Redetermination of dihydro-artemisinin at 103 (2) K.

Tthe structure of the title compound, C(15)H(24)O(5), has been redetermined at 103 (2) K, with much improved precision. The title compound was first reported by Luo, Yeh, Brossi, Flippen-Anderson & Gillardi [Helv. Chim. Acta (1984). 67, 1515-1522]. It is a derivative of the anti-malaria compound artemisinin and consists primarily of three substituted ring systems fused together. A cyclo-hexane ring (with a distorted chair conformation), is fused to a tetra-hydro-pyran group (also with a distorted chair conformation), and is adjacent to an oxacyclo-heptane unit containing an endoperoxide bridge. This gives the mol-ecule a unique three-dimensional arrangement. The crystal packing is stabilized by inter-molecular C-H⋯O and O-H⋯O inter-actions between an H atom from the cyclo-hexane ring and an O atom from the endoperoxide bridge, as well as between the hydroxyl H atom and an O atom from a tetra-hydro-pyran ring.

Related literature

For crystal structures of similar compounds, see: Flippen-Anderson et al. (1989 ▶), Yue et al. (2006 ▶), Li et al. (2006 ▶); Karle & Lin (1995 ▶); Brossi et al. (1988 ▶). For the biological activity of artemisinin derivatives in vitro and in vivo, see: Li et al. (2001 ▶); Yang et al. (1997 ▶); Grace et al. (1998 ▶); Maggs et al. (2000 ▶). For endoperoxide sesquiterpene lactone derivatives, see: Venugopalan et al. (1995 ▶); Wu et al. (2001 ▶); Saxena et al. (2003 ▶). For the synthesis of artemisinin and its derivatives, see: Lui et al. (1979 ▶); Liu (1980 ▶); Robert et al. (2001 ▶). For related literature, see: Allen et al. (1987 ▶); Cremer & Pople (1975 ▶); Lisgarten et al. (1998 ▶); Qinghaosu Research Group (1980 ▶); Shen & Zhuang (1984 ▶); Wu & Li (1995 ▶); Luo et al. (1984 ▶).

Experimental

Crystal data

C15H24O5

M = 284.34

Orthorhombic,

a = 5.5910 (6) Å

b = 14.1309 (14) Å

c = 18.8062 (19) Å

V = 1485.8 (3) Å3

Z = 4

Mo Kα radiation

μ = 0.09 mm−1

T = 103 (2) K

0.67 × 0.11 × 0.09 mm

Data collection

Bruker APEXII CCD area-detector diffractometer

Absorption correction: multi-scan (SADABS; Sheldrick, 1996 ▶) T min = 0.940, T max = 0.992

16573 measured reflections

2475 independent reflections

2130 reflections with I > 2σ(I)

R int = 0.044

Refinement

R[F 2 > 2σ(F 2)] = 0.038

wR(F 2) = 0.100

S = 1.06

2475 reflections

185 parameters

H-atom parameters constrained

Δρmax = 0.37 e Å−3

Δρmin = −0.22 e Å−3

Data collection: APEX2 (Bruker, 2006 ▶); cell refinement: APEX2; data reduction: SAINT (Bruker, 2006 ▶); program(s) used to solve structure: SHELXS97 (Sheldrick, 1990 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997 ▶); molecular graphics: SHELXTL (Bruker, 2000 ▶); software used to prepare material for publication: SHELXTL.

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536807063180/fj2084sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536807063180/fj2084Isup2.hkl

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

C15H24O5	F000 = 616
Mr = 284.34	Dx = 1.271 Mg m−3
Orthorhombic, P212121	Mo Kα radiation λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 4650 reflections
a = 5.5910 (6) Å	θ = 2.6–29.6º
b = 14.1309 (14) Å	µ = 0.09 mm−1
c = 18.8062 (19) Å	T = 103 (2) K
V = 1485.8 (3) Å3	Needle, colorless
Z = 4	0.67 × 0.11 × 0.09 mm

Bruker APEXII CCD area-detector diffractometer	2475 independent reflections
Radiation source: fine-focus sealed tube	2130 reflections with I > 2σ(I)
Monochromator: graphite	Rint = 0.044
T = 103(2) K	θmax = 30.5º
φ and ω scans	θmin = 1.8º
Absorption correction: multi-scan(SADABS; Sheldrick, 1996)	h = −5→7
Tmin = 0.940, Tmax = 0.992	k = −19→19
16573 measured reflections	l = −26→26

Refinement on F2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.038	H-atom parameters constrained
wR(F2) = 0.100	w = 1/[σ2(Fo2) + (0.0434P)2 + 0.5149P] where P = (Fo2 + 2Fc2)/3
S = 1.06	(Δ/σ)max = 0.002
2475 reflections	Δρmax = 0.37 e Å−3
185 parameters	Δρmin = −0.22 e Å−3
Primary atom site location: structure-invariant direct methods	Extinction correction: none

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
O1	0.2493 (3)	0.35457 (10)	0.85285 (7)	0.0212 (3)
O2	0.1910 (3)	0.31049 (9)	0.96710 (6)	0.0187 (3)
O3	−0.1579 (3)	0.36796 (11)	0.87194 (7)	0.0250 (3)
O4	−0.1419 (3)	0.45439 (10)	0.91529 (7)	0.0229 (3)
O5	0.4123 (3)	0.34511 (9)	1.06918 (7)	0.0198 (3)
H5	0.4953	0.2959	1.0648	0.024*
C1	0.1042 (4)	0.47570 (13)	0.93520 (9)	0.0178 (4)
C2	0.0886 (4)	0.50052 (13)	1.01511 (9)	0.0195 (4)
H2A	−0.0458	0.5467	1.0205	0.023*
C3	0.3158 (4)	0.55071 (13)	1.04118 (10)	0.0238 (4)
H3A	0.2942	0.5701	1.0914	0.029*
H3B	0.4523	0.5062	1.0390	0.029*
C4	0.3716 (5)	0.63737 (13)	0.99635 (10)	0.0269 (5)
H4A	0.5198	0.6674	1.0142	0.032*
H4B	0.2398	0.6837	1.0012	0.032*
C5	0.4035 (4)	0.61214 (13)	0.91802 (10)	0.0225 (4)
H5A	0.5412	0.5673	0.9140	0.027*
C6	0.1797 (4)	0.56209 (13)	0.88957 (9)	0.0195 (4)
H6A	0.0459	0.6089	0.8925	0.023*
C7	0.2078 (4)	0.53662 (14)	0.81060 (9)	0.0245 (4)
H7A	0.1986	0.5957	0.7825	0.029*
H7B	0.3697	0.5098	0.8035	0.029*
C8	0.0260 (5)	0.46691 (15)	0.78064 (10)	0.0269 (5)
H8A	0.0621	0.4558	0.7298	0.032*
H8B	−0.1353	0.4955	0.7836	0.032*
C9	0.0230 (4)	0.37149 (15)	0.81945 (10)	0.0247 (4)
C10	0.2609 (4)	0.38836 (12)	0.92316 (9)	0.0163 (4)
H10A	0.4306	0.4051	0.9343	0.020*
C11	0.1826 (4)	0.32865 (13)	1.04225 (9)	0.0184 (4)
H11A	0.1159	0.2713	1.0663	0.022*
C12	0.0176 (4)	0.41122 (14)	1.05737 (9)	0.0200 (4)
H12A	−0.1444	0.3922	1.0400	0.024*
C13	0.4636 (5)	0.70119 (16)	0.87466 (12)	0.0342 (6)
H13A	0.6048	0.7321	0.8950	0.051*
H13B	0.3278	0.7450	0.8760	0.051*
H13C	0.4967	0.6833	0.8253	0.051*
C14	−0.0293 (6)	0.28799 (17)	0.77187 (11)	0.0364 (6)
H14A	−0.0491	0.2310	0.8010	0.055*
H14B	0.1039	0.2788	0.7387	0.055*
H14C	−0.1765	0.2999	0.7451	0.055*
C15	−0.0068 (5)	0.42857 (16)	1.13739 (10)	0.0299 (5)
H15A	−0.0695	0.3715	1.1604	0.045*
H15B	−0.1169	0.4814	1.1456	0.045*
H15C	0.1503	0.4439	1.1574	0.045*

	U11	U22	U33	U12	U13	U23
O1	0.0215 (8)	0.0257 (6)	0.0163 (5)	−0.0011 (6)	0.0014 (6)	−0.0038 (5)
O2	0.0211 (7)	0.0181 (6)	0.0168 (6)	−0.0022 (6)	−0.0012 (6)	0.0004 (5)
O3	0.0209 (8)	0.0333 (7)	0.0208 (6)	−0.0074 (6)	−0.0017 (6)	0.0001 (6)
O4	0.0142 (7)	0.0317 (7)	0.0228 (6)	0.0013 (6)	−0.0024 (5)	−0.0013 (6)
O5	0.0172 (7)	0.0190 (6)	0.0232 (6)	0.0012 (5)	−0.0047 (6)	0.0003 (5)
C1	0.0132 (9)	0.0230 (8)	0.0171 (8)	0.0018 (7)	−0.0005 (7)	−0.0016 (7)
C2	0.0197 (10)	0.0210 (8)	0.0180 (8)	0.0061 (8)	0.0005 (8)	−0.0014 (6)
C3	0.0315 (12)	0.0206 (8)	0.0194 (8)	−0.0016 (9)	−0.0056 (9)	0.0010 (7)
C4	0.0385 (13)	0.0177 (8)	0.0245 (9)	−0.0005 (9)	−0.0043 (9)	−0.0011 (7)
C5	0.0267 (11)	0.0185 (8)	0.0223 (8)	−0.0003 (8)	−0.0016 (8)	0.0033 (7)
C6	0.0196 (10)	0.0191 (8)	0.0198 (8)	0.0021 (7)	−0.0019 (8)	0.0013 (7)
C7	0.0299 (12)	0.0257 (9)	0.0179 (8)	−0.0017 (9)	0.0000 (8)	0.0036 (7)
C8	0.0293 (13)	0.0346 (11)	0.0168 (8)	−0.0045 (10)	−0.0052 (8)	0.0032 (8)
C9	0.0245 (11)	0.0323 (10)	0.0175 (8)	−0.0066 (9)	−0.0010 (8)	−0.0005 (8)
C10	0.0165 (9)	0.0170 (7)	0.0156 (7)	−0.0003 (7)	−0.0006 (7)	−0.0007 (6)
C11	0.0160 (9)	0.0230 (8)	0.0161 (7)	−0.0023 (8)	−0.0016 (7)	0.0020 (7)
C12	0.0169 (10)	0.0265 (9)	0.0165 (8)	0.0011 (8)	0.0016 (7)	0.0016 (7)
C13	0.0446 (15)	0.0275 (10)	0.0304 (10)	−0.0116 (11)	−0.0032 (11)	0.0058 (9)
C14	0.0470 (17)	0.0386 (12)	0.0234 (10)	−0.0151 (12)	−0.0042 (11)	−0.0034 (9)
C15	0.0351 (14)	0.0370 (11)	0.0177 (9)	0.0037 (10)	0.0051 (9)	−0.0001 (8)

O1—C10	1.407 (2)	C6—C7	1.536 (3)
O1—C9	1.432 (3)	C6—H6A	1.0000
O2—C10	1.431 (2)	C7—C8	1.524 (3)
O2—C11	1.437 (2)	C7—H7A	0.9900
O3—C9	1.414 (3)	C7—H7B	0.9900
O3—O4	1.471 (2)	C8—C9	1.533 (3)
O4—C1	1.457 (2)	C8—H8A	0.9900
O5—C11	1.400 (2)	C8—H8B	0.9900
O5—H5	0.8400	C9—C14	1.509 (3)
C1—C10	1.531 (3)	C10—H10A	1.0000
C1—C2	1.546 (2)	C11—C12	1.514 (3)
C1—C6	1.551 (3)	C11—H11A	1.0000
C2—C3	1.535 (3)	C12—C15	1.531 (3)
C2—C12	1.543 (3)	C12—H12A	1.0000
C2—H2A	1.0000	C13—H13A	0.9800
C3—C4	1.519 (3)	C13—H13B	0.9800
C3—H3A	0.9900	C13—H13C	0.9800
C3—H3B	0.9900	C14—H14A	0.9800
C4—C5	1.526 (3)	C14—H14B	0.9800
C4—H4A	0.9900	C14—H14C	0.9800
C4—H4B	0.9900	C15—H15A	0.9800
C5—C6	1.533 (3)	C15—H15B	0.9800
C5—C13	1.537 (3)	C15—H15C	0.9800
C5—H5A	1.0000
C10—O1—C9	113.35 (15)	C7—C8—H8A	108.9
C10—O2—C11	116.08 (13)	C9—C8—H8A	108.9
C9—O3—O4	108.29 (14)	C7—C8—H8B	108.9
C1—O4—O3	111.82 (13)	C9—C8—H8B	108.9
C11—O5—H5	109.5	H8A—C8—H8B	107.7
O4—C1—C10	109.63 (15)	O3—C9—O1	108.65 (14)
O4—C1—C2	104.10 (15)	O3—C9—C14	104.33 (18)
C10—C1—C2	111.04 (14)	O1—C9—C14	107.5 (2)
O4—C1—C6	106.12 (15)	O3—C9—C8	111.78 (19)
C10—C1—C6	113.38 (16)	O1—C9—C8	110.25 (17)
C2—C1—C6	112.01 (15)	C14—C9—C8	114.03 (16)
C3—C2—C12	115.21 (16)	O1—C10—O2	105.60 (13)
C3—C2—C1	111.63 (17)	O1—C10—C1	112.70 (14)
C12—C2—C1	109.25 (15)	O2—C10—C1	112.21 (15)
C3—C2—H2A	106.8	O1—C10—H10A	108.7
C12—C2—H2A	106.8	O2—C10—H10A	108.7
C1—C2—H2A	106.8	C1—C10—H10A	108.7
C4—C3—C2	111.42 (17)	O5—C11—O2	110.82 (16)
C4—C3—H3A	109.3	O5—C11—C12	111.27 (15)
C2—C3—H3A	109.3	O2—C11—C12	110.01 (15)
C4—C3—H3B	109.3	O5—C11—H11A	108.2
C2—C3—H3B	109.3	O2—C11—H11A	108.2
H3A—C3—H3B	108.0	C12—C11—H11A	108.2
C3—C4—C5	111.80 (16)	C11—C12—C15	111.25 (16)
C3—C4—H4A	109.3	C11—C12—C2	112.14 (16)
C5—C4—H4A	109.3	C15—C12—C2	113.47 (17)
C3—C4—H4B	109.3	C11—C12—H12A	106.5
C5—C4—H4B	109.3	C15—C12—H12A	106.5
H4A—C4—H4B	107.9	C2—C12—H12A	106.5
C4—C5—C6	110.45 (18)	C5—C13—H13A	109.5
C4—C5—C13	110.27 (16)	C5—C13—H13B	109.5
C6—C5—C13	111.78 (17)	H13A—C13—H13B	109.5
C4—C5—H5A	108.1	C5—C13—H13C	109.5
C6—C5—H5A	108.1	H13A—C13—H13C	109.5
C13—C5—H5A	108.1	H13B—C13—H13C	109.5
C5—C6—C7	111.22 (18)	C9—C14—H14A	109.5
C5—C6—C1	113.09 (15)	C9—C14—H14B	109.5
C7—C6—C1	112.24 (15)	H14A—C14—H14B	109.5
C5—C6—H6A	106.6	C9—C14—H14C	109.5
C7—C6—H6A	106.6	H14A—C14—H14C	109.5
C1—C6—H6A	106.6	H14B—C14—H14C	109.5
C8—C7—C6	116.15 (18)	C12—C15—H15A	109.5
C8—C7—H7A	108.2	C12—C15—H15B	109.5
C6—C7—H7A	108.2	H15A—C15—H15B	109.5
C8—C7—H7B	108.2	C12—C15—H15C	109.5
C6—C7—H7B	108.2	H15A—C15—H15C	109.5
H7A—C7—H7B	107.4	H15B—C15—H15C	109.5
C7—C8—C9	113.55 (17)
C9—O3—O4—C1	−45.32 (18)	O4—O3—C9—C14	−172.27 (16)
O3—O4—C1—C10	−15.82 (18)	O4—O3—C9—C8	−48.58 (19)
O3—O4—C1—C2	−134.68 (13)	C10—O1—C9—O3	−32.1 (2)
O3—O4—C1—C6	106.97 (15)	C10—O1—C9—C14	−144.41 (16)
O4—C1—C2—C3	−164.53 (15)	C10—O1—C9—C8	90.75 (18)
C10—C1—C2—C3	77.58 (19)	C7—C8—C9—O3	96.3 (2)
C6—C1—C2—C3	−50.3 (2)	C7—C8—C9—O1	−24.6 (2)
O4—C1—C2—C12	66.88 (19)	C7—C8—C9—C14	−145.6 (2)
C10—C1—C2—C12	−51.0 (2)	C9—O1—C10—O2	92.17 (17)
C6—C1—C2—C12	−178.90 (17)	C9—O1—C10—C1	−30.7 (2)
C12—C2—C3—C4	179.84 (17)	C11—O2—C10—O1	−178.37 (16)
C1—C2—C3—C4	54.5 (2)	C11—O2—C10—C1	−55.2 (2)
C2—C3—C4—C5	−58.2 (3)	O4—C1—C10—O1	56.06 (19)
C3—C4—C5—C6	56.9 (2)	C2—C1—C10—O1	170.53 (16)
C3—C4—C5—C13	−179.1 (2)	C6—C1—C10—O1	−62.3 (2)
C4—C5—C6—C7	179.67 (16)	O4—C1—C10—O2	−63.01 (18)
C13—C5—C6—C7	56.5 (2)	C2—C1—C10—O2	51.5 (2)
C4—C5—C6—C1	−53.0 (2)	C6—C1—C10—O2	178.61 (14)
C13—C5—C6—C1	−176.14 (18)	C10—O2—C11—O5	−67.1 (2)
O4—C1—C6—C5	163.26 (15)	C10—O2—C11—C12	56.3 (2)
C10—C1—C6—C5	−76.35 (19)	O5—C11—C12—C15	−60.2 (2)
C2—C1—C6—C5	50.3 (2)	O2—C11—C12—C15	176.61 (17)
O4—C1—C6—C7	−69.9 (2)	O5—C11—C12—C2	68.1 (2)
C10—C1—C6—C7	50.5 (2)	O2—C11—C12—C2	−55.1 (2)
C2—C1—C6—C7	177.11 (18)	C3—C2—C12—C11	−72.8 (2)
C5—C6—C7—C8	166.05 (18)	C1—C2—C12—C11	53.8 (2)
C1—C6—C7—C8	38.2 (3)	C3—C2—C12—C15	54.3 (2)
C6—C7—C8—C9	−58.4 (3)	C1—C2—C12—C15	−179.07 (18)
O4—O3—C9—O1	73.30 (18)

D—H···A	D—H	H···A	D···A	D—H···A
O5—H5···O2i	0.84	1.95	2.7799 (19)	168
C5—H5A···O4ii	1.00	2.38	3.381 (3)	175

Table 1

Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O5—H5⋯O2i	0.84	1.95	2.7799 (19)	168
C5—H5A⋯O4ii	1.00	2.38	3.381 (3)	175

Symmetry codes: (i) ; (ii) .