Curcumin and derivatives

The title compound, 4-[7-(4-acetoxy-3-methoxy­phenyl)-5-hydroxy-3-oxohepta-1,4,6-trienyl]-2-methoxy­phenyl acetate [or bis­(acetoxy)curcumin, C₂₅H₂₄O₈], is shown unequivocally to exist in the keto-enol form, with only intramolecular hydrogen bonding. A redetermination of the structure of curcumin itself confirms the results of a previous report that it also exists in the keto-enol form.

S1. Comment

The active yellow pigment in turmeric, a popular spice and coloring agent for cosmetics and pharmaceuticals, is curcumin [often named diferuloylmethane or sometimes 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, (IIa)]. Recently, curcumin has attracted considerable interest because of its demonstrated ability to act as a cancer chemopreventive agent (Leu & Maa, 2002; Surh, 2003; Conney, 2003). It has also been found to inhibit the cytochrome P450-dependent activation of aflatoxin B₁ (Lee et al., 2001), to be an irreversible inhibitor of aminopeptidase N (CD13) (Shim et al., 2003), to inhibit the MRP1 and MRP2 efflux transporters (Wortelboer et al., 2003) and to correct cystic fibrosis defects in a mouse model (Egan et al., 2004). We have been investigating derivatives of curcumin as cancer chemoprotective agents and report here the structure of the bis(acetoxy) derivative (I).

A perspective view of (I) is given in Fig. 1, which, together with the data in Table 1, clearly indicates that (I) exists in the keto–enol form in the crystal structure. Difference maps calculated in the latter stages of refinement show the two largest peaks to be in appropriate positions to correspond to one H atom on C13 and an H atom on O5. A smaller peak near O4 suggests that the enol hydrogen is disordered between O4 and O5 as has also been found for curcumin itself (see below). Although these are included as riding contributions in the subsequent refinement, it is abundantly clear that there is only one hydrogen atom attached to C13 and that there is also clearly an adjacent hydroxyl group. Further evidence for the formulation of (I) in the keto–enol form comes from the fact (Table 1) that the C12—O4 distance is significantly shorter than the C14—O5 distance (Δ/σ = 8.8) and the C12—C13 distance is significantly longer than the C13—C14 distance (Δ/σ = 8). The aliphatic chain (C10–C16) is largely untwisted, as indicated by the relevant torsion angles (Table 1), while the benzene rings are inclined to a modest extent with respect to the the average plane of this unit. The conformation of the aliphatic chain is determined in part by the existence of a strong intramolecular hydrogen bond between the hydroxyl and keto groups (H5O and O4 (major component) or H4O and O5 (minor component), Table 2). The acetoxy groups are significantly twisted with respect to the mean planes of the benzene rings.

In a review of molecular mechanisms for the antitumorigenic effect of curcumin (Leu & Maa, 2002), its structure is explicitly described in terms of the β-diketone, (IIa), and keto–enol, (IIb), tautomers, recognizing that, with curcumin as well as with (I), the keto–enol form is of potential importance to the solution reactivity of curcumin. Indeed, a determination of the structure of curcumin (Tonnesen et al., 1982) found it to be (IIb), although the keto and enol groups were disordered. We have redetermined the structure of curcumin using a sample of commercial material (Fluka 28260) recrystallized from ethanol (Mague et al., 2004) and find, apart from that fact that our crystals are bright yellow while those used by Tonnesen et al. (1982) were reported to be dark red, an identical structure. As with (I), a difference map calculated with all atoms except the two H atoms associated with the keto–enol unit included showed unequivocally that there is only one H atom attached to the central C atom and that the other is disordered between the two O atoms. It thus seems clear that, at least in the solid state, curcumin and its bis(acetoxy) derivative exist wholly in the keto–enol form. Despite structural evidence dating from 1982 that the keto–enol tautomer is of importance, and two papers explicitly describing curcumin and derivatives in this form (Leu & Maa, 2002; Ireson et al., 2002), many current discussions of curcumin (Surh, 2003; Conney, 2003; Lee et al., 2001), as well as the drawings provided by the Cambridge Structural Database [(Allen, 2002); refcode BINMEQ for the Tonnesen et al. (1982) structure and refcode BINMEQ01 for a subsequent redetermination (Ishigami et al., 1999)], have shown it solely as the β-diketone tautomer. This extends to two highlight news stories on useful biological activities of curcumin (Dalton, 2003; Halford, 2004). We consider it particularly important to emphasize that, as illustrated by the structures of (I) and (II), curcumin tends to exist in the tautomeric keto–enol form. Thus, investigators studying molecular mechanisms responsible for the varied biological effects of curcumin and its derivatives or those modeling their interactions with proteins should be aware of this property since this structural feature may be involved in the action of curcumin as an inhibitor of the Zn-dependent aminopeptidase N (CD13; Shim et al., 2003) and/or its ability to correct cyctic fibrosis defects, perhaps by reducing the effective concentration of calcium ion in the lumen of the endoplastic reticulum (Egan et al., 2004).

S2. Experimental

Compound (I) was prepared according to a literature method (Gomes & Vilela, 2002) and recrystallized from chloroform/hexane. The product was characterized by comparison of its ¹H NMR and IR spectra with those in the literature.

S3. Refinement

H-atoms were placed in calculated positions (C—H = 0.95 − 0.99 Å) except for the disordered hydroxyl hydrogen (H4O, H5O) whose alternate locations were those derived from a difference map. All were included as riding contributions with isotropic displacement parameters 1.2 − 1.5 times those of the attached atoms. The absolute structure could not be determined reliably and Friedel opposites were averaged.

Computing details

Data collection: SMART (Bruker, 2000); cell refinement: SMART; data reduction: SAINT-Plus (Bruker, 2004); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL (Bruker, 2000); software used to prepare material for publication: SHELXTL.

Figures

Fig. 1. A perspective view of (I). Displacement ellipsoids are drawn at the 50% probability level and H atoms are drawn arbitrarily small.

4-[7-(4-Acetoxy-3-methoxyphenyl)-5-hydroxy-3-oxohepta-1,4,6-trienyl]-2- methoxyphenyl acetate

Crystal data

C25H24O8	F(000) = 476
Mr = 452.44	Dx = 1.357 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2yb	Cell parameters from 4191 reflections
a = 8.841 (2) Å	θ = 2.3–28.3°
b = 7.746 (1) Å	µ = 0.10 mm^−1
c = 16.326 (3) Å	T = 100 K
β = 98.092 (2)°	Plate, yellow
V = 1106.9 (4) Å^3	0.22 × 0.19 × 0.05 mm
Z = 2

Data collection

Bruker SMART APEX CCD area-detector diffractometer	2794 independent reflections
Radiation source: fine-focus sealed tube	2222 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.051
ϕ and ω scans	θmax = 27.9°, θmin = 1.3°
Absorption correction: multi-scan (SADABS; Sheldrick, 2002)	h = −11→11
Tmin = 0.948, Tmax = 0.995	k = −10→9
9606 measured reflections	l = −21→21

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)] = 0.046	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.113	H-atom parameters constrained
S = 1.03	w = 1/[σ^2(Fo^2) + (0.0576P)^2] where P = (Fo^2 + 2Fc^2)/3
2794 reflections	(Δ/σ)max < 0.001
304 parameters	Δρmax = 0.22 e Å^−3
1 restraint	Δρmin = −0.24 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	Occ. (<1)
O1	1.7999 (3)	0.6181 (4)	0.95585 (17)	0.0589 (7)
O2	1.6779 (2)	0.8235 (3)	0.87438 (12)	0.0344 (5)
O3	1.5224 (2)	0.7804 (3)	1.00457 (12)	0.0383 (5)
O4	0.8249 (2)	0.2979 (3)	0.80510 (12)	0.0404 (6)
H4O	0.7384	0.2615	0.7916	0.061*	0.37 (5)
O5	0.5708 (2)	0.2440 (3)	0.71494 (12)	0.0369 (5)
H5O	0.6430	0.2221	0.7527	0.055*	0.63 (5)
O6	−0.1248 (2)	0.2651 (4)	0.39979 (13)	0.0574 (8)
O7	−0.0244 (2)	0.4085 (3)	0.26887 (12)	0.0354 (5)
O8	−0.1160 (3)	0.6337 (4)	0.33415 (14)	0.0532 (7)
C1	1.9343 (3)	0.8779 (6)	0.9272 (2)	0.0449 (9)
H1A	2.0010	0.8620	0.9799	0.067*
H1B	1.8967	0.9970	0.9232	0.067*
H1C	1.9919	0.8543	0.8814	0.067*
C2	1.8025 (3)	0.7570 (5)	0.92287 (19)	0.0356 (7)
C3	1.5414 (3)	0.7294 (4)	0.86546 (17)	0.0294 (6)
C4	1.4580 (3)	0.7121 (4)	0.93153 (16)	0.0277 (6)
C5	1.3174 (3)	0.6293 (4)	0.91803 (17)	0.0290 (6)
H5	1.2608	0.6143	0.9628	0.035*
C6	1.2577 (3)	0.5674 (4)	0.83963 (17)	0.0277 (6)
C7	1.3427 (3)	0.5858 (4)	0.77447 (17)	0.0328 (7)
H7	1.3038	0.5435	0.7210	0.039*
C8	1.4852 (3)	0.6668 (4)	0.78802 (17)	0.0324 (7)
H8	1.5437	0.6787	0.7438	0.039*
C9	1.4364 (3)	0.7679 (5)	1.07217 (17)	0.0376 (7)
H9A	1.3368	0.8236	1.0571	0.056*
H9B	1.4920	0.8255	1.1207	0.056*
H9C	1.4213	0.6460	1.0850	0.056*
C10	1.1054 (3)	0.4876 (4)	0.82861 (18)	0.0312 (7)
H10	1.0692	0.4427	0.8764	0.037*
C11	1.0145 (3)	0.4735 (4)	0.75673 (18)	0.0330 (7)
H11	1.0493	0.5197	0.7088	0.040*
C12	0.8636 (3)	0.3908 (5)	0.74705 (17)	0.0334 (7)
C13	0.7635 (3)	0.4175 (5)	0.67279 (18)	0.0345 (7)
H13	0.7950	0.4897	0.6313	0.041*
C14	0.6206 (3)	0.3411 (4)	0.65902 (18)	0.0317 (7)
C15	0.5217 (3)	0.3657 (5)	0.58061 (18)	0.0351 (7)
H15	0.5560	0.4410	0.5412	0.042*
C16	0.3870 (3)	0.2898 (5)	0.56064 (17)	0.0345 (7)
H16	0.3531	0.2153	0.6006	0.041*
C17	0.2855 (3)	0.3117 (5)	0.48149 (18)	0.0349 (7)
C18	0.1306 (3)	0.2681 (5)	0.47871 (17)	0.0393 (8)
H18	0.0963	0.2163	0.5255	0.047*
C19	0.0275 (3)	0.3002 (5)	0.40827 (17)	0.0371 (7)
C20	0.0796 (3)	0.3764 (5)	0.34048 (17)	0.0344 (7)
C21	0.2311 (3)	0.4133 (5)	0.34066 (18)	0.0348 (7)
H21	0.2652	0.4605	0.2928	0.042*
C22	0.3350 (3)	0.3813 (5)	0.41129 (17)	0.0341 (7)
H22	0.4401	0.4072	0.4116	0.041*
C23	−0.1892 (3)	0.2297 (7)	0.4687 (2)	0.0578 (11)
H23A	−0.1479	0.1209	0.4930	0.087*
H23B	−0.3001	0.2195	0.4539	0.087*
H23C	−0.1659	0.3232	0.5089	0.087*
C24	−0.1231 (3)	0.5426 (5)	0.27468 (18)	0.0358 (7)
C25	−0.2348 (4)	0.5595 (5)	0.19709 (18)	0.0399 (8)
H25A	−0.3214	0.6306	0.2081	0.060*
H25B	−0.2715	0.4447	0.1784	0.060*
H25C	−0.1845	0.6142	0.1540	0.060*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0294 (12)	0.0589 (18)	0.0836 (19)	0.0047 (12)	−0.0089 (12)	0.0105 (16)
O2	0.0221 (9)	0.0426 (13)	0.0376 (11)	−0.0028 (9)	0.0009 (8)	0.0000 (10)
O3	0.0299 (10)	0.0511 (14)	0.0331 (10)	−0.0066 (10)	0.0018 (8)	−0.0077 (11)
O4	0.0296 (10)	0.0571 (16)	0.0318 (11)	−0.0085 (11)	−0.0051 (8)	0.0015 (11)
O5	0.0252 (9)	0.0519 (15)	0.0324 (11)	−0.0002 (10)	−0.0004 (8)	0.0003 (11)
O6	0.0252 (10)	0.111 (2)	0.0340 (11)	−0.0200 (14)	−0.0035 (8)	0.0078 (15)
O7	0.0304 (10)	0.0474 (13)	0.0265 (10)	0.0025 (10)	−0.0030 (8)	−0.0019 (10)
O8	0.0460 (13)	0.0744 (19)	0.0367 (13)	0.0137 (13)	−0.0027 (10)	−0.0167 (13)
C1	0.0251 (14)	0.065 (2)	0.0454 (18)	−0.0069 (16)	0.0067 (13)	−0.0092 (18)
C2	0.0244 (13)	0.043 (2)	0.0398 (16)	0.0018 (14)	0.0042 (12)	−0.0048 (15)
C3	0.0175 (12)	0.0360 (18)	0.0334 (15)	0.0010 (12)	−0.0005 (10)	−0.0006 (13)
C4	0.0210 (12)	0.0329 (16)	0.0265 (14)	0.0026 (12)	−0.0059 (10)	−0.0010 (12)
C5	0.0202 (12)	0.0371 (17)	0.0283 (14)	0.0024 (12)	−0.0010 (10)	0.0006 (13)
C6	0.0190 (12)	0.0314 (16)	0.0309 (15)	0.0046 (11)	−0.0031 (10)	0.0001 (12)
C7	0.0263 (14)	0.0416 (19)	0.0283 (14)	0.0036 (13)	−0.0034 (11)	−0.0055 (14)
C8	0.0255 (14)	0.0424 (19)	0.0298 (15)	0.0030 (13)	0.0055 (11)	0.0039 (13)
C9	0.0385 (16)	0.0442 (19)	0.0296 (15)	−0.0067 (15)	0.0029 (12)	−0.0021 (14)
C10	0.0235 (13)	0.0363 (17)	0.0324 (15)	0.0029 (12)	−0.0008 (11)	−0.0013 (13)
C11	0.0227 (13)	0.0400 (18)	0.0348 (16)	−0.0022 (13)	−0.0018 (12)	−0.0014 (14)
C12	0.0263 (14)	0.0416 (19)	0.0311 (15)	−0.0016 (13)	0.0000 (11)	−0.0039 (14)
C13	0.0223 (13)	0.0472 (19)	0.0319 (15)	−0.0043 (13)	−0.0030 (11)	−0.0006 (14)
C14	0.0225 (13)	0.0377 (18)	0.0331 (15)	0.0019 (13)	−0.0026 (11)	−0.0043 (13)
C15	0.0252 (14)	0.0461 (19)	0.0325 (15)	−0.0039 (14)	−0.0008 (11)	−0.0015 (14)
C16	0.0259 (13)	0.0450 (18)	0.0306 (14)	−0.0022 (14)	−0.0034 (11)	0.0007 (14)
C17	0.0214 (13)	0.0493 (19)	0.0324 (15)	−0.0036 (13)	−0.0022 (11)	−0.0051 (15)
C18	0.0291 (14)	0.061 (2)	0.0259 (14)	−0.0112 (15)	−0.0013 (11)	0.0060 (16)
C19	0.0234 (13)	0.057 (2)	0.0296 (15)	−0.0118 (14)	−0.0014 (11)	−0.0059 (15)
C20	0.0284 (14)	0.049 (2)	0.0235 (13)	−0.0004 (14)	−0.0036 (11)	−0.0023 (14)
C21	0.0314 (15)	0.0439 (18)	0.0286 (14)	−0.0024 (14)	0.0032 (12)	−0.0012 (14)
C22	0.0227 (13)	0.0441 (19)	0.0346 (15)	−0.0037 (13)	0.0014 (11)	−0.0040 (14)
C23	0.0281 (15)	0.094 (3)	0.052 (2)	−0.0125 (19)	0.0052 (14)	0.014 (2)
C24	0.0266 (14)	0.0468 (19)	0.0333 (16)	−0.0029 (14)	0.0023 (12)	−0.0044 (15)
C25	0.0359 (16)	0.042 (2)	0.0387 (17)	0.0010 (15)	−0.0063 (13)	−0.0003 (15)

Geometric parameters (Å, º)

O1—C2	1.204 (4)	C9—H9C	0.9800
O2—C2	1.364 (4)	C10—C11	1.330 (4)
O2—C3	1.399 (3)	C10—H10	0.9500
O3—C4	1.354 (3)	C11—C12	1.469 (4)
O3—C9	1.429 (3)	C11—H11	0.9500
O4—C12	1.274 (4)	C12—C13	1.412 (4)
O4—H4O	0.8160	C13—C14	1.384 (4)
O5—C14	1.306 (3)	C13—H13	0.9500
O5—H5O	0.8400	C14—C15	1.457 (4)
O6—C23	1.359 (4)	C15—C16	1.327 (4)
O6—C19	1.361 (3)	C15—H15	0.9500
O7—C24	1.368 (4)	C16—C17	1.475 (4)
O7—C20	1.404 (3)	C16—H16	0.9500
O8—C24	1.195 (4)	C17—C22	1.392 (4)
C1—C2	1.489 (5)	C17—C18	1.405 (4)
C1—H1A	0.9800	C18—C19	1.386 (4)
C1—H1B	0.9800	C18—H18	0.9500
C1—H1C	0.9800	C19—C20	1.389 (4)
C3—C8	1.380 (4)	C20—C21	1.369 (4)
C3—C4	1.396 (4)	C21—C22	1.392 (4)
C4—C5	1.388 (4)	C21—H21	0.9500
C5—C6	1.399 (4)	C22—H22	0.9500
C5—H5	0.9500	C23—H23A	0.9800
C6—C7	1.393 (4)	C23—H23B	0.9800
C6—C10	1.469 (4)	C23—H23C	0.9800
C7—C8	1.397 (4)	C24—C25	1.498 (4)
C7—H7	0.9500	C25—H25A	0.9800
C8—H8	0.9500	C25—H25B	0.9800
C9—H9A	0.9800	C25—H25C	0.9800
C9—H9B	0.9800
C2—O2—C3	118.6 (2)	C13—C12—C11	118.6 (3)
C4—O3—C9	116.8 (2)	C14—C13—C12	121.6 (3)
C12—O4—H4O	109.4	C14—C13—H13	119.2
C14—O5—H5O	109.5	C12—C13—H13	119.2
C23—O6—C19	118.7 (2)	O5—C14—C13	121.5 (3)
C24—O7—C20	115.2 (2)	O5—C14—C15	118.0 (2)
C2—C1—H1A	109.5	C13—C14—C15	120.5 (3)
C2—C1—H1B	109.5	C16—C15—C14	124.4 (3)
H1A—C1—H1B	109.5	C16—C15—H15	117.8
C2—C1—H1C	109.5	C14—C15—H15	117.8
H1A—C1—H1C	109.5	C15—C16—C17	125.3 (3)
H1B—C1—H1C	109.5	C15—C16—H16	117.3
O1—C2—O2	122.1 (3)	C17—C16—H16	117.3
O1—C2—C1	127.2 (3)	C22—C17—C18	119.0 (3)
O2—C2—C1	110.7 (3)	C22—C17—C16	122.9 (2)
C8—C3—C4	120.9 (2)	C18—C17—C16	118.1 (3)
C8—C3—O2	118.2 (2)	C19—C18—C17	120.6 (3)
C4—C3—O2	120.7 (2)	C19—C18—H18	119.7
O3—C4—C5	125.2 (2)	C17—C18—H18	119.7
O3—C4—C3	116.1 (2)	O6—C19—C18	125.1 (3)
C5—C4—C3	118.7 (2)	O6—C19—C20	116.0 (2)
C4—C5—C6	121.2 (3)	C18—C19—C20	118.9 (2)
C4—C5—H5	119.4	C21—C20—C19	121.4 (3)
C6—C5—H5	119.4	C21—C20—O7	119.4 (3)
C7—C6—C5	119.3 (3)	C19—C20—O7	119.2 (2)
C7—C6—C10	122.2 (3)	C20—C21—C22	119.7 (3)
C5—C6—C10	118.5 (3)	C20—C21—H21	120.1
C6—C7—C8	119.8 (3)	C22—C21—H21	120.1
C6—C7—H7	120.1	C21—C22—C17	120.3 (3)
C8—C7—H7	120.1	C21—C22—H22	119.9
C3—C8—C7	120.2 (3)	C17—C22—H22	119.9
C3—C8—H8	119.9	O6—C23—H23A	109.5
C7—C8—H8	119.9	O6—C23—H23B	109.5
O3—C9—H9A	109.5	H23A—C23—H23B	109.5
O3—C9—H9B	109.5	O6—C23—H23C	109.5
H9A—C9—H9B	109.5	H23A—C23—H23C	109.5
O3—C9—H9C	109.5	H23B—C23—H23C	109.5
H9A—C9—H9C	109.5	O8—C24—O7	122.9 (3)
H9B—C9—H9C	109.5	O8—C24—C25	126.1 (3)
C11—C10—C6	124.9 (3)	O7—C24—C25	111.0 (3)
C11—C10—H10	117.6	C24—C25—H25A	109.5
C6—C10—H10	117.6	C24—C25—H25B	109.5
C10—C11—C12	123.9 (3)	H25A—C25—H25B	109.5
C10—C11—H11	118.0	C24—C25—H25C	109.5
C12—C11—H11	118.0	H25A—C25—H25C	109.5
O4—C12—C13	121.4 (3)	H25B—C25—H25C	109.5
O4—C12—C11	120.1 (2)
C3—O2—C2—O1	2.4 (4)	C12—C13—C14—O5	1.6 (5)
C3—O2—C2—C1	−177.9 (2)	C12—C13—C14—C15	−177.7 (3)
C2—O2—C3—C8	−115.3 (3)	O5—C14—C15—C16	−3.1 (5)
C2—O2—C3—C4	70.1 (4)	C13—C14—C15—C16	176.2 (3)
C9—O3—C4—C5	−1.2 (4)	C14—C15—C16—C17	−179.5 (3)
C9—O3—C4—C3	178.3 (3)	C15—C16—C17—C22	16.0 (6)
C8—C3—C4—O3	−179.0 (3)	C15—C16—C17—C18	−160.7 (4)
O2—C3—C4—O3	−4.5 (4)	C22—C17—C18—C19	−2.5 (5)
C8—C3—C4—C5	0.5 (4)	C16—C17—C18—C19	174.3 (3)
O2—C3—C4—C5	175.0 (3)	C23—O6—C19—C18	14.4 (6)
O3—C4—C5—C6	177.9 (3)	C23—O6—C19—C20	−164.5 (4)
C3—C4—C5—C6	−1.5 (4)	C17—C18—C19—O6	−179.1 (4)
C4—C5—C6—C7	1.5 (4)	C17—C18—C19—C20	−0.1 (5)
C4—C5—C6—C10	−177.4 (3)	O6—C19—C20—C21	−178.1 (3)
C5—C6—C7—C8	−0.6 (4)	C18—C19—C20—C21	2.9 (5)
C10—C6—C7—C8	178.4 (3)	O6—C19—C20—O7	−1.2 (5)
C4—C3—C8—C7	0.5 (5)	C18—C19—C20—O7	179.8 (3)
O2—C3—C8—C7	−174.2 (3)	C24—O7—C20—C21	−109.7 (4)
C6—C7—C8—C3	−0.4 (5)	C24—O7—C20—C19	73.3 (4)
C7—C6—C10—C11	−21.5 (5)	C19—C20—C21—C22	−2.9 (5)
C5—C6—C10—C11	157.5 (3)	O7—C20—C21—C22	−179.8 (3)
C6—C10—C11—C12	179.0 (3)	C20—C21—C22—C17	0.2 (5)
C10—C11—C12—O4	−13.9 (5)	C18—C17—C22—C21	2.5 (5)
C10—C11—C12—C13	165.7 (3)	C16—C17—C22—C21	−174.2 (3)
O4—C12—C13—C14	−1.5 (5)	C20—O7—C24—O8	4.7 (4)
C11—C12—C13—C14	178.9 (3)	C20—O7—C24—C25	−176.7 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O4—H4O···O5	0.82	1.80	2.541 (3)	149
O5—H5O···O4	0.84	1.81	2.541 (3)	145