Precursor of a β-lactamase inhibitor: allyl (4S,8S,9R)-10-[(E)-ethyl­idene]-4-methoxy-11-oxo-1-aza­tri­cyclo­[7.2.0.0^3,8]­undec-2-ene-2-carboxyl­ate

The molecular structure of the title tricyclic compound, C₁₇H₂₁NO₄, which is the immediate precursor of a potent synthetic inhibitor {Lek157: sodium (8S,9R)-10-[(E)-ethyl­idene]-4-methoxy-11-oxo-1-aza­tri­cyclo­[7.2.0.0^3,8]­undec-2-ene-2-carboxyl­ate} with remarkable potency, provides experimental evidence for the previously modelled relative position of the fused cyclo­hexyl ring and the carbonyl group of the β-lactam ring, which takes part in the formation of the initial tetrahedral acyl–enzyme complex. In this hydro­phobic mol­ecule, the overall geometry is influenced by C—H...O intramolecular hydrogen bonds [3.046 (4) and 3.538 (6) Å, with corresponding normalized H...O distances of 2.30 and 2.46 Å], whereas the mol­ecules are interconnected through intermolecular C—H...O hydrogen bonds [3.335 (4)–3.575 (5) Å].

S1. Comment

Because of their effectiveness and safety, β-lactam antibiotics play a central role in the treatment of bacterial infections. However, the clinical use of these drugs has been compromised due to hydrolytic cleavage of the β-lactam ring by bacterial β-lactamases, which renders them inactive. In particular, the clinically used inhibitors which are employed to block lactamase activity and to preserve the antibacterial activity of the antibiotic are ineffective in bacterial strains bearing class C β-lactamases (Massova & Mobashery, 1997). Thus, the development of inhibitors of class C β-lactamases is an active area of antimicrobial research (Frère et al., 1999).

As part of our ongoing research program concerned with the structure-based design of β-lactamase inhibitors, we have designed and synthesized a series of potent tricyclic carbapenems (Čopar et al., 1998), which have been shown to exhibit very useful biological activity as inhibitors of class A, class C, and also class D β-lactamases (Vilar et al., 2001). Our design procedure introduces a hydrophobic cyclohexane ring at the C3—C4 position of the penem, which should block the access of the water molecules to the tetrahedral acyl–enzyme complex formed in the first step of the enzyme-inhibitor interaction process, thus stabilizing of the tetrahedral intermediate and preventing the deacylation step (Heinze-Krauss et al., 1998; Čopar et al., 2002).

Molecular-modelling studies (Šolmajer & Čopar, 1998) were performed to analyse the complexes of the designed compounds with the enzyme target, based on the reported crystal structure of class C β-lactamase from Enterobacter cloacae P99 (Lobkovsky et al., 1993). The present structural study was carried out to establish unequivocally the stereochemistry of the allyl precursor of the inhibitor Lek157 {sodium (8S,9R)-10-[(E)-ethylidene]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0^3,8]undec- 2-ene-2-carboxylate}, which can be obtained in high yields (94%) from the title precursor by a single-step deallylation.

The crystal structure of the title compound, (I) (Fig. 1), clearly shows the cis stereochemistry (8S,9R) of the azatricyclo[7.2.0.0^3,8]undec-2-ene ring system and demonstrates the spatial position of the 4-methoxy substituent with respect to the carbonyl group of the β-lactam ring, which takes part in the tetrahedral intermediate formed by a covalent interaction with Ser 64 of the class C enzymes or Ser 70 of the class A β-lactamases.

The structure of allyl Lek157 also confirms our initial hypothesis from modelling that the 4-methoxy substituent is suitably positioned in Lek157 to form a hydrogen bond with the side-chain amide of Asn 152 in the complex with Enterobacter cloacae P99 β-lactamase.

A precheck using the Cambridge Structural Database (Release 5.2.1 of April 2001; Allen & Kennard, 1993) gave no results on β-lactam-like compounds with a tricyclic structure.

The molecule of (I) with the atomic numbering scheme is depicted in Fig. 1. Selected geometric parameters are presented in Table 1. The bond lengths and angles are normal and in agreement with the values for related compounds, for example, 2-benzyloxycarbonyl-3-methoxycarbonyl-4-methyl-7-oxo-1- azabicyclo[3.2.0]heptane (Martel et al., 1997). The bond lengths of C2—C3 [1.341 (3) Å], C10—C20 [1.332 (4) Å] and C16—C17 [1.280 (6) Å] suggest double-bond character (International Tables for X-ray Crystallography, Vol. C, 1995).

The most interesting feature of the structure of (I) is the system of intra- and intermolecular C—H···O hydrogen bonds (Taylor & Kennard, 1982; Steiner, 1997), which govern the shape of the molecule. With regard to the C—H···O hydrogen bonding, which is relatively weak but important, the significance of the H···Y distances rather than the X···Y distances (hydrogen-bond type X—H···Y) was first clearly shown in the study of N—H···O═C hydrogen bonds by Taylor & Kennard (1983). It was also believed for a long time that the van der Waals sum cut-off definition of the hydrogen bond requires that the H···Y and X···Y distances must be smaller than the sum of the van der Waals radii. For C—H···O interactions, the H···O separation was taken as 2.6–2.7 Å. At this distance, the interaction was assumed to switch from a `hydrogen bond' to a `van der Waals'-type interaction. However, this definition was recently declared faulty, the argument being that the electrostatic field of dipoles does not terminate sharply at any cut-off distance. Longer H···O distances of up to 3.2 Å and an angular cut-off at angles greater than 90° (Steiner, 2002; Steiner & Saenger, 1992) were therefore suggested. An additional but necessary criterion for hydrogen bonding is a positive directionality preference, that is, linear C—H···O angles are statistically favoured over bent ones. However, the degree of directionality decreases with the polarity of the C—H group, namely C≡C—H > C═CH₂ > –CH₃. Even in C—H···O contacts involving methyl groups, there is a preference for linearity, whereas this is quite contrary to the van der Waals contacts of methyl groups (Steiner & Desiraju, 1998). Additionally, hydrogen bonds are directional also at the acceptor side. In the case of R₂C═O as an acceptor, the H···O═ C angles are expected to be spread around a value of 120° (Steiner, 2002, and references therein). Furthermore, the common opinion is that the H···O distances obtained from X-ray diffraction data are not worthy of mention because the C—H distances are less than those obtained from a more precise neutron diffraction study. However, this difference was found to be systematic and could well be accounted for with normalized C—H values (Taylor & Kennard, 1983) and the corresponding C—H···O angles could be calculated (Nardelli, 1983, 1995) from X-ray data.

Using all these findings, the shape of the title molecules can be explained as being the result of various C—H···O interactions. The allyl carboxylate moiety is curled in such a way that the terminal C17—H17A group forms a long contact to the carboxyl O11 atom of the β-lactam group, and also to atom O14 of the carboxyl group (see Table 2 for details of C—H···O interactions). This bond could be classified as a three-center C—H···O bond (Steiner, 2002). There is another short intermolecular bond, C4—H4···O13 [3.046 (4) Å], with a normalized H4···O13 distance of 2.30 Å, which forces atoms C2, C3, C4, C12 and O13 to be in a planar arrangement. The β-lactam and five-membered rings are nearly planar, the maximum deviations from the planes being 0.035 (1) and 0.066 (1) Å, respectively, with a corresponding dihedral angle of 53.7 (1)°. The cyclohexyl ring attached at the C3—C8 bond adopts a normal chair conformation. There are three intermolecular C—H···O interactions, with C···O distances ranging from 3.507 (5) to 3.575 (5) Å and normalized H···O distances ranging from 2.46 to 2.69 Å. The corresponding angles at the H···O—C acceptor site are H15A···O11ⁱ═C11ⁱ 141°, H20···O18ⁱⁱ—C4ⁱⁱ 134° and H21B···O13ⁱⁱⁱ═C12ⁱⁱⁱ 175° [symmetry codes: (i) x + 1/2, -y + 3/2, -z; (ii) 1 - x, y + 1/2, -z + 1/2; (iii) -x + 3/2, 1 - y, z + 1/2]. The molecules are interlinked in a columnar arrangement along the shorter a axis through C—H···O hydrogen bonds.

S2. Experimental

The synthesis and bioactivity characterization of Lek157 have been reported previously (Čopar et al., 1998; Vilar et al. 2001). Single crystals of the allyl precursor of Lek157 were obtained with difficulty by slow evaporation from a methanol solution at 289 K. The crystals exhibited bad scattering properties.

S3. Refinement

Space group P2₁2₁2₁ was deduced from the systematic absences and intensity statistics. All H atoms were found in a difference electron-density map and were placed at calculated positions (C—H = 0.93–0.98 Å) with isotropic displacement parameters taken from the adjacent atom multiplied by 1.2 (1.5 for methyl). The methyl H atoms of one group were found to be disordered over two positions and option AFIX 123 of SHELXL97 (Sheldrick, 1997)w as used. There were no suitable anomalous scatterers for Mo Kα radiation and therefore the determination of the absolute configuration was not possible from the X-ray data. The absolute configuration was assigned to agree with the chirality known by chemical means and the Friedel diffraction data were merged accordingly.

Computing details

Data collection: COLLECT (Nonius, 1999); cell refinement: DENZO and SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO and SCALEPACK; program(s) used to solve structure: SHELXS86 (Sheldrick, 1985); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPII (Johnson, 1971), PLUTON (Spek, 1991), PLATON (Spek, 1998; Farrugia, 2000) and ORTEP-3 (Farrugia, 1999b); software used to prepare material for publication: SHELXL97, PARST (Nardelli, 1983, 1995) and WinGX (Farrugia, 1999a).

Figures

Fig. 1. ORTEPII (Johnson, 1971) view of the title molecule with the atomic numbering. Displacement ellipsoids are drawn at the 30% probability level. H atoms are displayed as small circles of arbitrary scale.

allyl (4S,8S,9R)-10-[(E)-ethylidene]-4-methoxy-11-oxo-1- azatricyclo[7.2.0.0^3,8]undec-2-ene-2-carboxylate

Crystal data

C17H21NO4	F(000) = 648
Mr = 303.35	Dx = 1.241 Mg m^−3 Dm = 1.22 (5) Mg m^−3 Dm measured by flotation
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 1815 reflections
a = 7.6810 (2) Å	θ = 3–27.2°
b = 14.4610 (3) Å	µ = 0.09 mm^−1
c = 14.6190 (4) Å	T = 293 K
V = 1623.80 (7) Å^3	Plate, colourless
Z = 4	0.40 × 0.30 × 0.20 mm

Data collection

Nonius KappaCCD diffractometer	1710 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.016
Graphite monochromator	θmax = 27.2°, θmin = 3.0°
Detector resolution: 0.055 pixels mm^-1	h = −9→9
ω scans	k = −18→18
3538 measured reflections	l = −18→18
2008 independent reflections

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.043	H-atom parameters constrained
wR(F^2) = 0.127	w = 1/[σ^2(Fo^2) + (0.0691P)^2 + 0.1661P] where P = (Fo^2 + 2Fc^2)/3
S = 1.06	(Δ/σ)max = 0.001
2008 reflections	Δρmax = 0.14 e Å^−3
200 parameters	Δρmin = −0.12 e Å^−3
0 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.122 (17)

Special details

Experimental. KappaCCD Nonius diffractometer. 139 frames in 3 sets of ω scans. Rotation/frame=1°. Crystal-detector distance=26.3 mm. Measuring time=80 s/°.

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	Occ. (<1)
N1	0.7798 (3)	0.59637 (13)	0.22288 (15)	0.0599 (5)
C2	0.8588 (3)	0.54660 (15)	0.14886 (16)	0.0555 (5)
C3	0.7880 (3)	0.46227 (15)	0.14023 (15)	0.0536 (5)
C4	0.8201 (4)	0.38783 (16)	0.07029 (17)	0.0665 (7)
H4	0.9149	0.4058	0.0291	0.080*
C5	0.6529 (5)	0.3737 (2)	0.01714 (19)	0.0826 (9)
H5A	0.6319	0.4276	−0.0207	0.099*
H5B	0.6668	0.3209	−0.0231	0.099*
C6	0.4961 (4)	0.3578 (2)	0.0780 (2)	0.0787 (8)
H6A	0.5105	0.2999	0.1106	0.094*
H6B	0.3927	0.3526	0.0402	0.094*
C7	0.4704 (4)	0.4361 (2)	0.1473 (2)	0.0714 (7)
H7A	0.3730	0.4218	0.1871	0.086*
H7B	0.4447	0.4933	0.1154	0.086*
C8	0.6380 (3)	0.44776 (15)	0.20496 (15)	0.0541 (5)
H8	0.6580	0.3915	0.2408	0.065*
C9	0.6501 (3)	0.53274 (16)	0.26825 (16)	0.0584 (5)
H9	0.6827	0.5166	0.3311	0.070*
C10	0.5210 (3)	0.61155 (18)	0.26361 (19)	0.0667 (7)
C11	0.6504 (3)	0.66668 (17)	0.21131 (19)	0.0653 (6)
O11	0.6559 (3)	0.73935 (13)	0.17230 (18)	0.0898 (7)
C12	1.0027 (4)	0.58562 (19)	0.0944 (2)	0.0687 (7)
O13	1.0730 (4)	0.5457 (2)	0.0330 (2)	0.1314 (12)
O14	1.0455 (3)	0.66989 (13)	0.11910 (16)	0.0817 (6)
C15	1.1857 (5)	0.7139 (2)	0.0673 (3)	0.0962 (10)
H15A	1.1839	0.6923	0.0045	0.115*
H15B	1.2974	0.6977	0.0939	0.115*
C16	1.1621 (6)	0.8144 (3)	0.0696 (3)	0.1015 (11)
H16	1.2570	0.8493	0.0504	0.122*
C17	1.0279 (8)	0.8603 (3)	0.0947 (3)	0.1199 (15)
H17A	0.9288	0.8294	0.1146	0.144*
H17B	1.0296	0.9246	0.0929	0.144*
O18	0.8599 (3)	0.30247 (12)	0.11466 (13)	0.0707 (5)
C19	1.0209 (4)	0.3038 (2)	0.1623 (3)	0.0857 (9)
H19A	1.0399	0.2448	0.1908	0.128*
H19B	1.0180	0.3512	0.2083	0.128*
H19C	1.1137	0.3163	0.1201	0.128*
C20	0.3580 (4)	0.6278 (2)	0.2902 (2)	0.0788 (8)
H20	0.3109	0.6854	0.2765	0.095*
C21	0.2458 (4)	0.5611 (3)	0.3398 (3)	0.1043 (12)
H21A	0.1343	0.5888	0.3513	0.156*	0.50
H21B	0.2996	0.5449	0.3969	0.156*	0.50
H21C	0.2308	0.5065	0.3034	0.156*	0.50
H21D	0.3089	0.5047	0.3497	0.156*	0.50
H21E	0.1435	0.5485	0.3042	0.156*	0.50
H21F	0.2124	0.5870	0.3977	0.156*	0.50

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0539 (10)	0.0542 (10)	0.0717 (11)	−0.0043 (9)	0.0027 (10)	−0.0126 (9)
C2	0.0494 (10)	0.0536 (11)	0.0634 (12)	0.0016 (10)	0.0010 (10)	−0.0015 (10)
C3	0.0588 (11)	0.0492 (11)	0.0527 (11)	0.0007 (10)	0.0006 (10)	0.0001 (9)
C4	0.0860 (18)	0.0527 (12)	0.0606 (13)	0.0044 (12)	0.0084 (13)	−0.0039 (10)
C5	0.109 (2)	0.0756 (16)	0.0631 (14)	−0.0021 (18)	−0.0144 (18)	−0.0092 (13)
C6	0.0866 (19)	0.0710 (16)	0.0784 (16)	−0.0115 (15)	−0.0238 (16)	−0.0112 (14)
C7	0.0650 (14)	0.0704 (15)	0.0788 (16)	−0.0065 (13)	−0.0131 (14)	−0.0052 (13)
C8	0.0573 (12)	0.0493 (10)	0.0558 (11)	−0.0024 (10)	−0.0031 (10)	0.0011 (9)
C9	0.0562 (12)	0.0644 (12)	0.0547 (11)	−0.0052 (11)	0.0028 (11)	−0.0063 (10)
C10	0.0602 (14)	0.0649 (14)	0.0750 (15)	−0.0009 (11)	0.0070 (13)	−0.0187 (12)
C11	0.0587 (13)	0.0529 (12)	0.0844 (16)	−0.0024 (11)	0.0060 (14)	−0.0143 (12)
O11	0.0805 (13)	0.0554 (10)	0.1336 (18)	0.0027 (10)	0.0111 (14)	0.0031 (11)
C12	0.0596 (14)	0.0622 (14)	0.0844 (17)	0.0006 (11)	0.0134 (13)	0.0021 (13)
O13	0.145 (2)	0.0969 (16)	0.153 (2)	−0.0283 (17)	0.090 (2)	−0.0286 (17)
O14	0.0744 (11)	0.0680 (11)	0.1028 (14)	−0.0179 (10)	0.0240 (12)	−0.0043 (10)
C15	0.081 (2)	0.090 (2)	0.117 (3)	−0.0207 (17)	0.0247 (19)	0.0135 (19)
C16	0.109 (3)	0.090 (2)	0.105 (2)	−0.034 (2)	0.024 (2)	0.0053 (19)
C17	0.143 (4)	0.079 (2)	0.138 (3)	−0.016 (3)	0.024 (4)	0.007 (2)
O18	0.0761 (11)	0.0506 (8)	0.0853 (12)	0.0058 (9)	0.0023 (10)	−0.0022 (8)
C19	0.0726 (17)	0.0750 (17)	0.109 (2)	0.0168 (15)	0.0017 (18)	−0.0040 (17)
C20	0.0634 (14)	0.0835 (17)	0.0897 (19)	0.0020 (14)	0.0161 (15)	−0.0199 (15)
C21	0.076 (2)	0.139 (3)	0.097 (2)	−0.009 (2)	0.0303 (19)	−0.014 (2)

Geometric parameters (Å, º)

N1—C11	1.432 (3)	C10—C11	1.486 (4)
N1—C2	1.434 (3)	C11—O11	1.196 (3)
N1—C9	1.509 (3)	C12—O13	1.197 (4)
C2—C3	1.341 (3)	C12—O14	1.313 (3)
C2—C12	1.474 (3)	O14—C15	1.462 (4)
C3—C4	1.505 (3)	C15—C16	1.465 (5)
C3—C8	1.506 (3)	C15—H15A	0.9700
C4—O18	1.428 (3)	C15—H15B	0.9700
C4—C5	1.515 (4)	C16—C17	1.279 (6)
C4—H4	0.9800	C16—H16	0.9300
C5—C6	1.515 (5)	C17—H17A	0.9300
C5—H5A	0.9700	C17—H17B	0.9300
C5—H5B	0.9700	O18—C19	1.420 (4)
C6—C7	1.532 (4)	C19—H19A	0.9600
C6—H6A	0.9700	C19—H19B	0.9600
C6—H6B	0.9700	C19—H19C	0.9600
C7—C8	1.548 (3)	C20—C21	1.483 (5)
C7—H7A	0.9700	C20—H20	0.9300
C7—H7B	0.9700	C21—H21A	0.9600
C8—C9	1.541 (3)	C21—H21B	0.9600
C8—H8	0.9800	C21—H21C	0.9600
C9—C10	1.512 (4)	C21—H21D	0.9600
C9—H9	0.9800	C21—H21E	0.9600
C10—C20	1.332 (4)	C21—H21F	0.9600
C11—N1—C2	124.1 (2)	O11—C11—C10	137.7 (3)
C11—N1—C9	91.5 (2)	N1—C11—C10	91.3 (2)
C2—N1—C9	107.7 (2)	O13—C12—O14	122.8 (3)
C3—C2—N1	110.8 (2)	O13—C12—C2	123.9 (3)
C3—C2—C12	127.0 (2)	O14—C12—C2	113.3 (2)
N1—C2—C12	122.1 (2)	C12—O14—C15	116.5 (2)
C2—C3—C4	130.4 (2)	O14—C15—C16	109.2 (3)
C2—C3—C8	112.2 (2)	O14—C15—H15A	109.8
C4—C3—C8	116.9 (2)	C16—C15—H15A	109.8
O18—C4—C3	110.2 (2)	O14—C15—H15B	109.8
O18—C4—C5	107.3 (2)	C16—C15—H15B	109.8
C3—C4—C5	107.8 (2)	H15A—C15—H15B	108.3
O18—C4—H4	110.5	C17—C16—C15	128.4 (4)
C3—C4—H4	110.5	C17—C16—H16	115.8
C5—C4—H4	110.5	C15—C16—H16	115.8
C6—C5—C4	113.2 (2)	C16—C17—H17A	120.0
C6—C5—H5A	108.9	C16—C17—H17B	120.0
C4—C5—H5A	108.9	H17A—C17—H17B	120.0
C6—C5—H5B	108.9	C19—O18—C4	113.4 (2)
C4—C5—H5B	108.9	O18—C19—H19A	109.5
H5A—C5—H5B	107.8	O18—C19—H19B	109.5
C5—C6—C7	112.3 (2)	H19A—C19—H19B	109.5
C5—C6—H6A	109.2	O18—C19—H19C	109.5
C7—C6—H6A	109.2	H19A—C19—H19C	109.5
C5—C6—H6B	109.2	H19B—C19—H19C	109.5
C7—C6—H6B	109.2	C10—C20—C21	125.1 (3)
H6A—C6—H6B	107.9	C10—C20—H20	117.5
C6—C7—C8	109.5 (2)	C21—C20—H20	117.5
C6—C7—H7A	109.8	C20—C21—H21A	109.5
C8—C7—H7A	109.8	C20—C21—H21B	109.5
C6—C7—H7B	109.8	H21A—C21—H21B	109.5
C8—C7—H7B	109.8	C20—C21—H21C	109.5
H7A—C7—H7B	108.2	H21A—C21—H21C	109.5
C3—C8—C9	102.7 (3)	H21B—C21—H21C	109.5
C3—C8—C7	108.0 (2)	C20—C21—H21D	109.5
C9—C8—C7	117.7 (2)	H21A—C21—H21D	141.1
C3—C8—H8	109.4	H21B—C21—H21D	56.3
C9—C8—H8	109.4	H21C—C21—H21D	56.3
C7—C8—H8	109.4	C20—C21—H21E	109.5
N1—C9—C10	87.3 (2)	H21A—C21—H21E	56.3
N1—C9—C8	105.2 (2)	H21B—C21—H21E	141.1
C10—C9—C8	122.3 (2)	H21C—C21—H21E	56.3
N1—C9—H9	112.9	H21D—C21—H21E	109.5
C10—C9—H9	112.9	C20—C21—H21F	109.5
C8—C9—H9	112.9	H21A—C21—H21F	56.3
C20—C10—C11	133.2 (3)	H21B—C21—H21F	56.3
C20—C10—C9	137.4 (3)	H21C—C21—H21F	141.1
C11—C10—C9	89.4 (2)	H21D—C21—H21F	109.5
O11—C11—N1	131.0 (3)	H21E—C21—H21F	109.5
C11—N1—C2—C3	−101.5 (3)	C7—C8—C9—N1	−107.3 (2)
C9—N1—C2—C3	3.1 (3)	C3—C8—C9—C10	107.7 (2)
C11—N1—C2—C12	80.7 (3)	C7—C8—C9—C10	−10.7 (3)
C9—N1—C2—C12	−174.8 (2)	N1—C9—C10—C20	−177.3 (3)
N1—C2—C3—C4	176.2 (2)	C8—C9—C10—C20	76.3 (4)
C12—C2—C3—C4	−6.1 (4)	N1—C9—C10—C11	5.1 (2)
N1—C2—C3—C8	4.7 (3)	C8—C9—C10—C11	−101.3 (2)
C12—C2—C3—C8	−177.6 (2)	C2—N1—C11—O11	−61.2 (4)
C2—C3—C4—O18	127.3 (3)	C9—N1—C11—O11	−173.9 (3)
C8—C3—C4—O18	−61.6 (3)	C2—N1—C11—C10	118.1 (2)
C2—C3—C4—C5	−115.9 (3)	C9—N1—C11—C10	5.3 (2)
C8—C3—C4—C5	55.2 (3)	C20—C10—C11—O11	−4.0 (6)
O18—C4—C5—C6	66.9 (3)	C9—C10—C11—O11	173.8 (4)
C3—C4—C5—C6	−51.8 (3)	C20—C10—C11—N1	176.9 (3)
C4—C5—C6—C7	55.7 (3)	C9—C10—C11—N1	−5.3 (2)
C5—C6—C7—C8	−56.3 (3)	C3—C2—C12—O13	1.6 (5)
C2—C3—C8—C9	−10.1 (3)	N1—C2—C12—O13	179.1 (3)
C4—C3—C8—C9	177.2 (2)	C3—C2—C12—O14	−179.4 (3)
C2—C3—C8—C7	114.9 (2)	N1—C2—C12—O14	−1.9 (4)
C4—C3—C8—C7	−57.8 (3)	O13—C12—O14—C15	−0.1 (5)
C6—C7—C8—C3	55.0 (3)	C2—C12—O14—C15	−179.1 (3)
C6—C7—C8—C9	170.5 (2)	C12—O14—C15—C16	152.5 (3)
C11—N1—C9—C10	−5.2 (2)	O14—C15—C16—C17	−13.5 (7)
C2—N1—C9—C10	−132.0 (2)	C3—C4—O18—C19	−66.9 (3)
C11—N1—C9—C8	117.6 (2)	C5—C4—O18—C19	175.9 (2)
C2—N1—C9—C8	−9.1 (2)	C11—C10—C20—C21	177.4 (3)
C3—C8—C9—N1	11.1 (2)	C9—C10—C20—C21	0.7 (6)