6[beta]-Azido-7[alpha]-hydroxy-17-oxo-5[alpha]-androstan-3[beta]-yl acetate

In the title compound, C₂₁H₃₁N₃O₄, a potential inhibitor of aromatase, all rings are fused trans. Rings A, B and C have chair conformations which are slightly flattened. Ring D has a 14[alpha]-envelope conformation. The steroid nucleus has a small twist, as shown by the C19-C10...C13-C18 torsion angle of 6.6 (2)°. Ab initio calculations of the equilibrium geometry of the mol­ecule reproduce this small twist, which appears to be due to the steric effect of the 6[beta]-azide substituent rather than to packing effects.

S1. Comment

In the western world, breast cancer is the most common malignancy in women. About one third of tumours require a source of oestrogens for growth, and until recently the treatment was based mainly in chemotherapy, which blocks the uptake of oestrogens by the tumour cells (Miller & Ingle, 2002). Nowadays, an alternative strategy has emerged which involves the use of inhibitors of the biosynthesis of oestrogen, i.e. inhibitors of the aromatase enzyme. Aromatase is a cytochrome P-450 enzyme complex which catalyses the conversion of androgens into oestrogens (Thomson & Siiteri, 1974; Njar et al., 1993).

The therapeutic potential of aromatase inhibitors in the treatment of oestrogen-dependent diseases has raised much interest in this area. The result of the research of many different investigators has led to the synthesis and evaluation of various steroids (Brodie & Njar, 2000). Two of these, namely formestane (Lentaron) and, more recently, examestane (Aromasin), have already been approved for breast cancer treatment (Brueggemeier, 2002; Buzdar, 2003).

Most of the steroids which have been studied as aromatase inhibitors are analogues of androstenedione, with substitutions at C4, C6, C7 and C19 (Numazawa et al., 2002). Several 6- and 7-substituted analogues of androstenedione are powerful inhibitors of human placental aromatase (Njar et al., 1995).

The title compound, (I), a potential aromatase inhibitor, is a very promising molecule, as it combines the steric requirements that are important for the inhibition of the enzyme with the presence of three N atoms, which are thought to coordinate to the enzyme's heme Fe atom, leading to the formation of a type II competitive inhibitor (Cole & Robinson, 1990). \sch

A drawing of the molecule of (I), with the atomic numbering scheme, is shown in Fig. 1. Bond lengths and angles are within the expected ranges (Allen et al., 1987), with average bond lengths Csp³—Csp³ 1.54 (3), Csp³—Csp² 1.52 (2), O-Csp³ 1.449 (18), O-Csp² 1.325 (3) and O═Csp² 1.194 (10) Å. The C15—C16 bond length [1.585 (5) Å] in ring D is exceptionally large and a pronounced asymmetry is observed between the two Csp³—Csp² bonds in ring D [C13—C17 1.509 (2) and C16—C17 1.554 (6) Å], and as result this ring is considerably strained. However, the displacement tensor of atom C16 is significantly more anisotropic than those of its neighbours, and the C15—C16 and C16—C17 bond distances both fail the Hirshfeld rigid-bond test at the 5.6 and 7.2 s.u. levels, respectively. Therefore, some caution is recommended in attaching chemical significance to the deviation of these bond lengths from their average values.

All ring junctions are trans. Rings A, B and C have average torsion angles of 57.2 (7), 54.3 (3) and 56.7 (12)°, respectively, and slightly flattened chair conformations, as shown by the Cremer & Pople (1975) puckering parameters [for ring A (C1—C5/C10), Q = 0.587 (3) Å, θ = 1.9 (3)° and ϕ = 177 (8)°; for ring B (C5—C10), Q = 0.557 (2) Å, θ = 0.0 (2)° and ϕ = 257 (8)°; for ring C (C8/C9/C11—C14), Q = 0.579 (2) Å, θ = 3.3 (2)° and ϕ = 287 (4)°].

The five-membered ring D has a 14α-envelope conformation, with an average torsion angle of 32 (6)°. The puckering parameters calculated using the atom sequence C13—C17 are q₂ = 0.439 (3) Å and ϕ₂ = 211.3 (4)° [pseudo-rotation (Altona et al., 1968) and asymmetry parameters Δ = 24.4 (4), ϕ_m = 45.0 (1) and ΔC_s(14) = 5.6 (4)°].

The acetyl substituent is 3β-equatorial to ring A and is (+)-anti-clinal to the C2—C3 bond. The acetyl group is planar, with an average deviation of the non-H atoms from the least-squares plane of 0.005 (3) Å. The angle between this plane and the least-squares plane of ring A is 65.31 (15)°. The 6β-azide group is oriented axially to ring B and is (+)-anti-periplanar to the C5—C6 bond. It features a small but significant asymmetry between the two N≐N bonds [1.215 (4) and 1.132 (5) Å].

The distance between the terminal atoms O17···C3B is 13.124 (4) Å and the pseudo-torsion angle C19—C10···C13—C18 is 6.6 (2)°, showing that the molecule is slightly twisted. For trans-fused saturated rings, this torsion angle rarely exceeds 4°, except when bulky sustituents, e.g. attached to ring D at C17, induce larger deviations due to steric effects (Andrade et al., 2001).

In order to investigate whether this twist is indeed due to a steric effect of the azide group that would be present in the isolated molecule or rather due to packing effects, we have performed an ab initio molecular orbital Roothaan Hartree-Fock (MO-RHF) calculation of the equilibrium molecular geometry using the computer program GAMESS (Schmidt et al., 1993). An extended 6–31 G(d,p) basis set was used and tight conditions were applied for convergence of the self-consistent field (SCF) cycles and location of the equilibrium geometry. The final electron-density variation at the SCF cycles and the maximum energy gradient at the end of the geometry optimization were less than 10⁻⁵ atomic units. The code was run in parallel on a cluster of 12 Compac XP1000 workstations (Alpha EV67 processors, 667 MHz) running Linux.

The conformation of the steroid nucleus as determined from the X-ray data is well reproduced by the MO-RHF calculations, the mean deviations of the bond lengths and angles being 0.011 Å and 0.64°, respectively. However, the calculation does not reproduce the exceptionally long C15—C16 bond [calculated 1.543, observed 1.585 (5) Å], and also predicts a longer O3A—C3 bond [calculated 1.467, observed 1.430 Å]. The small asymmetry between the two N≐N bonds is well reproduced in the calculations [calculated 1.103 and 1.226 Å].

The conformations of the acetyl and azide susbtituents, which have some rotational freedom around the O3A—C3 and C6—N6A single bonds, are similar in the isolated molecule and in the crystal. The calculated values of the C3A—O3A—C3—C2 and C5—C6—N6A—N6B torsion angles for the isolated molecule are 84.2 and 145.7°, respectively, compared with the measured values of 94.2 (3) and 168.1 (3)°, respectively.

It was found that the equilibrium geometry of the isolated molecule also features a sizable twist of the steroid nucleus, as measured by the pseudo-torsion angle C19—C10···C13—C18 of 6.1°, compared with the experimental value of 6.6 (2)°. Therefore, we can conclude that this twist is most probably due to a steric interaction between the C19 methyl and azide groups, rather than to packing effects in the crystal.

The molecules of (I) are joined together in chains parallel to the b axis via strong hydrogen bonds between the hydroxyl group and the carbonyl atom O17. In addition, an inspection of the short contact distances shows that a weak intermolecular interaction appears to exist between the terminal N atom of the azide group and one methylenic H atom of a neighbouring molecule.

S2. Experimental

The compound 6,7α-epoxy-17-oxo-5α-androst-3β-yl acetate, prepared according to procedures to be described elsewhere, was treated with activated sodium azide and sulfuric acid in dimethyl sulfoxide to afford compound (I). Crystals of (I) were obtained by crystallization from ethyl acetate:n-hexane (Ratio?) (m.p. 501 K). Spectroscopic analysis: IR (ν, cm⁻¹): 1257, 1728, 2098, 2924, 3508; ¹H NMR (CDCl₃, 300 MHz, δ, p.p.m.): 0.89 (s, 18-H3), 1.00 (s, 19-H3), 3.50 (m, 6α-H), 3.90 (m, 7β-H); 4.75 (m, 3α-H); ¹³C NMR (CDCl₃, 75.5 MHz, δ, p.p.m.): 67.82 (C6), 68.62 (C7), 73.46 (C3), 170.98 (CH₃CO), 221.14 (C17).

S3. Refinement

All H atoms were refined as riding on their parent atoms, with C—H distances in the range 0.93–0.98 Å, and with U_iso(H) = 1.5U_eq(C) for methyl groups and 1.2U_eq(C) for the other H atoms, except for that of the hydroxyl group, for which the torsion angle was refined using the SHELXL97 AFIX 147 instruction. The absolute configuration was not determined from the X-ray data, as the Flack (1983) parameter of −0.5 (16) was inconclusive, but it was known from the synthesis route. Due to the lack of any significant anomalous scattering at the Mo Kα wavelength, Friedel pairs were merged before refinement.

Computing details

Data collection: CAD-4 Software (Enraf-Nonius, 1989); cell refinement: CAD-4 Software; data reduction: HELENA (Spek, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPII (Johnson, 1976); software used to prepare material for publication: SHELXL97.

Figures

Fig. 1. The molecular structure of (I), showing the atomic numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and the H atoms are shown as small spheres of arbitrary radii.

6β-Azido-7α-hydroxy-17-oxo-5α-androst-3β-yl acetate

Crystal data

C21H31N3O4	F(000) = 420
Mr = 389.49	Dx = 1.244 Mg m^−3
Monoclinic, P21	Melting point: 501 K
Hall symbol: P 2yb	Mo Kα radiation, λ = 0.71073 Å
a = 6.1997 (6) Å	Cell parameters from 25 reflections
b = 10.6324 (12) Å	θ = 8.1–16.8°
c = 15.8948 (14) Å	µ = 0.09 mm^−1
β = 97.145 (7)°	T = 293 K
V = 1039.61 (18) Å^3	Block, colourless
Z = 2	0.28 × 0.25 × 0.20 mm

Data collection

Enraf-Nonius CAD-4 diffractometer	2431 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.031
Graphite monochromator	θmax = 30.0°, θmin = 2.6°
profile data from ω/2θ scans	h = −8→8
Absorption correction: ψ scan (North et al., 1968)	k = −13→14
Tmin = 0.941, Tmax = 0.988	l = −22→22
9496 measured reflections	3 standard reflections every 180 min
3178 independent reflections	intensity decay: 1.9%

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.047	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.148	H atoms treated by a mixture of independent and constrained refinement
S = 1.02	w = 1/[σ^2(Fo^2) + (0.0957P)^2 + 0.1023P] where P = (Fo^2 + 2Fc^2)/3
3178 reflections	(Δ/σ)max < 0.001
257 parameters	Δρmax = 0.47 e Å^−3
1 restraint	Δρmin = −0.19 e Å^−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s 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 > σ(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 (Ų)

	x	y	z	Uiso*/Ueq
O3A	0.8187 (3)	0.6796 (3)	0.40755 (11)	0.0597 (6)
O7	1.0650 (2)	0.66121 (19)	0.80822 (11)	0.0442 (4)
O17	0.7289 (4)	1.0391 (3)	1.04558 (16)	0.0737 (7)
H7A	1.1322	0.6168	0.8447	0.066*
O3B	1.1035 (6)	0.7920 (4)	0.3813 (2)	0.1184 (14)
N6A	0.5724 (4)	0.5102 (3)	0.69646 (16)	0.0571 (6)
N6B	0.5649 (5)	0.4133 (3)	0.7365 (2)	0.0718 (8)
N6C	0.5412 (9)	0.3234 (4)	0.7724 (4)	0.1226 (17)
C1	0.7097 (5)	0.8935 (3)	0.58982 (15)	0.0489 (6)
H1A	0.6130	0.9649	0.5916	0.059*
H1B	0.8568	0.9226	0.6072	0.059*
C2	0.6938 (5)	0.8446 (3)	0.49804 (16)	0.0567 (7)
H2A	0.5442	0.8229	0.4781	0.068*
H2B	0.7393	0.9100	0.4615	0.068*
C3	0.8363 (4)	0.7304 (3)	0.49392 (15)	0.0494 (6)
H3	0.9876	0.7547	0.5115	0.059*
C4	0.7757 (4)	0.6262 (3)	0.55150 (15)	0.0474 (6)
H4A	0.8717	0.5548	0.5485	0.057*
H4B	0.6277	0.5989	0.5340	0.057*
C5	0.7969 (3)	0.6772 (2)	0.64224 (13)	0.0372 (4)
H5	0.9458	0.7096	0.6527	0.045*
C6	0.7881 (4)	0.5735 (2)	0.70771 (15)	0.0407 (5)
H6	0.8988	0.5107	0.6989	0.049*
C7	0.8406 (4)	0.6257 (2)	0.79751 (14)	0.0370 (4)
H7	0.8184	0.5593	0.8383	0.044*
C8	0.6982 (3)	0.7389 (2)	0.81345 (13)	0.0327 (4)
H8	0.5472	0.7104	0.8107	0.039*
C9	0.7104 (3)	0.8428 (2)	0.74563 (13)	0.0354 (4)
H9	0.8626	0.8697	0.7504	0.042*
C10	0.6509 (3)	0.7932 (2)	0.65351 (13)	0.0373 (4)
C11	0.5777 (5)	0.9591 (3)	0.76608 (17)	0.0491 (6)
H11A	0.4247	0.9371	0.7590	0.059*
H11B	0.5982	1.0250	0.7256	0.059*
C12	0.6404 (5)	1.0106 (2)	0.85649 (16)	0.0485 (6)
H12A	0.7877	1.0430	0.8620	0.058*
H12B	0.5439	1.0792	0.8668	0.058*
C13	0.6245 (3)	0.9077 (2)	0.92100 (14)	0.0379 (5)
C14	0.7665 (3)	0.7955 (2)	0.90074 (13)	0.0355 (4)
H14	0.9125	0.8298	0.8989	0.043*
C15	0.7830 (5)	0.7120 (3)	0.98072 (16)	0.0546 (7)
H15A	0.9066	0.6555	0.9837	0.066*
H15B	0.6514	0.6635	0.9831	0.066*
C16	0.8145 (6)	0.8151 (5)	1.05282 (18)	0.0741 (11)
H16A	0.7360	0.7921	1.0996	0.089*
H16B	0.9672	0.8249	1.0740	0.089*
C17	0.7218 (4)	0.9387 (3)	1.01036 (16)	0.0481 (6)
C18	0.3856 (4)	0.8728 (3)	0.92788 (19)	0.0520 (6)
H18A	0.3171	0.8445	0.8737	0.078*
H18B	0.3102	0.9452	0.9453	0.078*
H18C	0.3810	0.8068	0.9689	0.078*
C19	0.4052 (4)	0.7643 (3)	0.63513 (17)	0.0525 (7)
H19A	0.3774	0.7174	0.5833	0.079*
H19B	0.3250	0.8417	0.6298	0.079*
H19C	0.3607	0.7158	0.6809	0.079*
C3A	0.9652 (5)	0.7180 (3)	0.35923 (17)	0.0523 (6)
C3B	0.9305 (5)	0.6596 (4)	0.27359 (18)	0.0642 (8)
H3B1	0.9583	0.5709	0.2784	0.096*
H3B2	1.0277	0.6969	0.2382	0.096*
H3B3	0.7830	0.6732	0.2489	0.096*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O3A	0.0541 (10)	0.0922 (16)	0.0330 (8)	−0.0142 (11)	0.0066 (7)	−0.0066 (10)
O7	0.0346 (7)	0.0541 (10)	0.0424 (8)	0.0037 (7)	−0.0012 (6)	0.0101 (8)
O17	0.0789 (15)	0.0763 (16)	0.0612 (13)	−0.0040 (12)	−0.0102 (11)	−0.0263 (13)
O3B	0.146 (3)	0.140 (3)	0.0799 (19)	−0.085 (3)	0.057 (2)	−0.032 (2)
N6A	0.0608 (13)	0.0503 (13)	0.0594 (14)	−0.0199 (11)	0.0046 (11)	−0.0065 (11)
N6B	0.0829 (19)	0.0572 (16)	0.0780 (19)	−0.0254 (15)	0.0207 (15)	−0.0051 (15)
N6C	0.141 (4)	0.084 (3)	0.148 (4)	−0.043 (3)	0.038 (3)	0.034 (3)
C1	0.0624 (14)	0.0483 (14)	0.0343 (11)	0.0041 (12)	−0.0008 (10)	0.0070 (10)
C2	0.0629 (15)	0.074 (2)	0.0311 (10)	0.0021 (15)	−0.0006 (10)	0.0079 (12)
C3	0.0448 (11)	0.0707 (18)	0.0319 (10)	−0.0065 (12)	0.0015 (8)	−0.0035 (11)
C4	0.0491 (12)	0.0570 (15)	0.0364 (11)	−0.0026 (11)	0.0062 (9)	−0.0071 (11)
C5	0.0338 (9)	0.0442 (12)	0.0329 (9)	−0.0027 (9)	0.0017 (7)	−0.0012 (9)
C6	0.0436 (11)	0.0380 (12)	0.0409 (11)	−0.0039 (9)	0.0070 (9)	−0.0030 (9)
C7	0.0409 (10)	0.0350 (10)	0.0353 (10)	0.0004 (9)	0.0049 (8)	0.0045 (8)
C8	0.0327 (9)	0.0347 (11)	0.0304 (9)	−0.0040 (8)	0.0030 (7)	0.0002 (8)
C9	0.0366 (9)	0.0359 (11)	0.0322 (9)	0.0007 (8)	−0.0014 (8)	0.0018 (8)
C10	0.0337 (9)	0.0457 (12)	0.0310 (9)	0.0012 (9)	−0.0021 (7)	−0.0018 (9)
C11	0.0633 (15)	0.0429 (13)	0.0391 (12)	0.0126 (12)	−0.0015 (11)	−0.0001 (10)
C12	0.0651 (15)	0.0361 (12)	0.0432 (12)	0.0021 (11)	0.0024 (11)	−0.0039 (10)
C13	0.0375 (9)	0.0400 (11)	0.0355 (10)	−0.0051 (9)	0.0019 (8)	−0.0068 (9)
C14	0.0352 (9)	0.0409 (11)	0.0304 (9)	−0.0040 (9)	0.0034 (7)	0.0019 (9)
C15	0.0694 (17)	0.0577 (16)	0.0382 (11)	0.0125 (14)	0.0123 (11)	0.0119 (12)
C16	0.0752 (19)	0.117 (3)	0.0294 (11)	0.009 (2)	0.0018 (12)	0.0025 (16)
C17	0.0418 (11)	0.0621 (16)	0.0404 (12)	−0.0105 (11)	0.0053 (9)	−0.0161 (12)
C18	0.0392 (11)	0.0570 (15)	0.0606 (15)	−0.0041 (11)	0.0089 (10)	−0.0171 (13)
C19	0.0344 (10)	0.0752 (18)	0.0452 (13)	0.0038 (11)	−0.0061 (9)	−0.0088 (13)
C3A	0.0621 (15)	0.0527 (15)	0.0441 (12)	−0.0001 (13)	0.0145 (11)	0.0046 (12)
C3B	0.0742 (18)	0.079 (2)	0.0416 (13)	0.0073 (17)	0.0159 (12)	0.0011 (14)

Geometric parameters (Å, º)

O17—C17	1.204 (4)	C9—C11	1.542 (3)
O3A—C3A	1.325 (3)	C9—C10	1.557 (3)
O3A—C3	1.467 (3)	C9—H9	0.9800
O7—C7	1.431 (3)	C10—C19	1.546 (3)
O7—H7A	0.8200	C11—C12	1.542 (4)
O3B—C3A	1.184 (4)	C11—H11A	0.9700
N6A—N6B	1.215 (4)	C11—H11B	0.9700
N6A—C6	1.488 (3)	C12—C13	1.511 (4)
N6B—N6C	1.132 (5)	C12—H12A	0.9700
C1—C2	1.540 (4)	C12—H12B	0.9700
C1—C10	1.544 (4)	C13—C17	1.509 (3)
C1—H1A	0.9700	C13—C14	1.540 (3)
C1—H1B	0.9700	C13—C18	1.544 (3)
C2—C3	1.507 (4)	C14—C15	1.544 (3)
C2—H2A	0.9700	C14—H14	0.9800
C2—H2B	0.9700	C15—C16	1.581 (5)
C3—C4	1.514 (4)	C15—H15A	0.9700
C3—H3	0.9800	C15—H15B	0.9700
C4—C5	1.531 (3)	C16—C17	1.554 (6)
C4—H4A	0.9700	C16—H16A	0.9700
C4—H4B	0.9700	C16—H16B	0.9700
C5—C6	1.522 (3)	C18—H18A	0.9600
C5—C10	1.553 (3)	C18—H18B	0.9600
C5—H5	0.9800	C18—H18C	0.9600
C6—C7	1.528 (3)	C19—H19A	0.9600
C6—H6	0.9800	C19—H19B	0.9600
C7—C8	1.532 (3)	C19—H19C	0.9600
C7—H7	0.9800	C3A—C3B	1.487 (4)
C8—C14	1.523 (3)	C3B—H3B1	0.9600
C8—C9	1.552 (3)	C3B—H3B2	0.9600
C8—H8	0.9800	C3B—H3B3	0.9600
C3A—O3A—C3	116.9 (2)	C19—C10—C9	110.95 (19)
C7—O7—H7A	109.5	C5—C10—C9	107.70 (17)
N6B—N6A—C6	114.4 (3)	C9—C11—C12	113.7 (2)
N6C—N6B—N6A	174.8 (5)	C9—C11—H11A	108.8
C2—C1—C10	113.3 (2)	C12—C11—H11A	108.8
C2—C1—H1A	108.9	C9—C11—H11B	108.8
C10—C1—H1A	108.9	C12—C11—H11B	108.8
C2—C1—H1B	108.9	H11A—C11—H11B	107.7
C10—C1—H1B	108.9	C13—C12—C11	110.2 (2)
H1A—C1—H1B	107.7	C13—C12—H12A	109.6
C3—C2—C1	110.1 (2)	C11—C12—H12A	109.6
C3—C2—H2A	109.6	C13—C12—H12B	109.6
C1—C2—H2A	109.6	C11—C12—H12B	109.6
C3—C2—H2B	109.6	H12A—C12—H12B	108.1
C1—C2—H2B	109.6	C17—C13—C12	115.3 (2)
H2A—C2—H2B	108.1	C17—C13—C14	101.20 (19)
O3A—C3—C2	111.2 (2)	C12—C13—C14	109.38 (19)
O3A—C3—C4	107.5 (2)	C17—C13—C18	105.11 (19)
C2—C3—C4	111.9 (2)	C12—C13—C18	111.5 (2)
O3A—C3—H3	108.7	C14—C13—C18	114.0 (2)
C2—C3—H3	108.7	C8—C14—C13	113.29 (18)
C4—C3—H3	108.7	C8—C14—C15	120.3 (2)
C3—C4—C5	108.2 (2)	C13—C14—C15	104.74 (18)
C3—C4—H4A	110.1	C8—C14—H14	105.8
C5—C4—H4A	110.1	C13—C14—H14	105.8
C3—C4—H4B	110.1	C15—C14—H14	105.8
C5—C4—H4B	110.1	C14—C15—C16	100.8 (2)
H4A—C4—H4B	108.4	C14—C15—H15A	111.6
C6—C5—C4	112.4 (2)	C16—C15—H15A	111.6
C6—C5—C10	115.20 (18)	C14—C15—H15B	111.6
C4—C5—C10	114.02 (19)	C16—C15—H15B	111.6
C6—C5—H5	104.6	H15A—C15—H15B	109.4
C4—C5—H5	104.6	C17—C16—C15	105.4 (2)
C10—C5—H5	104.6	C17—C16—H16A	110.7
N6A—C6—C5	110.7 (2)	C15—C16—H16A	110.7
N6A—C6—C7	111.12 (19)	C17—C16—H16B	110.7
C5—C6—C7	110.70 (19)	C15—C16—H16B	110.7
N6A—C6—H6	108.1	H16A—C16—H16B	108.8
C5—C6—H6	108.1	O17—C17—C13	128.2 (3)
C7—C6—H6	108.1	O17—C17—C16	123.9 (2)
O7—C7—C6	107.33 (17)	C13—C17—C16	107.9 (2)
O7—C7—C8	110.17 (18)	C13—C18—H18A	109.5
C6—C7—C8	112.32 (18)	C13—C18—H18B	109.5
O7—C7—H7	109.0	H18A—C18—H18B	109.5
C6—C7—H7	109.0	C13—C18—H18C	109.5
C8—C7—H7	109.0	H18A—C18—H18C	109.5
C14—C8—C7	111.14 (17)	H18B—C18—H18C	109.5
C14—C8—C9	108.61 (17)	C10—C19—H19A	109.5
C7—C8—C9	111.44 (16)	C10—C19—H19B	109.5
C14—C8—H8	108.5	H19A—C19—H19B	109.5
C7—C8—H8	108.5	C10—C19—H19C	109.5
C9—C8—H8	108.5	H19A—C19—H19C	109.5
C11—C9—C8	110.57 (19)	H19B—C19—H19C	109.5
C11—C9—C10	113.56 (18)	O3B—C3A—O3A	123.8 (3)
C8—C9—C10	112.72 (18)	O3B—C3A—C3B	124.5 (3)
C11—C9—H9	106.5	O3A—C3A—C3B	111.7 (3)
C8—C9—H9	106.5	C3A—C3B—H3B1	109.5
C10—C9—H9	106.5	C3A—C3B—H3B2	109.5
C1—C10—C19	108.7 (2)	H3B1—C3B—H3B2	109.5
C1—C10—C5	106.50 (18)	C3A—C3B—H3B3	109.5
C19—C10—C5	113.2 (2)	H3B1—C3B—H3B3	109.5
C1—C10—C9	109.6 (2)	H3B2—C3B—H3B3	109.5
C10—C1—C2—C3	−56.5 (3)	C11—C9—C10—C1	64.4 (3)
C3A—O3A—C3—C2	94.2 (3)	C8—C9—C10—C1	−168.92 (18)
C3A—O3A—C3—C4	−143.0 (3)	C11—C9—C10—C19	−55.7 (3)
C1—C2—C3—O3A	178.2 (2)	C8—C9—C10—C19	71.0 (2)
C1—C2—C3—C4	57.9 (3)	C11—C9—C10—C5	179.8 (2)
O3A—C3—C4—C5	179.08 (19)	C8—C9—C10—C5	−53.4 (2)
C2—C3—C4—C5	−58.5 (3)	C8—C9—C11—C12	53.7 (3)
C3—C4—C5—C6	−167.5 (2)	C10—C9—C11—C12	−178.4 (2)
C3—C4—C5—C10	59.0 (3)	C9—C11—C12—C13	−54.8 (3)
N6B—N6A—C6—C5	168.1 (3)	C11—C12—C13—C17	168.8 (2)
N6B—N6A—C6—C7	−68.4 (3)	C11—C12—C13—C14	55.6 (3)
C4—C5—C6—N6A	−64.0 (3)	C11—C12—C13—C18	−71.4 (3)
C10—C5—C6—N6A	68.9 (3)	C7—C8—C14—C13	−178.49 (17)
C4—C5—C6—C7	172.28 (18)	C9—C8—C14—C13	58.6 (2)
C10—C5—C6—C7	−54.8 (2)	C7—C8—C14—C15	−53.5 (3)
N6A—C6—C7—O7	168.36 (19)	C9—C8—C14—C15	−176.5 (2)
C5—C6—C7—O7	−68.2 (2)	C17—C13—C14—C8	177.50 (18)
N6A—C6—C7—C8	−70.4 (3)	C12—C13—C14—C8	−60.3 (2)
C5—C6—C7—C8	53.1 (2)	C18—C13—C14—C8	65.2 (3)
O7—C7—C8—C14	−55.7 (2)	C17—C13—C14—C15	44.5 (2)
C6—C7—C8—C14	−175.34 (17)	C12—C13—C14—C15	166.7 (2)
O7—C7—C8—C9	65.6 (2)	C18—C13—C14—C15	−67.8 (3)
C6—C7—C8—C9	−54.0 (2)	C8—C14—C15—C16	−170.1 (2)
C14—C8—C9—C11	−53.6 (2)	C13—C14—C15—C16	−41.2 (3)
C7—C8—C9—C11	−176.40 (19)	C14—C15—C16—C17	22.2 (3)
C14—C8—C9—C10	178.06 (17)	C12—C13—C17—O17	33.3 (4)
C7—C8—C9—C10	55.3 (2)	C14—C13—C17—O17	151.2 (3)
C2—C1—C10—C19	−68.5 (3)	C18—C13—C17—O17	−89.9 (3)
C2—C1—C10—C5	53.8 (3)	C12—C13—C17—C16	−147.3 (2)
C2—C1—C10—C9	170.1 (2)	C14—C13—C17—C16	−29.4 (3)
C6—C5—C10—C1	171.82 (19)	C18—C13—C17—C16	89.5 (3)
C4—C5—C10—C1	−56.1 (2)	C15—C16—C17—O17	−176.0 (3)
C6—C5—C10—C19	−68.7 (2)	C15—C16—C17—C13	4.5 (3)
C4—C5—C10—C19	63.4 (3)	C3—O3A—C3A—O3B	−1.8 (5)
C6—C5—C10—C9	54.3 (2)	C3—O3A—C3A—C3B	179.8 (3)
C4—C5—C10—C9	−173.57 (19)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O7—H7A···O17^i	0.82	2.02	2.825 (3)	166
C3B—H3B3···N6C^ii	0.96	2.56	3.405 (6)	147

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