supplementary materials


HTML versionpdf versioncif file3d viewstructure factorssupplementary materialsCIF check reportcited insimilar papers Open access

Acta Cryst. (2009). E65, o358-o359    [ doi:10.1107/S1600536809002050 ]

5-{[(3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethylperhydro-3,12-epoxy-1,2-dioxepino[4,3-i]isochromen-10-yl]oxymethyl}benzene-1,3-diol

W. Gul, P. Carvalho, A. Galal, M. A. Avery and M. A. El Sohly

Abstract top

The title compound, C22H30O7, is a fused five-ring system that is of interest for its anticancer and antimalarial activity. The six-membered C6 and C5O rings display chair conformations. The six-membered C3O3 ring containing the ether and peroxy functionalities has a distorted boat conformation, with a C-O-O-C torsion angle of 42.6 (1)° for the peroxy group. The seven-membered C6O ring has a distorted boat-type conformation, while the seven-membered C5O2 ring has a very distorted chair-type conformation. The structure contains intermolecular O-H...O and O-H...(O,O) bonds that link the molecules into sheets parallel to the (100) planes.

Comment top

The title compound, a new dihydroartemisinin acetal monomeric derivative, has been prepared by reacting dihydroartemisinin with 1,3-dihydroxy-5-hydroxymethyl benzene using BF3.Et2O as the coupling catalyst. The compound exhibits anti-malarial, anti-cancer, and antiinfective activity.

Related literature top

For the crystallographic analysis of artemisinin, see: Lisgarten et al. (1998). For the compound's antimalarial and antitumoral activity, see Beekman et al. (1997, 1998); Pu et al. (1995); Zheng (1994).

Experimental top

To a stirred solution of dihydroartemisinin (120 mg, 0.42 mmol) in dry ether (40 ml) was added dry 3,5-dihydroxybenzyl alcohol (28 mg), followed by BF3.OEt2 (32 ml). Stirring was continued for two and half hours, after which time the reaction was quenched by addition of 10 ml of 2% aqueous solution of NaHCO3. The reaction mixture was then diluted with ether (50 ml), and transferred to a separatory funnel and extracted with ether (3 × 30 ml). The ether fractions were pooled, washed with water, and dried over Na2SO4. Removal of ether under reduced pressure left an oily crude product, which was purified over Si gel column using a gradient of EtOAc in hexanes (15% to 26%) to yield a colorless solid (35 mg, 28%).

Refinement top

All H atoms were visible in difference maps, but were placed geometrically and treated as riding atoms for refinement, with the following constraints: C—H = 0.93 Å, Uiso(H) = 1.2Ueq(C) for Csp2, C—H = 0.98 Å, Uiso(H) = 1.2Ueq(C) for CH, C—H = 0.97 Å, Uiso(H) = 1.2Ueq(C) for CH2, C—H = 0.96 Å, Uiso(H) = 1.5Ueq(C) CH3, O—H = 0.82 Å, Uiso(H) = 1.5Ueq(O) for OH.

Computing details top

Data collection: APEX2 (Bruker, 2005); cell refinement: SAINT (Bruker, 2005); data reduction: SAINT (Bruker, 2005); 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: ORTEP-3 for Windows (Farrugia, 1997).

Figures top
[Figure 1] Fig. 1. Molecular structure of the title compound with displacement ellipsoids drawn at the 50% probability level for non-H atoms.
5-{[(3R,5aS,6R,8aS,9R,10S,12R, 12aR)-3,6,9-Trimethylperhydro-3,12-epoxy-1,2-dioxepino[4,3- i]isochromen-10-yl]oxymethyl}benzene-1,3-diol top
Crystal data top
C22H30O7F(000) = 436
Mr = 406.46Dx = 1.341 Mg m−3
Monoclinic, P21Cu Kα radiation, λ = 1.54178 Å
Hall symbol: P 2ybCell parameters from 9920 reflections
a = 10.3088 (2) Åθ = 4.3–68.9°
b = 10.2844 (2) ŵ = 0.82 mm−1
c = 10.3218 (3) ÅT = 100 K
β = 113.14 (1)°Plate, colourless
V = 1006.29 (9) Å30.23 × 0.15 × 0.08 mm
Z = 2
Data collection top
Bruker APEXII CCD
diffractometer		3604 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube, Siemens KFF Cu 2 K90Rint = 0.019
graphiteθmax = 69.3°, θmin = 4.7°
φ and ω scansh = −12→12
15943 measured reflectionsk = −11→12
3623 independent reflectionsl = −12→12
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.026H-atom parameters constrained
wR(F2) = 0.069 w = 1/[σ2(Fo2) + (0.0416P)2 + 0.199P]
where P = (Fo2 + 2Fc2)/3
S = 1.08(Δ/σ)max < 0.001
3623 reflectionsΔρmax = 0.25 e Å−3
267 parametersΔρmin = −0.22 e Å−3
1 restraintAbsolute structure: Flack (1983), 1623 Friedel pairs
Primary atom site location: structure-invariant direct methodsFlack parameter: 0.04 (10)
Crystal data top
C22H30O7V = 1006.29 (9) Å3
Mr = 406.46Z = 2
Monoclinic, P21Cu Kα radiation
a = 10.3088 (2) ŵ = 0.82 mm−1
b = 10.2844 (2) ÅT = 100 K
c = 10.3218 (3) Å0.23 × 0.15 × 0.08 mm
β = 113.14 (1)°
Data collection top
Bruker APEXII CCD
diffractometer		3604 reflections with I > 2σ(I)
15943 measured reflectionsRint = 0.019
3623 independent reflectionsθmax = 69.3°
Refinement top
R[F2 > 2σ(F2)] = 0.026H-atom parameters constrained
wR(F2) = 0.069Δρmax = 0.25 e Å−3
S = 1.08Δρmin = −0.22 e Å−3
3623 reflectionsAbsolute structure: Flack (1983), 1623 Friedel pairs
267 parametersFlack parameter: 0.04 (10)
1 restraint
Special details top

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 (Å2) top
xyzUiso*/Ueq
O40.24620 (9)0.53498 (9)0.32197 (9)0.01671 (19)
O1−0.02356 (10)0.56559 (9)0.09293 (9)0.0177 (2)
O60.41598 (11)0.67491 (10)1.04175 (10)0.0238 (2)
H60.37350.60571.01940.036*
O50.34731 (9)0.70855 (9)0.47383 (9)0.01720 (19)
O30.07779 (9)0.40591 (9)0.33999 (9)0.0184 (2)
O70.71639 (10)0.95263 (9)0.93260 (10)0.0213 (2)
H70.76080.95780.88200.032*
O20.02421 (10)0.42912 (9)0.10142 (9)0.0191 (2)
C180.58553 (13)0.79300 (13)0.75672 (13)0.0177 (3)
H180.62490.82150.69460.021*
C1−0.01197 (14)0.36064 (14)0.20186 (14)0.0204 (3)
C200.56095 (14)0.81251 (13)0.97930 (13)0.0178 (3)
H200.58280.85541.06460.021*
C100.31061 (13)0.66001 (13)0.33627 (13)0.0172 (3)
H100.39730.65050.31950.021*
C80.06357 (14)0.75832 (13)0.22778 (13)0.0166 (3)
H80.00180.79650.13760.020*
C4−0.13890 (13)0.62313 (15)0.24865 (13)0.0193 (3)
H4−0.20790.65790.15990.023*
C110.11686 (13)0.53590 (13)0.34304 (13)0.0158 (3)
H110.13530.57130.43680.019*
C120.00544 (13)0.62013 (13)0.23280 (13)0.0161 (3)
C220.43232 (13)0.64640 (13)0.81424 (14)0.0184 (3)
H220.37030.57630.79050.022*
C70.05456 (14)0.84730 (14)0.34327 (14)0.0198 (3)
H7A0.11910.81610.43460.024*
H7B0.08340.93450.33050.024*
C5−0.13896 (13)0.71641 (15)0.36552 (13)0.0221 (3)
H5−0.06850.68480.45510.026*
C150.28159 (15)0.88607 (14)0.23539 (15)0.0233 (3)
H15A0.30430.92210.32760.035*
H15B0.21710.94280.16600.035*
H15C0.36620.87710.21830.035*
C14−0.28261 (14)0.71858 (18)0.37886 (15)0.0297 (3)
H14A−0.28270.78610.44300.044*
H14B−0.29860.63620.41370.044*
H14C−0.35610.73480.28810.044*
C170.48996 (13)0.69005 (13)0.72052 (13)0.0174 (3)
C6−0.09417 (15)0.85158 (15)0.34012 (14)0.0231 (3)
H6A−0.09710.91060.41230.028*
H6B−0.15900.88360.24930.028*
C160.44908 (14)0.62693 (14)0.57838 (14)0.0200 (3)
H16A0.53180.61600.55660.024*
H16B0.40870.54180.57880.024*
C90.21337 (13)0.75281 (13)0.22646 (13)0.0178 (3)
H90.20170.71670.13470.021*
C210.46825 (13)0.70848 (14)0.94374 (13)0.0186 (3)
C190.62111 (13)0.85242 (13)0.88701 (14)0.0173 (3)
C3−0.19196 (14)0.48755 (15)0.26635 (14)0.0237 (3)
H3A−0.14690.46320.36490.028*
H3B−0.29250.49320.24320.028*
C2−0.16688 (14)0.37942 (15)0.17856 (14)0.0234 (3)
H2A−0.22070.39820.07970.028*
H2B−0.20240.29860.20040.028*
C130.02745 (16)0.22097 (15)0.19089 (15)0.0262 (3)
H13A−0.03930.18350.10550.039*
H13B0.02670.17290.27030.039*
H13C0.12010.21760.18990.039*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O40.0160 (4)0.0163 (5)0.0179 (4)−0.0009 (3)0.0068 (4)−0.0024 (3)
O10.0225 (5)0.0173 (5)0.0130 (4)−0.0007 (4)0.0067 (4)−0.0007 (4)
O60.0285 (5)0.0254 (5)0.0221 (5)−0.0052 (4)0.0149 (4)0.0005 (4)
O50.0169 (4)0.0187 (5)0.0140 (4)0.0006 (4)0.0039 (3)−0.0015 (3)
O30.0215 (5)0.0181 (5)0.0140 (4)−0.0030 (4)0.0051 (4)−0.0005 (3)
O70.0232 (5)0.0217 (5)0.0232 (5)−0.0058 (4)0.0138 (4)−0.0047 (4)
O20.0234 (5)0.0183 (5)0.0170 (4)−0.0016 (4)0.0094 (4)−0.0024 (4)
C180.0191 (6)0.0192 (7)0.0165 (6)0.0030 (5)0.0088 (5)0.0022 (5)
C10.0246 (7)0.0215 (7)0.0146 (6)−0.0075 (5)0.0072 (5)−0.0028 (5)
C200.0185 (6)0.0203 (7)0.0145 (6)0.0029 (5)0.0063 (5)−0.0002 (5)
C100.0165 (6)0.0197 (7)0.0162 (6)−0.0034 (5)0.0074 (5)−0.0032 (5)
C80.0192 (6)0.0167 (7)0.0134 (6)0.0021 (5)0.0060 (5)0.0014 (5)
C40.0149 (6)0.0279 (7)0.0146 (6)0.0008 (5)0.0052 (5)0.0002 (5)
C110.0177 (6)0.0158 (7)0.0149 (6)−0.0018 (5)0.0075 (5)−0.0022 (5)
C120.0176 (6)0.0202 (7)0.0109 (6)−0.0015 (5)0.0060 (5)−0.0016 (5)
C220.0147 (6)0.0170 (7)0.0220 (6)−0.0001 (5)0.0055 (5)0.0005 (5)
C70.0229 (7)0.0170 (7)0.0185 (6)0.0017 (5)0.0072 (5)−0.0011 (5)
C50.0178 (6)0.0329 (8)0.0153 (6)0.0039 (6)0.0063 (5)0.0005 (6)
C150.0253 (7)0.0239 (8)0.0213 (7)−0.0053 (6)0.0097 (6)−0.0003 (6)
C140.0222 (7)0.0464 (10)0.0225 (7)0.0053 (7)0.0112 (6)−0.0023 (7)
C170.0150 (5)0.0182 (7)0.0174 (6)0.0050 (5)0.0045 (5)0.0015 (5)
C60.0249 (7)0.0269 (8)0.0177 (6)0.0080 (6)0.0086 (5)−0.0015 (6)
C160.0190 (6)0.0200 (7)0.0190 (6)0.0032 (5)0.0053 (5)0.0005 (5)
C90.0195 (6)0.0209 (7)0.0139 (6)−0.0036 (5)0.0075 (5)−0.0016 (5)
C210.0159 (6)0.0215 (7)0.0189 (6)0.0038 (5)0.0075 (5)0.0044 (5)
C190.0147 (6)0.0164 (7)0.0199 (6)0.0019 (5)0.0058 (5)0.0023 (5)
C30.0178 (6)0.0346 (8)0.0196 (6)−0.0045 (6)0.0082 (5)0.0006 (6)
C20.0227 (7)0.0279 (8)0.0190 (6)−0.0101 (6)0.0075 (5)−0.0011 (5)
C130.0335 (7)0.0225 (8)0.0213 (7)−0.0056 (6)0.0094 (6)−0.0031 (6)
Geometric parameters (Å, °) top
O4—C101.4280 (16)C11—H110.980
O4—C111.4328 (15)C22—C171.3936 (19)
O1—C121.4660 (15)C22—C211.3937 (19)
O1—O21.4785 (13)C22—H220.930
O6—C211.3644 (16)C7—C61.5214 (19)
O6—H60.820C7—H7A0.970
O5—C101.4092 (15)C7—H7B0.970
O5—C161.4423 (16)C5—C61.520 (2)
O3—C111.3930 (17)C5—C141.5403 (17)
O3—C11.4384 (15)C5—H50.980
O7—C191.3730 (16)C15—C91.5266 (19)
O7—H70.820C15—H15A0.960
O2—C11.4191 (16)C15—H15B0.960
C18—C191.3888 (18)C15—H15C0.960
C18—C171.3936 (19)C14—H14A0.960
C18—H180.930C14—H14B0.960
C1—C131.509 (2)C14—H14C0.960
C1—C21.5308 (19)C17—C161.5052 (18)
C20—C211.3845 (19)C6—H6A0.970
C20—C191.3874 (18)C6—H6B0.970
C20—H200.930C16—H16A0.970
C10—C91.5190 (18)C16—H16B0.970
C10—H100.980C9—H90.980
C8—C71.5344 (18)C3—C21.520 (2)
C8—C91.5506 (17)C3—H3A0.970
C8—C121.5512 (18)C3—H3B0.970
C8—H80.980C2—H2A0.970
C4—C31.535 (2)C2—H2B0.970
C4—C51.5415 (19)C13—H13A0.960
C4—C121.5598 (16)C13—H13B0.960
C4—H40.980C13—H13C0.960
C11—C121.5289 (17)
C10—O4—C11113.64 (9)C6—C5—H5107.7
C12—O1—O2111.75 (9)C14—C5—H5107.7
C21—O6—H6109.5C4—C5—H5107.7
C10—O5—C16112.09 (10)C9—C15—H15A109.5
C11—O3—C1113.63 (10)C9—C15—H15B109.5
C19—O7—H7109.5H15A—C15—H15B109.5
C1—O2—O1109.72 (9)C9—C15—H15C109.5
C19—C18—C17118.94 (12)H15A—C15—H15C109.5
C19—C18—H18120.5H15B—C15—H15C109.5
C17—C18—H18120.5C5—C14—H14A109.5
O2—C1—O3108.18 (10)C5—C14—H14B109.5
O2—C1—C13105.17 (11)H14A—C14—H14B109.5
O3—C1—C13107.17 (11)C5—C14—H14C109.5
O2—C1—C2112.33 (11)H14A—C14—H14C109.5
O3—C1—C2109.88 (10)H14B—C14—H14C109.5
C13—C1—C2113.79 (11)C22—C17—C18120.53 (12)
C21—C20—C19119.65 (12)C22—C17—C16120.35 (12)
C21—C20—H20120.2C18—C17—C16119.12 (12)
C19—C20—H20120.2C5—C6—C7109.99 (11)
O5—C10—O4110.67 (10)C5—C6—H6A109.7
O5—C10—C9111.50 (10)C7—C6—H6A109.7
O4—C10—C9110.18 (10)C5—C6—H6B109.7
O5—C10—H10108.1C7—C6—H6B109.7
O4—C10—H10108.1H6A—C6—H6B108.2
C9—C10—H10108.1O5—C16—C17108.73 (10)
C7—C8—C9113.15 (11)O5—C16—H16A109.9
C7—C8—C12112.23 (10)C17—C16—H16A109.9
C9—C8—C12111.46 (10)O5—C16—H16B109.9
C7—C8—H8106.5C17—C16—H16B109.9
C9—C8—H8106.5H16A—C16—H16B108.3
C12—C8—H8106.5C10—C9—C15111.45 (11)
C3—C4—C5111.25 (11)C10—C9—C8112.57 (10)
C3—C4—C12113.19 (11)C15—C9—C8113.79 (11)
C5—C4—C12112.84 (10)C10—C9—H9106.1
C3—C4—H4106.3C15—C9—H9106.1
C5—C4—H4106.3C8—C9—H9106.1
C12—C4—H4106.3O6—C21—C20115.57 (12)
O3—C11—O4105.56 (10)O6—C21—C22124.17 (12)
O3—C11—C12113.63 (10)C20—C21—C22120.26 (12)
O4—C11—C12111.25 (10)O7—C19—C20116.06 (11)
O3—C11—H11108.8O7—C19—C18122.91 (11)
O4—C11—H11108.8C20—C19—C18121.03 (12)
C12—C11—H11108.8C2—C3—C4116.22 (11)
O1—C12—C11108.60 (10)C2—C3—H3A108.2
O1—C12—C8104.45 (9)C4—C3—H3A108.2
C11—C12—C8110.91 (10)C2—C3—H3B108.2
O1—C12—C4106.09 (10)C4—C3—H3B108.2
C11—C12—C4113.69 (10)H3A—C3—H3B107.4
C8—C12—C4112.48 (11)C3—C2—C1114.21 (11)
C17—C22—C21119.54 (12)C3—C2—H2A108.7
C17—C22—H22120.2C1—C2—H2A108.7
C21—C22—H22120.2C3—C2—H2B108.7
C6—C7—C8111.64 (11)C1—C2—H2B108.7
C6—C7—H7A109.3H2A—C2—H2B107.6
C8—C7—H7A109.3C1—C13—H13A109.5
C6—C7—H7B109.3C1—C13—H13B109.5
C8—C7—H7B109.3H13A—C13—H13B109.5
H7A—C7—H7B108.0C1—C13—H13C109.5
C6—C5—C14111.72 (12)H13A—C13—H13C109.5
C6—C5—C4109.92 (11)H13B—C13—H13C109.5
C14—C5—C4112.02 (11)
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
O6—H6···O7i0.821.992.7279 (14)150
O7—H7···O2ii0.822.182.8409 (13)138
O7—H7···O4ii0.822.222.9269 (13)144
Symmetry codes: (i) −x+1, y−1/2, −z+2; (ii) −x+1, y+1/2, −z+1.
Table 1
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
O6—H6···O7i0.821.992.7279 (14)150
O7—H7···O2ii0.822.182.8409 (13)138
O7—H7···O4ii0.822.222.9269 (13)144
Symmetry codes: (i) −x+1, y−1/2, −z+2; (ii) −x+1, y+1/2, −z+1.
Acknowledgements top

The authors thank the Center for Disease Control and Prevention, USA, for providing financial assistance (CDC cooperative agreements 1UO1 CI000211–03 and1UO1 CI000362–01). This Investigation was conducted in a facility constructed with support from Research Facilities Improvement Program grant No. C06 Rr-14503–01 from the National Center for Research Resources, National Institutes of Health.

references
References top

Beekman, A. C., Barentsen, A. R. W., Woerdenbag, H. J., Uden, W. V., Pras, N., Konings, A. W. T., El-Feraly, F. S., Galal, A. M. & Wikström, H. V. (1997). J. Nat. Prod. 60, 325–330.

Beekman, A. C., Wierenga, P. K., Woerdenbag, H. J., Uden, W. V., Pras, N., Konings, A. W. T., El-Feraly, F. S., Galal, A. M. & Wikström, H. V. (1998). Planta Med. 64, 615–619.

Bruker (2005). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.

Farrugia, L. J. (1997). J. Appl. Cryst. 30, 565.

Flack, H. D. (1983). Acta Cryst. A39, 876–881.

Lisgarten, J. N., Potter, B. S., Bantuzeko, C. & Palmer, R. A. (1998). J. Chem. Crystallogr. 28, 539–543.

Pu, Y. M., Torok, D. S., Ziffer, H., Pan, X.-Q. & Meshnick, S. R. (1995). J. Med. Chem. 38, 4120–4124.

Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122.

Zheng, G. Q. (1994). Planta Med. 60, 54–58.