Crystal structure of (E)-13-(pyrimidin-5-yl)parthenolide

The title molecule possesses ten-, five- (lactone) and three-membered (epoxide) rings with a pyrimidine group as a substituent. The ten-membered ring displays an approximate chair–chair conformation, while the lactone ring shows a flattened envelope-type conformation.


Chemical context
Parthenolide (PTL) is a sesquiterpene lactone known to significantly target cancer stem cells, which are the putative roots of all types of cancer (Gopal et al., 2007). PTL has been isolated from several different plant species, feverfew leaf (Tanacetum parthenium) being one of the major sources (Awang, 1989). PTL exhibits a wide range of biological activities, such as anti-inflammatory, anti-bacterial, antifungal, and cytotoxic properties (Picman, 1986). Consequently, PTL was discovered to be capable of inducing robust apoptosis in primary acute myelogenous leukemia (AML) cells (Guzman et al., 2007), proving to be equally effective among all subpopulations within primary AML specimens, including leukemia stem cells (LSCs). Gopal et al. (2007) reported that PTL specifically depletes HDAC1 protein without affecting other class I/II HDACs (histone deacetylases). Nasim et al. (2008) reported the anti-leukemic activity of aminoparthenolide analogues. Han et al. (2009) reported on bioactive derivatives of Heck products of PTL. Recently, Penthala et al. (2014a) reported the anti-cancer activity of PTL-Heck products. Recently we (Penthala et al., 2014b) reported the crystal structure of 13-{4-[Z-2-cyano-2-(3,4,5trimethoxyphenyl)ethenyl]phenyl} parthenolide, an analog of PTL, which was found to have the E configuration at C-13. The interesting biological properties of PTL directed our attention to design and synthesize additional bioactive derivatives. In order to obtain detailed information on the structural conformation of the current molecule, including assignment of the absolute configuration of the four stereocentres, and to establish the geometry of the exocyclic double ISSN 2056-9890 bond, a single crystal X-ray structure determination has been carried out.

Structural commentary
The title compound is shown in Fig. 1. The PTL substructure of the molecule contains a ten-membered carbocyclic ring (chair-chair conformation) fused to a lactone ring (flattened envelope-type conformation), and an epoxide ring, as previously reported (Castañ eda-Acosta & Fisher, 1993). The title compound contains an E-exocyclic olefinic bond C11 C13. The pyrimidine ring is twisted out of the plane of the furan ring, making a dihedral angle of 29.43 (7) . The C11 C13-C16 bond angle of 127.89 (16) deviates from the ideal value of 120 , but other bond lengths and angles are largely unremarkable. The four chiral carbon atoms in PTL were determined using 1354 quotients (Parsons et al., 2013) as follows: C4(R),C5(R),C6(S),C7(S) for the arbitrary atomnumbering scheme used, and is consistent with previous studies (Penthala et al., 2013).

Supramolecular features
There are no classical hydrogen bonds and nointeractions. There are a few C-HÁ Á ÁN and C-HÁ Á ÁO short contacts, but none that have the right geometry to be considered as non-classical hydrogen bonds. Intermolecular contacts thus appear to be limited to van der Waals interactions.

Synthesis and crystallization
Synthetic procedures: The title compound, containing the PTL substructure, was synthesized by the previously reported literature procedure (Han et al., 2009). In brief, parthenolide (1 mmol), 5-bromopyrimidine (1.1 mmol), triethylamine (3.0 mmol) and 5 mol% of palladium acetate were charged into dimethylformamide (2 ml) at room temperature. The reactants were stirred at 333-343 K for 24 h. After completion of the reaction, the reaction mass was extracted into diethyl ether (2 Â 30 ml). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by The molecular structure of the title compound with probability ellipsoids drawn at the 50% probability level. column chromatography. The title compound was recrystallized from a mixture of hexane and acetone (9:1), which gave colourless needles upon slow evaporation of the solution at room temperature over 24 h.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 1. H atoms were found in difference Fourier maps, but subsequently included in the refinement using riding models, with constrained distances set to 0.95 Å (Csp 2 H), 0.98 Å (RCH 3 ), 0.99 Å (R 2 CH 2 ) and 1.00 Å (R 3 CH). U iso (H) parameters were set to values of either 1.2U eq or 1.5U eq (RCH 3 only) of the attached atom. The absolute structure parameter [À0.04 (3)] was determined directly from the diffraction data using 1354 Parsons quotients (Parsons et al., 2013), with the four chiral carbon atoms assigned to be R,R,S,S for the arbitrarily numbered atoms C4, C5, C6, C7, respectively. Refinement progress was checked using PLATON (Spek, 2009) and by an R-tensor (Parkin, 2000).

Special details
Experimental. The crystal was mounted with polyisobutene oil on the tip of a fine glass fibre, which was fastened in a copper mounting pin with electrical solder. It was placed directly into the cold gas stream of a liquid nitrogen based cryostat, according to published methods. Diffraction data were collected with the crystal at 90 K, which is standard practice in this laboratory for the majority of flash-cooled crystals. The crystals were large, and could not be cut to size without inducing damage by crushing, leading to shattered, frayed ends. These damaged parts could easily be dissolved away, however, to give solvent-rounded undamaged pieces of optimal size for data collection. 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 progress was checked using PLATON (Spek, 2009) and by an R-tensor (Parkin, 2000 (7) 0.0018 (7) 0.0051 (6) 0.0044 (7)  C10 0.0221 (8) 0.0190 (9) 0.0150 (7) 0.0003 (7) 0.0092 (7) 0.0026 (7)