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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
CCDC reference: 202365
Key indicators
- Single-crystal X-ray study
- T = 296 K
- Mean (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
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.
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.
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.
2(
S),6(
R)-Dimethyl-4-(4-methoxyphenyl)-5(
R)-ethyl-3-cyclohexene-1(S)- carboxylic acid
top
Crystal data top
C18H24O3 | Dx = 1.191 Mg m−3 |
Mr = 288.37 | Melting point = 462–463 K |
Monoclinic, P21/c | Mo Kα radiation, λ = 0.71069 Å |
a = 15.789 (4) Å | Cell parameters from 25 reflections |
b = 11.680 (5) Å | θ = 7.8–12.4° |
c = 8.7260 (13) Å | µ = 0.08 mm−1 |
β = 92.296 (16)° | T = 296 K |
V = 1607.9 (8) Å3 | Plate, colorless |
Z = 4 | 0.49 × 0.40 × 0.07 mm |
F(000) = 624 | |
Data collection top
Rigaku AFC-5S diffractometer | Rint = 0.020 |
Radiation source: fine-focus sealed tube | θmax = 25.0°, θmin = 2.2° |
Graphite monochromator | h = −18→18 |
ω scans | k = −13→0 |
3052 measured reflections | l = 0→10 |
2846 independent reflections | 3 standard reflections every 100 reflections |
1176 reflections with I > 2σ(I) | intensity decay: 0.6% |
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)] = 0.041 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.134 | H-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 parameters | Δρmax = 0.15 e Å−3 |
0 restraints | Δρmin = −0.16 e Å−3 |
Crystal data top
C18H24O3 | V = 1607.9 (8) Å3 |
Mr = 288.37 | Z = 4 |
Monoclinic, P21/c | Mo Kα radiation |
a = 15.789 (4) Å | µ = 0.08 mm−1 |
b = 11.680 (5) Å | T = 296 K |
c = 8.7260 (13) Å | 0.49 × 0.40 × 0.07 mm |
β = 92.296 (16)° | |
Data collection top
Rigaku AFC-5S diffractometer | Rint = 0.020 |
3052 measured reflections | 3 standard reflections every 100 reflections |
2846 independent reflections | intensity decay: 0.6% |
1176 reflections with I > 2σ(I) | |
Refinement top
R[F2 > 2σ(F2)] = 0.041 | 0 restraints |
wR(F2) = 0.134 | H-atom parameters constrained |
S = 0.98 | Δρmax = 0.15 e Å−3 |
2846 reflections | Δρmin = −0.16 e Å−3 |
195 parameters | |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
O1 | 0.59837 (12) | 0.5134 (2) | 0.9390 (2) | 0.0736 (6) | |
O2 | 0.48139 (11) | 0.4822 (2) | 0.7958 (2) | 0.0724 (6) | |
O3 | 0.94972 (12) | 0.37828 (17) | −0.0428 (2) | 0.0675 (6) | |
C1 | 0.61134 (16) | 0.4837 (2) | 0.6693 (3) | 0.0493 (7) | |
C2 | 0.66638 (16) | 0.3752 (2) | 0.6803 (3) | 0.0521 (7) | |
C3 | 0.72318 (19) | 0.3711 (3) | 0.5474 (3) | 0.0660 (9) | |
C4 | 0.74337 (16) | 0.4630 (2) | 0.4603 (3) | 0.0485 (7) | |
C5 | 0.71114 (19) | 0.5788 (2) | 0.4916 (3) | 0.0651 (9) | |
C6 | 0.66475 (17) | 0.5907 (2) | 0.6414 (3) | 0.0544 (7) | |
C7 | 0.56272 (16) | 0.4944 (2) | 0.8132 (3) | 0.0532 (7) | |
C8 | 0.61404 (19) | 0.2663 (2) | 0.6885 (4) | 0.0752 (10) | |
C9 | 0.77451 (19) | 0.6755 (2) | 0.4646 (4) | 0.0675 (9) | |
C10 | 0.8538 (2) | 0.6723 (3) | 0.5658 (4) | 0.0953 (12) | |
C11 | 0.6105 (2) | 0.6984 (2) | 0.6412 (4) | 0.0828 (10) | |
C12 | 0.79716 (17) | 0.4435 (2) | 0.3260 (3) | 0.0482 (7) | |
C13 | 0.77580 (17) | 0.4883 (3) | 0.1826 (3) | 0.0568 (7) | |
C14 | 0.82397 (18) | 0.4687 (2) | 0.0564 (3) | 0.0591 (8) | |
C15 | 0.89596 (18) | 0.4020 (2) | 0.0726 (3) | 0.0535 (7) | |
C16 | 0.91827 (17) | 0.3562 (2) | 0.2135 (3) | 0.0591 (8) | |
C17 | 0.86964 (17) | 0.3765 (2) | 0.3384 (3) | 0.0567 (7) | |
C18 | 0.9315 (2) | 0.4320 (3) | −0.1879 (3) | 0.0801 (10) | |
H1 | 0.5705 | 0.4747 | 0.5825 | 0.059* | |
H2 | 0.4605 | 0.4781 | 0.8802 | 0.109* | |
H2A | 0.7022 | 0.3803 | 0.7744 | 0.063* | |
H3 | 0.7464 | 0.3007 | 0.5225 | 0.079* | |
H5 | 0.6666 | 0.5906 | 0.4116 | 0.078* | |
H6 | 0.7075 | 0.5970 | 0.7255 | 0.065* | |
H8A | 0.5769 | 0.2607 | 0.5990 | 0.113* | |
H8B | 0.5810 | 0.2682 | 0.7785 | 0.113* | |
H8C | 0.6511 | 0.2011 | 0.6933 | 0.113* | |
H9A | 0.7905 | 0.6727 | 0.3585 | 0.081* | |
H9B | 0.7463 | 0.7482 | 0.4800 | 0.081* | |
H10A | 0.8390 | 0.6752 | 0.6714 | 0.143* | |
H10B | 0.8889 | 0.7368 | 0.5433 | 0.143* | |
H10C | 0.8842 | 0.6027 | 0.5474 | 0.143* | |
H11A | 0.6458 | 0.7643 | 0.6279 | 0.124* | |
H11B | 0.5829 | 0.7043 | 0.7370 | 0.124* | |
H11C | 0.5685 | 0.6946 | 0.5587 | 0.124* | |
H13 | 0.7273 | 0.5331 | 0.1708 | 0.068* | |
H14 | 0.8081 | 0.5002 | −0.0383 | 0.071* | |
H16 | 0.9666 | 0.3111 | 0.2247 | 0.071* | |
H17 | 0.8858 | 0.3447 | 0.4328 | 0.068* | |
H18A | 0.8789 | 0.4030 | −0.2311 | 0.120* | |
H18B | 0.9762 | 0.4157 | −0.2560 | 0.120* | |
H18C | 0.9271 | 0.5132 | −0.1739 | 0.120* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
O1 | 0.0561 (12) | 0.1116 (18) | 0.0530 (13) | −0.0050 (13) | 0.0007 (10) | −0.0121 (13) |
O2 | 0.0464 (12) | 0.1056 (18) | 0.0654 (13) | −0.0027 (12) | 0.0057 (10) | −0.0078 (14) |
O3 | 0.0750 (13) | 0.0661 (14) | 0.0625 (14) | −0.0069 (11) | 0.0178 (11) | −0.0052 (11) |
C1 | 0.0427 (14) | 0.0525 (17) | 0.0527 (16) | 0.0013 (14) | 0.0002 (12) | −0.0016 (14) |
C2 | 0.0504 (16) | 0.0521 (18) | 0.0540 (17) | 0.0014 (14) | 0.0043 (14) | 0.0031 (14) |
C3 | 0.078 (2) | 0.052 (2) | 0.069 (2) | 0.0118 (16) | 0.0208 (17) | 0.0048 (17) |
C4 | 0.0428 (15) | 0.0475 (18) | 0.0551 (17) | −0.0003 (13) | 0.0014 (13) | −0.0013 (14) |
C5 | 0.076 (2) | 0.0499 (19) | 0.070 (2) | −0.0028 (17) | 0.0193 (17) | −0.0003 (15) |
C6 | 0.0573 (17) | 0.0482 (17) | 0.0578 (18) | 0.0027 (15) | 0.0042 (14) | −0.0031 (14) |
C7 | 0.0449 (16) | 0.0537 (19) | 0.0611 (19) | 0.0008 (15) | 0.0021 (14) | −0.0019 (16) |
C8 | 0.078 (2) | 0.058 (2) | 0.091 (3) | −0.0069 (18) | 0.0125 (19) | 0.0076 (18) |
C9 | 0.077 (2) | 0.0489 (18) | 0.077 (2) | −0.0066 (17) | 0.0163 (18) | 0.0009 (17) |
C10 | 0.077 (2) | 0.100 (3) | 0.108 (3) | −0.016 (2) | 0.004 (2) | −0.004 (2) |
C11 | 0.090 (2) | 0.057 (2) | 0.103 (3) | 0.014 (2) | 0.019 (2) | 0.000 (2) |
C12 | 0.0477 (16) | 0.0436 (16) | 0.0534 (18) | −0.0028 (13) | 0.0016 (13) | 0.0009 (14) |
C13 | 0.0520 (16) | 0.0599 (19) | 0.0582 (18) | 0.0050 (15) | −0.0019 (15) | 0.0007 (16) |
C14 | 0.0666 (19) | 0.0614 (19) | 0.0488 (17) | −0.0050 (16) | −0.0047 (15) | 0.0016 (15) |
C15 | 0.0544 (17) | 0.0490 (18) | 0.0575 (19) | −0.0095 (15) | 0.0055 (15) | −0.0052 (15) |
C16 | 0.0563 (18) | 0.0535 (19) | 0.068 (2) | 0.0068 (15) | 0.0075 (16) | 0.0074 (16) |
C17 | 0.0568 (17) | 0.0564 (18) | 0.0568 (18) | 0.0061 (15) | 0.0019 (15) | 0.0079 (15) |
C18 | 0.096 (2) | 0.087 (2) | 0.058 (2) | −0.017 (2) | 0.0145 (18) | 0.0001 (19) |
Geometric parameters (Å, º) top
O1—C7 | 1.233 (3) | C1—H1 | 0.9800 |
O2—C7 | 1.295 (3) | C2—H2A | 0.9800 |
O3—C15 | 1.372 (3) | C3—H3 | 0.9300 |
O3—C18 | 1.431 (3) | C5—H5 | 0.9800 |
C1—C7 | 1.503 (4) | C6—H6 | 0.9800 |
C1—C6 | 1.533 (4) | C8—H8A | 0.9600 |
C1—C2 | 1.537 (3) | C8—H8B | 0.9600 |
C2—C3 | 1.495 (3) | C8—H8C | 0.9600 |
C2—C8 | 1.520 (4) | C9—H9A | 0.9700 |
C3—C4 | 1.360 (4) | C9—H9B | 0.9700 |
C4—C5 | 1.475 (4) | C10—H10A | 0.9600 |
C4—C12 | 1.492 (4) | C10—H10B | 0.9600 |
C5—C6 | 1.530 (4) | C10—H10C | 0.9600 |
C5—C9 | 1.534 (4) | C11—H11A | 0.9600 |
C6—C11 | 1.522 (4) | C11—H11B | 0.9600 |
C9—C10 | 1.504 (4) | C11—H11C | 0.9600 |
C12—C13 | 1.385 (4) | C13—H13 | 0.9300 |
C12—C17 | 1.387 (4) | C14—H14 | 0.9300 |
C13—C14 | 1.382 (4) | C16—H16 | 0.9300 |
C14—C15 | 1.381 (4) | C17—H17 | 0.9300 |
C15—C16 | 1.373 (4) | C18—H18A | 0.9600 |
C16—C17 | 1.379 (4) | C18—H18B | 0.9600 |
O2—H2 | 0.8200 | C18—H18C | 0.9600 |
| | | |
C15—O3—C18 | 116.9 (2) | C9—C5—H5 | 103.9 |
C7—C1—C6 | 111.6 (2) | C11—C6—H6 | 108.0 |
C7—C1—C2 | 108.8 (2) | C5—C6—H6 | 108.0 |
C6—C1—C2 | 111.6 (2) | C1—C6—H6 | 108.0 |
C3—C2—C8 | 110.7 (3) | C2—C8—H8A | 109.5 |
C3—C2—C1 | 109.4 (2) | C2—C8—H8B | 109.5 |
C8—C2—C1 | 112.7 (2) | H8A—C8—H8B | 109.5 |
C4—C3—C2 | 124.8 (3) | C2—C8—H8C | 109.5 |
C3—C4—C5 | 122.0 (3) | H8A—C8—H8C | 109.5 |
C3—C4—C12 | 118.2 (2) | H8B—C8—H8C | 109.5 |
C5—C4—C12 | 119.8 (2) | C10—C9—H9A | 108.5 |
C4—C5—C6 | 115.0 (2) | C5—C9—H9A | 108.5 |
C4—C5—C9 | 114.6 (2) | C10—C9—H9B | 108.5 |
C6—C5—C9 | 113.7 (2) | C5—C9—H9B | 108.5 |
C11—C6—C5 | 111.3 (3) | H9A—C9—H9B | 107.5 |
C11—C6—C1 | 111.1 (2) | C9—C10—H10A | 109.5 |
C5—C6—C1 | 110.3 (2) | C9—C10—H10B | 109.5 |
O1—C7—O2 | 122.6 (3) | H10A—C10—H10B | 109.5 |
O1—C7—C1 | 121.9 (2) | C9—C10—H10C | 109.5 |
O2—C7—C1 | 115.5 (2) | H10A—C10—H10C | 109.5 |
C10—C9—C5 | 115.1 (3) | H10B—C10—H10C | 109.5 |
C13—C12—C17 | 117.0 (3) | C6—C11—H11A | 109.5 |
C13—C12—C4 | 121.7 (3) | C6—C11—H11B | 109.5 |
C17—C12—C4 | 121.3 (3) | H11A—C11—H11B | 109.5 |
C14—C13—C12 | 122.4 (3) | C6—C11—H11C | 109.5 |
C15—C14—C13 | 119.3 (3) | H11A—C11—H11C | 109.5 |
O3—C15—C16 | 115.8 (3) | H11B—C11—H11C | 109.5 |
O3—C15—C14 | 124.8 (3) | C14—C13—H13 | 118.8 |
C16—C15—C14 | 119.5 (3) | C12—C13—H13 | 118.8 |
C15—C16—C17 | 120.6 (3) | C15—C14—H14 | 120.4 |
C16—C17—C12 | 121.3 (3) | C13—C14—H14 | 120.4 |
C7—O2—H2 | 109.5 | C15—C16—H16 | 119.7 |
C7—C1—H1 | 108.2 | C17—C16—H16 | 119.7 |
C6—C1—H1 | 108.2 | C16—C17—H17 | 119.4 |
C2—C1—H1 | 108.2 | C12—C17—H17 | 119.4 |
C3—C2—H2A | 107.9 | O3—C18—H18A | 109.5 |
C8—C2—H2A | 107.9 | O3—C18—H18B | 109.5 |
C1—C2—H2A | 107.9 | H18A—C18—H18B | 109.5 |
C4—C3—H3 | 117.6 | O3—C18—H18C | 109.5 |
C2—C3—H3 | 117.6 | H18A—C18—H18C | 109.5 |
C4—C5—H5 | 103.9 | H18B—C18—H18C | 109.5 |
C6—C5—H5 | 103.9 | | |
| | | |
C7—C1—C2—C3 | −172.9 (2) | C2—C1—C7—O1 | 66.9 (3) |
C6—C1—C2—C3 | −49.3 (3) | C6—C1—C7—O2 | 123.5 (3) |
C7—C1—C2—C8 | 63.4 (3) | C2—C1—C7—O2 | −112.9 (3) |
C6—C1—C2—C8 | −173.0 (2) | C4—C5—C9—C10 | −62.8 (4) |
C8—C2—C3—C4 | 144.4 (3) | C6—C5—C9—C10 | 72.2 (4) |
C1—C2—C3—C4 | 19.5 (4) | C3—C4—C12—C13 | 131.8 (3) |
C2—C3—C4—C5 | 1.0 (5) | C5—C4—C12—C13 | −45.9 (4) |
C2—C3—C4—C12 | −176.7 (3) | C3—C4—C12—C17 | −46.1 (4) |
C3—C4—C5—C6 | 8.5 (4) | C5—C4—C12—C17 | 136.2 (3) |
C12—C4—C5—C6 | −173.8 (2) | C17—C12—C13—C14 | −0.4 (4) |
C3—C4—C5—C9 | 142.9 (3) | C4—C12—C13—C14 | −178.5 (3) |
C12—C4—C5—C9 | −39.4 (4) | C12—C13—C14—C15 | 0.2 (4) |
C4—C5—C6—C11 | −162.0 (3) | C18—O3—C15—C16 | −175.4 (3) |
C9—C5—C6—C11 | 63.2 (3) | C18—O3—C15—C14 | 3.4 (4) |
C4—C5—C6—C1 | −38.1 (3) | C13—C14—C15—O3 | −178.7 (3) |
C9—C5—C6—C1 | −172.9 (2) | C13—C14—C15—C16 | 0.1 (4) |
C7—C1—C6—C11 | −54.2 (3) | O3—C15—C16—C17 | 178.7 (2) |
C2—C1—C6—C11 | −176.2 (2) | C14—C15—C16—C17 | −0.2 (4) |
C7—C1—C6—C5 | −178.2 (2) | C15—C16—C17—C12 | −0.1 (4) |
C2—C1—C6—C5 | 59.8 (3) | C13—C12—C17—C16 | 0.4 (4) |
C6—C1—C7—O1 | −56.7 (4) | C4—C12—C17—C16 | 178.4 (3) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
O2—H2···O1i | 0.82 | 1.87 | 2.679 (3) | 171 |
Symmetry code: (i) −x+1, −y+1, −z+2. |
Experimental details
Crystal data |
Chemical formula | C18H24O3 |
Mr | 288.37 |
Crystal system, space group | Monoclinic, P21/c |
Temperature (K) | 296 |
a, b, c (Å) | 15.789 (4), 11.680 (5), 8.7260 (13) |
β (°) | 92.296 (16) |
V (Å3) | 1607.9 (8) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.08 |
Crystal size (mm) | 0.49 × 0.40 × 0.07 |
|
Data collection |
Diffractometer | Rigaku AFC-5S diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 3052, 2846, 1176 |
Rint | 0.020 |
(sin θ/λ)max (Å−1) | 0.596 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.041, 0.134, 0.98 |
No. of reflections | 2846 |
No. of parameters | 195 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.15, −0.16 |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
O2—H2···O1i | 0.82 | 1.87 | 2.679 (3) | 171 |
Symmetry code: (i) −x+1, −y+1, −z+2. |
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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 C═O 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.