13-(N,N-Dimethylamino)micheliolide 0.08-hydrate

The title compound, C17H27NO3·0.08H2O {sytematic name: (3R,3aS,9R,9aS,9bS)-3-[(dimethylamino)methyl]-9-hydroxy-6,9-dimethyl-3,3a,4,5,7,8,9,9a-octahydroazuleno[4,5-b]furan-2(9bH)-one 0.08-hydrate}, exhibits intramolecular O—H⋯O hydrogen bonding to form a ring of graph-set motif S(6). As well as this intramolecular hydrogen bond with the lactone-ring O atom, the hydroxy H atom forms an O—H⋯O hydrogen bond to the low-occupancy partial water molecule [occupancy = 0.078 (2)]. The water molecule is correlated with disorder of the N(CH3)2 group [major–minor occupancy factors are 0.922 (2):0.078 (2)]. The dihedral angle between the mean planes of the trans-fused seven-membered ring and the lactone ring is 4.42 (9)°.


Comment
Micheliolide (MCL) is a natural product extracted from the plant Michelia champaca. MCL belongs to the class of guaianolide sesquiterpene lactones, which are used for the treatment of cancer (Sethi et al. 1984). The exocyclic double bond in such sesquiterpenes is believed to be responsible for their biological properties because of its exceptional chemical reactivity with nucleophilic groups (Rodriguez et al. 1976). The synthesis of MCL was first reported by Sethi et al. (1984) and its crystal structure was described by Acosta et al. (1991). Recently, the N,N-dimethyl amino analog of micheliolide was reported as a potent anti-leukemic agent (Zhang et al. 2012).
The N,N-dimethyl amino analog of micheliolide was synthesized as described by Zhang et al. (2012). Recrystallization of the compound from hexanes gave colorless needles that were suitable for X-ray analysis. The title molecule, Fig. 1, contains a central seven-membered carbocyclic ring fused to a 5-membered carbocylic ring and a trans lactone ring. The two five membered rings are in half-chair conformations, as reported in the literature (Acosta et al., 1991). The X-ray studies revealed that the title compound exhibits an O-H···O intramolecular hydrogen bond between the hydroxyl group and the lactone ring oxygen atom. The structure contains a low occupancy [7.8 (2)% occupancy] partial water molecule and a small amount of correlated disorder of the N(CH 3 ) 2 group. The bridge between the seven-membered ring and the lactone ring is trans, giving a dihedral angle between the mean planes of the rings of 4.42 (9)°.

Experimental
The title compound was prepared by the reported literature procedure (Zhang et al., 2012) and recrystallization from hexanes gave colorless needles suitable for X-ray analysis.

Refinement
H atoms were found in difference Fourier maps and 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 0.84 Å (OH). Partial occupancy water H atoms were fixed due to the low occupancy.
U iso (H) values were set to either 1.2U eq or 1.5U eq (RCH 3 , OH) 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 EADP) were used to fix parameters of superimposed or partially overlapping fragments. Restraints (SHELXL commands SAME, SADI, DFIX and RIGU) were used to maintain the integrity of ill-defined or disordered groups.

Figure 1
A view of the molecule with displacement ellipsoids drawn at the 50% probability level.

Special details
Experimental. The crystal was mounted with polyisobutene oil on the tip of a fine glass fibre, fastened in a copper mounting pin with electrical solder. It was placed directly into the cold stream of a liquid nitrogen based cryostat, according to published methods (Hope, 1994;Parkin & Hope, 1998). Diffraction data were collected with the crystal at 90 K, which is standard practice in this laboratory for the majority of flash-cooled crystals. 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). The final model was further checked with the IUCr utility checkCIF. The partial occupancy water molecule was modelled on the site of a difference map peak of approximately 0.67 e A-3. It must have the same or smaller occupancy as the minor disorder component of disorder in the main molecule, which is a very small amount (less than 8%). Nevertheless, it gave a noticeably better fit, and a much flatter difference map, and so was retained. Hydrogen atoms for this water were placed so as to make reasonable H-bonds to nearby acceptors. Overall, the fit is good and the absolute configuration is well established.