Nobiletin: a citrus flavonoid displaying potent physiological activity

Nobiletin [systematic name: 2-(3,4-di­meth­oxy­phen­yl)-5,6,7,8-tetra­meth­oxy-4H-chromen-4-one; C₂₁H₂₂O₈] is a flavonoid found in citrus peels, and has been reported to show a wide range of physiological properties, including anti-inflammatory, anti­cancer and anti­dementia activities. We have solved the crystal structure of nobiletin, which revealed that the chromene and arene rings of its flavone moiety, as well as the two meth­oxy groups bound to its arene ring, were coplanar. In contrast, the C atoms of the four meth­oxy groups bound to the chromene ring are out of the plane, making the mol­ecule conformationally chiral. A comparison of the crystal structures of nobiletin revealed that it could adopt a variety of different conformations through rotation of the covalent bond between the chromene and arene rings, and the orientations of meth­oxy groups bound to the chromene ring.

S1. Introduction

Nobiletin, (I), is a flavonoid compound that can be found in large qu­anti­ties in citrus peels. Nobiletin and its metabolites (Lai et al., 2008; Li et al., 2014) have been reported to possess a variety of inter­esting physiological properties, including anti-inflammatory (Lin et al., 2003), anti­cancer (Kunimasa et al., 2010), anti-apoptosis (Akao et al., 2008), anti­dementia (Nagase et al., 2005) and neuroprotective (Yasuda et al., 2014) activities. Based on its potent physiological activities, nobiletin has become an attractive candidate for use as a therapeutic agent. The physiological activities of nobiletin have been attributed to its ability to modulate cell signaling pathways, including cAMP response elements (Nagase et al., 2005) and NF-κB (Cui et al., 2010), as well as its ability to alter the expression of specific genes (Nemoto et al., 2013; Kimura et al., 2014). However, the molecular mechanisms of nobiletin are not clear because the target receptor molecules to which this compound might bind have not yet been definitively identified. Investigations to identify the receptors are currently underway.

The three-dimensional molecular structure of nobiletin had been identified as a complex structure with a porous material using the `crystalline sponge' method (Inokuma et al., 2013). However, the quality of the electron-density map for nobiletin did not appear to be satisfactory in terms of its atomic resolution, probably because of its high thermal vibrations, disorder or the low occupancy levels of the nobiletin molecules in the complex structure. We have determined a single-crystal structure of nobiletin and compared the differences in the molecular conformations of nobiletin in a variety of different crystal-packing environments.

S2. Experimental

S2.1. Synthesis, crystallization and PXRD analysis

Nobiletin was synthesized according to a previously reported procedure and crystallized from aqueous methanol to give the desired material as fine needles (Asakawa et al., 2011). Nobiletin was dissolved in ethyl acetate and the resulting solution was filtered through a 0.45 µm membrane filter. A sample of the filtered solution (500 µl) was then poured into a Petri dish with a diameter of 15 mm. The solution was allowed to evaporate slowly at 298 K over a period of 2 d to give fine white crystals with a columnar shape. The crystals were analyzed by powder X-ray diffraction (PXRD) using a Rigaku Mini Flex II X-ray diffractometer. The PXRD pattern of the crystals prepared from ethyl acetate was identical to that of the crystals prepared from an aqueous methanol solution. This result confirmed that the crystal form of nobiletin had not changed through the recrystallization process.

S2.2. Refinement and twinning

Crystal data, data collection and structure refinement details are summarized in Table 1. The diffraction images indicated that the crystal used for the data collection process was a twin crystal made of two separate crystals, and that the c axes of the two crystals were almost parallel. Given that the diffraction spots from each crystal were well separated in the diffraction images, it was possible to collect diffraction data from one of the crystals that diffracted more than sinθ/λ = 0.625 Å^-1. During the refinement process, the H atoms were located in a difference Fourier map and were constrained as riding, with U_iso(H) = 1.2U_eq(C).

S3. Results and discussion

The X-ray crystal structure of nobiletin, (I), solved in the current study revealed that the asymmetric unit contained one molecule (Fig. 1). Furthermore, no voids were identified in the crystal structure that could accommodate solvent molecules, confirming that this crystal had been isolated in the unsolvated form. The planes of the chromene and benzene rings of nobiletin were almost parallel, as exemplified by the torsion angle of the covalent bond between the chromene and benzene rings (O1—C2—C11—C12) of -0.6 (5)°. The C atoms of the two meth­oxy groups at the 3'- and 4'-positions of the benzene ring (see Scheme) were also located in the plane of the flavone. In contrast, the C atoms of the meth­oxy moieties on the chromene ring were not in the same plane as the flavone. The C5 methyl group projects forwards away from the plane of the chromene ring, whilst the C6, C7 and C8 methyl groups project backwards away from the plane of the ring. The molecular structure of nobiletin in this crystal was therefore chiral because of its conformational characteristics, despite the fact that nobiletin does not contain an asymmetric C atom. However, it was not possible to determine which enanti­omorph was responsible for this crystal based on the differences in the intensities of the Friedel pair reflections. This could be attributable to the scattering of the C and O atoms of the anomalous imaginary part being too small to be detected at the wavelength used for the data collection in this study [i.e. 0.7004 (1) Å]. The crystals grown from an ethyl acetate solution may therefore have been a mixture of two enanti­omorphic forms, as is often the case for the crystals of organic compounds (Koizumi et al., 2008).

The plane of best fit for the flavone ring of nobiletin forms an angle of 31° with the ab plane and is stacked along the c axis (Fig. 2). The distance between the planes of the flavone rings, as represented by the distance between atom C13 and atom C15 at (x, y, z+1), is 3.497 (7) Å. Table 2 shows details of the close inter­molecular contacts, which were less than the sum of the van der Waals radii, between the H atoms of the meth­oxy groups and the O atoms. The O2 atom of the carbonyl group, which is capable of forming a strong hydrogen bond as a hydrogen-bond acceptor, is in contact with atom H00E of the C22 methyl group. The distances between the C22—H22B···O2 and C22···O2 bonds are smaller than the average values reported for C—H···O and C···O contacts of methyl groups and carbonyl O atoms [2.761 (6) and 3.590 (7) Å, respectively; Steiner & Desiraju, 1998]. The C22—H22B···O2 angle is greater than 100°, which is the value needed for a C—H group to form a hydrogen-bonding inter­action (Jensen et al., 2003). The geometrical characteristics of this structure suggest that the C22—H22B···O2 contacts could possess a weak hydrogen-bonding characteristic. All of the other close contacts between the H and O atoms of the meth­oxy groups have C—H···O angles greater than 100°, which implies that these contacts also possess some hydrogen-bonding characteristics (Pingali et al., 2015). However, these hydrogen bonds are weaker than that of the C22—H22B···O2 hydrogen bond because a carbonyl O atom is a better hydrogen bond acceptor than a meth­oxy O atom.

Fig. 3 shows the superimposition of the molecular structure of nobiletin determined in this study (denoted NOB-1) on the molecular structure determined using the `crystalline sponge' method (denoted NOB-2). The O1—C2—C15—C16 torsion angle in NOB-2 is -172 (2)°, which shows that the benzene ring of the NOB-2 structure is almost flipped compared with that of the NOB-1 structure. Unlike the NOB-1 structure, the benzene and chromene rings of the NOB-2 structure are not coplanar and are distorted by approximately 8°. The other main difference between the two structures is the conformation of the meth­oxy groups bound to the chromene ring. The C20 methyl group in the NOB-1 structure extends towards the same side of the chromene ring as the C18 and C19 methyl groups, whereas the C20 methyl in the NOB-2 structure extends towards the opposite side of the ring. The superimposition of the two structures also suggests that it would not be possible to pack the NOB-1 structure into the cavities of the crystalline sponge in the same way as the NOB-2 structure because of the steric hindrance between the meth­oxy moieties of nobiletin and the sponge. Close contacts less than van der Waals distances were found between the C20 methyl group of the superimposed NOB1 structure and a pyridine ring of the sponge, and between the C21 methyl group of the NOB1 structure and an I atom bound to a Zn atom of the sponge. In solution, nobiletin may be in equilibrium with a variety of different conformers, which could differ, at least, in the conformation of the meth­oxy groups bound to the chromene ring and the torsion angle around the covalent bond between the chromene and benzene rings. The NOB1 and NOB2 structures may be involved in these conformers, with the former of these two structures crystalizing as single crystals and with the latter soaking and being bound into the sponge.

As mentioned above, nobiletin has been reported to elicit a wide range of physiological responses. The key steps in these physiological responses are presumed to involve the binding of nobiletin to the target receptor molecules responsible for each physiological response. Nobiletin could bind to a wide range of receptors based on its conformational variety.

Structure description

Nobiletin, (I), is a flavonoid compound that can be found in large qu­anti­ties in citrus peels. Nobiletin and its metabolites (Lai et al., 2008; Li et al., 2014) have been reported to possess a variety of inter­esting physiological properties, including anti-inflammatory (Lin et al., 2003), anti­cancer (Kunimasa et al., 2010), anti-apoptosis (Akao et al., 2008), anti­dementia (Nagase et al., 2005) and neuroprotective (Yasuda et al., 2014) activities. Based on its potent physiological activities, nobiletin has become an attractive candidate for use as a therapeutic agent. The physiological activities of nobiletin have been attributed to its ability to modulate cell signaling pathways, including cAMP response elements (Nagase et al., 2005) and NF-κB (Cui et al., 2010), as well as its ability to alter the expression of specific genes (Nemoto et al., 2013; Kimura et al., 2014). However, the molecular mechanisms of nobiletin are not clear because the target receptor molecules to which this compound might bind have not yet been definitively identified. Investigations to identify the receptors are currently underway.

The three-dimensional molecular structure of nobiletin had been identified as a complex structure with a porous material using the `crystalline sponge' method (Inokuma et al., 2013). However, the quality of the electron-density map for nobiletin did not appear to be satisfactory in terms of its atomic resolution, probably because of its high thermal vibrations, disorder or the low occupancy levels of the nobiletin molecules in the complex structure. We have determined a single-crystal structure of nobiletin and compared the differences in the molecular conformations of nobiletin in a variety of different crystal-packing environments.

The X-ray crystal structure of nobiletin, (I), solved in the current study revealed that the asymmetric unit contained one molecule (Fig. 1). Furthermore, no voids were identified in the crystal structure that could accommodate solvent molecules, confirming that this crystal had been isolated in the unsolvated form. The planes of the chromene and benzene rings of nobiletin were almost parallel, as exemplified by the torsion angle of the covalent bond between the chromene and benzene rings (O1—C2—C11—C12) of -0.6 (5)°. The C atoms of the two meth­oxy groups at the 3'- and 4'-positions of the benzene ring (see Scheme) were also located in the plane of the flavone. In contrast, the C atoms of the meth­oxy moieties on the chromene ring were not in the same plane as the flavone. The C5 methyl group projects forwards away from the plane of the chromene ring, whilst the C6, C7 and C8 methyl groups project backwards away from the plane of the ring. The molecular structure of nobiletin in this crystal was therefore chiral because of its conformational characteristics, despite the fact that nobiletin does not contain an asymmetric C atom. However, it was not possible to determine which enanti­omorph was responsible for this crystal based on the differences in the intensities of the Friedel pair reflections. This could be attributable to the scattering of the C and O atoms of the anomalous imaginary part being too small to be detected at the wavelength used for the data collection in this study [i.e. 0.7004 (1) Å]. The crystals grown from an ethyl acetate solution may therefore have been a mixture of two enanti­omorphic forms, as is often the case for the crystals of organic compounds (Koizumi et al., 2008).

The plane of best fit for the flavone ring of nobiletin forms an angle of 31° with the ab plane and is stacked along the c axis (Fig. 2). The distance between the planes of the flavone rings, as represented by the distance between atom C13 and atom C15 at (x, y, z+1), is 3.497 (7) Å. Table 2 shows details of the close inter­molecular contacts, which were less than the sum of the van der Waals radii, between the H atoms of the meth­oxy groups and the O atoms. The O2 atom of the carbonyl group, which is capable of forming a strong hydrogen bond as a hydrogen-bond acceptor, is in contact with atom H00E of the C22 methyl group. The distances between the C22—H22B···O2 and C22···O2 bonds are smaller than the average values reported for C—H···O and C···O contacts of methyl groups and carbonyl O atoms [2.761 (6) and 3.590 (7) Å, respectively; Steiner & Desiraju, 1998]. The C22—H22B···O2 angle is greater than 100°, which is the value needed for a C—H group to form a hydrogen-bonding inter­action (Jensen et al., 2003). The geometrical characteristics of this structure suggest that the C22—H22B···O2 contacts could possess a weak hydrogen-bonding characteristic. All of the other close contacts between the H and O atoms of the meth­oxy groups have C—H···O angles greater than 100°, which implies that these contacts also possess some hydrogen-bonding characteristics (Pingali et al., 2015). However, these hydrogen bonds are weaker than that of the C22—H22B···O2 hydrogen bond because a carbonyl O atom is a better hydrogen bond acceptor than a meth­oxy O atom.

Fig. 3 shows the superimposition of the molecular structure of nobiletin determined in this study (denoted NOB-1) on the molecular structure determined using the `crystalline sponge' method (denoted NOB-2). The O1—C2—C15—C16 torsion angle in NOB-2 is -172 (2)°, which shows that the benzene ring of the NOB-2 structure is almost flipped compared with that of the NOB-1 structure. Unlike the NOB-1 structure, the benzene and chromene rings of the NOB-2 structure are not coplanar and are distorted by approximately 8°. The other main difference between the two structures is the conformation of the meth­oxy groups bound to the chromene ring. The C20 methyl group in the NOB-1 structure extends towards the same side of the chromene ring as the C18 and C19 methyl groups, whereas the C20 methyl in the NOB-2 structure extends towards the opposite side of the ring. The superimposition of the two structures also suggests that it would not be possible to pack the NOB-1 structure into the cavities of the crystalline sponge in the same way as the NOB-2 structure because of the steric hindrance between the meth­oxy moieties of nobiletin and the sponge. Close contacts less than van der Waals distances were found between the C20 methyl group of the superimposed NOB1 structure and a pyridine ring of the sponge, and between the C21 methyl group of the NOB1 structure and an I atom bound to a Zn atom of the sponge. In solution, nobiletin may be in equilibrium with a variety of different conformers, which could differ, at least, in the conformation of the meth­oxy groups bound to the chromene ring and the torsion angle around the covalent bond between the chromene and benzene rings. The NOB1 and NOB2 structures may be involved in these conformers, with the former of these two structures crystalizing as single crystals and with the latter soaking and being bound into the sponge.

As mentioned above, nobiletin has been reported to elicit a wide range of physiological responses. The key steps in these physiological responses are presumed to involve the binding of nobiletin to the target receptor molecules responsible for each physiological response. Nobiletin could bind to a wide range of receptors based on its conformational variety.

Synthesis and crystallization

Nobiletin was synthesized according to a previously reported procedure and crystallized from aqueous methanol to give the desired material as fine needles (Asakawa et al., 2011). Nobiletin was dissolved in ethyl acetate and the resulting solution was filtered through a 0.45 µm membrane filter. A sample of the filtered solution (500 µl) was then poured into a Petri dish with a diameter of 15 mm. The solution was allowed to evaporate slowly at 298 K over a period of 2 d to give fine white crystals with a columnar shape. The crystals were analyzed by powder X-ray diffraction (PXRD) using a Rigaku Mini Flex II X-ray diffractometer. The PXRD pattern of the crystals prepared from ethyl acetate was identical to that of the crystals prepared from an aqueous methanol solution. This result confirmed that the crystal form of nobiletin had not changed through the recrystallization process.

Refinement details

Crystal data, data collection and structure refinement details are summarized in Table 1. The diffraction images indicated that the crystal used for the data collection process was a twin crystal made of two separate crystals, and that the c axes of the two crystals were almost parallel. Given that the diffraction spots from each crystal were well separated in the diffraction images, it was possible to collect diffraction data from one of the crystals that diffracted more than sinθ/λ = 0.625 Å^-1. During the refinement process, the H atoms were located in a difference Fourier map and were constrained as riding, with U_iso(H) = 1.2U_eq(C).

Computing details

Data collection: RAPID-AUTO (Rigaku, 2010); cell refinement: RAPID-AUTO (Rigaku, 2010); data reduction: RAPID-AUTO (Rigaku, 2010); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b) and shelXle (Hübschle et al., 2011); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: publCIF (Westrip, 2010).

Figures

	Fig. 1. The molecular structure of nobiletin, showing the atom-numbering scheme. C, H and O atoms are shown in grey, white and red, respectively. Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 2. The crystal packing of nobiletin. Close C—H···O contacts listed in Table 2 are shown in blue dotted lines.
	Fig. 3. Comparison of the different conformational structures of nobiletin. The non-H atoms of NOB1 and NOB2 are shown in red and green, respectively. The H atoms in both structures are shown in white. The crystal structure obtained by the sponge method contained a pair of enantiomers of nobiletin in the crystal lattice with the space group C2/c, and one of these enantiomers is shown in the figure.

2-(3,4-Dimethoxyphenyl)-5,6,7,8-tetramethoxy-4H-chromen-4-one

Crystal data

C21H22O8	Dx = 1.458 Mg m^−3
Mr = 402.38	Synchrotron (SPring-8 BL02B1) radiation, λ = 0.70041 Å
Orthorhombic, P212121	Cell parameters from 377 reflections
a = 19.3239 (17) Å	θ = 2.8–29.5°
b = 22.921 (2) Å	µ = 0.11 mm^−1
c = 4.1385 (4) Å	T = 100 K
V = 1833.0 (3) Å^3	Column, colourless
Z = 4	0.5 × 0.02 × 0.01 mm
F(000) = 848

Data collection

Rigaku Mercury2 CCD four-circle diffractometer	Rint = 0.043
ω scan	θmax = 29.6°, θmin = 1.4°
13177 measured reflections	h = −26→25
4894 independent reflections	k = −32→30
4091 reflections with I > 2σ(I)	l = −5→5

Refinement

Refinement on F^2	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F^2 > 2σ(F^2)] = 0.065	w = 1/[σ^2(Fo^2) + (0.1P)^2] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.192	(Δ/σ)max < 0.001
S = 1.29	Δρmax = 0.42 e Å^−3
4894 reflections	Δρmin = −0.29 e Å^−3
268 parameters	Absolute structure: An arbitrary choice of enantiomer has been made.
0 restraints

Special details

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O2	0.86158 (13)	0.29414 (11)	0.2767 (8)	0.0202 (6)
C2	0.70156 (19)	0.36216 (16)	0.4652 (10)	0.0159 (7)
O1	0.66854 (13)	0.32043 (11)	0.6357 (7)	0.0166 (6)
O3	0.85629 (13)	0.18115 (11)	0.5377 (7)	0.0165 (6)
C3	0.76441 (19)	0.35347 (16)	0.3380 (11)	0.0178 (8)
H3	0.7845	0.3837	0.2118	0.021*
O4	0.77681 (14)	0.10365 (12)	0.8750 (7)	0.0196 (6)
C4	0.80334 (18)	0.29972 (16)	0.3846 (10)	0.0157 (7)
C7	0.68406 (19)	0.17222 (16)	0.8978 (10)	0.0160 (7)
O7	0.49217 (13)	0.47574 (11)	0.7082 (8)	0.0213 (7)
O6	0.59535 (14)	0.24399 (13)	0.9566 (8)	0.0218 (6)
C6	0.7513 (2)	0.15775 (15)	0.7931 (10)	0.0164 (8)
O5	0.64380 (15)	0.13367 (12)	1.0635 (8)	0.0247 (7)
C5	0.79098 (18)	0.19812 (16)	0.6319 (10)	0.0154 (7)
C9	0.69935 (18)	0.26729 (15)	0.6807 (10)	0.0147 (7)
O8	0.53896 (14)	0.56400 (12)	0.4006 (8)	0.0220 (6)
C8	0.65893 (18)	0.22752 (17)	0.8452 (10)	0.0161 (8)
C10	0.76586 (18)	0.25431 (16)	0.5686 (10)	0.0143 (7)
C17	0.90960 (18)	0.20222 (16)	0.7489 (10)	0.0172 (8)
H17A	0.9536	0.1834	0.6937	0.021*
H17B	0.8975	0.1930	0.9731	0.021*
H17C	0.9141	0.2446	0.7240	0.021*
C11	0.66062 (19)	0.41593 (16)	0.4440 (10)	0.0164 (7)
C18	0.7924 (2)	0.06551 (17)	0.6135 (12)	0.0259 (9)
H18A	0.7526	0.0634	0.4673	0.031*
H18B	0.8027	0.0265	0.6977	0.031*
H18C	0.8327	0.0804	0.4956	0.031*
C12	0.59492 (19)	0.41848 (16)	0.5923 (10)	0.0169 (8)
H12	0.5775	0.3855	0.7054	0.020*
C19	0.6239 (2)	0.08263 (18)	0.8898 (14)	0.0314 (11)
H19A	0.6101	0.0935	0.6700	0.038*
H19B	0.5849	0.0639	0.9999	0.038*
H19C	0.6630	0.0555	0.8802	0.038*
C13	0.55586 (19)	0.46892 (16)	0.5732 (11)	0.0176 (8)
C20	0.5402 (2)	0.2274 (2)	0.7441 (13)	0.0325 (11)
H20A	0.5338	0.1850	0.7530	0.039*
H20B	0.5516	0.2390	0.5226	0.039*
H20C	0.4973	0.2467	0.8115	0.039*
C14	0.58174 (19)	0.51748 (16)	0.4071 (11)	0.0178 (8)
C15	0.64615 (19)	0.51500 (16)	0.2609 (10)	0.0179 (8)
H15	0.6635	0.5480	0.1478	0.021*
C16	0.68554 (19)	0.46417 (16)	0.2797 (11)	0.0183 (8)
H16	0.7297	0.4626	0.1793	0.022*
C21	0.4644 (2)	0.42762 (18)	0.8763 (12)	0.0229 (9)
H21A	0.4580	0.3950	0.7263	0.027*
H21B	0.4197	0.4385	0.9704	0.027*
H21C	0.4963	0.4160	1.0488	0.027*
C22	0.5608 (2)	0.61381 (17)	0.2152 (12)	0.0234 (9)
H22A	0.5690	0.6020	−0.0091	0.028*
H22B	0.6036	0.6296	0.3072	0.028*
H22C	0.5246	0.6438	0.2213	0.028*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O2	0.0153 (12)	0.0178 (12)	0.0276 (16)	0.0012 (10)	0.0076 (12)	0.0015 (12)
C2	0.0165 (16)	0.0169 (17)	0.0142 (18)	−0.0031 (14)	−0.0036 (15)	−0.0003 (14)
O1	0.0135 (11)	0.0127 (12)	0.0235 (15)	0.0001 (9)	0.0000 (11)	0.0013 (11)
O3	0.0160 (11)	0.0156 (12)	0.0181 (14)	0.0003 (10)	−0.0015 (11)	−0.0037 (11)
C3	0.0184 (17)	0.0144 (16)	0.020 (2)	0.0014 (14)	0.0019 (15)	0.0023 (16)
O4	0.0237 (13)	0.0166 (12)	0.0187 (15)	0.0024 (10)	−0.0003 (12)	0.0032 (11)
C4	0.0143 (15)	0.0151 (16)	0.0177 (19)	−0.0015 (13)	−0.0007 (15)	−0.0028 (15)
C7	0.0160 (15)	0.0181 (17)	0.0138 (18)	−0.0056 (13)	−0.0016 (15)	0.0018 (15)
O7	0.0149 (12)	0.0183 (13)	0.0306 (18)	0.0019 (10)	0.0031 (12)	0.0034 (13)
O6	0.0144 (12)	0.0283 (15)	0.0228 (16)	−0.0025 (11)	0.0022 (12)	−0.0031 (13)
C6	0.0188 (16)	0.0134 (16)	0.0169 (19)	0.0009 (13)	−0.0025 (15)	−0.0030 (15)
O5	0.0276 (14)	0.0228 (14)	0.0238 (17)	−0.0083 (12)	0.0021 (13)	0.0049 (13)
C5	0.0149 (15)	0.0163 (16)	0.0150 (18)	−0.0011 (13)	−0.0029 (15)	−0.0030 (15)
C9	0.0156 (16)	0.0125 (16)	0.0161 (18)	−0.0012 (13)	−0.0056 (14)	−0.0008 (14)
O8	0.0188 (12)	0.0181 (13)	0.0290 (17)	0.0040 (10)	0.0027 (12)	0.0030 (13)
C8	0.0101 (14)	0.0251 (19)	0.0132 (18)	−0.0014 (13)	−0.0010 (14)	−0.0018 (15)
C10	0.0138 (15)	0.0156 (16)	0.0136 (18)	−0.0020 (13)	−0.0012 (14)	−0.0026 (14)
C17	0.0123 (15)	0.0190 (17)	0.020 (2)	0.0041 (13)	−0.0013 (15)	0.0005 (16)
C11	0.0147 (15)	0.0156 (17)	0.0188 (19)	−0.0003 (13)	−0.0019 (15)	−0.0031 (15)
C18	0.033 (2)	0.0142 (17)	0.030 (2)	0.0000 (16)	0.001 (2)	−0.0003 (17)
C12	0.0165 (16)	0.0162 (17)	0.018 (2)	−0.0010 (13)	−0.0003 (15)	0.0001 (16)
C19	0.027 (2)	0.0213 (19)	0.046 (3)	−0.0099 (16)	0.001 (2)	0.002 (2)
C13	0.0131 (15)	0.0188 (17)	0.021 (2)	−0.0019 (13)	−0.0032 (15)	−0.0008 (16)
C20	0.0175 (19)	0.056 (3)	0.024 (2)	0.0059 (19)	−0.0008 (18)	−0.002 (2)
C14	0.0195 (16)	0.0157 (17)	0.018 (2)	−0.0006 (13)	−0.0058 (16)	0.0002 (16)
C15	0.0178 (16)	0.0135 (16)	0.022 (2)	−0.0006 (13)	0.0010 (16)	0.0003 (16)
C16	0.0127 (15)	0.0189 (18)	0.023 (2)	−0.0013 (13)	−0.0009 (15)	0.0001 (16)
C21	0.0199 (17)	0.025 (2)	0.024 (2)	−0.0033 (15)	0.0063 (17)	0.0017 (18)
C22	0.0254 (19)	0.0159 (17)	0.029 (2)	0.0043 (15)	−0.0011 (18)	0.0020 (17)

Geometric parameters (Å, º)

O2—C4	1.217 (4)	C17—H17B	0.9800
C2—C3	1.339 (5)	C17—H17C	0.9800
C2—O1	1.349 (4)	C11—C16	1.384 (5)
C2—C11	1.467 (5)	C11—C12	1.411 (5)
O1—C9	1.368 (4)	C18—H18A	0.9800
O3—C5	1.377 (4)	C18—H18B	0.9800
O3—C17	1.435 (5)	C18—H18C	0.9800
C3—C4	1.456 (5)	C12—C13	1.383 (5)
C3—H3	0.9500	C12—H12	0.9500
O4—C6	1.376 (4)	C19—H19A	0.9800
O4—C18	1.424 (5)	C19—H19B	0.9800
C4—C10	1.479 (5)	C19—H19C	0.9800
C7—O5	1.362 (5)	C13—C14	1.401 (5)
C7—C8	1.375 (5)	C20—H20A	0.9800
C7—C6	1.410 (5)	C20—H20B	0.9800
O7—C13	1.361 (4)	C20—H20C	0.9800
O7—C21	1.410 (5)	C14—C15	1.385 (5)
O6—C8	1.365 (4)	C15—C16	1.394 (5)
O6—C20	1.434 (5)	C15—H15	0.9500
C6—C5	1.374 (5)	C16—H16	0.9500
O5—C19	1.426 (5)	C21—H21A	0.9800
C5—C10	1.401 (5)	C21—H21B	0.9800
C9—C8	1.380 (5)	C21—H21C	0.9800
C9—C10	1.398 (5)	C22—H22A	0.9800
O8—C14	1.349 (4)	C22—H22B	0.9800
O8—C22	1.439 (5)	C22—H22C	0.9800
C17—H17A	0.9800
C3—C2—O1	122.0 (3)	O4—C18—H18B	109.5
C3—C2—C11	126.2 (4)	H18A—C18—H18B	109.5
O1—C2—C11	111.8 (3)	O4—C18—H18C	109.5
C2—O1—C9	119.8 (3)	H18A—C18—H18C	109.5
C5—O3—C17	113.0 (3)	H18B—C18—H18C	109.5
C2—C3—C4	122.8 (4)	C13—C12—C11	120.0 (3)
C2—C3—H3	118.6	C13—C12—H12	120.0
C4—C3—H3	118.6	C11—C12—H12	120.0
C6—O4—C18	116.2 (3)	O5—C19—H19A	109.5
O2—C4—C3	121.2 (3)	O5—C19—H19B	109.5
O2—C4—C10	124.6 (3)	H19A—C19—H19B	109.5
C3—C4—C10	114.2 (3)	O5—C19—H19C	109.5
O5—C7—C8	118.4 (3)	H19A—C19—H19C	109.5
O5—C7—C6	121.9 (3)	H19B—C19—H19C	109.5
C8—C7—C6	119.6 (3)	O7—C13—C12	124.5 (3)
C13—O7—C21	117.2 (3)	O7—C13—C14	115.7 (3)
C8—O6—C20	112.9 (3)	C12—C13—C14	119.8 (3)
C5—C6—O4	121.8 (3)	O6—C20—H20A	109.5
C5—C6—C7	120.3 (3)	O6—C20—H20B	109.5
O4—C6—C7	117.8 (3)	H20A—C20—H20B	109.5
C7—O5—C19	115.6 (3)	O6—C20—H20C	109.5
C6—C5—O3	117.3 (3)	H20A—C20—H20C	109.5
C6—C5—C10	121.1 (3)	H20B—C20—H20C	109.5
O3—C5—C10	121.6 (3)	O8—C14—C15	125.1 (4)
O1—C9—C8	114.1 (3)	O8—C14—C13	114.8 (3)
O1—C9—C10	123.0 (3)	C15—C14—C13	120.2 (3)
C8—C9—C10	122.9 (3)	C14—C15—C16	120.0 (4)
C14—O8—C22	117.3 (3)	C14—C15—H15	120.0
O6—C8—C7	121.3 (3)	C16—C15—H15	120.0
O6—C8—C9	119.6 (3)	C11—C16—C15	120.3 (3)
C7—C8—C9	119.2 (3)	C11—C16—H16	119.8
C9—C10—C5	116.9 (3)	C15—C16—H16	119.8
C9—C10—C4	118.1 (3)	O7—C21—H21A	109.5
C5—C10—C4	125.0 (3)	O7—C21—H21B	109.5
O3—C17—H17A	109.5	H21A—C21—H21B	109.5
O3—C17—H17B	109.5	O7—C21—H21C	109.5
H17A—C17—H17B	109.5	H21A—C21—H21C	109.5
O3—C17—H17C	109.5	H21B—C21—H21C	109.5
H17A—C17—H17C	109.5	O8—C22—H22A	109.5
H17B—C17—H17C	109.5	O8—C22—H22B	109.5
C16—C11—C12	119.6 (3)	H22A—C22—H22B	109.5
C16—C11—C2	120.8 (3)	O8—C22—H22C	109.5
C12—C11—C2	119.6 (3)	H22A—C22—H22C	109.5
O4—C18—H18A	109.5	H22B—C22—H22C	109.5