rac-2-Methyl-3,4,5,6-tetrahydro-2H-2,6-methano-1,3-benzoxazocin-4-one

The title compound, C12H13NO2, represents a conformationally restricted 2-pyridone analogue of 1,4-dihydropyridine-type calcium antagonists and was selected for a crystal structure determination in order to explore some aspects of drug-receptor interaction. In the molecule, two stereogenic centres are of opposite chirality, whereas a racemate occurs in the crystal. It was found that the formally aminic N atom of the heterocycle is essentially sp 2-hybridized with the lone-pair electrons partially delocalized through conjugation with the adjacent carbonyl bond. As a result, the central pyridone ring assumes an unsymmetrical half-chair conformation. The critical 4-phenyl ring is fixed in a pseudo-axial and perpendicular orientation [dihedral angle 85.8 (1)°] with respect to the pyridone ring via an oxygen bridge. In the crystal a pair of centrosymmetric N—H⋯O hydrogen bonds connect molecules of opposite chirality into a dimer. The dimers are packed by hydrophobic van der Waals interactions.

The title compound, C 12 H 13 NO 2 , represents a conformationally restricted 2-pyridone analogue of 1,4-dihydropyridinetype calcium antagonists and was selected for a crystal structure determination in order to explore some aspects of drug-receptor interaction. In the molecule, two stereogenic centres are of opposite chirality, whereas a racemate occurs in the crystal. It was found that the formally aminic N atom of the heterocycle is essentially sp 2 -hybridized with the lone-pair electrons partially delocalized through conjugation with the adjacent carbonyl bond. As a result, the central pyridone ring assumes an unsymmetrical half-chair conformation. The critical 4-phenyl ring is fixed in a pseudo-axial and perpendicular orientation [dihedral angle 85.8 (1) ] with respect to the pyridone ring via an oxygen bridge. In the crystal a pair of centrosymmetric N-HÁ Á ÁO hydrogen bonds connect molecules of opposite chirality into a dimer. The dimers are packed by hydrophobic van der Waals interactions.
Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: KP2259).  4,5, V. Kettmann, J. Svetlík and L. Veizerová Comment 1,4-Dihydropyridines (DHPs) are known as the most potent class of calcium-channel antagonists widely used in clinical medicine. It was reported that the essential pharmacophore, recognizable by the DHP receptor, consists of the NH moiety, (substituted) phenyl ring and two ester groups (Goldmann & Stoltefuss, 1991). Nevertheless, we have previously observed that the rigid compound (I), lacking the ester groups in positions 3 and 5, retains some level of activity (Kettmann et al., 1996). This implies that (I) presents its key pharmacophoric elements, viz. the NH and phenyl groups, in an optimal position and orientation for favourable binding to the complementary sites of the receptor. To establish the latter, a single-crystal X-ray analysis of (I) was undertaken.
The bond lengths and angles within the molecule ( Fig. 1) are normal. As expected, there is a strong conjugation between N1 and the C2=O2 carbonyl bond, as usually observed for cyclic amino acids (Benedetti et al., 1983).
As mentioned above, the main aim of this work was to determine the three-dimensional disposition of the key pharmacophoric groups, i.e. the phenyl and NH moieties (Fig. 1). The conformation of the central heterocycle acts as a scaffold to orient substituents in space. Thus, the pyridone ring adopts an unsymmetrical half-chair conformation in which atoms C6, N1, C2 and C3 are coplanar with r.m.s. deviation of 0.012 (1) Å, and atoms C4 and C5 are displaced from this plane by -0.348 (3) and 0.470 (3)  The crystal packing is governed by an intermolecular hydrogen bond N-H···O(carbonyl) ( Table 1); as a result, the molecules associate into pairs to form hydrogen-bonded dimers across the centre of symmetry at (1/2,1/2,1/2). The dimers are packed by van der Waals forces only.

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds 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 Rfactors(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.