Epibisdehydroneotuberostemonine J

The title compound, C22H29NO4, a stemona alkaloid, is composed of two lactone rings (A and E), a six-membered ring (B), a pyrrole ring (C) and a seven-membered ring (D). The five-membered rings A and E exhibit envelope conformations (C atoms as flaps) while ring C is planar. Ring B exhibits a twist-chair conformation due to fusion with pyrrole ring C while ring D adopts a chair conformation. The junction between rings A and B is cis. In the crystal, weak C—H⋯O interactions involving the two carbonyl groups, a methylene and a methyl group give rise to a three-dimensional network.

The title compound, C 22 H 29 NO 4 , a stemona alkaloid, is composed of two lactone rings (A and E), a six-membered ring (B), a pyrrole ring (C) and a seven-membered ring (D). The five-membered rings A and E exhibit envelope conformations (C atoms as flaps) while ring C is planar. Ring B exhibits a twist-chair conformation due to fusion with pyrrole ring C while ring D adopts a chair conformation. The junction between rings A and B is cis. In the crystal, weak C-HÁ Á ÁO interactions involving the two carbonyl groups, a methylene and a methyl group give rise to a three-dimensional network.

Comment
Radix Stemonae extracts derived from the root of Stemona tuberosa (Stemonaceae family) are often used as an antitussive drug to treat respiratory disorders. The alkaloids were found to be the major components responsible for the antitussive activity (Xu et al., 2010). The intriguing structures and pharmacological activities of this fascinating class of compounds have attracted considerable attention (Pilli et al., 2010), and a number of total syntheses (Frankowski et al., 2008), structural modifications (Frankowski et al., 2011) and phytochemical studies (Jiang et al., 2006, Zhang et al., 2011 on new Stemona alkaloids have appeared in recent years. The title compound C 22 H 29 N 1 O 4 (Fig. 1) is a Stemona alkaloid. It was first isolated from the roots of Stemona tuberosa ten years ago (Chung et al., 2003) and found to show antitussive activity (Chung et al., 2003); however, its crystal structure had not been reported.
During our on-going search for antitussive natural products, epibisdehydroneotuberostemonine J was isolated again from Stemona tuberosa. It is an isomer of bisdehydroneotuberostemonine (Pham et al., 2002) at C-9 and C-18. The molecule is composed of two lactone ring (A and E), a six-membered ring (B), a pyrrole ring (C) and a seven-membered ring (D). The five-membered rings A and E exhibit envelope conformations while ring C is planar. The six-membered ring B exhibits a twist chair conformation due to fusion with the pyrrole ring C. The seven-membered ring D adopts a chair conformation, in which the atoms C-5, C-6, C-8, C-9 form a plane with a mean deviation of 0.043 (2) Å, and the atoms C-9 A, N-4 and C-7 displaced by -1.070 (3), -1.040 (2) and 0.662 (4) Å from the plane, respectively.

Experimental
A dry ground herbal sample of Radix Stemonae (5.0 kg) was suspended in 95% EtOH (10 L) and heated for two hours to reflux of the solvent. After filtration, the solvent was evaporated under reduced pressure. The residue was acidified with 4% HCl (400 ml) and filtered with Whatman filter papers, then the filtrate (acidic aqueous solution) was washed with diethyl ether (500 ml). The H 2 O layer was basified to pH = 9 with aqueous ammonia (35%) and then extracted with Et 2 O (500 ml). The Et 2 O layer was evaporated to afford the crude alkaloids (15 g), which were subjected to column chromatography over silica gel, and eluted with chloroform: methanol: amonia (98: 2: 0.05) to yield ten fractions.
Fraction 3 (2 g), a low polar fraction with an Rf value larger than 0.7 on a normal phase TLC plate (mobile phase cyclohexane: ethyl acetate 1: 1), was subjected to a second separation by silica-gel chromatography with cyclohexane: ethyl acetate (7: 3) as the eluent to yield the title compound (180 mg, colorless powder, Rf = 0.76 at the same TLC condition as bulk fraction 3), which was identified by comparision of the physical and spectroscopic data with the literature (Chung et al., 2003). Colorless crystals suitable for single crystal diffraction were obtained from a mixture of cyclohexane: ethyl acetate at room temperature.

Refinement
The C-bound H atoms were positioned geometrically and were included in the refinement in the riding-model approximation, with C-H = 0.96 Å (CH 3 ) and U iso (H) = 1.5U eq (C); 0.97 Å (CH 2 ) and U iso (H) = 1.2U eq (C); 0.98 Å (CH) and U iso (H) = 1.2U eq (C). In the absence of anomalous scatterers and a low Friedel pair coverage the absolute configuration was assigned based on the closely related reference molecule neostenine with known configurations at C-10 and C-13 (Jiang et al. (2010)). The highest residual electron density is 0.13 and of no physical meaning.

Figure 1
The molecular structure of the title compound showing 30% probability displacement ellipsoids and the atom-numbering scheme.   where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.13 e Å −3 Δρ min = −0.13 e Å −3 Extinction correction: SHELXL97 (Sheldrick, 2008), Fc * =kFc[1+0.001xFc 2 λ 3 /sin(2θ)] -1/4 Extinction coefficient: 0.013 (2) Special details Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.