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The title bicyclic δ-lactone, C19H26O3, (I), was formed in the reaction of (\pm)-cis-2,6,6-tri­methyl-trans-3-ethyl-4-oxo­cyclo­hexane­carboxyl­ic acid with p-methoxy­phenyl­magnesium bromide, following acidification. The kinetically favored (I) was formed rapidly but reversibly, allowing the thermodynam­ically favored γ-lactone to be formed and isolated after a longer treatment with acid. The expected corresponding carboxyl­ic acids were not isolable under these conditions. In lactone (I), basically composed of an aromatic ring appended to a [2.2.2] bicyclic system, the O—C(O)—C group is asymmetric, its O—C=O angle being 119.46 (19)° and its O=C—C angle being 127.82 (19)°.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536803004276/om6133sup1.cif
Contains datablocks global, I

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S1600536803004276/om6133Isup2.hkl
Contains datablock I

CCDC reference: 209913

Key indicators

  • Single-crystal X-ray study
  • T = 296 K
  • Mean [sigma](C-C) = 0.003 Å
  • R factor = 0.041
  • wR factor = 0.129
  • Data-to-parameter ratio = 15.2

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry








Comment top

We recently reported the preparation, isolation and unequivocal diastereomer identification of (1RS,2RS,5SR,6SR)-2,6-dimethyl-4-(4-methoxyphenyl)-5-ethyl-3-cyclohexene- 1-carboxylic acid, (III), and noted that a preliminary study indicated that it definitely inhibits prostate cancer-cell proliferation (Xie et al., 2002a). Further study of (III) and related compounds in prostate therapy is being continued. The preparation and potent in vivo estrogenicity of diastereomeric carboxylic acid mixtures of (III), as well as of related (IV), were reported some time ago (Nathan & Hogg, 1956; Crenshaw et al., 1972, 1973, 1974; Dvolaitzky et al., 1974; Fouquey et al., 1975, 1976, 1978). However, single diastereomers and enantiomers apparently were neither isolated nor unequivocally characterized (nor were their estrogen-receptor binding affinities studied; cf. Meyers et al., 1988); consequently, the observed biological activities could not be associated with any one absolute structure. Based on our unequivocal characterization of the single diastereomer (III) and our study showing its potential utility in prostate therapy, we decided to prepare and unequivocally characterize diastereomer (IV) and study its biological activity. In this way, we hoped to relate such activity with distereomeric structure.

Having prepared and characterized the required starting material (V) (Xie et al., 2002b), we proceeded to convert it into (IV) in a manner similar to our synthesis of (III) (Xie et al., 2002a). However, instead of obtaining the expected carboxylic acid, (IV), we obtained the corresponding kinetically favored bicyclic δ-lactone, (I), when the reaction mixture in 3 N HCl was worked up within several hours. On repeating the reaction but allowing the mixture to remain in the 3 N HCl for several days before being worked up, the thermodynamically favored isomeric bicyclic γ-lactone, (II), was obtained (Xie et al., 2003). These transformations are illustrated in the Scheme.

The structure and atom numbering of (I) are shown in Fig. 1. Lactone (I) is basically composed of an aromatic ring appended to a [2.2.2] bicyclic system. The O—C(O)—C group is asymmetric, its O—CO angle being 119.46 (19)° and its OC—C angle being 127.82 (19)°. The four atoms comprising the lactone moiety, C1/O2/C3/C4, are essentially coplanar, as evidenced by the torsion angle, and the least-squares plane of this moiety is nearly perpendicular to the cyclohexane ring, the angle formed being 89.29°. Selected geometric parameters are presented in Table 1.

Experimental top

Compound (I) was prepared by adding a solution of p-methoxyphenylmagnesium bromide in tetrahydrofuran (11 ml, 0.5 M, 5.5 mmol) dropwise over a period of 30 min to a stirred solution of keto acid (V) (0.207 g, 0.98 mmol; Xie et al., 2002b) in tetrahydrofuran (20 ml) which was flushed with argon and maintained in an ice bath. The mixture was stirred in the ice bath for an additional 30 min, then at room temperature for 2 h, and finally under reflux for 30 min. It was acidified with 3 N HCl and extracted with ether. The extracts were dried and concentrated in vacuo to a brown pasty solid to which benzene (5 ml) and p-TsOH·H2O (0.07 g) were added, and the solution was refluxed for 2 h. The benzene was then removed by evaporation, water was added and the mixture was extracted with ether. Evaporation of the extracts and purification of the residue chromatographically provided a major fraction which crystallized on removal of the solvent; pure (I), m.p. 388–388.8 K (recrystallized, CH2Cl2-hexane). This fraction was the most polar, indicating the absence of a carboxylic acid, e.g. (IV). IR (neat): 1753 cm−1; NMR (CDCl3), 1H (300 MHz): δ 0.82 (t, J = 7.2 Hz, 3H), 1.10 (m, J = 7.2 Hz, 2H), 1.12 (s, 3H), 1.15 (d, J = 6.6 Hz, 3H), 1.23 (s, 3H), 1.35 (m, J = 6.3 Hz, 1H), 1.82 (dd, J = 13.8 Hz, 1.8 Hz, 1H), 2.08 (m, J = 7.2 Hz, 1H), 2.13 (d, J = 1.8 Hz, 1H), 2.19 (d, J = 13.8 Hz, 1H), 3.81 (s, 3H), 6.88 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H); 13C (75 MHz): δ 12.39, 22.85, 24.65, 27.53, 32.02, 32.12, 32.23, 38.80, 53.50, 55.25, 55.83, 88.05, 113.42, 127.13, 133.31 (2 C), 159.12 (2 C), 175.89.

Refinement top

The rotational orientations of the methyl H atoms were refined by the circular Fourier method available in SHELXL97 (Sheldrick, 1997). All H atoms were refined as riding, with C—H distances ranging from 0.93 to 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 (Farrugia, 1997); software used to prepare material for publication: TEXSAN, SHELXL97 and PLATON (Spek, 2000).

Figures top
[Figure 1] Fig. 1. The molecular structure and atom-numbering scheme for (I), with displacement ellipsoids at the 30% probability level.
(±)-anti-7-Ethyl-1-(4-methoxyphenyl)-5,5,syn-8-trimethyl-2- oxabicyclo[2.2.2]octan-3-one top
Crystal data top
C19H26O3F(000) = 1312
Mr = 302.40Dx = 1.155 Mg m3
Monoclinic, C2/cMelting point = 388–388.8 K
Hall symbol: -C 2ycMo Kα radiation, λ = 0.71069 Å
a = 32.326 (4) ÅCell parameters from 25 reflections
b = 7.1937 (12) Åθ = 16.1–19.3°
c = 15.4134 (19) ŵ = 0.08 mm1
β = 104.022 (9)°T = 296 K
V = 3477.5 (9) Å3Irregular fragment, colorless
Z = 80.49 × 0.33 × 0.27 mm
Data collection top
Rigaku AFC-5S
diffractometer
Rint = 0.012
Radiation source: fine-focus sealed tubeθmax = 25.1°, θmin = 2.6°
Graphite monochromatorh = 038
ω scansk = 08
3156 measured reflectionsl = 1817
3098 independent reflections3 standard reflections every 100 reflections
1775 reflections with I > 2σ(I) intensity decay: 0.3%
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) = 0.129H-atom parameters constrained
S = 1.02 w = 1/[σ2(Fo2) + (0.0578P)2 + 1.278P]
where P = (Fo2 + 2Fc2)/3
3098 reflections(Δ/σ)max = 0.001
204 parametersΔρmax = 0.13 e Å3
0 restraintsΔρmin = 0.19 e Å3
Crystal data top
C19H26O3V = 3477.5 (9) Å3
Mr = 302.40Z = 8
Monoclinic, C2/cMo Kα radiation
a = 32.326 (4) ŵ = 0.08 mm1
b = 7.1937 (12) ÅT = 296 K
c = 15.4134 (19) Å0.49 × 0.33 × 0.27 mm
β = 104.022 (9)°
Data collection top
Rigaku AFC-5S
diffractometer
Rint = 0.012
3156 measured reflections3 standard reflections every 100 reflections
3098 independent reflections intensity decay: 0.3%
1775 reflections with I > 2σ(I)
Refinement top
R[F2 > 2σ(F2)] = 0.0410 restraints
wR(F2) = 0.129H-atom parameters constrained
S = 1.02Δρmax = 0.13 e Å3
3098 reflectionsΔρmin = 0.19 e Å3
204 parameters
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
O10.93871 (5)1.1412 (2)0.49181 (13)0.0736 (5)
O20.88085 (4)0.97256 (18)0.43861 (9)0.0461 (4)
O30.68514 (4)0.8026 (2)0.32443 (11)0.0666 (5)
C10.86610 (6)0.7784 (3)0.41856 (13)0.0392 (5)
C30.92363 (6)0.9899 (3)0.47143 (14)0.0492 (5)
C40.94654 (6)0.8088 (3)0.47569 (14)0.0465 (5)
C50.93708 (6)0.7320 (3)0.37866 (13)0.0461 (5)
C60.88812 (6)0.7053 (3)0.34840 (13)0.0454 (5)
C70.88039 (6)0.6711 (3)0.50733 (13)0.0431 (5)
C80.92946 (6)0.6819 (3)0.53923 (13)0.0463 (5)
C90.95205 (7)0.8732 (4)0.31840 (16)0.0709 (7)
C100.96094 (7)0.5495 (4)0.37558 (16)0.0660 (7)
C110.86319 (7)0.4719 (3)0.50172 (15)0.0550 (6)
C120.87329 (9)0.3698 (4)0.59109 (17)0.0769 (8)
C130.94435 (8)0.7514 (4)0.63569 (14)0.0714 (7)
C140.81795 (6)0.7904 (3)0.38787 (13)0.0415 (5)
C150.79488 (6)0.6831 (3)0.31862 (14)0.0529 (6)
C160.75064 (6)0.6822 (3)0.29586 (15)0.0565 (6)
C170.72884 (6)0.7921 (3)0.34206 (14)0.0479 (5)
C180.75103 (6)0.9034 (3)0.41006 (15)0.0541 (6)
C190.79494 (6)0.9019 (3)0.43308 (14)0.0496 (5)
C200.66146 (7)0.6837 (4)0.2573 (2)0.0888 (9)
H40.97730.82780.49860.056*
H6A0.87720.77060.29250.054*
H6B0.88170.57430.33820.054*
H70.86870.73690.55170.052*
H80.94100.55680.53610.056*
H9A0.98220.89220.33950.106*
H9B0.93750.98900.31970.106*
H9C0.94590.82690.25820.106*
H10A0.95580.50720.31480.099*
H10B0.95100.45760.41100.099*
H10C0.99090.56910.39900.099*
H11A0.83250.47530.47850.066*
H11B0.87520.40240.45970.066*
H12A0.90360.36020.61330.115*
H12B0.86110.24750.58300.115*
H12C0.86150.43740.63320.115*
H13A0.97490.75130.65320.107*
H13B0.93340.67110.67460.107*
H13C0.93400.87550.63970.107*
H150.80940.60920.28630.063*
H160.73590.60730.24940.068*
H180.73630.98020.44070.065*
H190.80950.97690.47970.060*
H20A0.66910.70730.20190.133*
H20B0.63160.70660.25000.133*
H20C0.66770.55660.27460.133*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0492 (9)0.0464 (10)0.1211 (15)0.0014 (8)0.0125 (9)0.0143 (10)
O20.0371 (7)0.0388 (8)0.0598 (9)0.0058 (6)0.0066 (6)0.0011 (7)
O30.0359 (8)0.0801 (12)0.0837 (12)0.0028 (8)0.0141 (8)0.0207 (9)
C10.0376 (10)0.0366 (11)0.0429 (11)0.0050 (9)0.0087 (8)0.0013 (9)
C30.0410 (11)0.0476 (13)0.0588 (13)0.0035 (10)0.0114 (10)0.0029 (11)
C40.0348 (10)0.0515 (13)0.0504 (12)0.0068 (9)0.0050 (9)0.0055 (10)
C50.0384 (10)0.0559 (13)0.0444 (11)0.0099 (10)0.0111 (9)0.0002 (10)
C60.0415 (11)0.0533 (13)0.0410 (11)0.0074 (9)0.0091 (9)0.0015 (10)
C70.0465 (11)0.0441 (12)0.0401 (11)0.0111 (9)0.0130 (9)0.0012 (9)
C80.0447 (11)0.0512 (13)0.0408 (11)0.0134 (9)0.0060 (9)0.0017 (9)
C90.0567 (14)0.095 (2)0.0650 (16)0.0025 (14)0.0215 (12)0.0108 (15)
C100.0558 (13)0.0811 (17)0.0585 (15)0.0255 (13)0.0089 (11)0.0162 (13)
C110.0589 (14)0.0470 (13)0.0602 (14)0.0067 (11)0.0166 (11)0.0046 (11)
C120.107 (2)0.0589 (16)0.0715 (17)0.0128 (15)0.0353 (15)0.0160 (14)
C130.0694 (15)0.094 (2)0.0448 (13)0.0064 (15)0.0018 (11)0.0072 (13)
C140.0385 (10)0.0439 (12)0.0419 (11)0.0042 (9)0.0096 (9)0.0016 (9)
C150.0428 (11)0.0564 (14)0.0597 (14)0.0066 (10)0.0128 (10)0.0157 (11)
C160.0431 (12)0.0582 (14)0.0641 (14)0.0010 (10)0.0048 (11)0.0188 (12)
C170.0377 (11)0.0512 (13)0.0555 (13)0.0018 (10)0.0123 (9)0.0003 (11)
C180.0425 (12)0.0634 (14)0.0587 (14)0.0065 (11)0.0167 (10)0.0128 (12)
C190.0442 (12)0.0574 (14)0.0464 (12)0.0030 (10)0.0092 (9)0.0101 (10)
C200.0412 (13)0.097 (2)0.121 (2)0.0087 (14)0.0064 (14)0.0348 (19)
Geometric parameters (Å, º) top
C3—C41.492 (3)C6—H6A0.9700
O2—C31.358 (2)C6—H6B0.9700
O2—C11.484 (2)C7—H70.9800
O1—C31.203 (3)C8—H80.9800
O3—C171.374 (2)C9—H9A0.9600
O3—C201.415 (3)C9—H9B0.9600
C1—C141.516 (2)C9—H9C0.9600
C1—C61.525 (2)C10—H10A0.9600
C1—C71.541 (3)C10—H10B0.9600
C4—C81.536 (3)C10—H10C0.9600
C4—C51.554 (3)C11—H11A0.9700
C5—C101.529 (3)C11—H11B0.9700
C5—C91.532 (3)C12—H12A0.9600
C5—C61.550 (3)C12—H12B0.9600
C7—C111.532 (3)C12—H12C0.9600
C7—C81.545 (3)C13—H13A0.9600
C8—C131.531 (3)C13—H13B0.9600
C11—C121.525 (3)C13—H13C0.9600
C14—C151.380 (3)C15—H150.9300
C14—C191.391 (3)C16—H160.9300
C15—C161.388 (3)C18—H180.9300
C16—C171.368 (3)C19—H190.9300
C17—C181.375 (3)C20—H20A0.9600
C18—C191.377 (3)C20—H20B0.9600
C4—H40.9800C20—H20C0.9600
O1—C3—C4127.82 (19)C8—C7—H7107.1
O2—C3—C4112.70 (18)C13—C8—H8108.3
C3—O2—C1114.24 (14)C4—C8—H8108.3
C17—O3—C20117.34 (18)C7—C8—H8108.3
O2—C1—C14105.38 (15)C5—C9—H9A109.5
O2—C1—C6106.89 (15)C5—C9—H9B109.5
C14—C1—C6114.76 (16)H9A—C9—H9B109.5
O2—C1—C7105.92 (15)C5—C9—H9C109.5
C14—C1—C7111.70 (16)H9A—C9—H9C109.5
C6—C1—C7111.48 (16)H9B—C9—H9C109.5
O1—C3—O2119.46 (19)C5—C10—H10A109.5
C3—C4—C8107.20 (16)C5—C10—H10B109.5
C3—C4—C5106.74 (17)H10A—C10—H10B109.5
C8—C4—C5112.66 (17)C5—C10—H10C109.5
C10—C5—C9108.34 (18)H10A—C10—H10C109.5
C10—C5—C6111.74 (18)H10B—C10—H10C109.5
C9—C5—C6110.44 (17)C12—C11—H11A108.8
C10—C5—C4110.60 (17)C7—C11—H11A108.8
C9—C5—C4109.30 (19)C12—C11—H11B108.8
C6—C5—C4106.40 (15)C7—C11—H11B108.8
C1—C6—C5111.22 (16)H11A—C11—H11B107.7
C11—C7—C1113.06 (16)C11—C12—H12A109.5
C11—C7—C8113.29 (16)C11—C12—H12B109.5
C1—C7—C8108.74 (16)H12A—C12—H12B109.5
C13—C8—C4110.36 (19)C11—C12—H12C109.5
C13—C8—C7112.48 (17)H12A—C12—H12C109.5
C4—C8—C7109.08 (16)H12B—C12—H12C109.5
C12—C11—C7113.8 (2)C8—C13—H13A109.5
C15—C14—C19117.12 (18)C8—C13—H13B109.5
C15—C14—C1122.07 (18)H13A—C13—H13B109.5
C19—C14—C1120.66 (18)C8—C13—H13C109.5
C14—C15—C16121.91 (19)H13A—C13—H13C109.5
C17—C16—C15119.7 (2)H13B—C13—H13C109.5
C16—C17—O3124.28 (19)C14—C15—H15119.0
C16—C17—C18119.60 (19)C16—C15—H15119.0
O3—C17—C18116.11 (18)C17—C16—H16120.2
C17—C18—C19120.45 (19)C15—C16—H16120.2
C18—C19—C14121.2 (2)C17—C18—H18119.8
C3—C4—H4110.0C19—C18—H18119.8
C8—C4—H4110.0C18—C19—H19119.4
C5—C4—H4110.0C14—C19—H19119.4
C1—C6—H6A109.4O3—C20—H20A109.5
C5—C6—H6A109.4O3—C20—H20B109.5
C1—C6—H6B109.4H20A—C20—H20B109.5
C5—C6—H6B109.4O3—C20—H20C109.5
H6A—C6—H6B108.0H20A—C20—H20C109.5
C11—C7—H7107.1H20B—C20—H20C109.5
C1—C7—H7107.1
C1—O2—C3—C42.8 (2)C6—C1—C7—C855.9 (2)
C6—C1—C14—C19161.08 (19)C3—C4—C8—C1369.8 (2)
C6—C1—C14—C1523.4 (3)C5—C4—C8—C13173.08 (17)
C3—O2—C1—C14177.14 (16)C3—C4—C8—C754.3 (2)
C3—O2—C1—C660.3 (2)C5—C4—C8—C762.9 (2)
C3—O2—C1—C758.64 (19)C11—C7—C8—C13106.0 (2)
C1—O2—C3—O1178.3 (2)C1—C7—C8—C13127.4 (2)
O1—C3—C4—C8119.8 (3)C11—C7—C8—C4131.24 (18)
O2—C3—C4—C861.4 (2)C1—C7—C8—C44.6 (2)
O1—C3—C4—C5119.2 (3)C1—C7—C11—C12174.30 (18)
O2—C3—C4—C559.6 (2)C8—C7—C11—C1261.4 (2)
C3—C4—C5—C10177.53 (17)O2—C1—C14—C15140.74 (19)
C8—C4—C5—C1065.1 (2)C7—C1—C14—C15104.7 (2)
C3—C4—C5—C958.3 (2)O2—C1—C14—C1943.8 (2)
C8—C4—C5—C9175.72 (16)C7—C1—C14—C1970.8 (2)
C3—C4—C5—C660.9 (2)C19—C14—C15—C161.4 (3)
C8—C4—C5—C656.5 (2)C1—C14—C15—C16174.2 (2)
O2—C1—C6—C552.9 (2)C14—C15—C16—C170.9 (4)
C14—C1—C6—C5169.39 (17)C15—C16—C17—O3179.4 (2)
C7—C1—C6—C562.4 (2)C15—C16—C17—C180.6 (3)
C10—C5—C6—C1126.04 (19)C20—O3—C17—C163.7 (3)
C9—C5—C6—C1113.3 (2)C20—O3—C17—C18177.4 (2)
C4—C5—C6—C15.2 (2)C16—C17—C18—C191.4 (3)
O2—C1—C7—C11173.22 (15)O3—C17—C18—C19179.6 (2)
C14—C1—C7—C1159.0 (2)C17—C18—C19—C140.8 (4)
C6—C1—C7—C1170.9 (2)C15—C14—C19—C180.6 (3)
O2—C1—C7—C860.04 (18)C1—C14—C19—C18175.1 (2)
C14—C1—C7—C8174.26 (16)

Experimental details

Crystal data
Chemical formulaC19H26O3
Mr302.40
Crystal system, space groupMonoclinic, C2/c
Temperature (K)296
a, b, c (Å)32.326 (4), 7.1937 (12), 15.4134 (19)
β (°) 104.022 (9)
V3)3477.5 (9)
Z8
Radiation typeMo Kα
µ (mm1)0.08
Crystal size (mm)0.49 × 0.33 × 0.27
Data collection
DiffractometerRigaku AFC-5S
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
3156, 3098, 1775
Rint0.012
(sin θ/λ)max1)0.596
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.041, 0.129, 1.02
No. of reflections3098
No. of parameters204
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.13, 0.19

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 (Farrugia, 1997), TEXSAN, SHELXL97 and PLATON (Spek, 2000).

Selected bond and torsion angles (º) top
O1—C3—C4127.82 (19)C3—O2—C1114.24 (14)
O2—C3—C4112.70 (18)
C1—O2—C3—C42.8 (2)C6—C1—C14—C1523.4 (3)
C6—C1—C14—C19161.08 (19)
 

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