Ethyl 2-(4-methoxyphenyl)-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate: crystal structure and Hirshfeld analysis

In the title compound, the epoxide O atom and the 4-methoxyphenyl group lie on opposite sides of the pyrrolidyl ring, whereas the ethyl ester is approximately planar. Linear supramolecular chains sustained by methine-C—H⋯O(carbonyl) interactions are evident in the molecular packing.

The title compound, C 14 H 17 NO 4 , features an epoxide-O atom fused to a pyrrolidyl ring, the latter having an envelope conformation with the N atom being the flap. The 4-methoxyphenyl group is orthogonal to [dihedral angle = 85.02 (6) ] and lies to the opposite side of the five-membered ring to the epoxide O atom, while the N-bound ethyl ester group (r.m.s. deviation of the five fitted atoms = 0.0187 Å ) is twisted with respect to the ring [dihedral angle = 17.23 (9) ]. The most prominent interactions in the crystal are of the type methine-C-HÁ Á ÁO(carbonyl) and these lead to the formation of linear supramolecular chains along the c axis; weak benzene-C-HÁ Á ÁO(epoxide) and methine-C-HÁ Á ÁO(methoxy) interactions connect these into a threedimensional architecture. The analysis of the Hirshfeld surface confirms the presence of C-HÁ Á ÁO interactions in the crystal, but also the dominance of HÁ Á ÁH dispersion contacts.

Chemical context
-Glucosidase inhibitors have shown potential for the treatment of several health conditions such as cystic fibrosis, diabetes, influenza and cancer. In this context, a thorough patent review on -glucosidase inhibitors was published recently (Brá s et al., 2014). Among -glucosidase inhibitors are a series of natural products including aminociclitols (I) and (II); see Scheme 1. The tri-hydroxyl-substituted compound (I) is found in several plants, e.g. Morus alba (Asano et al., 1994), Arachniodes standishii (Furukawa et al., 1985), Angylocalyx boutiqueanus (Nash et al., 1985a), Hyacinthoides non-scripta (Watson et al., 1997) among others, whereas the di-hydroxyl substituted compound (II) is found in the seeds of Castanospermum austral (Nash et al., 1985b).
In a search for an effective synthetic path, e.g. good yield, to obtain both (I) and (II), it was found that they could be prepared starting from a common epoxide intermediate (III), which in turn could be prepared (Garcia, 2008) from (IV) when subjected to a Prilezhaev epoxidation (Prilezhaev, 1909;Swern, 1949). Herein, the crystal and molecular structures of (III) are described, motivated by the desire to unambiguously establish the relative configuration of the stereogenic centres. A further evaluation of the supramolecular association has been undertaken by analysing the Hirshfeld surface of (III).

Structural commentary
The molecular structure of (III), Fig. 1, comprises a pyrrolidyl ring fused to an epoxide O1 atom giving rise to a locally (mirror) symmetric fused-ring system. The nitrogen atom is connected to an ethyl ester group, with the carbonyl-O2 atom orientated towards the ring-methylene group. The pyrrolidyl ring is substituted in a 2-position by the 4-methoxyphenyl group. The conformation of the pyrrolidyl ring is an envelope with atom N1 being the flap atom and occupying a position syn to the epoxide-O1 atom. The dihedral angle between the fused three-and five-membered rings is 78.53 (10) , indicating an almost orthogonal relationship. To a first approximation, the ethyl carboxylate group (r.m.s. deviation of the five nonhydrogen atoms = 0.0187 Å ) is planar and forms a dihedral angle of 17.23 (9) with the five-membered ring. The 4-methoxyphenyl substituent is also approximately planar with an r.m.s. deviation of 0.0274 Å for the eight fitted non-hydrogen atoms; the small twist of the methoxy group out of the plane of the benzene ring to which is connected, i.e. the C14-O4-C11-C12 torsion angle is 175.67 (18) , is primarily responsible for the deviations from exact planarity. The orthogonal relationship between this plane and that through the pyrrolidyl ring is seen in the dihedral angle formed between them of 85.02 (6) . Globally, the molecule has an extended planar region, comprising the pyrrolidyl ring and the ethyl ester residue with the epoxide O atom lying to one side of this plane and the 4-methoxyphenyl substituent to the other.
The chirality of each of the methine-C1-C3 atoms in the molecule illustrated in Fig. 1, is S, S and R, respectively, with the centrosymmetric unit cell containing equal amounts of both enantiomers.

Supramolecular features
The most prominent feature in the packing of (III) is the formation of a linear supramolecular chain sustained by methine-C-HÁ Á ÁO(carbonyl) interactions, as illustrated in  and methine-C-HÁ Á ÁO(methoxy) contacts, shown as blue dashed lines.

Figure 1
The molecular structure of (III), showing the atom-labelling scheme and displacement ellipsoids at the 35% probability level. methine-C-HÁ Á ÁO(methoxy) contacts to sustain a threedimensional architecture, Fig. 2b. Further insight into the molecular packing is provided by an analysis of the Hirshfeld surface below.

Figure 4
Two views of the Hirshfeld surface for (III) mapped over the calculated electrostatic potential in the range À0.083 to + 0.042 au. The red and blue regions represent negative and positive electrostatic potentials, respectively.
The donor and acceptor of the C-HÁ Á ÁO hydrogen bond instrumental for the formation of the supramolecular chain, i.e. between the methine-C-H2 and carboxylate-O2 atoms, are viewed as the bright-red spots near these atoms on the Hirshfeld surface mapped over d norm in Fig. 3a and b. The bright-red spot, near methoxy-O4, and lighter spot, near methine-C3, and the diminutive red spot near methoxy-O4 and brighter spot near methylene-C4 in Fig. 3, are indicative of another C-HÁ Á ÁO interaction (Table 1) and the short interatomic CÁ Á ÁO/OÁ Á ÁC contact (Table 2), respectively. On the Hirshfeld surface mapped over electrostatic potential in Fig. 4, the donors and acceptors of intermolecular interactions are represented by blue and red regions, respectively, corresponding to positive and negative electrostatic potentials near the respective atoms. The immediate environment about a reference molecule within Hirshfeld surfaces mapped over the electrostatic potential highlighting intermolecular C-HÁ Á ÁO interactions and short inter-atomic OÁ Á ÁH/HÁ Á ÁO contacts (Table 2) is illustrated in Fig. 5.
The overall two dimensional fingerprint plot, Fig. 6a, and those delineated into HÁ Á ÁH, OÁ Á ÁH/HÁ Á ÁO and CÁ Á ÁH/HÁ Á ÁC contacts (McKinnon et al., 2007) are illustrated in Fig. 6b-d, respectively; the relative contributions from various contacts to the Hirshfeld surface are summarized in Table 3. The major contribution of 55.2% to the Hirshfeld surface is from interatomic HÁ Á ÁH contacts, Fig. 6b, and is indicative of dispersive forces operating in the crystal. In the fingerprint plot delineated into OÁ Á ÁH/HÁ Á ÁO contacts, Fig. 6c, the 29.7% contribution results from the intermolecular C-HÁ Á ÁO interactions and short inter-atomic OÁ Á ÁH/HÁ Á ÁO contacts, Tables 1 and 2. In the plot, Fig. 6c, a pair of spikes with their tips at d e + d i $2.4 Å (with label '1') indicate the most significant C-HÁ Á ÁO interaction whereas the pair of two adjoining parabola with their peaks at around d e + d i $2.7 Å (label '2') represent short inter-atomic OÁ Á ÁH/HÁ Á ÁO contacts. The presence of the short inter-atomic CÁ Á ÁH/HÁ Á ÁC contact, Table 2, hitherto not mentioned, in Fig. 6d, leads to nearly symmetrical, characteristic wings with the pair of tips at d e + d i $2.9 Å as highlighted with label '3'. The low contributions from other contacts, Table 3, have a negligible effect on the packing as their inter-atomic distances are greater than sum of their respective van der Waals radii.

Database survey
There are three structures in the crystallographic literature (Groom et al., 2016)      2010) in Scheme 2, has the same bonds in the framework. The common feature of (V)-(VII) is an envelope conformation for the pyrrolidyl ring with the flap atom being the N atom which is syn to the epoxide O1 atom, i.e. as for (III). Major conformational differences are evident, however. With reference to the pyrrolidyl ring, in (V) and (VI), in common with (III), the ring-bound substituents occupy positions opposite to that of the epoxide O atom but, in (VII), this substituent lies to the same side of the pyrrolidyl ring.

Synthesis and crystallization
The synthesis of (III) is as described in (Garcia, 2008). Crystals for the structure analysis were obtained by the slow evaporation of its CHCl 3 solution. M. p. 378-379 K.

Ethyl 2-(4-methoxyphenyl)-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate
Crystal data where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.17 e Å −3 Δρ min = −0.23 e Å −3 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.