14,15-Didehydro­hellebrigenin

Tong Yu; Hai-Yan Tian; Xiao-Feng Yuan; Shu-Zhi Hu; Ren-Wang Jiang

doi:10.1107/S1600536812018570

. 2012 May 5;68(Pt 6):o1614–o1615. doi: 10.1107/S1600536812018570

14,15-Didehydrohellebrigenin

Tong Yu ^a, Hai-Yan Tian ^a, Xiao-Feng Yuan ^a, Shu-Zhi Hu ^a, Ren-Wang Jiang ^a,^*

PMCID: PMC3379221 PMID: 22719419

Abstract

The title compound, C₂₄H₃₀O₅, is the didehydro product of the steroid hellebrigenin (systematic name: 3β,5,14-trihydroxy-19-oxo-5β-bufa-20,22-dienolide). It consists of three cyclohexane rings (A, B and C), a five-membered ring (D) and a six-membered lactone ring (E). The stereochemistry of the ring junctions are A/B cis, B/C trans and C/D cis. Cyclohexane rings A, B and C have normal chair conformations. The five-membered ring D with the C=C bond adopts an envelope conformation. Lactone ring E is essentially planar with a mean derivation of 0.006 (4) Å and is β-oriented at the C atom of ring D to which it is attached. There is an O—H⋯O hydrogen bond in the molecule involving the hydroxy groups. In the crystal, O—H⋯O hydrogen bonds link the molecules into chains propagating along [010]. The chains are linked by C—H⋯O contacts into a three-dimensional network.

Related literature

For previous isolations of hellebrigenin, see: Urscheler et al. (1955 ▶); Yang et al. (2010 ▶); Zhao et al. (2010 ▶). For its inhibitory activity against adenosinetriphosphatase of the 3-acetate, 3,5-diacetate, 3-iodoacetate and 3-bromoacetate of hellebrigenin, see: Ruoho et al. (1968 ▶). For the treatment of hellebrigenin with sodium hydroxide, see: Kupchan et al. (1969 ▶). For the stereochemistry of bufalin and secohellebrigeninamide, see: Rohrer et al. (1982 ▶); Yuan et al. (2012 ▶). graphic file with name e-68-o1614-scheme1.jpg

Experimental

Crystal data

C₂₄H₃₀O₅
M _r = 398.48
Monoclinic,
a = 10.7628 (4) Å
b = 6.6016 (2) Å
c = 14.6376 (5) Å
β = 94.224 (3)°
V = 1037.20 (6) Å³
Z = 2
Cu Kα radiation
μ = 0.71 mm⁻¹
T = 291 K
0.40 × 0.26 × 0.23 mm

Data collection

Oxford Gemini S Ultra Sapphire CCD diffractometer
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2011 ▶) T _min = 0.819, T _max = 1.000
3100 measured reflections
2238 independent reflections
2042 reflections with I > 2σ(I)
R _int = 0.023

Refinement

R[F ² > 2σ(F ²)] = 0.042
wR(F ²) = 0.115
S = 1.04
2238 reflections
266 parameters
1 restraint
H-atom parameters constrained
Δρ_max = 0.24 e Å⁻³
Δρ_min = −0.20 e Å⁻³

Data collection: CrysAlis PRO (Agilent, 2011 ▶); cell refinement: CrysAlis PRO; data reduction: XPREP (Sheldrick, 2008 ▶); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: XP in SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812018570/su2412sup1.cif

e-68-o1614-sup1.cif^{(25.6KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812018570/su2412Isup2.hkl

e-68-o1614-Isup2.hkl^{(110KB, 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
O2—H2⋯O1	0.82	2.05	2.773 (3)	147
O1—H1⋯O2ⁱ	0.82	2.01	2.786 (3)	158
C9—H9⋯O3ⁱⁱ	0.98	2.58	3.545 (4)	169
C15—H15⋯O4ⁱⁱⁱ	0.93	2.58	3.447 (4)	155
C22—H22⋯O4^iv	0.93	2.60	3.233 (6)	126

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

Acknowledgments

This work was supported by a grant from the National Science Foundation of China (21072078), Guangdong High Level Talent Scheme and the Fundamental Research Funds for the Central Universities (21609202).

supplementary crystallographic information

Comment

Hellebrigenin is a cardiac steroid that exists in the skin of toads (Urscheler, et al., 1955; Zhao, et al., 2010)) and the rhizomes of Helleborus thibetanus (Yang, et al., 2010). It is an inhibitor of adenosinetriphosphatase. The 3-acetate, 3,5-diacetate, 3-iodoacetate and 3-bromoacetate of hellebrigenin were shown to be potent irreversible inhibitors of the enzyme (Ruoho, et al., 1968). The lactone ring at atom C17 is not stable at base conditions. Treatment of hellebrigenin with sodium hydroxide in methanol afforded methyl isohellebrigeninate (Kupchan, et al., 1969). While treatment of hellebrigenin with N,N-dimethylformamide (DMF) resulted in a derivative named as secohellebrigeninamide (Yuan et al., 2012). Recently, hellebrigenin was treated with hydrochloric acid and the new derivative 14,15-didehydro hellebrigenin was obtained, and we report herein on its crystal structure.

The title molecule (Fig. 1) is composed of three cyclohexane rings (A, B and C), an unsaturated five-membered ring (D) and a six-membered lactone ring (E). The stereochemistry of the ring junctions are A/B cis, B/C trans and C/D cis. The cyclohexane rings A, B and C have normal chair conformations. The unsaturated five-membered ring D adopts an envelope conformation. The lactone ring E is planar with a mean derivation of 0.006 (4) Å and is β-oriented at C17 in ring D. The mean planes of the lactone ring E and ring D (atoms C13/C14/C15/C16) make a dihedral angle of 59.6 (1)°. There is an O-H···O hydrogen bond in the molecule involving the hydroxyl groups (Table 1).

In the crystal, O—H···O hydrogen bonds between the hydroxyl group at C3 and the hydroxyl group at C5 link adjacent molecules into dimers (Fig 2 and Table 1). Adjacent dimers are linked by short C–H···O contacts, between the methylene group at C6 and the lactone group, to form a three-dimensional network (Table 1 and Fig. 2).

The absolute configuration determined for bufalin (Rohrer et al., 1982) and secohellebrigeninamide, (Yuan et al., 2012), two similar steroids, were invoked, giving the assignments of the chiral centres in the molecule as shown in Fig. 1.

Experimental

Hellebrigenin (104.32 mg) was dissolved in a mixture of dichloromethane (2 ml) and methanol (3 ml). Hydrochloric acid (36%, 10 ml) was added. The solution was stirred for three hours at room temperature. Then the mixture was then poured into cold water and extracted with ethyl acetate. The organic phase was washed twice with water and concentrated under reduced pressure. The residue was subjected to preparative HPLC to afford the title compound (41 mg). The compound was recrystallized in methanol at room temperature to afford colourless prism-like crystals.