DiVersely Functionalized Pyrrolizidines and Indolizidines
4.55-4.48 (m, 1H,), 4.47 (t, J ) 8.4 Hz, 1H), 2.81-2.72 (m, 1H),
2.42-2.30 (m, 1H), 2.21-2.12 (m, 1H), 1.37-1.22 (m, 1H). 13C
NMR (100 MHz, CDCl3,) δ 171.6, 169.6, 149.9, 137.0, 129.3-128.8
(6C), 68.3, 67.7, 55.9, 35.6, 29.5. HRMS m/z calcd for C15H15NO3
257.1052, found 257.1025.
(3S,6R,7R,8aR)-6,7-Dihydroxy-5-oxooctahydroindolizine-3-
carboxylic Acid Benzyl Ester (8). To a solution of 4a (264 mg,
0.97 mmol) and trimethylamine N-oxide (172 mg, 1.55 mmol) in
5 mL of tert-butyl alcohol-water (3:1) was added a 2.5% solution
of osmium tetraoxide in tert-butyl alcohol (0.68 mL, 0.08 mmol).
The solution was stirred at 40 °C for 3 h. After cooling to room
temperature, sodium bisulfite (100 mg) was added, and stirring was
continued for 30 min. The mixture was then concentrated, AcOEt
was added, and the solution was filtered through Celite. The filtrate
was dried over sodium sulfate and concentrated in vacuo, and the
residue was purified by flash chromatography (AcOEt/MeOH 95:
and 65.6, 65.1 and 63.4, 63.0 and 62.3, 60.1 and 59.2, 58.7 and
57.1, 46.4 and 45.8, 32.9 and 31.1, 28.0 and 27.2, 24.7 and 24.2.
HRMS (ESI, M + 1 ion) calcd for C9H18NO3 188.1287, found
188.1291.
(2S,5S)-5-Vinylpyrrolidine-1,2-dicarboxylic Acid Dibenzyl
Ester (18). To a solution of 7 (100 mg, 0.43 mmol) and TEA (60
µL, 0.43 mmol) in dry THF (1 mL) was added benzyloxycarbon-
ylchloride (123 µL, 0.86 mmol), and the mixture was stirred at
room temperature for 4 h. The reaction mixture was diluted with
AcOEt (3 mL), washed with saturated aqueous NH4Cl, and dried
over Na2SO4. After evaporation of the solvent, the crude product
was purified by flash chromatography (AcOEt/hexane 1:3) to
provide 18 (121 mg, 77%) as an oil. Rf ) 0.40 (hexane/AcOEt
1
7:3). [R]25 ) -58.1 (c 0.9, CHCl3). H NMR (400 MHz,CDCl3,
D
mixture of conformers) δ 7.47-7.23 (m, 10H), 5.81 (m, 1H),
5.30-4.95 (m, 6H), 4.68 (br, t, J ) 5.6 Hz, 0.5H, conformer A),
4.62 (br, t, J ) 5.6 Hz, 0.5H, conformer B), 4.53 (br, d, J ) 9.7
Hz, 0.5H, conformer A), 4.48 (br, d, J ) 9.7 Hz, 0.5H, conformer
B), 2.32-2.10 (m, 2H), 2.01-1.93 (m, 1H), 1.80-1.72 (m, 1H).
13C NMR (100 MHz, CDCl3, mixture of conformers) δ 172.4 and
172.2, 155.0 and 154.0, 137.9 and 137.4, 136.6 and 136.5, 135.7
and 135.5, 128.6-127.7 (10C), 114.6 and 114.3, 67.1 and 67.0,
66.9 and 66.8, 60.1 and 59.7, 59.5, 31.0 and 29.6, 28.4 and 27.2.
HRMS m/z calcd for C22H23NO4 365.1627, found 365.1831.
(2S,5R)-5-Allylpyrrolidine-1,2-dicarboxylic Acid 1-Benzy-
lester 2-Methylester (19). To a solution of 13 (385 mg, 2.25 mmol)
and TEA (313 µL, 2.25 mmol) in dry THF (4 mL) was added
benzyloxycarbonylchloride (642 µL, 4.50 mmol), and the mixture
was stirred at room temperature for 4 h. The reaction mixture was
diluted with AcOEt (5 mL), washed with saturated aqueous NH4Cl,
and dried over Na2SO4. After evaporation of the solvent, the crude
product was purified by flash chromatography (AcOEt/hexane 1:4)
5), yielding 256 mg (86%) of 8 as a colorless oil. Rf ) 0.11 (hexane/
1
AcOEt 3:7). [R]25 ) -23.5 (c 1.2, CHCl3). H NMR (400 MHz,
D
CDCl3,) δ 7.40-7.25 (m, 5H), 5.22 (d, AB system, J ) 12.3 Hz,
1H), 5.14 (d, AB system, J ) 12.3 Hz, 1H), 4.50 (d, J ) 9.8 Hz,
1H), 4.35 (t, J ) 3.5 Hz, 1H), 4.08 (d, J ) 3.5 Hz, 1H), 4.05 (tt,
J ) 11.7, 4.1 Hz, 1H), 3.60-3.20 (br, s, 2H), 2.40 (dt, J ) 13.8,
4.0 Hz, 1H), 2.27-2.15 (m, 1H), 2.07-1.95 (m, 2H), 1.72 (t, J )
13.8 Hz, 1H), 1.72-1.60 (m, 1H). 13C NMR (100 MHz, CDCl3,)
δ 171.8, 170.8, 136.2, 129.2-128.7 (5C), 71.3, 67.7, 66.7, 58.1,
56.2, 33.1, 31.7, 29.5. HRMS m/z calcd for C16H19NO5 305.1263,
found 305.1269.
(3S,6S,7S,8aS)-6,7-Dihydroxy-5-oxo-octahydroindolizine-3-
carboxylic Acid Benzyl Ester (9). To a solution of 4b (132 mg,
0.49 mmol) and trimethylamine N-oxide dehydrate (88 mg, 0.79
mmol) in 3 mL of tert-butyl alcohol-water (3:1) was added a 2.5%
solution of osmium tetraoxide in tert-butyl alcohol (0.34 mL, 0.03
mmol). The solution was stirred at 40 °C for 3 h. After cooling to
room temperature, sodium bisulfite (40 mg) was added, and stirring
was continued for 30 min. The mixture was then concentrated,
AcOEt was added, and the solution was filtered through Celite.
The filtrate was dried over sodium sulfate and concentrated in
vacuo, and the residue was purified by flash chromatography
(AcOEt/MeOH 95:5), yielding 104 mg (72%) of 9 as a colorless
oil. Rf ) 0.12 (AcOEt). [R]25D ) -164.7 (c 0.4, CHCl3). 1H NMR
(400 MHz, CDCl3) δ 7.40-7.29 (m, 5H), 5.23 (d, AB system, J )
12.9 Hz, 1H), 5.16 (d, AB system, J ) 12.9 Hz, 1H), 4.50 (t, J )
9.4 Hz, 1H), 4.34 (t, J ) 3.3 Hz, 1H), 4.18-4.08 (m, 2H), 4.04 (d,
J ) 3.3 Hz, 1H), 3.28 (br, s, 1H), 2.47-2.38 (m, 2H), 2.13-2.06
(m, 1H), 1.93-1.82 (m, 1H), 1.63-1.45 (m, 2H). 13C NMR (100
MHz, CDCl3) δ 171.6, 169.6, 135.6, 128.5-128.0 (5C), 70.4, 66.8,
66.3, 57.5, 55.3, 32.4, 32.3, 28.1. HRMS m/z calcd for C16H19NO5
305.1263, found 305.1271.
to provide 19 (600 mg, 88%) as an oil. Rf ) 0.38 (hexane/AcOEt
1
7:3). [R]25 ) -16.1 (c 0.9, CHCl3). H NMR (400 MHz,CDCl3,
D
mixture of conformers) δ 7.42-7.30 (m, 5H), 5.82 (m, 1H),
5.22-5.01 (m, 4H), 4.39 (m, 1H), 4.02 (m, 1H) 3.79 (s, 1.5H,
conformer A), 3.61 (s, 1.5H, conformer B), 2.86-2.75 (m, 0.5H,
conformer A), 2.70-2.62 (m, 0.5H, conformer B), 2.32-2.18 (m,
2H), 2.10-2.90 (m, 2H), 1.88-1.77 (m, 1H). 13C NMR (100 MHz,
CDCl3, mixture of conformers) δ 173.4 and 173.3, 154.9 and 154.1,
136.6, 135.1, 128.4-127.1 (5C), 117.2, 67.1 and 66.9, 60.2 and
59.9, 58.7 and 58.1, 52.2 and 52.0, 39.0 and 38.2, 29.5 and 28.9,
28.7 and 28.0. HRMS m/z calcd for C17H21NO4 303.1471, found
303.1487.
(2S,5S)-5-((E)-3-Oxobut-1-enyl)-pyrrolidine-1,2-dicarboxyl-
ic Acid Dibenzyl Ester (11). To a stirred solution of olefin 18
(100 mg, 0.27 mmol) and methyl vinyl ketone (22 µL, 0.27 mmol)
in dry toluene (0.05 M, 5.5 mL) was added second generation
Grubbs-Hoveyda catalyst (8 mg, 5% mol). The reaction mixture
was stirred under N2 atmosphere for 4 h at 80 °C. The solvent was
evaporated, and the residue was purified by flash chromatography
on silica gel (AcOEt/hexane 1:1) yielding 70 mg (61%) of 11 as
(3S,6R,7S,8aS)-3-Hydroxymethyloctahydroindolizine-6,7-di-
ol Hydrochloride (10). LiAlH4 (1 mL, 1 M in THF) was added
dropwise over 10 min to a solution of 9 (104 mg, 0.34 mmol) in
dry THF (4 mL) cooled to 0 °C. The reaction was kept for 10 min
at 0 °C and then refluxed. After 4 h, the reaction mixture was cooled
at -5 °C and quenched with saturated aqueous NaHCO3 (3 mL).
AcOEt was added, and the mixture was filtered through Celite. The
organic phase was separated, dried, and concentrated in vacuo to
yield a yellow oil. The residue was suspended in MeOH (6 mL)
cooled at 0 °C, and the solution was saturated with gaseous HCl.
After 30 min, the reaction was warmed to room temperature and
concentrated in vacuo. The residue was crystallized from isopro-
an oil. Rf ) 0.11 (AcOEt/hexane 3:7). [R]25 ) -48.7 (c 1.1,
D
1
CHCl3). H NMR (400 MHz, CDCl3, mixture of two conformers)
δ 7.41-7.20 (m, 10H), 6.71 (dd, J ) 15.9, 5.5 Hz, 0.5H, conformer
A), 6.63 (dd, J ) 15.8, 5.8 Hz, 0.5H, conformer B), 6.15 (dd J )
15.8, 1.2 Hz, 0.5H, conformer A), 6.02 (dd, J ) 15.8, 1.0 Hz, 0.5H,
conformer B), 5.30-4.97 (m, 4H), 4.82 (m, 0.5H,conformer A),
4.72 (m, 0.5H, conformer B), 4.57 (br, d, J ) 9.0 Hz, 0.5H,
conformer B), 4.50 (br, d, J ) 9.0 Hz, 0.5H, conformer A),
2.40-2.18 (m, 2H), 2.28 (s, 1.5H, conformer A), 2.16 (s, 1.5H,
conformer B), 2.05-1.98 (m, 1H), 1.85-1.77 (m, 1H). 13C NMR
(100 MHz, CDCl3, mixture of two conformers) δ 199.8 and 198.8,
171.3, 159.7, 145.7 and 145.4, 136.5, 129.9 and 129.8, 129.7-128.5
(10C), 128.1, 67.4 and 67.3, 67.0 and 66.9, 59.9 and 59.6, 58.6
and 58.2, 29.8 and 28.8, 28.5 and 27.4, 27.6 and 27.5. HRMS m/z
calcd for C24H25NO5 407.1733, found 407.1738.
panol, yielding 37 mg (46%) of 10 (as hydrochloride). [R]25
)
D
1
-155.7 (c 2.1, MeOH). H NMR (400 MHz, DMSO, mixture of
two stereoisomers) δ 10.90 (br, s, 0.5H, stereoisomer A), 10.20
(br, s, 0.5H, stereoisomer B), 5.42 (br, s, 0.5H, stereoisomer B),
5.38 (br, s, 0.5H, stereoisomer A), 5.30 (d, 0.5H, J ) 5.4 Hz,
stereoisomer A), 5.23 (d, 0.5H, J ) 5.4 Hz, stereoisomer B), 5.07
(br, s, 0.5H, stereoisomer B), 5.02 (br, s, 0.5H, stereoisomer A),
4.03-3.48 (m, 6H), 3.30-3.08 (m, 2H), 2.20-1.55 (m, 6H). 13C
NMR (100 MHz, DMSO, mixture of two stereoisomers) δ 66.8
(2S,5R)-5-((E)-4-Oxopent-2-enyl)-pyrrolidine-1,2-dicarboxy-
lic Acid 1-Benzylester 2-Methylester (12). To a stirred solution
J. Org. Chem. Vol. 74, No. 2, 2009 595