Crystal structure of (4R,5S,6R)-6-azido-5-benzyloxy-3,3,4-trifluoroazepan-1-ium 2,2,2-trifluoroacetate from synchrotron data

This report describes the crystal structure of highly substituted trifluoroazepane as an important building block of therapeutic interest. Data were collected with synchrotron radiation on a very small crystal.


Chemical context
Fluorine is virtually absent in naturally occurring bioactive molecules. However, about 20% of pharmaceuticals and 30% of agrochemicals have at least one fluorine atom (Mü ller et al., 2007;Isanbor & O'Hagan, 2006). Because fluorine is the most electronegative atom, it is small and forms very strong C-F bonds. The replacement of hydrogen by the bioisosteric fluorine in pharmacophores can lead to improved physical, chemical and biological properties (Ritter, 2012;Bé gué & Bonnet-Delpon, 2006;Kirk, 2006).
Substituted azepane rings are prevalent in many bioactive natural compounds (Wipf & Spencer, 2005;Nú ñ ez-Villanueva et al., 2011). Recently, substituted azepane rings and related compounds (iminocyclitols or iminosugars) have attracted considerable attention from medicinal chemists because of their great potential as glycosidase inhibitors (Stü tz, 1999) and antidiabetic (Painter et al., 2004), anticancer (Zitzmann et al., 1999) and antiviral agents (Laver et al., 1999) and are also effective against HIV (Sinnott, 1990). The conformational control of such flexible ring structures is important to their bioactivity. ISSN 2056-9890 We have previously reported stereospecific deoxyfluorination reactions of substituted seven-membered N-heterocycles such as azepanes , 2015Patel et al., , 2014. The fluorine atoms that were added were found to regulate the conformational preferences of the N-heterocycle rings, and these fluorine-directed conformational changes were analysed by NMR techniques in solution in conjunction with computational modelling. Solution conformation analysis of the trifluorinated azepane was found to be difficult, and its direct solid-state structural analysis was also not feasible without having to add various substituents (Patel et al., 2014). Incorporation of benzyloxy and azide substituents in the 5and 6-positions of the seven-membered ring led to crystal formation. However, the crystals were extremely small (0.015 Â 0.01 Â 0.01 mm) and diffraction data were obtained on the title trifluorinated azepane compound, C 15 H 16 F 6 N 4 O 3 (1), directly using synchrotron radiation.

Structural commentary
The compound crystallizes in a chiral space group (monoclinic, P2 1 ) with two sets of cations and anions (molecule A and B) in the asymmetric unit. Each cation has the same stereochemistry. An ORTEP view of the cation in molecule A, Fig. 1, depicts the absolute configuration and atom-labelling scheme. The B cation and anion are labelled similarly but with trailing B characters after the atom numbers. The absolute configuration was assigned based on that of the known starting material.
An alternative ORTEP view, Fig. 2, shows the asymmetric unit with association between A and B molecules via two C-HÁ Á ÁF interactions to form dimers. The asymmetric unit is completed by the two triflate anions C and D. These are variously linked in an A to C and B to D fashion by N-HÁ Á ÁO, N-HÁ Á ÁF, C-HÁ Á ÁO and C-HÁ Á ÁF hydrogen bonds, Table 1.
The two molecules differ significantly in their sevenmembered ring conformations, in particular around C2 and C3 with significantly different torsion angles, Fig. 3, where the molecules are involved in making dimeric contacts. Torsion angles within the two rings are shown in Fig. 3 One of the two molecules (A) in the asymmetric unit, showing the atom numbering. Displacement ellipsoids are drawn at the 50% probability level.

Figure 2
A view of the complete asymmetric unit consisting of two molecules of (1) and two trifluoromethanesulfonate anions. In this and subsequent figures, hydrogen bonds are drawn as dashed lines.

Figure 3
Conformations and torsion angles of the seven-membered rings of molecules A and B.

Ring conformation analysis
A computational analysis of ring conformations of compound (1) was carried out using protocols reported earlier (Patel et al., , 2014. Conformers were first generated by the stochastic method and minimized in the MMFF94x force field with chloroform as the solvent to produce nine conformational clusters within 3-5 kcal mol À1 in energy that are distinct in their azepane-ring conformations, Fig. 4. Representative conformers were then subjected to DFT geometry optimization [SV(P) basis set at the B3LYP level in COSMO solvent chloroform]. Two of the nine ring geometries (geometries vi and vii, Fig. 4) found by this computational analysis matched to geometries A and B of compound (1) in the unit cell, respectively. Hence the X-ray structure reported here for (1) validates our conformational analysis methodology as reported earlier (Patel et al., , 2014.

Supramolecular features
In the crystal structure, C anions form chains along the a-axis direction through F3CÁ Á ÁO1C contacts at a distance of 2.78 (2) Å . Each anion further connects to an A cation with O1C accepting three interactions and N1A as a bifurcated donor, leading to the formation of N1A-H1AAÁ Á ÁO1C, N1A-H1ABÁ Á ÁO1C and C4A-H4AAÁ Á ÁO1C hydrogen bonds and generating R 1 2 (4) and R 1 2 (5) ring motifs, respectively (Bernstein et al., 1995). These contacts generate columns of A molecules along a. These columns are further supported by weak C7A-H7AAÁ Á ÁCg2 contacts (Cg2 is the mid-point of the C10A-C11A bond of the C8A-C13A phenyl ring), Fig. 5. Similarly, B cations are linked to D anions with O2D accepting three interactions and forming N1B--H1BAÁ Á ÁO2D, N1B-H1BBÁ Á ÁO2D and C4B-H4BAÁ Á ÁO2D hydrogen bonds. Unlike the AC system however, a C4B-H4BAÁ Á ÁF1D hydrogen bond completes the BÁ Á ÁD cation-anion contacts. Nine conformations of compound (1) found by computational analysis. The number in parenthesis is the relative energy in kcal mol À1 .

Figure 5
Intermolecular contacts between A cations and C anions viewed along c.
Cg1 and Cg2 are the mid-points of the C10A-C11A and C10B-C11B bonds, respectively.

D-HÁ
These generate R 1 2 (4) and R 2 1 (5) ring motifs respectively. Weak C7B-H7BAÁ Á ÁCg1 contacts (Cg1 is the midpoint of the C10B-C11B bond of the C8B-C13B phenyl ring) link adjacent B molecules, also forming columns of B cations and D anions along the a-axis direction, Fig. 6. Contacts between the A and B cations are limited to very weak C12B-H12BÁ Á ÁN4A hydrogen bonds linking adjacent columns of A and B cations, Fig. 7. This eclectic mixture of contacts generates columns with an ABCD repeat unit in the direction of the a axis, Fig. 8. Additional N-HÁ Á ÁO, C-HÁ Á ÁO and C-HÁ Á ÁF contacts result in a three-dimensional network of cations and anions stacked along c.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. All H atoms were refined using a riding model, with N-H = 0.91 Å , C-H = 0.95 Å for aromatic, 1.00 Å for methine and 0.99 Å for methylene, all with U iso (H) = 1.2U eq (N/C). Because of the lower reflectionsto-parameter ratio, anisotropic displacement parameters of several atoms in the least-squares refinement had to be   Intermolecular contacts between the A and B cations viewed along c. Mid-points of the C10A-C11A and C10B-C11B bonds are shown as coloured spheres.

Figure 8
Packing of molecules in the unit cell viewed along c. Molecules A (green) and B (blue), trifluoromethanesulfonate anions C (red) and D (yellow). Hydrogen-bonding contacts are shown as dashed lines. restrained using the RIGU command. These were applied to azide groups, atoms in the seven-membered and a few atoms in phenyl rings.  program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: OLEX2 (Dolomanov et al., 2009) and Mercury (Macrae et al., 2008); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).