Crystal structure of methyl (4R)-4-(4-meth­oxy­benzo­yl)-4-{[(1R)-1-phenyl­eth­yl]carbamo­yl}butano­ate

Manchado, A.; Salgado, M.M.; Vicente, Á.; Díez, D.; Sanz, F.; Garrido, N.M.

doi:10.1107/S2056989017003607

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Volume 73| Part 4| April 2017| Pages 503-506

https://doi.org/10.1107/S2056989017003607

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Crystal structure of methyl (4R)-4-(4-methoxybenzoyl)-4-{[(1R)-1-phenylethyl]carbamoyl}butanoate

Alejandro Manchado,^a Mateo M. Salgado,^a Álvaro Vicente,^a David Díez,^a Francisca Sanz ^b and Narciso M. Garrido ^a ^*

^aDepartamento de Química Orgánica, Universidad de Salamanca, Plaza de los Caidos, 37008-Salamanca, Spain, and ^bServicio de Difracción de Rayos X, Universidad de Salamanca, Plaza de los Caidos, 37008-Salamanca, Spain
^*Correspondence e-mail: nmg@usal.es

Edited by W. T. A. Harrison, University of Aberdeen, Scotland (Received 10 January 2017; accepted 7 March 2017; online 14 March 2017)

The title compound, C₂₂H₂₅NO₅, was prepared by CAN [cerium(IV) ammonium nitrate] oxidation of the corresponding β-lactam. The dihedral angle between the benzene rings is 13.3 (4)° and the C—N—C(=O)—C torsion angle is 176.1 (6)°. In the crystal, amide-C(4) N—H⋯O and reinforcing C—H⋯O hydrogen bonds link the molecules into infinite [010] chains. Further C—H⋯O hydrogen bonds cross-link the chains in the c-axis direction.

Keywords: crystal structure; hydrogen bonds; CAN oxidation; β-lactame; glutarate.

CCDC reference: 1524270

1. Chemical context

Cerium(IV) ammonium nitrate (CAN) is a powerful reagent in organic synthesis, which promotes a wide range of reactions that go well beyond its usual role as an oxidant (Sridharan & Menendez, 2010 ). Chemoselective mono-debenzylation of benzyl tertiary amines occurs in the presence of N-benzyl amides, O-benzyl ethers and esters (Bull et al., 2000 ); interestingly this reaction can be applied to mono-debenzylation of β-amino esters as a way to obtain β-lactams (Davies & Ichihara, 1998 ) or piperidone (Garrido et al., 2011 ), providing as well a new oxidative methodology as catch linker for reaction monitoring and optimization on solid phase support (Davies et al., 2008 ). Our group has demonstrated two different domino reactions, one by lithium amide addition to diendioate that can be applied to the synthesis of cyclopentanic (Urones et al., 2004 ) or cyclohexanic (Garrido et al., 2006 ) derivatives and the other by addition to Baylis–Hillman (Garrido et al., 2008 ) derivatives with application to the synthesis of non-peptidic neurokinin NK1 receptor antagonist (+)-L-733,060 (Garrido et al., 2010 ). Within this context of the synthesis of biologically active compounds, we are interested in the synthesis of β-lactam and its mono-deprotection, as shown in the Scheme, where the asymmetric 4-benzoyl glutarate is readily obtained by CAN oxidation of the appropriate substituted β-lactam. For the CAN oxidation reaction of a related trialkyl amine derivative providing monodeprotection, see Garrido et al. (2011).

2. Structural commentary

The molecular structure of the title compound is shown in Fig. 1. The molecule consists of an ester amide glutarate derivative with a p-metoxybenzoyl group as substituent: all the bond lengths and angles are within normal ranges. The almost planar conformation of the ester group is established from the torsion angle C20—C21—O4—C22 of 178.6 (3)°. The ether group atom C1 and the carbonyl group atom C8 are almost coplanar with the benzene ring, the C7—O1—C1—C6 and O2—C8—C4—C5 torsion angles being 177.9 (1) and 172.4 (8)°, respectively. The C11 methyl group is also almost coplanar with the its benzene ring, as indicated by the torsion angle C18—C11—C12—C13 of 176.68 (7)°. The dihedral angle between the aromatic rings is 13.3 (4)°.

Figure 1
The molecular structure of the title compound. Displacement ellipsoids are drawn at the 50% probability level. H atoms are shown as spheres of arbitrary radius.

3. Supramolecular features

In the extended structure of the title compound, hydrogen bonds are one of the primary factors in building the crystal network (Table 1). Intermolecular N1—H1⋯O3ⁱ (dotted light-blue lines), C9—H9⋯O3ⁱ dotted (orange lines) and C20—H20A⋯O2ⁱ (dotted blue lines) hydrogen bonds link neighboring molecules, generating infinite chains running along the b-axis direction (Fig. 2). These chains are joined to each other along c axis by C17—H17⋯O5ⁱⁱ interactions (dotted pink lines), as shown in Fig. 3. The packing viewed along the [010] direction is illustrated in Fig. 4.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯O3ⁱ	0.86	2.02	2.871 (6)	168
C9—H9⋯O3ⁱ	0.98	2.46	3.277 (7)	141
C20—H20A⋯O2ⁱ	0.97	2.49	3.410 (8)	158
C17—H17⋯O5ⁱⁱ	0.93	2.55	3.303 (11)	139
Symmetry codes: (i) x, y+1, z; (ii) $[-x, y+{\script{1\over 2}}, -z+{\script{5\over 2}}]$ .

Figure 2
A view of the C20—H20A⋯O2 (dotted blue lines), N1—H1⋯O3 (dotted light-blue lines) and C9—H9⋯O3 (dotted orange lines) hydrogen bonds (see Table 1

), which link the molecules into [010] chains.

Figure 3
A view of the C17—H17⋯O5 (dotted pink lines) hydrogen bonds in the extended structure of the title compound.

Figure 4
Crystal packing of the title compound, viewed along the [010] direction.

4. Synthesis and crystallization

(3S,4S,αR)-N-(α-methylbenzyl)-4-(para-methoxyphenyl)-3-methoxycarbonylethyl-β-lactam (I) (26.50 mg, 76.12 µmol) was dissolved in 12.00 ml of a mixture of MeCN–H₂O (5:1) and CAN (150.1 mg, 0.27 mmol) was added and allowed to stir for 15 minutes under an argon atmosphere. Solid NaHCO₃ was then added and the mixture allowed to stir for another 15 minutes. It was filtered over celite, washed with EtOAc and NaHSO₄ and the phases separated. The organic phase was treated with H₂O, brine and anhydrous Na₂SO₄, filtered and the solvent removed under reduced pressure to obtained the crude product (23.4 mg), which was purified by flash chromatography (silica gel, hexane/EtOAC 7:3) and crystallized from hexane/EtOAc solution to yield 7.7 mg of product (II) (28%), m.p. 440.6 K.

IR (film): 700, 802, 1026, 1171, 1260, 1373, 1456, 1512, 1601, 1736, 2849, 2918, 3333. ¹H NMR (200 MHz, CDCl₃) δ 8.33–7.78 (m, 2H, Ar), 7.48–7.25 (m, 5H, Ar), 6.99–6.81 (m, 2H, Ar), 5.05 (1H, quint, J = 6.9 Hz), 4.65 (1H, t, J = 5.5 Hz), 3.87 (s, 3H, COOMe), 3.65 (s, 3H, OMe), 2.50–2.20 (m, 4H), 1.47 (3H, d, J = 6.9 Hz, CH₃).¹³C NMR (50 MHz, CDCl₃) δ 193.4 (C, C=O), 169.4(C, C=O), 164.1 (C, C_ipso), 160.6 (C, C_ipso), 139.2(C, C_ipso), 127.5 (CH × 2, Ar), 125.0 (CH × 2, Ar), 122.3 (CH, Ar), 122.1 (CH × 2, Ar), 110.4 (CH × 2, Ar), 51.9 (CH₃, COOMe), 50.1 (CH), 48.1 (CH₃, OMe), 45.3 (CH), 27.6 (CH₂), 23.3 (CH₂), 18.4 (CH₃). HRMS (EI): C₂₂H₂₆NO₅ requires (M + H)⁺, 384.1803, found 384.1805.

5. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. The hydrogen atoms were positioned geometrically, with C–H distances constrained to 0.93 Å (aromatic CH), 0.97 Å (methylene CH₂), 0.98 methyne CH) and N—H = 0.86 Å (amine), and refined using a riding model with U_iso(H) = 1.2 or 1.5U_eq(C,N).

Table 2
Experimental details

Crystal data
Chemical formula	C₂₂H₂₅NO₅
M_r	383.43
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	298
a, b, c (Å)	23.739 (3), 4.7791 (5), 18.0722 (19)
V (Å³)	2050.3 (4)
Z	4
Radiation type	Cu Kα
μ (mm⁻¹)	0.72
Crystal size (mm)	0.12 × 0.10 × 0.08

Data collection
Diffractometer	Bruker APEXII CCD area-detector
Absorption correction	Multi-scan (SADABS; Bruker, 2006 )
T_min, T_max	0.917, 0.944
No. of measured, independent and observed [I > 2σ(I)] reflections	9316, 2913, 1854
R_int	0.053
(sin θ/λ)_max (Å⁻¹)	0.594

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.067, 0.163, 1.25
No. of reflections	2913
No. of parameters	256
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.15, −0.19
Absolute structure parameter	0.0 (8)
Computer programs: APEX2 and SAINT (Bruker 2006), SHELXS97, SHELXL97 and SHELXTL (Sheldrick, 2008 ) and Mercury (Macrae et al., 2008 ).

Supporting information

CCDC reference: 1524270

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S2056989017003607/hb7652sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989017003607/hb7652Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989017003607/hb7652Isup3.cml

checkCIF report

Computing details top

Data collection: APEX2 (Bruker 2006); cell refinement: SAINT (Bruker 2006); data reduction: SAINT (Bruker 2006); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Methyl (4R)-4-(4-methoxybenzoyl)-4-{[(1R)-1-phenylethyl]carbamoyl}butanoate top

Crystal data top

C₂₂H₂₅NO₅	F(000) = 816
M_r = 383.43	D_x = 1.242 Mg m⁻³
Orthorhombic, P2₁2₁2₁	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: P 2ac 2ab	Cell parameters from 3001 reflections
a = 23.739 (3) Å	θ = 3.1–60.0°
b = 4.7791 (5) Å	µ = 0.72 mm⁻¹
c = 18.0722 (19) Å	T = 298 K
V = 2050.3 (4) Å³	Prismatic, colorless
Z = 4	0.12 × 0.10 × 0.08 mm

Data collection top

Bruker APEXII CCD area-detector diffractometer	2913 independent reflections
Radiation source: fine-focus sealed tube	1854 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.053
phi and ω scans	θ_max = 66.3°, θ_min = 3.1°
Absorption correction: multi-scan (SADABS; Bruker, 2006)	h = −26→27
T_min = 0.917, T_max = 0.944	k = −5→4
9316 measured reflections	l = −18→21

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.067	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.163	H-atom parameters constrained
S = 1.25	w = 1/[σ²(F_o²) + (0.0115P)² + 2.2937P] where P = (F_o² + 2F_c²)/3
2913 reflections	(Δ/σ)_max < 0.001
256 parameters	Δρ_max = 0.15 e Å⁻³
0 restraints	Δρ_min = −0.19 e Å⁻³

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

	x	y	z	U_iso*/U_eq
O1	0.14092 (19)	0.5853 (12)	0.7501 (3)	0.0968 (16)
O2	−0.07814 (19)	0.4116 (10)	0.9431 (2)	0.0873 (15)
O3	0.0203 (2)	0.3173 (8)	1.0773 (3)	0.0954 (17)
O4	−0.2138 (2)	1.1081 (15)	1.0782 (4)	0.135 (2)
O5	−0.1868 (3)	0.7840 (19)	1.1507 (4)	0.172 (4)
N1	0.0500 (2)	0.7476 (10)	1.1092 (3)	0.0660 (15)
H1	0.0457	0.9243	1.1022	0.079*
C1	0.0970 (3)	0.5689 (16)	0.7980 (4)	0.0737 (19)
C2	0.0521 (3)	0.3913 (14)	0.7891 (4)	0.077 (2)
H2	0.0503	0.2712	0.7487	0.093*
C3	0.0090 (3)	0.3946 (15)	0.8420 (4)	0.0721 (19)
H3	−0.0216	0.2754	0.8359	0.087*
C4	0.0105 (3)	0.5687 (13)	0.9029 (4)	0.0620 (16)
C5	0.0563 (3)	0.7466 (14)	0.9097 (4)	0.0742 (19)
H5	0.0584	0.8673	0.9500	0.089*
C6	0.0987 (3)	0.7474 (16)	0.8579 (4)	0.081 (2)
H6	0.1288	0.8699	0.8632	0.098*
C7	0.1414 (3)	0.3946 (19)	0.6885 (5)	0.116 (3)
H7A	0.1399	0.2057	0.7065	0.173*
H7B	0.1754	0.4207	0.6605	0.173*
H7C	0.1094	0.4302	0.6575	0.173*
C8	−0.0366 (3)	0.5519 (12)	0.9563 (4)	0.0622 (16)
C9	−0.0306 (2)	0.7072 (11)	1.0286 (3)	0.0621 (17)
H9	−0.0205	0.9019	1.0180	0.075*
C10	0.0160 (3)	0.5753 (13)	1.0744 (4)	0.0628 (16)
C11	0.0948 (3)	0.6560 (14)	1.1592 (4)	0.077 (2)
H11	0.1005	0.4553	1.1508	0.093*
C12	0.1492 (3)	0.8035 (14)	1.1383 (4)	0.0658 (18)
C13	0.1712 (4)	0.7725 (19)	1.0682 (5)	0.106 (3)
H13	0.1523	0.6623	1.0339	0.127*
C14	0.2205 (4)	0.901 (3)	1.0482 (5)	0.128 (4)
H14	0.2350	0.8761	1.0009	0.154*
C15	0.2483 (4)	1.065 (2)	1.0980 (7)	0.120 (3)
H15	0.2817	1.1533	1.0845	0.144*
C16	0.2273 (4)	1.100 (2)	1.1666 (6)	0.118 (3)
H16	0.2465	1.2103	1.2006	0.142*
C17	0.1779 (3)	0.9729 (15)	1.1865 (4)	0.085 (2)
H17	0.1635	1.0022	1.2337	0.102*
C18	0.0765 (3)	0.692 (2)	1.2385 (4)	0.117 (3)
H18A	0.0712	0.8878	1.2487	0.176*
H18B	0.1049	0.6181	1.2708	0.176*
H18C	0.0417	0.5946	1.2464	0.176*
C19	−0.0847 (2)	0.7043 (12)	1.0759 (3)	0.0672 (17)
H19A	−0.0969	0.5120	1.0821	0.081*
H19B	−0.0760	0.7781	1.1245	0.081*
C20	−0.1329 (2)	0.8718 (15)	1.0434 (4)	0.078 (2)
H20A	−0.1190	1.0532	1.0277	0.093*
H20B	−0.1473	0.7757	1.0000	0.093*
C21	−0.1799 (3)	0.9125 (19)	1.0976 (5)	0.082 (2)
C22	−0.2616 (3)	1.157 (2)	1.1275 (6)	0.162 (5)
H22A	−0.2773	0.9809	1.1425	0.243*
H22B	−0.2898	1.2642	1.1020	0.243*
H22C	−0.2491	1.2583	1.1703	0.243*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.084 (3)	0.115 (4)	0.091 (4)	−0.005 (3)	0.004 (3)	−0.005 (4)
O2	0.099 (3)	0.090 (3)	0.072 (3)	−0.043 (3)	−0.008 (3)	−0.009 (3)
O3	0.135 (4)	0.031 (2)	0.120 (5)	0.001 (3)	−0.050 (4)	0.001 (3)
O4	0.108 (4)	0.149 (6)	0.149 (6)	0.035 (4)	0.045 (4)	0.051 (5)
O5	0.159 (6)	0.218 (8)	0.139 (6)	0.052 (6)	0.054 (5)	0.093 (6)
N1	0.087 (3)	0.034 (3)	0.078 (4)	0.003 (3)	−0.032 (3)	0.002 (3)
C1	0.074 (4)	0.068 (4)	0.079 (5)	0.007 (4)	−0.009 (4)	0.008 (5)
C2	0.089 (5)	0.064 (5)	0.078 (5)	−0.001 (4)	−0.008 (4)	−0.010 (4)
C3	0.080 (4)	0.063 (4)	0.073 (5)	−0.014 (4)	−0.008 (4)	−0.002 (4)
C4	0.072 (4)	0.047 (3)	0.067 (4)	−0.003 (3)	−0.013 (3)	0.003 (4)
C5	0.084 (4)	0.063 (4)	0.076 (5)	−0.013 (4)	−0.010 (4)	−0.007 (4)
C6	0.078 (4)	0.075 (5)	0.091 (6)	−0.019 (4)	−0.009 (4)	−0.004 (5)
C7	0.121 (7)	0.126 (7)	0.100 (7)	0.008 (6)	0.018 (5)	−0.032 (7)
C8	0.083 (4)	0.042 (3)	0.062 (4)	−0.012 (3)	−0.017 (4)	0.000 (3)
C9	0.077 (4)	0.036 (3)	0.074 (5)	−0.007 (3)	−0.018 (3)	0.002 (3)
C10	0.082 (4)	0.044 (3)	0.063 (4)	−0.001 (4)	−0.021 (3)	−0.001 (4)
C11	0.094 (5)	0.055 (4)	0.082 (5)	0.005 (4)	−0.037 (4)	0.006 (4)
C12	0.074 (4)	0.054 (4)	0.070 (5)	0.012 (3)	−0.018 (4)	−0.003 (4)
C13	0.104 (6)	0.126 (7)	0.088 (7)	0.009 (6)	−0.010 (5)	−0.034 (6)
C14	0.104 (7)	0.195 (12)	0.085 (7)	0.025 (7)	0.013 (5)	−0.009 (8)
C15	0.090 (6)	0.139 (9)	0.132 (10)	0.002 (6)	0.003 (7)	0.030 (9)
C16	0.097 (6)	0.128 (8)	0.128 (9)	−0.033 (6)	−0.005 (6)	−0.018 (8)
C17	0.092 (5)	0.086 (5)	0.078 (6)	−0.005 (4)	0.000 (4)	−0.013 (5)
C18	0.105 (5)	0.184 (10)	0.063 (5)	−0.036 (6)	−0.020 (4)	0.038 (7)
C19	0.088 (4)	0.054 (4)	0.059 (4)	−0.006 (3)	−0.009 (4)	0.007 (4)
C20	0.077 (4)	0.078 (5)	0.078 (5)	−0.009 (4)	−0.006 (4)	0.016 (4)
C21	0.083 (5)	0.088 (5)	0.075 (6)	−0.005 (5)	−0.001 (4)	0.014 (5)
C22	0.107 (6)	0.185 (11)	0.195 (11)	0.033 (7)	0.073 (7)	0.023 (9)

Geometric parameters (Å, º) top

O1—C1	1.357 (8)	C9—H9	0.9800
O1—C7	1.439 (8)	C11—C18	1.508 (9)
O2—C8	1.215 (6)	C11—C12	1.518 (9)
O3—C10	1.238 (6)	C11—H11	0.9800
O4—C21	1.282 (9)	C12—C17	1.371 (9)
O4—C22	1.461 (8)	C12—C13	1.379 (10)
O5—C21	1.151 (8)	C13—C14	1.369 (11)
N1—C10	1.314 (7)	C13—H13	0.9300
N1—C11	1.461 (7)	C14—C15	1.364 (12)
N1—H1	0.8600	C14—H14	0.9300
C1—C2	1.373 (9)	C15—C16	1.346 (11)
C1—C6	1.378 (9)	C15—H15	0.9300
C2—C3	1.398 (8)	C16—C17	1.369 (10)
C2—H2	0.9300	C16—H16	0.9300
C3—C4	1.380 (8)	C17—H17	0.9300
C3—H3	0.9300	C18—H18A	0.9600
C4—C5	1.386 (8)	C18—H18B	0.9600
C4—C8	1.481 (8)	C18—H18C	0.9600
C5—C6	1.374 (9)	C19—C20	1.515 (8)
C5—H5	0.9300	C19—H19A	0.9700
C6—H6	0.9300	C19—H19B	0.9700
C7—H7A	0.9600	C20—C21	1.498 (9)
C7—H7B	0.9600	C20—H20A	0.9700
C7—H7C	0.9600	C20—H20B	0.9700
C8—C9	1.509 (8)	C22—H22A	0.9600
C9—C10	1.519 (8)	C22—H22B	0.9600
C9—C19	1.542 (8)	C22—H22C	0.9600

C1—O1—C7	117.6 (6)	C12—C11—H11	107.4
C21—O4—C22	115.9 (7)	C17—C12—C13	117.3 (7)
C10—N1—C11	123.7 (5)	C17—C12—C11	122.6 (7)
C10—N1—H1	118.1	C13—C12—C11	120.1 (7)
C11—N1—H1	118.1	C14—C13—C12	121.3 (8)
O1—C1—C2	123.9 (7)	C14—C13—H13	119.4
O1—C1—C6	116.3 (7)	C12—C13—H13	119.4
C2—C1—C6	119.8 (7)	C15—C14—C13	119.8 (9)
C1—C2—C3	118.7 (7)	C15—C14—H14	120.1
C1—C2—H2	120.6	C13—C14—H14	120.1
C3—C2—H2	120.6	C16—C15—C14	120.0 (10)
C4—C3—C2	122.2 (6)	C16—C15—H15	120.0
C4—C3—H3	118.9	C14—C15—H15	120.0
C2—C3—H3	118.9	C15—C16—C17	120.3 (9)
C3—C4—C5	117.5 (6)	C15—C16—H16	119.9
C3—C4—C8	117.9 (6)	C17—C16—H16	119.9
C5—C4—C8	124.6 (6)	C16—C17—C12	121.4 (8)
C6—C5—C4	121.0 (7)	C16—C17—H17	119.3
C6—C5—H5	119.5	C12—C17—H17	119.3
C4—C5—H5	119.5	C11—C18—H18A	109.5
C5—C6—C1	120.8 (7)	C11—C18—H18B	109.5
C5—C6—H6	119.6	H18A—C18—H18B	109.5
C1—C6—H6	119.6	C11—C18—H18C	109.5
O1—C7—H7A	109.5	H18A—C18—H18C	109.5
O1—C7—H7B	109.5	H18B—C18—H18C	109.5
H7A—C7—H7B	109.5	C20—C19—C9	114.2 (5)
O1—C7—H7C	109.5	C20—C19—H19A	108.7
H7A—C7—H7C	109.5	C9—C19—H19A	108.7
H7B—C7—H7C	109.5	C20—C19—H19B	108.7
O2—C8—C4	121.0 (6)	C9—C19—H19B	108.7
O2—C8—C9	121.2 (6)	H19A—C19—H19B	107.6
C4—C8—C9	117.8 (5)	C21—C20—C19	112.2 (6)
C8—C9—C10	109.7 (5)	C21—C20—H20A	109.2
C8—C9—C19	113.3 (5)	C19—C20—H20A	109.2
C10—C9—C19	107.5 (5)	C21—C20—H20B	109.2
C8—C9—H9	108.7	C19—C20—H20B	109.2
C10—C9—H9	108.7	H20A—C20—H20B	107.9
C19—C9—H9	108.7	O5—C21—O4	121.9 (9)
O3—C10—N1	123.6 (6)	O5—C21—C20	125.6 (9)
O3—C10—C9	119.7 (6)	O4—C21—C20	112.5 (7)
N1—C10—C9	116.7 (5)	O4—C22—H22A	109.5
N1—C11—C18	110.0 (6)	O4—C22—H22B	109.5
N1—C11—C12	109.0 (5)	H22A—C22—H22B	109.5
C18—C11—C12	115.3 (6)	O4—C22—H22C	109.5
N1—C11—H11	107.4	H22A—C22—H22C	109.5
C18—C11—H11	107.4	H22B—C22—H22C	109.5

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O3ⁱ	0.86	2.02	2.871 (6)	168
C9—H9···O3ⁱ	0.98	2.46	3.277 (7)	141
C20—H20A···O2ⁱ	0.97	2.49	3.410 (8)	158
C17—H17···O5ⁱⁱ	0.93	2.55	3.303 (11)	139

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

Acknowledgements

The authors gratefully acknowledge the help of A. Lithgow (NMR) and C. Raposo (MS) of the Universidad de Salamanca.

Funding information

Funding for this research was provided by: Ministerio de Economía y Competitividad (award Nos. CTQ2015–68175-R, SAF2014–59716-R); FEDER, Junta de Castilla y León UCI21.

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