Synthesis of Lupeol from Betulin

Full text of DOI:10.1007/s10600-019-02805-5

DOI 10.1007/s10600-019-02805-5
Chemistry of Natural Compounds, Vol. 55, No. 4, July, 2019
SYNTHESIS OF LUPEOL FROM BETULIN
*
L. R. Garifullina, Yu. V. Myasoedova,
and N. M. Ishmuratova
Lupeol (1) is a pentacyclic lupane-type triterpenoid that exhibits important pharmacological properties, e.g.,
antiangiogenic, antimicrobial, antiproliferative, anti-inflammatory, and cholesterol-lowering. It has demonstrated high
pharmacological potential in in vitro and in vivo studies for treating inflammations, arthritis, diabetes, and cardiological and
oncological diseases [1, 2]. Therefore, the goal of the work was to develop a modified synthetic scheme for lupeol.
30
29
20 19
18
13
22
11
OH
OTr
25
26
1
28
c
a
10
8
15
27
4
HO
RO
6
3, 4
2
23
24
3: R = H
4: R = Ac
b
R
e
HO
AcO
5, 6
1
5: R = OH
6: R = O
d
a. TrCl, Py, DMAP, Δ, 76%; b. AcCl, Py, 98%; c. FeCl , THF, Δ, 70%; d. PCC, CH Cl , 90%; e. 1. N H ⋅H O, 2. KOH, 65%
3
2
2
2
4
2
Lupeol (1) is widely distributed in plant sources [3–9]. Birch bark contains various quantities of 1 (up to 10%)
[10–12], which is extracted and then purified by chromatography or recrystallization [13, 14]. Birch bark contains the triterpenoid
betulin (2) in significantly larger quantities (up to 40% [10]) than 1. The structure of 2 differs from 1 only by an additional OH
group on C-28 so that 2 can be used as an available substrate for its synthesis [2, 15].
A key intermediate in preparation of 1 from 2 is 3-acetyl-28-formylbetulin. Synthetic approaches to preparing it use
various methods to protect the C-3 OH group. A scheme based on sequential regioselective protection of the OH groups is
proposed by us; first, primary OH by refluxing 2 in DMF with trityl chloride in the presence of DMAP; then, acylation by
AcCl–Py. Selective removal of the trityl protection by refluxing 4 with FeCl in THF gave monoacetate 5 in 70% yield.
3
Subsequent transformations for preparing target 1 included oxidation by pyridinium chlorochromate (PCC) of 5 and
Wolff–Kishner reduction of the resulting aldehyde. The overall yield of 1 calculated for 2 was 30.5%.
13
28-O-Tritylbetulin (3) was prepared by the literature method and had identical PMR and C NMR spectra [16].
Ufa Institute of Chemistry, Subdivision of Ufa Federal Research Centre, Russian Academy of Sciences, 71 Prosp.
Oktyabrya, Ufa, 450054, e-mail: legostaevayuv@yandex.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 4,
July–August, 2019, pp. 654–655. Original article submitted December 19, 2018.
©
0009-3130/19/5504-0765 2019 Springer Science+Business Media, LLC
765

3-O-Acetyl-28-O-tritylbetulin (4). A solution of 3 (9.25 g, 13.5 mmol) in anhydrous Py (40 mL) was cooled to 0°C,
treated with AcCl (5.3 g, 67.4 mmol), stirred at room temperature for 48 h, and treated with CHCl (100 mL). The extract was
3
washed with HCl solution (5%, 3 × 50 mL) and saturated NaCl solution, dried over MgSO , and evaporated to afford
4
20
a resinous mixture (11.3 g) that was chromatographed (Al O , petroleum ether) to afford 4 (9.6 g, 98%). Ñ H O , [α] +5°
(ñ 1.35, ÑÍ Cl ). Í NMR spectrum (500 MHz, ÑDCl , δ, ppm, J/Hz): 0.56 (3H, s, CH -26), 0.75 (3H, s, CH -25), 0.77 (3H,
2
3
51 66
3
D
1
2
2
3
3
3
s, CH -24), 0.91 (3H, s, CH -27), 0.95 (3H, s, CH -23), 1.10–1.65 (20Í, m, Í-1, 2, 5, 6, 7, 9, 11, 12, 13, 15, 16, 18), 1.71 (3H,
3
3
3
s, CH -29), 2.04 (3Í, s, ÑÍ -32), 2.15–2.24 (4H, m, H-21, 22), 2.37–2.42 (1Í, m, Í-19), 3.02 (1H, d, J = 8.6, H-28),
3
3
3.15–3.20 (2H, m, H-28, 3), 4.54, 4.61 (1H each, br.s, H-30), 7.25 (3H, t, J = 7.2, H-4′), 7.31 (6H, t, J = 7.8, 7.4, H-3′, 5′), 7.50
13
(6H, d, J = 7.8, H-2′, 6′). C NMR spectrum (125 MHz, CDCl , δ, ppm): 38.73 (ÑÍ , C-1), 23.71 (ÑÍ , C-2), 80.99 (ÑÍ,
3
2
2
C-3), 38.73 (Ñ, C-4), 55.31 (ÑÍ, C-5), 18.20 (ÑÍ , C-6), 34.17 (ÑÍ , C-7), 40.62 (Ñ, C-8), 50.31 (ÑÍ, C-9), 37.16 (Ñ, C-10),
2
2
20.73 (ÑÍ , C-11), 25.17 (ÑÍ , C-12), 37.30 (ÑÍ, C-13), 42.48 (Ñ, C-14), 27.05 (ÑÍ , C-15), 30.14 (ÑÍ , C-16), 47.58 (Ñ,
2
2
2
2
C-17), 48.87 (ÑÍ, C-18), 47.82 (ÑÍ, C-19), 150.47 (Ñ, C-20), 29.89 (ÑÍ , C-21), 35.21 (ÑÍ , C-22), 27.96 (ÑÍ , C-23),
2
2
3
15.31 (ÑÍ , C-24), 16.20 (ÑÍ , C-25), 16.00 (ÑÍ , C-26), 14.74 (ÑÍ , C-27), 60.54 (ÑÍ , C-28), 20.86 (ÑÍ , C-29), 109.76
3
3
3
3
2
3
(ÑÍ , C-30), 171.13 (Ñ, Ñ-31), 21.35 (ÑÍ , Ñ-32), 85.83 (Ñ, Ñ-33), 144.50 (Ñ, C-1′), 127.73 (ÑÍ, C-2′, 6′), 128.79 (ÑÍ,
2
3
C-3′, 5′), 126.82 (ÑÍ, C-4′).
3-O-Acetylbetulin (5). A solution of 4 (9.6 g, 13.2 mmol) in THF (50 mL) was treated with anhydrous FeCl
3
(8.55 g, 52.8 mmol), refluxed for 48 h, and cooled to room temperature. The solvent was removed in vacuo. The residue was
diluted with CHCl , washed with H O and NaCl solution, dried over MgSO , filtered, and evaporated. Column chromatography
3
2
4
13
(SiO , petroleum ether–EtOAc, 2:1) afforded 5 (4.5 g, 70%), the PMR and C NMR spectra of which were identical to those
in the literature [15], mp 237–239°C (lit. mp 238–240°C [17]), [α] +21° (c 0.71, CH Cl ).
2
20
D
2
2
3-Acetylbetulinaldehyde (6). A solution of 5 (4.5 g, 9.3 mmol) in CH Cl (100 mL) was treated with PCC, stirred
2
2
at room temperature until the reaction was finished (TLC monitoring), treated with Et O (100 mL), stirred for another 30 min,
2
13
filtered through a thin layer of Al O on a Schott filter, and evaporated to afford 6 (4.0 g, 90%), the PMR and C NMR spectra
of which were identical to those in the literature [15], mp 177–179°C (lit. mp 173–175°C [18]), [α] +25° (c 0.62, CH Cl ).
2
3
20
D
2
2
Lupeol (1). A mixture of 6 (3.8 g, 7.89 mmol), KOH (6.55 g, 117 mmol), and hydrazine hydrate (80%, 5.7 mL,
94 mmol) in diethylene glycol was refluxed for 6 h (TLC monitoring), cooled, evaporated in vacuo, and extracted with EtOAc.
The extract was washed with H O (3 × 50 mL) and dried over MgSO . Column chromatography (SiO , petroleum
2
4
2
20
ether–EtOAc, 15:1) afforded 1 (2.17 g, 65%), R 0.48 (CH Cl –EtOAc, 40:1), mp 202–204°C, [α] +13° (c 2.71, CH Cl ).
The PMR and C NMR spectra were identical to those in the literature [2].
f
2
2
D
2
2
13
ACKNOWLEDGMENT
The work used equipment at the Khimiya CUC, UfIC, UFRC, RAS. The work was financially supported by Russian
Foundation for Basic Research Grant 17-03-01050 A.
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