α-Artemether

The title compound, C₁₆H₂₆O₅, a derivative of the anti­malaria compound artesunate, consists primarily of three substituted ring systems fused together. A cyclo­hexane ring (distorted chair configuration) fused to a tetra­hydro­pyran group (normal chair) is adjacent to an oxacyclo­heptane unit containing an endoperoxide bridge, giving the mol­ecule a unique three-dimensional arrangement.

Key indicators

• Single-crystal X-ray study
• T = 103 K
• Mean [sigma](C-C) = 0.002 Å
• R factor = 0.033
• wR factor = 0.087
• Data-to-parameter ratio = 8.3

checkCIF/PLATON results

No syntax errors found



Alert level B
PLAT063_ALERT_3_B Crystal Probably too Large for Beam Size .......       0.84 mm
PLAT222_ALERT_3_B Large Non-Solvent    H     Ueq(max)/Ueq(min) ...       4.91 Ratio

Alert level C
PLAT066_ALERT_1_C Predicted and Reported Transmissions Identical .          ?
PLAT125_ALERT_4_C No _symmetry_space_group_name_Hall Given .......          ?
PLAT147_ALERT_1_C su on Symmetry Constrained Cell Angle(s) .......          ?

Alert level G
REFLT03_ALERT_4_G Please check that the estimate of the number of Friedel pairs is
            correct. If it is not, please give the correct count in the
            _publ_section_exptl_refinement section of the submitted CIF.
           From the CIF: _diffrn_reflns_theta_max           29.40
           From the CIF: _reflns_number_total               2434
           Count of symmetry unique reflns         2434
           Completeness (_total/calc)            100.00%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured         0
           Fraction of Friedel pairs measured     0.000
           Are heavy atom types Z>Si present         no
PLAT791_ALERT_1_G Confirm the Absolute Configuration of C1     = .          R
PLAT791_ALERT_1_G Confirm the Absolute Configuration of C2     = .          S
PLAT791_ALERT_1_G Confirm the Absolute Configuration of C5     = .          R
PLAT791_ALERT_1_G Confirm the Absolute Configuration of C6     = .          S
PLAT791_ALERT_1_G Confirm the Absolute Configuration of C9     = .          R
PLAT791_ALERT_1_G Confirm the Absolute Configuration of C10    = .          R
PLAT791_ALERT_1_G Confirm the Absolute Configuration of C12    = .          R

   0 ALERT level A = In general: serious problem
   2 ALERT level B = Potentially serious problem
   3 ALERT level C = Check and explain
   8 ALERT level G = General alerts; check

   9 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   0 ALERT type 2 Indicator that the structure model may be wrong or deficient
   2 ALERT type 3 Indicator that the structure quality may be low
   2 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

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S1. Comment

Artemisinin and its derivatives, dihydroartemisinin, artemether, arteether and artesunate are antimalarial drugs which possess bioactivity with less toxicity (Wu & Li, 1995). Artemisinin is isolated from the leaves of plant Artemisia annua (Qinghao). It is a sesquiterpene lactone with an endoperoxide linkage. Artemisinin derivatives are more potent than artemisinin and are active by virtue of the endoperoxide. Because of their activity against strains of the parasite that has become resistant to conventional chloroquine therapy and due to the ability due to its lipophilic structure to cross the blood brain barrier, they are particularly effective for the deadly cerebral malaria (Shen & Zhuang, 1984). With their shorter life time and decreasing activity, they are used in combination with other antimalarial drugs. However, some derivatives of artimisinine showed moderate cytotoxicity in vitro. The electronegativity and bulk of the substituents attached to the aryl group plays an insignificant role in cytotoxicity. The endoperoxide moiety present in some sesquiterpenoids plays an important role in antimalarial activity. Its 1,2,4 trioxane ring is unique in nature. After being opened in the plasmodium it liberates singlet oxygen and forms free radicals which in turn produces oxidative damage to the parasites membrane. Artemisinin is hydrophobic in nature and is partitioned into the membrane of the plasmodium. In view of the importance of the title compound (I), C₂₃H₂₄O₅, as an antimalarial drug, this paper reports its crystal structure.

The six-membered cyclohexane ring (A, C1—C6) is a slightly distorted chair, with Cremer & Pople (1975) puckering parameters Q, θ and φ of 0.5395 (13) Å, 172.41 (14)° and 314.6 (10)°, respectively. The tetrahydropyran group (D, C1—C2—C12—C11—O2—C10) has a normal chair configuration with puckering parameters Q, θ and φ of 0.5512 (11) Å, 177.68 (11)° and 124 (3)°, respectively. For an ideal chair θ has a value of 0 or 180°. Similar conformations for rings A and D were found in 9,10-dehydrodeoxyartemisinin (Shu-Hui Li et al., 2006). The seven-membered ring B (C1/C6—C9/O1—C10) contains the important peroxy linkage [O3—O4 = 1.4745 (14) Å]. The six-membered ring C (O1—C9—O3—O4—C1—C10) which contains both an oxygen bridge and a peroxy bridge is best described by a twist-boat conformation with puckering parameters Q, θ and φ of 0.7460 (11) Å, 94.05 (8)° and 276.11 (7)°, respectively. For an ideal twist-boat conformation, θ and φ are 90° and (60n + 30)°, respectively. This conformation is consistent with both 9,10-dehydrodeoxyartemisinin (Shu-Hui Li et al.,(2006) and dihydroartemisinin (Qinghaosu Research Group, 1980).

Related literature

For crystal structures of similar compounds, see: Flippen-Anderson et al. (1989); Yue et al. (2006); Li et al. (2006); Karle & Lin (1995).

For biological activity of artemisinin derivatives in vitro and in vivo, see: Li et al. (2001); Yang et al. (1997); Grace et al. (1998); Maggs et al. (2000).

For endoperoxide sesquiterpene lactone derivatives, see: Venugopalan et al. (1995); Wu et al. (2001); Saxena et al. (2003).

For synthesis of artemisinin and its derivatives, see: Lui et al. (1979); Liu (1980); Robert et al. (2001).

For related literature, see: Allen et al. (1987); Cremer & Pople (1975); Lisgarten et al. (1998); Qinghaosu Research Group (1980); Shen & Zhuang (1984); Wu & Li (1995).

S2. Experimental

α-Artemether (C₁₆H₂₆O₅) was obtained in the pure form from Strides Arco Labs, Mangalore, India. X-ray diffraction quality crystals were grown from acetone (m.p.: 361 K).

S3. Refinement

All H atoms were initially located in a difference Fourier map. The methyl H atoms were then constrained to an ideal geometry with C—H distances of 0.98 Å and U_iso(H) = 1.5U_eq(C), but each group was allowed to rotate freely about its C—C bond. All other H atoms were placed in geometrically idealized positions and constrained to ride on their parent atoms with C—H distances in the range 0.95–1.00 Å and U_iso(H) = 1.2U_eq(C). The amine H was idealized with an N—H distance of 0.86 Å and U_iso(H) = 1.2U_eq(N). Because no strong anomalous scattering atoms are present, the Friedel pairs were merged in the refinement.

Computing details

Data collection: APEX2 (Bruker, 2006); cell refinement: APEX2; data reduction: SAINT (Bruker, 2006); program(s) used to solve structure: SHELXS90 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 (Farrugia, 1997); software used to prepare material for publication: SHELXTL (Bruker, 2000).

Figures

Fig. 1. ORTEP view of α-artemether, (I), showing the atom numbering scheme and 50% probability displacement ellipsoids.

α-Artemether

Crystal data

C16H26O5	Dx = 1.274 Mg m^−3
Mr = 298.37	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P212121	Cell parameters from 7832 reflections
a = 10.315 (2) Å	θ = 2.4–29.3°
b = 13.620 (3) Å	µ = 0.09 mm^−1
c = 11.073 (2) Å	T = 103 K
V = 1555.6 (5) Å^3	Chunk, colorless
Z = 4	0.84 × 0.47 × 0.34 mm
F(000) = 648

Data collection

Bruker APEX II CCD area-detector diffractometer	2434 independent reflections
Radiation source: fine-focus sealed tube	2305 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.029
φ and ω scans	θmax = 29.4°, θmin = 2.4°
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	h = −14→14
Tmin = 0.926, Tmax = 0.969	k = −18→18
17053 measured reflections	l = −15→15

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)] = 0.033	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.087	All H-atom parameters refined
S = 1.12	w = 1/[σ^2(Fo^2) + (0.0581P)^2 + 0.1127P] where P = (Fo^2 + 2Fc^2)/3
2434 reflections	(Δ/σ)max = 0.010
294 parameters	Δρmax = 0.38 e Å^−3
0 restraints	Δρmin = −0.18 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
O1	0.03875 (10)	0.94372 (8)	0.46788 (9)	0.0190 (2)
O2	0.06904 (10)	0.86438 (8)	0.29146 (9)	0.0185 (2)
O3	0.25631 (10)	0.96669 (7)	0.41839 (9)	0.0190 (2)
O4	0.29685 (9)	0.86551 (7)	0.44698 (9)	0.0178 (2)
O5	0.09732 (10)	0.80257 (9)	0.10277 (9)	0.0226 (2)
C1	0.18559 (12)	0.80176 (10)	0.46874 (12)	0.0153 (2)
C2	0.21488 (13)	0.70667 (10)	0.39781 (13)	0.0169 (3)
H2A	0.3047 (19)	0.6846 (15)	0.4181 (18)	0.023 (5)*
C3	0.12631 (15)	0.62201 (11)	0.43812 (14)	0.0217 (3)
H3A	0.032 (2)	0.6358 (17)	0.417 (2)	0.032 (5)*
H3B	0.154 (2)	0.5623 (17)	0.397 (2)	0.029 (5)*
C4	0.13763 (17)	0.60375 (12)	0.57331 (15)	0.0245 (3)
H4A	0.219 (3)	0.584 (2)	0.585 (2)	0.052 (8)*
H4B	0.081 (2)	0.5502 (16)	0.5970 (19)	0.025 (5)*
C5	0.10231 (14)	0.69445 (12)	0.64718 (14)	0.0221 (3)
H5A	0.008 (2)	0.7114 (16)	0.6347 (18)	0.026 (5)*
C6	0.18230 (13)	0.78510 (11)	0.60788 (12)	0.0179 (3)
H6A	0.274 (2)	0.7701 (16)	0.6266 (19)	0.029 (5)*
C7	0.14016 (15)	0.87730 (12)	0.67833 (13)	0.0216 (3)
H7A	0.049 (2)	0.8827 (16)	0.6777 (19)	0.026 (5)*
H7B	0.169 (2)	0.8672 (16)	0.762 (2)	0.029 (5)*
C8	0.19185 (15)	0.97536 (12)	0.63154 (13)	0.0216 (3)
H8A	0.282 (2)	0.9778 (17)	0.640 (2)	0.034 (5)*
H8B	0.1549 (19)	1.0310 (15)	0.6778 (18)	0.023 (5)*
C9	0.15630 (14)	0.99552 (11)	0.49904 (13)	0.0190 (3)
C10	0.06182 (13)	0.85073 (10)	0.41870 (13)	0.0160 (3)
H10A	−0.0143 (17)	0.8105 (14)	0.4358 (16)	0.013 (4)*
C11	0.08704 (13)	0.77595 (11)	0.22462 (12)	0.0174 (3)
H11A	0.0109 (18)	0.7349 (14)	0.2375 (15)	0.011 (4)*
C12	0.21300 (13)	0.72559 (10)	0.26021 (12)	0.0176 (3)
H12A	0.2810 (19)	0.7722 (13)	0.2414 (16)	0.015 (4)*
C13	0.1210 (2)	0.67245 (16)	0.78169 (16)	0.0353 (4)
H13A	0.074 (2)	0.6122 (19)	0.804 (2)	0.041 (6)*
H13B	0.088 (2)	0.7235 (19)	0.835 (2)	0.044 (7)*
H13C	0.208 (3)	0.664 (2)	0.800 (2)	0.054 (8)*
C14	0.13381 (18)	1.10288 (11)	0.46909 (15)	0.0247 (3)
H14A	0.128 (2)	1.1111 (14)	0.3787 (19)	0.023 (5)*
H14B	0.204 (2)	1.1413 (17)	0.499 (2)	0.033 (6)*
H14C	0.054 (2)	1.1227 (19)	0.508 (2)	0.040 (6)*
C15	−0.01422 (18)	0.85153 (13)	0.05639 (15)	0.0274 (3)
H15A	0.001 (2)	0.8640 (18)	−0.025 (2)	0.037 (6)*
H15B	−0.023 (2)	0.9115 (18)	0.093 (2)	0.036 (6)*
H15C	−0.093 (2)	0.8117 (19)	0.070 (2)	0.040 (6)*
C16	0.23452 (16)	0.63220 (12)	0.18597 (15)	0.0255 (3)
H16A	0.308 (2)	0.5962 (16)	0.214 (2)	0.034 (6)*
H16B	0.249 (2)	0.6487 (17)	0.102 (2)	0.036 (6)*
H16C	0.162 (2)	0.5883 (17)	0.194 (2)	0.032 (6)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0164 (4)	0.0208 (5)	0.0198 (5)	0.0027 (4)	−0.0010 (4)	−0.0062 (4)
O2	0.0221 (5)	0.0187 (5)	0.0148 (4)	0.0025 (4)	−0.0020 (4)	−0.0035 (4)
O3	0.0203 (5)	0.0174 (5)	0.0195 (4)	−0.0003 (4)	0.0030 (4)	0.0000 (4)
O4	0.0128 (4)	0.0173 (4)	0.0233 (5)	−0.0006 (4)	0.0008 (4)	0.0007 (4)
O5	0.0253 (5)	0.0278 (5)	0.0146 (4)	0.0030 (4)	−0.0013 (4)	−0.0020 (4)
C1	0.0119 (5)	0.0184 (6)	0.0157 (6)	−0.0011 (5)	0.0001 (5)	−0.0007 (5)
C2	0.0142 (6)	0.0176 (6)	0.0189 (6)	0.0006 (5)	0.0007 (5)	−0.0013 (5)
C3	0.0236 (7)	0.0178 (6)	0.0238 (7)	−0.0032 (5)	0.0012 (6)	−0.0003 (5)
C4	0.0261 (7)	0.0221 (7)	0.0253 (7)	−0.0017 (6)	0.0003 (6)	0.0055 (6)
C5	0.0201 (6)	0.0266 (7)	0.0198 (6)	−0.0046 (6)	0.0014 (6)	0.0022 (6)
C6	0.0142 (6)	0.0244 (7)	0.0151 (6)	−0.0022 (5)	−0.0014 (5)	0.0009 (5)
C7	0.0203 (7)	0.0286 (7)	0.0158 (6)	−0.0024 (6)	0.0008 (5)	−0.0027 (5)
C8	0.0234 (7)	0.0249 (7)	0.0165 (6)	−0.0031 (6)	−0.0017 (6)	−0.0046 (5)
C9	0.0187 (6)	0.0203 (6)	0.0181 (6)	−0.0007 (5)	0.0000 (5)	−0.0043 (5)
C10	0.0131 (5)	0.0190 (6)	0.0158 (6)	0.0011 (5)	−0.0007 (5)	−0.0032 (5)
C11	0.0184 (6)	0.0184 (6)	0.0152 (6)	0.0009 (5)	−0.0003 (5)	−0.0037 (5)
C12	0.0154 (6)	0.0192 (6)	0.0182 (6)	0.0005 (5)	0.0022 (5)	−0.0033 (5)
C13	0.0449 (11)	0.0397 (10)	0.0215 (7)	−0.0108 (8)	0.0022 (8)	0.0063 (7)
C14	0.0302 (8)	0.0199 (7)	0.0240 (7)	0.0018 (6)	−0.0002 (6)	−0.0043 (6)
C15	0.0338 (8)	0.0284 (8)	0.0200 (7)	0.0081 (7)	−0.0053 (7)	−0.0011 (6)
C16	0.0272 (7)	0.0245 (7)	0.0248 (7)	0.0052 (6)	0.0035 (6)	−0.0072 (6)

Geometric parameters (Å, º)

O1—C10	1.3990 (17)	C6—H6A	0.99 (2)
O1—C9	1.4447 (17)	C7—C8	1.529 (2)
O2—C10	1.4231 (16)	C7—H7A	0.94 (2)
O2—C11	1.4258 (17)	C7—H7B	0.98 (2)
O3—C9	1.4198 (17)	C8—C9	1.537 (2)
O3—O4	1.4745 (14)	C8—H8A	0.94 (2)
O4—C1	1.4591 (16)	C8—H8B	0.99 (2)
O5—C11	1.4011 (17)	C9—C14	1.517 (2)
O5—C15	1.426 (2)	C10—H10A	0.976 (18)
C1—C10	1.5434 (18)	C11—C12	1.5211 (19)
C1—C2	1.5445 (19)	C11—H11A	0.974 (19)
C1—C6	1.5576 (19)	C12—C16	1.531 (2)
C2—C3	1.537 (2)	C12—H12A	0.969 (19)
C2—C12	1.5454 (19)	C13—H13A	0.98 (3)
C2—H2A	1.00 (2)	C13—H13B	0.97 (3)
C3—C4	1.522 (2)	C13—H13C	0.92 (3)
C3—H3A	1.02 (2)	C14—H14A	1.01 (2)
C3—H3B	0.97 (2)	C14—H14B	0.95 (2)
C4—C5	1.526 (2)	C14—H14C	0.97 (3)
C4—H4A	0.89 (3)	C15—H15A	0.93 (3)
C4—H4B	0.97 (2)	C15—H15B	0.92 (2)
C5—C13	1.531 (2)	C15—H15C	0.99 (2)
C5—C6	1.547 (2)	C16—H16A	0.96 (2)
C5—H5A	1.01 (2)	C16—H16B	0.97 (2)
C6—C7	1.541 (2)	C16—H16C	0.97 (2)
C10—O1—C9	113.10 (10)	C9—C8—H8B	105.4 (11)
C10—O2—C11	114.23 (11)	H8A—C8—H8B	107.7 (19)
C9—O3—O4	109.24 (10)	O3—C9—O1	108.94 (11)
C1—O4—O3	111.62 (9)	O3—C9—C14	103.90 (12)
C11—O5—C15	114.01 (12)	O1—C9—C14	106.87 (12)
O4—C1—C10	109.52 (11)	O3—C9—C8	112.19 (12)
O4—C1—C2	105.14 (10)	O1—C9—C8	109.93 (12)
C10—C1—C2	109.97 (11)	C14—C9—C8	114.66 (12)
O4—C1—C6	105.50 (10)	O1—C10—O2	106.03 (11)
C10—C1—C6	113.58 (11)	O1—C10—C1	113.09 (11)
C2—C1—C6	112.65 (11)	O2—C10—C1	111.63 (10)
C3—C2—C12	113.82 (11)	O1—C10—H10A	107.2 (11)
C3—C2—C1	111.41 (11)	O2—C10—H10A	107.9 (10)
C12—C2—C1	111.05 (11)	C1—C10—H10A	110.7 (11)
C3—C2—H2A	105.1 (12)	O5—C11—O2	106.93 (11)
C12—C2—H2A	106.5 (12)	O5—C11—C12	107.55 (11)
C1—C2—H2A	108.6 (12)	O2—C11—C12	110.95 (11)
C4—C3—C2	111.26 (12)	O5—C11—H11A	110.5 (10)
C4—C3—H3A	109.5 (13)	O2—C11—H11A	107.6 (10)
C2—C3—H3A	111.2 (13)	C12—C11—H11A	113.1 (11)
C4—C3—H3B	107.2 (13)	C11—C12—C16	111.06 (12)
C2—C3—H3B	108.6 (14)	C11—C12—C2	109.96 (11)
H3A—C3—H3B	109.0 (18)	C16—C12—C2	112.90 (12)
C3—C4—C5	112.13 (13)	C11—C12—H12A	105.5 (11)
C3—C4—H4A	105.5 (18)	C16—C12—H12A	108.9 (11)
C5—C4—H4A	112.9 (18)	C2—C12—H12A	108.2 (10)
C3—C4—H4B	110.0 (12)	C5—C13—H13A	110.0 (15)
C5—C4—H4B	108.6 (13)	C5—C13—H13B	113.9 (15)
H4A—C4—H4B	108 (2)	H13A—C13—H13B	106 (2)
C4—C5—C13	109.45 (15)	C5—C13—H13C	111.1 (17)
C4—C5—C6	111.58 (12)	H13A—C13—H13C	109 (2)
C13—C5—C6	111.26 (14)	H13B—C13—H13C	107 (2)
C4—C5—H5A	110.0 (12)	C9—C14—H14A	109.5 (11)
C13—C5—H5A	107.4 (12)	C9—C14—H14B	109.8 (14)
C6—C5—H5A	107.0 (12)	H14A—C14—H14B	109.2 (19)
C7—C6—C5	110.94 (12)	C9—C14—H14C	107.5 (15)
C7—C6—C1	112.84 (12)	H14A—C14—H14C	111 (2)
C5—C6—C1	113.96 (12)	H14B—C14—H14C	110 (2)
C7—C6—H6A	109.3 (13)	O5—C15—H15A	107.2 (15)
C5—C6—H6A	106.6 (13)	O5—C15—H15B	109.5 (15)
C1—C6—H6A	102.5 (12)	H15A—C15—H15B	107 (2)
C8—C7—C6	116.24 (12)	O5—C15—H15C	110.8 (14)
C8—C7—H7A	106.1 (13)	H15A—C15—H15C	113 (2)
C6—C7—H7A	109.9 (13)	H15B—C15—H15C	110 (2)
C8—C7—H7B	109.7 (13)	C12—C16—H16A	111.5 (14)
C6—C7—H7B	106.2 (13)	C12—C16—H16B	110.2 (14)
H7A—C7—H7B	108.5 (18)	H16A—C16—H16B	108 (2)
C7—C8—C9	113.35 (12)	C12—C16—H16C	110.5 (14)
C7—C8—H8A	110.1 (15)	H16A—C16—H16C	105.7 (17)
C9—C8—H8A	109.1 (15)	H16B—C16—H16C	111 (2)
C7—C8—H8B	111.0 (11)
C9—O3—O4—C1	43.92 (13)	O4—O3—C9—C8	49.83 (14)
O3—O4—C1—C10	16.81 (13)	C10—O1—C9—O3	30.95 (16)
O3—O4—C1—C2	134.93 (10)	C10—O1—C9—C14	142.63 (12)
O3—O4—C1—C6	−105.80 (11)	C10—O1—C9—C8	−92.36 (13)
O4—C1—C2—C3	164.58 (11)	C7—C8—C9—O3	−95.08 (15)
C10—C1—C2—C3	−77.60 (14)	C7—C8—C9—O1	26.31 (17)
C6—C1—C2—C3	50.20 (15)	C7—C8—C9—C14	146.71 (14)
O4—C1—C2—C12	−67.41 (13)	C9—O1—C10—O2	−91.32 (12)
C10—C1—C2—C12	50.41 (14)	C9—O1—C10—C1	31.32 (15)
C6—C1—C2—C12	178.20 (11)	C11—O2—C10—O1	−177.53 (10)
C12—C2—C3—C4	177.13 (12)	C11—O2—C10—C1	58.91 (14)
C1—C2—C3—C4	−56.37 (16)	O4—C1—C10—O1	−57.04 (14)
C2—C3—C4—C5	58.87 (17)	C2—C1—C10—O1	−172.11 (11)
C3—C4—C5—C13	−177.72 (14)	C6—C1—C10—O1	60.61 (15)
C3—C4—C5—C6	−54.13 (18)	O4—C1—C10—O2	62.43 (14)
C4—C5—C6—C7	176.82 (12)	C2—C1—C10—O2	−52.64 (14)
C13—C5—C6—C7	−60.62 (18)	C6—C1—C10—O2	−179.92 (11)
C4—C5—C6—C1	48.15 (17)	C15—O5—C11—O2	−60.39 (15)
C13—C5—C6—C1	170.71 (14)	C15—O5—C11—C12	−179.62 (12)
O4—C1—C6—C7	71.41 (14)	C10—O2—C11—O5	−177.65 (11)
C10—C1—C6—C7	−48.55 (15)	C10—O2—C11—C12	−60.64 (14)
C2—C1—C6—C7	−174.43 (11)	O5—C11—C12—C16	−61.73 (15)
O4—C1—C6—C5	−160.89 (11)	O2—C11—C12—C16	−178.35 (12)
C10—C1—C6—C5	79.14 (15)	O5—C11—C12—C2	172.58 (11)
C2—C1—C6—C5	−46.73 (16)	O2—C11—C12—C2	55.96 (15)
C5—C6—C7—C8	−168.34 (12)	C3—C2—C12—C11	74.34 (14)
C1—C6—C7—C8	−39.08 (17)	C1—C2—C12—C11	−52.34 (15)
C6—C7—C8—C9	57.24 (17)	C3—C2—C12—C16	−50.30 (17)
O4—O3—C9—O1	−72.13 (13)	C1—C2—C12—C16	−176.99 (11)
O4—O3—C9—C14	174.24 (10)