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Acta Crystallogr Sect E Struct Rep Online. 2010 July 1; 66(Pt 7): o1839.
Published online 2010 June 26. doi:  10.1107/S1600536810024566
PMCID: PMC3006879

(1R,3S,4R,4aS,7R,7aS,10R,12aR)-3-Azido-4,7,10-trimethyl-1,10-epidioxy­per­hydropyrano[4,3-j][1,2]benzodiox­epine

Abstract

In the title compound, C15H23N3O4, the six-membered pyran, cyclo­hexane and trioxane rings adopt chair, chair and boat conformations, respectively, while the seven-membered rings adopt distorted boat and very distorted chair conformations. In the crystal, adjacent mol­ecules are connected by weak C—H(...)N and C—H(...)O inter­actions.

Related literature

For general background to artemisinin, a sesquiterpene endoperoxide widely used to treat drug-resistant malaria, see: Liu et al. (1979 [triangle]). For the anti­cancer properties of the title compound, see: Efferth et al. (1996 [triangle]); Chadwick et al. (2009 [triangle]); Galal et al. (2009 [triangle]). For structural analyses of highly related compounds, see: Gul et al. (2009 [triangle]); Jasinskiet al. (2008 [triangle]).

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Object name is e-66-o1839-scheme1.jpg

Experimental

Crystal data

  • C15H23N3O4
  • M r = 309.36
  • Orthorhombic, An external file that holds a picture, illustration, etc.
Object name is e-66-o1839-efi1.jpg
  • a = 7.9938 (9) Å
  • b = 11.207 (1) Å
  • c = 17.984 (2) Å
  • V = 1611.1 (3) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.09 mm−1
  • T = 298 K
  • 0.50 × 0.40 × 0.38 mm

Data collection

  • Bruker SMART CCD area-detector diffractometer
  • Absorption correction: multi-scan (SADABS; Sheldrick, 1996 [triangle]) T min = 0.955, T max = 0.965
  • 7585 measured reflections
  • 1657 independent reflections
  • 1130 reflections with I > 2σ(I)
  • R int = 0.043

Refinement

  • R[F 2 > 2σ(F 2)] = 0.040
  • wR(F 2) = 0.103
  • S = 1.09
  • 1657 reflections
  • 202 parameters
  • H-atom parameters constrained
  • Δρmax = 0.12 e Å−3
  • Δρmin = −0.16 e Å−3

Data collection: SMART (Bruker, 2003 [triangle]); cell refinement: SAINT (Bruker, 2003 [triangle]); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: SHELXTL (Sheldrick, 2008 [triangle]); software used to prepare material for publication: SHELXTL.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810024566/im2212sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810024566/im2212Isup2.hkl

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

The authors thank Liaocheng University for providing research facilities. This work was supported by the National S&T Major Project of China (No. 2009ZX09103–099) and the Science Project of Liaoning Province Education Department (No. L2010532).

supplementary crystallographic information

Comment

Artemisinin, a sesquiterpene endoperoxide isolated from Artemisia annua L, is being widely used to treat drug-resistant malaria (Liu et al., 1979). In addition, Artemisinin and its derivatives also showed potent and broad anticancer properties in different human cancer cell lines and animal models (Efferth et al., 1996). These compounds contain an endoperoxide bridge (R—O—O—R) which is required for their biological activities. Recently, there are many reports about significant anticancer activities of artemisinin derivatives, which were expected to be more stable toward the metabolism process (Chadwick et al., 2009; Galal et al., 2009). Herein, we present the synthesis and structure of an artemisinin derivatives, (1R,3S,4R,4aS,7R,7aS,10R,12aR)-3-Azido- 4,7,10-trimethyl-1,10-epoxy-decahydro- 12H-pyrano[4,3-j]-1,2-benzodioxepin.

The crystal structure of the title compound is given in Fig. 1. The bond lengths and angles in the title compound are found to have normal values with respect to highly related compounds (Gul et al., 2009; Jasinski et al., 2008). The six membered rings A, B and C adopt chair, chair and boat conformations, respectively. In the crystal, adjacent molecules are connected by non-classical C—H···N and C—H···O hydrogen bonding, with the distance of 3.628 (6), 3.508 (5) and 3.535 (5) Å (Table 1), respectively.

Experimental

Trimethylchlorosilane (300 mmol, 38.1 ml) was added gradually to a solution of dihydroartemisinin (200 mmol, 56.8 g, diastereomeric mixture with R and S configuration at C(3)) and sodium azide (300 mmol, 19.5 g) in CH2Cl2 (300 ml). Then sodium iodide (20 mmol, 3.0 g) was added to the reaction mixture at low temperature. The reaction mixture was stirred at room temperature for 28 h. The mixture was quenched with a saturated NaHCO3 solution (100 ml) and diluted with CH2Cl2. Two phases were separated and the organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by column chromatography (silica, 1%-5% EtOAc/hexanes) to furnish the product (94 mmol, 29.0 g) and it's diastereomer with R configuration at C(3). Colorless single crystals of the title compound was obtained in CH2Cl2 solution after 10 days by slow evaporation at room temperature.

Refinement

In the absence of significant anomalous dispersion effects, Friedel pairs were averaged. All H-atoms were positioned geometrically and refined using a riding model, with C—H = 0.96 Å (CH3), 0.97 Å (CH2), 0.98 Å (CH), and Uiso(H) =1.2Ueq(C).

Figures

Fig. 1.
Molecular structure of the title compound, showing 30% probability displacement ellipsoids and the atom-numbering scheme.

Crystal data

C15H23N3O4F(000) = 664
Mr = 309.36Dx = 1.275 Mg m3
Orthorhombic, P212121Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2abCell parameters from 2309 reflections
a = 7.9938 (9) Åθ = 2.3–21.4°
b = 11.207 (1) ŵ = 0.09 mm1
c = 17.984 (2) ÅT = 298 K
V = 1611.1 (3) Å3Block, colorless
Z = 40.50 × 0.40 × 0.38 mm

Data collection

Bruker SMART CCD area-detector diffractometer1657 independent reflections
Radiation source: fine-focus sealed tube1130 reflections with I > 2σ(I)
graphiteRint = 0.043
phi and ω scansθmax = 25.0°, θmin = 2.1°
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)h = −9→7
Tmin = 0.955, Tmax = 0.965k = −13→13
7585 measured reflectionsl = −16→21

Refinement

Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.040Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.103H-atom parameters constrained
S = 1.09w = 1/[σ2(Fo2) + (0.0312P)2 + 0.4488P] where P = (Fo2 + 2Fc2)/3
1657 reflections(Δ/σ)max < 0.001
202 parametersΔρmax = 0.12 e Å3
0 restraintsΔρmin = −0.16 e Å3

Special details

Experimental. We took dihydroartemisinin (mixture of 3R and 3S isomers of hydroxyl group) as the starting material in our experiment. During the course of synthesis, we got a mixture of two diastereomers with 3S and 3R and all other stereogenic centers are known and still in the configuration as they were in the starting compound. The mixture was separated by silica gel column chromatography and the title compound with 3S was crystallized under our conditions, while the other one (3R) was obtained as amorphous powder.
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)

xyzUiso*/Ueq
N10.4489 (5)0.4264 (3)0.41235 (17)0.0737 (10)
N20.3162 (6)0.4810 (3)0.41854 (19)0.0756 (10)
N30.2016 (6)0.5395 (4)0.4253 (3)0.1117 (15)
O10.3528 (3)0.3297 (2)0.30143 (11)0.0583 (6)
O20.3573 (3)0.3910 (2)0.18223 (12)0.0601 (7)
O30.4236 (3)0.1895 (2)0.17929 (14)0.0726 (8)
O40.5935 (3)0.2044 (2)0.20749 (13)0.0669 (7)
C10.4297 (5)0.3114 (3)0.37062 (18)0.0656 (10)
H10.35540.26010.39990.079*
C20.5957 (5)0.2491 (4)0.3652 (2)0.0738 (12)
H20.57120.16950.34540.089*
C30.7131 (5)0.3075 (4)0.3087 (2)0.0670 (11)
H30.80210.24950.29890.080*
C40.6214 (4)0.3259 (3)0.23485 (17)0.0528 (9)
C50.4547 (4)0.3878 (3)0.24650 (17)0.0495 (9)
H50.47590.46990.26270.059*
C60.3823 (5)0.2889 (4)0.13467 (19)0.0683 (11)
C70.5171 (5)0.3170 (4)0.0778 (2)0.0789 (12)
H7A0.57800.24440.06670.095*
H7B0.46380.34350.03220.095*
C80.6406 (6)0.4117 (4)0.1028 (2)0.0765 (12)
H8A0.58090.48670.10750.092*
H8B0.72340.42180.06390.092*
C90.7325 (5)0.3881 (3)0.1758 (2)0.0653 (10)
H90.82270.33190.16400.078*
C100.8171 (5)0.5007 (4)0.2052 (2)0.0798 (12)
H100.72930.55860.21720.096*
C110.9123 (5)0.4740 (5)0.2759 (3)0.0973 (16)
H11A0.96210.54700.29450.117*
H11B1.00200.41840.26500.117*
C120.7998 (5)0.4211 (4)0.3354 (2)0.0840 (13)
H12A0.71590.47950.34930.101*
H12B0.86610.40320.37910.101*
C130.6724 (7)0.2282 (5)0.4424 (2)0.1150 (19)
H13A0.69360.30370.46590.173*
H13B0.77560.18510.43740.173*
H13C0.59600.18280.47240.173*
C140.2153 (6)0.2572 (5)0.1011 (3)0.1060 (17)
H14A0.22930.19290.06650.159*
H14B0.17040.32550.07580.159*
H14C0.13980.23320.13980.159*
C150.9352 (6)0.5587 (5)0.1476 (3)0.124 (2)
H15A0.98290.63000.16830.186*
H15B0.87300.57850.10360.186*
H15C1.02290.50380.13510.186*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
N10.085 (2)0.083 (2)0.0530 (19)−0.002 (2)0.003 (2)−0.0156 (19)
N20.094 (3)0.079 (3)0.055 (2)−0.016 (2)0.017 (2)−0.015 (2)
N30.105 (3)0.112 (3)0.117 (4)0.005 (3)0.021 (3)−0.037 (3)
O10.0652 (14)0.0705 (16)0.0393 (12)−0.0044 (13)0.0041 (11)−0.0011 (12)
O20.0722 (15)0.0672 (15)0.0410 (13)0.0191 (14)−0.0084 (13)−0.0062 (13)
O30.101 (2)0.0608 (16)0.0560 (14)−0.0006 (16)−0.0084 (15)−0.0067 (15)
O40.0912 (19)0.0523 (15)0.0572 (14)0.0182 (14)0.0006 (14)−0.0024 (13)
C10.095 (3)0.065 (2)0.0366 (17)−0.013 (2)0.0044 (19)−0.0005 (19)
C20.107 (3)0.070 (3)0.044 (2)0.014 (3)−0.011 (2)0.005 (2)
C30.068 (2)0.071 (3)0.062 (2)0.019 (2)−0.010 (2)0.002 (2)
C40.061 (2)0.051 (2)0.0465 (18)0.0126 (19)0.0015 (17)−0.0009 (17)
C50.058 (2)0.054 (2)0.0362 (16)0.0069 (19)−0.0015 (18)−0.0046 (17)
C60.094 (3)0.068 (3)0.0431 (19)0.013 (2)−0.011 (2)−0.008 (2)
C70.111 (3)0.083 (3)0.043 (2)0.025 (3)0.003 (2)−0.002 (2)
C80.099 (3)0.082 (3)0.048 (2)0.013 (3)0.022 (2)0.010 (2)
C90.065 (2)0.068 (2)0.063 (2)0.017 (2)0.016 (2)−0.001 (2)
C100.067 (3)0.083 (3)0.090 (3)−0.003 (2)0.016 (2)0.000 (3)
C110.063 (3)0.118 (4)0.111 (4)−0.008 (3)−0.001 (3)−0.011 (3)
C120.076 (3)0.103 (3)0.073 (3)0.007 (3)−0.018 (2)−0.006 (3)
C130.160 (5)0.127 (4)0.057 (3)0.039 (4)−0.024 (3)0.018 (3)
C140.120 (4)0.124 (4)0.074 (3)0.003 (4)−0.035 (3)−0.030 (3)
C150.108 (4)0.121 (4)0.143 (5)−0.028 (4)0.040 (4)0.010 (4)

Geometric parameters (Å, °)

N1—N21.229 (5)C7—H7A0.9700
N1—C11.499 (5)C7—H7B0.9700
N2—N31.133 (5)C8—C91.528 (5)
O1—C11.403 (4)C8—H8A0.9700
O1—C51.437 (4)C8—H8B0.9700
O2—C51.394 (4)C9—C101.526 (5)
O2—C61.442 (4)C9—H90.9800
O3—C61.412 (4)C10—C111.511 (6)
O3—O41.459 (3)C10—C151.545 (6)
O4—C41.464 (4)C10—H100.9800
C1—C21.503 (6)C11—C121.518 (6)
C1—H10.9800C11—H11A0.9700
C2—C31.530 (5)C11—H11B0.9700
C2—C131.536 (5)C12—H12A0.9700
C2—H20.9800C12—H12B0.9700
C3—C121.527 (5)C13—H13A0.9600
C3—C41.531 (4)C13—H13B0.9600
C3—H30.9800C13—H13C0.9600
C4—C51.517 (5)C14—H14A0.9600
C4—C91.550 (5)C14—H14B0.9600
C5—H50.9800C14—H14C0.9600
C6—C141.507 (5)C15—H15A0.9600
C6—C71.518 (5)C15—H15B0.9600
C7—C81.518 (6)C15—H15C0.9600
N2—N1—C1112.6 (3)C7—C8—C9116.5 (3)
N3—N2—N1174.3 (4)C7—C8—H8A108.2
C1—O1—C5115.3 (3)C9—C8—H8A108.2
C5—O2—C6113.2 (3)C7—C8—H8B108.2
C6—O3—O4108.9 (3)C9—C8—H8B108.2
O3—O4—C4111.4 (2)H8A—C8—H8B107.3
O1—C1—N1111.3 (3)C10—C9—C8111.6 (3)
O1—C1—C2113.4 (3)C10—C9—C4112.8 (3)
N1—C1—C2110.0 (3)C8—C9—C4113.0 (3)
O1—C1—H1107.3C10—C9—H9106.3
N1—C1—H1107.3C8—C9—H9106.3
C2—C1—H1107.3C4—C9—H9106.3
C1—C2—C3112.7 (3)C11—C10—C9110.6 (4)
C1—C2—C13111.4 (3)C11—C10—C15109.9 (4)
C3—C2—C13114.9 (4)C9—C10—C15112.7 (4)
C1—C2—H2105.7C11—C10—H10107.9
C3—C2—H2105.7C9—C10—H10107.9
C13—C2—H2105.7C15—C10—H10107.9
C12—C3—C2115.3 (3)C10—C11—C12111.8 (3)
C12—C3—C4112.2 (3)C10—C11—H11A109.3
C2—C3—C4109.9 (3)C12—C11—H11A109.3
C12—C3—H3106.3C10—C11—H11B109.3
C2—C3—H3106.3C12—C11—H11B109.3
C4—C3—H3106.3H11A—C11—H11B107.9
O4—C4—C5109.7 (3)C11—C12—C3111.9 (4)
O4—C4—C3103.9 (3)C11—C12—H12A109.2
C5—C4—C3111.2 (3)C3—C12—H12A109.2
O4—C4—C9106.0 (3)C11—C12—H12B109.2
C5—C4—C9113.1 (3)C3—C12—H12B109.2
C3—C4—C9112.4 (3)H12A—C12—H12B107.9
O2—C5—O1105.4 (3)C2—C13—H13A109.5
O2—C5—C4112.8 (3)C2—C13—H13B109.5
O1—C5—C4112.7 (3)H13A—C13—H13B109.5
O2—C5—H5108.6C2—C13—H13C109.5
O1—C5—H5108.6H13A—C13—H13C109.5
C4—C5—H5108.6H13B—C13—H13C109.5
O3—C6—O2108.7 (3)C6—C14—H14A109.5
O3—C6—C14104.4 (4)C6—C14—H14B109.5
O2—C6—C14107.5 (3)H14A—C14—H14B109.5
O3—C6—C7112.4 (3)C6—C14—H14C109.5
O2—C6—C7109.5 (3)H14A—C14—H14C109.5
C14—C6—C7114.1 (3)H14B—C14—H14C109.5
C8—C7—C6114.0 (3)C10—C15—H15A109.5
C8—C7—H7A108.7C10—C15—H15B109.5
C6—C7—H7A108.7H15A—C15—H15B109.5
C8—C7—H7B108.7C10—C15—H15C109.5
C6—C7—H7B108.7H15A—C15—H15C109.5
H7A—C7—H7B107.6H15B—C15—H15C109.5
C1—N1—N2—N3−159 (4)O4—C4—C5—O162.1 (3)
C6—O3—O4—C444.7 (3)C3—C4—C5—O1−52.3 (4)
C5—O1—C1—N172.1 (4)C9—C4—C5—O1−179.9 (3)
C5—O1—C1—C2−52.6 (4)O4—O3—C6—O2−72.3 (3)
N2—N1—C1—O153.7 (4)O4—O3—C6—C14173.2 (3)
N2—N1—C1—C2−179.8 (3)O4—O3—C6—C749.0 (4)
O1—C1—C2—C350.7 (4)C5—O2—C6—O330.7 (4)
N1—C1—C2—C3−74.6 (4)C5—O2—C6—C14143.2 (3)
O1—C1—C2—C13−178.5 (4)C5—O2—C6—C7−92.4 (3)
N1—C1—C2—C1356.2 (5)O3—C6—C7—C8−95.2 (4)
C1—C2—C3—C1278.1 (4)O2—C6—C7—C825.7 (4)
C13—C2—C3—C12−50.9 (5)C14—C6—C7—C8146.2 (4)
C1—C2—C3—C4−49.8 (4)C6—C7—C8—C956.2 (5)
C13—C2—C3—C4−178.8 (3)C7—C8—C9—C10−165.3 (3)
O3—O4—C4—C516.4 (3)C7—C8—C9—C4−36.8 (5)
O3—O4—C4—C3135.4 (3)O4—C4—C9—C10−162.7 (3)
O3—O4—C4—C9−106.0 (3)C5—C4—C9—C1077.1 (4)
C12—C3—C4—O4162.9 (3)C3—C4—C9—C10−49.8 (4)
C2—C3—C4—O4−67.5 (4)O4—C4—C9—C869.6 (4)
C12—C3—C4—C5−79.1 (4)C5—C4—C9—C8−50.7 (4)
C2—C3—C4—C550.5 (4)C3—C4—C9—C8−177.6 (3)
C12—C3—C4—C948.8 (4)C8—C9—C10—C11−177.9 (3)
C2—C3—C4—C9178.4 (3)C4—C9—C10—C1153.5 (4)
C6—O2—C5—O1−91.5 (3)C8—C9—C10—C15−54.6 (5)
C6—O2—C5—C431.9 (4)C4—C9—C10—C15176.9 (3)
C1—O1—C5—O2177.1 (3)C9—C10—C11—C12−57.2 (5)
C1—O1—C5—C453.7 (4)C15—C10—C11—C12177.8 (4)
O4—C4—C5—O2−57.1 (4)C10—C11—C12—C357.2 (5)
C3—C4—C5—O2−171.5 (3)C2—C3—C12—C11−179.4 (3)
C9—C4—C5—O261.0 (4)C4—C3—C12—C11−52.6 (4)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
C7—H7B···N3i0.972.683.628 (6)167
C10—H10···O3ii0.982.673.535 (5)148
C12—H12A···O3ii0.972.653.508 (5)147

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

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: IM2212).

References

  • Bruker (2003). SMART and SAINT Bruker AXS Inc., Madison, Wisconsin, USA.
  • Chadwick, J., Mercer, A. E. & Park, B. K. (2009). Bioorg. Med. Chem.17, 1325–1338. [PubMed]
  • Efferth, T., Rucker, G. & Falkenberg, M. (1996). Arzneimittelforschung, 46, 196–200. [PubMed]
  • Galal, A. M., Gul, W. & Slade, D. (2009). Bioorg. Med. Chem.17, 741–745. [PubMed]
  • Gul, W., Carvalho, P., Galal, A., Avery, M. A. & El Sohly, M. A. (2009). Acta Cryst. E65, o358–o359. [PMC free article] [PubMed]
  • Jasinski, J. P., Butcher, R. J., Yathirajan, H. S., Narayana, B. & Sreevidya, T. V. (2008). Acta Cryst. E64, o585–o586. [PMC free article] [PubMed]
  • Liu, J. M., Ni, M. Y. & Fan, Y. (1979). Acta Chim. Sin.37, 129–141.
  • Sheldrick, G. M. (1996). SADABS University of Göttingen, Germany.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]

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