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

Lijun Xie; Xin Zhai; Jian Zuo; Yanfang Zhao; Ping Gong

doi:10.1107/S1600536810024566

. 2010 Jun 26;66(Pt 7):o1839. doi: 10.1107/S1600536810024566

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

Lijun Xie ^a, Xin Zhai ^a, Jian Zuo ^b, Yanfang Zhao ^a, Ping Gong ^a,^*

PMCID: PMC3006879 PMID: 21588040

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 ▶). For the anticancer properties of the title compound, see: Efferth et al. (1996 ▶); Chadwick et al. (2009 ▶); Galal et al. (2009 ▶). For structural analyses of highly related compounds, see: Gul et al. (2009 ▶); Jasinskiet al. (2008 ▶).

Experimental

Crystal data

C₁₅H₂₃N₃O₄
M _r = 309.36
Orthorhombic,
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 ▶) 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
Δρ_max = 0.12 e Å⁻³
Δρ_min = −0.16 e Å⁻³

Data collection: SMART (Bruker, 2003 ▶); cell refinement: SAINT (Bruker, 2003 ▶); data reduction: SAINT; 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: SHELXTL.

Supplementary Material

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

e-66-o1839-sup1.cif^{(21.9KB, cif)}

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

e-66-o1839-Isup2.hkl^{(81.7KB, hkl)}

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

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C7—H7B⋯N3ⁱ	0.97	2.68	3.628 (6)	167
C10—H10⋯O3ⁱⁱ	0.98	2.67	3.535 (5)	148
C12—H12A⋯O3ⁱⁱ	0.97	2.65	3.508 (5)	147

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Symmetry codes: (i) Inline graphic ; (ii) .

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.