Towards validating new enzymatic routes for synthetic conversion: 7,10-bis-O-(2,2,2-tri­chloro­eth­oxy­carbon­yl)-10-deacetyl baccatin III-ethyl acetate-water (1/1/1)

The title compound, C₃₄H₃₈Cl₆O₁₄·C₄H₈O₂·H₂O, prepared by the reaction of 10-deacetyl baccatin III with 2,2,2-tri­chloro­ethyl chloro­formate in pyridine, crystallizes via strong inter­molecular hydrogen bonds and noncovalent inter­actions between 7,10-bis-O-(2,2,2-tri­chloro­eth­oxy­carbon­yl)-10-de­ace­tyl baccatin III (7,10-di-Troc-DAB), water and ethyl acetate. A detailed comparison of the molecular conformation with those of related structures is presented.

S1. Introduction

Many natural products have been isolated and found to be effective in the treatment of cancer through chemotherapy. One important member of this class of natural anti­cancer agents is pacilitaxel, or Taxol. Taxol promotes the assembly of tubulin into stable microtubules and is therefore effective as an anti­mitotic drug. Baccatin III was isolated from the Pacific yew tree, Taxus brevifolia, and is a precursor to pacilitaxel. Taxol has an extremely complex structure and therefore its efficient synthesis continues to be of current inter­est. Over the past decade, researchers have reported the cloning and expression of 10-de­acetyl­baccatin III–10-O-acetyl­transferase (Walker & Croteau, 2000). Confirmation of the structure, conformation,and stereochemistry of baccatin III derivatives is important for fostering new synthetic approaches and validating new enzymatic routes for synthetic conversion. We report herein the structure of one such derivative namely 7,10-bis-O-(2,2,2-tri­chloro­eth­oxy­carbonyl)-10-de­acetyl baccatin III (7,10-di-Troc-DAB)–ethyl acetate–water (1/1/1), (I).

The taxane diterpenoids have attracted the attention of synthetic and medicinal chemists due to their unique structures and significant biological activities in relation to similar classes of compounds during the past 50 years. To date, more than 400 natural taxanes and hundreds of synthetic analogues have been discovered (Appendino, 1995; Ojima et al., 2005). Taxol and docetaxel, the most notable of the taxane diterpenoids, are two of the most widely used drugs in the fight against cancer among a variety of chemotherapeutic agents. Taxol was first isolated from Taxus brevifolia by Wani et al. (1971), who established its structure by chemical and X-ray crystallographic methods, but full details of the X-ray analysis were never published. However, docetaxel is a semisynthetic taxoid and its absolute configuration was established by X-ray analysis (Gueritte-Voegelein et al. 1990). 10-De­acetyl­baccatin III, the diterpenoid nucleus of taxol and docetaxel and a more readily available taxane diterpenoid precursor, can be isolated from the needles of Taxus baccata. It should be noted that this is a regenerable source, and harvest does not threaten the survival of the species (Denis et al., 1988). Ho et al. (1987) reported the crystal structures of baccatin analogues Taxusin and Taxusin derivatives. In 1992, the structure elucidation and a study of the reactivity of 14β-hy­droxy-10-de­acetyl­baccatin III were presented (Appendino et al., 1992). Structural modifications of naturally occurring bioactive substances by microbial transformations in a way [not] possible by conventional chemical methods are an important area of natural product chemistry. In our studies, a crystal of 7,10-bis-O-(2,2,2-tri­chloro­eth­oxy­carbonyl)-10-de­acetyl baccatin III (7,10-di-Troc-DAB)–ethyl acetate–water (1/1/1), (I), suitable for X-ray diffraction analysis was obtained and its structure elucidated.

S2. Experimental

S2.1. Synthesis and crystallization

Under a nitro­gen atmosphere, a solution of 10-de­acetyl­baccatin III (1.01 g, 2.0 mmol) in dry pyridine (18 ml) was heated at 353 K and 2,2,2-tri­chloro­ethyl chloro­formate (0.777 g, 3.68 mmol) was added dropwise. After 25 min, the flask was removed from the oil bath and the reaction quenched by the careful addition of a few drops of methanol and pieces of ice [OK or "few drops of ice-cold methanol"?]. The reaction mixture was extracted with CH₂Cl₂, and the organic phase was washed with dilute HCl and brine. After drying (MgSO₄) and removal of the solvent, a semi-solid residue was obtained, which was dissolved in ethyl acetate and recrystalized. 7,10-di-Troc-DAB was obtained as white crystals (yield 1.18 g, 72%) suitable for X-ray analysis.

S2.2. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1. All H atoms were placed in idealized positions and allowed to ride on their respective parent atom, with C—H = 0.93 (aromatic), 0.96 (CH₃) or 0.97 Å (CH₂) and N—H = 0.86 Å, and with U_iso(H) = 1.5U_eq(C,N) for methyl and hy­droxy H atoms or 1.2U_eq(C,N) otherwise. The H atoms of the water molecules were located in a difference map and were all permitted to ride at fixed O—H distances (0.87 Å) and with U_iso(H) = 1.2U_eq(O). Riding restraints were applied for the methyl and hy­droxy groups.

S3. Results and discussion

In the crystal of (I), t7,10-di-Troc-DAB exists as a 1:1:1 complex with ethyl acetate and water, the solvents from which the crystal was grown. In general, the tetra­cyclic ring structure is very compact and relatively rigid. As shown in Fig. 2, the core tetra­cyclic ring system has a rigid structure. The central eight-membered ring B (see Scheme) adopts the most stable boat–chair conformation, which is essentially identical to baccatin analogues and baccatin derivatives (Gao et al., 1987). The six-membered ring C is trans-fused to ring B with one common bond (C3–C8); atoms C5 and C8 deviate by 0.014 (5) and 0.785 (4) Å, respectively, from the mean plane of the other four atoms, viz. C3, C4, C6 and C7. The torsion angles C3—C4—C6—C7 [-8.5 (6)°], C4—C3—C7—C8 [-129.5 (7)°] and C4—C7—C6—C5 [3.0 (8)°] likewise suggest that atoms C3, C4, C6 and C7 are not coplanar, so the conformation of ring C is a distorted chair with atom C5 nearly coplanar. In contrast, the other six-membered ring, A, adjacent to eight-membered ring B is a nearly perfect boat, with atoms C13 and C15 above the plane [0.390 (5) and 0.697 (5) Å, respectively] of atoms C1, C11, C12 and C14. It is nearly perfect since C13 and C15 are not equal. The O10 hy­droxy group on C13 is oriented towards the concavity of the molecule, not unlike the conformation found in a derivative of 10-de­acetyl­baccatin III studied by X-ray crystallography (Gueritte-Voegelein et al., 1990).

No intra­molecular hydrogen bonds are found. However, the structure does display four inter­molecular hydrogen bonds and three kinds of noncovalent inter­action, which contribute significantly to the stability of the crystal lattice. As shown in Table 2, water atom O17 forms one inter­molecular hydrogen bond with O9 and one inter­molecular hydrogen bond with O1. Ethyl acetate atom O15 is involved, as accptor, in an inter­molecular hydrogen bond with atom O9 of 7,10-diTroc-DAB at C1. The O···O distance of this hydrogen bond [2.824 (5) Å] is shorter than the O17···O9 [3.079 (5) Å] and O17···O1 [3.260 (5) Å] distances, but is still reasonable. Likewise, the hydrogen bond between atoms O10 and O17, similar to O9···O15, with very similar H···A and D···A distances, is in good agreement with the value of 2.800 Å reported for 14β-hy­droxy-10-de­acetyl­baccatin III (Appendino et al., 1992).

Halogen bonding (XB) refers to the noncovalent inter­action of general structure DX···A between halogen-bearing compounds (DX = XB donor, where X = Cl, Br, I) and nucleophiles (A = XB acceptor) (Politzer et al., 2007; Clark et al., 2007). Since Hassel and Hvoslef first observed XB in cocrystal structures of 1,4-dioxane and Br₂ in 1954 (Politzer et al., 2007), it has been widely used in crystal engineering and solid-state supra­molecular chemistry (Desiraju, 1995; Metrangolo & Resnati, 2001; Sun et al., 2006). Molecules are held together by another noncovalent inter­action of the O8···Cl12 halogen bond; the inter­atomic distance of 3.037 (5) Å is in agreement with the analysis of halogen bonding in protein–ligand inter­actions (Hardegger et al., 2011). The agreement was also found in the molecular complex of CF₃Cl and H₂O, where the distance between the Cl and O atoms was estimated to be 3.028 Å versus 2.982 Å obtained by ab initio calculations (Evangelisti et al., 2011). It was noted that two intra­molecular O···O inter­actions also occur in the crystal. The unique feature of complex (I) is the O1···O12 [2.950 (4) Å] and O3···O14 [2.956 (6) Å] intra­molecular contacts, which are in the middle of O10···O17 [2.792 (5) Å] and O17···O9 [3.099 (6) Å] O17···O1 [3.217 (5) Å] range of distances in the hydrogen-bonded fragment.

Molecules of compound (I) are linked into chains by weak C···O hydrogen-bond and Cl···O halogen-bond contacts, viewed along the a axis (Fig. 4). In short, hydrogen bonds and noncovalent inter­actions also contribute significantly to the stability of the crystal lattice. In addition, the title compound is a chiral compound, and the absolute stereochemistry assignment is unambiguous. The Flack parameter is -0.04 (6). This suggests the assignment of the chirality at each of the chiral centers as C1S, C2S, C3R, C4S, C5R, C7S, C8S, C10R and C13S.

Compound (I) displayed good biological activity and the structure–activity relationship of the chemical scaffold core has been determined through the analysis of many studies, as shown in Fig. 5. While compound (I) was synthesized through chemical transformation from 10-de­acetyl baccatin III, there are enzymes that also react with these molecules, like transferases. Inter­estingly enough, the biosynthetic pathway strongly depends upon the conformation of the precursers, so structural studies like that of compound (I) presented here can shed light on the mechanisms of these transferases and the biosynthetic evolution of these structurally complex molecules.

Computing details

Data collection: APEX2 (Bruker, 2008); cell refinement: SAINT (Bruker, 2008); data reduction: SAINT (Bruker, 2008); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: Mercury (Macrae et al., 2006).

Figures

	Fig. 1. The molecular structure of (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.
	Fig. 2. A perspective view of (I), Displacement ellipsoids are drawn at the 30% probability level. The dashed lines indicates O—H···O hydrogen bonds.
	Fig. 3. Molecules of the title compound, linked into chains by weak Cl···O halogen bond and C···O contacts, viewed along the a axis. Dashed lines represent hydrogen bonds. Generic atom labels without symmetry codes have been used.
	Fig. 4. The structure–activity relationship of 10-deacetylbaccatin III.

7,10-Bis-O-(2,2,2-trichloroethoxycarbonyl)-10-deacetyl baccatin III–ethyl acetate–water (1/1/1)

Crystal data

C34H38Cl6O14·C4H8O2·H2O	F(000) = 2080
Mr = 1001.47	Dx = 1.444 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 2132 reflections
a = 14.7029 (12) Å	θ = 2.5–17.8°
b = 16.6256 (14) Å	µ = 0.44 mm^−1
c = 18.8428 (15) Å	T = 296 K
V = 4606.0 (7) Å^3	Block, colorless
Z = 4	0.45 × 0.42 × 0.40 mm

Data collection

Bruker APEXII CCD diffractometer	8208 independent reflections
Radiation source: fine-focus sealed tube	5474 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.070
ϕ and ω scans	θmax = 25.1°, θmin = 1.6°
Absorption correction: multi-scan (REQAB; Jacobson, 1998)	h = −16→17
Tmin = 0.826, Tmax = 0.843	k = −19→19
23553 measured reflections	l = −17→22

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)] = 0.053	w = 1/[σ^2(Fo^2) + (0.0436P)^2] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.115	(Δ/σ)max = 0.001
S = 0.98	Δρmax = 0.30 e Å^−3
8208 reflections	Δρmin = −0.22 e Å^−3
560 parameters	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
0 restraints	Extinction coefficient: 0.0028 (3)
Primary atom site location: structure-invariant direct methods	Absolute structure: Flack (1983), 3609 Friedel pairs
Secondary atom site location: difference Fourier map	Absolute structure parameter: −0.04 (6)

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
Cl1	0.45710 (8)	0.39676 (8)	1.07198 (6)	0.0574 (3)
Cl2	0.32384 (8)	0.52020 (9)	1.04635 (7)	0.0663 (4)
Cl3	0.47888 (11)	0.55326 (9)	1.13566 (6)	0.0781 (5)
Cl4	0.16971 (12)	0.74382 (10)	1.06871 (8)	0.0939 (6)
Cl5	0.21745 (10)	0.86644 (8)	0.96796 (8)	0.0728 (5)
Cl6	0.07996 (9)	0.74944 (10)	0.93393 (9)	0.0839 (5)
O1	0.46529 (17)	0.49094 (16)	0.93568 (13)	0.0365 (7)
O2	0.5847 (2)	0.5445 (2)	0.87752 (16)	0.0612 (10)
O3	0.47014 (17)	0.47830 (16)	0.82246 (13)	0.0345 (7)
O4	0.5596 (2)	0.34214 (16)	0.62594 (15)	0.0448 (8)
O5	0.64362 (17)	0.50854 (17)	0.57182 (15)	0.0382 (7)
O6	0.70100 (19)	0.5507 (2)	0.67610 (18)	0.0516 (8)
O7	0.48375 (18)	0.53226 (16)	0.50120 (13)	0.0364 (7)
O8	0.3530 (2)	0.4758 (2)	0.46317 (17)	0.0593 (9)
O9	0.3769 (2)	0.66053 (19)	0.48867 (14)	0.0482 (8)
H9	0.4072	0.6774	0.4553	0.072*
O10	0.66200 (19)	0.7436 (2)	0.59069 (17)	0.0611 (10)
H10	0.6852	0.7830	0.6096	0.092*
O11	0.34846 (18)	0.70530 (16)	0.78068 (14)	0.0384 (7)
O12	0.3934 (2)	0.6456 (2)	0.88308 (15)	0.0551 (9)
O13	0.2697 (2)	0.72537 (17)	0.87572 (15)	0.0460 (8)
O14	0.30866 (17)	0.55455 (19)	0.75760 (16)	0.0454 (8)
O15	0.4523 (4)	0.7217 (4)	0.3618 (2)	0.157 (3)
O16	0.5060 (3)	0.6814 (3)	0.2612 (2)	0.1055 (16)
C1	0.4330 (3)	0.6562 (2)	0.55093 (19)	0.0316 (10)
C2	0.4413 (3)	0.5639 (2)	0.56530 (19)	0.0306 (9)
H2	0.3800	0.5413	0.5692	0.037*
C3	0.4989 (2)	0.5342 (2)	0.63038 (18)	0.0272 (9)
H3	0.5347	0.5808	0.6457	0.033*
C4	0.5692 (3)	0.4686 (2)	0.6091 (2)	0.0309 (10)
C5	0.6032 (3)	0.4074 (2)	0.6642 (2)	0.0346 (10)
H5	0.6696	0.4022	0.6619	0.042*
C6	0.5721 (3)	0.4145 (3)	0.7402 (2)	0.0379 (11)
H6A	0.6250	0.4153	0.7709	0.045*
H6B	0.5364	0.3674	0.7523	0.045*
C7	0.5156 (3)	0.4892 (2)	0.75415 (19)	0.0317 (9)
H7	0.5565	0.5356	0.7575	0.038*
C8	0.4420 (3)	0.5073 (2)	0.6975 (2)	0.0290 (9)
C9	0.3810 (3)	0.5734 (2)	0.7324 (2)	0.0311 (10)
C10	0.4167 (3)	0.6584 (2)	0.7431 (2)	0.0332 (10)
H10A	0.4704	0.6549	0.7738	0.040*
C11	0.4451 (3)	0.6999 (2)	0.6761 (2)	0.0314 (10)
C12	0.5308 (3)	0.7261 (2)	0.6688 (2)	0.0355 (10)
C13	0.5655 (3)	0.7492 (3)	0.5956 (2)	0.0448 (11)
H13	0.5473	0.8048	0.5855	0.054*
C14	0.5273 (3)	0.6947 (3)	0.5378 (2)	0.0400 (11)
H14A	0.5706	0.6517	0.5298	0.048*
H14B	0.5238	0.7258	0.4943	0.048*
C15	0.3816 (3)	0.7014 (2)	0.6108 (2)	0.0348 (10)
C16	0.3627 (3)	0.7890 (3)	0.5880 (2)	0.0487 (12)
H16A	0.3320	0.7892	0.5430	0.073*
H16B	0.4192	0.8176	0.5838	0.073*
H16C	0.3251	0.8148	0.6228	0.073*
C17	0.2865 (3)	0.6643 (3)	0.6226 (2)	0.0464 (12)
H17A	0.2584	0.6888	0.6631	0.070*
H20D	0.2925	0.6075	0.6305	0.070*
H18D	0.2495	0.6734	0.5813	0.070*
C18	0.5997 (3)	0.7319 (3)	0.7285 (2)	0.0486 (12)
H18A	0.5684	0.7366	0.7731	0.073*
H18B	0.6375	0.7783	0.7215	0.073*
H18C	0.6368	0.6844	0.7289	0.073*
C19	0.3823 (3)	0.4340 (2)	0.6832 (2)	0.0362 (10)
H19A	0.4193	0.3908	0.6656	0.054*
H19B	0.3369	0.4475	0.6487	0.054*
H19C	0.3533	0.4175	0.7265	0.054*
C20	0.5377 (3)	0.3945 (2)	0.5674 (2)	0.0389 (10)
H20A	0.4734	0.3953	0.5559	0.047*
H20B	0.5738	0.3841	0.5253	0.047*
C21	0.7058 (3)	0.5467 (3)	0.6127 (3)	0.0449 (12)
C22	0.7808 (3)	0.5823 (3)	0.5686 (3)	0.0629 (15)
H22A	0.7773	0.6399	0.5705	0.094*
H22B	0.7745	0.5648	0.5203	0.094*
H22C	0.8386	0.5650	0.5867	0.094*
C23	0.4325 (4)	0.4918 (3)	0.4540 (2)	0.0438 (12)
C24	0.4857 (4)	0.4674 (3)	0.3912 (2)	0.0581 (14)
C25	0.4390 (5)	0.4371 (3)	0.3332 (3)	0.087 (2)
H25	0.3757	0.4354	0.3331	0.105*
C26	0.4882 (9)	0.4090 (5)	0.2749 (4)	0.137 (4)
H26	0.4573	0.3866	0.2366	0.164*
C27	0.5804 (10)	0.4137 (6)	0.2730 (5)	0.162 (6)
H27	0.6123	0.3967	0.2331	0.194*
C28	0.6257 (6)	0.4436 (4)	0.3304 (4)	0.121 (3)
H28	0.6889	0.4453	0.3300	0.145*
C29	0.5791 (5)	0.4714 (3)	0.3891 (3)	0.0780 (18)
H29	0.6110	0.4929	0.4273	0.094*
C30	0.5136 (3)	0.5093 (3)	0.8778 (2)	0.0386 (10)
C31	0.4953 (3)	0.5319 (3)	0.99803 (19)	0.0420 (11)
H31A	0.4865	0.5894	0.9927	0.050*
H31B	0.5595	0.5219	1.0058	0.050*
C32	0.4407 (3)	0.5012 (3)	1.0603 (2)	0.0449 (11)
C33	0.3426 (3)	0.6871 (3)	0.8494 (2)	0.0409 (11)
C34	0.2575 (3)	0.7095 (3)	0.9504 (2)	0.0535 (13)
H34A	0.3141	0.7185	0.9756	0.064*
H34B	0.2394	0.6540	0.9575	0.064*
C35	0.1848 (3)	0.7652 (3)	0.9783 (2)	0.0538 (13)
C36	0.3518 (4)	0.6914 (6)	0.2637 (4)	0.149 (4)
H36A	0.3335	0.6360	0.2642	0.224*
H36B	0.3594	0.7090	0.2155	0.224*
H36C	0.3061	0.7236	0.2864	0.224*
C37	0.4383 (5)	0.7002 (5)	0.3019 (4)	0.099 (2)
C38	0.5963 (5)	0.6867 (6)	0.2964 (5)	0.150 (4)
H38A	0.6126	0.7427	0.3032	0.180*
H38B	0.5935	0.6611	0.3426	0.180*
C39	0.6606 (5)	0.6495 (5)	0.2554 (4)	0.124 (3)
H39A	0.6461	0.5934	0.2511	0.186*
H39B	0.7192	0.6553	0.2772	0.186*
H39C	0.6615	0.6737	0.2092	0.186*
H17D	0.6749	0.9256	0.5910	0.149*
H17E	0.7575	0.8891	0.5773	0.149*
O17	0.7233 (2)	0.9006 (2)	0.6083 (2)	0.0931 (13)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.0728 (8)	0.0496 (8)	0.0498 (7)	0.0017 (7)	0.0000 (7)	0.0074 (6)
Cl2	0.0498 (7)	0.0778 (10)	0.0713 (9)	0.0094 (7)	0.0164 (7)	0.0136 (7)
Cl3	0.1216 (12)	0.0794 (10)	0.0334 (7)	−0.0244 (10)	0.0011 (8)	−0.0119 (6)
Cl4	0.1362 (14)	0.0831 (12)	0.0625 (9)	−0.0106 (10)	0.0569 (10)	−0.0013 (9)
Cl5	0.0825 (9)	0.0360 (7)	0.0998 (11)	−0.0083 (7)	0.0446 (9)	−0.0064 (7)
Cl6	0.0627 (8)	0.0750 (11)	0.1141 (12)	−0.0064 (8)	0.0251 (9)	−0.0110 (10)
O1	0.0414 (15)	0.0447 (18)	0.0235 (14)	−0.0093 (14)	−0.0010 (13)	0.0030 (13)
O2	0.0459 (19)	0.097 (3)	0.0413 (19)	−0.0285 (19)	0.0061 (16)	−0.0100 (19)
O3	0.0381 (15)	0.0422 (18)	0.0231 (14)	−0.0071 (14)	0.0002 (13)	0.0017 (13)
O4	0.0614 (19)	0.0298 (17)	0.0433 (17)	0.0031 (15)	−0.0031 (16)	0.0002 (14)
O5	0.0350 (15)	0.0388 (18)	0.0407 (16)	0.0010 (14)	0.0066 (14)	−0.0003 (15)
O6	0.0451 (18)	0.060 (2)	0.049 (2)	−0.0057 (17)	−0.0026 (17)	−0.0077 (18)
O7	0.0438 (16)	0.0350 (17)	0.0305 (15)	0.0051 (14)	0.0024 (13)	−0.0018 (13)
O8	0.055 (2)	0.061 (2)	0.062 (2)	−0.0007 (19)	−0.0129 (18)	−0.0138 (18)
O9	0.061 (2)	0.052 (2)	0.0320 (17)	0.0112 (17)	−0.0081 (15)	0.0047 (15)
O10	0.0412 (18)	0.063 (2)	0.079 (2)	−0.0066 (17)	0.0178 (17)	−0.0120 (19)
O11	0.0471 (17)	0.0361 (18)	0.0320 (16)	0.0137 (14)	0.0048 (14)	−0.0057 (14)
O12	0.069 (2)	0.058 (2)	0.0385 (19)	0.0259 (19)	0.0062 (17)	0.0019 (17)
O13	0.0565 (19)	0.0383 (19)	0.0433 (18)	0.0111 (16)	0.0163 (16)	0.0027 (15)
O14	0.0346 (16)	0.0442 (19)	0.057 (2)	−0.0007 (15)	0.0176 (15)	−0.0047 (16)
O15	0.195 (6)	0.227 (7)	0.048 (3)	−0.074 (5)	0.014 (3)	−0.009 (4)
O16	0.069 (3)	0.156 (5)	0.092 (3)	−0.007 (3)	0.015 (3)	−0.045 (3)
C1	0.042 (2)	0.029 (2)	0.024 (2)	0.003 (2)	−0.0041 (19)	0.0009 (17)
C2	0.035 (2)	0.029 (2)	0.028 (2)	0.0003 (19)	0.0036 (19)	−0.0059 (19)
C3	0.032 (2)	0.026 (2)	0.023 (2)	−0.0011 (18)	0.0019 (17)	−0.0024 (17)
C4	0.034 (2)	0.028 (2)	0.030 (2)	0.0018 (19)	0.0034 (19)	0.0006 (18)
C5	0.038 (2)	0.029 (2)	0.037 (2)	0.007 (2)	−0.003 (2)	0.0006 (19)
C6	0.042 (2)	0.036 (3)	0.036 (2)	0.008 (2)	0.004 (2)	0.005 (2)
C7	0.036 (2)	0.034 (2)	0.025 (2)	0.001 (2)	0.0056 (18)	0.0008 (18)
C8	0.033 (2)	0.020 (2)	0.034 (2)	0.0044 (19)	0.0011 (18)	0.0028 (17)
C9	0.029 (2)	0.033 (3)	0.032 (2)	0.0019 (19)	−0.0005 (19)	0.0046 (19)
C10	0.034 (2)	0.030 (2)	0.035 (2)	0.006 (2)	0.003 (2)	−0.0060 (19)
C11	0.035 (2)	0.026 (2)	0.033 (2)	0.003 (2)	−0.004 (2)	−0.0050 (19)
C12	0.041 (2)	0.024 (2)	0.042 (3)	0.005 (2)	−0.004 (2)	−0.0104 (19)
C13	0.050 (3)	0.032 (3)	0.053 (3)	−0.001 (2)	0.011 (2)	−0.001 (2)
C14	0.053 (3)	0.032 (3)	0.035 (2)	−0.002 (2)	0.013 (2)	0.003 (2)
C15	0.038 (2)	0.032 (3)	0.034 (2)	0.004 (2)	−0.002 (2)	0.000 (2)
C16	0.055 (3)	0.035 (3)	0.056 (3)	0.015 (2)	−0.003 (2)	−0.001 (2)
C17	0.045 (3)	0.045 (3)	0.049 (3)	0.003 (2)	−0.002 (2)	−0.003 (2)
C18	0.048 (3)	0.040 (3)	0.058 (3)	0.001 (2)	−0.007 (2)	−0.013 (2)
C19	0.037 (2)	0.030 (2)	0.042 (2)	−0.007 (2)	0.004 (2)	0.002 (2)
C20	0.053 (3)	0.031 (2)	0.033 (2)	0.008 (2)	0.000 (2)	−0.003 (2)
C21	0.030 (2)	0.035 (3)	0.070 (4)	0.008 (2)	0.003 (3)	0.004 (3)
C22	0.047 (3)	0.058 (4)	0.084 (4)	−0.006 (3)	0.019 (3)	0.000 (3)
C23	0.069 (3)	0.035 (3)	0.028 (2)	0.007 (3)	−0.009 (2)	−0.002 (2)
C24	0.102 (4)	0.045 (3)	0.028 (3)	0.008 (3)	0.005 (3)	0.004 (2)
C25	0.173 (6)	0.056 (4)	0.033 (3)	−0.008 (4)	−0.010 (4)	0.000 (3)
C26	0.306 (14)	0.074 (5)	0.030 (4)	−0.036 (9)	0.018 (7)	−0.005 (3)
C27	0.317 (16)	0.086 (7)	0.083 (7)	−0.009 (10)	0.100 (10)	−0.020 (5)
C28	0.181 (8)	0.088 (5)	0.093 (6)	0.036 (6)	0.082 (6)	0.008 (5)
C29	0.111 (5)	0.073 (4)	0.050 (3)	0.015 (4)	0.027 (4)	0.000 (3)
C30	0.040 (3)	0.046 (3)	0.029 (2)	0.006 (2)	0.003 (2)	0.005 (2)
C31	0.046 (3)	0.055 (3)	0.026 (2)	−0.012 (2)	−0.001 (2)	−0.005 (2)
C32	0.052 (3)	0.050 (3)	0.033 (2)	−0.003 (2)	0.003 (2)	−0.003 (2)
C33	0.051 (3)	0.030 (3)	0.042 (3)	0.002 (2)	0.006 (2)	−0.006 (2)
C34	0.066 (3)	0.045 (3)	0.049 (3)	0.007 (3)	0.019 (3)	0.007 (2)
C35	0.072 (3)	0.038 (3)	0.051 (3)	−0.004 (3)	0.029 (3)	−0.005 (2)
C36	0.064 (4)	0.244 (12)	0.140 (7)	−0.019 (6)	0.014 (5)	−0.056 (8)
C37	0.102 (6)	0.122 (6)	0.072 (5)	−0.016 (5)	0.016 (5)	0.009 (4)
C38	0.086 (5)	0.191 (10)	0.173 (8)	0.014 (6)	−0.049 (6)	−0.096 (8)
C39	0.077 (5)	0.134 (8)	0.162 (8)	0.002 (5)	−0.018 (5)	−0.013 (6)
O17	0.066 (2)	0.072 (3)	0.141 (4)	−0.009 (2)	0.013 (3)	0.027 (3)

Geometric parameters (Å, º)

Cl1—C32	1.767 (5)	C12—C13	1.520 (6)
Cl2—C32	1.766 (4)	C12—C18	1.518 (5)
Cl3—C32	1.755 (4)	C13—C14	1.523 (6)
Cl4—C35	1.755 (5)	C13—H13	0.9800
Cl5—C35	1.760 (5)	C14—H14A	0.9700
Cl6—C35	1.773 (5)	C14—H14B	0.9700
O1—C30	1.337 (5)	C15—C17	1.544 (6)
O1—C31	1.428 (4)	C15—C16	1.544 (6)
O2—C30	1.198 (5)	C16—H16A	0.9600
O3—C30	1.327 (5)	C16—H16B	0.9600
O3—C7	1.462 (4)	C16—H16C	0.9600
O4—C20	1.441 (5)	C17—H17A	0.9600
O4—C5	1.452 (5)	C17—H20D	0.9600
O5—C21	1.353 (5)	C17—H18D	0.9600
O5—C4	1.460 (4)	C18—H18A	0.9600
O6—C21	1.198 (5)	C18—H18B	0.9600
O7—C23	1.345 (5)	C18—H18C	0.9600
O7—C2	1.458 (4)	C19—H19A	0.9600
O8—C23	1.212 (5)	C19—H19B	0.9600
O9—C1	1.436 (4)	C19—H19C	0.9600
O9—H9	0.8200	C20—H20A	0.9700
O10—C13	1.425 (5)	C20—H20B	0.9700
O10—H10	0.8200	C21—C22	1.503 (6)
O11—C33	1.332 (5)	C22—H22A	0.9600
O11—C10	1.455 (4)	C22—H22B	0.9600
O12—C33	1.199 (5)	C22—H22C	0.9600
O13—C33	1.341 (5)	C23—C24	1.475 (6)
O13—C34	1.443 (5)	C24—C29	1.376 (8)
O14—C9	1.207 (4)	C24—C25	1.386 (7)
O15—C37	1.202 (7)	C25—C26	1.396 (11)
O16—C37	1.295 (7)	C25—H25	0.9300
O16—C38	1.487 (7)	C26—C27	1.359 (14)
C1—C14	1.548 (6)	C26—H26	0.9300
C1—C15	1.553 (5)	C27—C28	1.363 (13)
C1—C2	1.563 (5)	C27—H27	0.9300
C2—C3	1.570 (5)	C28—C29	1.381 (8)
C2—H2	0.9800	C28—H28	0.9300
C3—C4	1.555 (5)	C29—H29	0.9300
C3—C8	1.582 (5)	C31—C32	1.511 (6)
C3—H3	0.9800	C31—H31A	0.9700
C4—C5	1.538 (5)	C31—H31B	0.9700
C4—C20	1.534 (5)	C34—C35	1.509 (6)
C5—C6	1.507 (5)	C34—H34A	0.9700
C5—H5	0.9800	C34—H34B	0.9700
C6—C7	1.517 (5)	C36—C37	1.468 (9)
C6—H6A	0.9700	C36—H36A	0.9600
C6—H6B	0.9700	C36—H36B	0.9600
C7—C8	1.549 (5)	C36—H36C	0.9600
C7—H7	0.9800	C38—C39	1.369 (9)
C8—C19	1.526 (5)	C38—H38A	0.9700
C8—C9	1.564 (5)	C38—H38B	0.9700
C9—C10	1.521 (6)	C39—H39A	0.9600
C10—C11	1.498 (5)	C39—H39B	0.9600
C10—H10A	0.9800	C39—H39C	0.9600
C11—C12	1.341 (5)	O17—H17D	0.8855
C11—C15	1.544 (5)	O17—H17E	0.7953
C30—O1—C31	113.5 (3)	H20D—C17—H18D	109.5
C30—O3—C7	115.0 (3)	C12—C18—H18A	109.5
C20—O4—C5	91.6 (3)	C12—C18—H18B	109.5
C21—O5—C4	116.4 (3)	H18A—C18—H18B	109.5
C23—O7—C2	119.2 (3)	C12—C18—H18C	109.5
C1—O9—H9	109.5	H18A—C18—H18C	109.5
C13—O10—H10	109.5	H18B—C18—H18C	109.5
C33—O11—C10	113.3 (3)	C8—C19—H19A	109.5
C33—O13—C34	111.9 (4)	C8—C19—H19B	109.5
C37—O16—C38	114.0 (6)	H19A—C19—H19B	109.5
O9—C1—C14	111.3 (3)	C8—C19—H19C	109.5
O9—C1—C15	106.9 (3)	H19A—C19—H19C	109.5
C14—C1—C15	110.6 (3)	H19B—C19—H19C	109.5
O9—C1—C2	103.6 (3)	O4—C20—C4	91.5 (3)
C14—C1—C2	111.4 (3)	O4—C20—H20A	113.4
C15—C1—C2	112.8 (3)	C4—C20—H20A	113.4
O7—C2—C1	104.1 (3)	O4—C20—H20B	113.4
O7—C2—C3	107.6 (3)	C4—C20—H20B	113.4
C1—C2—C3	119.1 (3)	H20A—C20—H20B	110.7
O7—C2—H2	108.5	O6—C21—O5	123.7 (4)
C1—C2—H2	108.5	O6—C21—C22	124.9 (5)
C3—C2—H2	108.5	O5—C21—C22	111.4 (4)
C4—C3—C2	112.2 (3)	C21—C22—H22A	109.5
C4—C3—C8	111.0 (3)	C21—C22—H22B	109.5
C2—C3—C8	115.4 (3)	H22A—C22—H22B	109.5
C4—C3—H3	105.8	C21—C22—H22C	109.5
C2—C3—H3	105.8	H22A—C22—H22C	109.5
C8—C3—H3	105.8	H22B—C22—H22C	109.5
O5—C4—C5	112.5 (3)	O8—C23—O7	123.8 (4)
O5—C4—C20	110.1 (3)	O8—C23—C24	124.4 (5)
C5—C4—C20	84.9 (3)	O7—C23—C24	111.8 (4)
O5—C4—C3	107.7 (3)	C29—C24—C25	119.3 (6)
C5—C4—C3	120.5 (3)	C29—C24—C23	122.6 (5)
C20—C4—C3	119.7 (3)	C25—C24—C23	118.1 (6)
O4—C5—C6	113.3 (3)	C24—C25—C26	119.1 (8)
O4—C5—C4	90.9 (3)	C24—C25—H25	120.5
C6—C5—C4	119.3 (3)	C26—C25—H25	120.5
O4—C5—H5	110.6	C27—C26—C25	121.2 (9)
C6—C5—H5	110.6	C27—C26—H26	119.4
C4—C5—H5	110.6	C25—C26—H26	119.4
C5—C6—C7	113.3 (3)	C26—C27—C28	119.2 (9)
C5—C6—H6A	108.9	C26—C27—H27	120.4
C7—C6—H6A	108.9	C28—C27—H27	120.4
C5—C6—H6B	108.9	C27—C28—C29	121.1 (9)
C7—C6—H6B	108.9	C27—C28—H28	119.5
H6A—C6—H6B	107.7	C29—C28—H28	119.5
O3—C7—C6	107.6 (3)	C24—C29—C28	120.1 (7)
O3—C7—C8	108.1 (3)	C24—C29—H29	119.9
C6—C7—C8	114.9 (3)	C28—C29—H29	119.9
O3—C7—H7	108.7	O2—C30—O3	127.3 (4)
C6—C7—H7	108.7	O2—C30—O1	125.4 (4)
C8—C7—H7	108.7	O3—C30—O1	107.2 (4)
C19—C8—C7	111.6 (3)	O1—C31—C32	108.3 (3)
C19—C8—C9	107.8 (3)	O1—C31—H31A	110.0
C7—C8—C9	104.4 (3)	C32—C31—H31A	110.0
C19—C8—C3	112.9 (3)	O1—C31—H31B	110.0
C7—C8—C3	103.7 (3)	C32—C31—H31B	110.0
C9—C8—C3	116.1 (3)	H31A—C31—H31B	108.4
O14—C9—C10	119.6 (4)	C31—C32—Cl3	106.9 (3)
O14—C9—C8	119.2 (4)	C31—C32—Cl1	110.8 (3)
C10—C9—C8	120.8 (3)	Cl3—C32—Cl1	109.9 (2)
O11—C10—C11	110.8 (3)	C31—C32—Cl2	109.9 (3)
O11—C10—C9	108.9 (3)	Cl3—C32—Cl2	110.1 (2)
C11—C10—C9	114.3 (3)	Cl1—C32—Cl2	109.1 (2)
O11—C10—H10A	107.5	O12—C33—O11	127.3 (4)
C11—C10—H10A	107.5	O12—C33—O13	125.1 (4)
C9—C10—H10A	107.5	O11—C33—O13	107.7 (4)
C12—C11—C10	119.9 (4)	O13—C34—C35	108.4 (4)
C12—C11—C15	118.8 (4)	O13—C34—H34A	110.0
C10—C11—C15	120.7 (3)	C35—C34—H34A	110.0
C11—C12—C13	119.4 (4)	O13—C34—H34B	110.0
C11—C12—C18	124.8 (4)	C35—C34—H34B	110.0
C13—C12—C18	115.7 (3)	H34A—C34—H34B	108.4
O10—C13—C12	112.1 (4)	C34—C35—Cl4	107.6 (3)
O10—C13—C14	106.4 (3)	C34—C35—Cl5	110.8 (3)
C12—C13—C14	112.0 (3)	Cl4—C35—Cl5	109.6 (3)
O10—C13—H13	108.8	C34—C35—Cl6	111.1 (3)
C12—C13—H13	108.8	Cl4—C35—Cl6	108.5 (3)
C14—C13—H13	108.8	Cl5—C35—Cl6	109.1 (3)
C13—C14—C1	117.5 (3)	C37—C36—H36A	109.5
C13—C14—H14A	107.9	C37—C36—H36B	109.5
C1—C14—H14A	107.9	H36A—C36—H36B	109.5
C13—C14—H14B	107.9	C37—C36—H36C	109.5
C1—C14—H14B	107.9	H36A—C36—H36C	109.5
H14A—C14—H14B	107.2	H36B—C36—H36C	109.5
C17—C15—C16	104.8 (3)	O15—C37—O16	119.8 (7)
C17—C15—C11	115.3 (3)	O15—C37—C36	129.7 (8)
C16—C15—C11	110.3 (3)	O16—C37—C36	110.6 (6)
C17—C15—C1	110.5 (3)	C39—C38—O16	109.7 (6)
C16—C15—C1	110.0 (3)	C39—C38—H38A	109.7
C11—C15—C1	106.0 (3)	O16—C38—H38A	109.7
C15—C16—H16A	109.5	C39—C38—H38B	109.7
C15—C16—H16B	109.5	O16—C38—H38B	109.7
H16A—C16—H16B	109.5	H38A—C38—H38B	108.2
C15—C16—H16C	109.5	C38—C39—H39A	109.5
H16A—C16—H16C	109.5	C38—C39—H39B	109.5
H16B—C16—H16C	109.5	H39A—C39—H39B	109.5
C15—C17—H17A	109.5	C38—C39—H39C	109.5
C15—C17—H20D	109.5	H39A—C39—H39C	109.5
H17A—C17—H20D	109.5	H39B—C39—H39C	109.5
C15—C17—H18D	109.5	H17D—O17—H17E	110.4
H17A—C17—H18D	109.5

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O9—H9···O15	0.82	2.02	2.824 (5)	166
O10—H10···O17	0.82	2.03	2.782 (5)	151
O17—H17D···O1^i	0.89	2.38	3.260 (5)	170
O17—H17E···O9^ii	0.80	2.30	3.079 (5)	165

Symmetry codes: (i) −x+1, y+1/2, −z+3/2; (ii) x+1/2, −y+3/2, −z+1.