Synthesis and molecular structure of 3β,28-diacetoxy-(20R)-lupan-29- oic acid

Article abstract of DOI:10.1007/s10600-012-0163-y

The methyl ester of 3β,28-diacetoxy-(20R)-lupan-29-oic acid was synthesized and its molecular structure was determined.

Full text of DOI:10.1007/s10600-012-0163-y

Chemistry of Natural Compounds, Vol. 48, No. 1, March, 2012 [Russian original No. 1, January-February, 2012]
SYNTHESIS AND MOLECULAR STRUCTURE OF
3ꢀ,28-DIACETOXY-(20R)-LUPAN-29-OIC ACID
1*
1
2
O. B. Kazakova, N. I. Medvedeva, and K. Yu. Suponitskii
UDC 547.824:542.91:548.737
The methyl ester of 3ꢀ,28-diacetoxy-(20R)-lupan-29-oic acid was synthesized and its molecular structure
was determined.
Keywords: betulin, oxidation, 3ꢀ,28-diacetoxy-(20R)-lupan-29-oic acid, x-ray structure analysis.
Oxidation is an effective method for modifying the isopropenyl group of lupane-type triterpenoids. The reaction of
lupane derivatives with ozone and dimethyldioxirane has been studied [1, 2]. It was shown that oxidation of betulin and its
acetates by Cr(VI) oxide produced derivatives with keto- and carboxylic groups [3–6]. Thus, the formation of epimeric
C20-acids from the reaction of betulin diacetate (1) with CrO in acetic acid at 70°C was reported [5]. On the other hand, the
3
product from the reaction of 1 with CrO was purported to be a norketone (2) [6]. Herein data on the product composition
3
from the oxidation of 1 by CrO in refluxing acetic acid and an x-ray structure analysis (XSA) of one of the acids as the methyl
3
ester are reported.
The reaction of 1 and CrO in acetic acid at 100°C for 3 h produced a mixture of the norketone (2) and two epimeric
3
acids (3 and 4), which were isolated pure using column chromatography in yields of 50, 20, and 15%, respectively (Scheme 1).
NMR spectra of 3 and 4 were identical. The structure of ketone 2 was confirmed previously by an XSA [7].
30
O
COOH
20
30
20
20
30
ROOC
CH OAc
2
a
+
+
CH OAc
CH OAc
2
CH OAc
2
2
AcO
1
3, 5
b
4 (20S)
2
3: R = H (20R)
5: R = CH
3
a. CrO , AcOH, 100ꢁC, 3 h; b. CH N /Et O
3
2
2
2
Scheme 1
Methylation of acid 3 by diazomethane solution gave ester 5. An XSA established its molecular and crystal structure
(Fig. 1). All six-membered rings had the chair conformation. The five-membered ring had a slightly distorted envelope
conformation. This is usually observed for such compounds [8]. The absolute configuration of 5 was determined from the
retention of configuration of the chiral atoms during the reaction (Fig. 1). This suggested that C20 had the R-configuration.
According to the XSA of 5, it can be concluded that acids 3 and 4 were the 20R and 20S-epimers.
Thus, the structure of the methyl ester of 3ꢀ,28-diacetoxy-(20R)-lupan-29-oic acid was determined. Pure (20R)- and
(20S)-lupane acids are interesting as a platform for synthesizing triterpenoid derivatives at the C3, C28, and C29 positions.
1) Institute of Organic Chemistry, Ufa Scientific Center, RussianAcademy of Sciences, 450054, Ufa, Prosp. Oktyabrya,
71, e-mail: obf@anrb.ru; 2) N. A. Nesmeyanov Institute of Organoelement Compounds, RussianAcademy of Sciences, 119991,
Moscow, Ul. Vavilova, 28. Translated from Khimiya Prirodnykh Soedinenii, No. 1, January–February, 2012, pp. 78–80.
Original article submitted July 13, 2011.
©
0009-3130/12/4801-0083 2012 Springer Science+Business Media, Inc.
83

C30
O3
C29
O4
C35
C20
C19
C18
C17
C21
C22
C12
C13
O6
C27
C14
C11
C7
C1
C28
C2
C9
C16
C15
O1
C3
C10
C32
C31
C8
C25
C33
O2
C26
C5
O5
C23
C34
C6
C4
C24
Fig. 1. Molecular structure of the methyl ester of 3ꢀ,28-diacetoxy-(20R)-lupan-29-oic acid (5)
with 50% probability atomic ellipsoids.
EXPERIMENTAL
13
PMR and C NMR spectra were recorded in CDCl with TMS internal standard on a Bruker AM-300 spectrometer
3
(300 and 75.5 MHz). Melting points were determined on a Boetius microstage. Optical density was measured on a Perkin–
Elmer 241 MC polarimeter in a 1-dm tube. An Ozon-2K ozonizer was used for the ozonation. TLC was performed on Sorbfil
plates (Sorbpolimer, Russia) using CHCl :EtOAc (40:1). Compounds were detected by H SO solution (10%) with subsequent
3
2
4
heating at 100–120°C for 2–3 min. Betulin diacetate (1) was prepared as before [9].
3ꢀ,28-Diacetoxy-29-norlupan-20-one (2), 3ꢀ,28-Diacetoxy-(20R)-lupan-29-oicAcid (3), 3ꢀ,28-Diacetoxy-(20S)-
lupan-29-oic Acid (4). A solution of 1 (10 mmol, 5.15 g) in acetic acid (150 mL) was treated with CrO (0.1 mol, 1.0 g),
3
refluxed at 100°C for 3 h, and poured into water (300 mL). The precipitate was filtered off, washed until neutral, dried in air,
and chromatographed over a column with elution successively by petroleum ether, benzene, CHCl , and CHCl :MeOH mixtures
3
3
(100:1, 50:1, 10:1). Yield of 2, 2.43 g (50%); 3, 1.02 g (20%); 4, 0.75 g (15%). The physicochemical properties and NMR
20
spectra of 2 agreed with those published [7]. Compound 3: R 0.22, mp 238–240°C, [ꢂ] –56° (c 1.00, CHCl ) {lit. [5]
f
D
3
22
mp 239–241°C, [ꢂ] –44° (c 0.68)}, C H O (MW 558.789).
D
34 54 6
20
22
Compound 4: R 0.14, mp 248–251°C, [ꢂ] +8° (c 1.00, CHCl ) {lit. [5] mp 254–259°C, [ꢂ] +11° (c 0.65)}. NMR
f
D
3
D
spectra of 3 and 4 were identical.
PMR spectrum of 3/4 (ꢃ, ppm, J/Hz): 0.65, 0.65, 0.70, 0.90, 1.05 (3H each, s, CH ), 1.15–1.85 (29H, m, CH, CH ),
3
2
2.01 and 2.03 (3H each, s, OAc), 2.70–2.80 (1H, br.s, H-3), 3.55 and 4.20 (1H each, d, J = 7.8, H-28), 4.50 (1H, t, H-19).
13
C NMR spectrum of 3/4 (ꢃ, ppm): 14.5, 16.1, 16.1, 16.5, 17.1, 18.1, 20.8, 21.0, 21.2, 23.5, 23.7, 27.0, 27.9, 27.9,
29.8, 34.0, 34.2, 37.0, 37.0, 37.8, 38.4, 40.9, 42.0, 42.9, 43.3, 46.3, 49.0, 49.8, 55.3, 62.5 (C-28), 80.9 (C-3), 171.0, 171.6,
181.1 (C-20).
Methyl Ester of 3ꢀ,28-Diacetoxy-(20R)-lupan-29-oic Acid (5). A solution of 3 (1 mmol, 0.58 g) in MeOH was
stirred and treated with an Et O solution of diazomethane until the starting material disappeared completely (TLC monitoring).
2
The solvent was evaporated in vacuo. The product was crystallized from benzene. Yield 0.56 g (97%), R 0.82, mp 203–
f
20
205°C, [ꢂ] –69° (c 3, CHCl ), C H O .
D
3
35 56 6
PMR spectrum (CDCl , ꢃ, ppm, J/Hz): 0.74, 0.75, 0.76, 0.83, 0.94 (3H each, s, CH ), 1.02 (3H, d, J = 7, H-30), 1.10–
3
3
1.80 (22H, m, CH , CH), 1.94 and 1.95 (3H each, s, OAc), 2.65-2.67 (2H, m, H-19, H-20), 3.56 (3H, s, OCH ), 3.67 and 3.78
2
3
(1H each, d, H-28), 4.35–4.40 (1H, m, H-3).
84

13
C NMR spectrum (CDCl , ꢃ, ppm): 14.4, 16.0, 16.1, 16.5, 17.2, 18.1, 20.8, 21.0, 21.3, 23.3, 23.6, 26.8, 26.9, 27.9,
3
29.8, 33.9, 34.2, 36.9, 37.0, 37.8, 38.3, 40.9, 42.0, 42.8, 43.5, 46.2, 49.0, 49.9, 51.0, 55.3, 62.4 (C-28), 80.9 (C-3), 171.0,
171.6, 176.0 (C-30).
XSA of 5. Colorless thin needle-like crystals, C H O (MW = 572.80), were orthorhombic, a = 7.4502(12),
35 56
6
°
° 3
3
b = 11.8528(18), c = 35.658(6) A, V = 3148.8(8) A , space group P2 2 2 , Z = 4, d
= 1.124 g/cm . A data set of 32,322
1 1 1
calcd
reflections was obtained on a Bruker SMART APEX2 CCD diffractometer at 100 K (ꢄ Mo Kꢂ-radiation, ꢅ
= 27°) from a
max
single crystal of size 0.14 ꢆ 0.03 ꢆ 0.01 mm. The initial data set of measured intensities was processed using the SAINT and
SADABS programs included in the APEX2 programs [10]. The structure was solved by direct methods and refined by
2
anisotropic full-matrix least-squares methods for nonhydrogen atoms over F . Hydrogen atoms were placed in geometrically
hkl
calculated positions and refined using a rider model [U (H) = nU (C,O), where n = 1.5 for methyl H atoms and 1.2 for other
iso
eq
C atoms]. A total of 3904 independent reflections was used in the refinement. The refinement converged over all independent
reflections for wR = 0.1023 [R = 0.0504 over 2667 reflections with I > 2 (I)]. All calculations were performed on an IBM
2
1
PC using the SHELXTL program set [11]. Atomic coordinates and thermal factors were deposited in the Cambridge
Crystallographic Data Centre (CCDC No. 793691).
ACKNOWLEDGMENT
The work was financed in part by the RFBR (Project 09-03-00831) and a Grant of the RF President for State Support
of Young Russian Scientists (MK-7360.2010.3).
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