Taber and Storck
cis enone was based on NMR evidence. In 18, H-5 is
equatorial and does not couple with the axial H-4a. It
therefore appears as a simple singlet. In 17, in contrast,
these two protons, both axial, share a coupling constant
at 4.8 Hz. Moreover, in the carbon NMR, C-4a of 18
appears at a higher field (δ 41.8) than in 17 (δ 46.4). The
structures of 17 and 18 were confirmed by X-ray crystal-
lographic analysis. The pure ketones 17 and 18 were each
efficiently equilibrated by DBU to the 1:2 mixture of 17
and 18.
was brought to room temperature, stirred for 1 h, and then
concentrated in vacuo. The residue was chromatographed to
yield the ketone 14 as a colorless solid (790 mg, 89% yield from
2
0
1
3): TLC R
f
) 0.40 (petroleum ether-MTBE, 8:2); [R]
2 2
D
+2.2
); mp 53-55 °C (ethanol); H NMR δ 1.29 (s,
H), 1.30 (s, 3H), 1.52-2.00 (m, 8H), 2.25 (s, 3H), 3.01 (m, 1H),
1
(
3
3
c ) 1.0, CH Cl
13
.77-4.08 (m, 6H); C NMR δ u 207.9, 110.3, 110.1, 67.5, 63.3,
39.8, 31.0, 24.4, 22.6; d 78.2, 74.7, 52.2, 32.3, 26.1, 25.4; IR
(KBr) 3440, 1706 cm . Anal. Calcd for C15
H, 8.5. Found: C, 63.22; H, 8.55.
-
1
24 5
H O : C, 63.36;
Cyclop en ten e 15. A solution of n-BuLi (1.86 M in hexane,
2
.0 mL) was added over 2 min to a solution of TMS diazo-
methane (2 M in hexanes, 2.12 mL) in THF (8 mL) chilled at
78 °C. After 1 h, a solution of ketone 14 (790 mg, 2.74 mmol)
Con clu sion
-
in THF (2 mL) was added over 2 min, and the mixture was
stirred 1 h at -78 °C and 1 h at 0 °C. The reaction mixture
was partitioned between dichloromethane (10 mL) and, se-
As we had hoped, the synthesis of the enantiopure
cyclohexenone 18 has been successfully completed using
an alkylidene carbene insertion/ozonolysis/aldol se-
quence. The alkyidene carbene insertion proceeds with
retention of absolute configuration, so it can be used for
the asymmetric construction of quaternary stereogenic
centers. Our efforts toward the enantioselective synthesis
of (-)-tetrodotoxin are continuing.
quentially, 50% saturated aqueous NH
4
Cl (10 mL) and brine
SO ) and
(10 mL). The combined organic extract was dried (Na
2
4
concentrated in vacuo. The residue was chromatographed to
yield the cyclopentene 15 (650 mg, 83% yield from 14) as a
colorless oil: TLC R
f
) 0.45 (petroleum ether-MTBE, 9:1);
2
0
1
[
3
3
(
1
3
R]
D
2 2
+13.1 (c ) 1.0, CH Cl ); H NMR δ 1.28 (s, 3H), 1.29 (s,
H), 1.48-1.90 (m, H), 2.24 (m, 1H), 3.52 (d, 1H, J ) 8.39 Hz),
.62 (dd, 1H, J ) 11.2, 10.2 Hz), 3.67 (d, 1H, J ) 9.3 Hz), 3.97
Exp er im en ta l Section
dd, 1H, J ) 10.2, 4.1 Hz), 4.25 (d, 1H, J ) 8.3 Hz), 5.25 (m,
H); 13C NMR δ u 140.3, 112.2, 109.0, 89.4, 66.2, 65.2, 40.2,
Diol 12. A freshly made solution of isopropenylmagnesium
bromide in THF (1.0 M, 210 mL) was added over 20 min to a
2.3, 24.6, 22.9; d 128.9, 83.1, 46.0, 26.6, 15.0; IR (film) 1631
-
1
cm . Anal. Calcd for C16
8.19; H, 8.85.
Aceta te 16. A solution of the alkene 15 (500 mg, 1.78 mmol)
24 4
H O : C, 68.54; H, 8.63. Found: C,
slurry of CuBr‚SMe
2
(17.2 g, 83.7 mmol) in dry ether (320 mL)
6
cooled to -50 °C. The mixture was stirred for 10 min at -20
7
°
C, after which time a solution of the epoxy alcohol 11 (4.19
and a crystal of Sudan III in dichloromethane (10 mL) was
chilled at -78 °C and ozonized until the red color faded.
Nitrogen was bubbled through the solution for 10 min before
methyl sulfide (1 mL) was added. The reaction mixture was
brought to room temperature and stirred for 3 h before being
concentrated in vacuo. The residue was dissolved in 10 mL of
dry dichloromethane and cooled at 0 °C, and a solution of DBU
g, 24.1 mmol) in ether (100 mL) was added over 10 min. The
mixture was stirred at -20 °C for 36 h. The reaction mixture
was partitioned between ether (200 mL) and, sequentially, 75%
saturated aqueous NH
combined organic extract was dried (Na
in vacuo. The residue was chromatographed to yield the diol
4
Cl (400 mL) and brine (200 mL). The
2
SO ) and concentrated
4
1
0
CH
f
2 as white crystals (4.45 g, 86% yield from 11): TLC R )
2
0
(272 mg, 1.80 mmol) in CH
was stirred for 24 h at rt before a solution of Ac
.96 mmol) in CH Cl (1 mL) and DMAP (10 mg) were
sequentially added. After 60 min, the reaction was partitioned
2
Cl
2
(1 mL) was added. The mixture
.38 (petroleum ether-ethyl acetate, 1:1); [R]
D
+22 (c ) 1.0,
); mp 51-53 °C (petroleum ether-ethyl acetate); 1
2
O (185 µL,
2
Cl
2
H
1
2
2
NMR δ 1.36 (s, 3H), 1.44 (s, 3H), 1.73 (s, 3H), 2.19 (m, 1H),
3
1
0
1
3
.09 (d, 1H, J ) 2.7 Hz), 3.12 (m, 1H), 3.69 (m, 1H), 3.91 (m,
between water (10 mL) and CH
organic extract was dried (Na SO
2
Cl
2
(10 mL). The combined
H), 3.95 (s, 1H), 3.98 (s, 1H), 4.10 (m, 2H), 4.83 (d, 1H, J )
.5 Hz), 4.92 (t, 1H, J ) 1.5 Hz); 13C NMR δ u 142.4, 114.7,
2
4
) and concentrated in vacuo.
The residue was chromatographed to yield the acetate 16 (213
mg, 33% yield from 15) as a colorless solid: TLC R ) 0.25
petroleum ether-MTBE, 4:1); [R]20
+21.1 (c ) 1.47, CH
Cl ); mp 133-138 °C (petroleum ether-ethyl acetate); H NMR
δ 1.4-1.9 (m, 9Η), 1.47 (s, 3H), 1.49 (s, 3H), 2.12 (s, 3H), 2.44
m, 1H), 2.73 (dd, 1H, J ) 14.6, 11.7 Hz), 2.83 (dd, 1H, J )
4.6, 5.6 Hz), 3.26 (dd, 1H, J ) 11.7, 3.2 Hz), 3.75 (dd, 1H, J
3.4 Hz), 4.0 (AB system, 2H), 4.12 (d, 1H, J ) Hz), 4.57 (d,
09.1, 65.0, 63.7; d 76.7, 72.4, 51.1, 26.6, 25.3, 21.2; IR (film)
-1
+
f
418, 1645 cm ; HRMS calcd for C11
20 4
H O 217.1440 (M + H ),
(
D
2
-
found 217.1438.
1
2
Keta l 13. A mixture of cyclopentanone (0.43 mL, 4.86
mmol), trimethyl orthoformate (0.51 mL, 4.66 mmol). and
(
1
PTSA (48 mg, 0.25 mmol) in CH
min at rt and then cooled to 0 °C. A solution of diol 12 (1.00 g,
.63 mmol) in CH Cl (10 mL + 2 mL rinse) was then added
in one portion. After 3 min, the reaction mixture was parti-
tioned between a saturated solution of NaHCO (10 mL) and
CH Cl (10 mL). The combined organic extract was dried (Na
SO ) and concentrated in vacuo. The residue was chromato-
2 2
Cl (10 mL) was aged for 10
)
4
2
2
1
3
1
H, J ) 11.7 Hz), 5.33 (dd, 1H, J ) 11.9 Hz, J ) 5.61 Hz);
C
NMR δ u 204.7, 170.1, 111.3, 110.9, 81.4, 68.0, 59.3, 43.3, 40.0,
3
3
1
0.5, 24.5, 22.6; d 74.3, 68.2, 44.2, 27.8, 25.9; IR (KBr) 3426,
744, 1722 cm ; MS (CI, 70 eV) m/z, 354 (36), 325 (62),153
2
2
2
-
-
1
4
+
26 7
(71),135 (100); HRMS calcd for C18H O 354.1679 (M ), found
graphed to yield the alkene 13 as a colorless oil (1.00 g, 76%
yield from 12, 90% yield based on the recovered starting
3
54.1669.
2
0
Allylic Alcoh ols 19 a n d 20. To a solution of the acetate
material): TLC R
27 (c ) 1.0, CH
1
1
7
f
) 0.55 (petroleum ether-MTBE, 9:1); [R]
D
1
16 (162 mg, 0.46 mmol) in dichloromethane (4.6 mL) was
added DBU (72 mL, 0.48 mmol), and the mixture was stirred
for 24 h at rt. The reaction was then partitioned between water
+
2
Cl
2
); H NMR δ 1.36 (s, 3H), 1.39 (s, 3H),
1
3
.55-1.91 (m, 9H), 2.00 (m, 1H), 2.20 (m, 1H),; C NMR δ u
42.1, 114.2, 110.2, 109.2, 65.8, 64.7, 40.1, 30.8, 24.4, 22.7; d
6.8, 73.0, 45.9, 26.1, 26.1, 21.6; IR (film) 3076, 1644 cm-1
;
(10 mL) and CH Cl (10 mL). The combined organic extract
2
2
was dried (Na
2
SO
4
) and concentrated in vacuo. The residue
MS (CI, 70 eV) m/z 284 (36), 269 (26), 255 (62), 183 (60), 125
+
was chromatographed to yield a 2:1 mixture of trans- and cis-
cyclohexenones 17 and 18 (127 mg, 95% yield from 16) as a
colorless oil.
(100); HRMS calcd for C16
H
26
O
4
284.1625 (M ), found 284.1624.
Anal. Calcd for C16
H, 9.33.
26 4
H O : C, 68.06; H, 9.28. Found: C, 68.28;
Keton e 14. A solution of the alkene 13 (890 mg, 3.13 mmol)
and a crystal of Sudan III in CH Cl (18 mL) was chilled at
78 °C and ozonized until the red color faded. Nitrogen was
bubbled through the solution for 10 min before triphenylphos-
phine (910 mg, 3.47 mmol) was added. The reaction mixture
To a solution of ketones 17 and 18 (177 mg, 0.6 mmol) in
2
2
dry MeOH (6 mL) was added CeCl
The mixture was cooled with an ice-water bath, and solid
NaBH (24 mg, 0.63 mmol) was added over a 5 min period.
The mixture was stirred for 30 min and was then partitioned
3
2
‚7H O (225 mg, 0.61 mmol).
-
4
7
770 J . Org. Chem., Vol. 68, No. 20, 2003