Crystal structure of 13-(E)-(2-aminobenzylidene)parthenolide

The title molecule is composed of fused ten-, five- (lactone), and three-membered (epoxide) rings. The lactone ring shows a flattened envelope-type conformation and bears a 2-aminobenzylidene substituent that is disordered over two conformations. The ten-membered ring has an approximate chair–chair conformation. There are no conventional hydrogen bonds, but there are a number of weaker C—H⋯O-type interactions.


Chemical context
Sesquiterpene lactones (SLs) are a large family of natural products that have been widely investigated for their anticancer activity. Parthenolide (PTL), a naturally occurring germacranolide SL (Minnaard et al., 1999) isolated from the feverfew plant (Tanacetum parthenium) (Knight, 1995), has unique biological properties and selectively targets leukemia stem cells (LSC) compared to normal hematopoietic stem cells (Guzman et al., 2005). PTL has been demonstrated to inhibit the NFkB pathway in LSCs, and also increases reactive oxygen species, and inhibits STAT3 (signal transduction and activation of transcription) (Mathema et al., 2012). Synthetic analogues of SLs are also excellent sources of novel chemical entities for drug discovery, and over the last decade have been developed as efficacious anticancer drugs (Ghantous et al., 2010). Previous work from our laboratory (Nasim & Crooks, 2008) reported the amino analogues of PTL as anti-leukemic agents, and moreover a water-soluble analogue of PTL, dimethylaminoparthenolide (DMAPT), has advanced into clinical studies (Ghantous et al., 2010). Recently, Kempema et al. (2015) have reported C1 to C10-modified PTL analogues as anti-leukemic agents. Han et al. (2009) have also reported Heck products of PTL as anti-cancer agents. In continuing efforts from our group, Penthala et al. (2014a) reported Heck products of PTL and Melampomagnolide B as anti-cancer agents. Subsequently, Bommagani et al. (2015) reported the crystal structure of (E)-13-(pyrimidin-5-yl)-parthenolide, an analog of PTL, which was found to have an E-configuration at C-13. The useful biological properties of PTL and its analogs directed our attention to design and synthesize novel bioactive analogs. In order to obtain detailed information on the structural conformation of the current molecule and to determine the geometry of the exocyclic double bond, a single-crystal X-ray structure determination has been carried out.

Structural commentary
The title compound ( Fig. 1) is built from the PTL substructure, which contains a ten-membered carbocyclic ring (chair-chair conformation) merged to a lactone ring, and an epoxide ring, as previously reported (Castañ eda-Acosta et al., 1993). The lactone ring has a flattened envelope-type conformation, wherein atoms C6 and C7 reside 0.093 (4) and À0.105 (4) Å above and below the mean plane through atoms C11, C12, O2, and O3. The molecule also contains a 2-aminobenzylidene group attached by an E-exocyclic C11 C13 olefinic bond. The 2-aminobenzylidene ring is twisted out of the plane of the furan ring, subtending a dihedral angle of 59.93 (7) . All other bond lengths and angles are largely unremarkable.

Supramolecular features
There are no conventional hydrogen bonds in the crystal structure, although there are a number of weaker C-HÁ Á ÁO-type interactions (Table 1). The most striking packing feature consists of 2 1 screw-related (1 À x, 1 2 + y, Àz) stacking of lactone groups parallel to the b axis (Fig. 2). The distance between planes of adjacent lactone rings is therefore half the b-axis length.

Figure 1
The molecular structure of the title compound with ellipsoids drawn at the 50% probability level.

Figure 2
A packing plot showing the stacking of 2 1 screw-related adjacent lactone groups. The stacking direction, shown by a dashed line, is parallel to the crystallographic b axis. For emphasis, lactone-group atoms are depicted as solid balls. For clarity, hydrogen atoms and minor disorder components are omitted.

Refinement details
Crystal data, data collection and structure refinement details are summarized in Table 2. H atoms were found in difference-Fourier maps. Carbon-bound hydrogens were subsequently placed at idealized positions with constrained distances of 0.98 Å (RCH 3 ), 0.99 Å (R 2 CH 2 ), 1.00 Å (R 3 CH) and 0.95 Å (Csp 2 H). Nitrogen-bound hydrogens on the major disorder component were refined freely, while those on the minor component were heavily restrained. U iso (H) values were set to either 1.2U eq or 1.5U eq (RCH 3 ) of the attached atom.
To ensure satisfactory refinement of disordered groups in the structure, a combination of constraints and restraints were employed. The constraints (SHELXL commands EXYZ and EADP) were used to fix parameters of superimposed or partially overlapping fragments. Restraints (SHELXL command SADI) were used to maintain the integrity of illdefined or disordered groups. Refinement progress was checked using PLATON (Spek, 2009) and by an R-tensor (Parkin, 2000).
The minor component of disorder of the amine was apparent in a difference map. Given the small occupancy factor (only about 10%), the geometry of the minor component is approximate, and its hydrogen atoms were included merely to achieve the correct atom count.
The conventionally calculated Flack parameter does not convincingly indicate the proper assignment of absolute configuration. An alternative formulation of the chirality parameter using Parsons quotients (Parsons et al., 2013) [the so-called 'z 0 parameter = 0.07 (7)] as calculated by PLATON (Spek, 2009) is much more definitive.