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organic compounds
(+)-Geodin from Aspergillus terreus
aDepartment of Chemistry, Technical University of Denmark, Kemitorvet, Building 201 and 206, DK-2800 Kgs. Lyngby, Denmark, bCenter for Microbial Biotechnology, Department of Systems Biology, Søltofts Plads, Building 221 and 223, DK-2800 Kgs. Lyngby, Denmark, and cClinical Cooperation Unit for Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Im Neuenheimer Feld 280 (TP4), 69120 Heidelberg, Germany
*Correspondence e-mail: ph@kemi.dtu.dk
The fungal metabolite (+)-geodin [systematic name: (2R)-methyl 5,7-dichloro-4-hydroxy-6′-methoxy-6-methyl-3,4′-dioxospiro[benzofuran-2,1′-cyclohexa-2′,5′-diene]-2′-carboxylate], C17H12Cl2O7, was isolated from Aspergillus terreus. The contains two independent molecules in the Molecules denoted 1 interact through O—H⋯O hydrogen bonds creating chains of molecules parallel to the crystallographic 21 screw axis. Molecules denoted 2 interact through an O⋯Cl halogen bond, also creating chains of molecules parallel to the crystallographic 21 screw axis. Molecules 1 and 2 interact through another O⋯Cl halogen bond. The two molecules are similar but molecules 2 have a slightly more planar cyclohexadiene ring than molecules 1. The of (+)-geodin has been unequivocally assigned with the spiro centre having the R configuration in both molecules. The structurally related (+)-griseofulvin has an S configuration at the spiro centre, a difference of potential biological and biosynthetic relevance.
Comment
(+)-Geodin, (I), was originally isolated from Aspergillus terreus (Raistrick & Smith, 1936
) and elucidation of its structure was initiated (Clutterbuck et al., 1937
; Calam et al., 1939
, 1947
), eventually resulting in the correct relative structure (Barton & Scott, 1958
). A number of biological activities have been reported for (I)
, including antiviral (Takatsuki, Suzuki et al., 1969
; Takatsuki, Yamaguchi et al., 1969
), antimicrobial (Rinderknecht et al., 1947
), enhancement of fibrinolytic activity (Shinohara et al., 2000
) and stimulation of glucose uptake for rat adipocytes (Sato et al., 2005
). Furthermore, (I)
is a subunit of the compound Sch 202596, an antagonist of the galanin receptor subtype GALR1 (Chu et al., 1997
). In an effort to synthesize Sch 202596, the total synthesis of racemic geodin was completed (Katoh et al., 2002
; Katoh & Ohmori, 2000
). Geodin, (I)
, shares the same grisan backbone as (+)-griseofulvin, (II), consisting of ring systems A, B and C, as shown for (II) in the Scheme below (Grove et al., 1952
). Additionally, both compounds (I)
and (II) are dextrorotatory and this general similarity prompted our interest in (I)
since (II) has anticancer properties (Ho et al., 2001
; Panda et al., 2005
). (I)
was isolated from A. terreus and tested in our cellular anticancer assay (Rebacz et al., 2007
) but did not exhibit any activity (data not shown).
(I) crystallizes with two independent molecules in the (Fig. 1)
. Although the two molecules are quite similar, there are small differences in their geometries. Cyclohexadienone ring C in (I)
is almost planar, with an r.m.s. deviation of the least-square planes of 0.045 and 0.016 Å for molecules 1 and 2, respectively. The largest deviation from this plane is 0.070 (2)/0.024 (2) Å found for atoms C12/C22. The distances O15⋯O13/O25⋯O23 are 4.999 (3)/5.245 (4) Å, reflecting the fact that the C ring in (I)
for molecule 2 is slightly more planar than that of molecule 1. In comparison, cyclohexenone ring C in griseofulvin, (II) (Puttaraja et al., 1982
), has a half-chair conformation, with atoms C2 and C6′ on the opposite sides of the plane. This means that the distance O5⋯O3 is only 4.06 Å, i.e. much shorter than the equivalents O15⋯O13 and O25⋯O23 in (I)
. The ester groups in the two molecules in the of (I)
are rotated 21.4 (5)/16.9 (4)° with respect to the planes of the respective cyclohexadienone rings so that atoms O17/O27 are located more or less above the centre of the respective five-membered ring with short interatomic O17⋯O11/O27⋯O21 distances of 2.916 (4)/2.954 (3) Å. The five-membered B rings in the two molecules in (I)
are rotated 89.89 (9)/88.13 (10)° with respect to the C rings. They are almost planar, with an r.m.s. deviation of the five atoms of 0.028/0.034 Å for both molecules. However, atoms O11(O21) and C13(C23) are below the plane and C12(C22) above the plane. In both molecules, there is an intramolecular hydrogen bond from atom O12/O22 to O13/O23 (see Table 2
).
The crystal packing down the a axis is shown in Figs. 2 and 3
, with the view showing the different packing of molecules 1 (Fig. 3
a) and 2 (Fig. 3
b) down the c axis. Molecules 1 are hydrogen bonded with a hydrogen bond from atom O12 to atom O15 in a neighbouring molecule (see Table 2,
and Figs. 2
and 3
a). This creates a chain of molecules along the crystallographic 21 screw axis. A similar hydrogen bond is not found in molecules 2. They are tilted slightly and the distance between atoms O22 and O25(−x + 2, y +
, −z + 2) is 4.521 (4) Å. There are, however, halogen bonds between atoms O23 and Cl21 from neighbouring molecules (see Table 1,
and Figs. 2
and 3
b) creating chains of molecules along the crystallographic 21 screw axis. Furthermore, molecules of type 2 are oriented so that the AB ring system stacks with the C ring from the next molecule in the helix. Molecules 1 and 2 interact via halogen bonds between atoms O27 and Cl12 (see Table 1
).
To increase knowledge of the structure–activity relationship of these related compounds (Rønnest et al., 2009) the of (I)
presented here was determined using anomalous signal from all reflections (Flack, 1983
). This showed an R configuration at the spiro centre of both crystallographically independent molecules. In contrast, for (II) the was determined based on alcoholytic reactions (MacMillan, 1959
) and later verified by Brown & Sim (1963
) by determination of a brominated derivative using film data to be S at the spiro centre and R at atom C6′. This structural difference between (I)
and (II) could potentially contribute to the observed absence of anticancer activity (Rebacz et al., 2007
) for (I)
.
Based on enzymatic studies of the biosynthesis of geodin, (I) (Fujii et al., 1983
), the spirocyclization reaction joining the B and C rings is believed to be catalysed by an enzyme of the multicopper protein class. The same reaction in the griseofulvin, (II), biosynthesis, on the other hand, is presumed to be mediated by a enzyme. The latter assumption is founded on the identification of the griseofulvin, (II), biosynthesis gene cluster (Chooi et al., 2010
). These observations could explain the different configuration of the spiro centres of (I)
and (II) since it is reasonable that enzymes of different classes lead to a disparate outcome in a similar reaction with comparable substrates.
![]() | Figure 1 A perspective view of the two independent molecules of geodin, (I) ![]() |
![]() | Figure 2 The molecular packing of (I) ![]() ![]() ![]() |
![]() | Figure 3 Helical chains in (I) ![]() ![]() ![]() |
Experimental
A. terreus [IBT 28226, culture collection at Department of Systems Biology, Technical University of Denmark (Lyngby, Denmark)] was cultured on 50 plates of yeast extract sucrose agar at 298 K for 7 d, extracted with ethyl acetate (2 l) and then concentrated to afford 1.2 g of raw extract. The raw extract was dissolved in 10% H2O in MeOH (50 ml) and the aqueous phase was extracted with heptane (50 ml). The water content was increased to 50% by adding H2O (40 ml) and the resulting mixture was shaken with CH2Cl2 (90 ml). The CH2Cl2 phase was concentrated (0.86 g) and further purification was performed on a Phenomenex Luna(2) HPLC column (250 × 10 mm, 5 µm, C-18) using 5 ml min−1 H2O/CH3CN (isocratic run at 50/50 for 15 min) as the mobile phase to yield (I) (11.6 mg as a yellow oil). Geodin, (I)
, was crystallized using sitting-drop vapour diffusion, the drop consisting of EtOAc–heptane (4:1 v/v) and the reservoir containing heptane, to afford yellow crystals.
Crystal data
|
|
|
H atoms were observed in a difference synthesis and subsequently placed in idealized positions. They were refined using a riding model, with aryl C—H = 0.95 Å and Uiso(H) = 1.2Ueq(C), methyl C—H = 0.98 Å and Uiso(H) = 1.5Ueq(C), and hydroxy O—H = 0.84 Å and Uiso(H) = 1.2Ueq(O).
Data collection: SMART and SAINT (Bruker, 1998); cell SMART and SAINT; data reduction: SMART and SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008
); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008
); molecular graphics: ORTEP-3 (Farrugia, 1997
) and Mercury (Macrae et al., 2006
); software used to prepare material for publication: enCIFer (Allen et al., 2004
).
Supporting information
10.1107/S0108270111005816/lg3050sup1.cif
contains datablocks I, global. DOI:Structure factors: contains datablock I. DOI: 10.1107/S0108270111005816/lg3050Isup2.hkl
A. terreus [IBT 28226, culture collection at Department of Systems Biology, Technical University of Denmark (Lyngby, Denmark)] was cultured on 50 plates of yeast extract sucrose agar at 298 K for 7 d and extracted with ethyl acetate (2 l) then concentrated to afford 1.2 g raw extract. The raw extract was dissolved in 10% H2O in MeOH (50 ml) and the aqueous phase was extracted with heptane (50 ml). The water content was increased to 50% by adding 40 ml H2O and shaken with CH2Cl2 (90 ml). The CH2Cl2 phase was concentrated (0.86 g) and further purification was performed on a Phenomenex, Luna(2) HPLC column (250 × 10 mm, 5 µm, C-18) using 5 ml min-1 H2O/CH3CN (isocratic run at 50/50 for 15 min) as the mobile phase to yield (I) (11.6 mg as a yellow oil). Geodin, (I), was crystallized using sitting drop vapour diffusion, the drop consisting of EtOAc:heptane 4:1 and the reservoir containing heptane, to afford yellow crystals.
H atoms were observed in a difference synthesis and located in idealized positions. They were refined using a riding model with aryl C—H = 0.95 Å and Uiso(H) = 1.2Ueq(C), methyl C—H = 0.98 Å and Uiso(H) = 1.5Ueq(C), and hydroxy O—H = 0.84 Å and Uiso(H) = 1.2Ueq(O).
Data collection: SMART and SAINT (Bruker, 1998); cell
SMART and SAINT (Bruker, 1998); data reduction: SMART and SAINT (Bruker, 1998); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 (Farrugia, 1997) and Mercury (Macrae et al., 2006); software used to prepare material for publication: enCIFer (Allen et al., 2004).C17H12Cl2O7 | F(000) = 816 |
Mr = 399.17 | Dx = 1.589 Mg m−3 |
Monoclinic, P21 | Melting point = 503–505 K |
Hall symbol: P 2yb | Mo Kα radiation, λ = 0.71073 Å |
a = 8.9276 (3) Å | Cell parameters from 7659 reflections |
b = 11.3625 (4) Å | θ = 2.2–28.1° |
c = 16.5006 (6) Å | µ = 0.43 mm−1 |
β = 94.456 (1)° | T = 120 K |
V = 1668.76 (10) Å3 | Block, colourless |
Z = 4 | 0.25 × 0.15 × 0.08 mm |
Bruker SMART platform CCD diffractometer | 8165 independent reflections |
Radiation source: fine-focus sealed tube | 7496 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.029 |
ω scans | θmax = 28.3°, θmin = 2.2° |
Absorption correction: multi-scan (SADABS; Bruker, 2000) | h = −11→11 |
Tmin = 0.82, Tmax = 0.97 | k = −15→15 |
22828 measured reflections | l = −22→21 |
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.053 | H-atom parameters constrained |
wR(F2) = 0.145 | w = 1/[σ2(Fo2) + (0.0894P)2 + 0.6625P] where P = (Fo2 + 2Fc2)/3 |
S = 1.06 | (Δ/σ)max < 0.001 |
8165 reflections | Δρmax = 0.81 e Å−3 |
480 parameters | Δρmin = −0.36 e Å−3 |
1 restraint | Absolute structure: Flack (1983), ???? Friedel pairs |
Primary atom site location: structure-invariant direct methods | Absolute structure parameter: 0.04 (6) |
C17H12Cl2O7 | V = 1668.76 (10) Å3 |
Mr = 399.17 | Z = 4 |
Monoclinic, P21 | Mo Kα radiation |
a = 8.9276 (3) Å | µ = 0.43 mm−1 |
b = 11.3625 (4) Å | T = 120 K |
c = 16.5006 (6) Å | 0.25 × 0.15 × 0.08 mm |
β = 94.456 (1)° |
Bruker SMART platform CCD diffractometer | 8165 independent reflections |
Absorption correction: multi-scan (SADABS; Bruker, 2000) | 7496 reflections with I > 2σ(I) |
Tmin = 0.82, Tmax = 0.97 | Rint = 0.029 |
22828 measured reflections |
R[F2 > 2σ(F2)] = 0.053 | H-atom parameters constrained |
wR(F2) = 0.145 | Δρmax = 0.81 e Å−3 |
S = 1.06 | Δρmin = −0.36 e Å−3 |
8165 reflections | Absolute structure: Flack (1983), ???? Friedel pairs |
480 parameters | Absolute structure parameter: 0.04 (6) |
1 restraint |
Experimental. 1H NMR spectra were recorded using either a Varian Unity Inova 500 MHz or a Bruker Avance 800 MHz spectrometer. 13C NMR data were recorded using a Bruker Avance 800 MHz spectrometer. Chemical shifts were measured in ppm and coupling constants in Hz. When benzene-d6 was used as solvent the residual peak was used as internal reference at 7.15 for 1H NMR and δ 128.0 for 13C NMR spectra. For DMSO-d6 the value was δ 2.50 for 1H NMR. The IR spectrum was recorded using a Bruker Alpha ATR and measured in cm-1. The melting point is uncorrected. High-resolution LC-DAD-MS was performed on an Agilent 1100 system equipped with a photodiode array detector (DAD) and coupled to a LCT orthogonal time-of-flight mass spectrometer (Waters-Micromass, Manchester, UK) with a Z-spray electrospray ionisation (ESI) source and a LockSpray probe (M+H 556.2771) and controlled by MassLynx 4.0 software. LC-MS calibration from m/z 100-900 was done with a PEG mixture. Standard separation involved a LUNA 2 column with an acetonitrile (50 ppm formic acid) in water gradient starting from 15% to 100% over 25 minutes with a flow rate of 0.3 mL/min. Purity was assessed by UPLC-DAD on a Dionex ultimate 3000 system. The column used was a Kinetex (150 × 2.10 mm, 2.6 µm, C-18) at 357K with a flow of 0.8 mL. (R)-Methyl 5,7-dichloro-4-hydroxy-6'-methoxy-6-methyl-3,4'-dioxo-spiro[benzofuran-2,1' -cyclohexa-2',5'-diene]-2'-carboxylate (I) (geodin). m.p.: 503-505 K. (in agreement with litt. (Raistrick & Smith, 1936)). IR(neat): 3396, 1724, 1659, 1610, 1461, 1440; 1H NMR (800 MHz, benzene-d6): δ 7.04 (1H, d, J = 1.0 Hz), 5.43 (1H, d, J = 1.0 Hz), 2.91 (3H, s), 2.53 (3H, s), 2.00 (3H, s); 13C NMR (200 MHz, benzene-d6): δ 194.3, 184.8, 167.8, 166.4, 163.9, 150.4, 147.1, 137.9, 137.7, 115.5, 110.0, 110.0, 105.1, 85.4, 56.3, 52.5, 18.5; 1H NMR (800 MHz, CDCl3): δ 7.14 (1H, d, J = 1.5 Hz), 5.82 (1H, d, J = 1.5 Hz), 3.74 (3H, s), 3.70 (3H, s), 2.58 (3H, s) (in agreement with litt. (Sato et al., 2005)); 1H NMR (500 MHz, DMSO-d6): δ 7.05 (1H, d, J = 1.0 Hz), 6.05 (1H, d, J = 1.0 Hz), 3.72 (3H, s), 3.68 (3H, s), 2.52 (3H, s); HRMS (ESI+) calcd for [M + H]+ [C17H13Cl2O7]+ 399.0038, found 399.0041. [α]D21+129° (c = 1.16, CHCl3) (in agreement with litt. (Raistrick & Smith, 1936)). 1H NMR (800 MHz, benzene-d6), 13C NMR (200 MHz, benzene-d6) and UPLC-DAD chromatogram and UV spectrum may be provided. |
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. |
x | y | z | Uiso*/Ueq | ||
Cl11 | 0.77294 (8) | 1.10305 (7) | 0.51669 (5) | 0.02928 (18) | |
Cl12 | 0.68174 (9) | 0.76827 (7) | 0.74489 (5) | 0.02806 (17) | |
C12 | 0.2904 (3) | 1.0248 (3) | 0.46073 (17) | 0.0179 (5) | |
C13 | 0.2710 (3) | 0.9240 (3) | 0.52477 (17) | 0.0176 (5) | |
C14 | 0.4678 (3) | 0.8393 (3) | 0.63238 (17) | 0.0191 (6) | |
C15 | 0.6180 (3) | 0.8536 (3) | 0.66243 (18) | 0.0217 (6) | |
C16 | 0.7146 (3) | 0.9350 (3) | 0.62866 (19) | 0.0208 (6) | |
C17 | 0.6610 (3) | 1.0031 (3) | 0.56252 (18) | 0.0205 (6) | |
C18 | 0.5125 (3) | 0.9899 (3) | 0.53254 (17) | 0.0185 (5) | |
C19 | 0.4176 (3) | 0.9111 (3) | 0.56750 (18) | 0.0195 (6) | |
C110 | 0.1999 (4) | 1.2757 (3) | 0.5897 (2) | 0.0352 (8) | |
H10A | 0.2050 | 1.3402 | 0.5505 | 0.053* | |
H10B | 0.2567 | 1.2971 | 0.6407 | 0.053* | |
H10C | 0.0948 | 1.2610 | 0.5998 | 0.053* | |
C111 | 0.3348 (4) | 0.8830 (3) | 0.3471 (2) | 0.0264 (6) | |
C112 | 0.3791 (4) | 0.7635 (4) | 0.2364 (2) | 0.0356 (8) | |
H12A | 0.4880 | 0.7643 | 0.2498 | 0.053* | |
H12B | 0.3583 | 0.7585 | 0.1773 | 0.053* | |
H12C | 0.3351 | 0.6954 | 0.2621 | 0.053* | |
C113 | 0.8741 (3) | 0.9498 (3) | 0.6638 (2) | 0.0284 (7) | |
H13A | 0.9416 | 0.9500 | 0.6197 | 0.043* | |
H13B | 0.9008 | 0.8845 | 0.7009 | 0.043* | |
H13C | 0.8838 | 1.0244 | 0.6935 | 0.043* | |
C12' | 0.2441 (3) | 0.9830 (3) | 0.37629 (18) | 0.0204 (5) | |
C13' | 0.1215 (3) | 1.0253 (3) | 0.33437 (18) | 0.0248 (6) | |
H13' | 0.0921 | 0.9929 | 0.2825 | 0.030* | |
C14' | 0.0305 (3) | 1.1208 (3) | 0.36604 (19) | 0.0246 (6) | |
C15' | 0.0845 (3) | 1.1747 (3) | 0.44209 (18) | 0.0220 (6) | |
H15' | 0.0340 | 1.2414 | 0.4615 | 0.026* | |
C16' | 0.2052 (3) | 1.1315 (3) | 0.48547 (17) | 0.0179 (5) | |
O11 | 0.4490 (2) | 1.05172 (19) | 0.46832 (12) | 0.0181 (4) | |
O12 | 0.3804 (2) | 0.7615 (2) | 0.66797 (13) | 0.0234 (4) | |
H12 | 0.2995 | 0.7526 | 0.6391 | 0.028* | |
O13 | 0.1531 (2) | 0.8759 (2) | 0.53523 (14) | 0.0227 (4) | |
O15 | −0.0860 (3) | 1.1517 (3) | 0.32749 (15) | 0.0359 (6) | |
O16 | 0.3138 (3) | 0.8709 (2) | 0.26598 (14) | 0.0304 (5) | |
O17 | 0.4118 (3) | 0.8220 (3) | 0.39071 (16) | 0.0381 (6) | |
O18 | 0.2635 (3) | 1.1708 (2) | 0.55715 (14) | 0.0264 (5) | |
Cl21 | 0.21268 (10) | 0.68838 (9) | 0.98643 (6) | 0.0381 (2) | |
Cl22 | 0.29043 (14) | 1.02171 (10) | 0.75500 (5) | 0.0497 (3) | |
C22 | 0.6856 (4) | 0.8043 (3) | 1.0535 (2) | 0.0261 (7) | |
C23 | 0.7022 (4) | 0.8869 (3) | 0.97828 (19) | 0.0264 (7) | |
C24 | 0.5033 (4) | 0.9567 (3) | 0.8691 (2) | 0.0314 (7) | |
C25 | 0.3560 (5) | 0.9402 (3) | 0.8397 (2) | 0.0336 (8) | |
C26 | 0.2601 (4) | 0.8595 (4) | 0.8745 (2) | 0.0325 (8) | |
C27 | 0.3179 (4) | 0.7952 (3) | 0.9430 (2) | 0.0271 (7) | |
C28 | 0.4637 (4) | 0.8154 (3) | 0.97430 (19) | 0.0244 (6) | |
C29 | 0.5549 (4) | 0.8932 (3) | 0.93790 (19) | 0.0261 (7) | |
C210 | 0.5980 (4) | 1.0485 (3) | 1.1921 (2) | 0.0349 (8) | |
H10D | 0.5929 | 1.0065 | 1.2437 | 0.052* | |
H10E | 0.5124 | 1.1023 | 1.1841 | 0.052* | |
H10F | 0.6918 | 1.0935 | 1.1933 | 0.052* | |
C211 | 0.7857 (4) | 0.6341 (3) | 0.9804 (2) | 0.0276 (7) | |
C212 | 0.8641 (5) | 0.4635 (4) | 0.9149 (2) | 0.0443 (10) | |
H12D | 0.7613 | 0.4430 | 0.8946 | 0.066* | |
H12E | 0.9221 | 0.3914 | 0.9263 | 0.066* | |
H12F | 0.9113 | 0.5099 | 0.8738 | 0.066* | |
C213 | 0.0996 (5) | 0.8412 (4) | 0.8394 (2) | 0.0436 (10) | |
H13D | 0.0540 | 0.9176 | 0.8250 | 0.065* | |
H13E | 0.0418 | 0.8023 | 0.8798 | 0.065* | |
H13F | 0.0994 | 0.7919 | 0.7907 | 0.065* | |
C22' | 0.7923 (4) | 0.7050 (3) | 1.0540 (2) | 0.0264 (6) | |
C23' | 0.8995 (4) | 0.6864 (3) | 1.11702 (19) | 0.0254 (6) | |
H23' | 0.9668 | 0.6220 | 1.1148 | 0.030* | |
C24' | 0.9111 (4) | 0.7650 (3) | 1.1877 (2) | 0.0296 (7) | |
C25' | 0.8064 (4) | 0.8621 (3) | 1.1905 (2) | 0.0282 (7) | |
H25' | 0.8145 | 0.9140 | 1.2358 | 0.034* | |
C26' | 0.6970 (4) | 0.8808 (3) | 1.1301 (2) | 0.0267 (6) | |
O21 | 0.5323 (2) | 0.7591 (2) | 1.04053 (13) | 0.0259 (5) | |
O22 | 0.5966 (3) | 1.0313 (2) | 0.83171 (16) | 0.0391 (6) | |
H22 | 0.6864 | 1.0147 | 0.8462 | 0.047* | |
O23 | 0.8176 (3) | 0.9357 (2) | 0.96332 (16) | 0.0339 (6) | |
O25 | 1.0111 (3) | 0.7473 (3) | 1.24223 (15) | 0.0380 (6) | |
O26 | 0.8604 (3) | 0.5322 (2) | 0.98897 (15) | 0.0344 (6) | |
O27 | 0.7207 (3) | 0.6632 (3) | 0.91666 (15) | 0.0363 (6) | |
O28 | 0.5933 (3) | 0.9637 (2) | 1.12531 (15) | 0.0317 (5) |
U11 | U22 | U33 | U12 | U13 | U23 | |
Cl11 | 0.0183 (3) | 0.0322 (4) | 0.0374 (4) | −0.0052 (3) | 0.0023 (3) | 0.0098 (3) |
Cl12 | 0.0270 (4) | 0.0315 (4) | 0.0249 (4) | 0.0039 (3) | −0.0028 (3) | 0.0089 (3) |
C12 | 0.0139 (12) | 0.0215 (14) | 0.0182 (12) | −0.0012 (10) | 0.0008 (9) | 0.0013 (11) |
C13 | 0.0160 (13) | 0.0180 (13) | 0.0188 (13) | 0.0010 (10) | 0.0024 (10) | −0.0011 (10) |
C14 | 0.0193 (13) | 0.0203 (14) | 0.0181 (13) | 0.0008 (11) | 0.0036 (10) | −0.0003 (11) |
C15 | 0.0206 (14) | 0.0260 (15) | 0.0183 (13) | 0.0057 (11) | 0.0004 (11) | 0.0014 (11) |
C16 | 0.0150 (12) | 0.0243 (14) | 0.0227 (14) | −0.0001 (11) | −0.0003 (10) | 0.0003 (11) |
C17 | 0.0159 (13) | 0.0213 (14) | 0.0246 (14) | −0.0004 (10) | 0.0021 (10) | −0.0026 (11) |
C18 | 0.0148 (12) | 0.0222 (14) | 0.0186 (13) | 0.0006 (11) | 0.0020 (10) | −0.0010 (11) |
C19 | 0.0164 (13) | 0.0223 (14) | 0.0202 (13) | 0.0010 (11) | 0.0032 (10) | 0.0000 (11) |
C110 | 0.045 (2) | 0.0272 (17) | 0.0341 (17) | 0.0091 (16) | 0.0053 (15) | −0.0095 (15) |
C111 | 0.0285 (15) | 0.0232 (15) | 0.0284 (16) | −0.0056 (12) | 0.0088 (12) | −0.0056 (12) |
C112 | 0.045 (2) | 0.0326 (18) | 0.0300 (16) | 0.0024 (16) | 0.0106 (14) | −0.0131 (14) |
C113 | 0.0168 (14) | 0.0338 (18) | 0.0336 (17) | −0.0021 (12) | −0.0032 (12) | 0.0037 (14) |
C12' | 0.0225 (13) | 0.0191 (13) | 0.0200 (13) | −0.0049 (11) | 0.0043 (10) | −0.0020 (10) |
C13' | 0.0232 (14) | 0.0320 (16) | 0.0188 (13) | −0.0026 (12) | −0.0001 (11) | 0.0003 (12) |
C14' | 0.0194 (13) | 0.0282 (16) | 0.0261 (15) | 0.0009 (12) | 0.0016 (11) | 0.0064 (12) |
C15' | 0.0184 (13) | 0.0206 (14) | 0.0276 (14) | 0.0038 (11) | 0.0054 (11) | 0.0021 (11) |
C16' | 0.0146 (12) | 0.0191 (13) | 0.0203 (13) | −0.0001 (10) | 0.0033 (10) | 0.0004 (10) |
O11 | 0.0127 (9) | 0.0230 (10) | 0.0189 (9) | −0.0006 (8) | 0.0026 (7) | 0.0057 (8) |
O12 | 0.0215 (10) | 0.0260 (11) | 0.0224 (10) | −0.0040 (9) | −0.0001 (8) | 0.0055 (9) |
O13 | 0.0168 (9) | 0.0213 (10) | 0.0306 (11) | −0.0033 (8) | 0.0043 (8) | 0.0001 (9) |
O15 | 0.0256 (12) | 0.0488 (15) | 0.0322 (13) | 0.0091 (11) | −0.0048 (10) | 0.0041 (11) |
O16 | 0.0383 (13) | 0.0306 (12) | 0.0227 (11) | 0.0045 (10) | 0.0049 (9) | −0.0066 (9) |
O17 | 0.0437 (15) | 0.0376 (14) | 0.0326 (13) | 0.0189 (12) | 0.0005 (11) | −0.0057 (11) |
O18 | 0.0285 (11) | 0.0243 (11) | 0.0261 (11) | 0.0035 (9) | 0.0016 (9) | −0.0064 (9) |
Cl21 | 0.0256 (4) | 0.0407 (5) | 0.0470 (5) | −0.0043 (3) | −0.0025 (3) | −0.0020 (4) |
Cl22 | 0.0749 (7) | 0.0501 (6) | 0.0225 (4) | 0.0376 (5) | −0.0056 (4) | 0.0027 (4) |
C22 | 0.0216 (14) | 0.0313 (17) | 0.0251 (15) | −0.0013 (12) | −0.0007 (11) | 0.0076 (12) |
C23 | 0.0308 (16) | 0.0264 (16) | 0.0225 (14) | 0.0028 (13) | 0.0052 (12) | 0.0063 (12) |
C24 | 0.047 (2) | 0.0252 (16) | 0.0229 (15) | 0.0152 (15) | 0.0066 (14) | 0.0068 (13) |
C25 | 0.048 (2) | 0.0331 (18) | 0.0191 (15) | 0.0230 (16) | −0.0021 (14) | 0.0012 (13) |
C26 | 0.0330 (17) | 0.0387 (19) | 0.0245 (15) | 0.0197 (15) | −0.0060 (13) | −0.0102 (14) |
C27 | 0.0274 (16) | 0.0280 (17) | 0.0256 (15) | 0.0088 (12) | −0.0002 (12) | −0.0019 (12) |
C28 | 0.0260 (15) | 0.0271 (16) | 0.0202 (14) | 0.0072 (12) | 0.0022 (11) | 0.0038 (12) |
C29 | 0.0302 (16) | 0.0266 (16) | 0.0216 (14) | 0.0075 (12) | 0.0036 (12) | 0.0046 (12) |
C210 | 0.0380 (19) | 0.0325 (18) | 0.0342 (18) | 0.0047 (15) | 0.0034 (14) | −0.0090 (14) |
C211 | 0.0247 (15) | 0.0249 (16) | 0.0337 (17) | 0.0014 (12) | 0.0048 (13) | 0.0105 (13) |
C212 | 0.060 (3) | 0.038 (2) | 0.0341 (19) | 0.0152 (19) | 0.0048 (18) | −0.0075 (16) |
C213 | 0.044 (2) | 0.049 (2) | 0.036 (2) | 0.0201 (19) | −0.0140 (17) | −0.0143 (17) |
C22' | 0.0235 (14) | 0.0283 (16) | 0.0274 (16) | −0.0010 (12) | 0.0020 (12) | 0.0065 (12) |
C23' | 0.0274 (15) | 0.0248 (15) | 0.0241 (14) | −0.0044 (12) | 0.0033 (12) | 0.0077 (12) |
C24' | 0.0286 (16) | 0.0313 (16) | 0.0292 (16) | −0.0047 (14) | 0.0044 (13) | 0.0078 (14) |
C25' | 0.0291 (16) | 0.0289 (16) | 0.0267 (15) | −0.0051 (13) | 0.0023 (12) | −0.0021 (13) |
C26' | 0.0301 (16) | 0.0248 (16) | 0.0251 (15) | −0.0055 (13) | 0.0013 (12) | 0.0030 (12) |
O21 | 0.0194 (10) | 0.0333 (12) | 0.0243 (10) | 0.0013 (9) | −0.0019 (8) | 0.0087 (10) |
O22 | 0.0564 (17) | 0.0286 (13) | 0.0331 (13) | 0.0075 (12) | 0.0082 (12) | 0.0172 (11) |
O23 | 0.0353 (13) | 0.0286 (13) | 0.0387 (14) | −0.0032 (10) | 0.0095 (11) | 0.0057 (11) |
O25 | 0.0311 (13) | 0.0461 (16) | 0.0348 (13) | −0.0030 (11) | −0.0101 (10) | 0.0010 (11) |
O26 | 0.0418 (14) | 0.0313 (13) | 0.0305 (12) | 0.0133 (11) | 0.0056 (10) | 0.0008 (10) |
O27 | 0.0462 (15) | 0.0391 (14) | 0.0224 (11) | 0.0092 (12) | −0.0057 (10) | −0.0075 (10) |
O28 | 0.0355 (13) | 0.0309 (13) | 0.0291 (12) | 0.0039 (10) | 0.0054 (10) | −0.0052 (10) |
Cl11—C17 | 1.726 (3) | Cl21—C27 | 1.724 (4) |
Cl12—C15 | 1.731 (3) | Cl22—C25 | 1.740 (3) |
C12—O11 | 1.444 (3) | C22—O21 | 1.462 (4) |
C12—C12' | 1.500 (4) | C22—C22' | 1.477 (5) |
C12—C16' | 1.504 (4) | C22—C26' | 1.530 (5) |
C12—C13 | 1.577 (4) | C22—C23 | 1.572 (4) |
C13—O13 | 1.210 (4) | C23—O23 | 1.212 (4) |
C13—C19 | 1.445 (4) | C23—C29 | 1.429 (5) |
C14—O12 | 1.344 (4) | C24—O22 | 1.368 (5) |
C14—C19 | 1.392 (4) | C24—C25 | 1.378 (6) |
C14—C15 | 1.403 (4) | C24—C29 | 1.393 (4) |
C15—C16 | 1.408 (4) | C25—C26 | 1.407 (6) |
C16—C17 | 1.392 (4) | C26—C27 | 1.409 (5) |
C16—C113 | 1.505 (4) | C26—C213 | 1.517 (5) |
C17—C18 | 1.387 (4) | C27—C28 | 1.382 (5) |
C18—O11 | 1.358 (3) | C28—O21 | 1.369 (4) |
C18—C19 | 1.389 (4) | C28—C29 | 1.372 (5) |
C110—O18 | 1.441 (4) | C210—O28 | 1.461 (4) |
C110—H10A | 0.9800 | C210—H10D | 0.9800 |
C110—H10B | 0.9800 | C210—H10E | 0.9800 |
C110—H10C | 0.9800 | C210—H10F | 0.9800 |
C111—O17 | 1.180 (4) | C211—O27 | 1.207 (4) |
C111—O16 | 1.345 (4) | C211—O26 | 1.338 (4) |
C111—C12' | 1.497 (4) | C211—C22' | 1.456 (5) |
C112—O16 | 1.453 (4) | C212—O26 | 1.452 (4) |
C112—H12A | 0.9800 | C212—H12D | 0.9800 |
C112—H12B | 0.9800 | C212—H12E | 0.9800 |
C112—H12C | 0.9800 | C212—H12F | 0.9800 |
C113—H13A | 0.9800 | C213—H13D | 0.9800 |
C113—H13B | 0.9800 | C213—H13E | 0.9800 |
C113—H13C | 0.9800 | C213—H13F | 0.9800 |
C12'—C13' | 1.338 (4) | C22'—C23' | 1.373 (4) |
C13'—C14' | 1.475 (5) | C23'—C24' | 1.466 (5) |
C13'—H13' | 0.9500 | C23'—H23' | 0.9500 |
C14'—O15 | 1.227 (4) | C24'—O25 | 1.233 (4) |
C14'—C15' | 1.445 (4) | C24'—C25' | 1.450 (5) |
C15'—C16' | 1.340 (4) | C25'—C26' | 1.357 (5) |
C15'—H15' | 0.9500 | C25'—H25' | 0.9500 |
C16'—O18 | 1.332 (4) | C26'—O28 | 1.319 (4) |
O12—H12 | 0.8400 | O22—H22 | 0.8400 |
O27···Cl12 | 3.070 (3) | O23···Cl21i | 3.006 (3) |
O11—C12—C12' | 110.2 (2) | O21—C22—C22' | 109.2 (3) |
O11—C12—C16' | 108.6 (2) | O21—C22—C26' | 108.7 (3) |
C12'—C12—C16' | 113.5 (2) | C22'—C22—C26' | 115.3 (3) |
O11—C12—C13 | 104.7 (2) | O21—C22—C23 | 103.8 (2) |
C12'—C12—C13 | 110.8 (2) | C22'—C22—C23 | 111.1 (3) |
C16'—C12—C13 | 108.6 (2) | C26'—C22—C23 | 108.0 (3) |
O13—C13—C19 | 130.5 (3) | O23—C23—C29 | 130.4 (3) |
O13—C13—C12 | 124.5 (3) | O23—C23—C22 | 124.5 (3) |
C19—C13—C12 | 104.9 (2) | C29—C23—C22 | 105.0 (3) |
O12—C14—C19 | 124.0 (3) | O22—C24—C25 | 121.6 (3) |
O12—C14—C15 | 119.5 (3) | O22—C24—C29 | 120.9 (3) |
C19—C14—C15 | 116.5 (3) | C25—C24—C29 | 117.5 (3) |
C14—C15—C16 | 122.3 (3) | C24—C25—C26 | 122.6 (3) |
C14—C15—Cl12 | 117.4 (2) | C24—C25—Cl22 | 117.5 (3) |
C16—C15—Cl12 | 120.3 (2) | C26—C25—Cl22 | 119.8 (3) |
C17—C16—C15 | 119.5 (3) | C25—C26—C27 | 117.9 (3) |
C17—C16—C113 | 119.8 (3) | C25—C26—C213 | 121.3 (3) |
C15—C16—C113 | 120.7 (3) | C27—C26—C213 | 120.7 (4) |
C18—C17—C16 | 118.7 (3) | C28—C27—C26 | 119.3 (3) |
C18—C17—Cl11 | 119.0 (2) | C28—C27—Cl21 | 119.3 (3) |
C16—C17—Cl11 | 122.3 (2) | C26—C27—Cl21 | 121.4 (3) |
O11—C18—C17 | 123.5 (3) | O21—C28—C29 | 114.0 (3) |
O11—C18—C19 | 115.2 (2) | O21—C28—C27 | 124.8 (3) |
C17—C18—C19 | 121.2 (3) | C29—C28—C27 | 121.1 (3) |
C18—C19—C14 | 121.8 (3) | C28—C29—C24 | 121.4 (3) |
C18—C19—C13 | 106.9 (3) | C28—C29—C23 | 108.6 (3) |
C14—C19—C13 | 131.3 (3) | C24—C29—C23 | 129.8 (3) |
O18—C110—H10A | 109.5 | O28—C210—H10D | 109.5 |
O18—C110—H10B | 109.5 | O28—C210—H10E | 109.5 |
H10A—C110—H10B | 109.5 | H10D—C210—H10E | 109.5 |
O18—C110—H10C | 109.5 | O28—C210—H10F | 109.5 |
H10A—C110—H10C | 109.5 | H10D—C210—H10F | 109.5 |
H10B—C110—H10C | 109.5 | H10E—C210—H10F | 109.5 |
O17—C111—O16 | 125.2 (3) | O27—C211—O26 | 122.1 (3) |
O17—C111—C12' | 123.6 (3) | O27—C211—C22' | 124.1 (3) |
O16—C111—C12' | 111.1 (3) | O26—C211—C22' | 113.8 (3) |
O16—C112—H12A | 109.5 | O26—C212—H12D | 109.5 |
O16—C112—H12B | 109.5 | O26—C212—H12E | 109.5 |
H12A—C112—H12B | 109.5 | H12D—C212—H12E | 109.5 |
O16—C112—H12C | 109.5 | O26—C212—H12F | 109.5 |
H12A—C112—H12C | 109.5 | H12D—C212—H12F | 109.5 |
H12B—C112—H12C | 109.5 | H12E—C212—H12F | 109.5 |
C16—C113—H13A | 109.5 | C26—C213—H13D | 109.5 |
C16—C113—H13B | 109.5 | C26—C213—H13E | 109.5 |
H13A—C113—H13B | 109.5 | H13D—C213—H13E | 109.5 |
C16—C113—H13C | 109.5 | C26—C213—H13F | 109.5 |
H13A—C113—H13C | 109.5 | H13D—C213—H13F | 109.5 |
H13B—C113—H13C | 109.5 | H13E—C213—H13F | 109.5 |
C13'—C12'—C111 | 123.3 (3) | C23'—C22'—C211 | 121.9 (3) |
C13'—C12'—C12 | 121.5 (3) | C23'—C22'—C22 | 122.2 (3) |
C111—C12'—C12 | 115.0 (3) | C211—C22'—C22 | 115.7 (3) |
C12'—C13'—C14' | 122.2 (3) | C22'—C23'—C24' | 120.7 (3) |
C12'—C13'—H13' | 118.9 | C22'—C23'—H23' | 119.6 |
C14'—C13'—H13' | 118.9 | C24'—C23'—H23' | 119.6 |
O15—C14'—C15' | 122.7 (3) | O25—C24'—C25' | 122.2 (3) |
O15—C14'—C13' | 119.6 (3) | O25—C24'—C23' | 118.9 (3) |
C15'—C14'—C13' | 117.6 (3) | C25'—C24'—C23' | 118.9 (3) |
C16'—C15'—C14' | 120.6 (3) | C26'—C25'—C24' | 121.6 (3) |
C16'—C15'—H15' | 119.7 | C26'—C25'—H25' | 119.2 |
C14'—C15'—H15' | 119.7 | C24'—C25'—H25' | 119.2 |
O18—C16'—C15' | 126.4 (3) | O28—C26'—C25' | 128.1 (3) |
O18—C16'—C12 | 109.9 (2) | O28—C26'—C22 | 110.8 (3) |
C15'—C16'—C12 | 123.6 (3) | C25'—C26'—C22 | 121.1 (3) |
C18—O11—C12 | 107.8 (2) | C28—O21—C22 | 108.0 (2) |
C14—O12—H12 | 109.5 | C24—O22—H22 | 109.5 |
C111—O16—C112 | 113.0 (3) | C211—O26—C212 | 114.8 (3) |
C16'—O18—C110 | 118.0 (3) | C26'—O28—C210 | 116.5 (3) |
O11—C12—C13—O13 | −178.3 (3) | O21—C22—C23—O23 | −174.8 (3) |
C12'—C12—C13—O13 | −59.4 (4) | C22'—C22—C23—O23 | −57.5 (5) |
C16'—C12—C13—O13 | 65.9 (4) | C26'—C22—C23—O23 | 69.9 (4) |
O11—C12—C13—C19 | 5.1 (3) | O21—C22—C23—C29 | 7.8 (3) |
C12'—C12—C13—C19 | 123.9 (3) | C22'—C22—C23—C29 | 125.1 (3) |
C16'—C12—C13—C19 | −110.8 (3) | C26'—C22—C23—C29 | −107.5 (3) |
O12—C14—C15—C16 | −179.0 (3) | O22—C24—C25—C26 | 176.6 (3) |
C19—C14—C15—C16 | −0.7 (4) | C29—C24—C25—C26 | −2.5 (5) |
O12—C14—C15—Cl12 | 0.0 (4) | O22—C24—C25—Cl22 | −2.2 (5) |
C19—C14—C15—Cl12 | 178.3 (2) | C29—C24—C25—Cl22 | 178.7 (3) |
C14—C15—C16—C17 | −0.8 (5) | C24—C25—C26—C27 | 1.1 (5) |
Cl12—C15—C16—C17 | −179.8 (2) | Cl22—C25—C26—C27 | 179.9 (3) |
C14—C15—C16—C113 | 178.6 (3) | C24—C25—C26—C213 | −178.4 (3) |
Cl12—C15—C16—C113 | −0.3 (4) | Cl22—C25—C26—C213 | 0.4 (5) |
C15—C16—C17—C18 | 1.0 (4) | C25—C26—C27—C28 | 1.6 (5) |
C113—C16—C17—C18 | −178.4 (3) | C213—C26—C27—C28 | −178.9 (3) |
C15—C16—C17—Cl11 | −179.0 (2) | C25—C26—C27—Cl21 | −176.3 (3) |
C113—C16—C17—Cl11 | 1.6 (4) | C213—C26—C27—Cl21 | 3.2 (5) |
C16—C17—C18—O11 | −179.9 (3) | C26—C27—C28—O21 | 179.7 (3) |
Cl11—C17—C18—O11 | 0.1 (4) | Cl21—C27—C28—O21 | −2.4 (5) |
C16—C17—C18—C19 | 0.3 (5) | C26—C27—C28—C29 | −2.8 (5) |
Cl11—C17—C18—C19 | −179.7 (2) | Cl21—C27—C28—C29 | 175.1 (3) |
O11—C18—C19—C14 | 178.2 (3) | O21—C28—C29—C24 | 179.2 (3) |
C17—C18—C19—C14 | −2.0 (5) | C27—C28—C29—C24 | 1.4 (5) |
O11—C18—C19—C13 | −2.7 (3) | O21—C28—C29—C23 | 3.7 (4) |
C17—C18—C19—C13 | 177.0 (3) | C27—C28—C29—C23 | −174.1 (3) |
O12—C14—C19—C18 | −179.7 (3) | O22—C24—C29—C28 | −177.9 (3) |
C15—C14—C19—C18 | 2.1 (4) | C25—C24—C29—C28 | 1.2 (5) |
O12—C14—C19—C13 | 1.5 (5) | O22—C24—C29—C23 | −3.4 (6) |
C15—C14—C19—C13 | −176.6 (3) | C25—C24—C29—C23 | 175.7 (3) |
O13—C13—C19—C18 | −178.0 (3) | O23—C23—C29—C28 | 175.8 (4) |
C12—C13—C19—C18 | −1.7 (3) | C22—C23—C29—C28 | −7.0 (4) |
O13—C13—C19—C14 | 0.9 (6) | O23—C23—C29—C24 | 0.8 (7) |
C12—C13—C19—C14 | 177.2 (3) | C22—C23—C29—C24 | 178.0 (3) |
O17—C111—C12'—C13' | −156.1 (4) | O27—C211—C22'—C23' | −161.0 (3) |
O16—C111—C12'—C13' | 22.4 (4) | O26—C211—C22'—C23' | 18.3 (4) |
O17—C111—C12'—C12 | 17.6 (5) | O27—C211—C22'—C22 | 13.7 (5) |
O16—C111—C12'—C12 | −163.9 (3) | O26—C211—C22'—C22 | −166.9 (3) |
O11—C12—C12'—C13' | −132.9 (3) | O21—C22—C22'—C23' | −126.1 (3) |
C16'—C12—C12'—C13' | −10.9 (4) | C26'—C22—C22'—C23' | −3.3 (4) |
C13—C12—C12'—C13' | 111.6 (3) | C23—C22—C22'—C23' | 120.0 (3) |
O11—C12—C12'—C111 | 53.3 (3) | O21—C22—C22'—C211 | 59.2 (3) |
C16'—C12—C12'—C111 | 175.3 (2) | C26'—C22—C22'—C211 | −178.1 (3) |
C13—C12—C12'—C111 | −62.2 (3) | C23—C22—C22'—C211 | −54.7 (4) |
C111—C12'—C13'—C14' | 177.4 (3) | C211—C22'—C23'—C24' | 175.1 (3) |
C12—C12'—C13'—C14' | 4.2 (5) | C22—C22'—C23'—C24' | 0.7 (5) |
C12'—C13'—C14'—O15 | −175.6 (3) | C22'—C23'—C24'—O25 | −178.3 (3) |
C12'—C13'—C14'—C15' | 4.8 (5) | C22'—C23'—C24'—C25' | 0.7 (5) |
O15—C14'—C15'—C16' | 174.3 (3) | O25—C24'—C25'—C26' | 180.0 (3) |
C13'—C14'—C15'—C16' | −6.1 (4) | C23'—C24'—C25'—C26' | 1.0 (5) |
C14'—C15'—C16'—O18 | −178.0 (3) | C24'—C25'—C26'—O28 | 178.8 (3) |
C14'—C15'—C16'—C12 | −1.4 (4) | C24'—C25'—C26'—C22 | −3.9 (5) |
O11—C12—C16'—O18 | −50.3 (3) | O21—C22—C26'—O28 | −54.3 (3) |
C12'—C12—C16'—O18 | −173.2 (2) | C22'—C22—C26'—O28 | −177.3 (3) |
C13—C12—C16'—O18 | 63.0 (3) | C23—C22—C26'—O28 | 57.7 (3) |
O11—C12—C16'—C15' | 132.6 (3) | O21—C22—C26'—C25' | 128.0 (3) |
C12'—C12—C16'—C15' | 9.7 (4) | C22'—C22—C26'—C25' | 5.0 (4) |
C13—C12—C16'—C15' | −114.0 (3) | C23—C22—C26'—C25' | −120.0 (3) |
C17—C18—O11—C12 | −173.5 (3) | C29—C28—O21—C22 | 1.8 (4) |
C19—C18—O11—C12 | 6.3 (3) | C27—C28—O21—C22 | 179.5 (3) |
C12'—C12—O11—C18 | −125.9 (3) | C22'—C22—O21—C28 | −124.5 (3) |
C16'—C12—O11—C18 | 109.2 (2) | C26'—C22—O21—C28 | 108.9 (3) |
C13—C12—O11—C18 | −6.7 (3) | C23—C22—O21—C28 | −5.9 (3) |
O17—C111—O16—C112 | 8.3 (5) | O27—C211—O26—C212 | 3.4 (5) |
C12'—C111—O16—C112 | −170.2 (3) | C22'—C211—O26—C212 | −176.0 (3) |
C15'—C16'—O18—C110 | −5.3 (5) | C25'—C26'—O28—C210 | 1.7 (5) |
C12—C16'—O18—C110 | 177.8 (3) | C22—C26'—O28—C210 | −175.8 (3) |
Symmetry code: (i) −x+1, y+1/2, −z+2. |
D—H···A | D—H | H···A | D···A | D—H···A |
O12—H12···O15ii | 0.84 | 2.33 | 2.916 (3) | 128 |
O12—H12···O13 | 0.84 | 2.50 | 3.149 (3) | 135 |
O22—H22···O23 | 0.84 | 2.36 | 3.021 (4) | 136 |
Symmetry code: (ii) −x, y−1/2, −z+1. |
Experimental details
Crystal data | |
Chemical formula | C17H12Cl2O7 |
Mr | 399.17 |
Crystal system, space group | Monoclinic, P21 |
Temperature (K) | 120 |
a, b, c (Å) | 8.9276 (3), 11.3625 (4), 16.5006 (6) |
β (°) | 94.456 (1) |
V (Å3) | 1668.76 (10) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.43 |
Crystal size (mm) | 0.25 × 0.15 × 0.08 |
Data collection | |
Diffractometer | Bruker SMART platform CCD diffractometer |
Absorption correction | Multi-scan (SADABS; Bruker, 2000) |
Tmin, Tmax | 0.82, 0.97 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 22828, 8165, 7496 |
Rint | 0.029 |
(sin θ/λ)max (Å−1) | 0.667 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.053, 0.145, 1.06 |
No. of reflections | 8165 |
No. of parameters | 480 |
No. of restraints | 1 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.81, −0.36 |
Absolute structure | Flack (1983), ???? Friedel pairs |
Absolute structure parameter | 0.04 (6) |
Computer programs: SMART and SAINT (Bruker, 1998), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), ORTEP-3 (Farrugia, 1997) and Mercury (Macrae et al., 2006), enCIFer (Allen et al., 2004).
O27···Cl12 | 3.070 (3) | O23···Cl21i | 3.006 (3) |
Symmetry code: (i) −x+1, y+1/2, −z+2. |
D—H···A | D—H | H···A | D···A | D—H···A |
O12—H12···O15ii | 0.84 | 2.33 | 2.916 (3) | 128 |
O12—H12···O13 | 0.84 | 2.50 | 3.149 (3) | 135 |
O22—H22···O23 | 0.84 | 2.36 | 3.021 (4) | 136 |
Symmetry code: (ii) −x, y−1/2, −z+1. |
Acknowledgements
We thank the Danish Instrument Center for NMR Spectroscopy of Biological Macromolecules for NMR time. We thank the Danish Research Council (reference No. 274-07-0561) for financial support (MHR) and the Faculty of Life Sciences, University of Copenhagen, for scholarship financing for MTN.
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(+)-Geodin, (I) , was originally isolated from Aspergillus terreus (Raistrick & Smith, 1936) and elucidation of its structure was initiated (Clutterbuck et al., 1937; Calam et al., 1939, 1947), eventually resulting in the correct relative structure (Barton & Scott, 1958). A number of biological activities have been reported for (I) including antiviral (Takatsuki, Suzuki et al., 1969; Takatsuki, Yamaguchi et al., 1969), antimicrobial (Rinderknecht et al., 1947), enhancement of fibrinolytic activity (Shinohara et al., 2000) and stimulation of glucose uptake for rat adipocytes (Sato et al., 2005). Furthermore, (I) is a subunit of the compound Sch 202596, an antagonist of the galanin receptor subtype GALR1 (Chu et al., 1997). In an effort to synthesize Sch 202596, the total synthesis of racemic geodin was completed (Katoh et al., 2002; Katoh & Ohmori, 2000). Geodin, (I), shares the same grisan backbone as (+)-griseofulvin, (II), consisting of ring systems A, B and C as shown for (II) in the scheme (Grove et al., 1952). Additionally, both compounds (I) and (II) are dextrorotatory and this general similarity prompted our interest in (I) since (II) has anticancer properties (Ho et al., 2001; Panda et al., 2005). (I) was isolated from A. terreus and tested in our cellular anticancer assay (Rebacz et al., 2007) but did not exhibit any activity (data not shown).
(+)-Geodin, (I), crystallizes with two independent molecules in the asymmetric unit shown in Fig. 1. Although the two molecules are quite similar, there are small differences in their geometries. The cyclohexadienone C ring in (I) is almost planar, with an r.m.s. deviation of the least-square planes of 0.045 and 0.016 Å for molecules 1 and 2, respectively. The largest deviation from this plane is 0.070 (2)/0.024 (2) Å found for C12/C22. The distances O15—O13/O25—O23 are 4.999 (3)/5.245 (4) Å, reflecting the fact that the C ring in (I) for molecule 2 is slightly more planar than the C ring in (I) for molecule 1. In comparison, the cyclohexenone C ring in griseofulvin, (II) (Puttaraja et al., 1982), has a half-chair conformation, with C2 and C6' on the opposite sides of the plane. This means that the distance O5—O3 is only 4.06 Å, i. e. much shorter than the equivalents O15—O13 and O25—O23 in (I). The ester groups in the two molecules in the asymmetric unit of (I) are rotated 21.4 (5)/16.9 (4)° with respect to the respective cyclohexadienone rings so that O17/O27 are located more or less above the centre of the respective five-membered ring with short interatomic distances between O17—O11/O27—O21 of 2.916 (4)/2.954 (3) Å. The five-membered B rings in the two molecules in (I) are rotated 89.89 (9)/88.13 (10)° with respect to the C rings. They are almost planar, with an r.m.s. deviation of the five atoms of 0.028/0.034 Å for both molecules. However, O11(O21) and C13(C23) are below the plane and C12(C22) above the plane. In both molecules there is an intramolecular hydrogen bond from O12/O22 to O13/O23 (see Table 2).
The crystal packing down the a axis is shown in Figs. 2 and 3, with the view showing different packing of molecules 1 (Fig. 3a) and 2 (Fig. 3b) down the c axis. Molecules 1 are hydrogen bonded with a hydrogen bond from O12 to O15 in a neighbouring molecule (see Table 2 and Figs. 2, 3a). This creates a helical chain of molecules along the b axis. Molecules 2 are not interacting through a similar hydrogen bond. They are tilted slightly and the distance between O22 and O25 (symmetry code: 2 - x,1/2 + y, 2 - z) is 4.521 (4) Å. There are, however, halogen bonds between O23 and Cl21 from neighbouring molecules (see Table 1 and Figs. 2 and 3b) creating helical chains of molecules along the b axis. Furthermore, molecules of type 2 are oriented so that the AB ring system stacks with the C ring from the next molecule in the helix. Molecules 1 and 2 interact via halogen bonds between O27 and Cl12 (see Table 1).
To increase knowledge of the structure–activity relationship of these related compounds (Rønnest et al., 2009), the absolute structure of (I) presented here was determined using anomalous signal from all reflections (Flack, 1983) showing an R configuration at the spiro centre of both crystallographically independent molecules. In contrast, for (II) the absolute configuration was determined, based on alcoholytic reactions (MacMillan, 1959) and later verified by Brown & Sim (1963) by crystal structure determination of a brominated derivative using film data, to be S on the spiro centre and R on the C6' atom. This structural difference between (I) and (II) could potentially contribute to the observed absence of anticancer activity (Rebacz et al., 2007) for (I).
Based on enzymatic studies of the biosynthesis of geodin, (I) (Fujii et al., 1983), the spirocyclization reaction joining the B and C rings is believed to be catalysed by an enzyme of the multi-copper protein class. The same reaction in the griseofulvin, (II), biosynthesis, on the other hand, is presumed to be mediated by a cytochrome P450 enzyme. The latter assumption is founded on the identification of the griseofulvin, (II), biosynthesis gene cluster (Chooi et al., 2010). These observations could explain the different orientation of the spiro centres of (I) and (II), since it is reasonable that enzymes of different classes lead to a disparate outcome in a similar reaction with comparable substrates.