3-Oxo-18α-olean-28,13β-olide

The title terpene, C30H46O3, is a 28,13β-lactone of oleanolic acid prepared with bismuth trifluoromethanesulfonate (OTf), Bi(OTf)3·xH2O. All rings are trans-fused. The X-ray study shows the inversion of the orientation of 18-H in the lactonization reaction. A quantum chemical ab-initio Roothaan Hartree–Fock calculation of the equilibrium geometry of the isolated molecule gives values for bond lengths and valency angles in close agreement with experimental values. The calculation also reproduces the observed molecular conformation, with puckering parameters that agree well with those determined from the crystallographic study.

The title terpene, C 30 H 46 O 3 , is a 28,13-lactone of oleanolic acid prepared with bismuth trifluoromethanesulfonate (OTf), Bi(OTf) 3 ÁxH 2 O. All rings are trans-fused. The X-ray study shows the inversion of the orientation of 18-H in the lactonization reaction. A quantum chemical ab-initio Roothaan Hartree-Fock calculation of the equilibrium geometry of the isolated molecule gives values for bond lengths and valency angles in close agreement with experimental values. The calculation also reproduces the observed molecular conformation, with puckering parameters that agree well with those determined from the crystallographic study.

Comment
The natural products have been the source of the main anticancer drugs for centuries and represent 50% of drugs used in the clinic in developed countries (Koehn & Carter, 2005). As the largest class of natural products, pentacyclic triterpenoids biosynthesized in plants by squalene cyclization represent a varied class of bioactive natural products (Gershenzon & Dudareva, 2007;Salvador, 2010;Dzubak et al., 2006). Among them oleanolic acid was reported to display several biological effects including anti-inflammatory (Ringbom et al., 1998), anti-viral (Ma et al., 2000, anti-bacterial (Horiuchi et al., 2007) and in particular anti-cancer activities. It has been shown to act at various stages of tumor development, including inhibition of tumourigenesis, inhibition of tumor promotion (Tokuda et al., 1986), induction of tumor cell differentiation and apoptosis (Lee et al., 1994) and inhibition of angiogenesis, invasion tumor cells and metastasis (Sohn et al., 1995). The lactonization reaction of oleanane type triterpenoids, with a C12═C13 double bond, under acid conditions has been reported. This classical transformation involves a 28,13β-lactonization with 18-H inversion of orientation with the formation of an oleanane type γ-lactone (Cheriti et al., 1994). As part of our current interest on the application of bismuth(III) salts to the chemistry of triterpenoids (Salvador et al., 2009), we have recently reported the 28,13β-lactonization of oleanolic acid in CH 2 Cl 2 , using bismuth trifluoromethanesulfonate, Bi(OTf) 3 . xH 2 O (Salvador et al., 2009). Mindful of the biological and synthetic importance of such molecules, we report in this communication the molecular structure of the 3-oxo-18α-olean-28,13β-olide determined by single-crystal X-ray diffraction, and compare it with that of the free molecule as given by quantum mechanical ab-initio calculation.
The structure of this compound with the corresponding atomic numbering scheme is shown in Fig. 1. This triterpenoid compound is an oleanane type with a 28,13β-lactone. The typical C12═C13 double bond is absent. The inversion of orientation of 18-H in the lactonization reaction was unequivocally demonstrated by this X-ray crystallographic study. Bond lengths and angles are within the range of expected average values. All six-membered rings are fused trans-and have slightly distorted chair conformations, the D-ring being more heavily distorted towards a half-chair conformation due to the strain There are no strong hydrogen bonds in the crystal structure, due to the lack of strong H-donors. One weak C-H···O intramolecular interaction can be spotted in the molecule, involving atoms C26 and O13.
In order to gain some insight on how the crystal packing of title compound might affect the molecular geometry we have performed a quantum chemical calculation on the equilibrium geometry of the free molecule. These calculations were performed with the computer program GAMESS (Schmidt et al., 1993). A molecular orbital Roothan Hartree-Fock method was used with an extended 6-31 G(d,p) basis set. Tight conditions for convergence of both the self-consistent field cycles and maximum density and energy gradient variations were imposed (10 -6 atomic units). The program was run on the Milipeia cluster of UC-LCA (using 16 Opteron cores, 2.2 GHz runing Linux).

Refinement
All hydrogen atoms were refined as riding on their parent atoms using SHELXL97 defaults: C-H = 0.97Å with U iso (H) = 1.2U eq (C) for methylene H; C-H = 0.96Å with U iso (H) = 1.5U eq (C) for methyl H; C-H = 0.98Å with U iso (H) = 1.2U eq (C) for methine H. The absolute configuration was not determined from the X-ray data, as the molecule lacks any strong anomalous scatterer atom at the Mo Kα wavelength, but was known from the synthetic route. Friedel pairs of reflections (2247 pairs) were merged before refinement. Fig. 1. Molecular structure of the title compound with the atom numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. The H atoms are presented as a small spheres of arbitrary radius.