Crystal structure of (R)-6-fluoro-2-[(S)-oxiran-2-yl]chroman

The title compound, C11H11FO2, is a building block in the synthesis of the active pharmaceutical ingredient dl-nebivolol. The synthesis starting from the enantiomerically pure (R)-6-fluoro-4-oxo-3,4-dihydro-2H-chromene-2-carboxylic acid resulted in a mixture of two stereoisomers, namely (R)-6-fluoro-2-[(S)-oxiran-2-yl]chroman and (R)-6-fluoro-2-[(R)-oxiran-2-yl]chroman. The mixture was separated by column chromatography but only one stereoisomer crystallized. The X-ray structure analysis revealed that the solid consisted of the R,S isomer. A similar procedure was repeated for (S)-6-fluoro-4-oxo-3,4-dihydro-2H-chromene-2-carboxylic acid and, in this case, the S,R isomer was produced as a crystalline solid. Thus, all four stereoisomers of the title epoxide were obtained and their absolute configuration was assigned. The crystal studied was refined as an inversion twin.


Related literature
For the synthesis of the enantiopure title product, see: Jas et al. (2011). For pharmacological properties of nebivolol, see: Van Lommen et al. (1990). For a study of related isomers, see: Horiguchi et al. (1997). For the determination of absolute structure, see: Flack (2003  pure form (Fig. 2). These epoxide intermediates can be further used in a ring-opening reaction with benzylamine to yield, after catalytic hydrogenation, nebivolol isomer with four chiral center.
Of the four stereisomers of the title compound only two form solids, and the remaining two are liquids under normal conditions. X-ray structural analysis from a single crystal of a solid stereoisomer obtained from (R)-6-fluoro-4-oxo-3,4dihydro-2H-chromene-2-carboxylic acid revealed that it has R,S configuration at the stereogenic centers ( Fig. 1). Crystal data for this stereoisomer are reported in this paper. As expected, X-ray structural analysis of the solid epoxide obtained from the S enantiomer of the acid revealed the S,R configuration at the stereogenic centers.
Crystals suitable for X-ray analysis were obtained in a fraction from column chromatography with heptane/ethyl acetate as eluent.

S3. Refinement
Crystal data, data collection and structure refinement details are summarized in  View of the molecular structure of the title compound with 50% probability displacement ellipsoids for the non-hydrogen atoms.

Figure 2
Reaction scheme for the synthesis of nebivolol
[α] 29 D +67.5 o (c =1.0 in CHCl 3 ) HRMS (ESI) for C 18 H 21 FNO 2 [M+H] + m/z = 195.08158, found m/z = 195.08120. IR (cm -1 ) 3050, 3001, 2951, 1492, 1220 Data CCDC-1407326 contains the enantiomer structure of (S)-6-Fluoro-2-[(R)-oxiran-2-yl]chroman. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif 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. Refined as a 2-component inversion twin.