(11R)-13-Dimethyl­ammonio-11,13-dihydro-4,5-epoxy­costunolide semifumarate

Sundar Neelakantan; Sean Parkin; Peter A Crooks

doi:10.1107/S1600536809021941

. 2009 Jun 13;65(Pt 7):o1569. doi: 10.1107/S1600536809021941

(11R)-13-Dimethylammonio-11,13-dihydro-4,5-epoxycostunolide semifumarate

Sundar Neelakantan ^a, Sean Parkin ^b, Peter A Crooks ^a,^*

PMCID: PMC2969377 PMID: 21582849

Abstract

Crystals of the title salt, C₁₇H₂₈NO₃ ⁺·C₄H₃O₄ ⁻, were obtained by reacting parthenolide with dimethylamine followed by conversion of the amine adduct into a water-soluble fumarate salt. Subsequent crystallization of the fumarate salt from water afforded colorless orthorhombic crystals. The amine addition is highly stereospecific yielding exclusively a single diastereomer with R-configuration at the newly formed C-11 chiral carbon. In the crystal, intermolecular O—H⋯O and N—H⋯O hydrogen bonds help to establish the packing.

Related literature

Parthenolide (PTL) is a naturally occurring sesquiterpene lactone used in the treatment of fever, migraine headaches, rheumatoid arthritis, and also as an anti-inflammatory agent (Heptinstall et al. (1988 ▶). For the potent anti-tumor and cytotoxic properties of PTL, see: Crooks et al. (2007 ▶). The absolute stereochemistry of the C-11 chiral carbon is typical of such amine adducts of parthenolide, see: Nasim et al. (2007a ▶,b ▶). For bond-length data, see: Allen et al. (1987 ▶).

Experimental

Crystal data

C₁₇H₂₈NO₃ ⁺·C₄H₃O₄ ⁻
M _r = 409.47
Orthorhombic,
a = 6.3164 (1) Å
b = 15.1650 (2) Å
c = 22.0028 (3) Å
V = 2107.61 (5) Å³
Z = 4
Cu Kα radiation
μ = 0.80 mm⁻¹
T = 90 K
0.26 × 0.20 × 0.10 mm

Data collection

Bruker X8 Proteum diffractometer
Absorption correction: multi-scan (SADABS in APEX2; Bruker–Nonius, 2006 ▶) T _min = 0.788, T _max = 0.924
16991 measured reflections
3762 independent reflections
3640 reflections with I > 2σ(I)
R _int = 0.041

Refinement

R[F ² > 2σ(F ²)] = 0.027
wR(F ²) = 0.069
S = 1.04
3762 reflections
268 parameters
H-atom parameters constrained
Δρ_max = 0.20 e Å⁻³
Δρ_min = −0.14 e Å⁻³
Absolute structure: Flack (1983 ▶), 1525 Friedel pairs
Flack parameter: −0.01 (4)

Data collection: APEX2 (Bruker–Nonius, 2006 ▶); cell refinement: SAINT (Bruker–Nonius, 2006 ▶); data reduction: SAINT; 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: SHELXL97 and local procedures.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536809021941/hg2516sup1.cif

e-65-o1569-sup1.cif^{(23.2KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809021941/hg2516Isup2.hkl

e-65-o1569-Isup2.hkl^{(184.5KB, 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
N1—H1N⋯O6	0.93	1.83	2.7563 (14)	172
O4—H4⋯O6ⁱ	0.84	1.73	2.5544 (13)	169

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Symmetry code: (i) Inline graphic .

Acknowledgments

This research work was supported by the Kentucky Lung Cancer Research Program.

supplementary crystallographic information

Comment

Parthenolide (PTL) isolated from Tanacetum parthenium (commonly referred as feverfew), is a naturally occurring sesquiterpene lactone used in the treatment of fever, migraine headaches, rheumatoid arthritis, and also as an anti-inflammatory agent (Heptinstall et al., 1988). The PTL molecule and several structurally related analogs have become topics of recent interest because of their potent anti-tumor and cytotoxic properties (Crooks et al., 2007). Despite promising in vitro activity, this potent natural product has a major limitation which precludes its further development as a therapeutic agent, i.e. its poor water-solubility, thus limiting its potential as a promising clinical agent. The title compound crystallized from water as orthorombic crystals. Bond angles and bond distances within the molecule were quite regular with average normal bond lengths (Allen et al., 1987). The absolute stereochemistry of the newly formed C-11 chiral carbon was found to be R, which is typical of such amine adducts of parthenolide (Nasim et al., 2007a, 2007b). Hydrogen bonding was observed between N1—H and O6 of the carbonyl oxygen of the fumarate moiety and between O4—H and O6 (Table 1). The title compound is more water soluble and more biologically potent than the parent compound, in both in vitro and in vivo anti-leukemic activity screens. T he title compound is currently in phase 1 clinical trials.

Experimental

The title compound (Systematic name: 13-(N,N-dimethyl)-amino-4 α,5 β- epoxy-4,10-dimethyl-6 α-hydroxy-12-oicacid-γ-lactone-germacra-1(10)-ene monofumarate) was synthesized by dissolving PTL (25 mg, 0.1 mmol) in 8 ml of methanol followed by addition of dimethylamine (0.15 mmol, 2.0M solution in methanol). The mixture stirred under ambient conditions for 6 hrs. The crude product was subjected to flash silica gel column chromatography to afford the pure dimethylamino analog free base. The free base was then converted to the fumarate salt by dissolving it in diethyl ether followed by addition of one equivalent of fumaric acid. The white solid that precipitated out of the diethyl ether solution was filtered, washed with diethyl ether and then dried under vacuum. Crystallization of the obtained white solid from water afforded colorless crystals that were suitable for X-ray analysis. ¹H-NMR (D₂0, 300 MHz):δ 6.67 2H, s, (HOOC-CH)₂–), 5.24 (1H, dd, J=2.1, 12.0 Hz, 1-CH), 4.30 (1H, t, J=9.0 Hz, 6-CH), 1.88–3.60 (13H, m, 2-CH₂, 3-CH₂, 8-CH₂, 9-CH₂, 13-CH₂, 5-CH, 7-CH, 11-CH), 2.98 (6H, s, N-(CH₃)₂), 1.70 (3H, s, 14-CH₃), 1.34 (3H, s, 15-CH₃) p.p.m. ¹³C-NMR (DMSO-d₆, 75 MHz): δ 179.8 ((HOOC-CH)₂–), 173.8 (12-C=O), 138.2 ((HOOC-CH)₂–),137.2 (10-C), 127.3 (1-C), 85.8 (6-C), 69.2 (N-(CH₃)2), 67.1 (5-C), 58.3 (4-C), 49.6 (7-C), 44.9 (11-C), 42.5 (9-C), 38.1 (3-C), 30.9 (8-C), 26.1(2-C), 18.7 (15-C), 18.6 (14-C)p.p.m. Elemental analysis: calc. for C₂₁H₃₁NO₇: C 61.60%, H 7.63%, N 3.42%. Found: C 61.81%, H 7.64%, N 3.47%.