472) 35 60 66, e-mail: msyunusov@anrb.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 46-49, January-
February, 2002. Original article submitted January 2, 2002.
0009-3130/02/3801-0058$27.00 ©2002 Plenum Publishing Corporation
58

TABLE 1. Oxidation of Betulin ( ) by Cr(VI) Reagents
1
Product (yield, %),
Reagent
PDC
Solvent
Ratio 1:reagent, mol
Time*
1 conversion, %
C6H6
1:2
3 h
2 (68), 50
2 (86), 37
3 (4)
CHCl3
1:1.5
1h 15 min
PCC
CH2Cl2
C6H6
1:1.5
1:2
45 min
3 h
2 (74)**, 50
2 (62), 58
3 (23)
K2CrO7—9M H2SO4—TBAB
CH2Cl2
C6H6
1:6
45 min
12 h
3 (85), 100
2 (37), 70
3 (8)
1:1.05
4 (12)
CHCl3
1:1.5
2.5 h
2 (60), 50
3 (13)
______
*Reaction monitored by TLC with benzene—EA (5:1) eluent.
**Isolated as oxime of
2.
Incomplete conversion of the starting material under strictly controlled conditions (Table 1) produced hydroxyaldehyde
(68%). In CHCl , another minor ketoaldehyde was isolated in addition to . The : ratio was ~20:1. The product obtained
2
3
2
2 3
3
in CH Cl was boiled without purification with NH OH·HCl—Py in EtOH to give the oxime of
(
) in 74% yield calculated
2 2a
2
2
2
for reacted . The reaction of and PCC (2 equiv.) in benzene produced after 3 h a mixture of and . The effect of PCC
1
1
2
3
(6 equiv.) in CH Cl gave after 45 min the product of exhaustive oxidation, ketoaldehyde . Thus, using benzene, in which the
3
2
2
reaction is much slower than in CHCl or CH Cl , increases the selectivity. Oxidation of under phase-transfer conditions in
1
3
2
2
benzene or CHCl by K Cr O (1.05-1.5 equiv.) in H SO (9 M) can stop the reaction at the C-28 aldehyde stage, in contrast
3
2
2
7
2
4
with the effect of Na Cr O —H SO [9], which forms betulonic acid. The product of oxidation of the secondary hydroxyl
2
2
7
2
4
without affecting the primary one, ketoalcohol , was observed along with and in benzene.
4
2
3
The structures of the products were confirmed by 1H and 13C NMR spectra (Table 2). Two-dimensional heteronuclear
correlation of direct spin—spin coupling constants enabled a determination of the chemical shifts of H atoms and their
assignment to the corresponding C atoms and confirmed the chair conformation for rings A, B, C, and D in - .
2 4
CHO
CH
3
CH
3
CH
3
HO
CH
3
CH
3
H
Thus, we have developed a convenient route for synthesizing previously difficultly accessible derivatives of with
1
aldehyde and ketone groups that possess biological activity [10] and are interesting as intermediates in the synthesis of natural
compounds.
59

TABLE 2. 13C and 1H Chemical Shifts of 2-4
2
2a
3
4
Ci
δC
δH
δC
δH
δC
δH
δC
δH
1
2
3
38.73
27.39
78.99
0.90, 1.68
1.60
3.20 dd,
J 11.0, 5.3
38.93
27.46
79.07
0.90,1.83
39.57
34.08
218.04
1.43, 1.80
2.45
39.76
34.08
218.38
1.48, 1.89
2.43
3.20 dd,
J 11.0, 5.3
4
5
38.85
55.31
38.79
55.38
47.28
54.87
47.52
55.07
0.68 d,
J 10.0
0.72 d,
J 10.0
1.31
1.33
6
7
8
18.26
34.33
40.82
50.40
37.17
20.74
25.53
38.69
1.42, 1.55
1.37
18.37
34.38
40.97
50.47
37.09
20.87
25.29
38.66
1.36, 1.52
1.40
19.55
33.55
40.69
49.75
36.82
21.20
25.45
38.67
1.45
1.40
19.83
34.13
41.02
49.90
37.01
21.51
25.36
37.57
1.49
1.46
9
1.27
1.24
1.36
1.33
10
11
12
13
1.40, He
1.05, 1.76
2.02 ddd,
1.42, He
1.07, 1.70
1.83
1.40, He
1.05, 1.77
2.02 ddd,
1.10, 1.42
1.00, Ha
1.68
J 12.2, 12.2, 3.7
J 12.2, 12.2, 3.7
14
15
16
42.55
28.80
29.25
42.43
27.95
32.48
42.54
28.73
29.06
42.93
27.20
29.88
1.20, 1.42
1.46, He
1.15, 1.82
1.45, 1.98
1.20, 1.47
1.42
1.20, 1.73
1.50
2.05 dd, J 11.0, 2.9
2.05 dd, J 11.0,
2.9
1.75
2.90 ddd,
J 11.0, 11.0, 5.6
17
18
19
59.31
47.52
48.06
49.84
49.44
47.96
59.26
47.42
47.86
47.93
48.83
49.90
1.75
2.88 ddd,
J 11.0, 11.6, 5.6
1.64
2.55 ddd,
J 11.0, 11.0, 5.4
1.60
2.44
20
21
22
23
24
25
26
27
28
29
30
149.72
29.89
33.22
27.97
15.33
15.89
16.13
14.26
206.67
18.99
110.15
149.89
29.82
37.24
28.07
15.44
16.13
16.13
14.82
155.69
19.26
110.11
149.59
29.77
33.10
26.54
20.97
15.64
15.94
14.12
206.49
18.94
110.19
150.55
29.27
33.67
26.79
21.27
15.26
16.13
14.86
60.67
19.26
109.94
1.54, 1.87
1.33, He
0.97 s
0.75 s
0.92
0.83 s
0.98 s
9.7 d, J 1.5
1.7 s
4.65 d, J 2.0
4.78 s
1.50, 1.95, He
1.50, 1.84
1.37, 1.75
1.07 s
1.00 s
0.94 s
0.92 s
0.98 s
9.7 d, J 1.4
1.7 s
4.62 s
1.23, 1.92
1.81, He
1.10
1.03 s
1.07 s
0.95 s
1.00 s
3.35 d, J 10.0
1.7 s
0.99 s
0.77 s
0.98 s
0.83 s
0.99 s
7.52 s
1.70 s
4.60 s
4.70 s
7.70 br s
4.6 s
4.73 s
4.75 s
N-OH
EXPERIMENTAL
IR spectra were recorded on a Specord-M80 spectrophotometer in vaseline oil. 1H and 13C NMR spectra were recorded
at room temperature in a Bruker-AM-300 spectrometer at working frequencies 300 and 75 MHz, respectively, in CDCl without
3
a standard. Chemical shifts are given in ppm relative to the solvent signal at 7.27 (δ ) and 77.1 (δ ). The multiplicity of the
H
C
13C signals was found from 13C spectra with C–H decoupling. Heteronuclear 2D spectra were obtained by the standard C–H
correlation technique using direct spin—spin coupling constants (J = 140 Hz). Rotation angles were measured on a
Perkin—Elmer 141 instrument. Mass spectra were measured using direct sample introduction into the ion source of Varian
MAT CH-5 (2) and MX-1320 mass spectrometers.
TLC used Sorbfil (Russia) plates. Column chromatography was performed over Al O (Brockman neutral) or SiO .
2
3
2
Melting points were determined on a Kofler block. Anhydrous solvents were prepared by standard methods [11]. Acetone was
60

distilled over KMnO . Compound 1 was extracted from birch bark by the literature method [12] and recrystallized from
4
ethylacetate, mp 258-260 C, [α]D25 +20 (c 2, Py) {lit. mp 256-257°C, [α]D25 +19° (c 2, Py)} [13].
Oxidation of 1 by PCC and PDC. A solution of 1 (0.226 mmole) in the appropriate anhydrous solvent (12 mL) was
poured under a N atmosphere at room temperature into stirred suspension of the corresponding number of millimoles of PDC
2
or PCC in the same solvent (5 mL). When the reaction was finished, the mixture was diluted with absolute ether (12 mL),
stirred for 10 min, and filtered through a thin layer of Al O . The solvent was evaporated. The solid was chromatographed
2
3
over Al O (petroleum ether—ethylacetate, 5:1). Depending on the reaction conditions, 2 and unreacted 1 or 2 and 3 were
2
3
isolated. The solvent, reagent ratio, and yields of the products are listed in Table 1.
Compound 2. Mp 170-173°C, [α]D25 (c 8.7, C H ) {lit. mp 190-193°C (subl.), [α]D25 +19° (c 1.06, CHCl ) [14]}.
6
6
3
-1
+
+
IR spectrum (ν, cm ): 870, 1660, 1705, 2700, 3600. Mass spectrum (EI, 70 eV), m/z (Irel, %): 440 [M ] (20), 425 [M - CH ]
(3), 422 [M - H O] (7), 407 [M - CH - H O] (4), 412 [M - CO] (14), 411 [M - CHO] (10), 232 [C16H24O] (9), 207
3
+
+
+
+
2
3
2
+
+
+
+
[C14H23O] (30), 189 [C14H21] (34), 43 [C H O + C H ] (100), 41 [C H ] (84).
2
3
3
7
3 5
Compound 3. Mp 121-123°C, [α]D25 +53.8° (c 1.77, CHCl ) (lit. [15]). IR spectrum (ν, cm-1): 870, 1645, 1705, 1730,
3
2700, 3600.
3β-Hydroxylup-20(29)-en-28-al Oxime (2a). Compound 1 (0.226 mmole) and PDC (0.128 g, 0.339 mmole) in
absolute CH Cl (10 mL) were stirred at room temperature under an N atmosphere for 25 min and diluted with absolute ether
2
2
2
(3 mL). The reaction mixture was filtered through a thin layer of SiO . The filtrate was evaporated. The solid was dissolved
2
in absolute EtOH (1.3 mL), treated with absolute pyridine (0.5 mL) and NH OH·HCl (0.15 g, 2.16 mmole), and boiled for
2
15 h. The solvent was evaporated. The solid was chromatographed over SiO with elution by benzene—t-butylmethylether (5:1)
2
to give 1 (0.045 g) and 2a (0.043 g, 74%), mp 188-190°C, [α]D25 +6° (c 8.0, C H ). IR spectrum (ν, cm-1): 870, 1645, 1660,
6
6
+
+
+
1705, 2700, 3600. Mass spectrum (EI, 70 eV, 50-100°C), m/z (Irel, %): 455 [M] (12), 438 [M - OH] (14), 207 [C14H23O]
(25), 189 [C14H21] (46), 107 [C8H13] (58), 81 (50), 43 [C2H3O] , [C3H7] , [CNOH] , (100), 41 (92).
+
+
+
+
+
Phase-Transfer Oxidation of 1 by K2Cr2O7. A solution of 1 (0.10 g, 0.226 mmole) in the appropriate solvent
(20 mL) containing TBAB (6.4 mg, 0.0226 mmole) was stirred vigorously and treated with the corresponding amount of
K Cr O (Table 1) in H SO (9 M, 0.57 mL). After the reaction was finished (TLC monitoring), the mixture was treated with
2
2
7
2
4
FeSO (10 mL, 10%). The organic layer was separated, washed with NaOH (10 mL, 10%), dried over Na SO , and evaporated.
4
2
4
The solid was chromatographed over Al O (petroleum ether—ethylacetate, 5:1). Depending on the reaction conditions, 1, 2,
2
3
3, 4 or 1, 2, 3 were isolated (Table 1).
28-Hydroxylup-20(29)-en-3-one (4). Amorphous solid, [α]D25 +17.8° (c 1.52, CH Cl ). IR spectrum ( , cm-1): 870,
2
2
164, 1740, 3600.
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