550
Z.-S. Kang et al. / European Journal of Medicinal Chemistry 146 (2018) 541e553
4.10.4. Methyl 6-(4-(3-(3,4-bis(2-hydroxy-3,3-dimethylbutoxy)
phenyl)pentan-3-yl)-2-methylphenoxy)-2-methylhexanoate (10d)
Petroleum ether/ethyl acetate (15/1). Colorless oil. 74% yield. 1H
4.11.3. 1,1'-((4-(3-(4-((6-hydroxyhexyl)oxy)-3-methylphenyl)
pentan-3-yl)-1,2-phenylene)bis(oxy))bis(3,3-dimethylbutan-2-ol)
(11c)
NMR (500 MHz, CDCl3)
d
(ppm) 6.91 (d, J ¼ 8.5 Hz, 1H), 6.87 (s, 1H),
Dichloromethane/methanol (70/1). Colorless oil. 86% yield. 1H
6.83e6.78 (m, 2H), 6.76 (d, J ¼ 6.8 Hz, 1H), 6.67 (d, J ¼ 8.5 Hz, 1H),
4.17e4.14 (m, 1H), 4.13 (q, J ¼ 7.1 Hz, 2H), 4.10e4.03 (m, 1H), 3.92 (t,
J ¼ 6.2 Hz, 2H), 3.89e3.80 (m,1H), 3.78e3.72 (m,1H), 3.68e3.63 (m,
1H), 3.60e3.53 (m, 1H), 2.33 (t, J ¼ 7.4 Hz, 2H), 2.15 (s, 3H),
2.05e1.97 (m, 4H), 1.83e1.77 (m, 2H), 1.74e1.68 (m, 2H), 1.55e1.49
(m, 2H), 1.25 (t, J ¼ 7.1 Hz, 3H), 0.98 (s, 9H), 0.94 (d, J ¼ 4.6 Hz, 9H),
NMR (500 MHz, CDCl3)
d
(ppm) 6.90 (dd, J ¼ 8.5 Hz, 2.1 Hz,1H), 6.87
(d, J ¼ 2.1 Hz, 1H), 6.83e6.78 (m, 2H), 6.75 (dd, J ¼ 7.0 Hz, 1.6 Hz,
1H), 6.67 (d, J ¼ 8.4 Hz, 1H), 4.17e4.12 (m, 1H), 4.11e4.03 (m, 1H),
3.93 (t, J ¼ 6.3 Hz, 2H), 3.89e3.80 (m, 1H), 3.80e3.71 (m, 1H),
3.69e3.63 (m,1H), 3.65 (t, J ¼ 6.5 Hz, 2H), 3.60e3.52 (m,1H), 2.15 (s,
3H), 2.04e1.98 (m, 4H), 1.82e1.77 (m, 2H), 1.63e1.58 (m, 2H),
1.54e1.48 (m, 2H),1.47e1.42 (m, 2H), 0.98 (s, 9H), 0.94 (d, J ¼ 4.8 Hz,
0.61 (t, J ¼ 7.2 Hz, 6H). MS (TOF) m/z: 651.4 [MþNa] þ
.
9H), 0.61 (t, J ¼ 7.3 Hz, 6H). 13C NMR (125 MHz, CDCl3)
d (ppm)
4.10.5. Methyl 7-(4-(3-(3,4-bis(2-hydroxy-3,3-dimethylbutoxy)
phenyl)pentan-3-yl)-2-methylphenoxy)heptanoate (10e)
Petroleum ether/ethyl acetate (15/1). Colorless oil. 83% yield. 1H
154.97,148.09,147.20,143.48, 139.82, 130.39, 126.00,125.65, 122.32,
117.57, 114.47, 109.96, 77.31, 73.09, 72.04, 67.72, 62.91, 48.84, 33.45,
33.32, 32.72, 29.50, 29.42, 26.15, 26.11, 26.08, 26.03, 25.55, 16.47,
þ
NMR (500 MHz, CDCl3)
d
(ppm) 6.91 (dd, J ¼ 8.5 Hz, 2.2 Hz,1H), 6.87
8.46. ESI-HRMS calcd for C36H58O6 [MþNa]
609.4233, found
(d, J ¼ 2.2 Hz,1H), 6.82e6.78 (m, 2H), 6.76 (dd, J ¼ 7.1 Hz,1.7 Hz,1H),
6.67 (d, J ¼ 8.5 Hz, 1H), 4.17e4.14 (m, 1H), 4.12 (q, J ¼ 7.2 Hz, 2H),
4.10e4.03 (m, 1H), 3.92 (t, J ¼ 6.3 Hz, 2H), 3.89e3.84 (m, 1H),
3.84e3.72 (m, 1H), 3.68e3.63 (m, 1H), 3.60e3.52 (m, 1H), 2.30 (t,
J ¼ 7.4 Hz, 2H), 2.15 (s, 3H), 2.04e1.98 (m, 4H), 1.81e1.75 (m, 2H),
1.69e1.63 (m, 2H), 1.53e1.47 (m, 2H), 1.43e1.37 (m, 2H), 1.25 (t,
J ¼ 7.2 Hz, 3H), 0.98 (s, 9H), 0.94 (d, J ¼ 5.7 Hz, 9H), 0.61 (t, J ¼ 7.2 Hz,
609.4138.
4.11.4. 1,1'-((4-(3-(4-((7-hydroxyheptyl)oxy)-3-methylphenyl)
pentan-3-yl)-1,2-phenylene)bis(oxy))bis(3,3-dimethylbutan-2-ol)
(11d)
Dichloromethane/methanol (60/1). Colorless oil. 78% yield. 1H
NMR (500 MHz, CDCl3)
d
(ppm) 6.91 (dd, J ¼ 8.5 Hz, 2.0 Hz,1H), 6.87
6H). MS (TOF) m/z: 665.5 [MþNa] þ
.
(d, J ¼ 2.0 Hz,1H), 6.82e6.78 (m, 2H), 6.75 (d, J ¼ 7.0 Hz,1H), 6.67 (d,
J ¼ 8.5 Hz, 1H), 4.17e4.11 (m, 1H), 4.11e4.03 (m, 1H), 3.92 (t,
J ¼ 6.4 Hz, 2H), 3.89e3.80 (m,1H), 3.80e3.71 (m,1H), 3.67e3.62 (m,
1H), 3.64 (t, J ¼ 6.6 Hz, 2H), 3.60e3.52 (m, 1H), 2.15 (s, 3H),
2.03e1.98 (m, 4H), 1.81e1.75 (m, 2H), 1.59e1.56 (m, 2H), 1.50e1.47
(m, 2H), 1.40e1.38 (m, 4H), 0.98 (s, 9H), 0.94 (d, J ¼ 4.9 Hz, 9H), 0.61
4.11. General procedure 3 - synthesis of compounds 11a-11d
4.11.1. 1,1'-((4-(3-(4-(4-hydroxybutoxy)-3-methylphenyl)pentan-3-
yl)-1,2-phenylene)bis(oxy))bis(3,3-dimethylbutan-2-ol) (11a)
To a solution of appropriate ester 10b (198.01 mg, 0.33 mmol) in
THF (20 mL), LiAlH4 (31.58 mg, 0.83 mmol) was added portionwise
at 0 ꢁC. The reaction mixture was stirred at 25 ꢁC for 4 h and then
added H2O (10 mL). EtOAc (50 mL) was added and the organic
phase were washed with brine and dried over anhydrous Na2SO4,
filtered and concentrated. The residue was purified by silica gel
column chromatography eluting with dichloromethane/methanol
(t, J ¼ 7.2 Hz, 6H). 13C NMR (125 MHz, CDCl3)
d (ppm) 154.99, 148.07,
147.18, 143.47, 139.78, 130.37, 125.98, 125.65, 122.29, 117.52, 114.43,
109.94, 77.21, 76.69, 73.06, 72.02, 67.80, 62.96, 48.83, 33.44, 32.70,
29.50, 29.38, 29.19, 26.17, 26.14, 26.11, 26.07, 26.01, 25.70, 16.47,
þ
8.46. ESI-HRMS calcd for C37H60O6 [MþNa]
623.4390, found
623.4287.
(50/1). Colorless oil. 87% yield. 1H NMR (500 MHz, CDCl3)
d
(ppm)
4.12. General procedure 4 - synthesis of compounds 12a-12e
6.92 (dd, J ¼ 8.4 Hz, 1.9 Hz, 1H), 6.87 (d, J ¼ 1.9 Hz, 1H), 6.82e6.78
(m, 2H), 6.75 (d, J ¼ 7.0 Hz,1H), 6.68 (d, J ¼ 8.4 Hz,1H), 4.17e4.12 (m,
1H), 4.11e4.03 (m, 1H), 3.97 (t, J ¼ 6.0 Hz, 2H), 3.89e3.82 (m, 1H),
3.80e3.74 (m, 1H), 3.72 (t, J ¼ 6.3 Hz, 2H), 3.68e3.64 (m, 1H),
3.60e3.52 (m, 1H), 2.16 (s, 3H), 2.06e1.97 (m, 4H), 1.91e1.85 (m,
2H), 1.79e1.74 (m, 2H), 0.98 (s, 9H), 0.94 (d, J ¼ 5.0 Hz, 9H), 0.61 (t,
4.12.1. 2-(4-(3-(3,4-bis(2-hydroxy-3,3-dimethylbutoxy)phenyl)
pentan-3-yl)-2-methylphenoxy)acetic acid (12a)
To a stirred solution of appropriate ester 10a (2.2 g, 3.43 mmol)
in a mixture of EtOH/H2O 10:1 (40 mL) was added NaOH (1.37 g,
34.33 mmol) at 70 ꢁC. After 24 h, the solution was evaporated,
water (20 mL) and EtOAc (80 mL) was added. The organic phase
were washed with brine and dried over anhydrous Na2SO4, filtered
and concentrated. The residue was purified by silica gel column
chromatography with dichloromethane/methanol (50/1). Colorless
J ¼ 7.2 Hz, 6H). 13C NMR (125 MHz, CDCl3)
d (ppm) 154.78, 148.06,
147.18, 143.38, 140.03, 130.44, 126.03, 125.60, 122.27, 117.44, 114.40,
110.00, 77.26, 76.95, 76.68, 73.02, 71.99, 67.66, 62.60, 48.84, 33.44,
29.68, 26.13, 26.10, 26.06, 26.01, 25.99, 16.49, 8.44. ESI-HRMS calcd
for C34H54O6 [MþNa] þ 581.3920, found 581.3826.
oil. 86% yield. 1H NMR (500 MHz, CDCl3)
d (ppm) 6.93e6.91 (m, 2H),
6.81 (dd, J ¼ 8.4 Hz, 3.2 Hz, 1H), 6.78 (dd, J ¼ 8.4 Hz, 1.8 Hz, 1H), 6.73
(dd, J ¼ 7.3 Hz, 1.8 Hz, 1H), 6.61 (d, J ¼ 8.3 Hz, 1H), 4.63 (s, 2H),
4.17e4.12 (m, 1H), 4.10e4.02 (m, 1H), 3.89e3.81 (m, 1H), 3.81e3.72
(m, 1H), 3.69e3.65 (m, 1H), 3.61e3.53 (m, 1H), 2.22 (s, 3H),
2.04e1.98 (m, 4H), 0.98 (s, 9H), 0.94 (d, J ¼ 5.7 Hz, 9H), 0.60 (t,
4.11.2. 1,1'-((4-(3-(4-((5-hydroxypentyl)oxy)-3-methylphenyl)
pentan-3-yl)-1,2-phenylene)bis(oxy))bis(3,3-dimethylbutan-2-ol)
(11b)
Dichloromethane/methanol (50/1). Colorless oil. 66% yield. 1H
NMR (500 MHz, CDCl3)
d
(ppm) 6.92 (dd, J ¼ 8.4 Hz, 2.1 Hz, 1H), 6.87
J ¼ 7.3 Hz, 6H). 13C NMR (125 MHz, CDCl3)
d (ppm) 172.58, 153.59,
(d, J ¼ 2.1 Hz,1H), 6.83e6.78 (m, 2H), 6.76 (d, J ¼ 1.8 Hz, 1H), 6.67 (d,
J ¼ 8.4 Hz, 1H), 4.16 (dd, J ¼ 9.2 Hz, 2.2 Hz, 1H), 4.10 (dd, J ¼ 9.5 Hz,
2.2 Hz, 1H), 3.94 (t, J ¼ 6.3 Hz, 2H), 3.80 (t, J ¼ 9.2 Hz, 1H), 3.73 (t,
J ¼ 9.5 Hz, 1H), 3.67 (t, J ¼ 6.4 Hz, 2H), 3.67e3.65 (m, 1H), 3.59 (dd,
J ¼ 9.4 Hz, 2.2 Hz, 1H), 2.15 (s, 3H), 2.04e2.01 (m, 4H), 1.85e1.79 (m,
2H), 1.68e1.62 (m, 2H), 1.59e1.53 (m, 2H), 0.98 (s, 9H), 0.94 (s, 9H),
148.14, 147.27, 143.14, 141.75, 130.90, 126.19, 126.13, 122.28, 117.46,
114.47, 110.56, 77.43, 77.33, 72.99, 71.91, 65.36, 48.93, 33.36, 29.44,
26.14, 26.11, 26.07, 26.02, 16.43, 8.43. ESI-HRMS calcd for C32H48O7
[MþNa] þ 567.3400, found 567.3299.
4.12.2. 4-(4-(3-(3,4-bis(2-hydroxy-3,3-dimethylbutoxy)phenyl)
pentan-3-yl)-2-methylphenoxy)butanoic acid (12b)
0.61 (t, J ¼ 7.2 Hz, 6H). 13C NMR (125 MHz, CDCl3)
d (ppm) 154.93,
148.09, 147.20, 143.47, 139.87, 130.40, 126.00, 125.65, 122.33, 117.56,
114.47, 109.96, 77.31, 73.10, 72.04, 67.67, 62.86, 48.84, 33.45, 33.33,
32.47, 29.23, 26.15, 26.08, 22.48, 16.49, 8.46. ESI-HRMS calcd for
Dichloromethane/methanol (50/1). Colorless oil. 65% yield. 1H
NMR (500 MHz, CDCl3)
d
(ppm) 6.92 (dd, J ¼ 8.5 Hz, 1.8 Hz, 1H), 6.88
(s, 1H), 6.82e6.78 (m, 2H), 6.75 (dd, J ¼ 6.8 Hz, 1.8 Hz, 1H), 6.67 (d,
C
35H56O6 [MþNa] þ 595.4077, found 595.3981.
J ¼ 8.5 Hz, 1H), 4.17e4.12 (m, 1H), 4.09e4.03 (m, 1H), 3.98 (t,