Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 2 445
with l0-20% ethyl acetate in hexane to yield the desired
compound.
32.7, 32.8, 33.9, 34.0, 43.3, 45.8, 83.2, 114.4, 114.4, 123.2, 123.2,
123.2, 123.3, 128.1, 128.1, 128.2, 128.3, 140.8, 143.2, 143.4, 146.0,
146.1, 146.1, 146.2, 150.0, 152.4. Additional “aromatic peaks” are
recorded due to coupling to the F atoms on the ring.
1
Spectroscopic [1H and 13C NMR] and HRMS Data. 1a. H
NMR (400 MHz, acetone-d6) δ 1.35 (s, 3H), 1.24 (m, 1H), 1.30
(m, 1H), 1.65 (m, 5H), 1.80 (m, 2H), 2.09 (m, 1H), 2.21 (m, 1H),
2.65 (m, 1H), 3.67 (brs, 1H), 6.76 (d, J = 8.5 Hz, 2H), 7.07 (d, J =
8.5 Hz, 2H), 8.17 (OH); 13C NMR (acetone-d6, 100 MHz) δ 19.9,
28.2, 31.4, 33.7, 34.0, 34.2, 39.0, 43.3, 45.6, 83.2, 116.7, 129.4, 140.0,
157.1; mass (EI) m/z 246 (48.3%, Mþ), 228 (2.5%), 202 (4.2%), 146
(10.9%), 120 (100%); HREIMS m/z calculated for C16H22O2
246.1779.
1j. 1H NMR (400 MHz, CDCl3) δ 1.25 (s, 3H), 1.86-1.34 (m,
10H), 2.35-1.99 (m, 4H), 2.74-2.61 (m, 1H), 3.00-2.90 (m,
1H), 4.23 (d, J = 7.6 Hz, 1H), 5.18 (m, 1H), 6.69 (dd, J = 14.0,
9.6 Hz, 1H), 6.94 (dd, J = 15.2, 8.8 Hz, 1H).
1k. 1H NMR (400 MHz, acetone-d6) δ1.14 (3H, s), 1.33 (2H, m),
1.69 (4H, m), 1.85 (2H, m), 2.10 (1H, m), 2.26 (1H, m), 3.03
(1H, m), 3.66 (1H, d, J = 5.66 Hz), 6.85 (1H, m); 13C NMR
(100 MHz, CDCl3) δ 19.9, 28.17, 29.65, 32.60, 33.80, 33.86, 43.22,
45.77, 83.15, 110.10, 109.89, 127.15, 127.08, 134.72, 134.67, 141.90,
141.80, 144.32, 144.15, 146.13, 146.27, 148.54, 148.65, 149.05,
149.06, 151.41.
1b. 1H NMR (400 MHz, acetone-d6) δ 0.90 (3H, s), 1.12-1.39
(4H, m), 1.56-1.62 (4H, m), 1.72 (1H, quintet, J = 6.24 Hz),
1.92 (1H, dt, J = 13.73 and 3.09 Hz), 2.37-2.45 (1H, m), 3.44 (1H,
d, J = 5.60 Hz), 4.36-4.41 (1H, m), 6.84-6.91 (2H, m), 6.94-6.97
(1H, m), 8.33 (1H, s); 13C NMR (100 MHz, acetone-d6) δ24.0, 28.6,
34.9, 40.9, 44.4, 44.7, 46.9, 73.9, 115.7, 115.9, 119.3, 119.4, 124.4,
124.4, 141.8, 141.9, 152.0, 152.1. All of the aromatic carbons are
recorded as two peaks due to coupling with F.
1
1l. H NMR (400 MHz, CDCl3) δ 1.13 (s, 3H), 1.58 (s, 3H)
1.65-1.60 (m, 2H), 1.71-1.67 (m, 2H), 1.92-1.75 (m, 2H),
2.15-2.07 (m, 1H), 2.15 (d, J = 2 Hz, 3H), 2.31-2.22 (m, 1H),
3.02-2.94 (m, 1H), 3.73 (d, J = 5.6 Hz, 1H), 4.77 (m, 1H), 6.53 (d,
J = 8.4 Hz, 1H), 6.94 (t, J = 8.4 Hz, 1H), 6.97 (dd, J = 8.4, 2.4 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 18.7, 26.5, 29.6, 32.4, 32.4,
32.8, 41.8, 44.3, 77.6, 82.94, 113.0, 113.0, 119.1, 129.8, 153.6.
1o. 1H NMR (400 MHz, CDCl3) δ 1.14 (s, 3H), 1.31 (dd, J =
3.6, 8.4 Hz, 2H), 1.42-1.36 (m, 1H), 1.70-1.54 (m, 6H),
1.96-1.78 (m, 2H), 2.15-2.08 (m, 1H), 2.19 (s, 3H), 2.22 (s,
3H), 2.15-2.07 (m, 1H), 2.32-2.25 (m, 1H), 2.31-2.22 (m, 1H),
2.92 (tt, J = 4, 12 Hz, 1H), 3.74 (d, J = 5.6 Hz, 1H), 4.61 (m,
1H), 6.63 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 12.22, 14.97, 18.47, 26.54, 28.50,
31.93, 32.09, 32.59, 33.66, 41.76, 44.27, 82.62, 112.33, 122.61,
123.34, 135.57, 137.43, 151.37.
1c. 1H NMR (400 MHz, acetone-d6) δ 0.91 (3H, s), 1.13-1.20
(1H, m), 1.25-1.32 (1H, m), 1.37 (1H, dd, J = 13.10 and 4.62 Hz),
1.53-1.68 (4H, m), 1.74 (1H, quintet, J = 6.20 Hz), 1.93 (1H, dt,
J = 13.78 and 3.21 Hz), 2.09-2.15 (1H, m), 2.69 (1H, tt, J = 12.23
and 3.21 Hz), 2.89 (1H, s), 3.45 (1H, d, J = 5.04 Hz), 4.36-4.40
(1H, m), 6.52 (1H, dd, J = 12.26 and 2.46 Hz), 6.60 (1H, dd, J =
8.40 and 2.43 Hz), 7.10 (1H, t, J = 8.63 Hz), 8.49 (1H, s);13C NMR
(100 MHz, acetone-d6,) δ24.0, 28.6, 30.1, 34.9, 37.8, 37.9, 39.5, 44.4,
46.9, 73.9, 104.2, 104.5, 113.0, 113.1, 126.3, 126.5, 129.8, 129.9,
158.5, 158.6, 161.6, 164.0. All of the aromatic carbons are recorded
as two peaks due to coupling with F.
1d. 1H NMR (400 MHz, acetone-d6) δ 0.91 (s, 3H), 1.96-1.12
(m, 18H), 3.48 (m, 1H), 4.38 (t, J = 8.0 Hz, 1H), 6.75 (dd, J =
8.4, 2.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 20.9, 27.2, 30.4, 33.4, 34.1, 34.6,
39.8, 42.1, 44.5, 81.3, 114.1, 116.0, 124.7, 130.8, 134.0, 157.0.
1e. 1H NMR (400 MHz, acetone-d6) δ 1.14 (3H, s), 1.23-1.29
(1H, m), 1.36 (1H, td, J = 13.24 and 3.78 Hz), 1.48-1.54 (1H, m),
1.58-1.62 (3H, m), 1.64-1.71 (1H, m) 1.80-1.87 (2H, m), 2.23
(3H, s), 2.90 (3H, s), 3.42 (1H, d, J = 4.25 Hz), 3.65 (1H, t, J = 4.74
Compound 2. 1H NMR (400 MHz, acetone-d6) δ 1.11 (s, 3H),
1.17 (m, 1H), 1.59 (m, 3H), 1.82 (m, 3H), 2.12 (m, 3H), 2.43 (m,
1H), 2.74 (m, 1H), 6.76 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.5 Hz,
2H), 8.08 (OH) ppm; 13C NMR (100 MHz, acetone-d6) δ20.2, 24.6,
30.4, 34.5, 37.5, 39.0, 45.0, 47.9, 116.9, 129.5, 139.6, 157.4, 207.1 .
Compound 3. 1H NMR (400 MHz, acetone-d6) δ 1.21 (s, 3H),
1.40-1.80 (m, 10H), 2.04 (m, 1H), 2.64 (m, 1H), 6.74 (d, J = 8.4
Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H); 13C NMR (acetone-d6, 100
MHz) δ 18.8, 23.1, 28.3, 29.8, 33.2, 37.3, 37.6, 42.1, 73.0, 80.4,
88.3, 115.0, 127.7, 138.2, 155.4.
Hz), 6.61-6.64 (2H, m), 7.08 (1H, d, J = 8.34 Hz), 7.93 (1H, s);13
C
NMR (100 MHz, acetone-d6) δ 20.2, 20.4, 28.4, 33.9, 34.0, 34.6,
34.8, 43.7, 45.9, 83.3, 114.7, 118.8, 128.1, 138.0, 138.0, 156.8 .
1f. 1H NMR (400 MHz, CDCl3) δ 1.16 (s, 3H), 1.31-1.25 (m,
4H), 1.75-1.56 (m, 4H), 1.92-1.75 (m, 2H), 2.13-2.07 (m, 1H),
2.35-3.33 (m, 1H), 3.12-3.02 (m, 1H), 3.74 (d, J = 5.6 Hz), 5.30
(m, 1H), 6.97 (dd, J = 8.4, 2.4 Hz, 1H), 7.07 (d, J = 2.8 Hz, 1H),
7.35 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 18.4,
26.2, 29.3, 29.7, 32.1, 32.5, 33.1, 33.1, 41.5, 44.0, 82.6, 112.7,
118.7, 129.4, 138.3, 138.3, 153.3 .
Compound 4. 1H NMR (400 MHz, acetone-d6) δ 1.02 (s, 3H),
1.44-1.29 (m, 2H), 1.65-1.57 (m, 2H), 2.33-2.02 (m, 7H),),
3.88 (t, J = 6.0 Hz, 1H), 5.55 (m, 1H), 6.74 (dd, J = 8.4, 2.4 Hz,
1H), 6.85 (d, J = 2.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H); 13C
NMR (400 MHz, acetone-d6) δ 19.4, 26.3, 28.4, 28.6, 28.7, 28.8,
29.0, 29.2, 29.4, 29.5, 29.7, 30.2, 31.9, 42.2, 44.1, 77.5, 114.1,
115.9, 130.8, 131.0, 132.3, 134.3, 134.8, 156.8.
Compound 5. 1H NMR (400 MHz, acetone-d6) δ 1.07 (s, 3H),
1.56-1.44 (m, 2H), 1.75-1.69 (m, 1H), 1.84-1.77 (m, 1H), 1.88
(dq, 1H), 2.23-2.03 (m, 5H), 2.39 (m, 1H), 3.75 (dd, J = 6.0, 1.6
Hz, 1H), 5.50 (m, 1H), 6.74 (dd, J = 8.4, 2.4 Hz, 1H), 6.84 (d, J =
2.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H); 13C NMR (acetone-d6, 100
MHz) δ 19.8, 28.0, 28.4, 28.6, 28.8, 29.0, 29.2, 29.3, 29.4, 29.6, 29.7,
31.8, 32.2, 39.8, 42.1, 79.3, 114.1, 116.0, 124.7, 130.8, 132.3, 134.0,
135.0, 157.0.
Force Field Calculations. For calculations involving rota-
tional potential energy barriers resulting from twisting about
the A-C bond and for all docking calculations, we used the
MMFF94s force field as implemented in the MOE software
(Molecular Operating Environment 2009, Chemical Computing
Group, Montreal, Canada). This force field is parametrized for
use in medicinal chemistry. A distance-dependent dielectric
constant was used (from 1 to 80) with a cutoff at 10 A.
Docking and Scoring. X-ray crystallographic data for human
recombinant ERR and ERβ were obtained from the RCSB data-
base. All programs described here are available free of charge from
ERR (1GWR, 1G50, 1ERE, 1A52) and the two existing crystal
structures of the selective ligand genistein with ERβ (1QKM,
1
1g. H NMR (400 MHz, CDCl3) δ 1.10 (3H, s), 1.24-1.28
(3H, m), 1.46-1.57 (2H, m), 1.69-1.77 (2H, m), 1.82-1.91 (1H,
m), 2.06-2.13 (1H, m), 2.18-2.27 (1H, m), 2.61 (1H, tt, J = 12.38
and 3.69 Hz), 3.73 (1H, d, J = 5.84 Hz), 5.22 (1H, s), 6.76 (2H, d,
J = 9.00 Hz); 13C NMR (100 MHz, CDCl3) δ 18.3, 26.5, 29.2, 31.7,
32.0, 31.2, 37.4, 41.3, 44.0, 82.4, 109.7, 109.8, 109.8, 109.9, 110.0,
130.6, 139.5, 150.4, 150.4, 152.8, 152.8. Additional “aromatic
peaks” are recorded due to coupling to the F atoms on the ring.
1
1h. H NMR (400 MHz, CDCl3) δ 1.12 (3H, s), 1.25-1.29
(3H, m), 1.61-1.67 (3H, m), 1.70-1.77 (2H, m), 1.83-1.92 (1H,
m), 2.08-2.14 (1H, m), 2.19-2.28 (1H, m), 2.62 (1H, tt, J =
12.31 and 3.82 Hz), 3.73 (1H, d, J = 5.78 Hz), 5.73 (1H, s), 7.12
(2H, s); 13C NMR (100 MHz, CDCl3) δ 22.1, 26.8, 29.3, 29.9,
32.8, 38.6, 42.6, 42.8, 44.9, 73.6, 109.5, 109.6, 109.7, 109.8, 109.8,
130.5, 139.5, 152.7, 152.8.
1i. 1H NMR (400 MHz, acetone-d6) δ 1.12 (3H, s), 1.22-1.28
(1H, m), 1.35 (1H, td, J = 13.24 and 3.90 Hz), 1.54-1.62 (2H, m),
1.64-1.74 (3H, m), 1.76-1.84 (2H, m), 2.08-2.13 (1H, m), 2.18-
2.27 (1H, m), 3.01 (2H, tt, J = 12.35 and 3.84 Hz), 3.65 (1H, d, J =
5.66 Hz), 6.76 (1H, td, J= 8.42 and 1.96 Hz), 6.95 (1H, td, J = 8.19
and 2.26 Hz); 13C NMR (100 MHz, acetone-d6) δ 20.0, 28.2, 29.9,