A functionalized enol lactone containing a protected α-amino acid

The crystal structure of N-(3,9-dimethyl-4-phenyl-2,5-dioxo-3,4-dihydro-2H,5H-pyrano[3,2-c]chromen-3-yl)-N-methylbenzamide methanol monosolvate, C28H23NO5·CH3OH, has been determined at room temperature by X-ray diffraction. Structural parameters are discussed with reference to ab initio calculations.


Comment
Highly functionalized enol lactones constitute an attractive class of compounds not only because of their molecular architecture but also because of the interesting biopharmacological activity often shown by compounds possessing this subunit in their molecular skeleton (Murray et al., 1982;Harborne & Baxter, 1999;Qabaja et al., 2000).
The molecule 3 is mainly constituted by a cumarine system which is further [3,2-c]-fused with a 3,4-dihydro-pyran-2-one ring carrying at posistion 3 a methyl and a methyllbenzamide group while a phenyl moiety is placed at 4. Then these C atoms at 3 and 4 are chiral centers showing the same configuration. Due to the P2 1 /n centric space group, both the S,R and R,S diastereomers are present in the solid state and the crystals represent a perfect racemic mixture. The methyl cumarin fragment is planar within experimental error; bonds distances and angles of this moiety are in good agreement with the corresponding values reported for such fragments (Yu et al., 2003). The methylbenzamide fragment is not planar and shows the usual bond geometry values: the phenyl ring is rotated by 60.9 (3)° with respect to the amide moiety. The three carbonyl the not significant pyramidalization of the nitrogen. Therefore the nitrogen geometry appears planar and might be related to its sp 2 hybridization caused by the delocalization of its lone-pair over the carbonyl fragments as also suggested by the length of the bonds involving the N(24) atom. Phenyl group bonded to C(26) is rotated with respect to this system (the N(24)-C(26)-C(28)-C(29) torsion angle is 60.5 (3)°) and does not participate to the possible π-electronic delocalization as evidenced by the C(28)-C(26) single-bond length value [1.491 (3) Å]. In the crystal lattice, each pair of molecules related by an inversion centre shows a π-interaction of 3.4 (1) Å between their planar furo[3,2-c]coumarin fragments. The substituent phenyl rings, despite their out-of-plane rotation, are directed far from the flat central molecular bulk and do not obstacle the strong π-stacking in the formation of the centrosymmetric couple, remaing at its surface as the co-crystallized methanol. Therefore crystal packing is constituted by dimeric units interconnected by several weak hydrogen bonds involving the O atoms.
Ab initio and DFT calculations on some models have been performed in order to clarify the relevant observed asymmetry in the O-C-O bond angles of the cumarinic fragment. From these results we can conclude that the observed and calculated carbonyl distortion arises exclusively from electronic rather than steric factors. However further statistical and theoretical study are necessary to better clarify the real nature of this asymmetry.

Fig. 2.
We recently described a novel kind of cyclo-condensation process that converts two equivalents of a münchnone and a 1,3-dicarbonyl compound into a functionalized enol lactone containing a protected α-amino acid (Grassi et al., 2003).
In trying to get some insight regarding this important asymmetry in the O-C-O bond angle of the cumarinic fragment an ab initio and DFT calculations on some model compounds, such as the bicyclic 3,4-dyhidro-pyrano[4,3-b]pyran-2,5-dione, a series of 3-substituted pyran-2-one, the cumarine and 3-methyl-cumarine, were performed by using the basis set 6-31+G (d,p) in GAUSSIAN98 (Frisch et al., 1998). At all level of calculations this controversial asymmetry (Kokila et al., 1996) around carbonilic C atom is consistent with the X-ray structural observations.

Refinement
A suitable colourless single-crystal was mounted on a capillary glass fiber. The intensity data were collected at room temperature up to 2θ = 50° by using the ω-2θ scan technique with variable scan speed on a Siemens P4 4-cirlce diffractometer with graphite monochromated Mo Kα radiation. Lattice parameters were obtained from least-squares refinement of the setting angles of 59 reflections with 14 < 2θ < 35°. Intensities were corrected for Lonrentz polarization and then for absorption effetcts. No crystal deterioration was revealed during irradiation. The structure, solved by standard Direct Methods, was completed and refined by a combination of least squares technique and Fourier Syntheses. Whereas several H atoms were located on final ΔF map, the H atoms were included in the refinement among the "riding model" method with the X-H bond geometry and the H isotropic displacement parameter depending on the parent atom X. The refinement, with all non H atoms anisotropic and carried out by the full matrix least-square technique, has included a parameter for extinction correction. The last difference Fourier map showed no significant density residuals. One terminal methyl (C16) appeared to be affected by a significant rotational disorder and its H's group has to be split over two symmetric positions with equal occupancy 0.5; the disorder of the methanol molecule causes its large thermal ellipsoids. Fig. 1. Perspective view of the asymmetric unit with numbering scheme of compound 3. Dashed line represents H-bond with the co-crystallized methanol hydrogen. Ellipsoids are drawn at 20% of probability level while hydrogen size is arbitrary.