Total Synthesis of nor-1,6-Germacradien-5-ols
J . Org. Chem., Vol. 67, No. 5, 2002 1559
cooled to 0 °C. 2,6-Lutidine (980 µL, 8.4 mmol, 200 mol %)
and TBSOTf (1.16 mL, 5.0 mmol, 120 mol %) were added
sequentially, dropwise, and the resulting mixture was stirred
for 2 h and quenched with saturated K2CO3 solution (20 mL)
before the layers were separated. The aqueous phase was
extracted with CH2Cl2 (3 × 10 mL), the combined organic
extracts were washed with brine (2 × 10 mL), dried (MgSO4),
and filtered, and the solvent was removed in vacuo. The
residue was purified by flash chromatography (hex/CHCl3 3:1)
to give 3c as a clear liquid (1.36 g, 3.8 mmol, 92%) (2:1 syn/
3:1) to give 5 as a clear oil (20 mg, 0.10 mmol, 34%) as a 75:25
E,E/Z,E mixture, along with recovered starting material (51
mg, 0.16 mmol, 51%) (9:1 E/Z ). Rf ) 0.33 (hex/CHCl3, 1:2).
(()-E,E-5: 1H NMR (CDCl3) δ 6.02 (d, J ) 16.1 Hz, 1H),
5.94 (dd, J ) 16.1 Hz, J ) 9.3 Hz, 1H), 5.06 (dddd, J ) 15.6
Hz, J ) 10.3 Hz, J ) 3.7 Hz, J ) 1.5 Hz, 1H), 4.98 (ddd, J )
15.6 Hz, J ) 10.6 Hz, J ) 2.7 Hz, 1H), 2.53 (m, 2H), 2.43 (m,
2H), 2.30-2.10 (m, 3H), 1.83 (m, 1H), 1.58 (m, 1H), 1.38 (m,
1H), 0.90 (d, J ) 6.8 Hz, 3H), 0.84 (d, J ) 6.8 Hz, 3H). 13C
NMR (CDCl3) δ 202.0, 150.9, 140.6, 136.4, 131.3, 52.9, 42.1,
33.7, 32.3, 30.9, 30.7, 20.8, 19.4. HRMS: calcd for M+ (C13H20O)
192.1514, found 192.1521.
(()-(1S*,4S*)-4-Isop r op yl-1-m eth yl-cyclod eca -2,7(E/E)-
d ien ol [(()-2]. In a 25 mL two-necked round-bottom flask
under argon was placed enone E,E-5 (20 mg, 104 µmol) in dry
Et2O (1.7 mL), and the solution was cooled to -78 °C. MeLi
(1.6 M) in Et2O (130 µL, 208 µmol, 200 mol %) was added
dropwise, and the resulting mixture was stirred at -78 °C for
1 h, quenched with ice water (2 mL), and then allowed to warm
to rt. The layers were separated, and the aqueous one was
extracted with Et2O (2 × 2 mL). The combined organic extracts
were washed with brine (2 × 5 mL), dried (MgSO4), and
filtered, and the solvent was removed under reduced pressure.
The residue was purified by flash chromatography (hex/AcOEt,
15:1) to give 2 as a clear oil (18.8 mg, 90.4 µmol, 94%). Rf )
0.25 (hex/AcOEt, 9:1). 1H NMR (CDCl3) δ 5.13 (d, J ) 15.9 Hz,
1H), 5.02 (dd, J ) 15.9 Hz, J ) 9.5 Hz, 1H), 4.97 (m, 2H),
2.55-2.35 (m, 1H), 2.25-2.15 (m, 2H), 2.15-2.05 (m, 1H), 2.0-
1.75 (m, 1H), 1.70-1.60 (m, 3H), 1.55-1.40 (m, 2H), 1.35-
1.15 (m, 1H), 1.21 (s, 3H), 0.84 (d, J ) 6.8 Hz, 3H), 0.79 (d, J
) 6.8 Hz, 3H). 13C NMR (CDCl3) δ 141.1, 135.2, 132.4, 130.9,
73.6, 52.5, 38.5, 34.3, 33.0, 31.1, 29.9, 28.9, 20.6, 18.9. HRMS:
calcd for M+ (C14H24O) 208.1827, found 208.1825.
1
anti mixture). Rf ) 0.35 (hex/ CHCl3 2:1). H NMR (CDCl3) δ
5.80 (m, 2H), 5.00 (m, 4H), 4.40 (m, 1H), 2.63 (m, 1H), 2.53
(m, 2H), 2.42 (m, 1H), 2.32 (m, 2H), 2.10 (m, 2H), 1.87 (m,
1H), 1.58 (m, 1H), 1.38 (m, 1H), 1.25 (m, 2H), 0.95 (major) and
0.95 (minor) (2d, J ) 6.9 Hz, 3H), 0.90 (minor) and 0.87 (major)
(2d, J ) 6.9 Hz, 3H). 13C NMR (CDCl3) δ 209.1, 139.3 (minor),
139.1, 137.1, 115.2, 114.5, 114.1 (minor), 70.1, 69.9 (minor),
49.6 (minor), 49.1, 47.4, 46.7 (minor), 43.7 (minor), 43.6, 33.6
(minor), 33.1, 28.9, 27.5, 27.2, 26.4, 26.0 (minor), 25.9, 22.6,
21.6 (minor), 20.5 (minor), 19.9, 18.0, -4.5, -4.6, -4.8 (minor).
t
HRMS: calcd for (M+ - Bu) (C17H31O2Si) 295.2096, found
295.2047.
(()-cis/tr a n s-9-(ter t-Bu tyl-d im eth yl-sila n yloxy)-8-iso-
p r op yl-cyclod ec-4(E/Z)-en on e [(()-10]. In a 1 L three-
necked round-bottom flask under argon was placed bisolefin
3c (180 mg, 0.51 mmol) in degassed CH2Cl2 (888 mL) and Ti-
(OiPr)4 (16 µL, 51 µmol, 10 mol %), and the solution was heated
to reflux for 1 h. A solution of Grubbs’ catalyst (43 mg, 51 µmol,
10 mol %) in degassed CH2Cl2 (17 mL) was cannulated over
the bisolefin solution, and the resulting mixture was heated
under reflux for another 36 h. The reaction mixture was
allowed to cool to rt, a stream of air was bubbled through it,
and the solvent was evaporated under reduced pressure. The
residue was purified by flash chromatography (hex/CHCl3, 3:1)
to give (()-E-trans-10 (47% yield), (()-E-cis-10 (21% yield), and
(()-Z-trans-10 (8% yield) all as clear oils. Rf (E-trans) ) 0.24,
Rf (E-cis) ) 0.19, and Rf (Z-trans) ) 0.24 (hex/ CHCl3, 1:1).
(()-E-tr a n s-10: 1H NMR (CDCl3) δ 5.57 (ddd, J ) 15.3 Hz,
J ) 7.6 Hz, J ) 7.6 Hz, 1H), 5.52-5.40 (m, 1H), 4.38 (dd, J )
10.7 Hz, J ) 3.8 Hz, 1H), 2.92 (dd, J ) 17.7 Hz, J ) 10.7 Hz,
1H), 2.72-2.57 (m, 1H), 2.45-2.30 (m, 2H), 2.30-2.05 (m, 3H),
1.80-1.60 (m, 1H), 1.65-1.50 (m, 3H), 1.35-1.25 (m, 1H), 0.96
(d, J ) 6.6 Hz, 3H), 0.93 (d, J ) 6.6 Hz, 3H), 0.85 (s, 9H), 0.03
(s, 6H). 13C NMR (CDCl3) δ 212.0, 135.3, 128.3, 68.6, 51.4, 44.8,
42.4, 31.4, 30.0 (bs), 28.9 (bs), 27.9 (bs), 25.8, 21.3, 21.2, 18.1,
-3.8, -4.7. HRMS: calcd for M+ (C19H36O2Si) 324.2485, found
324.2475.
(()-8-Isop r op yl-5-m et h yl-d od eca -1,6(E),11-t r ien -5-ol
[(()-4a ]. In a 25 mL two-necked round-bottom flask under
argon was placed enone 9 (100 mg, 0.45 mmol) in dry Et2O (7
mL), and the solution was cooled to -78 °C. MeLi (1.6 M) in
Et2O (0.56 mL, 0.90 mmol, 200 mol %) was added dropwise,
and the resulting mixture was stirred for 30 min at -78 °C
and then allowed to warm slowly to -20 °C before being
quenched with ice water (10 mL) and allowed to warm to rt.
The layers were separated and the aqueous one was extracted
with Et2O (3 × 10 mL). The combined organic extracts were
washed with brine (2 × 10 mL), dried (MgSO4), and filtered,
and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography (hex/AcOEt, 15:
1) to give 4a as a colorless oil (102 mg, 0.43 mmol, 85%) in a
(()-E-cis-10: 1H NMR (CDCl3) δ 5.60-5.30 (m, 2H), 4.32
(ddd, J ) 9.5 Hz, J ) 6.5 Hz, J ) 2.7 Hz, 1H), 3.14 (dd, J )
15.6 Hz, J ) 10.4 Hz, 1H), 2.55-2.35 (m, 4H), 2.35-1.80 (m,
4H), 1.55-1.40 (m, 1H), 1.25-1.15 (m, 2H), 0.90 (d, J ) 6.9
Hz, 3H), 0.89 (s, 9H), 0.76 (d, J ) 6.9 Hz, 3H), 0.09 (2s, 6H).
13C NMR (CDCl3) δ 209.7, 131.8, 127.4, 68.9, 51.3, 48.9, 44.2,
42.3, 26.4, 26.3, 25.8, 23.7, 23.6, 22.0, 17.0, -4.3, -4.6.
(()-Z-tr a n s-10: 1H NMR (CDCl3) δ 5.47 (dddd, J ) 11.1
Hz, J ) 11.1 Hz, J ) 5.6 Hz, J ) 1.1 Hz, 1H), 5.32 (ddd, J )
11.1 Hz, J ) 11.1 Hz, J ) 5.0 Hz, 1H), 4.43 (dd, J ) 11.1 Hz,
J ) 5.9 Hz, 1H), 3.33 (dd, J ) 16.8 Hz, J ) 11.1 Hz, 1H), 2.95
(m, 1H), 2.61 (m, 1H), 2.53 (td, J ) 13.6 Hz, J ) 4.5 Hz, 1H),
2.31 (dd, J ) 13.2 Hz, J ) 4.2 Hz, 1H), 2.24 (dd, J ) 16.8 Hz,
J ) 5.9 Hz, 1H), 2.12 (m, 1H), 2.02 (m, 1H), 1.90 (m, 1H), 1.54
(m, 1H), 1.31 (m, 1H), 1.20 (m, 1H), 0.90 (d, J ) 6.8 Hz, 3H),
0.89 (s, 9H), 0.87 (d, J ) 6.8 Hz, 3H), 0.06 (s, 6H). 13C NMR
(CDCl3) δ 211.1, 131.7, 127.3, 70.3, 46.3, 44.5, 43.7, 32.1, 26.5,
25.9, 23.2, 22.9, 21.5, 20.8, 18.0, -3.6, -4.7.
(()-4-Isop r op yl-cyclod eca -2,7(E/E)-d ien on e [(()-5]. In
a 10 mL round-bottom flask under argon was placed 10 (E/Z,
11:1; cis/trans, 14:86) (100 mg, 0.31 mmol) in dry DMF (2.5
mL), and DBU (135 µL, 0.90 mmol, 290 mol %) was added
dropwise at rt. The resulting mixture was stirred at 50 °C for
18 h, allowed to cool to rt, and poured into Et2O (20 mL) and
brine (20 mL), and the biphasic mixture was stirred for 30
min. The layers were separated. The organic layer was dried
(MgSO4) and filtered, and the solvent was removed in vacuo.
The residue was purified by flash chromatography (hex/CHCl3
1:1 mixture of diastereomers. Rf ) 0.34 (hex/AcOEt, 15:1). H
1
NMR (CDCl3) δ 5.83 (m, 2H), 5.47 (2d, J ) 15.6 Hz, 1H), 5.37
and 5.34 (2d, J ) 15.6 Hz, 1H), 4.98 (m, 4H), 2.15-2.05 (m,
3H), 1.98-1.85 (m, 1H), 1.80 (m, 1H), 1.70-1.45 (m, 5H), 1.40-
1.25 (m, 1H), 1.29 (s, 3H), 0.89 and 0.87 (2d, J ) 6.8 Hz, 3H),
0.84 and 0.83 (2d, J ) 6.8 Hz, 3H). 13C NMR (CDCl3) δ 139.10,
139.09, 139.01, 138.98, 138.27, 129.65, 129.58, 114.37, 114.23,
73.03, 72.99, 48.45, 41.77, 31.89, 31.85, 31.67, 31.54, 28.70,
28.67, 28.56, 20.80, 20.76, 19.03, 18.97. HRMS: calcd for (M+
- OH) (C16H27) 219.2113, found 219.2137.
(()-[1-Bu t -3-en yl-4-isop r op yl-1-m et h yl-oct a -2,7-d ien -
yloxy]-ter t-bu tyl-d im eth yl-sila n e [(()-4b]. In a 25 mL two-
necked round-bottom flask under argon was placed Me3Al (2
M) in hex (348 µL, 0.68 mmol, 150 mol %) in dry THF (6 mL),
and the solution was cooled to -78 °C. MeLi (1.6 M) in Et2O
(426 µL, 0.68 mmol, 150 mol %) was added dropwise, and the
resulting mixture was stirred for 30 min and then cannulated
into a solution of enone 9 (100 mg, 0.45 mmol) and TBSOTf
(125 µL, 144 mg, 0.54 mmol, 120 mol %) in THF (3 mL) at
-78 °C. The resulting mixture was stirred for another 1 h at
-78 °C, quenched with sat. K2CO3 solution (5 mL), and allowed
to warm to rt. The layers were separated, and the aqueous
one was extracted with Et2O (3 × 5 mL). The combined organic
extracts were dried (MgSO4) and filtered, and the solvent was
removed under reduced pressure. The residue was purified by
flash chromatography (hex) to give 4b as a clear oil (142 mg,
0.41 mmol, 90%) in a 1:1 mixture of diastereomers. Rf ) 0.46
1
(hex). H NMR (CDCl3) δ 5.82 (m, 2H), 5.42 and 5.41 (2d, J )