13-(Imidazol-1-yl)-11,13-di­hydro­melampomagnolide B monohydrate

Venumadhav Janganati; Narsimha Reddy Penthala; Sean Parkin; Peter A Crooks

doi:10.1107/S1600536813029188

. 2013 Nov 6;69(Pt 12):o1734–o1735. doi: 10.1107/S1600536813029188

13-(Imidazol-1-yl)-11,13-dihydromelampomagnolide B monohydrate

Venumadhav Janganati ^a, Narsimha Reddy Penthala ^a, Sean Parkin ^b, Peter A Crooks ^a,^*

PMCID: PMC3885019 PMID: 24454194

Abstract

The title compound, C₁₈H₂₄N₂O₄·H₂O {systematic name: (1aR,7aS,8R,10aS,10bS,E)-5-hydroxymethyl-8-[(1H-imidazol-1-yl)methyl]-1a-methyl-2,3,6,7,7a,8,10a,10b-octahydrooxireno[2′,3′:9,10]cyclodeca[1,2-b]furan-9(1aH)-one monohydrate}, an imidazole derivative of melampomagnolide B was synthesized under Michael addition conditions. The molecule is built up from fused ten-, five- (lactone) and three-membered (epoxide) rings. The internal double bond of the ten-membered ring identifies it as the cis or E isomer. The lactone ring has an envelope-type conformation, with the (chiral) C atom opposite the lactone O atoms as the flap atom. In the crystal, O—H⋯O, O—H⋯N and weak C—H⋯O hydrogen bonds link the molecules (along with water) into sheets parallel to the bc plane.

Related literature

For the biological activity of similar compounds, see: El-Feraly (1984 ▶); Macias et al. (1992 ▶); Nasim et al. (2011 ▶); Nasim & Crooks (2008 ▶). For the structures of similar compounds, see; Neelakantan et al. (2009 ▶); Woods et al. (2011 ▶); Neukirch et al. (2003 ▶); Gonzalez et al. (1988 ▶). graphic file with name e-69-o1734-scheme1.jpg

Experimental

Crystal data

C₁₈H₂₄N₂O₄·H₂O
M _r = 350.41
Monoclinic,
a = 9.8073 (2) Å
b = 8.2784 (1) Å
c = 10.7741 (2) Å
β = 95.015 (1)°
V = 871.39 (3) Å³
Z = 2
Cu Kα radiation
μ = 0.80 mm⁻¹
T = 90 K
0.25 × 0.20 × 0.04 mm

Data collection

Bruker X8 Proteum diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 2008a ▶) T _min = 0.836, T _max = 0.942
10767 measured reflections
2437 independent reflections
2425 reflections with I > 2σ(I)
R _int = 0.030

Refinement

R[F ² > 2σ(F ²)] = 0.024
wR(F ²) = 0.061
S = 1.04
2437 reflections
235 parameters
1 restraint
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.16 e Å⁻³
Δρ_min = −0.15 e Å⁻³
Absolute structure: Flack parameter determined using 747 quotients [(I ⁺)−(I ⁻)]/[(I ⁺)+(I ⁻)] (Parsons et al., 2013 ▶)
Absolute structure parameter: −0.03 (5)

Data collection: APEX2 (Bruker, 2006 ▶); cell refinement: SAINT (Bruker, 2006 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008b ▶); program(s) used to refine structure: SHELXL2013 (Sheldrick, 2008b ▶); molecular graphics: XP in SHELXTL (Sheldrick, 2008b ▶); software used to prepare material for publication: SHELXL2013.

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536813029188/sj5362sup1.cif

e-69-o1734-sup1.cif^{(27.9KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536813029188/sj5362Isup2.hkl

e-69-o1734-Isup2.hkl^{(134KB, 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
O4—H4⋯N2ⁱ	0.84	1.93	2.7491 (17)	164
C13—H13B⋯O1W ⁱⁱ	0.99	2.45	3.388 (2)	157
C15—H15B⋯O3ⁱⁱⁱ	0.98	2.55	3.282 (2)	131
C16—H16A⋯O1W ^iv	0.95	2.44	3.370 (2)	167
C17—H17A⋯O3^v	0.95	2.54	3.377 (2)	147
C18—H18A⋯O1^v	0.95	2.57	3.5016 (19)	167
O1W—H1W⋯O4	0.87 (3)	1.93 (3)	2.7928 (17)	173 (3)
O1W—H2W⋯O3^vi	0.85 (3)	2.14 (3)	2.9534 (19)	162 (2)

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

Acknowledgments

This work was supported by NIH/NCI grant CA158275.

supplementary crystallographic information

1. Comment

Melampomagnolide B (MMB) was derived from parthenolide (PTL) via selenium oxide mediated oxidation of the C10 methyl group of PTL (Macias et al., 1992; Neukirch et al., 2003). MMB is a melampolide originally isolated from Magnolia grandiflora and characterized by X-ray diffraction analysis (El-Feraly, 1984; Gonzalez et al., 1988), and has been identified as a new anti-leukemic sesquiterpene with properties similar to PTL (Nasim et al., 2011).

Recently, Nasim et al. (2008) reported formation of amino-parthenolide derivatives under Michael addition reaction conditions. These compounds showed more potency as antileukemic agents and improved water solubility relative to PTL. To further improve water solubility of melampomagnolide B, we synthesized an imidazole derivative by the reaction of MMB with imidazole via Michael addition chemistry (Neelakantan et al., 2009; Woods et al., 2011) to afford the title compound, which was re-crystallized from chloroform.

To obtain detailed information on the structural conformation of this molecule, establish the geometry of the double bond (C9═C10) and orientation of the imidazole moiety, a single-crystal X-ray structure determination has been carried out. This has revealed that the double bond of the title compound has the E-geometry. In the crystal, intermolecular O—H···O, O—H···N and weak C—H···O hydrogen bonds link the molecules (along with water) into sheets parallel to the bc-plane.

2. Experimental

To a solution of MMB (50 mg, 0.189 m mol) in methanol, was added imidazole (19.31 mg, 0.284 m mol). The reaction mixture was stirred at ambient temperature for 24 h. After completion of the reaction (monitored by thin-layer chromatography), the reaction mixture was dissolved in dichloromethane. The organic layer was separated, washed with water, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford the crude product. The crude compound was recrystallized from chloroform to obtain the title compound as colorless crystals (56 mg, yield: 89%). Melting point 398-399°K. ¹H NMR (400 MHz, CDCl₃): δ 7.60 (s, 1H), 7.10 (s, 1H), 7.01 (s, 1H), 5.55 (t, J=8Hz, 1H), 4.48 (dd, J=14.4 Hz, 1H), 4.32 (dd, J=14.8, 1H),3.93 (s, 2H), 3.89(t, J=9.6Hz, 1H), 2.68 (d, J=9.2 Hz, 2H), 2.34-1.90 (m, 11H), 1.88-1.53 (m, 3H), 1.04 (t, J=9.6 Hz, 1H). ¹³C NMR (CDCl₃, 100 MHz): δ 174.9, 139.1, 138.0, 130.3, 126.8, 119.4, 81.2, 65.2, 62.5, 60.3, 48.4, 43.8, 41.6, 36.7, 26.9, 24.6, 23.4, 17.9 ppm.