Li et al.
for 1.5 h. The solvent was removed under reduced pressure.
Flash chromatography (hexanes:EtOAc 1:3 to EtOAc 100%)
provided alcohol 13 (1.62 g, 5.98 mmol) as a colorless oil. Yield
0.32, EtOAc:hexanes 1:1) as a colorless oil and aldol product
f
16 (145 mg, 0.60 mmol, R 0.25, EtOAc:hexanes 1:1). The total
combined yield for 16 and 17 was 82%. Spectral data for 17:
2
0
1
20
1
96%; [R]
D
-2 (c 1.0, CHCl
3
); H NMR (300 MHz, CDCl
3
) δ
D 3 3
[R] -15.1 (c 1.0, CHCl ); H NMR (300 MHz, 56 °C, CDCl )
1
.23 (t, J ) 6.9 Hz, 3 H), 1.55 (dt, J ) 14.4, 4.8 Hz, 1 H), 1.67
δ 1.28 (t, J ) 7.2 Hz, 3 H), 2.34 (dd, J ) 8.4, 3.6 Hz, 2 H), 2.89
(td, J ) 6.9, 1.2 Hz, 2 H), 3.46 (d, J ) 2.4 Hz, 1 H), 3.66 (m, 1
H), 3.79 (m, 1 H), 3.96 (s, br, 1 H), 4.18 (q, J ) 7.2 Hz, 2 H),
(
m, 2 H), 2.01 (s, 3 H), 2.76 (dt, J ) 14.4, 8.4 Hz, 1 H), 3.16
m, br, 2 H), 3.35 (m, br, 1 H), 3.55 (t, J ) 5.6 Hz, 2 H), 4.11
q, J ) 6.9 Hz, 2 H), 4.98 (m, br, 1 H), 5.48 (m, 1 H), 5.91 (m,
(
1
3
(
4.96 (m, br, 1 H), 9.83 (app. s, 1 H); C NMR (300 MHz, CDCl
3
)
13
2
H); C NMR (300 MHz, CDCl
9.7, 60.2, 61.7, 77.2, 132.7, 136.1, 157.1, 170.5; HRMS [MH ]
272.1498, found 272.1494.
1R,4S)-4-[N-(Carboethoxy)-N-(propanolamino)]-2-cy-
clopenten-1-ol (14). To a solution of alcohol 13 (1.43 g, 5.27
mmol) in ethanol (10 mL) was added K CO (800 mg, 5.79
3
) δ 14.7, 21.0, 33.5, 36.2, 40.0,
δ 14.7, 34.0, 37.4, 44.6, 51.6, 55.1, 58.2, 69.2, 156.2, 200.2,
+
+
5
203.8; HRMS [MH ] calcd for C11
5
H16NO 242.1028, found
calcd for C13H22NO
5
242.1033. Spectral data for 16 (as a mixture of diastereo-
1
mers): H NMR (500 MHz, CDCl
.93-1.99 (m, 1 H), 2.18-2.34 (m, 1 H), 2.62 (s, br, 1 H), 3.10
3.03) (td, J ) 13.0, 2 Hz, 1 H), 3.49 (d, J ) 2.5 Hz, 1 H), 3.96-
3
) δ 1.31 (t, J ) 7.0 Hz, 3 H),
(
1
(
2
3
4
1
2
.04 (m, 2 H), 4.11-4.27 (m, br, 3 H), 4.89 (4.78) (d, J ) 9.5,
H); HRMS [MH ] calcd for C11
mmol) at room temperature. The resulting reaction mixture
was stirred at room temperature for 3 h. TLC analysis (100%
EtOAc) showed that starting material was consumed. EtOH
+
5
H15NO 242.1028, found
42.1026.
was removed under reduced pressure then CH
2
Cl
Cl (saturated,
0 mL). The aqueous layer was extracted with CH Cl
(3 ×
0 mL), and the combined organic layers were dried over
and filtered. The solvent was evaporated to provide
2
(30 mL) was
(1S,8S,9S)-2-(Carboethoxy)-8,9-epoxy-2-azabicyclo[4.3.0]-
non-5-en-7-one (18). From aldehyde 17, alumina method:
A solution of aldehyde 17 (110 mg, 0.46 mmol) in CH Cl
added to redissolve the residue followed by NH
4
3
3
2
2
2
2
(5 mL) was treated with activated alumina (1.5 g, MCIB,
80-200 mesh, ALCOA, type F-20) and the resulting reaction
mixture was stirred at room temperature under an Ar atmo-
sphere for 8 h. The mixture was then filtered and the solid
retained and washed with 60 mL of 9:1 CH Cl :MeOH solvent.
MgSO
4
20
diol 14 (1.21 g, 5.27 mmol) as a colorless oil. Yield 100%; [R]
D
1
-
67.4 (c 1.0, CHCl
3 3
); H NMR (500 MHz, CD OD) δ 1.27 (t, J
)
6.9 Hz, 3 H), 1.46 (dt, J ) 13.8, 5.7 Hz, 1 H), 1.80 (m, 2 H),
2
2
2
.72 (dt, J ) 13.8, 8.1 Hz, 1 H), 3.24 (m, 1 H), 3.60 (m, br, 1
The solvent was evaporated and the crude product was purified
by flash chromatography (EtOAc hexanes 3:1) to provide enone
18 (48 mg, 0.21 mmol) as a colorless oil and aldol product 16
(32 mg, 0.13 mmol) as a colorless oil. Total yield 76%. From
aldehyde 17, L-proline method: To a solution of aldehyde
17 (60 mg, 0.25 mmol) in DMSO (3 mL) was added L-proline
(14 mg, 0.12 mmol) at room temperature. The resulting
reaction mixture was stirred at room temperature under Ar
atmosphere for 10 h. The solvent was evaporated under
reduced pressure and the crude product was purified by flash
chromatography (EtOAc:hexanes 3:1) to provide enone 18 (17
mg, 0.075 mmol) as a colorless oil and aldol product 16 (18
mg, 0.075 mmol) as a colorless oil. Total yield 60%. From
aldol product 16: To a solution of aldol product 16 (200 mg,
H), 3.56 (t, J ) 6.3 Hz, 2 H), 4.14 (q, J ) 6.9 Hz, 2 H), 4.66 (m,
1
3
br, 1 H), 5.02 (m, br, 1 H), 5.80 (m, 1 H), 5.97 (m, 1 H);
NMR (300 MHz, CD OD) δ 15.1, 34.52 (br), 39.9 (br), 41.6,
0.9, 61.7, 62.8, 75.5, 134.2, 138.2, 158.3; HRMS [MH ] calcd
for C11 230.1392, found 230.1404.
1R,2R,3S,4S)-4-[N-(Carboethoxy)-N-(propanolamino)]-
,3-epoxycyclopentan-1-ol (15). To a solution of diol 14 (1.21
g, 5.27 mmol) in CH Cl (10 mL) was added NaHCO (531 mg,
.32 mmol) and m-CPBA (77%, 1.3 g, 5.79 mmol) at room
C
3
+
6
H
20NO
4
(
2
2
2
3
6
temperature. The resulting reaction mixture was stirred at
room temperature overnight. TLC analysis showed that all of
the starting material was consumed. Then the reaction
mixture was diluted with CH
saturated Na SO solution (20 mL). The aqueous layer was
extracted with CH Cl
(2 × 50 mL). The combined organic
layers were washed with saturated NaHCO solution (20 mL),
and CH Cl
(2 × 30 mL) was used to extract the aqueous layer.
The combined organic layers were dried over MgSO and
2 2
Cl (30 mL) and quenched with
2 2
0.83 mmol) in CH Cl (6 mL) was added triethylamine (300
2
3
µL, 2.16 mmol) followed by MsCl (160 µL, 2.08 mmol) at room
temperature. The resulting reaction mixture was stirred at
room temperature under Ar atmosphere for 2 h and then
cooled to 0 °C. DBU (70 µL, 0.50 mmol) was added slowly. The
resulting reaction mixture was stirred for 10 min at 0 °C.
2
2
3
2
2
4
filtered. The solvent was evaporated and the crude product
was purified by flash chromatography (EtOAc 100% to
Saturated NH
reaction. The aqueous layer was extracted with CH
50 mL), and the combined organic layers were dried over
4
Cl solution (15 mL) was added to quench the
CH
as a colorless oil. Yield 92%; [R]
300 MHz, CD
overlapping, 1 H), 1.86 (apparent q, J ) 6.9 Hz, 2 H), 1.97 (dt,
J ) 12.3, 7.5 Hz, 1 H), 3.40-3.50 (m, 4 H), 3.60 (t, J ) 6.3 Hz,
3
OH:CH
2
Cl
2
1:15) to provide epoxide 15 (1.19 g, 4.85 mmol)
2
Cl
2
(3 ×
20
1
D
-3.4 (c 1.0, CHCl
3
); H NMR
(
3
OD) δ 1.27 (t, J ) 6.9 Hz, 3 H), 1.33 (m,
4
MgSO and filtered. The solvent was evaporated to provide
the crude product as a light yellow oil that was purified by
flash chromatography (EtOAc:hexanes 3:1) to give enone 18
1
3
20
2
H), 4.14 (m, 3 H), 4.45 (m, br, 1 H); C NMR (300 MHz,
(144 mg, 0.65 mmol) as a colorless oil. Yield 78%; [R]
D
-421
1
CD
3
OD) δ 15.1, 29.5, 34.4, 41.8, 55.6, 57.1, 57.4, 61.0, 62.9,
3 3
(c 0.1, CHCl ); H NMR (500 MHz, CDCl ) δ 1.34 (t, J ) 7.0
+
70.9; HRMS [MH ] calcd for C11
46.1338.
H
20NO
5
246.1341, found
Hz, 3 H), 2.28-2.15 (m, 1 H), 2.42-2.52 (m, 1 H), 2.89 (td, J
) 12.0, 2.7 Hz, 1 H), 3.48 (d, J ) 3.0 Hz, 1 H), 4.11 (m, br, 1
H), 4.25 (q, J ) 7.0 Hz, 2 H), 4.38 (m, br, 1 H),4.54 (s, 1 H),
2
(
2S,3S,4S)-4-[N-(Carboethoxy)-N-(propanalamino)]-
1
3
7
.07 (dt, J ) 7.5, 3.0 Hz, 1 H); C NMR 500 MHz, CDCl
3
) δ
2
,3-epoxycyclopentan-1-ol (17) and (1S,8S,9S)-2-(Carbo-
1
4.9, 25.7, 40.5, 53.9, 54.1, 55.7, 62.1, 133.4, 138.5, 156.0, 193.9;
HRMS [MH ] calcd for C11H14NO 224.0923, found 224.0932.
4
ethoxy)-8,9-epoxy-2-azabicyclo[4.3.0]non-5-ol-7-one (16).
+
To a solution of oxalyl chloride (0.76 mL, 8.68 mmol) in
CH
2
Cl
2
(10 mL) at -78 °C was added DMSO (1.85 mL, 26.05
(1S,8S,9S)-2-(Carboethoxy)-7-(Z/E)-8,9-epoxy-2-aza-
bicyclo[4.3.0]non-5-ene (19). To a stirred suspension of
powdered ethyltriphenylphosphonium bromide (372 mg, 1.00
mmol) in 5 mL of anhydrous ether at room temperature in a
sealed tube was added 1.6 N n-butyllithium (625 µL, 1.00
mmol) in hexanes. After 30 min, a solution of the enone 18
(112 mg, 0.50 mmol) in 1 mL of ether was added to the yellow
ylide solution. The mixture was heated at 65 °C for 4 h, cooled
to room temperature, and quenched with water (5 mL). The
mixture was extracted with ether (4 × 20 mL). The combined
organic extracts were dried over anhydrous potassium carbon-
ate, filtered, and concentrated under reduced pressure. Flash
chromatography of the residue on silica gel with 25% ethyl
mmol) dropwise. The mixture was stirred at -78 °C for 15
min. To this solution was then added diol 15 (710 mg, 2.90
mmol) in CH
at -78 °C for 40 min, after which triethylamine (4.04 mL,
8.95 mmol) was added dropwise. This resulting mixture was
2 2
Cl (6 mL). The reaction mixture was maintained
2
stirred at -78 °C for 30 min then warmed to room tempera-
ture. CH
reaction mixture and CH
2
Cl
2
(30 mL) and H
Cl
2
O (20 mL) were poured into the
(3 × 40 mL) was used to extract
2
2
the aqueous layer. The combined organic layers were dried
over MgSO
crude product was purified by flash chromatography (EtOAc:
hexanes 1:1) to provide aldehyde 17 (430 mg, 1.78 mmol, R
4
and filtered. The solvent was evaporated and the
f
8840 J. Org. Chem., Vol. 69, No. 25, 2004