Absolute configuration of 3-acetylbetulinic acid

Article abstract of DOI:10.1134/S0022476613010307

The absolute configuration of 3-acetoxybetulinic acid is determined by single crystal X-ray diffraction.

Full text of DOI:10.1134/S0022476613010307

Journal of Structural Chemistry. Vol. 54, No. 1, pp. 189-191, 2013
Original Russian Text Copyright © 2013 by E. M. Suleimen, K. Van Hecke, L. Van Meervelt, Wim Deborggraeve, Wim Dehaen
ABSOLUTE CONFIGURATION OF 3-ACETYLBETULINIC ACID
1 2
© E. M. Suleimen, K. Van Hecke, L. Van Meervelt,
2
DOI: 10.1134/S0022476613010307
2
Wim Deborggraeve, and Wim Dehaen
2
The absolute configuration of 3-acetoxybetulinic acid is determined by single crystal X-ray diffraction.
Keywords: betulinic acid, 3-acetoxybetulinic acid, single crystal X-ray diffraction analysis.
Betulinic acid 1 derived from betulin has a complex of valuable pharmacological properties: antiinflammatory,
wound-healing, hepatoprotecting antiviral, and antitumor [1-3]. Some derivatives of betulin were found to be effective as
anti-HIV agents [4].
In this paper we present the absolute configuration of 3-acetoxybetulinic acid 2, which was obtained by the interaction
of acetic anhydride in pyridine [5]. The spectral data of 2 proved to be identical to those described in the literature [6].
Compound 2 was characterized in the chiral space group P2 2 2 (No. 19) with one molecule in the asymmetric
1
1 1
center and one molecule of chloroform solvent (Fig. 1).
The cyclopentane ring adopts a twisted envelope conformation at C22-C23, while all cyclohexane rings adopt a
chair conformation.
The acetoxy group is in the equatorial position relative to the C3 atom. The C2-O2-C3-C4 torsion angle is 118.9(3)°.
Fig. 1. Molecular and crystal structure of 2 according to X-ray
crystallography. Thermal displacement ellipsoids are drawn at
the 40% probability level. A chloroform molecule is omitted.
1
2
L. N. Gumilev Eurasian National University, Astana, Kazakhstan; syerlan75@yandex.ru. Katholieke Universiteit
Leuven, Belgium; Kristof.VanHecke@chem.kuleuven.be. Translated from Zhurnal Strukturnoi Khimii, Vol. 54, No. 1,
pp. 195-197, January-February, 2013. Original article submitted April 16, 2012.
0022-4766/13/5401-0189
189

Fig. 2. Crystal packing of the structure of
compound 2 in the (100) plane. The molecules
are hydrogen bonded along the [010] direction.
The isopropyl group is also equatorially positioned on the C27 atom of the cyclopentane ring. The C32-C30-C27-C28 torsion
angle is 78.1(5)°. Other similar structures of betulinic acid derivatives, containing an acetoxy group at the same position,
have been reported in [7, 8].
Intermolecular hydrogen bonds between the carboxyl O-H group and the acetoxy C=O group of a symmetry-equivalent
molecule (O(H)…O distance of 2.682(4) Å) are observed, which link the molecules together in the [010] direction (Fig. 2).
The absolute configuration of the structure was determined and the following atoms were established as C3(S),
C6(R), C7(R), C12(S), C13(R), C19(R), C20(R), C23(S), C27(R).
Experimental. 3-Acetoxybetulinic acid. 500 mg (1.1 mmol) of betulinic acid was dissolved in 0.350 ml of pyridine
(4.38 mmol) and 4.76 ml (50.4 mmol) of acetic anhydride were added. The mixture was kept for 24 h at room temperature
and afterwards mixed with 20 ml of ice water. The mixture was stirred for 20 min at 0°C. The product was filtered and the
residue was chromatographed on Silicagel using a mixture of heptane and dichloromethane solvents (2/8). After
recrystallization white crystals (437 mg, 80%) were obtained.
Yield: 80%.
ESI: m/z 499 (M), m/z 500 (M+H).
HRMS: C H O . Calculated: 498.37091 Found: 498.37278.
32 50 4
3
IR: 2948 (CH sp ), 1722 (C=O), 1687 (C=C), 1246 (C–O).
1
29α
29b
3
H NMR: (300 MHz, CDCl , ppm): δ 4.75 (s, 1H, H , 4.61 (s, 1H, H ), 4.54-4.53 (m, 1H, H ), 3.08-2.94 (m,
3
19 32
1H, H ), 2.33-1.91 (m, 7H), 2.04 (s, 3H, H ), 1.80-1.14 (m, 21H), 0.99-0.76 (m, 18H), 0.97 (s, 3H, CH ), 0.84 (s, 3H, CH ),
3
3
0.84 (s, 3H, CH ).
3
13
C NMR: (100 MHz, CDCl , ppm): δ 181.49 (C28); 171.09 (C31); 150.39 (C20); 109.76 (C29); 80.95 (C3); 56.36
3
(C17); 55.40 (C5); 55,38 (C9); 49.24 (C18); 46.93 (C19); 42.41 (C14); 40.68 (C8); 38.39 (C1); 38.36 (CH ); 37.79 (CH );
2 2
37.10 (CH ); 36.80 (CH ); 34.22 (C7); 30.54 (CH ); 29.67 (CH ); 28.79 (CH ); 27.94 (CH ); 25.43 (C2); 23.70 (CH ); 21.34
2 2 2 2 2
2
2
(C32); 20.83 (C11); 19.34 (CH ); 18.15 (C6); 16.47; 16.18; 16.03 (C23, C26, C25); 14.65 (C27).
2
Single crystal X-ray diffraction analysis. Compound 2 was crystaliized from a mixture of heptane/
dichloromethane solvents (2/8) at room temperature.
The X-ray crystallographic data were collected on a SMART 6000 diffractometer equipped with a CCD detector
using CuK radiation (λ = 1.54178 Å), φ and ω scans. The data were interpreted and integrated with the program SAINT
α
2
(Bruker) [9]. Both structures were solved by a direct method and refined by full-matrix least-squares on F using the
190

SHELXTL program package [2]. Non-hydrogen atoms were refined anisotropically and the hydrogen atoms were refined in
the riding mode and isotropic temperature factors fixed at 1.2 times U(eq) of the parent atoms (1.5 times for methyl and
hydroxyl groups). CCDC-876596 contains the supplementary crystallographic data for this paper and can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44-1223-336033; or deposit@ccdc.cam.ac.uk).
Crystal data for compound 2. C H Cl O , М = 618.09, orthorhombic, P2 2 2 (No. 19), a = 11.651(1) Å, b =
33 51 3 4 1 1 1
3
14.835(2) Å, c = 19.131(2) Å, V = 3306.5(6) Å , T = 293(2) K, Z = 4, ρ = 1.242 g/cm , μ(CuK ) = 2.775 mm , F(000) =
3
–1
calc
α
1328, crystal dimensions 0.4×0.4×0.3 mm, 6249 independent reflections (R = 0.0877). Final R = 0.0569 for 4863 reflections
int
with I > 2σ(I ) and wR2 = 0.1650 for all data. The absolute configuration of the structure was determined with a final Flack
parameter of 0.01(3) [11].
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