1894 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9
Avery et al.
(d, 3H, J ) 6.6 Hz), 0.87 (d, 3H, J ) 6.6 Hz). 13C NMR: δ
156.17, 151.30, 117.29, 108.88, 65.96, 51.40, 50.64, 38.43,
35.92, 33.00, 31.61, 29.13, 23.42, 22.86, 18.03, 16.61, 14.07,
12.04. IR (neat): 2943, 2865, 2729, 1670, 1625, 1463, 1419,
1326, 1240, 1209, 1145, 1099, 1025, 914, 866, 826, 810, 791,
silica gel (40% EtOAc/hexane) to afford 20 (0.437 g, 89%) which
could be recrystallized from hexane to afford a white crystal-
line solid. Mp: 84.2-85.8 °C. 1H NMR: δ 6.30 (d, 1H, J )
9.8 Hz), 6.12 (d, 1H, J ) 9.8 Hz), 3.66 (dd, 1H, J ) 6.7, 11.0
Hz), 3.50 (dd, 1H, J ) 5.9, 11.0 Hz), 2.05 (m, 2H), 1.89 (m,
1H), 1.59-1.83 (m, 6H), 1.50 (m, 1H), 1.26 (s, 3H), 0.87-1.24
684 cm-1
.
(m, 3H), 1.00 (d, 3H, J ) 7.2 Hz), 0.85 (d, 3H, J ) 5.9 Hz). 13
C
(7S,8R,11S,2′S)-4,8r-Dim eth yl-11â-[1′-[(tr iisop r op ylsi-
lyl)oxy]p r op -2′-yl]bicyclo[5.4.0]u n d eca -1,4-d ien e (5). To
a slurry of CuI (2.49 g, 13.1 mmol) in 20 mL of THF at -5 °C
was added MeLi (20.65 mL, 19.6 mmol, 0.95 M solution in
ether). The triflate 15 (1.715 g, 3.27 mmol, in 2 mL of THF)
was then added to the above solution at -20 °C, and the
mixture was allowed to warm to -5 °C and stirred for 3 h.
The reaction mixture was then poured into saturated aqueous
NH4Cl (50 mL) and extracted with EtOAc (400 mL). The
organic layer was washed with 5 × 20 mL of saturated aqueous
NH4Cl and 2 × 20 mL of brine, filtered over anhydrous Na2-
SO4, and concentrated by rotary evaporation. The crude
product was purified by silica gel flash chromatography (1%
EtOAc/hexane) to afford the diene 5 as a clear oil (1.2 g, 94%).
1H NMR: δ 5.58 (dt, 1H, J ) 1.6, 7.8 Hz), 5.41 (d, 1H, J ) 7.8
Hz), 3.79 (dd, 1H, J ) 3.3, 9.6 Hz), 3.63 (dd, 1H, J ) 6.2, 9.5
Hz), 2.30 (m, 1H), 1.84 (s, 3H), 1.72-2.1 (m, 7H), 1.54 (m, 1H),
1.14-1.32 (m, 3H), 1.09 (m, 21H), 1.05 (d, 3H, J ) 6.4 Hz),
0.87 (d, 3H, J ) 6.4 Hz). 13C NMR: δ 149.23, 141.35, 120.48,
115.02, 66.27, 52.35, 49.98, 38.89, 36.32, 36.25, 32.49, 30.74,
27.15, 26.61, 18.52, 18.06, 16.88, 12.07. IR (neat): 3150, 3050,
2920, 2862, 2726, 1653, 1624, 1462, 1386, 1369, 1327, 1249,
1095, 1068, 1030, 994, 883, 825, 792, 682 cm-1. EIMS: m/z
(rel intensity) 390.35 (M, 0.98), 347 (6), 289 (0.5), 261 (0.7),
216 (55), 201 (37), 187 (17), 176 (100), 159 (27), 145 (24), 131
(40), 119 (26), 105 (43), 91 (30), 75 (45), 61 (24).
NMR: δ 134.63, 125.31, 86.61, 79.76, 66.60, 52.31, 46.27,
38.54, 38.28, 35.08, 34.55, 26.90, 26.32, 23.76, 19.91, 15.51.
IR (neat): 3412 (br, s), 3050, 2935, 2863, 2727, 1650 (w), 1459,
1374, 1342, 1236, 1168, 1121, 1032, 983, 918, 887, 846, 827
cm-1. DCIMS (NH3): m/z 267 (M + H), 249 (M - HO), 233,
175.
(1aS,3S,5aS,6R,8aS,9R,12S)-10-Deoxo-13-car baar tem isi-
n in (19). A solution of 18 (0.101 g, 0.240 mmol), TBAF (0.240
mL, 0.240 mmol, 1 M solution in THF), and THF (4 mL) was
stirred for 10 h at ambient temperature. The mixture was
then poured into saturated aqueous (NH4
Cl (20 mL) and
extracted with EtOAc (150 mL). The organic layer was
separated, washed with brine (2 × 20 mL), filtered over
anhydrous Na2SO4, and concentrated by rotary evaporation.
The crude product was purified by flash chromatography over
silica gel (40% EtOAc/hexane) to afford the alcohol (1R,
2S,2′S,5R,6S,9R)-5R,9-dimethyl-2â-(1′-hydroxyprop-2′-yl)-10,-
11-dioxatricyclo[7.2.2.01,6]tridec-12-ene as a white solid (0.045
g, 70%). 1H NMR: δ 6.25 (d, 1H, J ) 9.6 Hz), 6.04 (d, 1H, J
) 9.6 Hz), 3.63 (dd, 1H, J ) 9.2, 9.2 Hz), 3.42 (d, 1H, J ) 9.9
Hz), 3.27 (ddd, 1H, J ) 3.4, 10.9, 10.9 Hz), 2.16 (m, 1H), 1.98
(m, 1H), 1.83 (m, 1H), 1.65 (m, 3H), 1.35-1.6 (m, 3H), 1.28 (s,
3H), 0.85-1.34 (m, 3H), 0.92 (d, 3H, J ) 7.1 Hz), 0.89 (d, 3H,
J ) 7.3 Hz).
13C NMR: δ 134.60, 129.42, 83.25, 79.95, 64.55,
51.28, 48.75, 36.54, 35.59, 34.06, 28.28, 24.00, 22.19, 20.86,
20.31, 18.52. IR (CDCl3): 3531, 3459, 3049, 2951, 2870, 2848,
(1R,2S,2′S,5R,6S,9R)-5r-9-Dim et h yl-2â-[1′-[(t r iisop r o-
pylsilyl)oxy]pr op-2′-yl]-10,11-dioxatr icyclo[7.2.2.01,6]tr idec-
12-en e (17). To a 100 mL 2-necked round-bottomed flask
equipped with a reflux condenser were added rose bengal bis-
(triethylammonium) salt (0.7 g), EtOAc (80 mL), and the diene
5 (2.1 g, 5.38 mmol). Oxygen was bubbled through the above
solution during irradiation with a GE 300 W desk lamp. After
7 h, the reaction mixture was filtered through silica gel, the
column was rinsed with 30% EtOAc/hexane (400 mL), and the
product was concentrated by rotary evaporation. Flash chro-
matography on silica gel (3% EtOAc/hexane) afforded two
products. The more polar fraction was the desired R-peroxide
17 (0.70 g, 30%), and the less polar fraction was the â-peroxide
(1S,2S,2′S,5R,6S,9S)-5R,9-dimethyl-2â-[1′-[(triisopropylsilyl)-
oxy]prop-2′-yl]-10,11-dioxatricyclo[7.2.2.01,6]tridec-12-ene (18),
1.22 g (54%). 1H NMR (17): δ 6.28 (d, 1H, J ) 9.3 Hz), 6.13
(d, 1H, J ) 9.7 Hz), 3.70 (dd, 1H, J ) 4.7, 9.7 Hz), 3.58 (dd,
1H, J ) 6.5, 9.7 Hz), 2.05 (dddd, 1H, J ) 1.1, 4.0, 13.2, 13.2
Hz), 1.88 (m, 2H), 1.52-1.82 (m, 4H), 1.35-1.47 (m, 2H), 1.25
(s, 3H), 1.14-1.3 (m, 2H), 1.05 (m, 25H), 0.85 (m, 3H). 13C
NMR (17): δ 134.97, 125.74, 86.23, 79.39, 66.87, 52.21, 47.90,
38.29, 36.61, 35.17, 34.72, 26.53, 25.89, 19.96, 18.18, 18.09,
12.02. IR (17, neat): 3046, 2941, 2863, 2724, 1462, 1370, 1249,
1459, 1447, 1374, 1251, 1162, 1094, 1036 cm-1
.
To an ambient temperature solution of the above alcohol
(40 mg, 0.15 mmol) in THF (2 mL) under N2 was added Hg-
(OCOCF3)2 (0.120 g, 0.281 mmol). After 22 h, the reaction
mixture was cooled to 0 °C and a mixture of NaBH4 (10 mg)
and NaOH (3 M/H2O, 100 µL) was added. The mixture was
stirred for 5 min at 0 °C, poured into saturated aqueous NH4-
Cl (20 mL), and then extracted with EtOAc (100 mL). The
organic layer was separated, washed with brine (2 × 10 mL),
filtered over anhydrous Na2SO4, and concentrated by rotary
evaporation. The crude product was purified by flash chro-
matography over silica gel (20% EtOAc/hexane) to afford 19
as a white solid (31 mg, 78%). 1H NMR: δ 3.86 (dd, 1H, J )
1.1, 11.1 Hz), 3.60 (dd, 1H, J ) 1.1, 1.1 Hz), 3.56 (d, 1H, J )
1.1 Hz), 2.32 (dd, 1H, J ) 9.2, 14.5 Hz), 2.08 (ddd, 1H, J )
2.7, 14.5, 14.5 Hz), 1.91 (m, 1H), 1.75 (m, 5H), 1.54 (m, 5H),
1.0-1.3 (m, 4H), 1.20 (s, 3H), 0.87 (d, 3H, J ) 6.5 Hz). 13C
NMR: δ 78.48, 78.31, 74.41, 74.02, 50.09, 46.57, 38.37, 35.59,
35.19, 33.01, 29.63, 27.18, 25.39, 22.34, 20.19, 13.50. IR
(CDCl3): 2952, 2926, 2867, 2850, 1458, 1387, 1375, 1364, 1331,
1306, 1248, 1197, 1180, 1160, 1122, 1109, 1094, 1048, 1007,
971 cm-1. DCIMS (NH3): m/z 267 (M + H), 266 (M), 251, 249,
233, 223, 204, 195, 165.
1158, 1095, 1065, 1013, 995, 920, 885, 799, 685 cm-1
.
1H NMR (18): δ 6.21 (d, 1H, J ) 9.5 Hz), 6.01 (d, 1H, J )
9.5 Hz), 4.13 (dd, 1H, J ) 4.3, 9.7 Hz), 3.34 (dd, 1H, J ) 9.9,
9.9 Hz), 2.05 (m, 2H), 1.90 (m, 1H), 1.75 (m, 1H), 1.60 (m, 3H),
1.45 (m, 3H), 1.25 (s, 3H), 1.25 (m, 1H), 1.04 (m, 24H), 0.90
(m, 1H), 0.89 (d, 3H, J ) 6.5 Hz). 13C NMR (18): δ 134.50,
129.82, 82.89, 79.06, 65.15, 49.97, 48.58, 37.29, 35.80, 34.01,
28.41, 23.85, 22.40, 21.31, 20.92, 18.12, 17.13, 11.96. IR (18,
CDCl3): 3049, 2943, 2864, 1465, 1375, 1250, 1165, 1092, 1067
cm-1. DCIMS (NH3): m/z 423 (M + H), 381, 379, 273, 249,
229.
(+)-10-Deoxo-13-ca r ba a r tem isin in (21). A mixture of
alcohol 20 (25 mg, 0.094 mmol), Hg(OCOCF3)2 (0.130 g, 0.304
mmol), and 1 mL of THF under a N2 atmosphere was stirred
for 20 h at ambient temperature. NaBH4 (0.012 g) and NaOH
(aqueous, 3 M, 100 µL) were premixed at 0 °C and added to
the above reaction mixture via syringe at 0 °C. After 5 min,
the reaction was quenched with saturated aqueous NH4Cl (10
mL) and the mixture extracted with EtOAc (100 mL). The
organic layer was separated, washed with brine (2 × 10 mL),
filtered over anhydrous Na2SO4, and concentrated by rotary
evaporation. The crude product was purified by flash chro-
matography over silica gel (20% EtOAc/hexane) to afford 19
mg of a white solid (76%) which could be recrystallized from
hexane to afford 21. Mp: 137-138 °C. 1H NMR: δ 4.00 (d,
1H, J ) 8.3 Hz), 3.60 (dd, 1H, J ) 4.2, 11.3 Hz), 3.32 (dd, 1H,
J ) 11.5, 11.5 Hz), 2.59 (m, 1H), 2.18 (d, 2H, J ) 8.3, 14.6
Hz), 1.92 (m, 1H), 1.6-1.78 (m, 4H), 1.4-1.6 (m, 2H), 1.21 (s,
3H), 1.22 (m, 3H), 1.05 (m, 1H), 0.91 (d, 3H, J ) 5.8 Hz), 0.74
(d, 3H, J ) 7.3 Hz). 13C NMR: δ 80.73, 78.09, 67.19, 67.06,
53.41, 44.08, 37.27, 37.10, 36.77, 34.51, 28.16, 27.36, 26.76,
(1R,2S,2′S,5R,6S,9R)-5r,9-Dim eth yl-2â-(1′-h ydr oxypr op-
2′-yl)-10,11-d ioxa tr icyclo[7.2.2.01,6]tr id ec-12-en e (20).
A
solution of 17 (0.78 g, 1.848 mmol), tetrabutylammonium
fluoride (2.03 mL, 2.03 mmol, 1 M solution in THF), and THF
(15 mL) was stirred for 12 h at ambient temperature. The
mixture was then poured into saturated aqueous NH4Cl (50
mL) and extracted with EtOAc (300 mL). The organic layer
was separated, washed with brine (2 × 20 mL), filtered over
anhydrous Na2SO4, and concentrated by rotary evaporation.
The crude product was purified by flash chromatography on