6970 J . Org. Chem., Vol. 65, No. 21, 2000
Pourashraf et al.
Celite with ethyl acetate. The crude product was isolated with
ethyl acetate in the usual way and purified by dry silica gel
column chromatography with methanol in ethyl acetate to give
1H NMR (300 MHz) δ 1.21-1.47 (m, 2 H), 1.53-1.70 (m, 3 H),
1.93-1.98 (m, 1 H), 2.32 (dd, J ) 17.3, 1.7 Hz, 1 H), 2.37-
2.53 (br s, 1 H), 2.55-2.67 (m, 2 H), 6.78 (ddd, J ) 10.9, 4.9,
4.9 Hz, 1 H), 4.04-4.10 (m, 1 H), 4.33-4.38 (m, 1 H); 13C NMR
(75.5 MHz) δ 23.2 (CH2), 24.0 (CH2), 24.6 (CH2), 40.3 (CH2),
41.0 (CH2), 61.7 (CH), 66.3 (CH), 172.2 (C); mass spectrum
0.622 g (75%) of alcohol 7a : mp 145-147 °C; [R]21 +68.0 (c
D
0.2, chloroform); IR 3432, 3242, 1693, 1608 cm-1; 1H NMR (300
MHz) δ 1.13-1.27 (m, 19 H), 1.52 (d, J ) 6.7 Hz, 3 H), 1.30-
1.78 (m, 5 H), 1.87-2.10 (br s, 1 H), 2.46 (AB of ABX, δa
)
(CI), m/z 156 (MH+, 81%), 134 (1%). HRMS m/e calcd for C8H13
-
2.48, δb ) 2.44, J ab ) 16.5 Hz, J ax ) 7.3 Hz, J bx ) 6.9 Hz, 2 H),
2.83 (hept, J ) 6.9 Hz, 1H), 3.12 (hept, J ) 6.8 Hz, 1H), 3.54-
3.63 (m, 3 H), 3.84 (hept, J ) 6.6 Hz, 1 H), 4.11 (pseudo q, X
of ABX, J ax ) 7.3 Hz, J bx ) 6.9 Hz, 1 H), 5.03 (q, J ) 6.7 Hz,
1 H), 6.65-6.90 (br s, 1 H), 6.93 (s, 1 H), 7.02 (s, 1 H); 13C
NMR (75.5 MHz) δ 22.4 (CH2), 23.3 (CH3), 24.0 (CH3), 24.4
(CH3), 25.0 (CH3), 25.1 (CH3), 25.3 (CH3), 28.2 (CH), 29.2 (CH),
29.3 (CH2), 32.3 (CH2), 34.1 (CH), 36.7 (CH2), 57.9 (CH), 62.4
(CH2), 71.5 (CH), 73.0 (CH), 120.7 (CH), 123.4 (CH), 132.4 (C),
145.9 (C), 147.8 (C), 148.9 (C), 175.6 (C); mass spectrum (CI),
m/z 404 (MH+, 100%), 264 (10%), 231 (44%). Anal. Calcd for
NO2 (M+): 155.0946. Found: 155.0959.
(1S,8a S)-Octa h yd r oin d olizin -1-ol (1). A mixture of alco-
hol 8b (0.130 g 0.84 mmol) and lithium aluminum hydride
(0.255 g, 6.72 mmol) in 18 mL of THF was stirred at 20 °C for
24 h. After being diluted with 13 mL of THF, the mixture was
cooled to 0 °C and carefully treated with 0.255 mL of water,
0.255 mL of 10% aqueous sodium hydroxide, and 0.770 mL
water. The resulting mixture was stirred for 40 min at 20 °C
and then treated with anhydrous sodium sulfate. Filtration
of the mixture and concentration of the filtrate under reduced
pressure gave the crude product, which was purified by column
chromatography on silica gel with 0-15% methanol saturated
with ammonia in chloroform to give 0.090 g (76%) of indolizi-
dine 1, as a clear oil: [R]25D +22.5 (c 1.0, ethanol) (lit. +20.2,5f
C
25H41NO3: C, 74.40; H, 10.24; N, 3.47. Found: C, 74.32; H,
10.08; N, 3.58.
(1S,8a S)-1-[(R)-1-(2,4,6-Tr iisop r op ylp h en yl)et h oxy]-
h exa h yd r oin d olizin -3-on e (8a ). To a stirred solution of
0.622 g (1.54 mmol) of alcohol 7a and 0.500 mL (0.363 g, 3.59
mmol) of triethylamine in 6.2 mL of dichloromethane at 0 °C
was added dropwise 0.275 mL (0.407 g, 3.55 mmol) of meth-
anesulfonyl chloride. The resulting solution was stirred at 0
°C for 1.5 h, diluted with 30 mL dichloromethane, and then
treated with 2 mL of water. The crude product was isolated
in the usual way to afford 0.701 g of crude mesylate 7b, which
was used without further purification: IR 3225, 1696, 1607,
1355 cm-1; 1H NMR (300 MHz) δ 1.14-1.40 (m, 20 H), 1.45-
1.56 (m, 4 H), 1.63-1.78 (m, 3 H), 2.44 (AB of ABX, δa ) 2.46,
δb ) 2.42, J ab ) 16.4 Hz, J ax ) 7.2 Hz, J bx ) 7.2 Hz, 2 H), 2.82
(hept, J ) 6.9 Hz, 1 H), 2.97 (s, 3 H), 3.09-3.15 (m, 1 H), 3.51-
3.57 (m, 1 H), 3.82 (hept, J ) 6.6 Hz, 1 H), 4.11 (pseudo q, X
of ABX, J ax ) 7.2 Hz, J bx ) 7.2 Hz, 1H), 4.19 (t, J ) 6.5 Hz, 2
H), 5.03 (q, J ) 6.7 Hz, 1 H), 6.92 (s, 1 H), 7.01 (s, 1 H), 7.03
(s, 1 H); 13C NMR (75.5 MHz) δ 22.2 (CH2), 23.1 (CH3), 23.9
(CH3), 24.2 (CH3), 24.9 (CH3), 25.1 (CH3), 28.1 (CH), 29.1 (CH2),
29.1 (CH), 29.4 (CH2), 33.9 (CH), 36.4 (CH2), 37.4 (CH3), 57.5
(CH), 69.6 (CH2), 71.4 (CH), 72.7 (CH), 120.6 (CH), 123.2 (CH),
132.1 (C), 145.8 (C), 147.7 (C), 148.7 (C), 175.2 (C); mass
spectrum (CI), m/z 482 (MH+, 100%), 386 (94%), 264 (28%),
231 (90%).
+275d), [R]22 +17.4 (c 0.4, chloroform) (lit.5h +16.4, +18.1);
D
IR 3386 cm-1; 1H NMR (300 MHz) δ 1.21 (m, 1 H), 1.42-1.70
(m, 6 H), 1.80-1.99 (m, 3 H), 2.13 (m, 1 H), 2.26 (m, 1 H),
3.07 (m, 2 H), 4.03 (br s, 1 H); 13C NMR (50.3 MHz) δ 23.9
(CH2), 25.2 (CH2), 25.3 (CH2), 33.3 (CH2), 52.8 (CH2), 53.6
(CH2), 68.8 (CH), 73.0 (CH); mass spectrum (CI), m/z 142
(MH+, 61%), 124 (10%), 110 (100%). The 1H NMR spectrum
was in perfect agreement with that of an independently
prepared5d sample (spectrum kindly provided by Professor C.
Harris). HRMS m/e calcd for C8H15NO (M+): 141.1154. Found:
141.1151.
Ben zyl (2S,3S)-2-Bu t-3-en yl-5-oxo-3-[(R)-1-(2,4,6-tr iiso-
p r op ylp h en yl)eth oxy]p yr r olid in e-1-ca r boxyla te (9). To a
solution of lactam 6b (1.80 g, 4.67 mmol) in 36 mL of dry THF
at -78 °C were added 2.50 mL (5.25 mmol) of a 2.1 M solution
of n-butyllithium in hexane and, after 30 min, 1.40 mL (1.67
g, 9.81 mmol) of benzyl chloroformate. The reaction mixture
was allowed to warm to 0 °C and stirred at this temperature
for 1 h. The crude product was isolated with ether in the usual
manner and purified by dry silica gel chromatography with
15% ethyl acetate in hexane to give 2.22 g (92%) of pyrrolidi-
none 9: mp 73 °C (methanol-water); [R]25 +90 (c 1.5,
D
chloroform); IR 3065, 1788, 1754, 1724, 1607, 1288, 1266 cm-1
;
A solution of 0.701 g (ca. 1.46 mmol) of crude mesylate 7b
in 10 mL of THF was added to a stirred mixture of 0.300 g of
sodium hydride (7.50 mmol, 60% in mineral oil) in 12 mL of
THF and 4 mL of freshly distilled DMF at 20 °C. The resulting
mixture was stirred for 2 h, cooled to 0 °C, and then carefully
treated with water. The crude reaction product was isolated
with ether in the normal way and purified by dry silica gel
column chromatography with ethyl acetate in pentane to afford
1H NMR (300 MHz) δ 1.07-1.33 (m, 18 H), 1.54 (d, J ) 6.5
Hz, 3 H), 1.58-1.72 (m, 2 H), 1.92-2.20 (m, 3 H), 2.66 (AB of
ABX, δa ) 2.63, δb ) 2.70, J ab ) 15.8 Hz, J ax ) 8.7 Hz, J bx
)
6.7 Hz, 2 H), 2.83 (hept, J ) 7.0 Hz, 1 H), 3.02-3.18 (m, 1 H),
3.74-3.88 (m, 1 H), 4.03-4.15 (m, 2 H), 4.18-4.29 (m, 1 H),
4.86-4.97 (m, 2 H), 5.04 (q, J ) 6.7 Hz, 1 H), 5.15-5.30 (m, 2
H), 5.64-5.80 (m, 1 H), 6.93 (br s, 1 H), 7.03 (br s, 1 H), 7.25-
7.40 (m, 5 H); 13C NMR (50.3 MHz) δ 22.9 (CH3), 23.8 (CH3),
24.0 (CH3), 24.9 (CH3), 28.0 (CH), 28.3 (CH2), 29.0 (CH), 30.2
(CH2), 33.8 (CH), 38.0 (CH2), 59.6 (CH), 60.0 (CH), 67.9 (CH2),
69.5 (CH), 69.7 (CH), 71.5 (CH), 114.6 (CH2), 120.5 (CH), 123.2
(CH), 128.0 (CH), 128.2(CH), 128.4 (CH), 131.5 (C), 131.8 (C),
135.0 (C), 137.8 (CH), 145.7 (C), 147.6 (C), 148.5 (C), 151.0
(C), 170.4 (C); mass spectrum (CI) m/z 520 (MH+, 100%), 519
(M+, 10%), 231 (6%). Anal. Calcd for C33H45NO4: C, 76.26; H,
8.73; N, 2.70. Found: C, 76.06; H, 8.65; N, 2.63.
Ben zyl (2S,3S)-2-Bu t-3-en yl-3-[(R)-1-(2,4,6-tr iisop r op y-
lp h en yl)et h oxy]p yr r olid in e-1-ca r b oxyla t e (10a ). To a
stirred solution of lactam 9 (2.20 g, 4.23 mmol) in 14 mL of
THF at -78 °C under argon was added dropwise 7.10 mL (7.10
mmol) of a 1 M solution of lithium triethylborohydride in THF.
The resulting solution was stirred for 30 min at -78 °C,
quenched with saturated aqueous sodium bicarbonate solution
(11 mL), and then allowed to warm to 0 °C. Ten drops of 30%
aqueous hydrogen peroxide were added, and the mixture was
then stirred for 30 min at 0 °C. The crude product was isolated
with dichloromethane in the usual way to yield 2.06 g of the
corresponding R-hydroxypyrrolidine, which was used im-
mediately below.
0.525 g (88%) of indolizidinone 8a : mp 144-145 °C; [R]20
D
+86.3 (c 1.0, chloroform); IR 1682, 1608 cm-1; H NMR (300
1
MHz) δ 1.15-1.26 (m, 19 H), 1.29-1.40 (m, 2 H), 1.49 (d, J )
6.8 Hz, 3 H), 1.54-1.72 (m, 2 H), 1.85-1.96 (m, 1 H), 2.49-
2.59 (m, 3 H), 2.83 (hept, J ) 6.9 Hz, 1 H), 3.14 (hept, J ) 6.9
Hz, 1 H), 3.39-3.45 (m, 1 H), 3.85 (hept, J ) 6.8 Hz, 1 H),
4.01 (m, 1 H), 4.08-4.14 (m, 1 H), 5.06 (q, J ) 6.8 Hz, 1 H),
6.92 (s, 1 H), 7.01 (s, 1 H); 13C NMR (75.5 MHz) δ 23.4 (CH3),
24.0 (CH2), 24.2 (CH3), 24.6 (CH3), 24.8 (CH2), 25.2 (CH3), 25.5
(CH3), 25.5 (CH3), 25.8 (CH2), 28.2 (CH), 29.4 (CH), 34.2 (CH),
37.6 (CH2), 40.6 (CH2), 61.5 (CH), 69.8 (CH), 70.7 (CH), 121.0
(CH), 123.5 (CH), 132.3 (C), 146.4 (C), 147.9 (C), 149.1 (C),
171.4 (C). Anal. Calcd for C25H39NO2: C, 77.87; H, 10.19; N,
3.63. Found: C, 77.92; H, 10.35; N, 3.63.
(1S,8a S)-1-Hyd r oxyh exa h yd r oin d olizin -3-on e (8b). A
0.618-g (1.60 mmol) sample of lactam 8a in 10 mL of dichlo-
romethane was stirred with 1.00 mL (1.48 g, 13.0 mmol) of
trifluoroacetic acid at 20 °C for 2.5 h, whereupon chloroform
was added, and the reaction mixture was concentrated to
dryness under reduced pressure. Purification of the resulting
solid by dry silica gel column chromatography with methanol
in ethyl acetate afforded 0.217 g (87%) of alcohol 8b: mp 149-
A stirred solution of this material and 0.700 mL (0.509 g,
4.38 mmol) of triethylsilane in 60 mL of dry dichloromethane
157 °C (dec); [R]20D +26.9 (c 1.5, acetone); IR 3268, 1651 cm-1
;