6950 J . Org. Chem., Vol. 61, No. 20, 1996
Almqvist and Frejd
aqueous saturated NaHCO3 (10.0 mL) was added, and the
resultant mixture was extracted with EtOAc. The combined
organic phase was washed in sequence with aqueous saturated
CuSO4 and brine and dried. Concentration at reduced pres-
sure and chromatography (SiO2, heptane:EtOAc 1:2) gave 1d
2a and dry ZnCl2 gave 3a (48%), 4 (27%), and 1d (16%).
For 3a : mp 84.5-85.5 °C; [R] -55° (c 9.9, CHCl3); IR (neat)
2960, 2880, 1740, 1650, 1610, 1245 cm-1; 1H NMR (400 MHz,
CDCl3) δ 14.24 (s, 1H) 5.06 (dm, J ) 9.2 Hz, 1H) 2.85 (m, 1H)
2.69 (m, 1H) 2.20 (ddd, J ) 14.0, 9.2, 2.6 Hz, 1H) 2.04 (s, 3H)
1.98 (s, 3H) 1.70 (m, 2H) 1.57 (m, 1H) 1.46 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 200.05, 174.59, 170.41, 112.54, 71.29,
44.89, 36.10, 29.38, 25.09, 21.13, 19.97, 18.78; HRCIMS (CH4)
calcd for C12H16O4 224.1049, observed 224.1047.
For 4: [R] -40° (c 3.9, CHCl3); IR (neat) 2930, 2860, 1730,
1695, 1600 1225 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.10 (dm,
J ) 9.5 Hz, 1H) 3.43 (m, 1H) 2.65 (d, J ) 0.8 Hz, 3H) 2.65 (m,
1H) 2.26 (m, 1H) 1.99 (d, J ) 1.0 Hz, 3H) 1.71-1.87 (m, 2H)
1.58-1.68 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 199.14,
170.19, 143.99, 134.77, 70.81, 48.40, 34.13, 33.33, 25.06, 23.18,
21.06, 19.73; HRCIMS (CH4) calcd for C12H15O3Cl 242.0710,
observed 242.0710.
as an oil (123 mg, 95%); [R] -30° (c 3.1, CHCl3) (lit.23 [R]20.0
D
-27.6° (c 1.4, CHCl3)); IR and NMR data were as reported.23
(1R,4S,6S)-6-Meth oxybicyclo[2.2.2]octa n -2-on e (1e). Io-
domethane (1.1 mL, 17.7 mmol) was added dropwise to a
solution of (-)-1a (200 mg, 1.43 mmol) in acetonitrile (2.5 mL)
under argon at rt. After 5 min Ag2O (460 mg, 1.98 mmol) was
added in portions, and the mixture was heated at reflux for
36 h and then filtered through a pad of Hyflo-Supercel. The
pad was washed with CH2Cl2, and the combined solution was
concentrated at reduced pressure. Chromatography (SiO2,
heptane:EtOAc 1:1) gave 1e as an oil (178 mg, 81%): [R] -26°
(c 1.9, CHCl3); IR (neat) 2940, 2870, 2820, 1725, 1100 cm-1
;
1H NMR (400 MHz, CDCl3) δ 3.67 (ddd, J ) 8.9, 3.7, 2.5 Hz,
1H) 3.26 (s, 3H) 2.65 (m, 1H) 2.27 (dm, J ) 18.3 Hz, 1H) 2.22
(m, 1H) 2.15 (dm, J ) 18.3 Hz, 1H) 2.04 (m, 1H) 1.80 (m, 1H)
1.45-1.68 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 214.39, 77.84,
55.67, 46.39, 44.31, 33.98, 27.56, 24.06, 19.78; HRCIMS (CH4)
calcd for C9H15O2 155.1072, observed 155.1075.
2d and dry ZnCl2 gave 3b (13%) and 1e (27%). For 3b: [R]
-36° (c 0.15, CHCl3); IR (neat) 2930, 2860, 1640, 1590, 1255
1
cm-1; H NMR (400 MHz, CDCl3) δ 14.27 (s, 1H) 3.66 (dm, J
) 9.4 Hz, 1H) 3.32 (s, 3H) 2.87 (m, 1H) 2.84 (m, 1H) 2.02-
2.10 (m, 1H) 2.03 (s, 3H) 1.71 (m, 1H) 1.42-1.76 (m, 4H); 13
C
NMR (100 MHz, CDCl3) δ 201.17, 173.87, 112.67, 78.45, 55.94,
44.41, 36.12, 29.52, 25.72, 19.81, 18.68; HRCIMS (CH4) calcd
for C11H17O3 197.1177, observed 197.1177.
Methods utilizing basic conditions for the protection accord-
ing to standard procedures25 were unsuccessful.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e TMS-
En ol Eth er s 2a -d a n d 5. The silyl enol ethers 2a , 2b, 2d ,
and 5 were prepared according to a literature procedure12 in
over 90% yields. Silyl enol ether 2c was synthesized by
applying a method developed for the preparation of silyloxy
dienes as follows.26 TMSCl (0.52 mL, 4.10 mmol), 1d (748 mg,
4.10 mmol), and NEt3 (0.57 mL, 4.38 mmol) were added in
sequence to a solution of dry LiBr (714 mg, 8.22 mmol) in THF
(3 mL) at -20 °C. After 1 h at -20 °C, the temperature was
raised to 40 °C, and the mixture was kept at that temperature
for 48 h. The solvent was then removed at reduced pressure
and replaced with cold pentane. The resulting mixture was
filtered through Hyflo-Supercel, and then the solvent was
removed at reduced pressure to give an oil which was diluted
with heptane:EtOAc 3:1, and the solution was filtered through
a pad of silica. The solvent was removed at reduced pressure
to give 2c as a pale yellow oil (877 mg, 84%). Due to their
sensibility toward hydrolysis, all the TMS-enol ethers were
used directly in the next step without further purification. The
purity of the TMS-enol ethers was generally g90% according
to GC; NMR data were as reported for 2a 12 and 5.27
5 and dry ZnCl2 gave 6 (62%) as an oil: [R] +141° (c 1.40,
CHCl3); IR (neat) 2960, 2920, 2870, 1755, 1730, 1665, 1370,
1
1200, 1175 cm-1; H NMR (400 MHz, CDCl3) δ 2.59 (d, J )
4.2 Hz, 1H) 2.28 (s, 3H) 2.17 (s, 3H) 1.92 (m, 1H) 1.64 (m, 1H)
1.42 (m, 2H) 0.94 (s, 3H) 0.91 (s, 3H) 0.80 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 207.55, 168.06, 151.24, 130.21, 58.82,
47.95, 46.10, 30.31, 25.65, 20.86, 20.27, 18.30, 17.20, 9.35;
HRCIMS (CH4) calcd for C14H20O3 237.1491, observed 237.1490.
(1R,4S,6S)-6-Acetoxy-3-vin ylid en ebicyclo[2.2.2]octa n -
2-on e (7). Potassium tert-butoxide (180 mg, 1.61 mmol) was
added in one portion under a stream of argon to a solution of
4 (300 mg, 1.24 mmol) in THF (55 mL) at -50 °C. After 90
min at this temperature aqueous saturated NH4Cl was added
cautiously, and the mixture was extracted with EtOAc and
dried. Concentration at reduced pressure followed by chro-
matography (SiO2, heptane:EtOAc 70:30) gave 7 (255 mg,
100%): mp 131-132 °C; [R] -39° (c 0.7, CHCl3); IR (KBr) 2950,
2880, 1960, 1930, 1735, 1680, 1240 cm-1; 1H NMR (400 MHz,
CDCl3) δ 5.24 (s, 2H) 5.15 (dm, J ) 9.6 Hz, 1H) 2.86 (m, 1H)
2.69 (m, 1H) 2.30 (m, 1H) 2.00 (s, 3H) 1.62-1.92 (m, 5H); 13
C
NMR (100 MHz, CDCl3) δ 206.57, 200.23, 170.29, 106.88,
79.86, 70.74, 46.67, 34.89, 33.48, 24.08, 21.11, 19.62; HRMS
calcd for C12H14O3 206.0943, observed 206.0946.
For 2b: 1H NMR (300 MHz, CDCl3) δ 7.27 (d, J ) 8.6 Hz,
2H) 6.86 (d, J ) 8.6 Hz, 2H) 5.17 (dd, J ) 7.3, 2.2 Hz, 1H)
4.51 (d, J ) 11.7 Hz, 1H) 4.40 (d, J ) 11.6 Hz, 1H) 3.80 (s,
3H) 3.65 (m, 1H) 2.69 (m, 1H) 2.53 (m, 1H) 1.78 (ddd, J )
13.0, 8.2, 2.4 Hz, 1H) 1.46 (m, 1H) 1.12-1.38 (m, 4H) 0.21 (s,
9H).
(1R,4S,6S)-(E)-3-(1-Ch lor oeth yliden e)-6-h ydr oxybicyclo-
[2.2.2]octa n -2-on e (8). Compound 4 (614 mg, 2.54 mmol) was
diluted with EtOH (14 mL) and 1 M HCl (43 mL). After 6 h
at 50 °C ice was added, and the mixture was extracted with
EtOAc. The combined organic phase was washed with satu-
rated aqueous NaHCO3 and dried. Concentration at reduced
pressure followed by chromatography (SiO2, heptane:EtOAc
1:2) gave 8 (462 mg, 91%): mp 83-84 °C; [R] -0.4° (c 7.7,
CHCl3); IR (KBr) 3420, 1690, 1600, 635 cm-1 1H NMR (400
MHz, CDCl3) δ 4.16 (dm, J ) 9.0 Hz, 1H) 3.38 (m, 1H) 2.81-
3.06 (s, 1H) 2.60 (d, J ) 1.2 Hz, 3H) 2.56 (m, 1H) 2.15 (m, 1H)
1.52-1.81 (m, 5H) 13C NMR (100 MHz, CDCl3) δ 201.33,
143.61, 135.09, 68.68, 52.14, 36.10, 33.42, 25.09, 23.22, 19.58;
HRCIMS (CH4) calcd for C10H12OCl 183.0576, observed
183.0577.
For 2c: 1H NMR (300 MHz, CDCl3) δ 5.1 (dd, J ) 7.2, 2.3
Hz, 1H) 4.88 (m, 1H) 2.53 (m, 1H) 1.97 (s, 3H) 1.89-1.99 (m,
1H) 1.40-1.50 (m, 2H) 1.12-1.36 (m, 3H) 0.19 (s, 9H).
For 2d : 1H NMR (400 MHz, CDCl3) δ 5.16 (dd, J ) 7.2, 2.3
Hz, 1H) 3.48 (m, 1H) 3.28 (s, 3H) 2.64 (m, 1H) 2.53 (m, 1H)
1.77 (dd, J ) 12.9, 7.9, 2.4 Hz, 1H) 1.46 (m, 1H) 1.14-1.38
(m, 4H) 0.19 (s, 9H).
Gen er a l P r oced u r e for th e Acetyla tion of th e TMS-
En ol Eth er s 2a -d a n d 5. Acetyl chloride (2.7 mmol) was
added to a slurry of Lewis acid (2.3 mmol) in CH2Cl2 (1.2 mL)
and diethyl ether (0.2 mL) at 0 °C (-72 °C when TiCl4 or SnCl4
were used). After 5 min the TMS-enol ether (1.0 mmol) was
added. The mixture was kept at 0 °C for 1 h and then allowed
to reach rt within 45 min. After 30 min at rt ice was added,
and then the mixture was extracted with CH2Cl2. The
combined organic phase was washed with saturated aqueous
NaHCO3 and dried. Concentration at reduced pressure gave
a crude oil which was purified by chromatography (SiO2,
heptane:EtOAc 70:30).
(1R ,4S ,6S )-(Z)-6-H yd r oxy-3-(1-h yd r oxye t h ylid e n e )-
bicyclo[2.2.2]octa n -2-on e (9). Compound 4 (218 mg, 0.90
mmol) was diluted with EtOH (5 mL) and 1 M HCl (15 mL).
After 14 h at reflux ice was added, and the mixture was
extracted with EtOAc. The combined organic phase was
washed with saturated aqueous NaHCO3 and dried. Concen-
tration at reduced pressure followed by chromatography (SiO2,
heptane:EtOAc 1:3) gave 9 (136 mg, 83%): mp 137-143 °C;
[R] -24° (c 0.3, CHCl3); IR (KBr) 3400, 1630, 1585, 705 cm-1
;
1H NMR (400 MHz, CDCl3) δ 4.18 (dm, J ) 8.7 Hz, 1H) 2.85
(m, 1H) 2.63 (m, 1H) 2.15 (ddd, J ) 13.7, 8.9, 2.6 Hz, 1H) 2.04
(s, 3H) 1.39-1.91 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
(26) Hansson, L.; Carlson, R. Acta Chem. Scand. 1989, 43, 188-
192.
(27) J oshi, G. C.; Pande, L. M. Synthesis 1975, 450-451.