(3R,4S,5S,8S,10R,13R)-3-Hy­droxy­kaura-9(11),16-dien-18-oic acid

Karren D Beattie; Mohan M Bhadbhade; Donald C Craig; David N Leach

doi:10.1107/S1600536812002206

. 2012 Jan 25;68(Pt 2):o526–o527. doi: 10.1107/S1600536812002206

(3R,4S,5S,8S,10R,13R)-3-Hydroxykaura-9(11),16-dien-18-oic acid

Karren D Beattie ^a,^*, Mohan M Bhadbhade ^b, Donald C Craig ^b, David N Leach ^a

PMCID: PMC3275267 PMID: 22347123

Abstract

The title compound, C₂₀H₂₈O₃, was isolated during our investigation into the chemical composition and pharmacological activity of Centipeda cunninghamii (DC.) A. Braun & Asch. (Asteraceae). The enantiopure compound, a diterpene with a carbon skeleton, is composed of three six- and one five-membered rings in chair, twist-boat, half-chair and envelope conformations, respectively. Each molecule makes one intra- and one intermolecular O—H⋯O hydrogen bond in the crystal lattice, forming hydrogen-bonded chains along [010]. The absolute configuration of the compound was assigned on the basis of optical rotation measurements.

Related literature

For the characterization of related kaurane diterpenes, see: Reynolds et al. (1991 ▶); Piozzi et al. (1972 ▶). For literature on the occurrence of the 3S isomer of the title compound isolated from Ichthyothere terminalis and Pseudognaphalium cheiranthifolium, see: Bohlmann et al. (1982 ▶); Mendoza & Urzúa (1998 ▶). For the antibacterial activity of the 3S isomer, see: Mendoza et al. (1997 ▶). For phytopharmacological aspects of Centipeda cunninghamii, see: Campbell (1973 ▶); Cribb (1988 ▶); D’Amelio & Mirhom, (1998 ▶); Maiden (1975 ▶); Webb (1948 ▶). For optical rotation data of related compounds, see: Bohlmann et al. (1982 ▶); Brieskorn & Pöhlmann (1968 ▶); Reynolds et al. (1991 ▶).

Experimental

Crystal data

C₂₀H₂₈O₃
M _r = 316.4
Monoclinic,
a = 8.064 (2) Å
b = 10.775 (3) Å
c = 10.462 (4) Å
β = 109.70 (2)°
V = 855.8 (5) Å³
Z = 2
Mo Kα radiation
μ = 0.08 mm⁻¹
T = 296 K
0.30 × 0.25 × 0.10 mm

Data collection

Enraf–Nonius CAD-4 diffractometer
1586 measured reflections
1586 independent reflections
1254 reflections with I > 2σ(I)
R _int = 0.000
1 standard reflections every 30 min intensity decay: none

Refinement

R[F ² > 2σ(F ²)] = 0.044
wR(F ²) = 0.112
S = 1.05
1586 reflections
218 parameters
1 restraint
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.15 e Å⁻³
Δρ_min = −0.17 e Å⁻³

Data collection: CAD-4 Software (Enraf–Nonius, 1989 ▶); cell refinement: CAD-4 Software; data reduction: CAD-4 Software; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 ▶) and Mercury (Macrae et al., 2008 ▶); software used to prepare material for publication: publCIF (Westrip, 2010 ▶).

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536812002206/qk2025sup1.cif

e-68-0o526-sup1.cif^{(21.7KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812002206/qk2025Isup2.hkl

e-68-0o526-Isup2.hkl^{(78.2KB, 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
O3—H1O3⋯O1ⁱ	0.82 (5)	1.83 (5)	2.637 (4)	169 (5)
O1—H1O1⋯O2	0.96 (7)	1.94 (6)	2.651 (4)	129 (5)

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Symmetry code: (i) Inline graphic .

Acknowledgments

We would like to acknowledge Dr Kim Dastlick from the Institute of Molecular Biosciences at The University of Queensland for performing optical rotations, and the Chemical Analysis Laboratories, Bulleen, Victoria, for performing high resolution-mass spectrometric analyses. This research was supported by the Centre for Phytochemistry and Pharmacology at Southern Cross University and the University of New South Wales. KB is grateful to the Australian Federal Government for an Australian Postgraduate Award and to Bioactive Exports Pty. Ltd for financial assistance.

supplementary crystallographic information

Comment

The title compound C₂₀H₂₈O₃ [Fig. 1., systematic name (3R,4S,5S,8S,10R,13R)-3-hydroxykaura-9(11),16-dien-18-oic acid], a diterpene, was isolated during our investigation into the chemical composition and pharmacological activity of active components of Centipeda cunninghamii. The herb is native to Australia and New Zealand and has been utilized by the Aboriginals to treat infection (Campbell, 1973; Cribb, 1988; D'Amelio & Mirhom, 1998) and inflammation (Maiden, 1975; Webb, 1948). Compound (I) crystallizes in the monoclinic chiral space group P2₁. The carbon skeleton is composed of three six- and one five-membered rings in chair (ring A), twist-boat (ring B), half-chair (ring C) and envelope conformations (ring D). In the unit cell, two symmetry equivalent molecules make an intramolecular O—H···O bond between the 3-OH (O1) and the carbonyl oxygen (O2) and are linked by intermolecular O—H···O hydrogen bonds involving the carboxylic hydroxyl group (O3, donor) and the 3-OH group (O1, acceptor) into infinite chains extending parallel to the b axis (Fig. 2; Table 1).

The majority of the ent-kaurane diterpenes characteristically exhibit negative values for optical rotation with the exception of those that feature a double bond between C9 and C11. Piozzi and co-workers (Piozzi et al., 1972) have demonstrated that sequential catalytic hydrogenation of the exocyclic C16—C17 and the endocyclic C9—C11 double bonds in grandiflorenic acid [(4α)-kaura-9(11),16-dien-18-oic acid] transforms the optical rotation from +38 to +43° and subsequently to -80° in the saturated product. More recently Reynolds and co-workers (Reynolds et al., 1991) have analysed the solid state and solution characteristics of grandiflorenic acid, and have determined that the introduction of the C9—C11 double bond in grandiflorenic acid has a drastic effect on the molecular conformation and consequently on optical rotation, whereby the B ring adopts a boat conformation compared to the regular chair conformation in kaurenoic acid. In the case of compound (I) the observed rotation is [α]_D²² + 30.8° (c 0.12, MeOH), which is in agreement with values for the methyl ester derivative of the 3S isomer, +15° (Bohlmann et al., 1982) and the closely related grandiflorenic acid +32.1° (Brieskorn & Pöhlmann, 1968) and + 46° (Reynolds et al., 1991) and establishes the 3R,4S,5S,8S,10R,13R absolute stereochemistry of compound (I). The 3S isomer of compound (I) has been obtained previously from Ichthyothere terminalis (Bohlmann et al., 1982) and Pseudognaphalium cheiranthifolium (Mendoza & Urzúa, 1998). The antibacterial activity of the 3S isomer has also been evaluated and is described in Mendoza et al. (1997).

Experimental

The whole, air-dried flowers of Centipeda cunninghamii (100 g) were extracted in 100% ethanol (1 L) overnight at ambient temperatures with stirring. The resulting extract was filtered and then partitioned with hexane (3 × 200 ml). The hexane soluble fraction (2.8 g, 2.8% yield w/w) was evaporated and then subjected to reverse phase preparative HPLC (Gilson preparative HPLC system; Phenomenex Luna C18 column, 5 µm, 50 mm × 21.2 mm; sample loading 50 - 100 mg/injection). The column was eluted using a stepwise gradient of H₂O/CH₃CN containing 0.05% CF₃COOH (3:2 to 1:3 over 16.4 min; 1:3 isocratic for 3.6 min; then 1:3 to 1:9 over 1.0 min; then 1:9 isocratic for 7 minutes) at a flow rate of 15 ml/min. Crystals suitable for X-ray diffraction were obtained by slow evaporation of the H₂O/CH₃CN HPLC eluent of (I).

(3R,4S,5S,8S,10R,13R)- 3-Hydroxykaura-9(11),16-dien-18-oic acid (I): Colourless needles (ACN/H₂O) (26.5 mg, 1.0% yield w/w, not optimized); [α]_D²² + 30.8° (c 0.12, MeOH); ¹H NMR (500 MHz, CD₃OD): δ 5.26 (1H, t, J = 3.3 Hz, H-11), 4.89 (1H, d, J = 1.1 Hz, H-17a), 4.77 (1H, br s, H-17b), 3.17 (1H, dd, J = 4.4, 12.1 Hz, H-3), 2.74 (1H, br s, H-13), 2.61 (1H, br d, J = 14.8 Hz, H-15a), 2.44 - 2.40 (1H, m, H-12a), 2.41 - 2.35 (1H, m, H-6a), 2.29 - 2.16 (1H, m, H-2a), 2.20 - 2.16 (1H, m, H-15b), 2.04 (1H, m, H-1a), 1.99 - 1.95 (1H, m. H-7a), 1.99 - 1.95 (1H, m, H-12b), 1.93 – 1.85 (1H, m, H-6 b), 1.68 - 1.74 (1H, m, H-2 b), 1.65 – 1.62 (1H, m, H-5), 1.63 - 1.60 (1H, m, H-14a), 1.51 - 1.47 (1H, m, H-7 b), 1.51 - 1.47 (1H, m, H-14b), 1.38 - 1.32 (1H, m, H-1 b), 1.36 (3H, s, H-19), 1.10 (3H, s, H-20); Lit. (3S isomer as the methyl ester derivative, see Bohlmann et al., 1982); ¹³C NMR (126 MHz, CD₃OD): δ 180.1 (C, C-18), 159.6 (C, C-16), 157.3 (C, C-9), 116.3 (CH, C-11), 106.2 (CH₂, C-17), 79.4 (CH, C-3), 51.5 (CH₂, C-15), 51.3 (C, C-4), 47.0 (CH, C-5), 46.2 (CH₂, C-14), 43.6 (C, C-8), 42.8 (CH, C-13), 40.4 (CH₂, C-1), 39.7 (C, C-10), 39.1 (CH₂, C-12), 31.0 (CH₂, C-7), 29.9 (CH₂, C-2), 24.6 (CH₃, C-19), 24.4 (CH₃, C-20), 19.8 (CH₂, C-6); (+)-LRAPCIMS m/z (rel. int.): 316 [M+H⁺, 0%], 299 (100), 271 (59), 253 (93), 225 (6); (+)-HRAPCIMS m/z (rel. int): 317.2109 calcd for C₂₀H₂₉O₃, 317.2118 (Δ0.0009 a.m.u.).