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The synthesis, isolation, and definitive diasteriomeric characterization of the racemic title compound, C18H24O3, (I), was accomplished. The two enantiomers are hydrogen bonded through their respective carboxyl­ic acid groups, forming an octagonal bridge. A preliminary study indicates that (I) definitely inhibits prostate cancer-cell proliferation.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536802021748/om6121sup1.cif
Contains datablocks global, I

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S1600536802021748/om6121Isup2.hkl
Contains datablock I

CCDC reference: 202365

Key indicators

  • Single-crystal X-ray study
  • T = 296 K
  • Mean [sigma](C-C) = 0.004 Å
  • R factor = 0.041
  • wR factor = 0.134
  • Data-to-parameter ratio = 14.6

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry








Comment top

In the reported synthesis of (I) by Crenshaw et al. (1974), a multitude of isomeric compounds was concurrently formed. Compound (I), with four different asymmetric centers, has eight different diastereomeric isomers, each possessing two enantiomers. Moreover, the synthesis employed also produces related compounds whose double bond is shifted from that in (I), producing three different asymmetric centers, which further increases the number of possible diastereomeric and enantiomeric isomers formed. The Crenshaw group employed a mixture of such isomers in their study of in vivo estrogenic activity, thereby leaving unsolved the important question of which compound, diastereomer, and corresponding enantiomer was responsible for the observed activity. Moreover, without doing binding studies, they assumed that these compounds would exhibit correspondingly high estrogen-receptor affinity. However, some years prior to the Crenshaw group's publication, early mouse studies by Terenius (1967, 1968) suggested that 3-methoxy-substituted carboxylic acids, like (-)-3-MeO-bisdehydrodoisynolic and (-)-3-MeO-allenolic acids, exhibit significant in vivo estrogenic activity but bind poorly to ER receptors; the corresponding 3-OH acids likewise exhibited high in vivo estrogenicity, but showed relatively less reduction in their receptor-binding affinity. Our more recent studies with those carboxylic acids confirmed that dichotomy between in vivo activity and binding affinity, although we found a substantially greater differential than did Terenius between the in vivo and binding activities of the 3-OH compounds (Meyers et al., 1988, 1997, 2002; Soto et al., 1988; Banz et al., 1998).

We have now successfully carried out a total synthesis and isolation of racemic (I), affording for the first time the unequivocal characterization of a single diastereomer from the mixture and a study of the biological activity of that diastereomer. We previously reported preparing and characterizing only the non-aromatic moiety of a compound related to (I) (Xie et al., 2002). Our preliminary study indicates that racemic (I) definitely inhibits prostate cancer-cell proliferation.

The structure and atom numbering of one enantiomer of (I) are shown in Fig. 1. It is unequivocally 2(S),6(R)-dimethyl-4-(4-methoxyphenyl)- 5(R)-ethyl-3-cyclohexene-1(S)-carboxylic acid. Fig. 2 shows the two enantiomers of (I) hydrogen bonded with each other via their respective carboxyl OH and CO groups, forming an octagonal bridge. The hydrogen-bond geometry is given in Table 1. The overall packing (Fig. 3) shows layers of these hydrogen-bonded enantiomeric pairs.

Experimental top

Compound (I) was synthesized following the general method reported by Crenshaw et al. (1974). The intermediates and products were separated from the mixture of formed compounds by column chromatography and recrystallizations. Isolated (I) was recrystallized twice from hexane–ethyl acetate; colorless crystals, m.p. 462–463 K; IR (neat, cm−1): 3420, 2960, 1698; 1H NMR (300 MHz, CDCl3): δ 7.20 (d, J = 8.7 Hz, 2H), 6.52 (d, J = 9.0 Hz, 2H), 5.61 (s, 1H), 3.81 (s, 3H), 2.50 (m, 2H), 2.00 (m, 2H), 1.51 (m, 2H), 1.12 (d, J = 6.0 Hz, 3H), 1.07 (d, J = 7.2 Hz, 3H), 0.59 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 220.90, 158.42, 139.80, 134.53, 131.27, 127.41 (2 C), 113.52 (2 C), 55.34, 55.24, 43.70, 33.95, 33.67, 21.44, 20.16, 18.47, 7.70.

Refinement top

The rotational orientations of the methyl and hydroxyl groups were determined by the circular Fourier refinement method available in SHELXL97 (Sheldrick, 1997). All H atoms were treated as riding, with an O—H distance of 0.83 Å and C—H distances in the range 0.93–0.98 Å.

Computing details top

Data collection: MSC/AFC Diffractometer Control Software (Molecular Structure Corporation, 1996); cell refinement: MSC/AFC Diffractometer Control Software; data reduction: PROCESS in TEXSAN (Molecular Structure Corporation, 1997); program(s) used to solve structure: SIR92 (Burla et al., 1989); program(s) used to refine structure: LS in TEXSAN and SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997) and PLATON (Spek, 2000); software used to prepare material for publication: TEXSAN, SHELXL97 and PLATON.

Figures top
[Figure 1] Fig. 1. The molecular structure and atom numbering scheme for (I), with displacement ellipsoids at the 30% probablilty level.
[Figure 2] Fig. 2. Dimer formation through hydrogen bonding in (I) [symmetry code: (i) 1 − x, 1 − y, 2 − z].
[Figure 3] Fig. 3. A c axis projection of the molecular packing in (I) showing the dimerized molecular layers.
2(S),6(R)-Dimethyl-4-(4-methoxyphenyl)-5(R)-ethyl-3-cyclohexene-1(S)- carboxylic acid top
Crystal data top
C18H24O3Dx = 1.191 Mg m3
Mr = 288.37Melting point = 462–463 K
Monoclinic, P21/cMo Kα radiation, λ = 0.71069 Å
a = 15.789 (4) ÅCell parameters from 25 reflections
b = 11.680 (5) Åθ = 7.8–12.4°
c = 8.7260 (13) ŵ = 0.08 mm1
β = 92.296 (16)°T = 296 K
V = 1607.9 (8) Å3Plate, colorless
Z = 40.49 × 0.40 × 0.07 mm
F(000) = 624
Data collection top
Rigaku AFC-5S
diffractometer
Rint = 0.020
Radiation source: fine-focus sealed tubeθmax = 25.0°, θmin = 2.2°
Graphite monochromatorh = 1818
ω scansk = 130
3052 measured reflectionsl = 010
2846 independent reflections3 standard reflections every 100 reflections
1176 reflections with I > 2σ(I) intensity decay: 0.6%
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.041Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.134H-atom parameters constrained
S = 0.98 w = 1/[σ2(Fo2) + (0.05P)2 + 0.1653P]
where P = (Fo2 + 2Fc2)/3
2846 reflections(Δ/σ)max < 0.001
195 parametersΔρmax = 0.15 e Å3
0 restraintsΔρmin = 0.16 e Å3
Crystal data top
C18H24O3V = 1607.9 (8) Å3
Mr = 288.37Z = 4
Monoclinic, P21/cMo Kα radiation
a = 15.789 (4) ŵ = 0.08 mm1
b = 11.680 (5) ÅT = 296 K
c = 8.7260 (13) Å0.49 × 0.40 × 0.07 mm
β = 92.296 (16)°
Data collection top
Rigaku AFC-5S
diffractometer
Rint = 0.020
3052 measured reflections3 standard reflections every 100 reflections
2846 independent reflections intensity decay: 0.6%
1176 reflections with I > 2σ(I)
Refinement top
R[F2 > 2σ(F2)] = 0.0410 restraints
wR(F2) = 0.134H-atom parameters constrained
S = 0.98Δρmax = 0.15 e Å3
2846 reflectionsΔρmin = 0.16 e Å3
195 parameters
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
O10.59837 (12)0.5134 (2)0.9390 (2)0.0736 (6)
O20.48139 (11)0.4822 (2)0.7958 (2)0.0724 (6)
O30.94972 (12)0.37828 (17)0.0428 (2)0.0675 (6)
C10.61134 (16)0.4837 (2)0.6693 (3)0.0493 (7)
C20.66638 (16)0.3752 (2)0.6803 (3)0.0521 (7)
C30.72318 (19)0.3711 (3)0.5474 (3)0.0660 (9)
C40.74337 (16)0.4630 (2)0.4603 (3)0.0485 (7)
C50.71114 (19)0.5788 (2)0.4916 (3)0.0651 (9)
C60.66475 (17)0.5907 (2)0.6414 (3)0.0544 (7)
C70.56272 (16)0.4944 (2)0.8132 (3)0.0532 (7)
C80.61404 (19)0.2663 (2)0.6885 (4)0.0752 (10)
C90.77451 (19)0.6755 (2)0.4646 (4)0.0675 (9)
C100.8538 (2)0.6723 (3)0.5658 (4)0.0953 (12)
C110.6105 (2)0.6984 (2)0.6412 (4)0.0828 (10)
C120.79716 (17)0.4435 (2)0.3260 (3)0.0482 (7)
C130.77580 (17)0.4883 (3)0.1826 (3)0.0568 (7)
C140.82397 (18)0.4687 (2)0.0564 (3)0.0591 (8)
C150.89596 (18)0.4020 (2)0.0726 (3)0.0535 (7)
C160.91827 (17)0.3562 (2)0.2135 (3)0.0591 (8)
C170.86964 (17)0.3765 (2)0.3384 (3)0.0567 (7)
C180.9315 (2)0.4320 (3)0.1879 (3)0.0801 (10)
H10.57050.47470.58250.059*
H20.46050.47810.88020.109*
H2A0.70220.38030.77440.063*
H30.74640.30070.52250.079*
H50.66660.59060.41160.078*
H60.70750.59700.72550.065*
H8A0.57690.26070.59900.113*
H8B0.58100.26820.77850.113*
H8C0.65110.20110.69330.113*
H9A0.79050.67270.35850.081*
H9B0.74630.74820.48000.081*
H10A0.83900.67520.67140.143*
H10B0.88890.73680.54330.143*
H10C0.88420.60270.54740.143*
H11A0.64580.76430.62790.124*
H11B0.58290.70430.73700.124*
H11C0.56850.69460.55870.124*
H130.72730.53310.17080.068*
H140.80810.50020.03830.071*
H160.96660.31110.22470.071*
H170.88580.34470.43280.068*
H18A0.87890.40300.23110.120*
H18B0.97620.41570.25600.120*
H18C0.92710.51320.17390.120*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0561 (12)0.1116 (18)0.0530 (13)0.0050 (13)0.0007 (10)0.0121 (13)
O20.0464 (12)0.1056 (18)0.0654 (13)0.0027 (12)0.0057 (10)0.0078 (14)
O30.0750 (13)0.0661 (14)0.0625 (14)0.0069 (11)0.0178 (11)0.0052 (11)
C10.0427 (14)0.0525 (17)0.0527 (16)0.0013 (14)0.0002 (12)0.0016 (14)
C20.0504 (16)0.0521 (18)0.0540 (17)0.0014 (14)0.0043 (14)0.0031 (14)
C30.078 (2)0.052 (2)0.069 (2)0.0118 (16)0.0208 (17)0.0048 (17)
C40.0428 (15)0.0475 (18)0.0551 (17)0.0003 (13)0.0014 (13)0.0013 (14)
C50.076 (2)0.0499 (19)0.070 (2)0.0028 (17)0.0193 (17)0.0003 (15)
C60.0573 (17)0.0482 (17)0.0578 (18)0.0027 (15)0.0042 (14)0.0031 (14)
C70.0449 (16)0.0537 (19)0.0611 (19)0.0008 (15)0.0021 (14)0.0019 (16)
C80.078 (2)0.058 (2)0.091 (3)0.0069 (18)0.0125 (19)0.0076 (18)
C90.077 (2)0.0489 (18)0.077 (2)0.0066 (17)0.0163 (18)0.0009 (17)
C100.077 (2)0.100 (3)0.108 (3)0.016 (2)0.004 (2)0.004 (2)
C110.090 (2)0.057 (2)0.103 (3)0.014 (2)0.019 (2)0.000 (2)
C120.0477 (16)0.0436 (16)0.0534 (18)0.0028 (13)0.0016 (13)0.0009 (14)
C130.0520 (16)0.0599 (19)0.0582 (18)0.0050 (15)0.0019 (15)0.0007 (16)
C140.0666 (19)0.0614 (19)0.0488 (17)0.0050 (16)0.0047 (15)0.0016 (15)
C150.0544 (17)0.0490 (18)0.0575 (19)0.0095 (15)0.0055 (15)0.0052 (15)
C160.0563 (18)0.0535 (19)0.068 (2)0.0068 (15)0.0075 (16)0.0074 (16)
C170.0568 (17)0.0564 (18)0.0568 (18)0.0061 (15)0.0019 (15)0.0079 (15)
C180.096 (2)0.087 (2)0.058 (2)0.017 (2)0.0145 (18)0.0001 (19)
Geometric parameters (Å, º) top
O1—C71.233 (3)C1—H10.9800
O2—C71.295 (3)C2—H2A0.9800
O3—C151.372 (3)C3—H30.9300
O3—C181.431 (3)C5—H50.9800
C1—C71.503 (4)C6—H60.9800
C1—C61.533 (4)C8—H8A0.9600
C1—C21.537 (3)C8—H8B0.9600
C2—C31.495 (3)C8—H8C0.9600
C2—C81.520 (4)C9—H9A0.9700
C3—C41.360 (4)C9—H9B0.9700
C4—C51.475 (4)C10—H10A0.9600
C4—C121.492 (4)C10—H10B0.9600
C5—C61.530 (4)C10—H10C0.9600
C5—C91.534 (4)C11—H11A0.9600
C6—C111.522 (4)C11—H11B0.9600
C9—C101.504 (4)C11—H11C0.9600
C12—C131.385 (4)C13—H130.9300
C12—C171.387 (4)C14—H140.9300
C13—C141.382 (4)C16—H160.9300
C14—C151.381 (4)C17—H170.9300
C15—C161.373 (4)C18—H18A0.9600
C16—C171.379 (4)C18—H18B0.9600
O2—H20.8200C18—H18C0.9600
C15—O3—C18116.9 (2)C9—C5—H5103.9
C7—C1—C6111.6 (2)C11—C6—H6108.0
C7—C1—C2108.8 (2)C5—C6—H6108.0
C6—C1—C2111.6 (2)C1—C6—H6108.0
C3—C2—C8110.7 (3)C2—C8—H8A109.5
C3—C2—C1109.4 (2)C2—C8—H8B109.5
C8—C2—C1112.7 (2)H8A—C8—H8B109.5
C4—C3—C2124.8 (3)C2—C8—H8C109.5
C3—C4—C5122.0 (3)H8A—C8—H8C109.5
C3—C4—C12118.2 (2)H8B—C8—H8C109.5
C5—C4—C12119.8 (2)C10—C9—H9A108.5
C4—C5—C6115.0 (2)C5—C9—H9A108.5
C4—C5—C9114.6 (2)C10—C9—H9B108.5
C6—C5—C9113.7 (2)C5—C9—H9B108.5
C11—C6—C5111.3 (3)H9A—C9—H9B107.5
C11—C6—C1111.1 (2)C9—C10—H10A109.5
C5—C6—C1110.3 (2)C9—C10—H10B109.5
O1—C7—O2122.6 (3)H10A—C10—H10B109.5
O1—C7—C1121.9 (2)C9—C10—H10C109.5
O2—C7—C1115.5 (2)H10A—C10—H10C109.5
C10—C9—C5115.1 (3)H10B—C10—H10C109.5
C13—C12—C17117.0 (3)C6—C11—H11A109.5
C13—C12—C4121.7 (3)C6—C11—H11B109.5
C17—C12—C4121.3 (3)H11A—C11—H11B109.5
C14—C13—C12122.4 (3)C6—C11—H11C109.5
C15—C14—C13119.3 (3)H11A—C11—H11C109.5
O3—C15—C16115.8 (3)H11B—C11—H11C109.5
O3—C15—C14124.8 (3)C14—C13—H13118.8
C16—C15—C14119.5 (3)C12—C13—H13118.8
C15—C16—C17120.6 (3)C15—C14—H14120.4
C16—C17—C12121.3 (3)C13—C14—H14120.4
C7—O2—H2109.5C15—C16—H16119.7
C7—C1—H1108.2C17—C16—H16119.7
C6—C1—H1108.2C16—C17—H17119.4
C2—C1—H1108.2C12—C17—H17119.4
C3—C2—H2A107.9O3—C18—H18A109.5
C8—C2—H2A107.9O3—C18—H18B109.5
C1—C2—H2A107.9H18A—C18—H18B109.5
C4—C3—H3117.6O3—C18—H18C109.5
C2—C3—H3117.6H18A—C18—H18C109.5
C4—C5—H5103.9H18B—C18—H18C109.5
C6—C5—H5103.9
C7—C1—C2—C3172.9 (2)C2—C1—C7—O166.9 (3)
C6—C1—C2—C349.3 (3)C6—C1—C7—O2123.5 (3)
C7—C1—C2—C863.4 (3)C2—C1—C7—O2112.9 (3)
C6—C1—C2—C8173.0 (2)C4—C5—C9—C1062.8 (4)
C8—C2—C3—C4144.4 (3)C6—C5—C9—C1072.2 (4)
C1—C2—C3—C419.5 (4)C3—C4—C12—C13131.8 (3)
C2—C3—C4—C51.0 (5)C5—C4—C12—C1345.9 (4)
C2—C3—C4—C12176.7 (3)C3—C4—C12—C1746.1 (4)
C3—C4—C5—C68.5 (4)C5—C4—C12—C17136.2 (3)
C12—C4—C5—C6173.8 (2)C17—C12—C13—C140.4 (4)
C3—C4—C5—C9142.9 (3)C4—C12—C13—C14178.5 (3)
C12—C4—C5—C939.4 (4)C12—C13—C14—C150.2 (4)
C4—C5—C6—C11162.0 (3)C18—O3—C15—C16175.4 (3)
C9—C5—C6—C1163.2 (3)C18—O3—C15—C143.4 (4)
C4—C5—C6—C138.1 (3)C13—C14—C15—O3178.7 (3)
C9—C5—C6—C1172.9 (2)C13—C14—C15—C160.1 (4)
C7—C1—C6—C1154.2 (3)O3—C15—C16—C17178.7 (2)
C2—C1—C6—C11176.2 (2)C14—C15—C16—C170.2 (4)
C7—C1—C6—C5178.2 (2)C15—C16—C17—C120.1 (4)
C2—C1—C6—C559.8 (3)C13—C12—C17—C160.4 (4)
C6—C1—C7—O156.7 (4)C4—C12—C17—C16178.4 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O2—H2···O1i0.821.872.679 (3)171
Symmetry code: (i) x+1, y+1, z+2.

Experimental details

Crystal data
Chemical formulaC18H24O3
Mr288.37
Crystal system, space groupMonoclinic, P21/c
Temperature (K)296
a, b, c (Å)15.789 (4), 11.680 (5), 8.7260 (13)
β (°) 92.296 (16)
V3)1607.9 (8)
Z4
Radiation typeMo Kα
µ (mm1)0.08
Crystal size (mm)0.49 × 0.40 × 0.07
Data collection
DiffractometerRigaku AFC-5S
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
3052, 2846, 1176
Rint0.020
(sin θ/λ)max1)0.596
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.041, 0.134, 0.98
No. of reflections2846
No. of parameters195
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.15, 0.16

Computer programs: MSC/AFC Diffractometer Control Software (Molecular Structure Corporation, 1996), MSC/AFC Diffractometer Control Software, PROCESS in TEXSAN (Molecular Structure Corporation, 1997), SIR92 (Burla et al., 1989), LS in TEXSAN and SHELXL97 (Sheldrick, 1997), ORTEP-3 for Windows (Farrugia, 1997) and PLATON (Spek, 2000), TEXSAN, SHELXL97 and PLATON.

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O2—H2···O1i0.821.872.679 (3)171
Symmetry code: (i) x+1, y+1, z+2.
 

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