Design of new anti-Alzheimer drugs: ring-expansion synthesis and synchrotron X-ray diffraction study of dimethyl 4-ethyl-11-fluoro-1,4,5,6,7,8-hexa-hydro-azonino[5,6-b]indole-2,3-di-carboxyl-ate.

The title compound, C20H23FN2O4, is the product of a ring-expansion reaction from a seven-membered fluorinated hexa-hydro-azepine to a nine-membered azonine. The nine-membered azonine ring of the mol-ecule adopts a chair-boat conformation. The C=C and C-N bond lengths [1.366 (3) and 1.407 (3) Å, respectively] indicate the presence of conjugation within the enamine CH2-C=C-N-CH2 fragment. The substituent planes at the C=C double bond of this fragment are twisted by 16.0 (3)° as a result of steric effects. The amine N(Et) N atom has a trigonal-pyramidal configuration (sum of the bond angles = 346.3°). The inter-planar angle between the two carboxyl-ate substituents is 60.39 (8)°. In the crystal, mol-ecules form zigzag chains along [010] by inter-molecular N-H⋯O hydrogen-bonding inter-actions, which are further packed in stacks toward [100]. The title azonino-indole might be considered as a candidate for the design of new Alzheimer drugs.

Chemical context

Eight-, nine-, and ten-membered heterocycles, often referred to as medium-sized rings, remain largely unexplored because of the lack of general convenient routes for their synthesis. Meanwhile, such medium-sized heterocycles, in particular azonine, frequently occur in natural products, such as n class="Chemical">alkaloids (Neuss et al., 1959 ▸, 1962 ▸; Uprety & Bhakuni, 1975 ▸), and thus they are considered to be promising fragments in drug design.

Voskressensky and his group have pioneered the tandem transformation of fused tetra­hydro­pyridines into azines bearing an n class="Chemical">enamine moiety in the eight-membered ring under the action of activated alkynes. Based on this reaction, convenient preparative routes to tetra­hydro­pyrrolo­[2,3-d]azocines (Varlamov et al., 2002 ▸), tetra­hydro­azocino[5,4-b]indoles, and tetra­hydro­azocino[4,5-b]indoles (Voskressensky et al., 2004 ▸) have been elaborated. The application of a similar approach to hexa­hydro­azepine gives rise to azonino­indoles (Nguyen et al., 2017 ▸), which are otherwise hard to obtain.

Azonino­indole I was successfully synthesized from the initial 2-ethyl-9-fluoro-1,2,3,4,5,6-hexa­hydro­azepino[4,3-b]indole via a domino reaction under the action of dimethyl acetyl­enedi­carboxyl­ate in methanol at room temperature (Fig. 1 ▸). The domino reaction results in the expansion of the hexa­hydro­azepine ring to the n class="Chemical">azonine viz. dimethyl 4-ethyl-11-fluoro-1,4,5,6,7,8-hexa­hydro­azonino[5,6-b]indole-2,3-dicarb­oxyl­ate (I). 3-Meth­oxy­methyl-substituted indole II was isolated as a by-product of this reaction.

Figure 1

The synthesis of dimethyl 4-ethyl-11-fluoro-1,4,5,6,7,8-hexa­hydro­azonino[5,6-b]indole-2,3-dicarboxyl­ate I in methanol.

The azonine systems, as a result of their specific structure, are known to act as ligands towards different receptors, thus demonstrating diverse types of biological activity (Magnus et al., 1987 ▸; Kuehne, Bornman et al., 2003 ▸; Kuehne, He et al., 2003 ▸; Afsah et al., 2009 ▸; Rostom, 2010 ▸; Tanaka et al., 2014 ▸; Soldi et al., 2015 ▸; Hartman & Kuduk, 2016 ▸), including anti-Alzheimer’s disease activity (n class="Chemical">Nguyen et al., 2017 ▸).

The title compound I, C20H23FN2O4, is the product of a ring expansion reaction from a seven-membered fluorinated hexa­hydro­azepine to a nine-membered n class="Chemical">azonine. The mol­ecular structure of I is unambiguously confirmed by the X-ray diffraction study (Fig. 2 ▸).

Figure 2

The mol­ecular structure of I. Displacement ellipsoids are drawn at the 50% probability level. H atoms are shown as small spheres of arbitrary radius.

Structural commentary

Compound I is isostructural to the non-fluorinated analog published by us very recently (Nguyen et al., 2017 ▸). The nine-membered n class="Chemical">azonine ring of the mol­ecule adopts a chair–boat conformation (the basal planes are N4–C5/C1–C12B and C5–C6/C7A–C12B, respectively). It should be noted that the analogous nine-membered azonine ring in the related compound methyl 4-ethyl-11-methyl-1,4,5,6,7,8-hexa­hydro­azonino[5,6-b]indole-2-carboxyl­ate adopts a twisted boat conformation (Voskressensky, et al., 2006 ▸). The C2=C3 and C3—N4 bond lengths [1.366 (3) and 1.407 (3) Å, respectively] indicate the presence of conjugation within the enamine C2=C3—N4 fragment. The substituent planes at the C2=C3 double bond are twisted by 16.0 (3)° because of steric effects. The N4 nitro­gen atom has a trigonal–pyramidal configuration (sum of the bond angles is 346.3°). The inter­planar angle between the two carboxyl­ate substituents is 60.39 (8)°.

Supra­molecular features

In the crystal, mol­ecules of I form zigzag chains along [010] by inter­molecular N—H⋯Oi n class="Chemical">hydrogen-bonding inter­actions (Table 1 ▸, Fig. 3 ▸), which are further packed in stacks towards [100].

Table 1

Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N8—H8⋯O1i	0.93 (3)	2.17 (3)	3.025 (3)	153 (2)

Symmetry code: (i) .

Figure 3

The crystal packing of I viewed along the a-axis direction showing the zigzag chains along [010]. Dashed lines indicate inter­molecular N—H⋯O hydrogen bonds.

Synthesis and crystallization

Dimethyl acetyl­enedi­carboxyl­ate (170 mg, 1.2 mmol) was added to 2-ethyl-9-fluoro-1,2,3,4,5,6-hexa­hydro­azepino[4,3-b]indole (232 mg, 1 mmol) dissolved in methanol (10 ml). The reaction mixture was stirred for 2 h at room temperature with the TLC real-time control. Then the solvent was removed in vacuo and the residue was chromatographed over n class="Chemical">silica with ethyl­acetate:hexane as eluent to yield the target fluorinated azonino­indole I (22%) and 3-meth­oxy­methyl­indole II. Light-yellow crystals of azonino­indole I suitable for X-ray crystallographic analysis were grown by slow evaporation of an ethyl­acetate:hexane (1:1) solution, m.p. 456–458 K.

1H NMR (CDCl3, δ/ppm, J/Hz): 0.98 (t, 3H, J = 7.2, CH3CH2), 1.78 (m, 2H, 6-CH2), 2.74 (q, 2H, J = 7.2, CH3CH2), 2.93 (m, 2H, n class="CellLine">7-CH2), 3.06 (m, 2H, 5-CH2), 3.96 (s, 2H, 1-CH2), 3.74 (s, 3H, CO2CH3), 3.77 (s, 3H, CO2CH3), 6.82 (ddd, 2H, 1,3 J = 9.0, 1,3 J = 9.0, 1,4 J = 2.3, CH-Ar), 7.13 (m, 2H, CH-Ar), 7.74 (br s 1H, NH). 13C NMR (DMSO-d 6, δ/ppm, J/Hz): 15.2 (CH3), 21.9 (CH2), 23.8 (CH2), 27.1 (CH2), 44.5 (CH2), 52.3 (CH3), 52.3 (CH3), 55.5 (CH2), 102.5 (d, J = 22, CH), 108.2 (d, J = 26, CH), 108.6 (C), 111.8 (d, J = 9, CH), 122.3 (C), 128.3 (C), 132.2 (C), 137.9 (C), 151.7 (C), 157.1 (d, J = 231, C), 166.4 (C), 169.3 (C). IR (KBr): ν (cm−1) = 1723, 3373. Found (%): C, 64.16; H, 6.19; N, 7.48. C20H23FN2O4. Calculated (%): C, 64.46; H, 6.86; N, 7.82. Mass-spectrometry, m/z [Irel(%)]: 374 [M+] (100), 345 (20), 315 (100), 285 (30), 227 (10), 198 (20), 174 (30), 161 (30), 148 (10), 58 (40), 45 (10).

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2 ▸. The X-ray diffraction study was carried out on the "Belok" beamline of the National Research Center "Kurchatov Institute" (Moscow, Russian Federation) using a Rayonix SX165 CCD detector. A total of 360 images were collected using an oscillation range of 1.0° (φ scan mode, two different crystal orientations) and corrected for absorption using the SCALA program (Evans, 2006 ▸). The data were indexed, integrated and scaled using the utility iMOSFLM in the CCP4 program suite (Battye et al., 2011 ▸).

Table 2

Experimental details

Crystal data
Chemical formula	C20H23FN2O4
M r	374.40
Crystal system, space group	Monoclinic, P21/c
Temperature (K)	100
a, b, c (Å)	8.4632 (17), 10.993 (2), 20.520 (4)
β (°)	99.60 (3)
V (Å3)	1882.4 (7)
Z	4
Radiation type	Synchrotron, λ = 0.96990 Å
μ (mm−1)	0.21
Crystal size (mm)	0.22 × 0.02 × 0.02
Data collection
Diffractometer	Rayonix SX165 CCD
Absorption correction	Multi-scan (SCALA; Evans, 2006 ▸)
T min, T max	0.940, 0.980
No. of measured, independent and observed [I > 2σ(I)] reflections	21117, 3850, 2463
R int	0.086
(sin θ/λ)max (Å−1)	0.640
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.072, 0.184, 1.01
No. of reflections	3850
No. of parameters	251
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3)	0.34, −0.43

Computer programs: MarCCD (Doyle, 2011 ▸), i MOSFLM (Battye et al., 2011 ▸), SHELXT (Sheldrick, 2015a ▸), SHELXL2014 (Sheldrick, 2015b ▸) and SHELXTL (Sheldrick, 2008 ▸).

The hydrogen atoms of the amino groups were localized in the difference-Fourier map and refined isotropically with fixed displacement parameters [U iso(H) = 1.2U eq(n class="Chemical">N)]. The other hydrogen atoms were placed in calculated positions with C—H = 0.95–0.99 Å and refined in the riding model with fixed isotropic displacement parameters [U iso(H) = 1.2U eq(C)].

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S2056989018001329/kq2018sup1.cif

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989018001329/kq2018Isup2.hkl

Click here for additional data file.

Supporting information file. DOI: 10.1107/S2056989018001329/kq2018Isup3.cml

CCDC reference: 1818381

Additional supporting information: crystallographic information; 3D view; checkCIF report

C20H23FN2O4	F(000) = 792
Mr = 374.40	Dx = 1.321 Mg m−3
Monoclinic, P21/c	Synchrotron radiation, λ = 0.96990 Å
a = 8.4632 (17) Å	Cell parameters from 600 reflections
b = 10.993 (2) Å	θ = 3.3–33.0°
c = 20.520 (4) Å	µ = 0.21 mm−1
β = 99.60 (3)°	T = 100 K
V = 1882.4 (7) Å3	Needle, yellow
Z = 4	0.22 × 0.02 × 0.02 mm

Rayonix SX165 CCD diffractometer	2463 reflections with I > 2σ(I)
/f scan	Rint = 0.086
Absorption correction: multi-scan (SCALA; Evans, 2006)	θmax = 38.4°, θmin = 3.3°
Tmin = 0.940, Tmax = 0.980	h = −10→10
21117 measured reflections	k = −12→10
3850 independent reflections	l = −26→25

Refinement on F2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.072	H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.184	w = 1/[σ2(Fo2) + (0.090P)2] where P = (Fo2 + 2Fc2)/3
S = 1.01	(Δ/σ)max < 0.001
3850 reflections	Δρmax = 0.34 e Å−3
251 parameters	Δρmin = −0.43 e Å−3
0 restraints	Extinction correction: SHELXL, Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: difference Fourier map	Extinction coefficient: 0.016 (2)

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.

	x	y	z	Uiso*/Ueq
F1	−0.11330 (17)	0.18565 (15)	0.14176 (8)	0.0428 (5)
O1	0.35878 (18)	0.12235 (17)	0.40043 (8)	0.0254 (5)
O2	0.13856 (17)	0.24026 (16)	0.37589 (8)	0.0256 (5)
O3	0.72767 (18)	0.17340 (16)	0.45020 (8)	0.0265 (5)
O4	0.54751 (18)	0.24913 (16)	0.50997 (7)	0.0245 (5)
C1	0.3100 (3)	0.4423 (2)	0.33722 (11)	0.0220 (6)
H1A	0.1961	0.4424	0.3430	0.026*
H1B	0.3592	0.5174	0.3581	0.026*
C2	0.3917 (3)	0.3338 (2)	0.37585 (11)	0.0197 (6)
C3	0.5500 (3)	0.3353 (2)	0.40360 (11)	0.0197 (6)
N4	0.6592 (2)	0.41914 (19)	0.38442 (9)	0.0215 (5)
C5	0.7014 (3)	0.3978 (2)	0.31780 (11)	0.0225 (6)
H5A	0.6179	0.3459	0.2920	0.027*
H5B	0.8041	0.3528	0.3229	0.027*
C6	0.7174 (3)	0.5148 (2)	0.27897 (12)	0.0265 (6)
H6A	0.7461	0.4933	0.2356	0.032*
H6B	0.8060	0.5642	0.3032	0.032*
C7	0.5632 (3)	0.5921 (3)	0.26769 (12)	0.0249 (6)
H7A	0.5426	0.6237	0.3107	0.030*
H7B	0.5783	0.6625	0.2393	0.030*
C7A	0.4212 (3)	0.5196 (2)	0.23562 (11)	0.0214 (6)
N8	0.3906 (2)	0.5038 (2)	0.16787 (9)	0.0229 (5)
H8	0.437 (3)	0.547 (2)	0.1368 (12)	0.028*
C8A	0.2622 (3)	0.4257 (2)	0.15110 (11)	0.0225 (6)
C9	0.1871 (3)	0.3838 (2)	0.08913 (12)	0.0268 (6)
H9	0.2220	0.4098	0.0497	0.032*
C10	0.0602 (3)	0.3033 (3)	0.08712 (13)	0.0299 (7)
H10	0.0070	0.2722	0.0461	0.036*
C11	0.0114 (3)	0.2683 (3)	0.14629 (13)	0.0283 (6)
C12	0.0805 (3)	0.3085 (2)	0.20795 (12)	0.0248 (6)
H12	0.0424	0.2828	0.2467	0.030*
C12A	0.2112 (2)	0.3900 (2)	0.21103 (11)	0.0214 (6)
C12B	0.3143 (3)	0.4501 (2)	0.26446 (11)	0.0201 (6)
C13	0.2988 (3)	0.2225 (3)	0.38597 (11)	0.0221 (6)
C14	0.0434 (3)	0.1308 (3)	0.38115 (13)	0.0292 (7)
H14A	0.0642	0.0713	0.3480	0.044*
H14B	−0.0707	0.1519	0.3735	0.044*
H14C	0.0730	0.0958	0.4254	0.044*
C15	0.6182 (3)	0.2417 (2)	0.45594 (11)	0.0212 (6)
C16	0.5946 (3)	0.1559 (3)	0.55942 (12)	0.0295 (7)
H16A	0.5529	0.0769	0.5422	0.044*
H16B	0.5509	0.1755	0.5995	0.044*
H16C	0.7118	0.1522	0.5700	0.044*
C17	0.7970 (3)	0.4562 (3)	0.43429 (11)	0.0248 (6)
H17A	0.8687	0.5087	0.4131	0.030*
H17B	0.8583	0.3829	0.4514	0.030*
C18	0.7454 (3)	0.5244 (3)	0.49167 (13)	0.0317 (7)
H18A	0.6843	0.5969	0.4750	0.048*
H18B	0.8404	0.5489	0.5230	0.048*
H18C	0.6782	0.4714	0.5140	0.048*

	U11	U22	U33	U12	U13	U23
F1	0.0287 (8)	0.0431 (12)	0.0508 (10)	−0.0170 (7)	−0.0099 (7)	0.0069 (8)
O1	0.0152 (8)	0.0275 (12)	0.0328 (10)	0.0029 (8)	0.0016 (7)	0.0025 (8)
O2	0.0108 (8)	0.0301 (12)	0.0356 (10)	−0.0008 (7)	0.0034 (7)	0.0043 (8)
O3	0.0172 (8)	0.0318 (12)	0.0300 (10)	0.0066 (7)	0.0024 (7)	0.0008 (8)
O4	0.0215 (9)	0.0338 (12)	0.0189 (9)	0.0030 (7)	0.0052 (6)	0.0043 (8)
C1	0.0127 (11)	0.0284 (17)	0.0241 (13)	0.0018 (10)	0.0003 (9)	0.0018 (11)
C2	0.0133 (11)	0.0260 (16)	0.0195 (12)	−0.0001 (10)	0.0016 (9)	0.0000 (10)
C3	0.0147 (11)	0.0262 (16)	0.0181 (11)	0.0016 (10)	0.0020 (8)	−0.0007 (10)
N4	0.0135 (9)	0.0308 (14)	0.0194 (10)	−0.0041 (9)	0.0006 (7)	0.0001 (9)
C5	0.0147 (11)	0.0326 (17)	0.0198 (12)	0.0000 (10)	0.0018 (9)	−0.0001 (11)
C6	0.0165 (12)	0.0375 (18)	0.0243 (13)	−0.0068 (11)	0.0005 (9)	0.0023 (12)
C7	0.0205 (12)	0.0309 (17)	0.0222 (13)	−0.0044 (11)	0.0004 (10)	0.0032 (11)
C7A	0.0182 (12)	0.0251 (16)	0.0196 (13)	0.0021 (10)	−0.0007 (9)	0.0005 (11)
N8	0.0173 (10)	0.0313 (15)	0.0190 (11)	−0.0035 (9)	0.0000 (8)	0.0028 (10)
C8A	0.0137 (11)	0.0286 (17)	0.0235 (13)	0.0018 (10)	−0.0016 (9)	0.0001 (11)
C9	0.0201 (12)	0.0321 (19)	0.0267 (14)	0.0026 (11)	0.0000 (10)	0.0002 (12)
C10	0.0194 (12)	0.0363 (19)	0.0295 (14)	0.0012 (12)	−0.0088 (10)	−0.0024 (12)
C11	0.0147 (12)	0.0284 (18)	0.0377 (15)	−0.0034 (11)	−0.0073 (10)	0.0043 (13)
C12	0.0150 (11)	0.0277 (17)	0.0299 (14)	0.0019 (10)	−0.0015 (9)	0.0073 (12)
C12A	0.0122 (11)	0.0267 (17)	0.0237 (13)	0.0035 (10)	−0.0019 (9)	0.0048 (11)
C12B	0.0143 (11)	0.0261 (16)	0.0193 (12)	0.0040 (10)	0.0009 (9)	0.0045 (11)
C13	0.0116 (11)	0.0356 (19)	0.0182 (12)	0.0015 (11)	0.0000 (8)	−0.0008 (11)
C14	0.0144 (11)	0.0300 (18)	0.0441 (16)	−0.0057 (11)	0.0076 (10)	0.0043 (13)
C15	0.0141 (11)	0.0280 (17)	0.0204 (12)	−0.0026 (10)	−0.0001 (9)	−0.0015 (11)
C16	0.0231 (13)	0.0402 (19)	0.0229 (13)	−0.0009 (12)	−0.0027 (10)	0.0095 (12)
C17	0.0159 (11)	0.0321 (17)	0.0248 (13)	−0.0033 (11)	−0.0013 (9)	0.0019 (11)
C18	0.0208 (12)	0.0424 (19)	0.0305 (14)	−0.0068 (12)	−0.0002 (10)	−0.0059 (13)

F1—C11	1.383 (3)	C7A—N8	1.382 (3)
O1—C13	1.228 (3)	C7A—C12B	1.390 (3)
O2—C13	1.352 (3)	N8—C8A	1.383 (3)
O2—C14	1.461 (3)	N8—H8	0.93 (3)
O3—C15	1.213 (3)	C8A—C9	1.401 (3)
O4—C15	1.347 (3)	C8A—C12A	1.425 (3)
O4—C16	1.451 (3)	C9—C10	1.388 (3)
C1—C12B	1.502 (3)	C9—H9	0.9500
C1—C2	1.532 (3)	C10—C11	1.400 (4)
C1—H1A	0.9900	C10—H10	0.9500
C1—H1B	0.9900	C11—C12	1.376 (3)
C2—C3	1.366 (3)	C12—C12A	1.417 (3)
C2—C13	1.487 (4)	C12—H12	0.9500
C3—N4	1.407 (3)	C12A—C12B	1.442 (3)
C3—C15	1.530 (3)	C14—H14A	0.9800
N4—C17	1.475 (3)	C14—H14B	0.9800
N4—C5	1.488 (3)	C14—H14C	0.9800
C5—C6	1.531 (4)	C16—H16A	0.9800
C5—H5A	0.9900	C16—H16B	0.9800
C5—H5B	0.9900	C16—H16C	0.9800
C6—C7	1.542 (3)	C17—C18	1.520 (4)
C6—H6A	0.9900	C17—H17A	0.9900
C6—H6B	0.9900	C17—H17B	0.9900
C7—C7A	1.499 (3)	C18—H18A	0.9800
C7—H7A	0.9900	C18—H18B	0.9800
C7—H7B	0.9900	C18—H18C	0.9800
C13—O2—C14	114.88 (19)	C8A—C9—H9	121.0
C15—O4—C16	115.13 (19)	C9—C10—C11	119.3 (2)
C12B—C1—C2	118.4 (2)	C9—C10—H10	120.4
C12B—C1—H1A	107.7	C11—C10—H10	120.4
C2—C1—H1A	107.7	C12—C11—F1	118.4 (2)
C12B—C1—H1B	107.7	C12—C11—C10	124.6 (2)
C2—C1—H1B	107.7	F1—C11—C10	117.0 (2)
H1A—C1—H1B	107.1	C11—C12—C12A	117.0 (2)
C3—C2—C13	117.2 (2)	C11—C12—H12	121.5
C3—C2—C1	122.2 (2)	C12A—C12—H12	121.5
C13—C2—C1	120.61 (19)	C12—C12A—C8A	118.8 (2)
C2—C3—N4	122.4 (2)	C12—C12A—C12B	133.8 (2)
C2—C3—C15	120.9 (2)	C8A—C12A—C12B	107.3 (2)
N4—C3—C15	116.65 (18)	C7A—C12B—C12A	106.40 (19)
C3—N4—C17	117.83 (18)	C7A—C12B—C1	125.5 (2)
C3—N4—C5	115.06 (19)	C12A—C12B—C1	128.1 (2)
C17—N4—C5	113.43 (16)	O1—C13—O2	122.0 (2)
N4—C5—C6	113.7 (2)	O1—C13—C2	124.4 (2)
N4—C5—H5A	108.8	O2—C13—C2	113.6 (2)
C6—C5—H5A	108.8	O2—C14—H14A	109.5
N4—C5—H5B	108.8	O2—C14—H14B	109.5
C6—C5—H5B	108.8	H14A—C14—H14B	109.5
H5A—C5—H5B	107.7	O2—C14—H14C	109.5
C5—C6—C7	113.24 (19)	H14A—C14—H14C	109.5
C5—C6—H6A	108.9	H14B—C14—H14C	109.5
C7—C6—H6A	108.9	O3—C15—O4	124.7 (2)
C5—C6—H6B	108.9	O3—C15—C3	123.6 (2)
C7—C6—H6B	108.9	O4—C15—C3	111.68 (19)
H6A—C6—H6B	107.7	O4—C16—H16A	109.5
C7A—C7—C6	111.7 (2)	O4—C16—H16B	109.5
C7A—C7—H7A	109.3	H16A—C16—H16B	109.5
C6—C7—H7A	109.3	O4—C16—H16C	109.5
C7A—C7—H7B	109.3	H16A—C16—H16C	109.5
C6—C7—H7B	109.3	H16B—C16—H16C	109.5
H7A—C7—H7B	107.9	N4—C17—C18	112.19 (18)
N8—C7A—C12B	109.5 (2)	N4—C17—H17A	109.2
N8—C7A—C7	120.7 (2)	C18—C17—H17A	109.2
C12B—C7A—C7	129.5 (2)	N4—C17—H17B	109.2
C7A—N8—C8A	109.62 (19)	C18—C17—H17B	109.2
C7A—N8—H8	126.5 (15)	H17A—C17—H17B	107.9
C8A—N8—H8	123.3 (15)	C17—C18—H18A	109.5
N8—C8A—C9	130.4 (2)	C17—C18—H18B	109.5
N8—C8A—C12A	107.2 (2)	H18A—C18—H18B	109.5
C9—C8A—C12A	122.4 (2)	C17—C18—H18C	109.5
C10—C9—C8A	117.9 (2)	H18A—C18—H18C	109.5
C10—C9—H9	121.0	H18B—C18—H18C	109.5
C12B—C1—C2—C3	88.1 (3)	N8—C8A—C12A—C12	−179.6 (2)
C12B—C1—C2—C13	−93.4 (3)	C9—C8A—C12A—C12	0.4 (4)
C13—C2—C3—N4	163.5 (2)	N8—C8A—C12A—C12B	0.1 (3)
C1—C2—C3—N4	−18.0 (3)	C9—C8A—C12A—C12B	−179.9 (2)
C13—C2—C3—C15	−14.3 (3)	N8—C7A—C12B—C12A	−0.9 (3)
C1—C2—C3—C15	164.2 (2)	C7—C7A—C12B—C12A	−174.2 (2)
C2—C3—N4—C17	150.5 (2)	N8—C7A—C12B—C1	179.6 (2)
C15—C3—N4—C17	−31.6 (3)	C7—C7A—C12B—C1	6.3 (4)
C2—C3—N4—C5	−71.5 (3)	C12—C12A—C12B—C7A	−179.9 (2)
C15—C3—N4—C5	106.4 (2)	C8A—C12A—C12B—C7A	0.5 (3)
C3—N4—C5—C6	141.0 (2)	C12—C12A—C12B—C1	−0.4 (4)
C17—N4—C5—C6	−79.1 (2)	C8A—C12A—C12B—C1	−180.0 (2)
N4—C5—C6—C7	−58.9 (2)	C2—C1—C12B—C7A	−98.2 (3)
C5—C6—C7—C7A	−54.3 (3)	C2—C1—C12B—C12A	82.3 (3)
C6—C7—C7A—N8	−83.2 (3)	C14—O2—C13—O1	−2.1 (3)
C6—C7—C7A—C12B	89.4 (3)	C14—O2—C13—C2	176.11 (18)
C12B—C7A—N8—C8A	1.0 (3)	C3—C2—C13—O1	−21.2 (3)
C7—C7A—N8—C8A	174.9 (2)	C1—C2—C13—O1	160.2 (2)
C7A—N8—C8A—C9	179.3 (3)	C3—C2—C13—O2	160.6 (2)
C7A—N8—C8A—C12A	−0.6 (3)	C1—C2—C13—O2	−18.0 (3)
N8—C8A—C9—C10	179.1 (2)	C16—O4—C15—O3	−8.8 (3)
C12A—C8A—C9—C10	−1.0 (4)	C16—O4—C15—C3	174.42 (19)
C8A—C9—C10—C11	0.7 (4)	C2—C3—C15—O3	122.1 (3)
C9—C10—C11—C12	0.2 (4)	N4—C3—C15—O3	−55.9 (3)
C9—C10—C11—F1	−178.6 (2)	C2—C3—C15—O4	−61.1 (3)
F1—C11—C12—C12A	178.0 (2)	N4—C3—C15—O4	121.0 (2)
C10—C11—C12—C12A	−0.7 (4)	C3—N4—C17—C18	−64.2 (3)
C11—C12—C12A—C8A	0.4 (3)	C5—N4—C17—C18	157.2 (2)
C11—C12—C12A—C12B	−179.2 (3)

D—H···A	D—H	H···A	D···A	D—H···A
N8—H8···O1i	0.93 (3)	2.17 (3)	3.025 (3)	153 (2)