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The title compound, C12H20O3, (IV), the ethyl ester of which is an intermediate in the synthesis of a compound reported to be highly estrogenic, has been prepared. After the initial steps reported for the synthesis of this ester intermediate were followed, it was converted into the crystalline acid, (IV), for X-ray analysis. It was verified that (IV) was racemic when prepared. X-ray analysis showed that anti-hydrogenation of the double bond had occurred in the synthesis, making the orientation of the carboxyl group cis to the 2-methyl group and trans to the 3-ethyl group. NMR spectroscopy showed that the stereochemistry of (IV) was identical with that of its ester precursor. While the earlier report did not note the stereochemistry of this ester, it pointed out that the estrogenic product derived from it possessed the opposite carboxyl-2-methyl orientation, i.e. trans, although no X-ray analysis was performed. In the light of these results and the importance of correlating biological activity with compound structure, the unequivocal characterization of the highly estrogenic compound is warranted.
Supporting information
CCDC reference: 183004
Compound (I) was synthesized following the method reported by Surmatis et
al. (1970) and converted sequentially into compounds (II) and (III), as
reported by Crenshaw et al. (1974). Via hydrolysis in refluxing 48% HBr
containing a catalytic amount of (n-Bu)4NBr, we converted (III) into (IV).
White crystals of (IV) were recrystallized twice from hexane (m.p.
394.8–396.2 K). 1H NMR (CDCl3, δ, p.p.m.): 0.881 (t, J = 7.5 Hz, 3H),
0.986 (s, 3H), 1.096 (s, 3H), 1.123 (d, J = 6.9 Hz, 3H), 1.512 (m, 1H), 1.710
(m, 1H), 1.984 (dd, J = 13.5 and 1.8 Hz, 1H), 2.158 (m, 1H), 2.479 (dd, J =
4.5 and 1.5 Hz, 1H), 2.657 (m, 1H), 2.963 (d, J = 13.8 Hz, 1H); 13C NMR
(CDCl3, δ, p.p.m.): 10.51, 17.65, 17.88, 27.87, 28.83, 33.39, 36.44, 50.26,
50.93, 56.67, 179.66, 220.97. The determination of the racemic nature of (IV)
as prepared was conducted as follows: (i) an absolute ethanol solution of
0.046 mol l-1 of (IV), as prepared, exhibited an optical rotation of 0.0;
(ii) the 1H NMR (CDCl3) resonance of H5 cis to the carboxyl of
(IV), as prepared, δ 2.963 (d), became δ 3.032 (d) and δ
2.997 (d) in an approximately equimolar solution with
(S)-(-)-1-phenylethylamine (Aldrich); (iii) likewise, the resonance of
H5 trans to carboxyl, δ 1.984 (dd), became δ 1.897 and δ 1.863 in
the same solution with (S)-(-)-1-phenylethylamine.
The absolute configuration of the molecule could not be determined because of
the lack of heavy atoms. The rotational orientations of the methyl and
hydroxyl H atoms were refined by the circular Fourier method available in
SHELXL97 (Sheldrick, 1997). All H atoms were treated as riding, with
C—H = 0.96–0.98 Å and O—H = 0.82 Å. Are these the correct
constraints?
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, 1989); program(s) used to refine structure: LS in TEXSAN and SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-III (Farrugia, 1997); software used to prepare material for publication: TEXSAN, SHELXL97 and PLATON (Spek, 2000).
2-
cis-3-
trans-3-Ethyl-2,6,6-trimethyl-4-oxocyclohexanecarboxylic
acid
top
Crystal data top
C12H20O3 | Dx = 1.173 Mg m−3 |
Mr = 212.28 | Melting point = 394.8–396.2 K |
Orthorhombic, P212121 | Mo Kα radiation, λ = 0.71069 Å |
Hall symbol: P 2ac 2ab | Cell parameters from 25 reflections |
a = 13.716 (3) Å | θ = 9.6–9.9° |
b = 14.103 (3) Å | µ = 0.08 mm−1 |
c = 6.214 (4) Å | T = 296 K |
V = 1202.0 (9) Å3 | Irregular fragment, colorless |
Z = 4 | 0.41 × 0.33 × 0.27 mm |
F(000) = 464 | |
Data collection top
Rigaku AFC-5S diffractometer | Rint = 0.025 |
Radiation source: fine-focus sealed tube | θmax = 25.1°, θmin = 2.1° |
Graphite monochromator | h = 0→16 |
ω scans | k = 0→16 |
2313 measured reflections | l = −7→7 |
1265 independent reflections | 3 standard reflections every 100 reflections |
890 reflections with I > 2σ(I) | intensity decay: 0.7% |
Refinement top
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.034 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.092 | H-atom parameters constrained |
S = 1.03 | w = 1/[σ2(Fo2) + (0.0509P)2] where P = (Fo2 + 2Fc2)/3 |
1265 reflections | (Δ/σ)max < 0.001 |
141 parameters | Δρmax = 0.10 e Å−3 |
0 restraints | Δρmin = −0.13 e Å−3 |
Crystal data top
C12H20O3 | V = 1202.0 (9) Å3 |
Mr = 212.28 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 13.716 (3) Å | µ = 0.08 mm−1 |
b = 14.103 (3) Å | T = 296 K |
c = 6.214 (4) Å | 0.41 × 0.33 × 0.27 mm |
Data collection top
Rigaku AFC-5S diffractometer | Rint = 0.025 |
2313 measured reflections | 3 standard reflections every 100 reflections |
1265 independent reflections | intensity decay: 0.7% |
890 reflections with I > 2σ(I) | |
Refinement top
R[F2 > 2σ(F2)] = 0.034 | 0 restraints |
wR(F2) = 0.092 | H-atom parameters constrained |
S = 1.03 | Δρmax = 0.10 e Å−3 |
1265 reflections | Δρmin = −0.13 e Å−3 |
141 parameters | |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
O1 | 0.00322 (19) | 0.46507 (17) | 0.8007 (3) | 0.0866 (8) | |
O2 | 0.11705 (15) | 0.37785 (12) | 0.6441 (3) | 0.0640 (5) | |
O3 | −0.11480 (14) | 0.74515 (12) | 0.5400 (3) | 0.0668 (6) | |
C1 | 0.06744 (18) | 0.51509 (15) | 0.4579 (4) | 0.0396 (6) | |
C2 | −0.02975 (17) | 0.52046 (15) | 0.3359 (4) | 0.0396 (6) | |
C3 | −0.10728 (17) | 0.58157 (16) | 0.4493 (4) | 0.0406 (6) | |
C4 | −0.06654 (17) | 0.67269 (17) | 0.5414 (4) | 0.0421 (6) | |
C5 | 0.03150 (17) | 0.66974 (18) | 0.6450 (5) | 0.0499 (6) | |
C6 | 0.10828 (17) | 0.61406 (17) | 0.5165 (4) | 0.0439 (6) | |
C7 | 0.05804 (19) | 0.45200 (17) | 0.6528 (4) | 0.0477 (6) | |
C8 | −0.0684 (2) | 0.42062 (17) | 0.2848 (5) | 0.0583 (8) | |
C9 | −0.19889 (18) | 0.59936 (19) | 0.3139 (5) | 0.0572 (7) | |
C10 | −0.1801 (2) | 0.6456 (2) | 0.0973 (5) | 0.0725 (9) | |
C11 | 0.20128 (19) | 0.6041 (2) | 0.6514 (5) | 0.0632 (8) | |
C12 | 0.13336 (19) | 0.66809 (18) | 0.3110 (5) | 0.0565 (7) | |
H1 | 0.1148 | 0.4851 | 0.3613 | 0.047* | |
H2 | 0.1075 | 0.3438 | 0.7489 | 0.096* | |
H2A | −0.0160 | 0.5510 | 0.1976 | 0.048* | |
H3 | −0.1290 | 0.5443 | 0.5735 | 0.049* | |
H5A | 0.0251 | 0.6413 | 0.7864 | 0.060* | |
H5B | 0.0545 | 0.7342 | 0.6646 | 0.060* | |
H8A | −0.0890 | 0.3904 | 0.4155 | 0.087* | |
H8B | −0.0177 | 0.3838 | 0.2189 | 0.087* | |
H8C | −0.1227 | 0.4254 | 0.1880 | 0.087* | |
H9A | −0.2315 | 0.5392 | 0.2902 | 0.069* | |
H9B | −0.2429 | 0.6394 | 0.3955 | 0.069* | |
H10A | −0.1438 | 0.7031 | 0.1177 | 0.109* | |
H10B | −0.2412 | 0.6600 | 0.0292 | 0.109* | |
H10C | −0.1435 | 0.6030 | 0.0078 | 0.109* | |
H11A | 0.2489 | 0.5686 | 0.5719 | 0.095* | |
H11B | 0.1864 | 0.5716 | 0.7830 | 0.095* | |
H11C | 0.2267 | 0.6659 | 0.6836 | 0.095* | |
H12A | 0.1668 | 0.7257 | 0.3474 | 0.085* | |
H12B | 0.0745 | 0.6830 | 0.2346 | 0.085* | |
H12C | 0.1746 | 0.6296 | 0.2218 | 0.085* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
O1 | 0.1171 (18) | 0.0871 (15) | 0.0557 (12) | 0.0325 (14) | 0.0391 (15) | 0.0269 (13) |
O2 | 0.0734 (12) | 0.0458 (10) | 0.0728 (12) | 0.0116 (10) | 0.0072 (12) | 0.0237 (10) |
O3 | 0.0666 (12) | 0.0465 (10) | 0.0873 (14) | 0.0195 (10) | −0.0200 (12) | −0.0267 (11) |
C1 | 0.0448 (13) | 0.0340 (12) | 0.0400 (12) | 0.0035 (10) | 0.0100 (12) | 0.0020 (11) |
C2 | 0.0499 (14) | 0.0321 (12) | 0.0368 (12) | −0.0037 (10) | 0.0073 (12) | −0.0021 (11) |
C3 | 0.0445 (13) | 0.0389 (12) | 0.0384 (12) | −0.0044 (11) | 0.0052 (12) | −0.0028 (11) |
C4 | 0.0453 (13) | 0.0421 (13) | 0.0391 (12) | 0.0042 (12) | 0.0015 (12) | −0.0084 (11) |
C5 | 0.0550 (15) | 0.0428 (13) | 0.0519 (14) | 0.0016 (12) | −0.0103 (14) | −0.0108 (13) |
C6 | 0.0401 (13) | 0.0410 (13) | 0.0506 (15) | 0.0008 (11) | −0.0019 (12) | 0.0027 (12) |
C7 | 0.0565 (15) | 0.0378 (13) | 0.0488 (15) | 0.0035 (12) | 0.0028 (15) | 0.0059 (13) |
C8 | 0.0736 (18) | 0.0403 (14) | 0.0611 (16) | −0.0112 (14) | 0.0075 (16) | −0.0137 (14) |
C9 | 0.0419 (14) | 0.0549 (16) | 0.075 (2) | −0.0084 (12) | −0.0026 (15) | −0.0121 (16) |
C10 | 0.0670 (19) | 0.085 (2) | 0.066 (2) | 0.0071 (16) | −0.0192 (16) | −0.0026 (18) |
C11 | 0.0499 (15) | 0.0621 (17) | 0.078 (2) | −0.0011 (13) | −0.0132 (16) | 0.0091 (17) |
C12 | 0.0535 (15) | 0.0485 (14) | 0.0674 (18) | −0.0076 (13) | 0.0043 (15) | 0.0150 (15) |
Geometric parameters (Å, º) top
O1—C7 | 1.201 (3) | C3—H3 | 0.9800 |
O2—C7 | 1.323 (3) | C5—H5A | 0.9700 |
O3—C4 | 1.218 (3) | C5—H5B | 0.9700 |
C1—C7 | 1.509 (4) | C8—H8A | 0.9600 |
C1—C2 | 1.535 (3) | C8—H8B | 0.9600 |
C1—C6 | 1.547 (3) | C8—H8C | 0.9600 |
C2—C8 | 1.538 (3) | C9—H9A | 0.9700 |
C2—C3 | 1.539 (3) | C9—H9B | 0.9700 |
C3—C4 | 1.514 (3) | C10—H10A | 0.9600 |
C3—C9 | 1.533 (4) | C10—H10B | 0.9600 |
C4—C5 | 1.491 (3) | C10—H10C | 0.9600 |
C5—C6 | 1.537 (3) | C11—H11A | 0.9600 |
C6—C12 | 1.526 (4) | C11—H11B | 0.9600 |
C6—C11 | 1.533 (4) | C11—H11C | 0.9600 |
C9—C10 | 1.518 (4) | C12—H12A | 0.9600 |
O2—H2 | 0.8200 | C12—H12B | 0.9600 |
C1—H1 | 0.9800 | C12—H12C | 0.9600 |
C2—H2A | 0.9800 | | |
| | | |
C7—C1—C2 | 110.56 (19) | C6—C5—H5A | 108.7 |
C7—C1—C6 | 112.0 (2) | C4—C5—H5B | 108.7 |
C2—C1—C6 | 112.71 (19) | C6—C5—H5B | 108.7 |
C1—C2—C8 | 110.9 (2) | H5A—C5—H5B | 107.6 |
C1—C2—C3 | 113.67 (19) | C2—C8—H8A | 109.5 |
C8—C2—C3 | 111.7 (2) | C2—C8—H8B | 109.5 |
C4—C3—C9 | 111.8 (2) | H8A—C8—H8B | 109.5 |
C4—C3—C2 | 113.16 (19) | C2—C8—H8C | 109.5 |
C9—C3—C2 | 114.0 (2) | H8A—C8—H8C | 109.5 |
O3—C4—C5 | 121.1 (2) | H8B—C8—H8C | 109.5 |
O3—C4—C3 | 120.6 (2) | C10—C9—H9A | 108.6 |
C5—C4—C3 | 118.2 (2) | C3—C9—H9A | 108.6 |
C4—C5—C6 | 114.1 (2) | C10—C9—H9B | 108.6 |
C12—C6—C11 | 108.4 (2) | C3—C9—H9B | 108.6 |
C12—C6—C5 | 109.5 (2) | H9A—C9—H9B | 107.6 |
C11—C6—C5 | 109.4 (2) | C9—C10—H10A | 109.5 |
C12—C6—C1 | 109.6 (2) | C9—C10—H10B | 109.5 |
C11—C6—C1 | 110.33 (19) | H10A—C10—H10B | 109.5 |
C5—C6—C1 | 109.57 (19) | C9—C10—H10C | 109.5 |
O1—C7—O2 | 122.4 (2) | H10A—C10—H10C | 109.5 |
O1—C7—C1 | 125.2 (2) | H10B—C10—H10C | 109.5 |
O2—C7—C1 | 112.4 (2) | C6—C11—H11A | 109.5 |
C10—C9—C3 | 114.7 (2) | C6—C11—H11B | 109.5 |
C7—O2—H2 | 109.5 | H11A—C11—H11B | 109.5 |
C7—C1—H1 | 107.1 | C6—C11—H11C | 109.5 |
C2—C1—H1 | 107.1 | H11A—C11—H11C | 109.5 |
C6—C1—H1 | 107.1 | H11B—C11—H11C | 109.5 |
C1—C2—H2A | 106.7 | C6—C12—H12A | 109.5 |
C8—C2—H2A | 106.7 | C6—C12—H12B | 109.5 |
C3—C2—H2A | 106.7 | H12A—C12—H12B | 109.5 |
C4—C3—H3 | 105.7 | C6—C12—H12C | 109.5 |
C9—C3—H3 | 105.7 | H12A—C12—H12C | 109.5 |
C2—C3—H3 | 105.7 | H12B—C12—H12C | 109.5 |
C4—C5—H5A | 108.7 | | |
| | | |
C7—C1—C2—C8 | −52.8 (3) | C4—C5—C6—C11 | −172.3 (2) |
C6—C1—C2—C8 | −179.0 (2) | C4—C5—C6—C1 | −51.2 (3) |
C7—C1—C2—C3 | 73.9 (2) | C7—C1—C6—C12 | 169.9 (2) |
C6—C1—C2—C3 | −52.2 (2) | C2—C1—C6—C12 | −64.7 (3) |
C1—C2—C3—C4 | 42.3 (3) | C7—C1—C6—C11 | 50.6 (3) |
C8—C2—C3—C4 | 168.6 (2) | C2—C1—C6—C11 | 176.0 (2) |
C1—C2—C3—C9 | 171.5 (2) | C7—C1—C6—C5 | −69.9 (2) |
C8—C2—C3—C9 | −62.2 (3) | C2—C1—C6—C5 | 55.4 (3) |
C9—C3—C4—O3 | 13.9 (3) | C2—C1—C7—O1 | −60.5 (3) |
C2—C3—C4—O3 | 144.2 (3) | C6—C1—C7—O1 | 66.0 (3) |
C9—C3—C4—C5 | −169.7 (2) | C2—C1—C7—O2 | 118.7 (2) |
C2—C3—C4—C5 | −39.4 (3) | C6—C1—C7—O2 | −114.7 (2) |
O3—C4—C5—C6 | −138.6 (3) | C4—C3—C9—C10 | 73.0 (3) |
C3—C4—C5—C6 | 44.9 (3) | C2—C3—C9—C10 | −56.9 (3) |
C4—C5—C6—C12 | 69.0 (3) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
O2—H2···O3i | 0.82 | 1.91 | 2.712 (3) | 164 |
Symmetry code: (i) −x, y−1/2, −z+3/2. |
Experimental details
Crystal data |
Chemical formula | C12H20O3 |
Mr | 212.28 |
Crystal system, space group | Orthorhombic, P212121 |
Temperature (K) | 296 |
a, b, c (Å) | 13.716 (3), 14.103 (3), 6.214 (4) |
V (Å3) | 1202.0 (9) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.08 |
Crystal size (mm) | 0.41 × 0.33 × 0.27 |
|
Data collection |
Diffractometer | Rigaku AFC-5S diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 2313, 1265, 890 |
Rint | 0.025 |
(sin θ/λ)max (Å−1) | 0.596 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.034, 0.092, 1.03 |
No. of reflections | 1265 |
No. of parameters | 141 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.10, −0.13 |
Selected geometric parameters (Å, º) topC2—C8 | 1.538 (3) | C6—C12 | 1.526 (4) |
C3—C9 | 1.533 (4) | C6—C11 | 1.533 (4) |
| | | |
C7—C1—C2 | 110.56 (19) | C9—C3—C2 | 114.0 (2) |
C1—C2—C8 | 110.9 (2) | C12—C6—C1 | 109.6 (2) |
C8—C2—C3 | 111.7 (2) | C11—C6—C1 | 110.33 (19) |
C4—C3—C9 | 111.8 (2) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
O2—H2···O3i | 0.82 | 1.91 | 2.712 (3) | 164 |
Symmetry code: (i) −x, y−1/2, −z+3/2. |
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Some years ago, Crenshaw et al. (1974) reported syntheses of a series of p-methoxyphenylalkylcyclohexanecarboxylic and -cyclohexenecarboxylic acids, some of which they found to be highly estrogenic. Although they showed these compounds to be uterotropically potent, they presumed them to possess high estrogen-receptor binding affinity as well, but they did not test this property. In contrast, our more recent studies of estrogenic carboxylic acids have revealed that they exhibit the paradox of high uterotropic activity with very poor binding affinity for estrogen receptors (Meyers et al., 1988, 1997, 2000; Banz et al., 1998; Robinson et al., 1999; Hou & Meyers, 2000), hence our interest in preparing the Crenshaw compounds, unequivocally determining their structures and correlating them with their uterotropic activities and estrogen-receptor binding affinities. The structure of one of these, the title compound, (IV), is presented here. \sch
The syntheses are shown in the Scheme. We repeated the methods used by Crenshaw et al. (1974) to prepare the initial ester intermediates (I), (II) and (III), then hydrolyzed ester (III) with aqueous HBr to give (IV). The Crenshaw group treated (III) with a Grignard reagent and hydrolyzed the product under acidic conditions to provide their carboxylic acid estrogen, (V), also shown in the Scheme. Unlike ester (III), an oil, the corresponding carboxylic acid, (IV) is crystalline, permitting its diastereomeric structure to be unequivocally characterized by X-ray analysis.
The structure of (IV) is shown in Fig. 1. The space group for this chiral structure is P212121. However, (IV) was racemic when prepared by polarimetric analysis as well as by 1H NMR shift analysis in the presence of a chiral amine. Thus, either the crystal used is the result of spontaneous resolution which produced a mechanical mixture of pure enantiomers (a `conglomerate'; Jacques et al., 1981), or it is an inversion twin (Flack & Bernardinelli, 1999). The latter choice is the more common but we cannot be sure, since the Flack parameter cannot discriminate in this case (Flack & Bernardinelli, 2000).
Fig. 1 shows the trans orientation of the C2 methyl group with respect to the C3 ethyl group, indicating that antihydrogenation of the double bond has occurred in converting (II) to (III), which is also responsible for the cis orientation of the C1 carboxyl group with respect to the C2 methyl group, likewise clearly exhibited. The stereochemistry of ester (III) is the same as that of its carboxylic acid, (IV), as ascertained from their virtually identical 1H and 13C NMR spectra, the only differences being the resonances of their different carboxyl groups.
The Crenshaw report provided no geometric characterization for their ester (III). In the absence of an unforseen isomerization, it is reasonable to believe that their Grignard reaction at the carbonyl group of (III), followed by acidification, dehydration to form the C3═C4 double bond, and ester hydrolysis, would provide estrogenic carboxylic acid (V) without altering the cis orientation of the C1 carboxyl group with respect to the C2 methyl group. However, on the basis of the NMR H1—H2 coupling constant exhibited by (V), they reported a trans orientation for the C1 carboxyl with respect to the C2 methyl. No X-ray crystal-structure analysis was reported. In the light of these results and the importance of correlating biological activity with compound structure, X-ray characterization of crystalline (V) is warranted so that the structure can be correlated with its uterotropic activity and receptor-binding affinity.
Fig. 1 also shows that (IV) has the chair conformation, in which the C1 carboxyl group is axial and the C2 methyl group equatorial, providing the cis configurations of these groups, while the C3 ethyl group is also equatorial, making it trans to both of these groups. Thus, the C6—C1—C2—C8 torsion angle subtended by the C2 methyl group with the ring is essentially linear [-179.0 (2)°], while the C1—C2—C3—C9 torsion angle subtended by the C3 ethyl group with the ring is somewhat less than linear [171.5 (2)°].
Bond distances and angles of interest are given in Table 1. It is noted that, while the angle subtended by the ring with all but one of the substituents is between 109.6 (2) and 111.8 (2)°, that involving the C3 ethyl group, C2—C3—C9, is 114.0 (2)°, suggesting a steric repulsion between this equatorial group and the vicinal equatorial C2 methyl group.
The molecular packing (Fig. 2) shows that the molecules of (IV) form infinite one-dimensional chains parallel to the b axis via intermolecular hydrogen bonding between the carbonyl O atom and the carboxyl H atom. Table 2 lists the hydrogen-bond geometry.