1-Ethyl 2-methyl 3,4-bis(acetyloxy)pyrrolidine-1,2-dicarboxylate: crystal structure, Hirshfeld surface analysis and computational chemistry

The tetra-substituted pyrrolidine ring in the title compound has a twisted conformation about the central C—C bond with the N-bound ethylcarboxylate group in an equatorial position and the remaining substituents in axial positions. In the crystal, methyl- and methylene-C—H⋯O(carbonyl) interactions involving all four carbonyl-O atoms lead to supramolecular double-layers.

The title compound, C 13 H 19 NO 8 , is based on a tetra-substituted pyrrolidine ring, which has a twisted conformation about the central C-C bond; the C m -C a -C a -C me torsion angle is 38.26 (15) [m = methylcarboxylate, a = acetyloxy and me = methylene]. While the N-bound ethylcarboxylate group occupies an equatorial position, the remaining substituents occupy axial positions. In the crystal, supramolecular double-layers are formed by weak methyl-and methylene-C-HÁ Á ÁO(carbonyl) interactions involving all four carbonyl-O atoms. The two-dimensional arrays stack along the c axis without directional interactions between them. The Hirshfeld surface is dominated by HÁ Á ÁH (55.7%) and HÁ Á ÁC/CÁ Á ÁH (37.0%) contacts; HÁ Á ÁH contacts are noted in the inter-double-layer region. The interaction energy calculations point to the importance of the dispersion energy term in the stabilization of the crystal.

Chemical context
A number of diseases, especially diabetes but also including viral diseases, cystic fibrosis and cancer, can be treated withglucosidase inhibitors (Dhameja & Gupta, 2019;Kiappes et al., 2018); for a review of the relevant patent literature, see Brá s et al. (2014). Imino-and aza-sugars are strong inhibitors of the enzyme and are attracting current interest for chaperone therapy of Gaucher disease (Matassini et al., 2020). The trihydroxyl-substituted compound, aminociclitol, (I), is a known -glucosidase inhibitor and is a natural product, being found in several plants (Assefa et al., 2020). The synthesis of (I) can proceed from several key intermediates (Garcia, 2008;Liu & Ma, 2017) and it is this consideration that prompted the structural investigation of the title compound, C 13 H 19 NO 8 , (II). Specifically, the HCl salt of (I) can be prepared from (II) after being subjected to a sequence of reactions comprising a reduction step, reflux acid hydrolysis, chromatographic purification on ion-exchange resin Dowex-H + and, finally, hydrochloride formation. In this way, (I)ÁHCl was obtained in 67% yield (Garcia, 2008). In connection with supporting structural studies (Zukerman-Schpector et al., 2017) of crucial intermediates related to the synthesis of pharmacologically active (I), herein, the crystal and molecular structures of (II) are described. This is complemented by a detailed analysis of the supramolecular architecture by Hirshfeld surface analysis, non-covalent interactions plots and computational chemistry.

Structural commentary
The molecular structure of (II), Fig. 1, features a tetrasubstituted pyrrolidine ring. The conformation of the fivemembered ring is best described as being twisted about the C2-C3 bond; the C1-C2-C3-C4 torsion angle is 38.26 (15) indicating a (+)syn-clinal configuration. With respect to the five-membered ring, the N-bound methylcarboxylate substituent occupies an equatorial position; the sum of angles about the N1 atom amounts to 360 , indicating this is an sp 2 centre. At the C1-C3 centres, the methylcarboxylate and 2 Â acetyloxy substituents, respectively, occupy axial positions. For the molecule illustrated in Fig. 1, the chirality of each of the C1-C3 atoms is R, S and S, respectively; the centrosymmetric unit cell contains equal numbers of each enantiomer. When viewed towards the approximate plane through the pyrrolidine ring, the N-bound substituent is approximately co-planar, the C2-acetyloxy lies to one side of the plane, and the C1-and C3-substituents lie to the other side.

Supramolecular features
There are two classes of identifiable non-covalent C-HÁ Á ÁO interactions occurring in the crystal of (II). As identified in PLATON (Spek, 2020), methyl-C9-HÁ Á ÁO5(carbonyl) contacts (Table 1) occur between centrosymmetrically related molecules to form a dimeric aggregate and an 18-membered {Á Á ÁOCOC 3 OCH} 2 synthon, Fig. 2(a). The second level, i.e. weaker, of C-HÁ Á ÁO interactions assemble molecules into a supramolecular layer in the ab plane, Fig. 2(b), at separations beyond normally accepted values in PLATON (Spek, 2020). Here, a methylene-C3-H atom is bifurcated, forming contacts with the carbonyl-O1 and O3 atoms of a translationally related molecule along the a-axis direction. This is complemented by a methyl-C11-HÁ Á ÁO7(carbonyl) interaction occurring along the b-axis direction, Fig. 2(c). The layer thus formed by these contacts is connected into a double-layer via the methyl-C9-HÁ Á ÁO5(carbonyl) interactions mentioned above. The double-layers stack along the c axis without directional interactions between them.

Non-covalent interaction plots
Before embarking on a more detailed analysis of the overall molecular packing of (II), in particular of the inter-layer region along the c axis, non-covalent interaction plots    The molecular structure of (II), showing the atom-labelling scheme and displacement ellipsoids at the 35% probability level. Table 1 Hydrogen-bond geometry (Å , ). Symmetry codes: (i) Àx; Ày; Àz þ 2; (ii) x À 1; y; z; (iii) x; y À 1; z. (Johnson et al., 2010;Contreras-García et al., 2011) were calculated to analyse in more detail the nature of the specified C-HÁ Á ÁO contacts described in Supramolecular features. This method analyses the electron density (and derivatives) around the specified intermolecular contacts and generates colourbased isosurfaces as detailed in the cited literature. The results, through a three-colour scheme, enable the visualization of contacts as being attractive (blue isosurface), repulsive (red) or otherwise. For the weak interactions in focus, a green isosurface indicates a weakly attractive interaction. The isosurfaces for three identified C-HÁ Á ÁO contacts are given in the upper view of Fig. 3, and each displays a green isosurface indicating weakly attractive interactions. The lower views of Fig. 3 show the plots of RDG versus sign( 2 )(r) for the three sets of C-HÁ Á ÁO interactions. The green peaks apparent at density values less than 0.0 a.u. indicate these are weakly attractive interactions.

Hirshfeld surface analysis
In order to understand further the interactions operating in the crystal of (II), the calculated Hirshfeld surfaces were mapped over the normalized contact distance, d norm (McKinnon et al., 2004) and electrostatic potential (Spackman et al., 2008) with associated two-dimensional (2-D) (full and delineated) fingerprint (FP) plots (Spackman & McKinnon, 2002). These were generated using Crystal Explorer 17 (Turner et al., 2017) following literature procedures (Tan et al., 2019). The potentials were calculated using the STO-3G basis set at the Hartree-Fock level of theory. The bright-red spots on the Hirshfeld surface mapped over d norm , Fig. 4(a), near the carbonyl-O (O1, O3, O5 and O7) and methyl-C-H (H3 and H9B) atoms correspond to the C-HÁ Á ÁO interactions listed in Table 1. These observations were confirmed through the Hirshfeld surface mapped over the calculated electrostatic potential in Fig. 4(b), where the surface around carbonyl-O and methyl-C-H atoms are shown in red (negative electrostatic potential) and blue (positive electrostatic potential), respectively. Besides the C-HÁ Á ÁO interactions listed in Table 1, a long C13-H13AÁ Á ÁO5 interaction is reflected in the d norm surface as a faint red spot in Fig. 5    Two views of the Hirshfeld surface mapped for (II) over (a) d norm in the range of À0.083 to +1.828 arbitrary units and (b) the calculated electrostatic potential in the range of À0.077 to 0.054 a.u.

Figure 5
Views of the Hirshfeld surface mapped over d norm for (II) in the range À0.083 to +1.828 arbitrary units, highlighting within red circles (a) a weak C-HÁ Á ÁO interaction and (b) CÁ Á ÁO contacts. intra-layer CÁ Á ÁO contacts with separations 0.01-0.04 Å shorter than the sum of their van der Waals radii, Table 2, are observed as faint red spots on the d norm surface in Fig. 5(b), reflecting the specific influence of the C8, C10 and O1 atoms participating in these contacts.
The corresponding two-dimensional fingerprint plot for the Hirshfeld surface of (II) is shown with characteristic pseudosymmetric wings in the upper left and lower right sides of the d e and d i diagonal axes, respectively, in Fig. 6(a). The individual HÁ Á ÁH, HÁ Á ÁO/OÁ Á ÁH, HÁ Á ÁC/CÁ Á ÁH, OÁ Á ÁO, OÁ Á ÁC/ CÁ Á ÁO and HÁ Á ÁN/NÁ Á ÁH contacts are illustrated in the delineated two-dimensional fingerprint plots (FP) in Fig. 6(b)-(g), respectively; the percentage contributions from different interatomic contacts are summarized in Table 3. The HÁ Á ÁH contacts contribute 55.7% to the overall Hirshfeld surface with a beak-shape distribution in the FP with shortest d e = d i $2.4 Å . This short interatomic HÁ Á ÁH contact involving the methyl-H11C and methylene-H4B atoms, Table 2, is around the sum of their van der Waals separation and occurs in the intra-layer region along the b axis. Consistent with the C-HÁ Á ÁO interactions making the major contribution to the directional interactions in the crystal, HÁ Á ÁO/OÁ Á ÁH contacts contribute 37.0% to the overall Hirshfeld surface. A distinctive feature in the FP of Fig. 6(c), is the two symmetric spikes at d e + d i $2.4 Å . Although HÁ Á ÁC/CÁ Á ÁH, OÁ Á ÁO, OÁ Á ÁC/ CÁ Á ÁO and HÁ Á ÁN/NÁ Á ÁH appear as splash-like distributions of points at d e + d i $3.0 Å , Fig. 6(d)-(g), their contributions to the overall Hirshfeld surface are each below than 3.0%. These contacts and the remaining interatomic contacts have only a small effect on the packing, as the sum of their contributions to the overall Hirshfeld surface is less than 8%.

Energy frameworks
The pairwise interaction energies between the molecules in the crystal of (II) were calculated using the wave function at the B3LYP/6-31G(d,p) level of theory. The total energy comprise four terms: electrostatic (E ele ), polarization (E pol ), dispersion (E dis ) and exchange-repulsion (E rep ) and were scaled as 1.057, 0.740, 0.871 and 0.618, respectively (Edwards et al., 2017). The characteristics of the intermolecular interactions in term of their energies are collated in     contacts and long-range HÁ Á ÁH contacts. Whereas molecules between the supramolecular double layers are stabilized by long-range HÁ Á ÁH contacts. Views of the energy framework diagrams down the b axis are shown in Fig. 7 and serve to emphasize the contribution of dispersion forces in the stabilization of the crystal.

Database survey
There are no close precedents for the substitution pattern observed in the tetra-substituted pyrrolidine ring of (II) with, arguably, the most closely related structure being that of (III) (KULQEP; Szcześniak et al., 2015), at least in terms of the substitution pattern around the ring; the chemical diagram for (III) is shown in Fig. 8.

Figure 7
Perspective views of the energy frameworks calculated for (II) and viewed down the b axis showing (a) electrostatic potential force, (b) dispersion force and (c) total energy. The radii of the cylinders are proportional to the relative magnitudes of the corresponding energies and were adjusted to the same scale factor of 55 with a cut-off value of 5 kJ mol À1 within 2 Â 2 Â 2 unit cells.

Refinement details
Crystal data, data collection and structure refinement details are summarized in Table 5. The carbon-bound H atoms were placed in calculated positions (C-H = 0.96-0.98 Å ) and were included in the refinement in the riding-model approximation, with U iso (H) set to 1.2-1.5U eq (C).