S. Ducki et al. / Bioorg. Med. Chem. 17 (2009) 7698–7710
7707
oxyphenylethan-1-one (14.5 mmol) in alcohol (ROH where R = Me,
Et, Pr, 40 mL) was added silver carbonate (5.00 g, 18.2 mmol) and
boron trifluoride etherate (2.10 mL, 16.7 mmol). The solution was
stirred at room temperature under argon for 2 days, filtered, di-
luted with dichloromethane (100 mL), washed with water
(50 mL) and the organic fraction dried over anhydrous magnesium
sulfate, filtered and evaporated in vacuo. The crude residue was
purified by flash column chromatography on silica to provide the
under an atmosphere of nitrogen overnight. The resulting precipi-
tate was collected, washed with cold methanol and recrystallized
from methanol to give the pure epoxide 5.
(2RS,3SR)-2,3-Epoxy-3-(400-methylphenyl)-1-(30,40,50-trimethoxyp
henyl)propan-1-one (5a): As a white powder (83%); mp 128–
130 °C; 1H NMR (300 MHz, CDCl3) d 2.43 (3H, s), 3.86 (3H, s),
3.87 (6H, s), 4.02 (1H, d, J 1.8 Hz), 4.23 (1H, d, J 1.8 Hz), 6.58 (2H,
s), 7.29 (2H, d, J 8.2 Hz), 7.92 (2H, d, J 8.2 Hz); 13C NMR (75 MHz,
CDCl3) d 21.7, 56.1, 59.4, 60.7, 60.8, 102.9, 128.4, 129.5, 131.2,
following a-alkoxyacetophenones.
2-Methoxy-1-(30,40,50-trimethoxyphenyl)-1-ethanone:48
As
a
133.0, 138.4, 145.0, 153.6, 192.3; kmax (EtOH) 207.0 (log e 4.76)
white solid (74%); mp 54–55 °C [lit. mp 54 °C]; 1H NMR
(300 MHz, CDCl3) d 3.51 (3H, s), 3.93 (9H, s), 4.68 (2H, s), 7.20
(2H, s).
and 261.9 nm (log e
4.27); LRMS (FAB) 329 [(M+H)+, 50%], 328
(M+, 60), 181 (50), 154 (40), 119 (100). Anal. (C19H20O5) C, H.
2-Ethoxy-1-(30,40,50-trimethoxyphenyl)-1-ethanone: As a pale yel-
low oil (91%); 1H NMR (400 MHz, CDCl3) d 1.28 (3H, t, J 7.0 Hz),
3.63 (2H, q, J 7.0 Hz), 3.90 (9H, s), 4.68 (2H, s), 7.22 (2H, s, H-20);
13C NMR (100 MHz, CDCl3) d 15.5, 56.7, 61.3, 67.6, 74.1, 105.9,
130.5, 143.3, 153.5, 195.8; LRMS (FAB) 255 [(M+H)+, 100%]; HRMS
calcd 254.1153; found 354.1154 for C13H18O5 for M+.
4.1.4. Reduction of chalcones
(E)-3-(300-Hydroxy-400-methoxyphenyl)-2-methyl-1-(30,40,50-trime-
thoxyphenyl)prop-2-en-1-ol (6a): A mixture of (E)-chalcone 3a
(0.30 g, 0.84 mmol), sodium borohydride (0.06 g, 1.70 mmol), and
cerium(III) chloride heptahydrate (0.31 g, 0.84 mmol) in methanol
(20 cm3) and water (1 mL) was stirred at 0 °C for 1 h. The subse-
quent mixture was diluted with water (20 cm3) and extracted with
chloroform (2 ꢂ 30 mL). The organic layer was washed with satu-
rated aqueous ammonium chloride solution (30 mL), separated,
dried (MgSO4), and evaporated in vacuo to give the alcohol 6a as
2-Propoxy-1-(30,40,50-trimethoxyphenyl)-1-ethanone: As a color-
less oil (62%); 1H NMR (400 MHz, CDCl3) d 0.95 (3H, t, J 7.2 Hz),
1.68 (2H, sextet, J 7.2 Hz), 3.53 (2H, t, J 7.2 Hz), 3.91 (9H, s), 4.68
(2H, s), 7.25 (2H, s); 13C NMR (100 MHz, CDCl3) d 10.9, 23.3, 56.7,
61.4, 73.9, 74.4, 106.0, 130.6, 143.3, 153.5, 196.0; LRMS (FAB)
269 [(M+H)+, 70%], 195 (100). Anal. (C14H20O5) C, H.
a
pale yellow solid (0.30 g, 99%) mp 100–102 °C; 1H NMR
(400 MHz, CDCl3) d 1.79 (3H, s), 2.03 (1H, s, OH), 3.88 (3H, s),
3.89 (6H, s), 3.93 (3H, s), 5.23 (1H, s), 5.63 (1H, s), 6.68–6.73 (3H,
m), 6.84–6.88 (2H, m), 6.96 (1H, d, J 1.5 Hz); 13C NMR (75 MHz,
CDCl3) d 14.4, 56.4, 56.5, 61.2, 80.0, 103.8, 110.8, 115.5, 121.5,
126.2, 131.3, 137.6, 138.2, 138.6, 145.6, 145.8, 153.6; LRMS (FAB)
360 (M+, 100%). Anal. (C20H24O6) C, H.
4.1.3.2. General procedure for the preparation of the
chalcones 4. The following chalcones were prepared using the
same procedure used to make the -alkylchalcones of type 3.
a-alkoxy-
a
(Z)-3-(300-Hydroxy-400-methoxyphenyl)-2-methoxy-1-(30,40,50-time
thoxyphenyl)prop-2-en-1-one (4a): As a yellow solid (31%). Mp
120–122 °C; 1H NMR (300 MHz, CDCl3) d 3.77 (3H, s), 3.91 (6H,
s), 3.93 (3H, s), 3.94 (3H, s), 5.62 (1H, s), 6.85 (1H, d, J 8.6 Hz),
6.46 (1H, s), 7.18 (2H, s), 7.21 (1H, dd, J 8.6 and 2.1 Hz), 7.53 (1H,
d, J 2.1 Hz); 13C NMR (75 MHz, CDCl3) d 56.3, 56.7, 58.9, 61.3,
107.5, 110.8, 116.3, 123.7, 124.6, 127.8, 133.2, 142.6, 145.8,
147.7, 152.5, 153.4, 192.0; LRMS (FAB) 374 [M+, 100%], 195
(100). Anal. (C20H22O7) C, H.
3-(300-Hydroxy-400-methoxyphenyl)-2-methyl-1-(30,40,50-trimethox
yphenyl)propan-1-one (8a): (E)-Chalcone 3a (0.3 g, 0.84 mmol) in
ethyl acetate (10 mL) as added to a suspension of activated 10%
Pd/C (1 spatula) in ethyl acetate (10 mL) under a hydrogen atmo-
sphere. The mixture was stirred at room temperature for 2 h and
then filtered through celite and evaporated in vacuo. Purification
by column chromatography (SiO2, hexane:ethyl acetate 3:2) affor-
ded the ketone 8a as a beige solid (0.17 g, 57%); mp 113–114 °C; 1H
NMR (300 MHz, CDCl3) d 1.22 (3H, d, J 6.8 Hz), 2.63 (1H, dd, J 13.9
and 7.2 Hz), 3.05 (1H, dd, J 13.9 and 6.8 Hz), 3.66 (1H, m), 3.86 (3H,
s), 3.90 (6H, s), 3.92 (3H, s), 5.59 (1H, s), 6.67 (1H, dd, J 8.3 and
1.9 Hz), 6.75 (1H, d, J 8.3 Hz), 6.81 (1H, d, J 1.9 Hz), 7.16 (2H, s);
13C NMR (75 MHz, CDCl3) d 18.1, 39.7, 43.1, 56.3, 56.6, 61.3,
106.2, 110.9, 115.4, 121.0, 132.3, 133.6, 142.8, 145.4, 145.9,
153.4, 203.2; LRMS (FAB) 360 (M+, 28%), 137 (100); Anal. Calcd
(C20H24O6), C, H. Further elution of the column gave 3-(300-hydro-
xy-400-methoxy-phenyl)-2-methyl-1-(30,40,50-trimethoxyphenyl)pr
opan-1-ol (7a) as a clear liquid (0.13 g, 44%); 1H NMR (300 MHz,
CDCl3) d 0.71 and 0.89 (3H, d, J 6.8 Hz), 1.86 and 1.95 (1H, s, OH),
2.00–2.06 and 2.07–2.14 (1H, m), 2.37–2.34 and 2.35–2.41 (1H,
m), 2.66–2.72 and 2.94–3.00 (1H, m), 3.86 and 3.86 (3H, s), 3.88
and 3.88 (6H, s), 3.89 and 3.89 (3H, s), 4.41 and 4.52 (1H, d, J
4.9 Hz), 5.59 and 5.59 (1H, s), 6.56 and 6.58 (2H, s), 6.65 and
6.69 (1H, dd, J 8.3 and 2.3 Hz), 6.78 and 6.79 (1H, d, J 8.3 Hz),
6.76 and 6.81 (1H, d, J 2.3 Hz); LRMS (FAB) 362 (M+, 54%), 41
(100). HRMS calcd 362.1729; found 362.1729 for C20H26O6 (M+).
2-(400-Methoxyphenyl)-1-(30,40,50-trimethoxyphenyl)propane
(Z)-3-(300-Fluoro-400-methoxyphenyl)-2-methoxy-1-(30,40,50-trime-
thoxyphenyl)prop-2-en-1-one (4c): As a yellow solid (62%). Mp 110–
112 °C; 1H NMR (400 MHz, CDCl3) d 3.78 (3H, s), 3.92 (3H, s), 3.93
(6H, s), 3.95 (3H, s), 6.41 (1H, s), 6.95 (1H, t, J 8.6 Hz), 7.19 (2H, s),
7.37 (1H, dd, J 10.1 and 2.0 Hz), 7.74 (1H, ddd, J 8.6, 2.0, and
1.6 Hz); 13C NMR (100 MHz, CDCl3) d 56.6, 56.8, 59.0, 61.4, 107.4,
113.2 (d, J 3.0 Hz), 117.6 (d, J 15.0 Hz), 122.8 (d, J 3.0 Hz), 127.3
(d, J 6.0 Hz), 127.5 (d, J 6.0 Hz), 132.9, 142.7, 148.6 (d, J 15.0 Hz),
152.4 (d, J 245.0 Hz), 152.9, 153.4, 191.7 (C); 19F NMR (188 MHz,
CDCl3) d ꢀ57.0 (m); LRMS (FAB) 377 [(M+H)+, 100%]. Anal.
(C20H21O6F) C, H.
(Z)-2-Ethoxy-3-(300-fluoro-400-methoxyphenyl)-1-(30,40,50-trimetho
xyphenyl)prop-2-en-1-one (4d): As a yellow solid (54%); mp 89–
90 °C; 1H NMR (300 MHz, CDCl3) d 1.38 (3H, t, J 7.0 Hz), 3.92 (6H,
s), 3.93 (3H, s), 3.95 (3H, s), 3.99 (2H, q, J 7.0 Hz), 6.43 (1H, s),
6.95 (1H, t, J 8.8 Hz), 7.22 (2H, s, H-2), 7.40 (1H, dd, J 10.1 and
1.9 Hz), 7.80 (1H, ddd, J 8.8, 1.9, and 1.6 Hz); 13C NMR (75 MHz,
CDCl3) 16.0, 56.6, 56.7, 61.4, 67.4, 107.4, 113.3 (d, J 3.0 Hz), 117.6
(d, J 15.0 Hz), 122.6 (d, J 3.0 Hz), 127.2 (d, J 6.0 Hz), 127.7 (d, J
6.0 Hz), 132.7, 142.8, 148.5 (d, J 15.0 Hz), 152.1, 152.4 (d, J
245.0 Hz), 153.3, 191.9; 19F NMR (188 MHz, CDCl3) d –55.6 (m);
LRMS (FAB) 391 [(M+H)+, 100%]. Anal. (C21H23O6F) C, H.
(9a):49 (E)-Chalcone 2ii (5.0 g, 15.2 mmol) in dichloromethane
(50 mL) was added to a stirring activated suspension of 10% Pd/C
(1 spatula) in dichloromethane (10 mL) under a hydrogen atmo-
sphere. The mixture was stirred at room temperature for 30 min,
filtered through celite and evaporated in vacuo. Purification by col-
umn chromatography (SiO2, hexane:chloroform 1:1, long column)
afforded the diarylpropane 9a as an off-white solid (1.6 g, 33%); mp
57–59 °C (lit. mp 57.5–58.5 °C); 1H NMR (CDCl3) d 1.91–1.99 (2H,
m), 2.59–2.66 (4H, m), 3.83 (3H, s), 3.86 (3H, s), 3.88 (6H, s), 6.42
4.1.3.3. General synthesis of the chalcone epoxides 5. A mixture
of chalcone 2 (10.0 mmol), t-butyl hydroperoxide (70% aqueous
solution, 1.5 mL, 10.9 mmol), and Triton BÒ (40% methanolic solu-
tion
of
benzyltrimethylammonium
hydroxide,
0.25 mL,
0.55 mmol) in methanol (20 mL) was stirred at room temperature