Synthesis of Betulonic and Betulinic Acids from Betulin

Full text of DOI:10.1007/s10600-018-2479-8

DOI 10.1007/s10600-018-2479-8
Chemistry of Natural Compounds, Vol. 54, No. 4, July, 2018
SYNTHESIS OF BETULONIC AND BETULINIC
ACIDS FROM BETULIN
*
M. P. Yakovleva, V. A. Vydrina, R. R. Sayakhov,
and G. Yu. Ishmuratov
Lupane-type triterpenes are common secondary metabolites of many plant products [1]. Betulonic acid exhibits
antiviral, antitumor, antimicrobial, hepatoprotective, immunostimulating, and other useful properties. Betulinic acid gave
positive results in medico-biological tests, especially experiments studying the cytotoxicity against oncologically transformed cells [1].
Several synthetic approaches to the syntheses of these pharmacologically important compounds start with betulin (1),
which is isolated from Betula pendula bark.
Betulinic acid is prepared from betulonic acid via hydride reduction in 99% yield and up to 97:3 selectivity for the
3
ꢀ/3ꢁ-OH epimers [2–7]. The proposed reduction methods have several drawbacks. First, toxic benzene and MeOH in
addition to boron compounds that are hazardous for humans are used in many instances. Second, a large excess of NaBH4
up to 8-fold) is always required for the reduction. Third, recrystallization from EtOH or MeOH is necessary to isolate the
(
active 3ꢀ-epimer. Aluminum hydrides, in particular diisobutylaluminum hydride (DIBAH), have not been used to reduce
betulonic acid.
Greater than 30 publications on the preparation of betulonic acid in yields from 44 to 97% via oxidation of betulin by
Jones reagent are known. The main drawback is the use of toxic Cr salts [7–9]. Two-step oxidation of betulin first via Swern
oxidation and then by KMnO solution in a 1,4-dioxane–H O mixture with an overall yield of 65% is also known [10]. In this
4
2
instance, toxic Mn compounds are used. Two-step oxidation of betulin first by O in the presence of Pd(OAc) and then by a
2
2
mixture of NaClO , Me C=CHMe, and NaH PO 4H O in t-BuOH–H O produced betulonic acid in yields up to 76% without
2
2
2
4
2
2
the aforementioned drawbacks [10–12]. However, this method also has its drawbacks. First, a Pd compound is used for the
oxidation. Second, the amino acid N-acetyl-L-serine is used to remove them from the reaction mixture. This makes the
process rather costly. Also, volatile 2-methylbutene-2 is used for NaClO oxidation and hinders the preparative synthesis.
2
A communication about a two-step oxidation of 2-[(4S,6R)-2,2-dimethyl-6-pentyl-1,3-dioxan-4-yl]ethanol into the
acid using Dess–Martin periodate and then NaClO in the presence of not 2-methyl-2-butene but H O (30%) appeared [13].
2
2 2
This system was not used to oxidize betulin.
A new method for synthesizing betulonic (3) and betulinic acids (4) from betulin (1) was proposed by us. The former
was prepared via two-step Swern oxidation of the alcohol of 1 [10] and then the oxidative system NaClO , H O , and
2
2 2
NaH PO 4H O in t-BuOH–H O. The latter was produced via reduction of 3 by DIBAH in CH Cl at 0°C. The yields of 3 and
2
4
2
2
2
2
1
3
4
were 86 and 92%, respectively, as only the ꢀ-epimer according to the C NMR spectrum near 79.0 ppm and the PMR
spectrum at 3.22 ppm.
H
H
H
H
OH
[
O
H
H
H
COOH
H
COOH
10]
a
b
H
H
H
HO
H
O
HO
H
H
1
2
3
4
a. NaClO , H O , NaH PO –H O, t-BuOH–H O; b. DIBAH, CH Cl
2
2
2
2
2
4
2
2
2
Ufa Institute of Chemistry, RussianAcademy of Sciences, 71 Prosp. Oktyabrya, Ufa, 450054; e-mail: insect@anrb.ru.
Translated from Khimiya Prirodnykh Soedinenii, No. 4, July–August, 2018, pp. 672–673. Original article submitted January
1
9, 2018.
0
009-3130/18/5404-0795 ©2018 Springer Science+Business Media, LLC
795

Equipment at the Khimiya Common Use Center, UfIC, RAS, was used in the work. IR spectra were recorded from
thin layers on an FTIR-Prestige-21 instrument (Shimadzu). NMR spectra were recorded in CDCl on a Bruker AM-500
3
1
13
spectrometer (operating frequency 500.13 MHz for H and 126.76 MHz for C). Resonances of the deuterated solvent
C(H)DCl [ꢂ 7.27; ꢂ 77.00 ppm] were used as internal standards. TLC monitoring used Sorbfil SiO (Russia). Optical
3
H
C
2
rotation was measured on a 141-MC polarimeter (PerkinElmer). Betulin (100% optical purity) that was isolated from the
extract of B. pendula outer bark was used in the work [14]. t-BuOH, t-BuOMe (MTBE), benzene, CH Cl , and EtOAc were
2
2
purified and dried by standard methods before use in reactions and isolation of products [15]. Elemental analyses of all
compounds agreed with those calculated.
Betulonic [3-oxolup-20(29)-en-28-oic] Acid (3). A solution of betulonic aldehyde (2, 10.0 g, 22.3 mmol) that was
prepared from betulin (1) via Swern oxidation [10] in t-BuOH (100 mL) at 0–10°C was treated simultaneously with solutions
of NaH PO (16.2 g, 136.8 mmol) in H O (60 mL) and NaClO (12.4 g, 136.8 mmol) in H O (50 mL) and then with H O
2
4
2
2
2
2 2
(
30%, 12 mL), stirred at 10°C for 15 min (TLC monitoring), diluted with H O (200 mL), and extracted with MTBE (3 ꢃ 100 mL).
2
The organic layer was washed with saturated NaCl solution, dried over Na SO , and evaporated. The solid (10.5 g) was
2
4
dissolved in benzene (150 mL), treated with KOH solution (75 mL, 15%), and refluxed for 1 h. The precipitate was filtered
off, rinsed sequentially with H O and MTBE, dissolved in HCl solution (10%, 200 mL), and refluxed for 1 h. The precipitate
2
2
0
25
was filtered off, rinsed with H O, and dried to afford 3 (8.62 g, 85%). [ꢁ] +43° (c 0.65, CHCl ); lit. [ꢁ] +45° (c 0.51,
2
D
3
D
1
3
CHCl ) [10]. PMR and C NMR spectral parameters were identical to those reported earlier [10].
3
Betulinic [3ꢀ-hydroxylup-20(29)-en-28-oic] Acid (4). A solution of 3 (1.00 g, 2.2 mmol) in anhydrous CH Cl2
2
(
(
20 mL) at 0°C was treated dropwise with a solution of DIBAH (1.1 mL, 73%) in toluene (4.4 mmol) in anhydrous CH Cl
2
2
10 mL), stirred at 0°C for 1 h, and treated dropwise with H O (5 mL). The precipitate was dissolved in HCl solution (10%,
2
1
5 mL) and extracted with EtOAc (3 ꢃ 30 mL). The organic extract was washed with saturated NaCl solution, dried over
2
0
25
Na SO , and evaporated to afford 4 (0.87 g, 87%). [ꢁ] +9.2° (c 0.62, CHCl ); lit. [ꢁ] +9.5° (c 0.4, CHCl ) [10]. PMR and
2
4
D
3
D
3
1
3
C NMR spectral parameters were identical to those reported earlier [8].
ACKNOWLEDGMENT
The work was financially supported by RFBR Grant No. 17-03-01050 “Synthesis of new macroheterocycles with
ester, oxime, hydrazide, and amide fragments based on natural mono- and triterpenoids as promising biological and
pharmaceutical compounds.”
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