Crystal structure of the (1R,2S,5R) diastereomer of acoltremon, C18H27NO2, from synchrotron powder diffraction data and density functional theory calculations

Salazar, J.K.; Kaduk, J.A.; Dosen, A.; Blanton, T.N.

doi:10.1107/S2056989026006572

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ISSN: 2056-9890

Volume 82| Part 7| July 2026| Pages 877-882

https://doi.org/10.1107/S2056989026006572

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Crystal structure of the (1R,2S,5R) diastereomer of acoltremon, C₁₈H₂₇NO₂, from synchrotron powder diffraction data and density functional theory calculations

Jacob K. Salazar,^a James A. Kaduk,^b,^c ^* Anja Dosen ^d and Thomas N. Blanton ^d

^aNorth Central College, Department of Chemistry, 131 S. Loomis St., Naperville IL 60540, USA, ^bNorth Central College, Department of Physics, 131 S. Loomis St., Naperville IL 60540, USA, ^cIllinois Institute of Technology, Department of Chemistry, 3101 S. Dearborn St., Chicago IL 60616, USA, and ^dICDD, 12 Campus Blvd., Newtown Square, PA 19073-3273, USA
^*Correspondence e-mail: [email protected]

Edited by W. T. A. Harrison, University of Aberdeen, United Kingdom (Received 21 April 2026; accepted 22 June 2026; online 26 June 2026)

The crystal structure of the (1R,2S,5R) diastereomer of acoltremon [systematic name: (1R,2S,5R)-2-isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide], C₁₈H₂₇NO₂, has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional theory techniques. Acoltremon crystallizes in space group P2₁2₁2₁ and the crystal structure consists of corrugated layers lying parallel to the bc plane. N—H⋯O hydrogen bonds link the molecules into chains propagating along the a-axis direction, with graph-set descriptor C¹₁(4).

Keywords: powder diffraction; acoltremon; Tryptyr; Rietveld refinement; density functional theory.

CCDC references: 2564140; 2564139; 2564138

1. Chemical context

Acoltremon, C₁₈H₂₇NO₂ (sold under the brand name Tryptyr in the United States, and also known as AR-15512) is used to treat dry-eye syndrome. It is administered as a preservative free dilute solution in eye drops for the purpose of increasing basal tears production. The systematic name (CAS Registry Number 68489-09-8) is (1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-propan-2-ylcyclohexane-1-carboxamide.

A crystal structure of acoltremon at 100 K has been reported (Rodriguez-Arévalo et al., 2021 ), but it is of the (1S,2S,5R) diastereomer, 4, and not the active pharmaceutical. We are unaware of any published powder diffraction data on the (1R,2S,5R) diastereomer.

This work was carried out as part of a project (Kaduk et al., 2014 ) to determine the crystal structures of large-volume commercial pharmaceuticals, and includes depositing high-quality powder diffraction data for them in the Powder Diffraction File (Kabekkodu et al., 2024 ).

2. Structural commentary

The dispersion-corrected VASP calculations indicate that the structure of the (1R,2S,5R) diastereomer determined here is 23.3 kcal mol⁻¹ lower in energy than that of the (1S,2S,5R) diastereomer determined by Rodriguez-Arévalo et al. (2021) (see Table 5 in the supporting information). As expected, the molecules are quite different (Fig. 1), with a root-mean-square Cartesian displacement of 1.206 Å.

Figure 1
Comparison of the (1R,2S,5R) diastereomer characterized in this study (blue) to the (1S,2S,5R) diastereomer characterized by Rodriguez-Arévalo et al. (2021

; orange). The root-mean-square Cartesian displacement is 1.206 Å.

The root-mean-square difference of the non-H atoms in the Rietveld-refined and VASP-optimized structures of acoltremon, calculated using the Mercury (Macrae et al., 2020 ) CSD-Materials/Search/Crystal Packing Similarity tool is 0.133 Å (Fig. 2); the structures are essentially identical. The root-mean-square Cartesian displacement of the non-H atoms in the refined and optimized structures, calculated using the Mercury Calculate/molecule overlay tool, is 0.108 Å (Fig. 3). The agreements are within the normal range for correct structures (van de Streek & Neumann, 2014 ). The asymmetric unit is illustrated in Fig. 4. The remaining discussion will emphasize the VASP-optimized structure.

Figure 2
Comparison of the Rietveld-refined (colored by atom type) and VASP-optimized (pale green) structures of acoltremon, calculated using the Mercury CSD-Materials/Search/Crystal Packing Similarity tool. The root-mean-square Cartesian displacement is 0.133 Å.

Figure 3
Comparison of the refined structure of acoltremon (red) to the VASP-optimized structure (blue). The comparison was generated using the Mercury Calculate/Molecule Overlay tool; the root-mean-square Cartesian displacement is 0.108 Å.

Figure 4
The asymmetric unit of acoltremon, with the atom numbering. The atoms are represented by 50% probability spheroids.

All the bond distances, bond angles, and torsion angles fall within the normal ranges indicated by a Mercury Mogul geometry check (Macrae et al., 2020). Quantum chemical geometry optimization of the isolated acoltremon molecule (DFT/B3LYP/6-31G*/water) using Spartan '24 (Wavefunction, 2025 ) indicated that the observed conformation lies 2.7 kcal mol⁻¹ above a local minimum, which has a similar overall conformation (r.m.s. displacement = 0.338 Å); the difference is mainly in the orientation of the phenyl ring. Similarly, the observed conformation of the (1S,2S,5R) diastereomer lies 3.4 kcal mol⁻¹ higher in energy than a local minimum, which differs more (r.m.s. displacement = 0.653 Å), mainly in the orientations of the isopropyl, methyl, and phenyl groups. These single-molecule calculations indicate that the diastereomer of this study is 2.4 kcal mol⁻¹ more stable than the other one.

3. Supramolecular features

A view down the a axis of the crystal structure (Fig. 5) shows the molecules clearly, but a view down the c axis (Fig. 6) makes it clear that the structure consists of corrugated layers lying parallel to the bc plane. The Mercury aromatics analyser indicates only extremely weak phenyl–phenyl interactions, with distances ≥ 8.56 Å. The mean Miller plane of the molecule is approximately (721).

Figure 5
The unit-cell packing of acoltremon, viewed down the a-axis direction.

Figure 6
The unit-cell packing of acoltremon, viewed down the c-axis direction.

Analysis of the contributions to the total crystal energy of the structure using the forcite module of Materials Studio (Dassault Systèmes, 2025 ) indicated that bond, angle, and torsion distortion terms contribute about equally to the intramolecular energy. The intermolecular energy is dominated by van der Waals attractions, which in this force field based analysis include hydrogen bonds. The hydrogen bonds are better discussed using the results of the DFT calculation.

The hydrogen bonds are summarized in Tables 1 and 2. In both the (1R,2S,5R) diastereomer studied here and the (1S,2S,5R) diastereomer of Rodriguez-Arévalo et al. (2021), the amino and carbonyl groups link the molecules into chains (Fig. 7) propagating along the a-axis direction, with graph-set descriptor (Etter, 1990 ; Bernstein et al., 1995 ; Motherwell et al., 2000 ) C₁¹(4). These chains link the corrugated layers. However, the patterns of C—H⋯O and C—H⋯C hydrogen bonds are almost completely different between the two diastereomers.

Table 1
Hydrogen-bond geometry (Å, °) for VASP-optimized acoltremon

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A	Mulliken overlap	H-bond energy
N3—H41⋯O1ⁱ	1.04	1.80	2.836	175	0.064	5.8
C5—H23⋯O1ⁱ	1.10	2.47	3.428	145	0.014	–
C13—H35⋯O2	1.10	2.61	3.594	148	0.010	–
C10—H31⋯C11ⁱⁱ	1.11	2.50	2.991	106	0.012	–
Symmetry codes: (i) −x − 1, y + $[{1\over 2}]$ , −z + $[{3\over 2}]$ ; (ii) x + $[{5\over 2}]$ , −y − $[{1\over 2}]$ , −z + 1.

Table 2
Hydrogen-bond geometry (Å, °) for VASP-optimized (1S,2S,5R) diastereomer

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A	Mulliken overlap	H-bond energy
N1—H1N⋯O1ⁱ	1.03	1.89	2.922	176	0.048	5.1
C18—H18B⋯O1ⁱⁱ	1.10	2.30	3.383	169	0.022
C10—H10⋯O1ⁱⁱⁱ	1.10	2.48	3.466	149	0.016
C9–H9B⋯O2	1.10	2.61	3.526	140	0.011
C3–H00F⋯C11	1.11	2.55	2.963	101	0.011
Symmetry codes: (i) −x + 1, y + $[{3\over 2}]$ , −z + $[{3\over 2}]$ ; (ii) x + $[{5\over 2}]$ , −y − $[{1\over 2}]$ , −z + 1; (iii) −x − 1, y + $[{3\over 2}]$ , −z + $[{3\over 2}]$ .

Figure 7
The hydrogen bond chains in the (1R,2S,5R) diastereomer characterized in this study (left) and the (1S,2S,5R) diastereomer (right) characterized by Rodríguez-Arévalo et al. (2021

). In each case the crystallographic a axis is horizontal.

The volume enclosed by the Hirshfeld surface of acoltremon (Fig. 9; Spackman et al., 2021 ) is 424.36 Å³, 98.31% of 1/4 of the unit-cell volume. The packing density is thus typical. The only significant close contacts (red in Fig. 8) involve the hydrogen bonds. The volume/non-hydrogen atom is larger than normal, at 20.5 Å³.

Figure 9
The Rietveld plot for acoltremon. The blue crosses represent the observed data points, and the green line is the calculated pattern. The cyan curve is the normalized error plot, and the red line is the background curve. The blue tick marks indicate the peak positions. The vertical scale has been multiplied by a factor of 10× for 2θ > 9.0° and by a factor of 40× for 2θ > 16.0°.

Figure 8
The Hirshfeld surface of acoltremon. Intermolecular contacts longer than the sums of the van der Waals radii are colored blue, and contacts shorter than the sums of the radii are colored red. Contacts equal to the sums of radii are white.

The Bravais–Friedel–Donnay–Harker (Bravais, 1866 ; Friedel, 1907 ; Donnay & Harker, 1937 ) algorithm suggests that we might expect isotropic morphology for acoltremon. A second-order spherical harmonic model for preferred orientation was included. The texture index was 1.034, indicating that the preferred orientation was slight in this rotated capillary specimen.

4. Database survey

A reduced cell search in the Cambridge Structural Database (CSD 2026.1.0; Groom et al., 2016 ), combined with the chemistry C, H, N, and O only, yielded 22 hits, but no structures for acoltremon or its derivatives.

5. Synthesis and crystallization

Acoltremon is a commercial reagent and was purchased from TargetMol (Batch #141432) and used as-received.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3. The white powder was packed into a 1.5 mm diameter Kapton capillary, and rotated during the measurement at ∼50 Hz. The powder pattern was measured at 295 K at beam line 11-BM (Lee et al., 2008 ; Wang et al., 2008 ; Antao et al., 2008 ) of the Advanced Photon Source at Argonne National Laboratory using a wavelength of 0.4687342 Å from 0.5–50° 2θ with a step size of 0.001° and a counting time of 0.1 sec step⁻¹. The high-resolution powder diffraction data were collected using twelve silicon crystal analyzers that allow for high angular resolution, high precision, and accurate peak positions. A mixture of silicon (NIST SRM 640c) and alumina (NIST SRM 676a) standards (ratio Al₂O₃:Si = 2:1 by weight) was used to calibrate the instrument and refine the monochromatic wavelength used in the experiment.

Table 3
Experimental details

	acoltremon_2
Crystal data
Chemical formula	C₁₈H₂₇NO₂
M_r	289.42
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	295
a, b, c (Å)	9.320220 (15), 11.39111 (3), 16.26284 (4)
V (Å³)	1726.59 (1)
Z	4
Radiation type	Synchrotron, λ = 0.46873 Å
μ (mm⁻¹)	0.005
Specimen shape, size (mm)	Cylinder, 2.0 × 1.5

Data collection
Diffractometer	11-BM, APS
Specimen mounting	Kapton capillary
Data collection mode	Transmission
Scan method	Step
2θ values (°)	2θ_min = 0.510, 2θ_max = 49.995, 2θ_step = 0.001

Refinement
R factors and goodness of fit	R_p = 0.113, R_wp = 0.133, R_exp = 0.038, R(F²) = 0.10052, χ² = 12.888
No. of parameters	83
No. of restraints	53
(Δ/σ)_max	1.712
Computer programs: GSAS-II (Toby & Von Dreele, 2013) and DIAMOND (Brandenburg & Putz, 2025 ).

The pattern was indexed on a primitive orthorhombic unit cell with a = 9.32059, b = 11.39187, c = 16.25977 Å, V = 1727.5 Å³, and Z = 4 using N-TREOR as incorporated into EXPO2014 (Altomare et al., 2013 ). The suggested space group was P2₁2₁2₁, which was confirmed by successful solution and refinement of the structure.

The a, b, and c lattice parameters at 298 K were 2.0% larger, 9.7% larger, and 7.0% smaller than those reported at 100 K. Refinement was started using the fractional coordinates of Rodriguez-Arévalo et al. (2021), before we realized that they were for a different diastereomer. The refinement changed the chiralities to result in the enantiomer of the correct diastereomer.

To make a cleaner narrative, the molecular structure of (1R,2S,5R)-acoltremon was downloaded from PubChem (Kim et al., 2023 ) as Conformer3D_COMPOUND_CID_11266244.sdf. It was converted to a *.mol2 file using Mercury (Macrae et al., 2020). The structure was solved using Monte Carlo simulated annealing techniques as implemented in EXPO2014 (Altomare et al., 2013).

Rietveld refinement was carried out using GSAS-II (Toby & Von Dreele, 2013 ). Only the 2.5–30.0° portion of the pattern was included in the refinements (d_min = 0.905 Å). The μR value was fixed at 0.00, calculated using the 11-BM website (https://11bm.xray.aps.anl.gov/absorb/). All non-H bond distances and angles were subjected to restraints, based on a Mercury Mogul geometry check (Sykes et al., 2011 ; Bruno et al., 2004 ). The Mogul average and standard deviation for each quantity were used as the restraint parameters. The aromatic ring was restrained to be planar. The restraints contributed 4.0% to the overall χ². The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using Materials Studio (Dassault Systèmes, 2024). The U_iso(H) values were grouped by chemical similarity. The peak profiles were described using an isotropic microstrain model, with the strain fixed at 10 ppm. The background was modeled using a six-term shifted Chebyshev polynomial, with a peak at 6.17° to model the scattering from the Kapton capillary and any amorphous component of the sample.

The final refinement of 83 variables using 27,501 observations and 53 restraints yielded the residuals R_wp = 0.1352 and GOF = 3.59. The largest peak (0.13 Å from C15) and hole (1.19 Å from C10) in the difference Fourier map are 1.07 (16) and −0.67 (16) e Å⁻³, respectively. The final Rietveld plot is shown in Fig. 9. The largest features in the normalized error plot are in the positions and shapes of some of the strong low-angle peaks, and may indicate a change in the specimen during the measurement.

The crystal structures of both diastereomers were optimized (fixed experimental unit cells) with density functional theory techniques using VASP (Kresse & Furthmüller, 1996 ) through the MedeA graphical interface (Materials Design, 2024 ). The calculations were carried out on 32 cores of a 144-core (768 Gb memory) HPE Superdome Flex 280 Linux server at North Central College. The calculation used the GGA-PBE functional, a plane wave cutoff energy of 400.0 eV, and a k-point spacing of 0.5 Å⁻¹ leading to a 2 × 2 × 1 mesh. To permit comparison of the energies and lattice parameters of the two diastereomers, dispersion-corrected DFT calculations were also carried out using VASP, incorporating the DFT-D3 approach of Grimme and allowing the lattice parameters to optimize. Single-point density functional theory calculations (fixed experimental cell) and population analysis were carried out using CRYSTAL23 (Erba et al., 2023 ). (fixed experimental cell) and population analysis were carried out using CRYSTAL17 (Dovesi et al., 2018 ). The basis sets for the H, C, N and O atoms in the calculation were those of Gatti et al. (1994 ). The calculations were run on a 3.5 GHz PC using 8 k-points and the B3LYP functional.

Supporting information

CCDC references: 2564140; 2564139; 2564138

Crystal structure: contains datablocks acoltremon_2, Molecules_100K_VASP, acoltremon_2_VASP. DOI: https://doi.org/10.1107/S2056989026006572/hb8218sup1.cif

Supporting information file. DOI: https://doi.org/10.1107/S2056989026006572/hb8218acoltremon_2sup2.cml

Table 5, with experimental and calculated lattice parameters for the two diastereomers. DOI: https://doi.org/10.1107/S2056989026006572/hb8218sup3.docx

checkCIF report

Computing details top

(1R,2S,5R)-2-Isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexane-1-carboxamide (acoltremon_2) top

Crystal data top

C₁₈H₂₇NO₂	V = 1726.59 (1) Å³
M_r = 289.42	Z = 4
Orthorhombic, P2₁2₁2₁	D_x = 1.113 Mg m⁻³
a = 9.320220 (15) Å	Synchrotron radiation, λ = 0.46873 Å
b = 11.39111 (3) Å	T = 295 K
c = 16.26284 (4) Å	cylinder, 2.0 × 1.5 mm

Data collection top

11-BM, APS diffractometer	Scan method: step
Specimen mounting: Kapton capillary	2θ_min = 0.510°, 2θ_max = 49.995°, 2θ_step = 0.001°
Data collection mode: transmission

Refinement top

Least-squares matrix: full	83 parameters
R_p = 0.113	53 restraints
R_wp = 0.133	16 constraints
R_exp = 0.038	Weighting scheme based on measured s.u.'s
R(F²) = 0.10052	(Δ/σ)_max = 1.712
49486 data points	Background function: Background function: "chebyschev-1" function with 6 terms: 47.29(16), -6.65(24), -12.59(16), 2.79(16), -3.99(17), -0.00(16), Background peak parameters: pos, int, sig, gam: 6.167(16), 1.122(32)e4, 1.24(5)e4, 0.100,
Profile function: Finger-Cox-Jephcoat function parameters U, V, W, X, Y, SH/L: peak variance(Gauss) = Utan(Th)²+Vtan(Th)+W: peak HW(Lorentz) = X/cos(Th)+Ytan(Th); SH/L = S/L+H/L U, V, W in (centideg)², X & Y in centideg 2.543, -0.174, 0.052, 0.000, 0.000, 0.002,	Preferred orientation correction: Simple spherical harmonic correction Order = 2 Coefficients: 0:0:C(2,0) = 0.290(5); 0:0:C(2,2) = 0.295(3)

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	1.0060 (5)	0.3097 (4)	0.5123 (3)	0.0774 (13)*
O2	0.9044 (5)	0.1119 (5)	0.8745 (3)	0.122 (2)*
N3	0.7965 (5)	0.2314 (5)	0.5481 (3)	0.0774 (13)*
C4	0.8275 (6)	0.4484 (4)	0.4087 (3)	0.0785 (11)*
C5	0.8154 (5)	0.3208 (4)	0.4181 (3)	0.0785 (11)*
C6	0.7586 (6)	0.4837 (5)	0.3279 (4)	0.0785 (11)*
C7	0.8365 (6)	0.2953 (5)	0.2633 (3)	0.0785 (11)*
C8	0.8992 (6)	0.2713 (5)	0.3472 (4)	0.0785 (11)*
C9	0.8316 (7)	0.4299 (6)	0.2550 (3)	0.0785 (11)*
C10	0.7665 (7)	0.5165 (6)	0.4855 (4)	0.124 (2)*
C11	0.8833 (5)	0.2836 (5)	0.4956 (3)	0.0774 (13)*
C12	0.9335 (7)	0.2360 (6)	0.1913 (3)	0.0785 (11)*
C13	0.7878 (7)	0.6442 (7)	0.4737 (4)	0.124 (2)*
C14	0.5992 (7)	0.5117 (7)	0.4841 (5)	0.124 (2)*
C15	0.8281 (7)	0.2023 (6)	0.6291 (3)	0.0637 (11)*
C16	0.7831 (7)	0.0934 (5)	0.6598 (3)	0.0637 (11)*
C17	0.8947 (7)	0.2790 (4)	0.6808 (4)	0.0637 (11)*
C18	0.8106 (7)	0.0608 (5)	0.7419 (4)	0.0637 (11)*
C19	0.9405 (6)	0.2401 (5)	0.7600 (4)	0.0637 (11)*
C20	0.8859 (7)	0.1368 (6)	0.7939 (3)	0.0637 (11)*
C21	0.8311 (7)	0.0201 (7)	0.9119 (4)	0.122 (2)*
H22	0.94662	0.47012	0.40403	0.0942*
H23	0.69849	0.29161	0.41551	0.0942*
H24	0.76261	0.58335	0.32187	0.0942*
H25	0.64173	0.45417	0.32732	0.0942*
H26	0.72280	0.25865	0.26023	0.0942*
H27	1.01186	0.31027	0.34713	0.0942*
H28	0.90827	0.17223	0.35567	0.0942*
H29	0.77023	0.45365	0.19669	0.0942*
H30	0.94572	0.46530	0.25046	0.0942*
H31	0.81334	0.48356	0.54600	0.1482*
H32	1.05097	0.26012	0.20108	0.0942*
H33	0.92100	0.13649	0.19352	0.0942*
H34	0.89651	0.26980	0.12882	0.0942*
H35	0.68069	0.69145	0.48081	0.1482*
H36	0.83250	0.66107	0.40953	0.1482*
H37	0.86659	0.67839	0.52166	0.1482*
H38	0.56192	0.41944	0.50089	0.1482*
H39	0.55441	0.57720	0.53046	0.1482*
H40	0.55903	0.53493	0.41992	0.1482*
H41	0.69380	0.20820	0.53000	0.0928*
H42	0.72320	0.02953	0.61815	0.0764*
H43	0.91356	0.37362	0.66070	0.0764*
H44	0.77148	−0.02757	0.76598	0.0764*
H45	1.02243	0.29354	0.79616	0.0764*
H46	0.91141	−0.04652	0.93674	0.1460*
H47	0.75825	−0.02427	0.86494	0.1460*
H48	0.76348	0.05576	0.96470	0.1460*

Geometric parameters (Å, º) top

O1—C11	1.213 (4)	C15—N3	1.391 (4)
O2—C20	1.352 (5)	C15—C16	1.402 (5)
O2—C21	1.389 (7)	C15—C17	1.362 (4)
N3—C11	1.317 (5)	C16—C15	1.402 (5)
N3—C15	1.391 (4)	C16—C18	1.410 (4)
N3—H41	1.035 (4)	C16—H42	1.140 (4)
C4—C5	1.465 (5)	C17—C15	1.362 (4)
C4—C6	1.517 (5)	C17—C19	1.428 (5)
C4—C10	1.575 (5)	C17—H43	1.139 (4)
C4—H22	1.140 (5)	C18—C16	1.410 (4)
C5—C4	1.465 (5)	C18—C20	1.399 (5)
C5—C8	1.502 (4)	C18—H44	1.140 (4)
C5—C11	1.472 (4)	C19—C17	1.428 (5)
C5—H23	1.140 (5)	C19—C20	1.395 (5)
C6—C4	1.517 (5)	C19—H45	1.140 (4)
C6—C9	1.498 (5)	C20—O2	1.352 (5)
C6—H24	1.141 (6)	C20—C18	1.399 (5)
C6—H25	1.140 (6)	C20—C19	1.395 (5)
C7—C8	1.509 (6)	C21—O2	1.389 (7)
C7—C9	1.540 (6)	C21—H46	1.139 (8)
C7—C12	1.626 (6)	C21—H47	1.140 (7)
C7—H26	1.140 (6)	C21—H48	1.140 (7)
C8—C5	1.502 (4)	H22—C4	1.140 (5)
C8—C7	1.509 (6)	H23—C5	1.140 (5)
C8—H27	1.140 (6)	H24—C6	1.141 (6)
C8—H28	1.140 (6)	H25—C6	1.140 (6)
C9—C6	1.498 (5)	H26—C7	1.140 (6)
C9—C7	1.540 (6)	H27—C8	1.140 (6)
C9—H29	1.140 (5)	H28—C8	1.140 (6)
C9—H30	1.140 (6)	H29—C9	1.140 (5)
C10—C4	1.575 (5)	H30—C9	1.140 (6)
C10—C13	1.481 (8)	H31—C10	1.140 (6)
C10—C14	1.561 (6)	H32—C12	1.140 (7)
C10—H31	1.140 (6)	H33—C12	1.140 (7)
C11—O1	1.213 (4)	H34—C12	1.140 (6)
C11—N3	1.317 (5)	H35—C13	1.140 (7)
C11—C5	1.472 (4)	H36—C13	1.140 (7)
C12—C7	1.626 (6)	H37—C13	1.140 (7)
C12—H32	1.140 (7)	H38—C14	1.140 (7)
C12—H33	1.140 (7)	H39—C14	1.140 (7)
C12—H34	1.140 (6)	H40—C14	1.140 (7)
C13—C10	1.481 (8)	H41—N3	1.035 (4)
C13—H35	1.140 (7)	H42—C16	1.140 (4)
C13—H36	1.140 (7)	H43—C17	1.139 (4)
C13—H37	1.140 (7)	H44—C18	1.140 (4)
C14—C10	1.561 (6)	H45—C19	1.140 (4)
C14—H38	1.140 (7)	H46—C21	1.139 (8)
C14—H39	1.140 (7)	H47—C21	1.140 (7)
C14—H40	1.140 (7)	H48—C21	1.140 (7)

C20—O2—C21	121.3 (5)	H32—C12—H33	109.5 (5)
C11—N3—C15	126.2 (4)	H32—C12—H34	109.5 (5)
C11—N3—H41	119.9 (4)	H33—C12—H34	109.4 (5)
C15—N3—H41	113.8 (5)	C10—C13—H35	109.4 (6)
C5—C4—C6	108.7 (4)	C10—C13—H36	109.4 (6)
C5—C4—H22	107.3 (4)	H35—C13—H36	109.5 (6)
C6—C4—H22	107.3 (5)	C10—C13—H37	109.5 (7)
C4—C5—C8	104.6 (4)	H35—C13—H37	109.5 (6)
C4—C5—C11	110.0 (3)	H36—C13—H37	109.5 (5)
C8—C5—C11	109.0 (4)	C10—C14—H38	109.4 (6)
C4—C5—H23	111.1 (4)	C10—C14—H39	109.5 (6)
C8—C5—H23	111.0 (4)	H38—C14—H39	109.5 (6)
C11—C5—H23	111.0 (4)	C10—C14—H40	109.4 (5)
C4—C6—C9	112.7 (4)	H38—C14—H40	109.5 (6)
C4—C6—H24	108.9 (5)	H39—C14—H40	109.5 (6)
C9—C6—H24	108.9 (5)	N3—C15—C16	119.0 (5)
C4—C6—H25	109.5 (5)	N3—C15—C17	121.9 (5)
C9—C6—H25	107.9 (5)	C16—C15—C17	119.0 (3)
H24—C6—H25	108.9 (4)	C15—C16—C18	121.0 (3)
C8—C7—C9	105.7 (4)	C15—C16—H42	120.0 (5)
C8—C7—H26	109.5 (5)	C18—C16—H42	119.0 (5)
C9—C7—H26	109.4 (5)	C15—C17—C19	119.6 (3)
C5—C8—C7	115.1 (4)	C15—C17—H43	120.0 (5)
C5—C8—H27	109.5 (5)	C19—C17—H43	120.4 (5)
C7—C8—H27	106.5 (5)	C16—C18—C20	120.1 (3)
C5—C8—H28	108.5 (5)	C16—C18—H44	119.9 (5)
C7—C8—H28	108.4 (5)	C20—C18—H44	120.0 (5)
H27—C8—H28	108.5 (4)	C17—C19—C20	120.6 (3)
C6—C9—C7	110.5 (4)	C17—C19—H45	120.0 (6)
C6—C9—H29	109.5 (5)	C20—C19—H45	119.4 (6)
C7—C9—H29	108.9 (5)	O2—C20—C18	121.3 (5)
C6—C9—H30	109.3 (6)	O2—C20—C19	120.9 (5)
C7—C9—H30	109.3 (5)	C18—C20—C19	117.8 (3)
H29—C9—H30	109.3 (4)	O2—C21—H46	109.5 (6)
C13—C10—C14	99.6 (5)	O2—C21—H47	109.4 (5)
C13—C10—H31	112.5 (6)	H46—C21—H47	109.5 (7)
C14—C10—H31	112.5 (6)	O2—C21—H48	109.4 (7)
O1—C11—N3	123.0 (4)	H46—C21—H48	109.5 (5)
O1—C11—C5	121.7 (3)	H47—C21—H48	109.5 (6)
N3—C11—C5	114.9 (3)

(acoltremon_2_VASP) top

Crystal data top

C₁₈H₂₇NO₂	b = 11.39111 Å
M_r = 289.42	c = 16.26284 Å
Orthorhombic, P2₁2₁2₁	V = 1726.59 Å³
a = 9.32022 Å	Z = 4

Data collection top

h = →	l = →
k = →

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	B_iso*/B_eq
O1	1.01413	0.30651	0.51100
O2	0.90354	0.11941	0.87778
N3	0.79574	0.23233	0.54912
C4	0.82622	0.46054	0.40507
C5	0.81815	0.32519	0.41433
C6	0.76351	0.49545	0.32138
C7	0.84080	0.30145	0.25810
C8	0.89693	0.26450	0.34276
C9	0.84152	0.43556	0.25010
C10	0.76145	0.52847	0.47885
C11	0.88472	0.28716	0.49524
C12	0.92763	0.24298	0.18986
C13	0.80650	0.65778	0.47776
C14	0.59804	0.51763	0.48653
C15	0.83074	0.19945	0.63072
C16	0.77289	0.09627	0.66346
C17	0.91421	0.27182	0.68170
C18	0.79465	0.06595	0.74578
C19	0.93765	0.24165	0.76324
C20	0.87726	0.13914	0.79624
C21	0.81861	0.03231	0.91816
H22	0.94183	0.48270	0.40418
H23	0.70449	0.29852	0.41349
H24	0.76879	0.59126	0.31368
H25	0.64871	0.47176	0.31927
H26	0.72797	0.27240	0.25317
H27	1.01212	0.28588	0.34672
H28	0.88899	0.16829	0.34954
H29	0.79251	0.46137	0.19103
H30	0.95403	0.46632	0.24810
H31	0.80890	0.48978	0.53495
H32	1.04086	0.27042	0.19257
H33	0.92576	0.14661	0.19508
H34	0.88640	0.26639	0.12866
H35	0.75606	0.70558	0.42664
H36	0.92354	0.66743	0.47264
H37	0.77364	0.70176	0.53494
H38	0.56228	0.42571	0.48786
H39	0.56132	0.55978	0.54368
H40	0.54279	0.56176	0.43530
H41	0.69185	0.21534	0.52992
H42	0.70813	0.03924	0.62428
H43	0.95775	0.35348	0.65753
H44	0.74655	−0.01411	0.76994
H45	0.99958	0.29888	0.80367
H46	0.84877	0.03673	0.98317
H47	0.84234	−0.05661	0.89556
H48	0.70326	0.05132	0.91125

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N3—H41···O1ⁱ	1.04	1.80	2.836	175
C5—H23···O1ⁱ	1.10	2.47	3.428	145
C13—H35···O2	1.10	2.61	3.594	148
C10—H31···C11ⁱⁱ	1.11	2.50	2.991	106

Symmetry codes: (i) −x−1, y+1/2, −z+3/2; (ii) x+5/2, −y−1/2, −z+1.

(Molecules_100K_VASP) top

Crystal data top

C₁₈H₂₇NO₂	α = 90°
M_r = 289.42	β = 90°
P2₁2₁2₁	γ = 90°
a = 9.13710 Å	V = 1659.07 Å³
b = 10.38210 Å	Z = 4
c = 17.48930 Å

Data collection top

h = →	l = →
k = →

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.8885	0.6624	0.5105	?
O2	0.9034	0.0242	0.8026	?
N1	0.6836	0.7769	0.5428	?
C1	0.4621	0.4887	0.5510	?
C2	0.6165	0.2918	0.5384	?
C3	0.6132	0.4381	0.5276	?
C4	0.6568	0.4789	0.4455	?
C5	0.7971	0.4126	0.4174	?
C6	0.8423	0.4550	0.3372	?
C7	0.8627	0.6007	0.3317	?
C8	0.9099	0.6428	0.2520	?
C9	0.7217	0.6676	0.3564	?
C10	0.6655	0.6279	0.4362	?
C11	0.7566	0.6895	0.4990	?
C12	0.7420	0.8372	0.6090	?
C13	0.8065	0.7644	0.6670	?
C14	0.8608	0.8232	0.7329	?
C15	0.8508	0.9571	0.7411	?
C16	0.7842	0.0306	0.6835	?
C17	0.7303	0.9709	0.6182	?
C18	0.9601	0.9513	0.8652	?
H1N	0.5786	0.8009	0.5264	?
H1A	0.4530	0.5939	0.5468	?
H1B	0.4372	0.4617	0.6104	?
H1C	0.3768	0.4467	0.5142	?
H2A	0.5461	0.2438	0.4959	?
H2B	0.5744	0.2658	0.5953	?
H2C	0.7273	0.2517	0.5331	?
H00F	0.6953	0.4796	0.5671	?
H4	0.5669	0.4483	0.4070	?
H5A	0.8866	0.4336	0.4578	?
H5B	0.7817	0.3074	0.4178	?
H6A	0.9438	0.4055	0.3201	?
H6B	0.7577	0.4254	0.2955	?
H7	0.9499	0.6281	0.3720	?
H8A	0.8272	0.6157	0.2090	?
H8B	0.0141	0.5972	0.2357	?
H8C	0.9255	0.7478	0.2491	?
H9A	0.6348	0.6435	0.3149	?
H9B	0.7337	0.7731	0.3539	?
H10	0.5539	0.6665	0.4413	?
H13	0.8143	0.6603	0.6610	?
H14	0.9108	0.7635	0.7769	?
H16	0.7757	0.1346	0.6910	?
H17	0.6780	0.0285	0.5738	?
H18A	0.8752	0.8875	0.8892	?
H18B	0.9948	0.0218	0.9082	?
H18C	0.0551	0.8926	0.8477	?

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1N···O1	1.03	1.89	2.922	176
C18—H18B···O1	1.10	2.30	3.383	169
C10—H10···O1	1.10	2.48	3.466	149
C9—H9B···O2	1.10	2.61	3.526	140
C3—H00F···C11	1.11	2.55	2.963	101

Hydrogen-bond geometry (Å, °) for VASP-optimized acoltremon top

D—H···A	D—H	H···A	D···A	D—H···A	Mulliken overlap	H-bond energy
N3—H41···O1ⁱ	1.04	1.80	2.836	175	0.064	5.8
C5—H23···O1ⁱ	1.10	2.47	3.428	145	0.014	–
C13—H35···O2	1.10	2.61	3.594	148	0.010	–
C10—H31···C11ⁱⁱ	1.11	2.50	2.991	106	0.012	–

Symmetry codes: (i) -x - 1, y + 1/2, -z + 3/2; (ii) x + 5/2, -y - 1/2, -z + 1.

Hydrogen-bond geometry (Å, °) for VASP-optimized (1S,2S,5R) diastereomer top

D—H···A	D—H	H···A	D···A	D—H···A	Mulliken overlap	H-bond energy
N1—H1N···O1ⁱ	1.03	1.89	2.922	176	0.048	5.1
C18—H18B···O1ⁱⁱ	1.10	2.30	3.383	169	0.022
C10—H10···O1ⁱⁱⁱ	1.10	2.48	3.466	149	0.016
C9–H9B···O2	1.10	2.61	3.526	140	0.011
C3–H00F···C11	1.11	2.55	2.963	101	0.011

Symmetry codes: (i) -x + 1, y + 3/2, -z + 3/2; (ii) x + 5/2, -y - 1/2, -z + 1; (iii) -x - 1, y + 3/2, -z + 3/2.

Acknowledgements

Use of the Advanced Photon Source at Argonne National Laboratory was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02–06CH11357. We thank Saul Lapidus for his assistance in the data collection. We also thank the ICDD team – Megan Rost, Steve Trimble, and Dave Bohnenberger – for their contribution to research, sample preparation, and in-house XRD data collection and verification.

Funding information

Funding for this research was provided by: International Centre for Diffraction Data (grant No. 09-03).

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