10002 J. Am. Chem. Soc., Vol. 121, No. 43, 1999
Huang et al.
(1S,4aR,4bR,7S,8aR,10aR)-1-[2-(2-Bromo-4,4-dimethylcyclohex-
1-enyl)ethyl]-7-tert-butyldimethylsiloxy-1,4b,8,8,10a-pentamethyl-
dodecahydrophenanthren-2-one (8). A solution of 7 (30 mg, 48 µmol)
dissolved in a mixture of 3.6 mL of hexanes and 1.2 mL of CH2Cl2
was cooled to -78 °C. A solution of 1.0 M MeAlCl2 (56 µL, 56 µmol)
in hexanes was diluted in a mixture of 2.1 mL of hexanes and 0.70
mL of CH2Cl2 and also cooled to -78 °C. The diluted solution of
MeAlCl2 was added to the solution of 7 via cannula. After the addition
was complete, the mixture was stirred at -78 °C for another 30 min.
Et3N (57 mg, 0.56 mmol) was added, followed by 0.5 mL of 4:1
MeOH-H2O. The mixture was warmed to room temperature and
poured into 5 mL of water. After separation of the layers, the aqueous
phase was extracted three times with 5 mL of ether. The combined
organic extract was washed with brine, dried over Na2SO4, and
evaporated in vacuo to give the crude product as a white foam, which
was azeotropically dried by evaporating with toluene. To a solution of
the dried crude product in 1.0 mL of CH2Cl2 was added TBSCl (11
mg, 72 µmol) and imidazole (6.6 mg, 96 µmol). The resulting mixture
was refluxed for 20 h. After the mixture had been cooled to 23 °C, the
whole was passed through a short column of silica gel, which was
further eluted with 20 mL of CH2Cl2. The eluent was concentrated in
vacuo to give the crude product as a white foam, which was purified
by preparative TLC (eluted with benzene) to give two pure products.
Analytical data for 8: 15.6 mg (52%) of white solid; mp 210-211
1H), 2.24 (br s, 2H), 2.19-2.03 (m, 5H), 1.66-1.43 (m, 9H), 1.43-
1.31 (m, 4H), 1.15 (s, 3H), 0.98 (s, 3H), 0.97 (m, 1H), 0.93 (s, 3H),
0.91 (s, 6H), 0.89 (s, 3H), 0.87 (s, 9H), 0.73 (s, 3H), 0.02 (s, 6H) ppm;
13C NMR (126 MHz, CDCl3) δ 155.6, 135.1, 118.4 (q, J ) 321 Hz),
118.3, 115.2, 79.2, 55.3, 50.2, 47.8, 46.0, 42.1, 39.4, 38.9, 37.1, 35.4,
34.4, 33.6, 32.1, 30.1, 28.6, 28.4, 28.1, 27.7, 27.6, 26.0, 21.8, 20.2,
18.4, 18.2, 16.7, 16.2, -3.7, -4.9 ppm.
Aegiceradienol (3). To a solution of 9 (30 mg, 40 µmol) and Pd-
(PPh3)4 (0.9 mg, 0.80 µmol) in 1.0 mL of THF was added 0.48 mL of
a 0.5 M LiCl solution in THF (0.24 mmol), followed by Me3SnSnMe3
(26 mg, 80 µmol) via syringe. The resulting light yellow solution was
heated at reflux for 16 h. The reaction mixture was cooled to room
temperature. Et3N (0.10 mL) and cyclohexane (7 mL) were added with
stirring. The resulting mixture was then filtered through a short column
of basic alumina (0.8 × 3 cm), which was further eluted with 20 mL
of cyclohexane. The eluent was concentrated in vacuo to give the crude
product as a white foam, which was dried azeotropically by evaporating
with toluene.
To the above crude product was added 3.0 mL of DMF and the
mixture was heated to 60 °C to give a clear solution. A suspension of
CuCl (12 mg, 0.12 mmol) in 1.5 mL of DMF was also heated to 60
°C. This suspension of CuCl was added to the warm solution of crude
product via cannula. The resulting mixture was stirred at 60 °C for 20
min and cooled to room temperature. A 1:1 mixture of concentrated
NH4OH and saturated NH4Cl (2 mL) was added. The mixture was
stirred open to air for 1 h. The mixture was further diluted with 10 mL
of water and extracted three times with 10 mL of cyclohexane. The
combined organic extract was washed once with 10 mL of brine, dried
over Na2SO4, and concentrated in vacuo to give the crude product as
a white foam, which was purified by preparative TLC impregnated
with AgNO3, eluted with pentane, to give 12.5 mg (60%) of 10 as a
white solid. Mp 196.2-197.5 °C; [R]23D +71.8 (c 0.11, benzene); UV
λmax ) 244 nm; Rf ) 0.33 (hexanes, CAM); FTIR (film) 2934, 2904,
2877, 2856, 2835, 1465 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.52 (m,
1H), 3.19 (dd, J ) 11.2, 4.7 Hz, 1H), 2.15-1.83 (m, 7H), 1.78-1.18
(m, 15H), 0.97 (s, 3H), 0.96 (s, 3H), 0.910 (s, 3H), 0.906 (s, 3H), 0.89
°C (recrystalized from CH2Cl2-pentane); [R]23 +12.8 (c 1.04,
D
benzene); Rf ) 0.47 (benzene, CAM); FTIR (film) 2947, 1706, 1466,
1433, 1389, 1252 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.19 (dd, J )
11.4, 4.7 Hz, 1H), 2.54 (td, J ) 13.4, 7.0 Hz, 1H), 2.36 (dt, J ) 17.7,
5.6 Hz, 1H), 2.28-2.01 (m, 4H), 2.23 (br s, 2H), 1.95-1.42 (m, 12H),
1.40-1.31 (m, 1H), 1.38 (t, J ) 6.3 Hz, 2H), 1.20 (s, 3H), 1.02 (m,
1H), 0.91 (br s, 6H), 0.89 (s, 3H), 0.88 (s, 9H), 0.86 (s, 3H), 0.82 (s,
3H), 0.71 (s, 3H), 0.02 (s, 6H) ppm; 13C NMR (101 MHz, CDCl3) δ
216.1, 135.9, 117.4, 79.2, 55.5, 55.2, 50.7, 50.2, 44.5, 39.5, 39.1, 38.1,
37.6, 35.5, 34.2, 32.7, 32.2, 28.5, 27.8, 27.4, 27.0, 26.0, 22.9, 18.5,
18.2, 17.9, 16.8, 16.7, 16.0, -3.7, -4.9 ppm. HRMS (FAB, M + Na+)
calculated for [C35H61O2SiBr + Na]+ 643.3522, found 643.3513.
The byproduct is (1R,4aR,4bR,7S,8aR,10aR)-1-[2-(2-Bromo-4,4-
dimethylcyclohex-1-enyl)ethyl]-7-tert-butyldimethylsiloxy-1,4b,8,8,-
10a-pentamethyldodecahydrophenanthren-2-one (11): 6.9 mg (23%)
of a colorless oil; [R]23D -6.35 (c 0.63, benzene); Rf ) 0.30 (benzene,
CAM); FTIR (film) 2952, 2899, 2857, 1708, 1466, 1390, 1363, 1253
cm-1; 1H NMR (500 MHz, CDCl3) δ 3.23 (dd, J ) 11.4, 4.7 Hz, 1H),
2.57 (td, J ) 13.7, 7.1 Hz, 1H), 2.33-2.21 (m, 3H), 2.12-1.99 (m,
3H), 1.88-1.69 (m, 5H), 1.65-1.30 (m, 10H), 1.06 (td, J ) 13.0, 3.5
Hz, 1H), 0.93 (s, 3H), 0.92 (s, 3H), 0.91 (s, 6H), 0.88 (s, 3H), 0.87 (s,
9H), 0.83 (s, 3H), 0.72 (s, 3H), 0.03 (s, 6H) ppm; 13C NMR (126 MHz,
CDCl3) δ 215.9, 134.2, 118.8, 79.2, 56.7, 55.4, 50.2, 50.0, 43.7, 39.5,
39.1, 39.0, 37.6, 35.4, 34.6, 32.13, 32.08, 31.4, 28.7, 28.5, 28.3, 27.8,
27.6, 26.0, 22.3, 18.4, 18.2, 18.0, 16.8, 16.1, 13.7, -3.7, -4.8 ppm.
HRMS (FAB, M + Na+) calculated for [C35H61O2SiBr + Na]+
643.3522, found 643.3530.
(s, 9H), 0.88 (s, 3H), 0.86 (s, 6H), 0.74 (s, 3H), 0.02 (s, 6H) ppm; 13
C
NMR (101 MHz, CDCl3) δ 140.3, 129.1, 125.4, 116.7, 79.5, 55.6, 47.5,
41.2, 39.6, 39.4, 38.9, 38.7, 37.0, 35.3, 34.0, 29.5, 29.4, 28.9, 28.6,
28.45, 28.37, 27.8, 27.3, 23.6, 21.1, 18.6, 18.2, 16.9, 16.2, 16.1, -3.7,
-4.8 ppm. HRMS (FAB, M+) calculated for [C35H60OSi]+ 524.4414,
found 524.4410. These are identical with the data obtained from an
authentic sample.
The product obtained above was dissolved in 0.10 mL of a 1.0 M
solution of TBAF in THF (0.10 mmol) and stirred at 50 °C for 14 h.
The solution was cooled to room temperature. NH4Cl (20 mg) was
added. After the mixture was stirred at room temperature for another
15 min, it was diluted with 5 mL of EtOAc. The whole was filtered
through a short column of silica gel, which was further eluted with 10
mL of EtOAc. The eluent was concentrated in vacuo to give the crude
product as a white foam, which was purified by preparative TLC and
eluted with 20% EtOAc in hexanes to give 9.0 mg (92%) of pure
aegiceradienol (3) as a white solid. Mp 191-192 °C [lit.15 mp 185-
188 °C]; [R]23D +74.3 (c 0.33, benzene) [lit. [R]23D +74 (c 0.83)];15 Rf
) 0.31 (20% EtOAc in hexanes, CAM); FTIR (film) 3327, 3053, 2945,
2931, 2904, 2874, 2834, 1451, 1264 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.49 (m, 1H), 3.20 (dd, J ) 10.8, 5.7 Hz, 1H), 2.08-1.82 (m, 7H),
1.74-1.20 (m, 16H), 0.98 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H), 0.88 (s,
3H), 0.85 (s, 6H), 0.77 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ
140.3, 129.1, 125.3, 116.6, 79.0, 55.5, 47.4, 41.2, 39.6, 38.8, 38.6, 37.1,
35.3, 33.9, 29.5, 29.3, 28.9, 28.4, 28.3, 28.1, 27.35, 27.30, 23.5, 21.1,
18.4, 16.9, 16.0, 15.7 ppm. HRMS (EI, M+) calculated for [C29H46O]+
410.3549, found 410.3533. These are identical in all aspects with the
authentic sample.
1,1,1-Trifluoromethanesulfonic Acid (1S,4aR,4bR,7S,8aR,10aR)-
1-[2-(2-Bromo-4,4-dimethylcyclohex-1-enyl)ethyl]-7-tert-butyl-
dimethylsiloxy-1,4b,8,8,10a-pentamethyl-1,4,4a,4b,5,6,7,8,8a,9,-
10,10a-dodecahydrophenanthren-2-yl Ester (9). To a solution of 8
(45 mg, 72 µmol) in 0.36 mL of THF cooled at -78 °C was added a
freshly prepared 0.50 M LDA solution in THF (220 µL, 0.11 mmol,).
After the mixture was stirred at -78 °C for 30 min, it was warmed to
0 °C and stirred for another 1 h. The solution was cooled to -78 °C,
and solid PhNTf2 (41 mg, 0.12 mmol, 1.6 equiv) was added. After the
mixture was stirred at -78 °C for 30 min, it was warmed to 23 °C and
stirred at that temperature for 1.5 h. The reaction was quenched by the
addition of 3 mL of water. After the aqueous phase was extracted three
times with 10 mL of hexanes, the combined hexanes extract was dried
over MgSO4, passed through a short column of silica gel, and
concentrated in vacuo to give crude 9 as a yellow solid, which was
purified by preparative TLC (eluted with 3% EtOAc in hexanes) to
2-Bromo-1-hydroxymethyl-4,4-dimethyl-1-cyclohexene. PBr3 (23.2
g, 86 mmol) was added dropwise to a solution of DMF (6.95 g, 95
mmol) in 25 mL of chloroform at 0 °C. The white suspension was
warmed to 70 °C for 30 min. 3,3-Dimethylcyclohexanone (4.0 g, 32
give 46 mg of pure 9 (84%) as a white foam. [R]23 +1.43 (c 0.63,
D
benzene); Rf ) 0.59 (5% EtOAc in hexanes, CAM); FTIR (film) 2954,
(15) Vidari, G.; Dapiaggi, A.; Zanoni, G.; Garlaschelli, L. Tetrahedron
Lett. 1993, 34, 6485.
1
2930, 2857, 1413, 1390, 1247 cm-1; H NMR (500 MHz, CDCl3) δ
5.63 (t, J ) 4.1 Hz, 1H), 3.17 (dd, J ) 11.2, 4.5 Hz, 1H), 2.29 (m,
(16) Rao, K. V.; Bose, P. K. J. Org. Chem. 1962, 27, 1470.