A new potent fusidic acid analogue

The crystal structure of the compound, 17S,20S-di­hydro­fusidic acid diethyl­ene glycol hydrate, C₃₁H₅₀O₆·C₄H₁₀O₃·H₂O, consists of 17S,20S-di­hydro­fusidic acid, diethyl­ene glycol and water. The fusidic acid moiety contains three six-membered rings and one five-membered ring. The fused-ring system adopts a chair, a twist boat, a chair and an envelope conformation. The crystal packing is influenced by hydrogen bonds.

Key indicators

• Single-crystal X-ray study
• T = 120 K
• Mean [sigma](C-C) = 0.005 Å
• R factor = 0.069
• wR factor = 0.175
• Data-to-parameter ratio = 12.5

checkCIF results

No syntax errors found



ADDSYM reports no extra symmetry


 Alert Level B:



RINTA_01  Alert B The value of Rint is greater than 0.15
          Rint given   0.182


 Alert Level C:



REFLT_03
         From the CIF: _diffrn_reflns_theta_max           29.66
         From the CIF: _reflns_number_total               5146
         TEST2: Reflns within _diffrn_reflns_theta_max
         Count of symmetry unique reflns         5491
         Completeness (_total/calc)             93.72%
          Alert C: < 95% complete

PLAT_213  Alert C Atom  C21    has ADP max/min Ratio ...........       3.20

General Notes



REFLT_03
         From the CIF: _diffrn_reflns_theta_max           29.66
         From the CIF: _reflns_number_total               5146
         Count of symmetry unique reflns         5491
         Completeness (_total/calc)             93.72%
         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
          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.


 0 Alert Level A = Potentially serious problem

 1 Alert Level B = Potential problem

 2 Alert Level C = Please check

---

S1. Comment

Fusidic acid belongs to a family of naturally occurring antibiotics known as fusidanes having in common a tetracyclic ring system with the unique chair–boat–chair conformation, a carboxylic acid bearing side chain linked to the ring system at C17 via a double bond and an acetate group at C16. The fusidanes show high degree of antibacterial activity and have a similar spectrum. Fusidic acid, the most potent of the fusidanes, was first isolated from Fusidium coccineum in 1960 (Godtfredsen et al., 1962) and has since 1962 been used clinically in treatment of both topical and systemic infections caused by staphylococci. The clinical importance of fusidic acid is furthermore due to its excellent distribution in various tissues, low degree of toxicity and allergic reactions and the absence of cross-resistance with other clinically used antibiotics (Christiansen, 1999; Turnidge & Collign, 1999; Collign & Turnidge, 1999; Spelman, 1999). The structure–activity relationship (SAR) of fusidic acid has earlier undergone extensive studies (von Daehne et al., 1979) and a large number of related analogues have been prepared. However, only a very few of these analogues showed activities comparable with that of fusidic acid and most of them had a similar antibacterial spectrum and were cross-resistant. In spite of extensive functional and structural modifications of the fusidic acid molecule, studies of including side-chain modifications are limited (Godtfredsen et al., 1965; von Daehne et al., 1979). As part of our renewed interest in improving the antibiotic properties of fusidic acid, we decided to focus on the relatively unexplored side chain. Two saturated fusidic acid analogues were synthesized several years ago (Godtfredsen et al., 1966). They have in common the 17R configuration but are epimers at C20 and were both found to be virtually inactive. The corresponding analogues with the opposite 17S configuration have not been available until now due to the lack of appropriate synthetic methodology. We recently developed such a methodology for the preparation of 17S,20R– and 17S,20S-dihydrofusidic acid (Duvold et al., 2001). Antibacterial testing has revealed potent antibacterial activities of one of these epimers, the 17S,20S-dihydrofusidic acid.

The molecule of 17S,20S-dihydrofusidic acid is composed of four fused rings of which three are six-membered rings, A (C1—C5,C10), B (C5—C10) and C (C8—C9,C11—C14) and one is five-membered, D (C13—C17). The rings A, B and C adopt chair, twist boat, chair conformations respectively and D is in an envelope form with apex at C14. The same conformations of the tetracyclic ring system were found in fusidic acid methyl ester 3-p-bromobenzen (Cooper & Hodgkin, 1968). Bond lengths and angles of the present structure are in the expected ranges. The molecular geometry and the numbering are displayed in Fig. 1. The acetate group at C16 is twisted from the plane E (C13/C15—C17) with torsion angles of 92.3 (4) (C15—C16—O3—C1A) and -150.3 (3)° (C17—C16—O3—C1A). Also, the carboxylic acid group is twisted from plane E the torsion angles being -179.2 (3) (C13—C17—C20—C21) and 57.5 (4)° (C16—C17—C20—C21). The major side chain attached at C17 is elongated as is the case with saturated side chains. It does not curl back on itself as found in fusidic acid methyl ester 3-p-bromobenzen (Cooper & Hodgkin, 1968), where the C17–C20 bond is a double bond. The crystal packing is influenced by hydrogen bonds (Table 2). The O1 and O2 hydroxyl groups form hydrogen bonds with the carboxylic acid group.

There are also hydrogen bonds between the water molecule and the O1 and O2 hydoxyl groups. The carbolic acid group is involved in hydrogen bonds with the diethylene ether. Finally, the symetry related diethylene glycol molecules are linked by hydrogen-bond interactions through O8 and O9.

S2. Experimental

See above for synthesis details.

S3. Refinement

The absolute configuration of the structure could not be determined due to the lack of heavy atoms. Therefore, the Friedel pairs were merged. The high values of R_int and R are related to the rather poor quality of the crystals. The H atoms were placed in calculated positions (C—H = 0.99 and 1.00 Å and O—H = 0.84 Å).

Computing details

Data collection: SMART (Siemens, 1995); cell refinement: SAINT (Siemens, 1995); data reduction: SAINT; program(s) used to solve structure: SHELXTL/PC (Sheldrick, 1994); program(s) used to refine structure: SHELXTL/PC; molecular graphics: SHELXTL/PC; software used to prepare material for publication: SHELXTL/PC.

Figures

Fig. 1. A view of 17S,20S-dihydrofisidic acid showing the atomic numbering. Displacement ellipsoids are drawn at the 50% probability level. Selected H atoms have been omitted for clarity.

17S,20S-Dihydrofusidic acid diethylene glycol hydrate

Crystal data

C31H50O6·C4H10O3·H2O	Dx = 1.217 Mg m^−3 Dm = no Mg m^−3 Dm measured by not measured
Mr = 642.85	Melting point: no K
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
a = 12.6246 (3) Å	Cell parameters from no reflections
b = 13.0962 (3) Å	θ = 1.8–29.7°
c = 21.2134 (5) Å	µ = 0.09 mm^−1
V = 3507.30 (14) Å^3	T = 120 K
Z = 4	Block, colourless
F(000) = 1408	0.33 × 0.33 × 0.26 mm

Data collection

Siemens SMART CCD Platform diffractometer	Rint = 0.182
Radiation source: rmal-focus sealed tube	θmax = 29.7°, θmin = 1.8°
ω scans	h = −17→17
24333 measured reflections	k = −17→10
5146 independent reflections	l = −28→28
4433 reflections with I > 2σ(I)

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)] = 0.069	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.175	H-atom parameters constrained
S = 1.15	w = 1/[σ^2(Fo^2) + (0.0767P)^2 + 2.9938P] where P = (Fo^2 + 2Fc^2)/3
5146 reflections	(Δ/σ)max = 0.003
412 parameters	Δρmax = 0.53 e Å^−3
0 restraints	Δρmin = −0.52 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 on F² for ALL reflections except for 4 with very negative F² or flagged by the user for potential systematic errors. Weighted R-factors wR and all goodnesses of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The observed criterion of F² > σ(F²) is used only for calculating R-factors etc. and is t 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
C1	−0.1826 (3)	0.8289 (2)	−0.2993 (2)	0.0171 (7)
H10	−0.1625 (3)	0.7569 (2)	−0.2917 (2)	0.021*
H12	−0.2481 (3)	0.8428 (2)	−0.2751 (2)	0.021*
C2	−0.2058 (3)	0.8433 (3)	−0.3701 (2)	0.0202 (7)
H21	−0.1431 (3)	0.8220 (3)	−0.3949 (2)	0.024*
H22	−0.2660 (3)	0.7991 (3)	−0.3824 (2)	0.024*
C3	−0.2323 (3)	0.9537 (3)	−0.3851 (2)	0.0195 (7)
H3	−0.2437 (3)	0.9606 (3)	−0.4316 (2)	0.023*
O1	−0.3298 (2)	0.9757 (2)	−0.35296 (13)	0.0204 (5)
H1	−0.3474	1.0365	−0.3600	0.024*
C4	−0.1419 (3)	1.0246 (3)	−0.3651 (2)	0.0181 (7)
H4	−0.0770 (3)	1.0047 (3)	−0.3891 (2)	0.022*
C5	−0.1180 (3)	1.0120 (2)	−0.2939 (2)	0.0159 (6)
H5	−0.1844 (3)	1.0314 (2)	−0.2711 (2)	0.019*
C6	−0.0310 (3)	1.0848 (3)	−0.2698 (2)	0.0199 (7)
H61	−0.0618 (3)	1.1539 (3)	−0.2652 (2)	0.024*
H62	0.0255 (3)	1.0888 (3)	−0.3020 (2)	0.024*
C7	0.0198 (3)	1.0533 (3)	−0.2059 (2)	0.0182 (7)
H71	0.0833 (3)	1.0111 (3)	−0.2142 (2)	0.022*
H72	0.0428 (3)	1.1155 (3)	−0.1832 (2)	0.022*
C8	−0.0573 (3)	0.9928 (2)	−0.1639 (2)	0.0145 (6)
C9	−0.0795 (3)	0.8903 (2)	−0.2003 (2)	0.0127 (6)
H9	−0.0105 (3)	0.8534 (2)	−0.1963 (2)	0.015*
C10	−0.0936 (3)	0.8990 (2)	−0.2749 (2)	0.0153 (6)
C11	−0.1559 (3)	0.8195 (2)	−0.1653 (2)	0.0145 (6)
H11	−0.1640 (3)	0.7553 (2)	−0.1904 (2)	0.017*
O2	−0.2589 (2)	0.8644 (2)	−0.15731 (12)	0.0179 (5)
H2	−0.2985	0.8234	−0.1380	0.022*
C12	−0.1107 (3)	0.7915 (2)	−0.1003 (2)	0.0141 (6)
H121	−0.1630 (3)	0.7503 (2)	−0.0766 (2)	0.017*
H122	−0.0457 (3)	0.7501 (2)	−0.1056 (2)	0.017*
C13	−0.0849 (3)	0.8888 (2)	−0.0638 (2)	0.0143 (6)
H13	−0.1534 (3)	0.9272 (2)	−0.0638 (2)	0.017*
C14	−0.0074 (3)	0.9621 (2)	−0.0980 (2)	0.0155 (6)
C15	−0.0006 (3)	1.0475 (2)	−0.0484 (2)	0.0201 (7)
H151	−0.0628 (3)	1.0932 (2)	−0.0515 (2)	0.024*
H152	0.0644 (3)	1.0886 (2)	−0.0546 (2)	0.024*
C16	0.0019 (3)	0.9933 (2)	0.0164 (2)	0.0171 (7)
H16	−0.0382 (3)	1.0345 (2)	0.0482 (2)	0.020*
O3	0.1096 (2)	0.9774 (2)	0.03791 (13)	0.0198 (5)
C17	−0.0531 (3)	0.8859 (2)	0.0072 (2)	0.0140 (6)
H17	−0.1211 (3)	0.8894 (2)	0.0313 (2)	0.017*
C28	−0.1687 (3)	1.1358 (3)	−0.3818 (2)	0.0239 (8)
H281	−0.1084 (3)	1.1798 (3)	−0.3714 (2)	0.029*
H282	−0.2309 (3)	1.1577 (3)	−0.3578 (2)	0.029*
H283	−0.1839 (3)	1.1408 (3)	−0.4270 (2)	0.029*
C30	−0.1550 (3)	1.0622 (2)	−0.1521 (2)	0.0178 (7)
H301	−0.1931 (3)	1.0383 (2)	−0.1146 (2)	0.021*
H302	−0.2022 (3)	1.0596 (2)	−0.1887 (2)	0.021*
H303	−0.1314 (3)	1.1327 (2)	−0.1454 (2)	0.021*
C19	0.0120 (3)	0.8648 (3)	−0.3060 (2)	0.0197 (7)
H191	0.0698 (3)	0.9084 (3)	−0.2910 (2)	0.024*
H192	0.0061 (3)	0.8707 (3)	−0.3519 (2)	0.024*
H193	0.0268 (3)	0.7937 (3)	−0.2947 (2)	0.024*
C18	0.1049 (3)	0.9161 (3)	−0.1050 (2)	0.0175 (7)
H181	0.1045 (3)	0.8646 (3)	−0.1385 (2)	0.021*
H182	0.1261 (3)	0.8841 (3)	−0.0652 (2)	0.021*
H183	0.1552 (3)	0.9703 (3)	−0.1158 (2)	0.021*
C1A	0.1532 (4)	1.0492 (3)	0.0746 (2)	0.0242 (8)
O4	0.1087 (3)	1.1294 (2)	0.0873 (2)	0.0385 (8)
C2A	0.2609 (3)	1.0186 (3)	0.0967 (2)	0.0273 (8)
H2A1	0.3077 (3)	1.0095 (3)	0.0603 (2)	0.033*
H2A2	0.2561 (3)	0.9543 (3)	0.1202 (2)	0.033*
H2A3	0.2897 (3)	1.0720 (3)	0.1242 (2)	0.033*
C20	0.0106 (3)	0.7963 (2)	0.0365 (2)	0.0155 (6)
H20	0.0808 (3)	0.7903 (2)	0.0151 (2)	0.019*
C21	0.0270 (3)	0.8168 (2)	0.1074 (2)	0.0176 (7)
O5	0.1139 (2)	0.7954 (2)	0.13239 (13)	0.0208 (5)
O6	−0.0517 (2)	0.8505 (2)	0.13700 (12)	0.0221 (6)
H6	−0.0354	0.8593	0.1750	0.027*
C22	−0.0498 (3)	0.6941 (2)	0.0314 (2)	0.0213 (8)
H221	−0.1227 (3)	0.7042 (2)	0.0474 (2)	0.026*
H222	−0.0551 (3)	0.6752 (2)	−0.0136 (2)	0.026*
C23	0.0010 (3)	0.6042 (2)	0.0676 (2)	0.0213 (7)
H231	0.0762 (3)	0.5972 (2)	0.0551 (2)	0.026*
H232	−0.0015 (3)	0.6181 (2)	0.1135 (2)	0.026*
C24	−0.0573 (4)	0.5064 (3)	0.0535 (2)	0.0239 (8)
H24	−0.1324	0.5107	0.0530	0.029*
C25	−0.0158 (4)	0.4141 (3)	0.0414 (2)	0.0249 (8)
C26	−0.0863 (5)	0.3250 (3)	0.0250 (2)	0.0401 (12)
H261	−0.0699 (5)	0.2673 (3)	0.0528 (2)	0.048*
H262	−0.0742 (5)	0.3050 (3)	−0.0189 (2)	0.048*
H263	−0.1606 (5)	0.3447 (3)	0.0306 (2)	0.048*
C27	0.0996 (4)	0.3915 (3)	0.0432 (2)	0.0356 (11)
H271	0.1195 (4)	0.3524 (3)	0.0057 (2)	0.043*
H272	0.1160 (4)	0.3516 (3)	0.0811 (2)	0.043*
H273	0.1395 (4)	0.4557 (3)	0.0442 (2)	0.043*
O10	0.1041 (2)	0.5226 (2)	0.22720 (14)	0.0215 (5)
H101	0.120 (4)	0.527 (4)	0.269 (2)	0.026*
H102	0.145 (4)	0.551 (4)	0.200 (3)	0.026*
O7	0.0607 (3)	0.3187 (2)	0.2373 (2)	0.0313 (7)
C31	−0.1206 (3)	0.3673 (3)	0.2040 (2)	0.0242 (8)
H311	−0.0894 (3)	0.4255 (3)	0.1806 (2)	0.029*
H312	−0.1826 (3)	0.3428 (3)	0.1797 (2)	0.029*
C32	−0.0388 (3)	0.2816 (3)	0.2077 (2)	0.0235 (8)
H321	−0.0679 (3)	0.2243 (3)	0.2327 (2)	0.028*
H322	−0.0234 (3)	0.2560 (3)	0.1647 (2)	0.028*
O8	−0.1553 (3)	0.4019 (2)	0.26314 (15)	0.0360 (8)
H8	−0.1402	0.3609	0.2903	0.053*
C33	0.1545 (3)	0.2500 (3)	0.2275 (2)	0.0228 (8)
H331	0.2196 (3)	0.2856 (3)	0.2414 (2)	0.027*
H332	0.1618 (3)	0.2346 (3)	0.1820 (2)	0.027*
C34	0.1429 (4)	0.1505 (3)	0.2641 (3)	0.0361 (11)
H341	0.1318 (4)	0.1650 (3)	0.3094 (3)	0.043*
H342	0.0810 (4)	0.1116 (3)	0.2483 (3)	0.043*
O9	0.2362 (3)	0.0933 (2)	0.2556 (2)	0.0319 (7)
H90	0.2210	0.0348	0.2451	0.038*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.023 (2)	0.0058 (12)	0.022 (2)	−0.0003 (12)	−0.0022 (14)	−0.0007 (12)
C2	0.028 (2)	0.0103 (14)	0.022 (2)	0.0020 (13)	−0.0001 (15)	−0.0022 (13)
C3	0.028 (2)	0.0096 (13)	0.021 (2)	0.0001 (13)	−0.0017 (15)	0.0014 (13)
O1	0.0222 (13)	0.0107 (10)	0.0282 (13)	0.0005 (10)	−0.0012 (11)	0.0052 (10)
C4	0.022 (2)	0.0100 (13)	0.022 (2)	0.0002 (13)	−0.0013 (14)	0.0045 (13)
C5	0.020 (2)	0.0075 (12)	0.020 (2)	−0.0004 (12)	0.0008 (13)	0.0010 (12)
C6	0.023 (2)	0.0087 (13)	0.028 (2)	−0.0055 (13)	−0.0005 (15)	0.0039 (13)
C7	0.020 (2)	0.0107 (13)	0.024 (2)	−0.0064 (13)	−0.0022 (14)	0.0033 (13)
C8	0.017 (2)	0.0052 (12)	0.021 (2)	−0.0011 (11)	−0.0022 (13)	0.0013 (12)
C9	0.0150 (14)	0.0039 (11)	0.0191 (15)	0.0005 (11)	−0.0007 (12)	−0.0002 (11)
C10	0.020 (2)	0.0057 (12)	0.020 (2)	0.0008 (12)	0.0020 (13)	−0.0001 (12)
C11	0.019 (2)	0.0047 (12)	0.020 (2)	−0.0030 (12)	0.0003 (13)	−0.0005 (11)
O2	0.0172 (12)	0.0085 (9)	0.0280 (13)	−0.0034 (9)	0.0012 (10)	0.0037 (10)
C12	0.018 (2)	0.0054 (12)	0.0185 (15)	−0.0022 (11)	−0.0025 (13)	0.0017 (11)
C13	0.017 (2)	0.0056 (12)	0.020 (2)	−0.0006 (11)	−0.0022 (13)	0.0021 (11)
C14	0.019 (2)	0.0052 (12)	0.022 (2)	−0.0005 (12)	−0.0008 (13)	−0.0010 (11)
C15	0.031 (2)	0.0037 (12)	0.026 (2)	0.0000 (13)	−0.005 (2)	0.0003 (12)
C16	0.021 (2)	0.0080 (13)	0.022 (2)	0.0007 (12)	−0.0031 (14)	−0.0012 (12)
O3	0.0255 (14)	0.0093 (10)	0.0248 (12)	−0.0010 (10)	−0.0054 (11)	−0.0027 (10)
C17	0.018 (2)	0.0042 (12)	0.0196 (15)	0.0014 (11)	−0.0015 (13)	−0.0014 (11)
C28	0.030 (2)	0.0116 (14)	0.030 (2)	−0.0029 (14)	−0.003 (2)	0.0065 (14)
C30	0.024 (2)	0.0052 (12)	0.024 (2)	0.0023 (12)	0.0009 (15)	−0.0007 (12)
C19	0.021 (2)	0.0127 (14)	0.025 (2)	0.0039 (13)	0.0037 (14)	0.0016 (14)
C18	0.015 (2)	0.0119 (13)	0.025 (2)	−0.0011 (12)	−0.0023 (14)	0.0014 (13)
C1A	0.031 (2)	0.017 (2)	0.025 (2)	−0.006 (2)	−0.004 (2)	−0.0010 (14)
O4	0.048 (2)	0.0171 (13)	0.050 (2)	0.0016 (14)	−0.013 (2)	−0.0132 (14)
C2A	0.027 (2)	0.026 (2)	0.029 (2)	−0.010 (2)	−0.005 (2)	−0.001 (2)
C20	0.021 (2)	0.0058 (12)	0.0194 (15)	0.0033 (12)	−0.0011 (14)	−0.0012 (11)
C21	0.026 (2)	0.0031 (12)	0.024 (2)	−0.0019 (12)	−0.0028 (14)	−0.0019 (12)
O5	0.0266 (14)	0.0097 (10)	0.0260 (13)	0.0055 (10)	−0.0055 (12)	−0.0029 (10)
O6	0.0284 (14)	0.0185 (12)	0.0195 (11)	0.0065 (11)	0.0006 (11)	0.0027 (10)
C22	0.028 (2)	0.0075 (13)	0.028 (2)	0.0010 (13)	−0.009 (2)	0.0015 (13)
C23	0.031 (2)	0.0060 (13)	0.027 (2)	0.0002 (14)	−0.004 (2)	0.0004 (13)
C24	0.035 (2)	0.0107 (14)	0.026 (2)	−0.0001 (15)	−0.003 (2)	0.0013 (13)
C25	0.043 (2)	0.0105 (15)	0.022 (2)	−0.004 (2)	−0.003 (2)	0.0008 (13)
C26	0.066 (4)	0.012 (2)	0.042 (3)	−0.010 (2)	−0.008 (2)	0.004 (2)
C27	0.047 (3)	0.012 (2)	0.048 (3)	0.001 (2)	0.009 (2)	−0.001 (2)
O10	0.0250 (14)	0.0124 (10)	0.0271 (14)	−0.0032 (10)	0.0027 (12)	0.0032 (10)
O7	0.038 (2)	0.0199 (13)	0.036 (2)	−0.0035 (13)	−0.0006 (14)	−0.0011 (12)
C31	0.031 (2)	0.0146 (15)	0.027 (2)	−0.0030 (15)	−0.004 (2)	0.0026 (14)
C32	0.030 (2)	0.0129 (15)	0.028 (2)	−0.0043 (14)	0.001 (2)	−0.0034 (14)
O8	0.057 (2)	0.0208 (14)	0.030 (2)	0.0200 (15)	0.006 (2)	0.0061 (12)
C33	0.028 (2)	0.0121 (15)	0.029 (2)	−0.0044 (14)	0.004 (2)	−0.0034 (14)
C34	0.031 (2)	0.015 (2)	0.063 (3)	0.002 (2)	0.015 (2)	0.008 (2)
O9	0.027 (2)	0.0179 (12)	0.050 (2)	−0.0013 (12)	−0.0005 (14)	−0.0047 (13)

Geometric parameters (Å, º)

C1—C2	1.541 (5)	C14—C18	1.547 (5)
C1—C10	1.541 (5)	C15—C16	1.548 (5)
C2—C3	1.518 (5)	C16—O3	1.449 (5)
C3—O1	1.437 (5)	C16—C17	1.581 (4)
C3—C4	1.532 (5)	O3—C1A	1.338 (4)
C4—C28	1.537 (5)	C17—C20	1.552 (4)
C4—C5	1.549 (5)	C1A—O4	1.221 (5)
C5—C6	1.540 (5)	C1A—C2A	1.494 (6)
C5—C10	1.564 (4)	C20—C21	1.540 (5)
C6—C7	1.555 (5)	C20—C22	1.545 (5)
C7—C8	1.539 (5)	C21—O5	1.250 (5)
C8—C30	1.553 (5)	C21—O6	1.256 (5)
C8—C9	1.574 (4)	C22—C23	1.544 (5)
C8—C14	1.585 (5)	C23—C24	1.507 (5)
C9—C11	1.530 (4)	C24—C25	1.342 (5)
C9—C10	1.598 (5)	C25—C27	1.488 (7)
C10—C19	1.554 (5)	C25—C26	1.509 (6)
C11—O2	1.437 (4)	O7—C32	1.487 (5)
C11—C12	1.535 (5)	O7—C33	1.502 (5)
C12—C13	1.528 (4)	C31—O8	1.405 (5)
C13—C14	1.551 (5)	C31—C32	1.528 (6)
C13—C17	1.558 (5)	C33—C34	1.524 (5)
C14—C15	1.538 (5)	C34—O9	1.408 (5)
C2—C1—C10	113.1 (3)	C15—C14—C18	107.3 (3)
C3—C2—C1	111.3 (3)	C15—C14—C13	99.5 (3)
O1—C3—C2	106.3 (3)	C18—C14—C13	112.5 (3)
O1—C3—C4	112.6 (3)	C15—C14—C8	116.1 (3)
C2—C3—C4	110.8 (3)	C18—C14—C8	112.2 (3)
C3—C4—C28	110.3 (3)	C13—C14—C8	108.6 (3)
C3—C4—C5	110.6 (3)	C14—C15—C16	106.0 (3)
C28—C4—C5	111.7 (3)	O3—C16—C15	111.3 (3)
C6—C5—C4	113.3 (3)	O3—C16—C17	108.9 (3)
C6—C5—C10	111.1 (3)	C15—C16—C17	106.8 (3)
C4—C5—C10	112.9 (3)	C1A—O3—C16	117.9 (3)
C5—C6—C7	114.7 (3)	C20—C17—C13	122.7 (3)
C8—C7—C6	112.4 (3)	C20—C17—C16	113.3 (3)
C7—C8—C30	107.1 (3)	C13—C17—C16	102.2 (3)
C7—C8—C9	105.5 (3)	O4—C1A—O3	122.9 (4)
C30—C8—C9	115.9 (3)	O4—C1A—C2A	125.4 (4)
C7—C8—C14	113.0 (3)	O3—C1A—C2A	111.7 (3)
C30—C8—C14	108.8 (3)	C21—C20—C22	106.6 (3)
C9—C8—C14	106.7 (2)	C21—C20—C17	109.3 (3)
C11—C9—C8	113.1 (3)	C22—C20—C17	111.8 (3)
C11—C9—C10	117.0 (3)	O5—C21—O6	124.1 (3)
C8—C9—C10	116.4 (2)	O5—C21—C20	119.6 (3)
C1—C10—C19	108.2 (3)	O6—C21—C20	116.2 (3)
C1—C10—C5	109.5 (3)	C23—C22—C20	114.9 (3)
C19—C10—C5	109.5 (3)	C24—C23—C22	110.3 (3)
C1—C10—C9	111.8 (3)	C25—C24—C23	127.8 (4)
C19—C10—C9	107.7 (3)	C24—C25—C27	123.8 (4)
C5—C10—C9	110.1 (3)	C24—C25—C26	120.7 (4)
O2—C11—C9	112.3 (3)	C27—C25—C26	115.5 (4)
O2—C11—C12	109.2 (3)	C32—O7—C33	114.3 (3)
C9—C11—C12	110.2 (3)	O8—C31—C32	113.7 (3)
C13—C12—C11	109.6 (2)	O7—C32—C31	110.6 (3)
C12—C13—C14	114.4 (3)	O7—C33—C34	111.5 (3)
C12—C13—C17	121.6 (3)	O9—C34—C33	108.0 (3)
C14—C13—C17	107.8 (3)
C10—C1—C2—C3	−56.0 (4)	C12—C13—C14—C18	−66.4 (4)
C1—C2—C3—O1	−65.0 (4)	C17—C13—C14—C18	72.2 (3)
C1—C2—C3—C4	57.6 (4)	C12—C13—C14—C8	58.4 (3)
O1—C3—C4—C28	−62.3 (4)	C17—C13—C14—C8	−163.0 (3)
C2—C3—C4—C28	178.8 (3)	C7—C8—C14—C15	77.0 (4)
O1—C3—C4—C5	61.7 (4)	C30—C8—C14—C15	−41.8 (4)
C2—C3—C4—C5	−57.2 (4)	C9—C8—C14—C15	−167.5 (3)
C3—C4—C5—C6	−177.4 (3)	C7—C8—C14—C18	−47.0 (3)
C28—C4—C5—C6	−54.2 (4)	C30—C8—C14—C18	−165.8 (3)
C3—C4—C5—C10	55.1 (4)	C9—C8—C14—C18	68.5 (3)
C28—C4—C5—C10	178.3 (3)	C7—C8—C14—C13	−172.0 (3)
C4—C5—C6—C7	−161.9 (3)	C30—C8—C14—C13	69.3 (3)
C10—C5—C6—C7	−33.5 (4)	C9—C8—C14—C13	−56.4 (3)
C5—C6—C7—C8	−28.7 (4)	C18—C14—C15—C16	−77.8 (3)
C6—C7—C8—C30	−59.1 (4)	C13—C14—C15—C16	39.5 (4)
C6—C7—C8—C9	65.0 (4)	C8—C14—C15—C16	155.7 (3)
C6—C7—C8—C14	−178.9 (3)	C14—C15—C16—O3	94.0 (3)
C7—C8—C9—C11	−179.8 (3)	C14—C15—C16—C17	−24.7 (4)
C30—C8—C9—C11	−61.5 (4)	C15—C16—O3—C1A	92.3 (4)
C14—C8—C9—C11	59.8 (4)	C17—C16—O3—C1A	−150.3 (3)
C7—C8—C9—C10	−40.1 (4)	C12—C13—C17—C20	33.2 (5)
C30—C8—C9—C10	78.2 (4)	C14—C13—C17—C20	−101.8 (4)
C14—C8—C9—C10	−160.5 (3)	C12—C13—C17—C16	161.4 (3)
C2—C1—C10—C19	−67.3 (4)	C14—C13—C17—C16	26.4 (3)
C2—C1—C10—C5	52.0 (4)	O3—C16—C17—C20	12.6 (4)
C2—C1—C10—C9	174.3 (3)	C15—C16—C17—C20	132.9 (3)
C6—C5—C10—C1	179.6 (3)	O3—C16—C17—C13	−121.3 (3)
C4—C5—C10—C1	−51.9 (4)	C15—C16—C17—C13	−1.0 (4)
C6—C5—C10—C19	−62.0 (4)	C16—O3—C1A—O4	−4.6 (6)
C4—C5—C10—C19	66.6 (4)	C16—O3—C1A—C2A	175.8 (3)
C6—C5—C10—C9	56.2 (4)	C13—C17—C20—C21	−179.2 (3)
C4—C5—C10—C9	−175.2 (3)	C16—C17—C20—C21	57.5 (4)
C11—C9—C10—C1	−2.0 (4)	C13—C17—C20—C22	−61.4 (4)
C8—C9—C10—C1	−140.1 (3)	C16—C17—C20—C22	175.3 (3)
C11—C9—C10—C19	−120.7 (3)	C22—C20—C21—O5	98.7 (4)
C8—C9—C10—C19	101.2 (3)	C17—C20—C21—O5	−140.3 (3)
C11—C9—C10—C5	120.0 (3)	C22—C20—C21—O6	−78.1 (4)
C8—C9—C10—C5	−18.1 (4)	C17—C20—C21—O6	42.9 (4)
C8—C9—C11—O2	62.4 (4)	C21—C20—C22—C23	−52.5 (4)
C10—C9—C11—O2	−77.0 (3)	C17—C20—C22—C23	−171.9 (3)
C8—C9—C11—C12	−59.5 (3)	C20—C22—C23—C24	−173.7 (3)
C10—C9—C11—C12	161.0 (3)	C22—C23—C24—C25	137.0 (4)
O2—C11—C12—C13	−69.0 (3)	C23—C24—C25—C27	3.2 (7)
C9—C11—C12—C13	54.8 (4)	C23—C24—C25—C26	−177.0 (4)
C11—C12—C13—C14	−56.7 (4)	C33—O7—C32—C31	−164.3 (3)
C11—C12—C13—C17	171.0 (3)	O8—C31—C32—O7	−65.0 (4)
C12—C13—C14—C15	−179.7 (3)	C32—O7—C33—C34	−69.6 (4)
C17—C13—C14—C15	−41.2 (3)	O7—C33—C34—O9	−176.4 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···O6^i	0.84	1.954	2.732 (4)	153.7
O2—H2···O5^ii	0.84	1.913	2.690 (3)	153.4
O6—H6···O7^iii	0.84	1.961	2.701 (4)	147.0
O8—H8···O5^iv	0.81	1.880	2.670 (4)	164.6
O9—H90···O8^iv	0.82	1.936	2.736 (4)	164.6
O10—H101···O1^v	0.91 (4)	1.89 (4)	2.795 (4)	172.0
O10—H102···O2^v	0.86 (6)	1.88 (5)	2.717 (4)	166.0

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