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

Janganati, V.; Penthala, N.R.; Parkin, S.; Crooks, P.A.

doi:10.1107/S1600536813029188

organic compounds

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ISSN: 2056-9890

Volume 69| Part 12| December 2013| Pages o1734-o1735

doi:10.1107/S1600536813029188

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

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

^aDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA, and ^bDepartment of Chemistry, University of Kentucky, Lexington KY 40506, USA
^*Correspondence e-mail: pacrooks@uams.edu

(Received 22 October 2013; accepted 23 October 2013; online 6 November 2013)

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.

CCDC reference: 967941

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 ).

Experimental

Crystal data

C₁₈H₂₄N₂O₄·H₂O
M_r = 350.41
Monoclinic, P 2₁
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[F² > 2σ(F²)] = 0.024
wR(F²) = 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)

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⋯O1Wⁱⁱ	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)
Symmetry codes: (i) $[-x+1, y+{\script{1\over 2}}, -z+1]$ ; (ii) $[-x+1, y-{\script{1\over 2}}, -z]$ ; (iii) $[-x+2, y+{\script{1\over 2}}, -z+1]$ ; (iv) x, y, z+1; (v) x, y-1, z; (vi) x, y, z-1.

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.

Supporting information

CCDC reference: 967941

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536813029188/sj5362sup1.cif

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

checkCIF report

Comment top

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.

Related literature top

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).

Experimental top

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.

Computing details top

Data collection: APEX2 (Bruker, 2006); cell refinement: SAINT (Bruker, 2006); data reduction: SAINT (Bruker, 2006); 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 (Sheldrick, 2008b).

Figures top

Fig. 1. The title molecule with the atom numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.

(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 top

Crystal data top

C₁₈H₂₄N₂O₄·H₂O	F(000) = 376
M_r = 350.41	D_x = 1.335 Mg m⁻³
Monoclinic, P2₁	Cu Kα radiation, λ = 1.54178 Å
a = 9.8073 (2) Å	Cell parameters from 9966 reflections
b = 8.2784 (1) Å	θ = 4.1–68.1°
c = 10.7741 (2) Å	µ = 0.80 mm⁻¹
β = 95.015 (1)°	T = 90 K
V = 871.39 (3) Å³	Tablet, colourless
Z = 2	0.25 × 0.20 × 0.04 mm

Data collection top

Bruker X8 Proteum diffractometer	2437 independent reflections
Radiation source: fine-focus rotating anode	2425 reflections with I > 2σ(I)
Detector resolution: 5.6 pixels mm^-1	R_int = 0.030
ϕ and ω scans	θ_max = 68.1°, θ_min = 4.5°
Absorption correction: multi-scan (SADABS; Sheldrick, 2008a)	h = −11→11
T_min = 0.836, T_max = 0.942	k = −9→7
10767 measured reflections	l = −12→11

Refinement top

Refinement on F²	Hydrogen site location: difference Fourier map
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F² > 2σ(F²)] = 0.024	w = 1/[σ²(F_o²) + (0.0332P)² + 0.170P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.061	(Δ/σ)_max < 0.001
S = 1.04	Δρ_max = 0.16 e Å⁻³
2437 reflections	Δρ_min = −0.15 e Å⁻³
235 parameters	Extinction correction: SHELXL2013 (Sheldrick, 2008a), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
1 restraint	Extinction coefficient: 0.0090 (15)
Primary atom site location: structure-invariant direct methods	Absolute structure: Flack parameter determined using 747 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
Secondary atom site location: difference Fourier map	Absolute structure parameter: −0.03 (5)

Crystal data top

C₁₈H₂₄N₂O₄·H₂O	V = 871.39 (3) Å³
M_r = 350.41	Z = 2
Monoclinic, P2₁	Cu Kα radiation
a = 9.8073 (2) Å	µ = 0.80 mm⁻¹
b = 8.2784 (1) Å	T = 90 K
c = 10.7741 (2) Å	0.25 × 0.20 × 0.04 mm
β = 95.015 (1)°

Data collection top

Bruker X8 Proteum diffractometer	2437 independent reflections
Absorption correction: multi-scan (SADABS; Sheldrick, 2008a)	2425 reflections with I > 2σ(I)
T_min = 0.836, T_max = 0.942	R_int = 0.030
10767 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.024	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.061	Δρ_max = 0.16 e Å⁻³
S = 1.04	Δρ_min = −0.15 e Å⁻³
2437 reflections	Absolute structure: Flack parameter determined using 747 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
235 parameters	Absolute structure parameter: −0.03 (5)
1 restraint

Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
N1	0.63838 (13)	0.11358 (19)	0.56147 (12)	0.0159 (3)
N2	0.61292 (14)	−0.0075 (2)	0.74068 (12)	0.0197 (3)
O1	0.92738 (12)	0.85603 (16)	0.33577 (10)	0.0183 (3)
O2	0.83645 (12)	0.60393 (16)	0.51264 (9)	0.0185 (3)
O3	0.71648 (13)	0.48872 (17)	0.65518 (10)	0.0221 (3)
O4	0.47506 (11)	0.43708 (16)	0.02773 (10)	0.0179 (3)
H4	0.4364	0.4648	0.0910	0.027*
C1	0.71890 (15)	0.6089 (2)	0.02275 (13)	0.0161 (3)
H1A	0.6293	0.6497	0.0017	0.019*
C2	0.83497 (16)	0.7229 (2)	0.00040 (14)	0.0163 (3)
H2A	0.8112	0.7803	−0.0791	0.020*
H2B	0.9178	0.6576	−0.0099	0.020*
C3	0.87106 (16)	0.8502 (2)	0.10296 (14)	0.0166 (4)
H3A	0.9320	0.9330	0.0713	0.020*
H3B	0.7864	0.9046	0.1245	0.020*
C4	0.94124 (16)	0.7722 (2)	0.21808 (14)	0.0153 (3)
C5	0.85016 (16)	0.7092 (2)	0.30889 (14)	0.0152 (3)
H5A	0.7506	0.7274	0.2847	0.018*
C6	0.87955 (16)	0.5643 (2)	0.38885 (14)	0.0152 (4)
H6A	0.9790	0.5362	0.3940	0.018*
C7	0.79086 (15)	0.4188 (2)	0.34526 (13)	0.0141 (3)
H7A	0.7011	0.4603	0.3069	0.017*
C8	0.85003 (16)	0.3049 (2)	0.25191 (14)	0.0165 (4)
H8A	0.7947	0.2047	0.2465	0.020*
H8B	0.9442	0.2750	0.2844	0.020*
C9	0.85478 (15)	0.3742 (2)	0.11888 (14)	0.0164 (4)
H9A	0.9322	0.4511	0.1193	0.020*
H9B	0.8734	0.2847	0.0618	0.020*
C10	0.72548 (15)	0.4597 (2)	0.06786 (13)	0.0147 (3)
C11	0.76625 (16)	0.3373 (2)	0.46888 (14)	0.0153 (3)
H11A	0.8457	0.2653	0.4942	0.018*
C12	0.76819 (16)	0.4785 (2)	0.55787 (14)	0.0168 (3)
C13	0.63503 (16)	0.2376 (2)	0.46427 (14)	0.0179 (4)
H13A	0.5567	0.3107	0.4735	0.021*
H13B	0.6201	0.1848	0.3817	0.021*
C14	0.59851 (15)	0.3551 (2)	0.06538 (14)	0.0168 (4)
H14A	0.6089	0.2634	0.0080	0.020*
H14B	0.5918	0.3099	0.1497	0.020*
C15	1.08469 (16)	0.7115 (2)	0.20694 (15)	0.0181 (4)
H15A	1.1182	0.6563	0.2841	0.027*
H15B	1.1448	0.8029	0.1925	0.027*
H15C	1.0843	0.6358	0.1370	0.027*
C16	0.58471 (15)	0.1233 (2)	0.67287 (14)	0.0178 (4)
H16A	0.5334	0.2126	0.6989	0.021*
C17	0.68861 (16)	−0.1053 (2)	0.66946 (15)	0.0186 (4)
H17A	0.7239	−0.2084	0.6940	0.022*
C18	0.70535 (15)	−0.0320 (2)	0.55829 (14)	0.0167 (3)
H18A	0.7534	−0.0731	0.4923	0.020*
O1W	0.45357 (13)	0.47330 (19)	−0.23096 (12)	0.0248 (3)
H1W	0.458 (2)	0.470 (4)	−0.150 (2)	0.037*
H2W	0.534 (3)	0.492 (4)	−0.249 (2)	0.037*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
N1	0.0161 (6)	0.0167 (8)	0.0149 (6)	−0.0029 (6)	0.0018 (5)	0.0004 (6)
N2	0.0210 (7)	0.0198 (8)	0.0187 (6)	−0.0055 (6)	0.0036 (5)	0.0015 (6)
O1	0.0228 (5)	0.0157 (7)	0.0168 (5)	−0.0042 (5)	0.0042 (4)	−0.0020 (5)
O2	0.0261 (6)	0.0167 (7)	0.0131 (5)	−0.0028 (5)	0.0043 (4)	−0.0003 (5)
O3	0.0317 (6)	0.0194 (7)	0.0163 (5)	0.0021 (6)	0.0088 (5)	0.0018 (5)
O4	0.0141 (5)	0.0227 (7)	0.0170 (5)	0.0000 (5)	0.0021 (4)	−0.0003 (5)
C1	0.0143 (7)	0.0191 (9)	0.0149 (7)	0.0006 (7)	0.0003 (5)	−0.0004 (7)
C2	0.0173 (7)	0.0167 (9)	0.0147 (7)	0.0001 (7)	0.0005 (5)	0.0041 (7)
C3	0.0163 (7)	0.0151 (9)	0.0186 (7)	−0.0016 (7)	0.0022 (6)	0.0021 (7)
C4	0.0175 (7)	0.0134 (9)	0.0150 (7)	−0.0018 (6)	0.0014 (6)	−0.0012 (6)
C5	0.0161 (7)	0.0138 (9)	0.0157 (7)	0.0000 (7)	0.0022 (6)	−0.0008 (7)
C6	0.0161 (7)	0.0168 (10)	0.0130 (7)	0.0004 (6)	0.0031 (6)	0.0003 (6)
C7	0.0157 (7)	0.0130 (9)	0.0139 (7)	0.0004 (7)	0.0019 (5)	0.0019 (6)
C8	0.0185 (7)	0.0144 (9)	0.0166 (7)	0.0023 (7)	0.0016 (6)	0.0006 (7)
C9	0.0170 (7)	0.0172 (9)	0.0154 (7)	0.0014 (7)	0.0038 (6)	−0.0005 (7)
C10	0.0160 (7)	0.0174 (9)	0.0109 (6)	−0.0005 (7)	0.0021 (5)	−0.0018 (6)
C11	0.0171 (7)	0.0152 (9)	0.0135 (7)	0.0000 (7)	0.0012 (5)	0.0023 (6)
C12	0.0186 (7)	0.0159 (9)	0.0156 (7)	0.0002 (7)	−0.0008 (6)	0.0030 (6)
C13	0.0182 (7)	0.0188 (10)	0.0165 (7)	−0.0015 (7)	0.0001 (6)	0.0045 (7)
C14	0.0184 (7)	0.0157 (9)	0.0164 (7)	−0.0006 (7)	0.0019 (5)	0.0001 (7)
C15	0.0152 (7)	0.0223 (10)	0.0168 (7)	−0.0015 (7)	0.0006 (6)	0.0013 (7)
C16	0.0162 (7)	0.0190 (10)	0.0187 (7)	−0.0020 (7)	0.0044 (6)	−0.0017 (7)
C17	0.0194 (7)	0.0144 (9)	0.0216 (8)	−0.0017 (7)	−0.0005 (6)	0.0009 (7)
C18	0.0174 (7)	0.0141 (9)	0.0186 (7)	−0.0012 (6)	0.0014 (6)	−0.0039 (7)
O1W	0.0252 (6)	0.0304 (8)	0.0190 (6)	0.0031 (6)	0.0024 (5)	0.0011 (6)

Geometric parameters (Å, º) top

N1—C16	1.354 (2)	C7—C8	1.529 (2)
N1—C18	1.374 (2)	C7—C11	1.531 (2)
N1—C13	1.465 (2)	C7—H7A	1.0000
N2—C16	1.322 (2)	C8—C9	1.549 (2)
N2—C17	1.377 (2)	C8—H8A	0.9900
O1—C5	1.448 (2)	C8—H8B	0.9900
O1—C4	1.4623 (19)	C9—C10	1.513 (2)
O2—C12	1.350 (2)	C9—H9A	0.9900
O2—C6	1.4709 (18)	C9—H9B	0.9900
O3—C12	1.207 (2)	C10—C14	1.515 (2)
O4—C14	1.416 (2)	C11—C12	1.511 (2)
O4—H4	0.8400	C11—C13	1.526 (2)
C1—C10	1.327 (3)	C11—H11A	1.0000
C1—C2	1.514 (2)	C13—H13A	0.9900
C1—H1A	0.9500	C13—H13B	0.9900
C2—C3	1.545 (2)	C14—H14A	0.9900
C2—H2A	0.9900	C14—H14B	0.9900
C2—H2B	0.9900	C15—H15A	0.9800
C3—C4	1.510 (2)	C15—H15B	0.9800
C3—H3A	0.9900	C15—H15C	0.9800
C3—H3B	0.9900	C16—H16A	0.9500
C4—C5	1.477 (2)	C17—C18	1.365 (2)
C4—C15	1.509 (2)	C17—H17A	0.9500
C5—C6	1.490 (2)	C18—H18A	0.9500
C5—H5A	1.0000	O1W—H1W	0.87 (3)
C6—C7	1.536 (2)	O1W—H2W	0.85 (3)
C6—H6A	1.0000

C16—N1—C18	107.33 (15)	C7—C8—H8B	108.5
C16—N1—C13	127.27 (16)	C9—C8—H8B	108.5
C18—N1—C13	125.28 (14)	H8A—C8—H8B	107.5
C16—N2—C17	105.71 (14)	C10—C9—C8	114.69 (13)
C5—O1—C4	60.97 (10)	C10—C9—H9A	108.6
C12—O2—C6	110.30 (13)	C8—C9—H9A	108.6
C14—O4—H4	109.5	C10—C9—H9B	108.6
C10—C1—C2	128.70 (15)	C8—C9—H9B	108.6
C10—C1—H1A	115.6	H9A—C9—H9B	107.6
C2—C1—H1A	115.7	C1—C10—C9	125.51 (15)
C1—C2—C3	116.07 (13)	C1—C10—C14	120.80 (14)
C1—C2—H2A	108.3	C9—C10—C14	113.61 (15)
C3—C2—H2A	108.3	C12—C11—C13	113.76 (13)
C1—C2—H2B	108.3	C12—C11—C7	102.53 (14)
C3—C2—H2B	108.3	C13—C11—C7	113.99 (12)
H2A—C2—H2B	107.4	C12—C11—H11A	108.8
C4—C3—C2	110.81 (14)	C13—C11—H11A	108.8
C4—C3—H3A	109.5	C7—C11—H11A	108.8
C2—C3—H3A	109.5	O3—C12—O2	121.27 (17)
C4—C3—H3B	109.5	O3—C12—C11	128.51 (17)
C2—C3—H3B	109.5	O2—C12—C11	110.21 (13)
H3A—C3—H3B	108.1	N1—C13—C11	112.93 (12)
O1—C4—C5	59.05 (10)	N1—C13—H13A	109.0
O1—C4—C15	112.65 (12)	C11—C13—H13A	109.0
C5—C4—C15	123.88 (15)	N1—C13—H13B	109.0
O1—C4—C3	116.05 (14)	C11—C13—H13B	109.0
C5—C4—C3	115.89 (13)	H13A—C13—H13B	107.8
C15—C4—C3	116.01 (13)	O4—C14—C10	114.33 (14)
O1—C5—C4	59.98 (10)	O4—C14—H14A	108.7
O1—C5—C6	119.25 (12)	C10—C14—H14A	108.7
C4—C5—C6	124.74 (15)	O4—C14—H14B	108.7
O1—C5—H5A	114.0	C10—C14—H14B	108.7
C4—C5—H5A	114.0	H14A—C14—H14B	107.6
C6—C5—H5A	114.0	C4—C15—H15A	109.5
O2—C6—C5	106.78 (14)	C4—C15—H15B	109.5
O2—C6—C7	104.61 (12)	H15A—C15—H15B	109.5
C5—C6—C7	112.27 (12)	C4—C15—H15C	109.5
O2—C6—H6A	111.0	H15A—C15—H15C	109.5
C5—C6—H6A	111.0	H15B—C15—H15C	109.5
C7—C6—H6A	111.0	N2—C16—N1	111.24 (16)
C8—C7—C11	113.47 (14)	N2—C16—H16A	124.4
C8—C7—C6	116.59 (13)	N1—C16—H16A	124.4
C11—C7—C6	102.00 (12)	C18—C17—N2	109.84 (16)
C8—C7—H7A	108.1	C18—C17—H17A	125.1
C11—C7—H7A	108.1	N2—C17—H17A	125.1
C6—C7—H7A	108.1	C17—C18—N1	105.87 (14)
C7—C8—C9	115.08 (14)	C17—C18—H18A	127.1
C7—C8—H8A	108.5	N1—C18—H18A	127.1
C9—C8—H8A	108.5	H1W—O1W—H2W	106 (2)

C10—C1—C2—C3	−98.0 (2)	C2—C1—C10—C14	−170.69 (14)
C1—C2—C3—C4	72.09 (17)	C8—C9—C10—C1	126.24 (17)
C5—O1—C4—C15	−117.00 (17)	C8—C9—C10—C14	−56.95 (19)
C5—O1—C4—C3	105.88 (16)	C8—C7—C11—C12	156.85 (12)
C2—C3—C4—O1	−154.00 (13)	C6—C7—C11—C12	30.61 (15)
C2—C3—C4—C5	−87.53 (18)	C8—C7—C11—C13	−79.73 (17)
C2—C3—C4—C15	70.32 (19)	C6—C7—C11—C13	154.03 (14)
C4—O1—C5—C6	115.52 (17)	C6—O2—C12—O3	−175.49 (14)
C15—C4—C5—O1	97.94 (17)	C6—O2—C12—C11	3.08 (17)
C3—C4—C5—O1	−106.14 (16)	C13—C11—C12—O3	32.8 (2)
O1—C4—C5—C6	−106.62 (16)	C7—C11—C12—O3	156.40 (16)
C15—C4—C5—C6	−8.7 (3)	C13—C11—C12—O2	−145.62 (13)
C3—C4—C5—C6	147.24 (15)	C7—C11—C12—O2	−22.05 (16)
C12—O2—C6—C5	136.46 (13)	C16—N1—C13—C11	97.44 (18)
C12—O2—C6—C7	17.28 (15)	C18—N1—C13—C11	−78.22 (19)
O1—C5—C6—O2	67.27 (17)	C12—C11—C13—N1	−85.46 (18)
C4—C5—C6—O2	139.25 (15)	C7—C11—C13—N1	157.44 (14)
O1—C5—C6—C7	−178.64 (13)	C1—C10—C14—O4	−8.0 (2)
C4—C5—C6—C7	−106.66 (17)	C9—C10—C14—O4	174.99 (12)
O2—C6—C7—C8	−153.79 (12)	C17—N2—C16—N1	0.21 (18)
C5—C6—C7—C8	90.80 (17)	C18—N1—C16—N2	−0.26 (18)
O2—C6—C7—C11	−29.62 (15)	C13—N1—C16—N2	−176.55 (14)
C5—C6—C7—C11	−145.03 (13)	C16—N2—C17—C18	−0.07 (17)
C11—C7—C8—C9	170.63 (12)	N2—C17—C18—N1	−0.08 (17)
C6—C7—C8—C9	−71.29 (17)	C16—N1—C18—C17	0.20 (17)
C7—C8—C9—C10	−45.1 (2)	C13—N1—C18—C17	176.58 (13)
C2—C1—C10—C9	5.9 (3)

Hydrogen-bond geometry (Å, º) top

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···O1Wⁱⁱ	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)

Symmetry codes: (i) −x+1, y+1/2, −z+1; (ii) −x+1, y−1/2, −z; (iii) −x+2, y+1/2, −z+1; (iv) x, y, z+1; (v) x, y−1, z; (vi) x, y, z−1.

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O4—H4···N2ⁱ	0.84	1.93	2.7491 (17)	164.2
C13—H13B···O1Wⁱⁱ	0.99	2.45	3.388 (2)	157.1
C15—H15B···O3ⁱⁱⁱ	0.98	2.55	3.282 (2)	131.1
C16—H16A···O1W^iv	0.95	2.44	3.370 (2)	166.6
C17—H17A···O3^v	0.95	2.54	3.377 (2)	146.7
C18—H18A···O1^v	0.95	2.57	3.5016 (19)	167.0
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)

Symmetry codes: (i) −x+1, y+1/2, −z+1; (ii) −x+1, y−1/2, −z; (iii) −x+2, y+1/2, −z+1; (iv) x, y, z+1; (v) x, y−1, z; (vi) x, y, z−1.

Acknowledgements

This work was supported by NIH/NCI grant CA158275.

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