research communications\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

Journal logoCRYSTALLOGRAPHIC
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ISSN: 2056-9890
Volume 72| Part 5| May 2016| Pages 683-686
doi:10.1107/S2056989016005855

Crystal structure of (1S*,2R*)-7-benz­yl­oxy-2-methyl-3-tosyl-2,3,4,5-tetra­hydro-1H-3-benz­azepin-1-ol: elucidation of the relative configuration of potent allosteric GluN2B selective NMDA receptor antagonists

CROSSMARK_Color_square_no_text.svg
Bastian Tewes,a Bastian Frehland,a Roland Fröhlichb and Bernhard Wünscha,c*

aInstitut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstrasse 48, D-48149 Münster, Germany, bOrganisch-chemisches Institut der Westfälischen Wilhelms-Universität Münster, Corrensstr. 40, D-48149-Münster, Germany, and cCells-in-Motion Cluster of Excellence (EXC 1003 – CiM), Universität Münster, Germany
*Correspondence e-mail: wuensch@uni-muenster.de

Edited by H. Stoeckli-Evans, University of Neuchâtel, Switzerland (Received 4 March 2016; accepted 8 April 2016; online 15 April 2016)

In the title compound, C25H27NO4S, which crystallized as a racemate, the relative configuration of the adjacent OH and CH3 groups on the azepine ring is trans. The seven-membered azepin ring has a chair-like conformation. The planar aromatic rings of the benzyl and tosyl­ate moiety are inclined to the planar 3-benzazepine ring by 78.39 (15) and 77.03 (14)°, respectively, and to each another by 13.82 (15)°. In the crystal, mol­ecules are linked via O—H⋯O and C—H⋯O hydrogen bonds, forming double-stranded chains along the a-axis direction. The chains are linked via C—H⋯π inter­actions, forming a three-dimensional architecture.

CCDC reference: 1472947

1. Chemical context

Inhibition of overactive N-methyl-D-aspartate (NMDA) receptors represents a promising strategy for the treatment of acute (e.g. stroke, epilepsy, traumatic brain injury) and chronic neuronal disorders (e.g. neuropathic pain, depression, Alzheimer's and Parkinson's disease) (Bräuner-Osborne et al., 2000[Bräuner-Osborne, H., Egebjerg, J., Nielsen, E. Ø., Madsen, U. & Krogsgaard-Larsen, P. (2000). J. Med. Chem. 43, 2609-2645.]; Kew & Kemp, 2005[Kew, J. N. C. & Kemp, J. A. (2005). Psychopharmacology, 179, 4-29.]; Paoletti et al., 2013[Paoletti, P., Bellone, C. & Zhou, Q. (2013). Nat. Rev. Neurosci. 14, 383-400.]; Wu & Zhou, 2009[Wu, L.-J. & Zhou, M. (2009). Neurotherapeutics, 6, 693-702.]). The NMDA receptor consists of four proteins (hetero­tetra­mer), which form a cation channel allowing the penetration of Ca2+ and Na+ ions into the neuron (Furukawa et al., 2005[Furukawa, H., Singh, S. K., Mancusso, R. & Gouaux, E. (2005). Nature, 438, 185-192.]). In particular, NMDA receptors containing the GluN2B subunit are an attractive target for the development of innovative drugs, since the expression of the GluN2B subunit is limited to only a few regions of the central nervous system, including cortex, striatum and hippocampus (Borza & Domány, 2006[Borza, I. & Domány, G. (2006). Curr. Top. Med. Chem. 6, 687-695.]; Layton et al., 2006[Layton, M. E., Kelly, M. J. III & Rodzinak, K. J. (2006). Curr. Top. Med. Chem. 6, 697-709.]; Mony et al., 2009[Mony, L., Kew, J. N. C., Gunthorpe, M. J. & Paoletti, P. (2009). Br. J. Pharmacol. 157, 1301-1317.]). Moreover, the GluN2B subunit can be addressed selectively by ligands inter­acting with the so-called ifenprodil binding site, which is formed at the inter­face between GluN2B and GluN1 subunits (Karakas et al., 2011[Karakas, E., Simorowski, N. & Furukawa, H. (2011). Nature, 475, 249-253.]; Paoletti et al., 2013[Paoletti, P., Bellone, C. & Zhou, Q. (2013). Nat. Rev. Neurosci. 14, 383-400.]).

The 2-piperidino-1-phenyl­propan-1-ol derivative ifenprodil (Paoletti et al., 2013[Paoletti, P., Bellone, C. & Zhou, Q. (2013). Nat. Rev. Neurosci. 14, 383-400.]; Williams, 2001[Williams, K. (2001). Curr. Drug Targets, 2, 285-298.]) (Fig. 1[link]) represents the first ligand inter­acting with this binding site at the NMDA receptor. As a result of its poor selectivity and low bioavailability, ifenprodil has not been developed as a drug for clinical use. In order to improve the selectivity and metabolic stability, the flexible β-amino­alcohol substructure of ifenprodil has been incorporated into a rigid tetra­hydro-3-benzazepine ring (Tewes et al., 2010a[Tewes, B., Frehland, B., Schepmann, D., Schmidtke, K.-U., Winckler, T. & Wünsch, B. (2010a). Chem. Med. Chem. 5, 687-695.],b[Tewes, B., Frehland, B., Schepmann, D., Schmidtke, K.-U., Winckler, T. & Wünsch, B. (2010b). Bioorg. Med. Chem. 18, 8005-8015.]; Schepmann et al., 2010[Schepmann, D., Frehland, B., Lehmkuhl, K., Tewes, B. & Wünsch, B. (2010). J. Pharm. Biomed. Anal. 53, 603-608.]; Falck et al., 2014[Falck, E., Begrow, F., Verspohl, E. & Wünsch, B. (2014). J. Pharm. Biomed. Anal. 88, 96-105.]).

[Figure 1]
Figure 1
Synthesis of GluN2B antagonists including the lead compound ifenprodil and the target compound (S,R)-4. Reagents and reaction conditions: (a) NaBH4, CH3OH, (S,R)-2 50%, (R,R)-3 23%.

2. Elucidation of the relative configuration

For the synthesis of 3-benzazepine analogs of ifenprodil, we developed a chiral pool synthesis starting with (R)-alanine. In a five step synthesis (Fig. 1[link]), the central inter­mediate ketone (R)-1 was prepared from (R)-alanine (Tewes et al., 2015[Tewes, B., Frehland, B., Schepmann, D., Robaa, D., Uengwetwanit, T., Gaube, F., Winckler, T., Sippl, W. & Wünsch, B. (2015). J. Med. Chem. 58, 6293-6305.]).

The reduction of the ketone (R)-1 with NaBH4 led to the diastereomeric alcohols (S,R)-2 and (R,R)-3, which were further transformed into potent GluN2B antagonists by reductive removal of the tosyl group, alkyl­ation with 1-chloro-4-phenyl­butane and finally, hydrogeno­lytic cleavage of the benzyl ether. For example, the phenol (S,R)-4 displays very high affinity towards the ifenprodil binding site of the NMDA receptor (Ki = 26 nM) and, moreover, (S,R)-4 is able to reduce the glutamate- and glycine-induced cytotoxicity with an IC50 value of 9.0 nM (Tewes et al., 2015[Tewes, B., Frehland, B., Schepmann, D., Robaa, D., Uengwetwanit, T., Gaube, F., Winckler, T., Sippl, W. & Wünsch, B. (2015). J. Med. Chem. 58, 6293-6305.]).

[Scheme 1]

The diastereomeric alcohols (S,R)-2 and (R,R)-3 were separated by flash column chromatography and isolated in 50% and 23% yield, respectively. However, as a result of flexibility of the seven-membered tetra­hydro-3-benzazepine ring, it was not possible to assign the relative configuration of the methyl and hy­droxy moiety. Therefore, the main diastereomer (1S,2R)-2 was crystallized and we report herein on its crystal structure.

3. Structural commentary

The mol­ecular structure of the title compound (1S,2R)-2 is illustrated in Fig. 2[link]. Since the starting material was not enanti­omerically pure, the compound crystallized as a racemate. However, the relative trans-configuration of the OH and CH3 groups in the 1- and 2-positions on the azepine ring is clearly shown, leading to a trans-configuration for compound (S*,R*)-2. The CH3 and the OH groups adopt an axial orientation in the seven-membered azepine ring which has a chair conformation. The phenyl group of the benzyl moiety (C16–C21) and the phenyl group of the tosyl­ate moiety (C25–C30) are inclined to the benzene ring of the 3-benzazepine ring (C6–C11) by 78.39 (15) and 77.03 (14)°, respectively, and to each another by 13.82 (15)°. In the azepine ring, the bonds between the N atom, N3, and its adjacent C atoms, C2 and C4 [1.483 (3) and 1.480 (3) Å, respectively] are naturally shorter than the corresponding C—C bonds [1.509 (4)–1.519 (4) Å]. The exocyclic N3—S22 bond is considerably longer at 1.622 (2) Å. The bond angles within the azepine ring are close to the tetra­hedral angle [106.2 (2)–116.3 (2) °]. Fig. 2[link] also shows the tetra­hedral geometry around the S atom, S22, of the sulfon-amide.

[Figure 2]
Figure 2
The mol­ecular structure of the title compound (1S,2R)-2 with atom labelling. Displacement ellipsoids are drawn at the 30% probability level.

4. Supra­molecular features

In the crystal, mol­ecules are linked via O—H⋯O and C—H⋯O hydrogen bonds, forming double-stranded chains along the a-axis direction (Table 1[link] and Fig. 3[link]). The chains are linked via C—H⋯π inter­actions (Table 1[link]), forming a three-dimensional architecture.

Table 1
Hydrogen-bond geometry (Å, °)

Cg1, Cg2 and Cg3 are the centroids of rings C6–C11, C16–C21 and C25–C30, respectively.
D—H⋯A D—H H⋯A D⋯A D—H⋯A
O12—H12⋯O23i 0.83 2.22 3.034 (3) 169
C2—H2⋯O24ii 0.99 2.52 3.265 (3) 132
C18—H18⋯Cg3iii 0.94 2.89 3.738 (4) 150
C20—H20⋯Cg1iv 0.94 2.83 3.631 (3) 144
C29—H29⋯Cg2v 0.94 2.76 3.545 (3) 142
Symmetry codes: (i) x-1, y, z; (ii) [x-{\script{1\over 2}}, y, -z+{\script{1\over 2}}]; (iii) [x-{\script{3\over 2}}, -y+{\script{1\over 2}}, -z+1]; (iv) -x-1, -y+1, -z+1; (v) [x+{\script{1\over 2}}, -y+{\script{1\over 2}}, -z+1].
[Figure 3]
Figure 3
A view along the a axis of the crystal packing of the title compound (1S,2R)-2. The hydrogen bonds are shown as dashed lines (see Table 1[link]); for clarity, H atoms not involved in these inter­actions are omitted.

5. Synthesis and crystallization

(1S,2R)-7-Benz­yloxy-2-methyl-3-(4-tos­yl)-2,3,4,5-tetra­hydro-1H-3-benzazepin-1-ol [(S,R)-2] and (1R,2R)-7-benz­yloxy-2-methyl-3-(4-tos­yl)-2,3,4,5-tetra­hydro-1H-3-benzazepin-1-ol [(R,R)-3]

Details of the synthesis of the title compound are illustrated in Fig. 1[link].

As described for the synthesis of (R,S)-2 and (S,S)-3 (Tewes et al. (2015[Tewes, B., Frehland, B., Schepmann, D., Robaa, D., Uengwetwanit, T., Gaube, F., Winckler, T., Sippl, W. & Wünsch, B. (2015). J. Med. Chem. 58, 6293-6305.]), the ketone (R)-1 (5.20 g, 12.0 mmol) was reduced with NaBH4 (909 mg, 23.9 mmol) in CH3OH (125 ml).

(S,R)-2 (Rf = 0.29): Colourless solid, m.p. 417 K, yield 2.60 g (50%). Purity (HPLC): 98.1%, tR = 22.6 min. [α]D = +1.20 (c = 0.91, CH3OH, 2.1% ee). Spectroscopic data are given in Tewes et al. (2015[Tewes, B., Frehland, B., Schepmann, D., Robaa, D., Uengwetwanit, T., Gaube, F., Winckler, T., Sippl, W. & Wünsch, B. (2015). J. Med. Chem. 58, 6293-6305.]).

(R,R)-3 (Rf = 0.44): Colourless solid, m.p. 425 K, yield 1.20 g (23%). Purity (HPLC): 95.6%, tR = 22.2 min. [α]D = +1.89 (c = 0.98, CH3OH, 8.5% ee). Spectroscopic data are given in Tewes et al. (2015[Tewes, B., Frehland, B., Schepmann, D., Robaa, D., Uengwetwanit, T., Gaube, F., Winckler, T., Sippl, W. & Wünsch, B. (2015). J. Med. Chem. 58, 6293-6305.]).

Crystals of the title compound, suitable for X-ray diffraction analysis, were obtained by recrystallization from EtOAc.

6. Refinement details

Crystal data, data collection and structure refinement details are summarized in Table 2[link]. The OH and C-bound H atoms were included in calculated positions and treated as riding atoms: O—H = 0.83 Å, C—H = 0.94–0.99 Å with Uiso(H) = 1.5Ueq(O or C-meth­yl) and 1.2Ueq(C) for other H atoms.

Table 2
Experimental details

Crystal data
Chemical formula C25H27NO4S
Mr 437.54
Crystal system, space group Orthorhombic, Pbca
Temperature (K) 223
a, b, c (Å) 7.5071 (2), 23.6113 (8), 24.5180 (8)
V (Å3) 4345.9 (2)
Z 8
Radiation type Cu Kα
μ (mm−1) 1.59
Crystal size (mm) 0.25 × 0.15 × 0.08
 
Data collection
Diffractometer Nonius KappaCCD APEXII
Absorption correction Multi-scan (DENZO; Otwinowski et al., 2003[Otwinowski, Z., Borek, D., Majewski, W. & Minor, W. (2003). Acta Cryst. A59, 228-234.])
Tmin, Tmax 0.692, 0.884
No. of measured, independent and observed [I > 2σ(I)] reflections 40664, 3874, 3543
Rint 0.064
(sin θ/λ)max (Å−1) 0.600
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.058, 0.151, 1.10
No. of reflections 3874
No. of parameters 283
H-atom treatment H-atom parameters constrained
Δρmax, Δρmin (e Å−3) 0.64, −0.27
Computer programs: COLLECT (Nonius, 1998[Nonius (1998). COLLECT. Nonius BV, Delft, The Netherlands.]), DENZO–SMN (Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]), SHELXS97, SHELXL97 and XP in SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]), Mercury (Macrae et al., 2008[Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466-470.]) and PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]).

Supporting information

CCDC reference: 1472947

Crystal structure: contains datablocks I, global. DOI: 10.1107/S2056989016005855/su5286sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S2056989016005855/su5286Isup2.hkl

Supporting information file. DOI: 10.1107/S2056989016005855/su5286Isup3.cml

checkCIF report


Chemical context top

Inhibition of overactive N-methyl-D-aspartate (NMDA) receptors represents a promising strategy for the treatment of acute (e.g. stroke, epilepsy, traumatic brain injury) and chronic neuronal disorders (e.g. neuropathic pain, depression, Alzheimer's and Parkinson's disease) (Bräuner-Osborne et al., 2000; Kew & Kemp, 2005; Paoletti et al., 2013; Wu & Zhou, 2009). The NMDA receptor consists of four proteins (hetero­tetra­mer), which form a cation channel allowing the penetration of Ca2+ and Na+ ions into the neuron (Furukawa et al., 2005). In particular, NMDA receptors containing the GluN2B subunit are an attractive target for the development of innovative drugs, since the expression of the GluN2B subunit is limited to only a few regions of the central nervous system, including cortex, striatum and hippocampus (Borza & Domány, 2006; Layton et al., 2006; Mony et al., 2009). Moreover, the GluN2B subunit can be addressed selectively by ligands inter­acting with the so-called ifenprodil binding site, which is formed at the inter­face between GluN2B and GluN1 subunits (Karakas et al., 2011; Paoletti et al., 2013).

The 2-piperidino-1-phenyl­propan-1-ol derivative ifenprodil (Paoletti et al., 2013; Williams, 2001) (Fig. 1) represents the first ligand inter­acting with this binding site at the NMDA receptor. As a result of its poor selectivity and low bioavailability, ifenprodil has not been developed as a drug for clinical use. In order to improve the selectivity and metabolic stability, the flexible β-amino­alcohol substructure of ifenprodil has been incorporated into a rigid tetra­hydro-3-benzazepine ring (Tewes et al., 2010a,b; Schepmann et al., 2010; Falck et al., 2014).

Elucidation of the relative configuration top

For the synthesis of 3-benzazepine analogs of ifenprodil, we developed a chiral pool synthesis starting with (R)-alanine. In a five step synthesis (Fig. 1), the central inter­mediate ketone (R)-1 was prepared from (R)-alanine (Tewes et al., 2015). Synthesis of GluN2B antagonists included the lead compound ifenprodil and the target compound (S,R)-4.

The reduction of the ketone (R)-1 with NaBH4 led to the diastereomeric alcohols (S,R)-2 and (R,R)-3, which were further transformed into potent GluN2B antagonists by reductive removal of the tosyl group, alkyl­ation with 1-chloro-4-phenyl­butane and finally, hydrogeno­lytic cleavage of the benzyl ether. For example, the phenol (S,R)-4 displays very high affinity towards the ifenprodil binding site of the NMDA receptor (Ki = 26 nM) and, moreover, (S,R)-4 is able to reduce the glutamate- and glycine-induced cytotoxicity with an IC50 value of 9.0 nM (Tewes et al., 2015).

The diastereomeric alcohols (S,R)-2 and (R,R)-3 were separated by flash column chromatography and isolated in 50% and 23% yield, respectively. However, as a result of flexibility of the seven-membered tetra­hydro-3-benzazepine ring, it was not possible to assign the relative configuration of the methyl and hy­droxy moiety. Therefore, the main diastereomer (1S,2R-2) was crystallized and we report herein on its crystal structure.

Structural commentary top

The molecular structure of the title compound (1S,2R-2) is illustrated in Fig. 2. Since the starting material was not enanti­omerically pure, the compound crystallized as a racemate. However, the relative trans-configuration of the OH and CH3 groups in the 1- and 2-positions on the azepin ring is clearly shown, leading to a (1S,2R)-configuration for compound (S*,R*)-2. The CH3 and the OH groups adopt an axial orientation in the seven-membered azepine ring which has a chair conformation. The benzyl ring (C16–C21) and the tosyl­ate ring (C25–C30) are inclined to the benzo ring (C6–C11) by 78.39 (15) and 77.03 (14)°, respectively, and to one another by 13.82 (15)°. In the azepine ring, the bonds between the N atom, N3, and its adjacent C atoms, C2 and C4 [1.483 (3) and 1.480 (3) Å, respectively] are naturally shorter than the corresponding C—C bonds [1.509 (4)–1.519 (4) Å]. The exocyclic N3—S22 bond is considerably longer at 1.622 (2) Å. The bond angles within the azepine ring are close to the tetra­hedral angle [106.2 (2)–116.3 (2) °]. Fig. 2 also shows the tetra­hedral geometry around the S atom, S22, of the sulfonamide.

Supra­molecular features top

In the crystal, molecules are linked via O—H···O and C—H···O hydrogen bonds, forming double-stranded chains along the a-axis direction (Table 1 and Fig. 3). The chains are linked via C—H···π inter­actions (Table 1), forming a three-dimensional architecture.

Synthesis and crystallization top

\ (1S,2R)-7-Benzyl­oxy-2-methyl-3-\ (4-tosyl)-2,3,4,5-tetra­hydro-1H-3-benzazepin-1-ol [(S,R)-2] and (1R,2R)-7-benzyl­oxy-2-methyl-3-(4-\ tosyl)-2,3,4,5-tetra­hydro-1H-3-benzazepin-1-ol [(R,R)-3]

Details of the synthesis of the title compound are illustrated in Fig. 1.

As described for the synthesis of (R,S)-2 and (S,S)-3 (Tewes et al. (2015), the ketone (R)-1 (5.20 g, 12.0 mmol) was reduced with NaBH4 (909 mg, 23.9 mmol) in CH3OH (125 ml).

(S,R)-2 (Rf = 0.29): Colourless solid, m.p. 417 K, yield 2.60 g (50%). Purity (HPLC): 98.1%, tR = 22.6 min. [α]D = +1.20 (c = 0.91, CH3OH, 2.1% ee). Spectroscopic data are given in Tewes et al. (2015).

(R,R)-3 (Rf = 0.44): Colourless solid, m.p. 425 K, yield 1.20 g (23%). Purity (HPLC): 95.6%, tR = 22.2 min. [α]D = +1.89 (c = 0.98, CH3OH, 8.5% ee). Spectroscopic data are given in Tewes et al. (2015).

Crystals of the title compound, suitable for X-ray diffraction analysis, were obtained by ??????

Refinement details top

Crystal data, data collection and structure refinement details are summarized in Table 3. The OH and C-bound H atoms were included in calculated positions and treated as riding atoms: O—H = 0.83 Å, C—H = 0.94–0.99 Å with Uiso(H) = 1.5Ueq(O or C-methyl) and 1.2Ueq(C) for other H atoms.

Structure description top

Inhibition of overactive N-methyl-D-aspartate (NMDA) receptors represents a promising strategy for the treatment of acute (e.g. stroke, epilepsy, traumatic brain injury) and chronic neuronal disorders (e.g. neuropathic pain, depression, Alzheimer's and Parkinson's disease) (Bräuner-Osborne et al., 2000; Kew & Kemp, 2005; Paoletti et al., 2013; Wu & Zhou, 2009). The NMDA receptor consists of four proteins (hetero­tetra­mer), which form a cation channel allowing the penetration of Ca2+ and Na+ ions into the neuron (Furukawa et al., 2005). In particular, NMDA receptors containing the GluN2B subunit are an attractive target for the development of innovative drugs, since the expression of the GluN2B subunit is limited to only a few regions of the central nervous system, including cortex, striatum and hippocampus (Borza & Domány, 2006; Layton et al., 2006; Mony et al., 2009). Moreover, the GluN2B subunit can be addressed selectively by ligands inter­acting with the so-called ifenprodil binding site, which is formed at the inter­face between GluN2B and GluN1 subunits (Karakas et al., 2011; Paoletti et al., 2013).

The 2-piperidino-1-phenyl­propan-1-ol derivative ifenprodil (Paoletti et al., 2013; Williams, 2001) (Fig. 1) represents the first ligand inter­acting with this binding site at the NMDA receptor. As a result of its poor selectivity and low bioavailability, ifenprodil has not been developed as a drug for clinical use. In order to improve the selectivity and metabolic stability, the flexible β-amino­alcohol substructure of ifenprodil has been incorporated into a rigid tetra­hydro-3-benzazepine ring (Tewes et al., 2010a,b; Schepmann et al., 2010; Falck et al., 2014).

For the synthesis of 3-benzazepine analogs of ifenprodil, we developed a chiral pool synthesis starting with (R)-alanine. In a five step synthesis (Fig. 1), the central inter­mediate ketone (R)-1 was prepared from (R)-alanine (Tewes et al., 2015). Synthesis of GluN2B antagonists included the lead compound ifenprodil and the target compound (S,R)-4.

The reduction of the ketone (R)-1 with NaBH4 led to the diastereomeric alcohols (S,R)-2 and (R,R)-3, which were further transformed into potent GluN2B antagonists by reductive removal of the tosyl group, alkyl­ation with 1-chloro-4-phenyl­butane and finally, hydrogeno­lytic cleavage of the benzyl ether. For example, the phenol (S,R)-4 displays very high affinity towards the ifenprodil binding site of the NMDA receptor (Ki = 26 nM) and, moreover, (S,R)-4 is able to reduce the glutamate- and glycine-induced cytotoxicity with an IC50 value of 9.0 nM (Tewes et al., 2015).

The diastereomeric alcohols (S,R)-2 and (R,R)-3 were separated by flash column chromatography and isolated in 50% and 23% yield, respectively. However, as a result of flexibility of the seven-membered tetra­hydro-3-benzazepine ring, it was not possible to assign the relative configuration of the methyl and hy­droxy moiety. Therefore, the main diastereomer (1S,2R-2) was crystallized and we report herein on its crystal structure.

The molecular structure of the title compound (1S,2R-2) is illustrated in Fig. 2. Since the starting material was not enanti­omerically pure, the compound crystallized as a racemate. However, the relative trans-configuration of the OH and CH3 groups in the 1- and 2-positions on the azepin ring is clearly shown, leading to a (1S,2R)-configuration for compound (S*,R*)-2. The CH3 and the OH groups adopt an axial orientation in the seven-membered azepine ring which has a chair conformation. The benzyl ring (C16–C21) and the tosyl­ate ring (C25–C30) are inclined to the benzo ring (C6–C11) by 78.39 (15) and 77.03 (14)°, respectively, and to one another by 13.82 (15)°. In the azepine ring, the bonds between the N atom, N3, and its adjacent C atoms, C2 and C4 [1.483 (3) and 1.480 (3) Å, respectively] are naturally shorter than the corresponding C—C bonds [1.509 (4)–1.519 (4) Å]. The exocyclic N3—S22 bond is considerably longer at 1.622 (2) Å. The bond angles within the azepine ring are close to the tetra­hedral angle [106.2 (2)–116.3 (2) °]. Fig. 2 also shows the tetra­hedral geometry around the S atom, S22, of the sulfonamide.

In the crystal, molecules are linked via O—H···O and C—H···O hydrogen bonds, forming double-stranded chains along the a-axis direction (Table 1 and Fig. 3). The chains are linked via C—H···π inter­actions (Table 1), forming a three-dimensional architecture.

Synthesis and crystallization top

\ (1S,2R)-7-Benzyl­oxy-2-methyl-3-\ (4-tosyl)-2,3,4,5-tetra­hydro-1H-3-benzazepin-1-ol [(S,R)-2] and (1R,2R)-7-benzyl­oxy-2-methyl-3-(4-\ tosyl)-2,3,4,5-tetra­hydro-1H-3-benzazepin-1-ol [(R,R)-3]

Details of the synthesis of the title compound are illustrated in Fig. 1.

As described for the synthesis of (R,S)-2 and (S,S)-3 (Tewes et al. (2015), the ketone (R)-1 (5.20 g, 12.0 mmol) was reduced with NaBH4 (909 mg, 23.9 mmol) in CH3OH (125 ml).

(S,R)-2 (Rf = 0.29): Colourless solid, m.p. 417 K, yield 2.60 g (50%). Purity (HPLC): 98.1%, tR = 22.6 min. [α]D = +1.20 (c = 0.91, CH3OH, 2.1% ee). Spectroscopic data are given in Tewes et al. (2015).

(R,R)-3 (Rf = 0.44): Colourless solid, m.p. 425 K, yield 1.20 g (23%). Purity (HPLC): 95.6%, tR = 22.2 min. [α]D = +1.89 (c = 0.98, CH3OH, 8.5% ee). Spectroscopic data are given in Tewes et al. (2015).

Crystals of the title compound, suitable for X-ray diffraction analysis, were obtained by ??????

Refinement details top

Crystal data, data collection and structure refinement details are summarized in Table 3. The OH and C-bound H atoms were included in calculated positions and treated as riding atoms: O—H = 0.83 Å, C—H = 0.94–0.99 Å with Uiso(H) = 1.5Ueq(O or C-methyl) and 1.2Ueq(C) for other H atoms.

Computing details top

Data collection: COLLECT (Nonius, 1998); cell refinement: COLLECT (Nonius, 1998); data reduction: DENZO–SMN (Otwinowski & Minor, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP in SHELXTL (Sheldrick, 2008) and Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).

Figures top
[Figure 1] Fig. 1. Synthesis of GluN2B antagonists including the lead compound ifenprodil and the target compound (S,R)-4. Reagents and reaction conditions: (a) NaBH4, CH3OH, (S,R)-2 50%, (R,R)-3 23%.
[Figure 2] Fig. 2. The molecular structure of the title compound, with atom labelling. Displacement ellipsoids are drawn at the 30% probability level.
[Figure 3] Fig. 3. A view along the a axis of the crystal packing of the title compound. The hydrogen bonds are shown as dashed lines (see Table 1); for clarity, H atoms not involved in these interactions are omitted.
(1S*,2R*)-7-Benzyloxy-2-methyl-3-tosyl-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ol top
Crystal data top
C25H27NO4SF(000) = 1856
Mr = 437.54Dx = 1.337 Mg m−3
Orthorhombic, PbcaCu Kα radiation, λ = 1.54178 Å
Hall symbol: -P 2ac 2abCell parameters from 5365 reflections
a = 7.5071 (2) Åθ = 0.9–68.3°
b = 23.6113 (8) ŵ = 1.59 mm−1
c = 24.5180 (8) ÅT = 223 K
V = 4345.9 (2) Å3Plate, colourless
Z = 80.25 × 0.15 × 0.08 mm
Data collection top
Nonius KappaCCD APEXII
diffractometer		3874 independent reflections
Radiation source: fine-focus sealed tube3543 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.064
ω and φ scansθmax = 67.7°, θmin = 4.2°
Absorption correction: multi-scan
(DENZO; Otwinowski et al., 2003)		h = 0→9
Tmin = 0.692, Tmax = 0.884k = 0→27
40664 measured reflectionsl = 0→29
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.058Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.151H-atom parameters constrained
S = 1.10 w = 1/[σ2(Fo2) + (0.0619P)2 + 5.5349P]
where P = (Fo2 + 2Fc2)/3
3874 reflections(Δ/σ)max = 0.001
283 parametersΔρmax = 0.64 e Å−3
0 restraintsΔρmin = −0.27 e Å−3
Crystal data top
C25H27NO4SV = 4345.9 (2) Å3
Mr = 437.54Z = 8
Orthorhombic, PbcaCu Kα radiation
a = 7.5071 (2) ŵ = 1.59 mm−1
b = 23.6113 (8) ÅT = 223 K
c = 24.5180 (8) Å0.25 × 0.15 × 0.08 mm
Data collection top
Nonius KappaCCD APEXII
diffractometer		3874 independent reflections
Absorption correction: multi-scan
(DENZO; Otwinowski et al., 2003)		3543 reflections with I > 2σ(I)
Tmin = 0.692, Tmax = 0.884Rint = 0.064
40664 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0580 restraints
wR(F2) = 0.151H-atom parameters constrained
S = 1.10Δρmax = 0.64 e Å−3
3874 reflectionsΔρmin = −0.27 e Å−3
283 parameters
Special details top

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.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > 2sigma(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
C1−0.2632 (4)0.25588 (13)0.33843 (12)0.0433 (7)
H1−0.33270.26140.30450.052*
C2−0.0688 (4)0.26290 (13)0.32342 (11)0.0444 (7)
H2−0.04620.23830.29140.053*
N30.0518 (3)0.24359 (10)0.36757 (9)0.0382 (5)
C40.0510 (4)0.27343 (13)0.42068 (11)0.0448 (7)
H4A0.06560.31410.41420.054*
H4B0.15300.26050.44230.054*
C5−0.1175 (4)0.26389 (14)0.45294 (11)0.0480 (7)
H5A−0.09340.27210.49140.058*
H5B−0.15040.22380.45020.058*
C6−0.2745 (4)0.29959 (12)0.43450 (11)0.0408 (6)
C7−0.3588 (4)0.33478 (12)0.47111 (11)0.0403 (6)
H7−0.31620.33690.50710.048*
C8−0.5061 (4)0.36736 (11)0.45600 (10)0.0360 (6)
C9−0.5624 (4)0.36714 (11)0.40220 (11)0.0384 (6)
H9−0.65740.39020.39090.046*
C10−0.4758 (4)0.33218 (12)0.36548 (11)0.0415 (7)
H10−0.51360.33220.32890.050*
C11−0.3365 (4)0.29737 (12)0.38014 (11)0.0411 (6)
O12−0.2846 (3)0.19835 (9)0.35386 (10)0.0508 (6)
H12−0.38730.19330.36550.076*
C13−0.0263 (5)0.32466 (13)0.30574 (13)0.0515 (8)
H13A−0.04120.34980.33670.077*
H13B−0.10670.33590.27670.077*
H13C0.09560.32680.29280.077*
O14−0.5837 (3)0.39821 (8)0.49686 (7)0.0425 (5)
C15−0.7379 (4)0.43106 (13)0.48158 (12)0.0459 (7)
H15A−0.82730.40650.46460.055*
H15B−0.70390.46030.45510.055*
C16−0.8140 (4)0.45824 (12)0.53175 (11)0.0393 (6)
C17−0.9211 (4)0.42782 (14)0.56697 (13)0.0520 (8)
H17−0.94280.38920.56050.062*
C18−0.9964 (5)0.45419 (17)0.61180 (14)0.0611 (9)
H18−1.06920.43340.63570.073*
C19−0.9651 (5)0.51087 (16)0.62151 (13)0.0582 (9)
H19−1.01680.52870.65190.070*
C20−0.8587 (4)0.54114 (13)0.58683 (12)0.0499 (8)
H20−0.83680.57970.59360.060*
C21−0.7835 (4)0.51513 (12)0.54197 (12)0.0424 (7)
H21−0.71100.53620.51820.051*
S220.22307 (9)0.20715 (3)0.34775 (3)0.0364 (2)
O230.3341 (2)0.19811 (9)0.39487 (8)0.0422 (5)
O240.3039 (3)0.23240 (9)0.30048 (8)0.0447 (5)
C260.1770 (4)0.12036 (12)0.27553 (12)0.0431 (7)
H260.23490.14340.24980.052*
C270.1279 (4)0.06527 (13)0.26233 (12)0.0483 (7)
H270.15440.05110.22740.058*
C280.0412 (4)0.03100 (13)0.29945 (12)0.0476 (7)
C31−0.0091 (6)−0.02894 (14)0.28515 (16)0.0657 (10)
H31A−0.0590−0.02990.24870.099*
H31B−0.0968−0.04270.31100.099*
H31C0.0960−0.05280.28660.099*
C290.0012 (4)0.05326 (14)0.35077 (12)0.0512 (8)
H29−0.05910.03060.37630.061*
C300.0483 (4)0.10756 (14)0.36461 (12)0.0467 (7)
H300.01930.12220.39920.056*
C250.1392 (3)0.14065 (12)0.32714 (11)0.0373 (6)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0446 (16)0.0458 (16)0.0396 (14)0.0026 (13)−0.0051 (13)−0.0044 (12)
C20.0442 (16)0.0598 (18)0.0294 (13)0.0093 (14)−0.0050 (12)−0.0057 (12)
N30.0338 (11)0.0522 (14)0.0287 (11)0.0052 (10)−0.0015 (9)−0.0057 (10)
C40.0424 (16)0.0570 (18)0.0349 (14)0.0026 (14)−0.0042 (12)−0.0040 (13)
C50.0465 (17)0.065 (2)0.0320 (14)0.0151 (15)0.0018 (13)0.0027 (13)
C60.0420 (15)0.0484 (16)0.0322 (14)0.0081 (13)−0.0002 (12)−0.0002 (12)
C70.0445 (16)0.0467 (15)0.0295 (13)0.0076 (13)−0.0026 (12)0.0003 (11)
C80.0392 (14)0.0344 (13)0.0345 (13)0.0005 (12)0.0011 (11)−0.0008 (10)
C90.0397 (15)0.0369 (14)0.0387 (14)0.0057 (12)−0.0057 (12)0.0002 (11)
C100.0465 (16)0.0453 (16)0.0328 (13)0.0080 (13)−0.0084 (12)−0.0028 (11)
C110.0399 (15)0.0465 (16)0.0368 (14)0.0039 (13)−0.0019 (12)−0.0005 (12)
O120.0405 (12)0.0410 (11)0.0709 (15)−0.0013 (9)−0.0018 (11)−0.0050 (10)
C130.0531 (18)0.0531 (18)0.0483 (17)0.0045 (15)0.0078 (15)0.0148 (14)
O140.0424 (11)0.0503 (11)0.0346 (10)0.0144 (9)−0.0010 (8)−0.0037 (8)
C150.0469 (16)0.0475 (16)0.0432 (15)0.0129 (14)−0.0060 (13)−0.0047 (13)
C160.0356 (14)0.0421 (15)0.0401 (14)0.0084 (12)−0.0039 (12)−0.0004 (12)
C170.0545 (19)0.0481 (17)0.0533 (18)−0.0031 (15)−0.0016 (15)0.0022 (14)
C180.0516 (19)0.082 (3)0.0494 (19)−0.0063 (18)0.0107 (15)0.0127 (17)
C190.0538 (19)0.078 (2)0.0425 (17)0.0188 (18)0.0036 (15)−0.0082 (16)
C200.0566 (19)0.0456 (17)0.0473 (17)0.0131 (15)−0.0035 (15)−0.0065 (13)
C210.0411 (16)0.0430 (15)0.0432 (15)0.0047 (13)0.0000 (12)0.0006 (12)
S220.0295 (3)0.0466 (4)0.0330 (3)0.0008 (3)0.0022 (3)−0.0022 (3)
O230.0300 (9)0.0565 (12)0.0401 (10)0.0032 (9)−0.0036 (8)−0.0038 (9)
O240.0428 (11)0.0533 (12)0.0379 (10)−0.0057 (9)0.0086 (9)−0.0006 (9)
C260.0448 (16)0.0470 (16)0.0374 (14)−0.0002 (13)0.0059 (12)0.0012 (12)
C270.0576 (19)0.0493 (17)0.0380 (16)0.0012 (15)0.0049 (14)−0.0051 (13)
C280.0494 (17)0.0473 (16)0.0461 (16)−0.0006 (14)−0.0014 (14)−0.0003 (13)
C310.084 (3)0.0484 (19)0.065 (2)−0.0099 (18)0.003 (2)−0.0034 (16)
C290.0523 (19)0.0571 (19)0.0443 (17)−0.0119 (16)0.0052 (14)0.0047 (14)
C300.0468 (17)0.0580 (18)0.0354 (14)−0.0075 (14)0.0084 (13)−0.0043 (13)
C250.0313 (13)0.0460 (15)0.0347 (13)0.0014 (12)0.0012 (11)−0.0004 (12)
Geometric parameters (Å, º) top
C1—O121.419 (4)C15—C161.500 (4)
C1—C21.514 (4)C16—C171.381 (4)
C1—C111.519 (4)C16—C211.386 (4)
C2—N31.483 (3)C17—C181.384 (5)
C2—C131.554 (4)C18—C191.379 (5)
N3—C41.480 (3)C19—C201.368 (5)
N3—S221.622 (2)C20—C211.380 (4)
C4—C51.509 (4)S22—O241.438 (2)
C5—C61.518 (4)S22—O231.441 (2)
C6—C71.377 (4)S22—C251.765 (3)
C6—C111.413 (4)C26—C251.382 (4)
C7—C81.397 (4)C26—C271.390 (4)
C8—O141.369 (3)C27—C281.381 (4)
C8—C91.385 (4)C28—C291.396 (4)
C9—C101.384 (4)C28—C311.506 (4)
C10—C111.377 (4)C29—C301.373 (4)
O14—C151.443 (3)C30—C251.386 (4)
O12—C1—C2106.2 (2)C17—C16—C21119.2 (3)
O12—C1—C11113.4 (2)C17—C16—C15120.8 (3)
C2—C1—C11116.3 (3)C21—C16—C15120.0 (3)
N3—C2—C1112.2 (2)C16—C17—C18120.0 (3)
N3—C2—C13111.5 (2)C19—C18—C17120.2 (3)
C1—C2—C13111.6 (3)C20—C19—C18120.0 (3)
C4—N3—C2119.5 (2)C19—C20—C21120.1 (3)
C4—N3—S22121.29 (18)C20—C21—C16120.5 (3)
C2—N3—S22115.37 (17)O24—S22—O23117.62 (12)
N3—C4—C5113.2 (2)O24—S22—N3110.87 (12)
C4—C5—C6114.3 (2)O23—S22—N3107.28 (11)
C7—C6—C11119.1 (3)O24—S22—C25106.78 (12)
C7—C6—C5119.9 (2)O23—S22—C25107.70 (12)
C11—C6—C5121.1 (2)N3—S22—C25105.96 (13)
C6—C7—C8121.5 (2)C25—C26—C27118.9 (3)
O14—C8—C9124.7 (2)C28—C27—C26121.3 (3)
O14—C8—C7115.8 (2)C27—C28—C29118.3 (3)
C9—C8—C7119.5 (2)C27—C28—C31121.0 (3)
C10—C9—C8118.6 (3)C29—C28—C31120.6 (3)
C11—C10—C9122.9 (3)C30—C29—C28121.3 (3)
C10—C11—C6118.3 (3)C29—C30—C25119.3 (3)
C10—C11—C1119.0 (3)C26—C25—C30120.8 (3)
C6—C11—C1122.6 (3)C26—C25—S22119.8 (2)
C8—O14—C15116.0 (2)C30—C25—S22119.2 (2)
O14—C15—C16108.8 (2)
O12—C1—C2—N3−53.8 (3)O14—C15—C16—C17−80.1 (3)
C11—C1—C2—N373.3 (3)O14—C15—C16—C21102.7 (3)
O12—C1—C2—C13−179.8 (2)C21—C16—C17—C180.0 (5)
C11—C1—C2—C13−52.6 (3)C15—C16—C17—C18−177.2 (3)
C1—C2—N3—C4−64.1 (3)C16—C17—C18—C190.0 (5)
C13—C2—N3—C461.9 (3)C17—C18—C19—C20−0.2 (5)
C1—C2—N3—S22137.5 (2)C18—C19—C20—C210.3 (5)
C13—C2—N3—S22−96.4 (3)C19—C20—C21—C16−0.3 (5)
C2—N3—C4—C569.7 (3)C17—C16—C21—C200.1 (4)
S22—N3—C4—C5−133.3 (2)C15—C16—C21—C20177.4 (3)
N3—C4—C5—C6−79.2 (3)C4—N3—S22—O24−114.3 (2)
C4—C5—C6—C7−123.1 (3)C2—N3—S22—O2443.7 (2)
C4—C5—C6—C1156.9 (4)C4—N3—S22—O2315.4 (3)
C11—C6—C7—C81.3 (4)C2—N3—S22—O23173.3 (2)
C5—C6—C7—C8−178.6 (3)C4—N3—S22—C25130.2 (2)
C6—C7—C8—O14176.6 (3)C2—N3—S22—C25−71.8 (2)
C6—C7—C8—C9−4.1 (4)C25—C26—C27—C280.7 (5)
O14—C8—C9—C10−177.5 (3)C26—C27—C28—C290.8 (5)
C7—C8—C9—C103.2 (4)C26—C27—C28—C31−179.1 (3)
C8—C9—C10—C110.3 (5)C27—C28—C29—C30−0.8 (5)
C9—C10—C11—C6−3.1 (5)C31—C28—C29—C30179.1 (3)
C9—C10—C11—C1173.4 (3)C28—C29—C30—C25−0.8 (5)
C7—C6—C11—C102.2 (4)C27—C26—C25—C30−2.3 (4)
C5—C6—C11—C10−177.9 (3)C27—C26—C25—S22172.5 (2)
C7—C6—C11—C1−174.1 (3)C29—C30—C25—C262.4 (5)
C5—C6—C11—C15.8 (5)C29—C30—C25—S22−172.4 (2)
O12—C1—C11—C10−116.8 (3)O24—S22—C25—C267.2 (3)
C2—C1—C11—C10119.7 (3)O23—S22—C25—C26−120.0 (2)
O12—C1—C11—C659.5 (4)N3—S22—C25—C26125.5 (2)
C2—C1—C11—C6−64.0 (4)O24—S22—C25—C30−177.9 (2)
C9—C8—O14—C151.8 (4)O23—S22—C25—C3054.9 (3)
C7—C8—O14—C15−178.9 (2)N3—S22—C25—C30−59.7 (3)
C8—O14—C15—C16175.5 (2)
Hydrogen-bond geometry (Å, º) top
Cg1, Cg2 and Cg3 are the centroids of rings C6–C11, C16–C21 and C25–C30, respectively.
D—H···AD—HH···AD···AD—H···A
O12—H12···O23i0.832.223.034 (3)169
C2—H2···O24ii0.992.523.265 (3)132
C18—H18···Cg3iii0.942.893.738 (4)150
C20—H20···Cg1iv0.942.833.631 (3)144
C29—H29···Cg2v0.942.763.545 (3)142
Symmetry codes: (i) x−1, y, z; (ii) x−1/2, y, −z+1/2; (iii) x−3/2, −y+1/2, −z+1; (iv) −x−1, −y+1, −z+1; (v) x+1/2, −y+1/2, −z+1.
Hydrogen-bond geometry (Å, º) top
Cg1, Cg2 and Cg3 are the centroids of rings C6–C11, C16–C21 and C25–C30, respectively.
D—H···AD—HH···AD···AD—H···A
O12—H12···O23i0.832.223.034 (3)169
C2—H2···O24ii0.992.523.265 (3)132
C18—H18···Cg3iii0.942.893.738 (4)150
C20—H20···Cg1iv0.942.833.631 (3)144
C29—H29···Cg2v0.942.763.545 (3)142
Symmetry codes: (i) x−1, y, z; (ii) x−1/2, y, −z+1/2; (iii) x−3/2, −y+1/2, −z+1; (iv) −x−1, −y+1, −z+1; (v) x+1/2, −y+1/2, −z+1.

Experimental details

Crystal data
Chemical formulaC25H27NO4S
Mr437.54
Crystal system, space groupOrthorhombic, Pbca
Temperature (K)223
a, b, c (Å)7.5071 (2), 23.6113 (8), 24.5180 (8)
V (Å3)4345.9 (2)
Z8
Radiation typeCu Kα
µ (mm−1)1.59
Crystal size (mm)0.25 × 0.15 × 0.08
Data collection
DiffractometerNonius KappaCCD APEXII
Absorption correctionMulti-scan
(DENZO; Otwinowski et al., 2003)
Tmin, Tmax0.692, 0.884
No. of measured, independent and
observed [I > 2σ(I)] reflections		40664, 3874, 3543
Rint0.064
(sin θ/λ)max (Å−1)0.600
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.058, 0.151, 1.10
No. of reflections3874
No. of parameters283
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å−3)0.64, −0.27

Computer programs: COLLECT (Nonius, 1998), DENZO–SMN (Otwinowski & Minor, 1997), SHELXS97 (Sheldrick, 2008), XP in SHELXTL (Sheldrick, 2008) and Mercury (Macrae et al., 2008), SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).

 

Acknowledgements

Financial support by the Deutsche Forschungsgemeinschaft is gratefully acknowledged.

References

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ISSN: 2056-9890
Volume 72| Part 5| May 2016| Pages 683-686
doi:10.1107/S2056989016005855
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