Synthesis and EValuation of (()-Abyssinone II
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 12 2805
H), 5.35 (dd, J ) 13.2, 2.7 Hz, 1 H), 5.26 (t, J ) 7.2 Hz, 1 H),
3.82 (s, 3 H), 3.32 (d, J ) 7.2 Hz, 2 H), 3.06 (dd, J ) 13.2, 3.9
Hz, 1 H), 2.77 (dd, J ) 17.1, 3.0 Hz, 1 H), 1.71 (s, 3 H), 1.68 (s,
3 H); 13C NMR (75 MHz, CDCl3) δ 190.3, 167.4, 163.9, 157.7,
132.9, 130.6, 130.2, 129.3, 127.5, 125.1, 121.8, 118.1, 110.2, 103.4,
79.8, 55.4, 28.4, 25.8, 17.7; EIMS (m/z, rel intensity) 338 (M+,
100), 307 (20), 269 (17), 189 (76), 137 (51), 115 (25), 69 (23);
HRMS m/z calcd for C21H22O4, 338.1518; found, 338.1522. Anal.
(C21H22O4‚3.25H2O) C, H.
7-Methoxy-2-[4-(methoxymethoxy)-3-(3-methylbut-2-enyl)-
phenyl]chroman-4-one (8e). The compound was isolated as a clear
light yellow oil in 50% (isolated) and 97% (based on recovered
starting material) yield. Rf ) 0.53 (25% EtOAc-hexanes); IR (neat)
2911, 1686, 1610, 1574, 1503, 1446, 1374, 1332, 1292, 1250, 1154,
1128 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J ) 9.3 Hz, 1
H), 7.23 (m, 2 H), 7.07 (d, J ) 8.4 Hz, 1 H), 6.57 (dd, J ) 8.7, 2.7
Hz, 1 H), 6.44 (d, J ) 2.4 Hz, 1 H), 5.36 (dd, J ) 13.2, 3.0 Hz, 1
H), 5.27 (t, J ) 7.8 Hz, 1 H), 5.20 (s, 2 H), 3.80 (s, 3 H), 3.45 (s,
3 H), 3.34 (d, J ) 7.2 Hz, 2 H), 3.03 (dd, J ) 13.2, 3.6 Hz, 1 H),
2.75 (dd, J ) 17.1, 3.3 Hz, 1 H), 1.70 (s, 3 H), 1.69 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 190.9, 166.1, 163.6, 155.2, 132.8, 131.6,
131.2, 128.7, 127.7, 125.0, 122.0, 114.7, 113.8, 110.1, 100.8, 94.2,
79.9, 55.9, 55.6, 44.1, 28.7, 25.8, 17.8; positive ESIMS (m/z, rel
intensity) 383 (MH+, 100), 351 (15), 283 (16), 214 (10), 150 (14);
HRMS m/z calcd for C23H26O5, 382.1780; found, 382.1778. Anal.
(C23H26O5‚0.25H2O) C, H.
intensity) 322 (M+, 73), 267 (10), 253 (23), 189 (46), 147 (72),
121 (100), 92 (60), 65 (36), 55 (21). Anal. (C21H22O3) C, H.
7-Methoxy-2-[3-(3-methylbut-2-enyl)phenyl]chroman-4-one
(8i). The compound was isolated as a clear very light yellow oil in
55% (isolated) and 95% based on recovered starting material) yield.
Rf ) 0.48 (15% EtOAc-hexanes); IR (neat) 2923, 1683, 1607,
1574, 1442, 1259, 1158, 1113 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.82 (d, J ) 8.7 Hz, 1 H), 7.32 (m, 4 H), 7.15 (d, J ) 7.2 Hz,
1 H), 6.56 (dd, J ) 8.7, 2.1 Hz, 1 H), 6.49 (s, 1 H), 5.39 (dd, J )
13.2, 2.7 Hz, 1 H), 5.28 (t, J ) 7.2 Hz, 1 H), 5.20 (s, 2 H), 3.78
(s, 3 H), 3.33 (d, J ) 7.2 Hz, 2 H), 3.01 (dd, J ) 13.8, 2.7 Hz, 1
H), 2.76 (dd, J ) 16.5, 2.1 Hz, 1 H), 1.71 (s, 3 H), 1.68 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 190.6, 166.0, 163.5, 142.5, 138.7,
132.9, 128.8, 128.5, 126.2, 123.5, 122.6, 114.7, 110.1, 100.8, 80.1,
55.6, 44.2, 34.2, 25.7, 16.9; EIMS (m/z, rel intensity) 322 (M+,
88), 253 (29), 177 (100), 151 (77), 122 (55), 107 (53), 69 (71), 55
(73); HRMS m/z calcd for C21H22O3, 322.1569; found, 322.1571;
Anal. (C21H22O3‚0.2H2O) C, H.
7-Methoxy-2-(4-methoxyphenyl)chroman-4-one (8j). The com-
pound was isolated as a yellow solid in 65% (isolated) and 99%
(based on recovered starting material) yield: mp 79-81 °C; Rf )
0.5 (15% EtOAc-hexanes); IR (neat) 3003, 2961, 1680, 1609,
1
1574, 1515, 1444, 1275, 1257, 1158, 1113 cm-1; H NMR (300
MHz, CDCl3) δ 7.83 (d, J ) 8.7 Hz, 1 H), 7.36 (m, 2 H), 6.92 (m,
2 H), 6.57 (dd, J ) 8.7, 2.7 Hz, 1 H), 6.44 (d, J ) 2.4 Hz, 1 H),
5.37 (d, J ) 13.8, 3.3 Hz, 1 H), 3.79 (s, 3 H), 3.78 (s, 3 H), 3.01
2-[4-Hydroxy-3-(3-methylbut-2-enyl)phenyl]-7-methoxychro-
man-4-one (8f). The compound was isolated as a yellow semisolid
in 40% (isolated) and 88% (based on recovered starting material)
yield. Rf ) 0.31 (20% EtOAc-hexanes); IR (neat) 3338, 2924,
(dd, J ) 13.2, 3.3 Hz, 1 H), 2.76 (dd, J ) 17.1, 3.0 Hz, 1 H); 13
C
NMR (75 MHz, CDCl3) δ 190.7, 166.0, 163.5, 159.8, 130.7, 128.6,
127.7, 114.7, 114.1, 110.1, 100.8, 79.7, 55.5, 55.3, 44.0; EIMS (m/
z, rel intensity) 284 (M+, 80), 269 (7), 177 (13), 134 (100), 121
(53), 108 (9), 91 (24); HRMS m/z calcd for C17H16O4, 284.1049;
found, 284.1051. Anal. (C17H16O4) C, H.
1663, 1605, 1573, 1508, 1443, 1364, 1335, 1260, 1159, 1115 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.84 (m, 1 H), 7.37 (m, 2 H), 6.84
(m, 1 H), 6.57 (dd, J ) 8.7, 2.1 Hz, 1 H), 6.45 (m, 1 H), 5.82 (s,
1 H), 5.31 (m, 2 H), 3.79 (s, 3 H), 3.45 (s, 3 H), 3.35 (d, J ) 6.6
Hz, 2 H), 3.03 (dd, J ) 13.8, 3.3 Hz, 1 H), 2.76 (dd, J ) 16.8, 2.7
Hz, 1 H), 1.75 (s, 3 H), 1.74 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 190.7, 166.4, 163.0, 155.4, 132.7, 131.6, 130.7, 128.6, 126.1,
122.4, 116.3, 106.9, 101.3, 80.4, 56.1, 45.7, 26.3, 17.5; CIMS (m/
z, rel intensity) 339 (MH+, 73), 327 (9), 299 (24), 215 (15), 177
(76), 151 (38), 123 (11); HRMS m/z calcd for C21H22O4, 338.1518;
found, 338.1520. Anal. (C21H22O4‚0.3H2O) C, H.
7-Methoxy-2-[4-(3-methylbut-2-enyloxy)phenyl]chroman-4-
one (8k). The compound was isolated as a solid in 50% (isolated)
and 88% (based on recovered starting material) yield: mp 108-
110 °C; Rf ) 0.31 (25% EtOAc-hexanes); IR (neat) 2917, 1723,
1
1680, 1609, 1513, 1444, 1385, 1257, 1158, 1113 cm-1; H NMR
(300 MHz, CDCl3) δ 7.83 (d, J ) 8.7 Hz, 1 H), 7.36 (m, 2 H),
6.93 (m, 2 H), 6.57 (dd, J ) 8.7, 2.1 Hz, 1 H), 6.44 (d, J ) 2.1 Hz,
1 H), 5.46 (m, 1 H), 5.37 (dd, J ) 13.2, 2.7 Hz, 1 H), 4.50 (d, J
) 6.6 Hz, 2 H), 3.79 (s, 3 H), 3.03 (dd, J ) 13.8, 3.9 Hz, 1 H),
2.76 (dd, J ) 17.1, 3.3 Hz, 1 H), 1.77 (s, 3 H), 1.72 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 190.8, 166.1, 163.5, 159.1, 138.4, 130.6,
128.6, 127.6, 119.3, 114.8, 110.1, 100.8, 79.7, 64.7, 55.5, 44.0,
25.8, 18.1; CIMS (m/z, rel intensity) 339 (MH+, 100), 299 (5), 271
(30), 215 (6), 177 (32), 151 (6); HRMS m/z calcd for C21H22O4,
338.1518; found, 338.1522. Anal. (C21H22O4) C, H.
3-Hydroxy-1-(2-hydroxy-4-methoxyphenyl)-3-[4-methoxy-3-
(3-methylbut-2-enyl)phenyl]propan-1-one (9). A solution of
LiHMDS in THF (1 M, 7.2 mL, 7.2 mmol) was added to a well-
stirred solution of acetophenone 6b (500 mg, 3.0 mmol) in THF
(15 mL) under argon at -78 °C. The reaction mixture was stirred
at -78 °C for 1 h and at -10 °C for 2 h and was cooled again to
-78 °C, and a solution of aldehyde 5b (615 mg, 3.0 mmol) in
THF (2 mL) was added in one portion. Stirring was continued at
-78 °C for 30 min and then the cooling bath was removed and the
reaction mixture was stirred at room temperature. Stirring was
continued for 24 h and the reaction mixture was quenched by the
addition of saturated NH4Cl (10 mL). The aqueous layer was
extracted with ethyl acetate, washed with brine, dried (Na2SO4),
and then concentrated in vacuo. The residue was column chro-
matographed on silica gel, eluting with 50% ethyl acetate in
hexanes, to afford compound 15 as a clear oil (430 mg, 39% yield).
Rf ) 0.27 (50% EtOAc-hexanes); IR (neat) 1631 cm-1; 1H NMR
(500 MHz, CDCl3) δ 12.67 (s, 1 H), 7.65 (d, J ) 10.0 Hz, 1 H),
7.20 (m, 2 H), 6.88 (d, J ) 5.0 Hz, 1 H), 6.44 (m, 2 H), 5.31 (t, J
) 2.7 Hz, 1 H), 5.28 (dd, J ) 8.3, 1.2 Hz, 1 H), 3.83 (s, 6 H), 3.33
(m, 4 H), 1.79 (s, 3 H), 1.77 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 203.7, 166.5, 165.6, 157.0, 134.8, 132.6, 131.9, 130.4, 127.0,
124.4, 122.4, 113.7, 110.3, 108.0, 101.0, 70.0, 55.7, 55.6, 46.8,
28.7, 25.9, 17.9; EIMS (m/z, rel intensity) 370 (M+, 1), 352 (5),
7-Methoxy-2-[4-methoxy-3-(3-methylbut-2-enyl)phenyl]chro-
man-4-one (8g). The compound was isolated as a clear light yellow
oil in 56% (isolated) and 99% (based on recovered starting material)
yield. Rf ) 0.47 (20% EtOAc-hexanes); IR (neat) 3341, 2924,
1
2851, 1679, 1607, 1499, 1443, 1334, 1254, 1159 cm-1; H NMR
(300 MHz, CDCl3) δ 7.83 (d, J ) 8.7 Hz, 1 H), 7.23 (dd, J ) 8.4,
2.1 Hz, 1 H), 7.19 (d, J ) 2.4 Hz, 1 H), 6.85 (d, J ) 8.1 Hz, 1 H),
6.58 (dd, J ) 8.7, 2.7 Hz, 1 H), 6.45 (d, J ) 2.4 Hz, 1 H), 5.37
(dd, J ) 13.8, 3.0 Hz, 1 H), 5.27 (t, J ) 7.2 Hz, 1 H), 3.82 (s, 3
H), 3.79 (s, 3 H), 3.31 (d, J ) 7.5 Hz, 2 H), 3.03 (dd, J ) 13.5, 3.3
Hz, 1 H), 2.75 (dd, J ) 17.1, 2.7 Hz, 1 H), 1.71 (s, 3 H), 1.68 (s,
3 H); 13C NMR (75 MHz, CDCl3) δ 190.9, 166.0, 163.6, 157.6,
132.8, 130.5, 130.3, 128.6, 127.5, 125.0, 121.9, 114.7, 110.1, 100.8,
79.9, 55.4, 44.2, 28.4, 25.8, 17.7; EIMS (m/z, rel intensity) 352
(M+, 73), 321 (21), 283 (11), 202 (25), 189 (100), 151 (55), 115
(22), 69 (17); HRMS m/z calcd for C22H24O4, 352.1675; found,
352.1676. Anal. (C22H24O4‚3.0H2O) C, H.
2-[4-Methoxy-3-(3-methylbut-2-enyl)phenyl]chroman-4-one
(8h). The compound was isolated as a clear light yellow oil in 65%
(isolated) and 97% (based on recovered starting material) yield. Rf
) 0.49 (15% EtOAc-hexanes); IR (neat) 2975, 1689, 1606, 1577,
1
1500, 1464, 1305, 1254, 1223, 1148, 1119 cm-1; H NMR (300
MHz, CDCl3) δ 7.92 (d, J ) 8.7 Hz, 1 H), 7.32 (m, 4 H), 7.15 (d,
J ) 7.2 Hz, 1 H), 6.56 (dd, J ) 8.7, 2.1 Hz, 1 H), 6.49 (s, 1 H),
5.39 (dd, J ) 13.2, 2.7 Hz, 1 H), 5.28 (t, J ) 7.2 Hz, 1 H), 5.20
(s, 2 H), 3.78 (s, 3 H), 3.33 (d, J ) 7.2 Hz, 2 H), 3.01 (dd, J )
13.8, 2.7 Hz, 1 H), 2.76 (dd, J ) 16.5, 2.1 Hz, 1 H), 1.71 (s, 3 H),
1.68 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 192.4, 161.8, 157.6,
136.0, 132.9, 130.5, 130.2, 127.5, 126.9, 125.0, 121.9, 121.3, 120.8,
118.1, 110.1, 79.5, 55.4, 44.3, 28.4 25.7, 17.7; EIMS (m/z, rel