supplementary materials


Acta Cryst. (2007). E63, o3922    [ doi:10.1107/S1600536807041712 ]

(11R)-13-(Benzylamino)-4,5-epoxy-11,13-dihydrocostunolide

S. Nasim, S. Parkin and P. A. Crooks

Abstract top

The title compound, C22H29NO3, was obtained by the reaction of benzylamine with parthenolide. X-ray crystal structure determination revealed that the configuration of the new chiral center at C11 is R, establishing the stereospecificity of the amination reaction.

Comment top

Parthenolide, is a germacrene sesquiterpene lactone. It has been isolated from several different species of plant in the Asteraceae (Compositae) family, feverfew (Tanacetum parthenium) being one of them (de Kraker et al., 2002). Its remarkable cytotoxic, antitumor, antiviral and antileishmanic properties have made it the focus of a large number of investigations. Its ability to induce tumor apoptosis through the inhibition of NF-kappaB make it a potential therapeutic for the treatment of leukemia (Guzman et al., 2005). Its development in this regard has been impeded by its low polarity and low water solubility. We saw a potential solution to this problem in the formation of a conjugate adduct of an amine species at the C-13, α-methylene group of the γ-butyrolactone function of parthenolide (Crooks et al., 2005). The title compound was synthesized as part of an ongoing drug discovery effort by reaction of benzylamine with parthenolide. The benzylamine adduct obtained was shown to be a single diastereomer by NMR analysis. The crystal structure of the title compound was determined to obtain the configuration of the newly formed stereocenter at C-11. An R absolute configuration was found. Bond distances and angles within the molecule are quite regular with average normal bonds (Allen et al., 1987). A hydrogen bond is observed between N-1H and O3 (2.30 (17) A°, 2.97 (17) A°, 130.2 (8) °) (Table 1) of the carbonyl oxygen of the 5-membered lactone ring, which can be considered as a weak hydrogen bond (Desiraju & Steiner, 1999).

Related literature top

For related literature, see: Allen et al. (1987); Crooks et al. (2005); Desiraju & Steiner (1999); Guzman et al. (2005); de Kraker et al. (2002); Parsons & Flack (2004).

Experimental top

The title compound was prepared by dissolving parthenolide (100 mg, 0.403 mmol) in MeOH (10 ml) and adding benzylamine (43.1 mg, 0.403 mmol) to the solution. The mixture was stirred at room temperature for 18 h. The solvent was evaporated and the title compound was purified by column chromatography over silica gel by eluting with 15% acetone in hexane. Crystals suitable for X-ray diffraction were obtained by slow evaporation of a solution of the title compound in chloroform/hexane at room temperature. The title compound was obtained as white crystals. 1H NMR (CDCl3, p.p.m.): δ 7.35–7.26 (m, 5H), 5.19 (app. d, 1H, J = 10.2), 3.92–3.75 (m, 3H), 3.02 (dd, 1H, J = 3.6 and 12.3 Hz), 2.74 (m, 2H), 2.44–1.78 (m, 11 H), 1.69 (s, 3H), 1.29 (s, 3H); 13C NMR (CDCl3, δ, p.p.m.): 176.7, 140.0, 134.6, 128.5, 128.1, 127.1, 125.2, 82.7, 66.5, 61.7, 54.1, 48.4, 46.7, 46.2, 41.2, 36.8, 30.2, 24.3, 17.5, 17.2.

Refinement top

H atoms were found in difference Fourier maps and those attached to carbon atoms were subsequently placed in idealized positions with constrained C—H distances of 0.98Å (RCH3), 0.99 Å (R2CH2), 1.00 Å (R3CH) and 0.95 Å (CArH) with Uiso(H) values set to either 1.5Ueq(methyl) or 1.2Ueq of the attached C atom respectively. Since the NH hydrogen was clearly not planar, and there being no suitable riding model available, the coordinates of this H atom were refined but its Uiso was set to 1.5Ueq of the attached N atom.

Since this crystal structure was known to be of an all light-atom chiral compound, Cu Kα x-rays were used so that the absolute configuration could be determined from the anomalous scattering of the oxygen atoms. The value of the Flack parameter (Flack, 1983) based on refinement with unmerged Friedel pairs, as determined by the Parsons' quotient method (Parsons & Flack, 2004) was x(u) = 0.13 (6).

Computing details top

Data collection: APEX2 (Bruker–Nonius, 2004); cell refinement: APEX2; data reduction: APEX2; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: XP in SHELXTL/PC (Sheldrick, 1995); software used to prepare material for publication: SHELXL97 (Sheldrick, 1997) and local procedures.

Figures top
[Figure 1] Fig. 1. A view of the asymmetric unit of the title compound, with displacement ellipsoids drawn at the 50% probability level; H atoms are shown as small spheres of arbitrary radii.
[Figure 2] Fig. 2. A packing diagram, viewed down the a axis, hydrogen atoms have been omitted for clarity.
(11R)-13-(Benzylamino)-4,5-epoxy-11,13-dihydrocostunolide top
Crystal data top
C22H29NO3F(000) = 768
Mr = 355.46Dx = 1.208 Mg m3
Orthorhombic, P212121Cu Kα radiation, λ = 1.54178 Å
Hall symbol: P 2ac 2abCell parameters from 7188 reflections
a = 8.3772 (6) Åθ = 4.1–68.0°
b = 13.7441 (10) ŵ = 0.63 mm1
c = 16.9684 (12) ÅT = 90 K
V = 1953.7 (2) Å3Rod, colourless
Z = 40.35 × 0.08 × 0.08 mm
Data collection top
X8 Proteum
diffractometer
3446 reflections with I > 2σ(I)
Radiation source: fine-focus rotating anodeRint = 0.043
Helios multilayer opticsθmax = 68.0°, θmin = 4.1°
Detector resolution: 18 pixels mm-1h = 1010
ω and φ scansk = 1616
21942 measured reflectionsl = 2020
3531 independent reflections
Refinement top
Refinement on F2Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: fullH atoms treated by a mixture of independent and constrained refinement
R[F2 > 2σ(F2)] = 0.036 w = 1/[σ2(Fo2) + (0.0636P)2 + 0.2363P]
where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.096(Δ/σ)max = 0.001
S = 1.08Δρmax = 0.26 e Å3
3531 reflectionsΔρmin = 0.19 e Å3
241 parametersExtinction correction: SHELXL97 (Sheldrick, 1997), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
1 restraintExtinction coefficient: 0.0055 (5)
Primary atom site location: structure-invariant direct methodsAbsolute structure: Flack (1983), with 0000 Friedel pairs
Secondary atom site location: difference Fourier mapFlack parameter: 0.13 (6)
Crystal data top
C22H29NO3V = 1953.7 (2) Å3
Mr = 355.46Z = 4
Orthorhombic, P212121Cu Kα radiation
a = 8.3772 (6) ŵ = 0.63 mm1
b = 13.7441 (10) ÅT = 90 K
c = 16.9684 (12) Å0.35 × 0.08 × 0.08 mm
Data collection top
X8 Proteum
diffractometer
3446 reflections with I > 2σ(I)
21942 measured reflectionsRint = 0.043
3531 independent reflectionsθmax = 68.0°
Refinement top
R[F2 > 2σ(F2)] = 0.036H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.096Δρmax = 0.26 e Å3
S = 1.08Δρmin = 0.19 e Å3
3531 reflectionsAbsolute structure: Flack (1983), with 0000 Friedel pairs
241 parametersFlack parameter: 0.13 (6)
1 restraint
Special details top

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

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Flack parameter from normal least-squares (unmerged data): is x = 0.09232; su = 0.07777 Flack parameter from Parson's quotients: CC = 15.45, GooF 1.2789, Flack x = 0.1327; su = 0.0656 Result from Parsons quotients given in this CIF.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
N10.48723 (15)0.32099 (8)0.46644 (9)0.0325 (3)
H1N0.422 (3)0.3350 (9)0.4245 (12)0.049*
O10.24522 (12)0.80545 (7)0.50257 (5)0.0269 (2)
O20.26117 (12)0.60530 (7)0.47005 (6)0.0282 (2)
O30.28650 (15)0.47566 (7)0.39368 (6)0.0397 (3)
C10.54615 (17)0.79131 (10)0.68316 (8)0.0260 (3)
H10.63430.78560.64820.031*
C20.46528 (19)0.88816 (10)0.68533 (8)0.0309 (3)
H2A0.54540.94010.69380.037*
H2B0.38830.89010.72960.037*
C30.37714 (17)0.90558 (10)0.60700 (8)0.0292 (3)
H3A0.30960.96440.61160.035*
H3B0.45600.91700.56450.035*
C40.27459 (16)0.81977 (10)0.58600 (8)0.0266 (3)
C50.35340 (15)0.74075 (9)0.54297 (7)0.0211 (3)
H50.46880.75250.53130.025*
C60.30846 (16)0.63576 (10)0.54922 (7)0.0233 (3)
H60.21740.62750.58680.028*
C70.44529 (16)0.56754 (10)0.57132 (8)0.0247 (3)
H70.54620.59410.54840.030*
C80.4736 (2)0.54673 (11)0.65905 (9)0.0349 (4)
H8A0.36890.54720.68610.042*
H8B0.51780.48020.66400.042*
C90.58504 (19)0.61685 (10)0.70247 (9)0.0331 (3)
H9A0.62380.58480.75110.040*
H9B0.67890.63000.66870.040*
C100.50933 (17)0.71205 (11)0.72440 (8)0.0305 (3)
C110.40039 (16)0.47539 (10)0.52589 (8)0.0263 (3)
H110.32460.43650.55870.032*
C120.31212 (17)0.51417 (10)0.45586 (9)0.0277 (3)
C130.53912 (17)0.41115 (11)0.50311 (10)0.0335 (3)
H13A0.60910.44690.46610.040*
H13B0.60250.39580.55080.040*
C140.3954 (3)0.70842 (16)0.79204 (11)0.0502 (5)
H14A0.34380.77200.79810.075*
H14B0.45360.69220.84040.075*
H14C0.31410.65870.78200.075*
C150.13073 (18)0.80289 (13)0.63629 (10)0.0369 (4)
H15A0.06420.86150.63660.055*
H15B0.16450.78780.69020.055*
H15C0.06920.74820.61500.055*
C2'0.62254 (18)0.26381 (12)0.44003 (13)0.0444 (4)
H2'10.68920.24640.48610.053*
H2'20.68850.30360.40390.053*
C3'0.57217 (17)0.17232 (10)0.39836 (10)0.0329 (3)
C4'0.62586 (19)0.15239 (12)0.32291 (10)0.0389 (4)
H4'0.69130.19830.29640.047*
C5'0.58531 (19)0.06646 (13)0.28581 (9)0.0391 (4)
H5'0.62370.05320.23420.047*
C6'0.48934 (19)0.00007 (12)0.32352 (9)0.0351 (3)
H6'0.46140.05900.29800.042*
C7'0.43343 (18)0.01924 (11)0.39868 (9)0.0329 (3)
H7'0.36640.02640.42470.039*
C8'0.47545 (17)0.10493 (10)0.43568 (9)0.0307 (3)
H8'0.43750.11780.48740.037*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
N10.0196 (6)0.0285 (6)0.0494 (7)0.0004 (5)0.0044 (6)0.0005 (5)
O10.0237 (5)0.0322 (5)0.0248 (5)0.0057 (4)0.0060 (4)0.0004 (4)
O20.0274 (5)0.0280 (5)0.0291 (5)0.0004 (4)0.0113 (4)0.0012 (4)
O30.0516 (7)0.0332 (5)0.0345 (6)0.0028 (5)0.0147 (5)0.0036 (4)
C10.0213 (7)0.0332 (7)0.0236 (6)0.0046 (5)0.0039 (5)0.0001 (5)
C20.0319 (8)0.0324 (7)0.0284 (7)0.0029 (6)0.0016 (6)0.0044 (5)
C30.0296 (7)0.0284 (6)0.0296 (7)0.0051 (6)0.0017 (6)0.0031 (6)
C40.0207 (6)0.0351 (7)0.0238 (6)0.0069 (5)0.0025 (5)0.0024 (5)
C50.0148 (6)0.0274 (6)0.0213 (6)0.0011 (5)0.0027 (5)0.0007 (5)
C60.0182 (6)0.0300 (6)0.0215 (6)0.0040 (5)0.0026 (5)0.0002 (5)
C70.0209 (6)0.0256 (6)0.0276 (7)0.0063 (5)0.0060 (5)0.0071 (5)
C80.0408 (9)0.0327 (7)0.0311 (7)0.0118 (7)0.0147 (7)0.0110 (6)
C90.0313 (8)0.0329 (7)0.0350 (7)0.0068 (6)0.0134 (6)0.0088 (6)
C100.0266 (7)0.0373 (7)0.0277 (7)0.0061 (6)0.0065 (6)0.0044 (6)
C110.0204 (6)0.0251 (6)0.0334 (7)0.0053 (5)0.0055 (5)0.0045 (6)
C120.0238 (6)0.0261 (6)0.0331 (7)0.0016 (6)0.0048 (6)0.0006 (5)
C130.0196 (7)0.0279 (7)0.0531 (9)0.0040 (6)0.0065 (6)0.0043 (6)
C140.0538 (11)0.0618 (11)0.0350 (8)0.0059 (9)0.0059 (8)0.0136 (8)
C150.0239 (7)0.0512 (9)0.0357 (8)0.0058 (7)0.0040 (6)0.0041 (6)
C2'0.0202 (7)0.0344 (8)0.0784 (12)0.0009 (6)0.0010 (8)0.0026 (8)
C3'0.0150 (6)0.0324 (7)0.0514 (9)0.0046 (5)0.0011 (6)0.0049 (7)
C4'0.0224 (7)0.0471 (9)0.0473 (9)0.0084 (6)0.0067 (6)0.0191 (7)
C5'0.0255 (7)0.0611 (10)0.0308 (7)0.0157 (7)0.0014 (6)0.0070 (7)
C6'0.0260 (7)0.0422 (8)0.0371 (7)0.0095 (6)0.0029 (6)0.0046 (6)
C7'0.0233 (7)0.0362 (7)0.0391 (8)0.0006 (6)0.0007 (6)0.0022 (6)
C8'0.0194 (7)0.0364 (7)0.0361 (7)0.0028 (6)0.0043 (6)0.0005 (6)
Geometric parameters (Å, °) top
N1—C2'1.450 (2)C9—C101.501 (2)
N1—C131.4532 (19)C9—H9A0.9900
N1—H1N0.92 (2)C9—H9B0.9900
O1—C51.4429 (15)C10—C141.494 (2)
O1—C41.4502 (16)C11—C121.4975 (19)
O2—C121.3450 (17)C11—C131.510 (2)
O2—C61.4617 (15)C11—H111.0000
O3—C121.1998 (18)C13—H13A0.9900
C1—C101.331 (2)C13—H13B0.9900
C1—C21.494 (2)C14—H14A0.9800
C1—H10.9500C14—H14B0.9800
C2—C31.539 (2)C14—H14C0.9800
C2—H2A0.9900C15—H15A0.9800
C2—H2B0.9900C15—H15B0.9800
C3—C41.502 (2)C15—H15C0.9800
C3—H3A0.9900C2'—C3'1.503 (2)
C3—H3B0.9900C2'—H2'10.9900
C4—C51.4658 (18)C2'—H2'20.9900
C4—C151.495 (2)C3'—C8'1.384 (2)
C5—C61.4950 (18)C3'—C4'1.384 (2)
C5—H51.0000C4'—C5'1.381 (3)
C6—C71.5277 (19)C4'—H4'0.9500
C6—H61.0000C5'—C6'1.374 (2)
C7—C111.5297 (18)C5'—H5'0.9500
C7—C81.5343 (18)C6'—C7'1.384 (2)
C7—H71.0000C6'—H6'0.9500
C8—C91.531 (2)C7'—C8'1.380 (2)
C8—H8A0.9900C7'—H7'0.9500
C8—H8B0.9900C8'—H8'0.9500
C2'—N1—C13111.13 (12)H9A—C9—H9B107.6
C2'—N1—H1N109.8 (8)C1—C10—C14125.41 (16)
C13—N1—H1N109.4 (8)C1—C10—C9119.03 (13)
C5—O1—C460.88 (8)C14—C10—C9115.56 (14)
C12—O2—C6110.20 (10)C12—C11—C13112.65 (12)
C10—C1—C2127.67 (14)C12—C11—C7103.10 (10)
C10—C1—H1116.2C13—C11—C7115.08 (11)
C2—C1—H1116.2C12—C11—H11108.6
C1—C2—C3109.56 (11)C13—C11—H11108.6
C1—C2—H2A109.8C7—C11—H11108.6
C3—C2—H2A109.8O3—C12—O2120.76 (13)
C1—C2—H2B109.8O3—C12—C11128.99 (13)
C3—C2—H2B109.8O2—C12—C11110.25 (11)
H2A—C2—H2B108.2N1—C13—C11112.21 (11)
C4—C3—C2110.92 (11)N1—C13—H13A109.2
C4—C3—H3A109.5C11—C13—H13A109.2
C2—C3—H3A109.5N1—C13—H13B109.2
C4—C3—H3B109.5C11—C13—H13B109.2
C2—C3—H3B109.5H13A—C13—H13B107.9
H3A—C3—H3B108.0C10—C14—H14A109.5
O1—C4—C559.32 (8)C10—C14—H14B109.5
O1—C4—C15113.54 (12)H14A—C14—H14B109.5
C5—C4—C15122.17 (13)C10—C14—H14C109.5
O1—C4—C3115.80 (12)H14A—C14—H14C109.5
C5—C4—C3116.26 (12)H14B—C14—H14C109.5
C15—C4—C3116.59 (13)C4—C15—H15A109.5
O1—C5—C459.80 (8)C4—C15—H15B109.5
O1—C5—C6118.06 (10)H15A—C15—H15B109.5
C4—C5—C6124.50 (11)C4—C15—H15C109.5
O1—C5—H5114.4H15A—C15—H15C109.5
C4—C5—H5114.4H15B—C15—H15C109.5
C6—C5—H5114.4N1—C2'—C3'112.29 (12)
O2—C6—C5106.23 (10)N1—C2'—H2'1109.1
O2—C6—C7104.67 (10)C3'—C2'—H2'1109.1
C5—C6—C7114.89 (11)N1—C2'—H2'2109.1
O2—C6—H6110.3C3'—C2'—H2'2109.1
C5—C6—H6110.3H2'1—C2'—H2'2107.9
C7—C6—H6110.3C8'—C3'—C4'118.74 (15)
C6—C7—C11101.53 (10)C8'—C3'—C2'120.59 (15)
C6—C7—C8117.94 (12)C4'—C3'—C2'120.63 (15)
C11—C7—C8111.88 (11)C5'—C4'—C3'120.73 (15)
C6—C7—H7108.3C5'—C4'—H4'119.6
C11—C7—H7108.3C3'—C4'—H4'119.6
C8—C7—H7108.3C6'—C5'—C4'119.98 (15)
C9—C8—C7116.34 (12)C6'—C5'—H5'120.0
C9—C8—H8A108.2C4'—C5'—H5'120.0
C7—C8—H8A108.2C5'—C6'—C7'120.04 (15)
C9—C8—H8B108.2C5'—C6'—H6'120.0
C7—C8—H8B108.2C7'—C6'—H6'120.0
H8A—C8—H8B107.4C8'—C7'—C6'119.70 (14)
C10—C9—C8114.22 (13)C8'—C7'—H7'120.2
C10—C9—H9A108.7C6'—C7'—H7'120.2
C8—C9—H9A108.7C7'—C8'—C3'120.81 (14)
C10—C9—H9B108.7C7'—C8'—H8'119.6
C8—C9—H9B108.7C3'—C8'—H8'119.6
C10—C1—C2—C3110.86 (17)C2—C1—C10—C9168.37 (13)
C1—C2—C3—C450.01 (16)C8—C9—C10—C1104.86 (16)
C5—O1—C4—C15114.63 (14)C8—C9—C10—C1474.63 (17)
C5—O1—C4—C3106.53 (13)C6—C7—C11—C1229.69 (13)
C2—C3—C4—O1152.77 (11)C8—C7—C11—C12156.36 (12)
C2—C3—C4—C585.95 (15)C6—C7—C11—C13152.74 (12)
C2—C3—C4—C1569.67 (16)C8—C7—C11—C1380.59 (16)
C4—O1—C5—C6115.63 (13)C6—O2—C12—O3179.43 (13)
C15—C4—C5—O1100.10 (14)C6—O2—C12—C110.25 (15)
C3—C4—C5—O1105.76 (13)C13—C11—C12—O335.0 (2)
O1—C4—C5—C6105.09 (13)C7—C11—C12—O3159.65 (16)
C15—C4—C5—C65.0 (2)C13—C11—C12—O2144.11 (12)
C3—C4—C5—C6149.15 (12)C7—C11—C12—O219.44 (15)
C12—O2—C6—C5141.96 (11)C2'—N1—C13—C11175.89 (14)
C12—O2—C6—C720.01 (14)C12—C11—C13—N167.32 (15)
O1—C5—C6—O248.47 (14)C7—C11—C13—N1174.88 (12)
C4—C5—C6—O2119.49 (13)C13—N1—C2'—C3'177.25 (14)
O1—C5—C6—C7163.67 (11)N1—C2'—C3'—C8'57.4 (2)
C4—C5—C6—C7125.31 (13)N1—C2'—C3'—C4'124.74 (16)
O2—C6—C7—C1130.40 (13)C8'—C3'—C4'—C5'0.7 (2)
C5—C6—C7—C11146.50 (11)C2'—C3'—C4'—C5'177.20 (14)
O2—C6—C7—C8152.99 (11)C3'—C4'—C5'—C6'0.7 (2)
C5—C6—C7—C890.90 (14)C4'—C5'—C6'—C7'0.1 (2)
C6—C7—C8—C988.67 (17)C5'—C6'—C7'—C8'0.5 (2)
C11—C7—C8—C9154.15 (14)C6'—C7'—C8'—C3'0.4 (2)
C7—C8—C9—C1078.04 (18)C4'—C3'—C8'—C7'0.2 (2)
C2—C1—C10—C1411.1 (2)C2'—C3'—C8'—C7'177.73 (14)
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
N1—H1N···O30.92 (2)2.30 (2)2.9784 (17)130 (1)
Table 1
Hydrogen-bond geometry (Å, °)
top
D—H···AD—HH···AD···AD—H···A
N1—H1N···O30.92 (2)2.30 (2)2.9784 (17)130 (1)
Acknowledgements top

Financial support from the Kentucky Lung Cancer Research Program is gratefully acknowleged.

references
References top

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