(E)-1-(2-Hydro­xy-4-methoxy­phenyl)-2-(3,4,5-tri­methoxy­phenyl)­ethene

In the crystal structure of the title compound, C₁₈H₂₀O₅, all geometric parameters fall within experimental error of the expected values. Analysis of the molecular-packing plots reveals an infinite one-dimensional linear array running parallel to the c axis, formed by an O-H...O intermolecular hydrogen-bonding interaction. The stilbene framework and most of the substituents are approximately coplanar.

S1. Comment

The microtubule system of eukaryotic cells is an important target for the development of anticancer agents. Novel drugs have been developed that bind to tubulin, disrupting cellular microtuble structure and function, thus resulting in mitotic arrest. The combretastatins are tubulin polymerization inhibitors isolated from the bark of the South African tree Combretum caffrum (Pettit et al., 1982, 1989). The most potent of these is combretastatin A-4 (CA-4), (I), which is a potent cytotoxic agent and which strongly inhibits the polymerization of tubulin by binding to the colchicine site (Hamel, et al., 1983).

CA-4 shows potent cytotoxicity against a wide variety of human cancers, including multidrug resistant cell lines (El-Zayat et al., 1993), and is thus attractive as a lead compound for development of anticancer drugs. However, CA-4 has demonstrated lack of efficacy in vivo, presumably due to poor pharmacokinetics which arise from its high lipophilicity and limited aqueous solubility. A phosphate prodrug of CA-4 (CA-4P), (II) (Pettit et al., 1998), has been synthesized in order to improve aqueous solubility and pharmacokinetics.

To obtain compounds with pharmaceutically acceptable properties and improved antitumor activities, we have designed and synthesized a number of CA-4 analogs and their corresponding sodium phosphate prodrugs. Compounds (III) and (IV) are two isomeric derivatives that we have recently prepared. In order to unequivocally confirm the molecular structure, and to gather information for our molecular recognition studies, we have determined the crystal structure of (III). Fig. 1 shows the crystallographically determined molecular structure of (III), while selected parameters are presented in Table 1. A l l internuclear distances and angles fall within the range of expected values. The stilbene system exhibits only minor deviations from ideal planarity, as evidenced by the torsion angles (Table 1.). Each methoxy substituent is approximately coplanar with the aromatic rings, with the exception of the O4 methoxy group, which is twisted by approximately 75° relative to the plane of the aromatic ring. This twist minimizes steric interactions with the neighboring O3 and O5 methoxy groups.

The crystal packing of (III) (Fig. 2) consists of corrugated ribbons formed by an infinite linear array of molecules linked by an intermolecular O1—H···O4 hydrogen-bonding interaction that has an O–O distance of 2.705 (2) Å.

S2. Experimental

To a dimethylformamide (7 ml) solution containing an isomeric mixture of the silyl-protected precursor to (III) and (IV) [_{3:1 Z:E-1-(2-tert-butyldimethylsiloxy-4- methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethane] (1.12 g, 2.6 mmol) were added KF (150 mg, 2.6 mmol) and HBr (462 mg, 0.3 ml, 2.5 mmol). Additional HBr (0.3 ml) was added after 12 h, and the reaction mixture was stirred for total of a two days. Water (15 ml) was then added to the solution, and the resulting suspension was extracted with ethyl acetate (3 × 15 ml). The combined organic extracts were washed with water, dried over sodium sulfate, and evaporated to dryness. The residue was applied to a silica-gel column and eluted with hexane/ethyl acetate (75:25). Compound (III) was obtained as a white powder, which was crystallized from methanol to afford pure (III) as white crystals (210 mg, 0.49 mmol; yield 18%).}

S3. Refinement

Systematic conditions suggested the unambiguous space group P2(1)/n. Atom H1 was located from a difference map, and H atoms were treated as riding. The space group was confirmed by successful convergence of the full-matrix least-squares refinement on F^{2 (Sheldrick, 1993). The highest peaks in the final difference Fourier map were in the vicinity of atom C16, and the final map had no other significant features.}

Computing details

Program(s) used to solve structure: SHELXS86 (Sheldrick, 1990); program(s) used to refine structure: SHELXL93 (Sheldrick, 1993).

Figures

	Fig. 1. SHELXTL (Sheldrick, 1994) plot of (III), showing displacement ellipsoids at the 35% probability level for non-H atoms. H atoms are shown as circles of arbitrary size for.
	Fig. 2. The crystal packing in (III), viewed along the b axis, showing the intermolecular hydrogen bonding (dotted lines).

(E)-1-(2-hydroxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene

Crystal data

C18H20O5	F(000) = 672
Mr = 316.34	Dx = 1.284 Mg m^−3
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
a = 11.6693 (15) Å	Cell parameters from 25 reflections
b = 7.9790 (8) Å	θ = 12.5–21.3°
c = 17.5818 (13) Å	µ = 0.09 mm^−1
β = 90.673 (9)°	T = 293 K
V = 1636.9 (3) Å^3	Block, colorless
Z = 4	0.54 × 0.47 × 0.41 mm

Data collection

Enraf-NoniusCAD 4 diffractometer	Rint = 0.016
Radiation source: fine-focus sealed tube	θmax = 24.9°, θmin = 2.1°
Graphite monochromator	h = −1→13
ω scan	k = 0→9
3369 measured reflections	l = −20→20
2867 independent reflections	3 standard reflections every 600 reflections
2420 reflections with I > 2σ(I)	intensity decay: 2.1%

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.050	H-atom parameters constrained
wR(F^2) = 0.128	w = 1/[σ^2(Fo^2) + (0.0813P)^2 + 0.3079P] where P = (Fo^2 + 2Fc^2)/3
S = 1.10	(Δ/σ)max < 0.001
2867 reflections	Δρmax = 0.74 e Å^−3
209 parameters	Δρmin = −0.20 e Å^−3
0 restraints	Extinction correction: SHELXL, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.164 (8)

Special details

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 on F^{2 for ALL reflections except for 0 with very negative F}2 or flagged by the user for potential systematic errors. Weighted R-factors wR and all goodnesses of fit S are based on F^{2, conventional R-factors R are based on F, with F set to zero for negative F}2. The observed criterion of F^{2 > σ(F}2) is used only for calculating R factor_obs etc. and is not relevant to the choice of reflections for refinement. R-factors based on F^{2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.}

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O1	−0.01721 (11)	−0.27129 (17)	−0.20934 (7)	0.0470 (4)
H1	−0.076 (2)	−0.312 (3)	−0.2367 (13)	0.071*
O2	0.10768 (11)	−0.07871 (16)	−0.44871 (7)	0.0426 (3)
O3	0.08719 (10)	−0.26337 (16)	0.15941 (7)	0.0458 (4)
O4	0.27702 (9)	−0.14811 (14)	0.22835 (6)	0.0351 (3)
O5	0.41793 (9)	0.05986 (14)	0.16041 (6)	0.0365 (3)
C1	0.13402 (13)	−0.0753 (2)	−0.21153 (9)	0.0330 (4)
C2	0.05354 (13)	−0.1737 (2)	−0.25163 (9)	0.0326 (4)
C3	0.04788 (13)	−0.1716 (2)	−0.33008 (9)	0.0341 (4)
H3	−0.0062	−0.2371	−0.3555	0.041*
C4	0.12232 (13)	−0.0723 (2)	−0.37109 (9)	0.0333 (4)
C5	0.20393 (14)	0.0245 (2)	−0.33347 (10)	0.0383 (4)
H5	0.2550	0.0901	−0.3607	0.046*
C6	0.20797 (14)	0.0217 (2)	−0.25498 (10)	0.0384 (4)
H6	0.2624	0.0874	−0.2300	0.046*
C7	0.13840 (14)	−0.0842 (2)	−0.12881 (10)	0.0352 (4)
H7	0.0869	−0.1576	−0.1064	0.042*
C8	0.20736 (13)	0.0001 (2)	−0.08117 (9)	0.0352 (4)
H8	0.2541	0.0819	−0.1021	0.042*
C9	0.21574 (13)	−0.0253 (2)	0.00132 (9)	0.0337 (4)
C10	0.13741 (14)	−0.1251 (2)	0.04066 (10)	0.0368 (4)
H10	0.0726	−0.1659	0.0156	0.044*
C11	0.15574 (13)	−0.1633 (2)	0.11647 (10)	0.0349 (4)
C12	0.25160 (13)	−0.0991 (2)	0.15493 (9)	0.0321 (4)
C13	0.32740 (13)	0.00532 (19)	0.11699 (9)	0.0310 (4)
C14	0.30978 (13)	0.0426 (2)	0.04074 (9)	0.0327 (4)
H14	0.3605	0.1128	0.0157	0.039*
C15	0.17861 (18)	0.0273 (3)	−0.49368 (11)	0.0510 (5)
H15A	0.1602	0.0113	−0.5466	0.077*
H15B	0.2576	−0.0005	−0.4846	0.077*
H15C	0.1656	0.1422	−0.4801	0.077*
C16	−0.00427 (16)	−0.3492 (2)	0.12219 (12)	0.0515 (5)
H16A	−0.0455	−0.4146	0.1587	0.077*
H16B	0.0261	−0.4218	0.0838	0.077*
H16C	−0.0552	−0.2693	0.0989	0.077*
C17	0.20878 (16)	−0.0721 (2)	0.28674 (10)	0.0420 (4)
H17A	0.2327	−0.1139	0.3356	0.063*
H17B	0.1295	−0.0990	0.2781	0.063*
H17C	0.2186	0.0473	0.2854	0.063*
C18	0.50324 (14)	0.1574 (2)	0.12366 (11)	0.0441 (5)
H18A	0.5618	0.1879	0.1599	0.066*
H18B	0.4689	0.2570	0.1029	0.066*
H18C	0.5366	0.0931	0.0834	0.066*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0465 (7)	0.0571 (8)	0.0372 (7)	−0.0226 (6)	−0.0084 (6)	0.0115 (6)
O2	0.0495 (7)	0.0458 (7)	0.0326 (6)	−0.0051 (6)	0.0037 (5)	0.0000 (5)
O3	0.0374 (7)	0.0501 (8)	0.0499 (7)	−0.0114 (6)	−0.0019 (6)	0.0152 (6)
O4	0.0369 (6)	0.0375 (7)	0.0309 (6)	0.0070 (5)	0.0006 (5)	0.0017 (5)
O5	0.0337 (6)	0.0395 (7)	0.0362 (6)	−0.0055 (5)	−0.0042 (5)	−0.0033 (5)
C1	0.0287 (8)	0.0314 (8)	0.0387 (9)	0.0032 (6)	−0.0029 (7)	0.0015 (7)
C2	0.0284 (8)	0.0311 (8)	0.0381 (9)	0.0001 (6)	−0.0027 (6)	0.0063 (7)
C3	0.0318 (8)	0.0318 (8)	0.0385 (9)	−0.0006 (7)	−0.0049 (7)	0.0008 (7)
C4	0.0326 (8)	0.0327 (8)	0.0345 (9)	0.0065 (6)	0.0015 (7)	−0.0002 (7)
C5	0.0320 (8)	0.0407 (9)	0.0425 (9)	−0.0029 (7)	0.0043 (7)	0.0040 (8)
C6	0.0324 (8)	0.0396 (9)	0.0431 (9)	−0.0060 (7)	−0.0048 (7)	0.0020 (8)
C7	0.0318 (8)	0.0354 (9)	0.0383 (9)	−0.0009 (7)	−0.0026 (7)	0.0051 (7)
C8	0.0311 (8)	0.0343 (9)	0.0401 (9)	−0.0013 (7)	−0.0016 (7)	0.0035 (7)
C9	0.0315 (8)	0.0318 (8)	0.0378 (9)	0.0021 (7)	−0.0024 (7)	0.0019 (7)
C10	0.0287 (8)	0.0386 (9)	0.0429 (10)	−0.0006 (7)	−0.0057 (7)	0.0023 (7)
C11	0.0298 (8)	0.0322 (9)	0.0427 (9)	0.0004 (7)	0.0016 (7)	0.0056 (7)
C12	0.0309 (8)	0.0319 (8)	0.0334 (8)	0.0056 (6)	0.0003 (6)	0.0027 (7)
C13	0.0285 (8)	0.0286 (8)	0.0360 (9)	0.0035 (6)	−0.0018 (6)	−0.0040 (7)
C14	0.0312 (8)	0.0307 (8)	0.0363 (9)	−0.0009 (6)	0.0022 (7)	−0.0003 (7)
C15	0.0578 (12)	0.0560 (12)	0.0396 (10)	−0.0080 (10)	0.0124 (9)	0.0016 (9)
C16	0.0371 (10)	0.0450 (11)	0.0722 (13)	−0.0093 (8)	−0.0037 (9)	0.0144 (10)
C17	0.0473 (10)	0.0391 (9)	0.0400 (10)	0.0033 (8)	0.0107 (8)	−0.0007 (7)
C18	0.0329 (9)	0.0501 (11)	0.0491 (10)	−0.0093 (8)	−0.0012 (8)	−0.0054 (8)

Geometric parameters (Å, º)

O1—C2	1.3623 (19)	C8—C9	1.467 (2)
O1—H1	0.89 (3)	C8—H8	0.93
O2—C4	1.374 (2)	C9—C14	1.400 (2)
O2—C15	1.428 (2)	C9—C10	1.401 (2)
O3—C11	1.365 (2)	C10—C11	1.381 (2)
O3—C16	1.421 (2)	C10—H10	0.93
O4—C12	1.3778 (19)	C11—C12	1.397 (2)
O4—C17	1.4405 (19)	C12—C13	1.391 (2)
O5—C13	1.3671 (19)	C13—C14	1.386 (2)
O5—C18	1.425 (2)	C14—H14	0.93
C1—C6	1.394 (2)	C15—H15A	0.96
C1—C2	1.407 (2)	C15—H15B	0.96
C1—C7	1.456 (2)	C15—H15C	0.96
C2—C3	1.380 (2)	C16—H16A	0.96
C3—C4	1.384 (2)	C16—H16B	0.96
C3—H3	0.93	C16—H16C	0.96
C4—C5	1.388 (2)	C17—H17A	0.96
C5—C6	1.380 (2)	C17—H17B	0.96
C5—H5	0.93	C17—H17C	0.96
C6—H6	0.93	C18—H18A	0.96
C7—C8	1.336 (2)	C18—H18B	0.96
C7—H7	0.93	C18—H18C	0.96
C2—O1—H1	112.4 (15)	O3—C11—C12	114.69 (15)
C4—O2—C15	117.49 (13)	C10—C11—C12	120.00 (15)
C11—O3—C16	117.98 (14)	O4—C12—C13	119.21 (14)
C12—O4—C17	115.69 (12)	O4—C12—C11	120.78 (14)
C13—O5—C18	117.40 (12)	C13—C12—C11	119.82 (14)
C6—C1—C2	116.68 (15)	O5—C13—C14	125.21 (14)
C6—C1—C7	124.05 (15)	O5—C13—C12	114.49 (13)
C2—C1—C7	119.23 (15)	C14—C13—C12	120.28 (14)
O1—C2—C3	122.02 (14)	C13—C14—C9	120.15 (15)
O1—C2—C1	116.79 (14)	C13—C14—H14	119.9
C3—C2—C1	121.19 (15)	C9—C14—H14	119.9
C2—C3—C4	120.30 (15)	O2—C15—H15A	109.5
C2—C3—H3	119.8	O2—C15—H15B	109.5
C4—C3—H3	119.8	H15A—C15—H15B	109.5
O2—C4—C3	115.13 (14)	O2—C15—H15C	109.5
O2—C4—C5	124.79 (15)	H15A—C15—H15C	109.5
C3—C4—C5	120.09 (15)	H15B—C15—H15C	109.5
C6—C5—C4	118.86 (15)	O3—C16—H16A	109.5
C6—C5—H5	120.6	O3—C16—H16B	109.5
C4—C5—H5	120.6	H16A—C16—H16B	109.5
C5—C6—C1	122.87 (15)	O3—C16—H16C	109.5
C5—C6—H6	118.6	H16A—C16—H16C	109.5
C1—C6—H6	118.6	H16B—C16—H16C	109.5
C8—C7—C1	127.95 (16)	O4—C17—H17A	109.5
C8—C7—H7	116.0	O4—C17—H17B	109.5
C1—C7—H7	116.0	H17A—C17—H17B	109.5
C7—C8—C9	125.67 (15)	O4—C17—H17C	109.5
C7—C8—H8	117.2	H17A—C17—H17C	109.5
C9—C8—H8	117.2	H17B—C17—H17C	109.5
C14—C9—C10	119.19 (15)	O5—C18—H18A	109.5
C14—C9—C8	118.61 (15)	O5—C18—H18B	109.5
C10—C9—C8	122.03 (14)	H18A—C18—H18B	109.5
C11—C10—C9	120.47 (15)	O5—C18—H18C	109.5
C11—C10—H10	119.8	H18A—C18—H18C	109.5
C9—C10—H10	119.8	H18B—C18—H18C	109.5
O3—C11—C10	125.30 (15)
C18—O5—C13—C14	−2.6 (2)	C17—O4—C12—C11	−77.41 (19)
O5—C13—C14—C9	177.77 (14)	O4—C12—C11—O3	5.4 (2)
C13—C14—C9—C8	−172.71 (14)	C12—C11—O3—C16	−172.68 (15)
C14—C9—C8—C7	164.89 (16)	C16—O3—C11—C10	6.6 (2)
C9—C8—C7—C1	−173.83 (15)	C2—C1—C7—C8	−179.23 (17)
C8—C7—C1—C2	−179.23 (17)	C15—O2—C4—C5	−2.7 (2)
C17—O4—C12—C13	107.59 (16)	C15—O2—C4—C3	177.12 (15)
C18—O5—C13—C12	175.59 (14)	C6—C1—C7—C8	3.0 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···O4^i	0.89 (3)	1.85 (3)	2.7052 (16)	161 (2)

Symmetry code: (i) x−1/2, −y−1/2, z−1/2.