New Asymmetric Approach to Natural Pyrrolizidines
+ isobutane) m/z 388 (MH+, 100), 387 (M+), 231, 184. More
polar diastereomer: 1H NMR (300 MHz) δ 1.13-1.34 (m, 18
H), 1.59 (d, J ) 6.8 Hz, 3 H), 2.50 (A of ABX, J ) 16.6, 6.7 Hz,
1 H), 2.59 (B of ABX, J ) 16.6, 8.7 Hz, 1 H), 2.86 (sept, J )
6.9 Hz, 1 H), 3.03 (br s, 1 H), 3.14 (sept, J ) 6.7 Hz, 1 H), 3.63
(dd, J ) 7.7, 1.7 Hz, 1 H), 3.82 (sept, J ) 6.8 Hz, 1 H), 4.32
(m: ddd, J ) 7.3, 7.3, 7.3 Hz, 1 H), 4.59 (d, J ) 2.2 Hz, 1 H),
5.16 (q, J ) 6.8 Hz, 1 H), 5.25 (m: ddd, J ) 10.7, 1.6, 1.6 Hz,
1 H), 5.42 (m: ddd, J ) 17.3, 1.6, 1.6 Hz, 1 H), 5.82 (m: ddd,
J ) 17.3, 10.7, 4.6 Hz, 1 H), 6.26 (br s, 1 H), 6.97 (s, 1 H), 7.06
(s, 1 H); 13C NMR (75.5 MHz) δ 23.2 (CH3), 23.8 (CH3), 28.2
(CH), 29.1 (CH), 33.9 (CH), 37.4 (CH2), 60.6 (CH), 70.5 (CH),
71.6 (CH), 72.3 (CH), 116.5 (CH2), 120.9 (CH), 123.4 (CH),
130.8 (C), 136.4 (CH), 146.3 (C), 148.1 (C), 148.6 (C), 175.3
(C). Anal. Calcd for C24H35NO3‚1/3H2O (mixture of diastereo-
mers): C, 73.24; H, 9.65; N, 3.56. Found: C, 73.32; H, 9.57;
N, 3.49.
and brine, dried over Na2SO4, filtered, and concentrated. The
crude material was purified by silica gel chromatography with
ethyl acetate in pentane to give 0.934 g (75%) of sulfonate 18b
as a mixture of diastereomers. Less polar diastereomer: mp
132-133 °C (pentane); [R]25 -51.4 (c 0.4, CHCl3). IR 3200,
D
2958, 2928, 2871, 1701, 1601, 1460 cm-1; 1H NMR (300 MHz)
δ 1.10-1.35 (m, 36 H), 1.59 (d, J ) 6.7 Hz, 3 H), 1.81 (m: dddd,
J ) 14.0, 10.2, 5.0, 5.0 Hz, 1 H), 1.95-2.07 (m, 1 H), 2.50 (dd,
J ) 8.2, 1.2 Hz, 2 H), 2.85 (sept, J ) 7.1 Hz, 1 H), 2.91 (sept,
J ) 7.1 Hz, 1 H), 3.14 (sept, J ) 6.9 Hz, 1 H), 3.54 (m: ddd,
J ) 9.1, 9.1, 1.5 Hz, 1 H), 3.58-3.68 (m, 2 H), 4.03 (m: dddd,
J ) 11.1, 2.8, 2.8, 2.8 Hz, 1 H), 4.13 (sept, J ) 6.8 Hz, 1 H),
4.08-4.18 (m, 1 H), 4.20-4.31 (m, 2 H), 4.36 (m: ddd, J )
8.2, 8.2, 8.2 Hz, 1 H), 5.17 (q, J ) 6.7 Hz, 1 H), 5.97 (br s, 1
H), 6.97 (d, J ) 1.8 Hz, 1 H), 7.05 (d, J ) 1.8 Hz, 1 H), 7.18 (s,
2 H); 13C NMR (75.5 MHz) δ 23.2 (CH3), 23.7 (CH3), 24.0 (CH3),
24.1 (CH3), 24.2 (CH3), 24.9 (CH3), 25.5 (CH3), 29.4 (CH3), 29.8
(CH), 34.2 (CH), 34.4 (CH), 35.7 (CH2), 59.6 (CH), 65.9 (CH2),
67.4 (CH), 72.6 (CH), 73.7 (CH), 121.3 (CH), 123.6 (CH), 123.9
(CH), 124.0 (CH), 129.3 (C), 130.4 (C), 146.5 (C), 148.5 (C),
148.8 (C), 151.0 (C), 153.9 (C), 173.8 (C). Anal. Calcd for C39H61-
NO6S: C 69.71, H 9.15, N 2.09. Found: C 69.71, H 9.37, N
2.00. More polar diastereomer: IR 2958, 2928, 2871, 1701,
(4R,5R)-5-(1,3-Dihydroxypropyl)-4-[(S)-1-(2,4,6-triiso-
propylphenyl)ethoxy]pyrrolidin-2-one (18a). A 1 M solu-
tion of catecholborane in THF (3.25 mL, 3.25 mmol) was added
dropwise to a solution of 0.250 g (0.645 mmol) of alcohol 17
and 0.060 g (0.065 mmol) of Rh(P(C6H5)3)3Cl in 2.5 mL of THF.
The mixture was stirred at 20 °C for 2 h, cooled to 0 °C, and
carefully treated with 2 M NaOH (0.5 mL), water (1.5 mL),
and 35% aqueous hydrogen peroxide (0.5 mL). The resulting
mixture was stirred overnight and then extracted with ethyl
acetate. The organic phase was washed with 1 M NaOH until
the aqueous wash was colorless, dried over Na2SO4, filtered,
and concentrated. The crude product was triturated with ethyl
acetate to provide 0.129 g of solid diol 18a after filtration. The
filtrate was then concentrated and the residue was purified
by silica gel chromatography to give an additional 0.059 g (72%
combined yield) of diol 18a. Less polar diastereomer: 1H NMR
(300 MHz, CD3COCD3) δ 1.13-1.35 (m, 18 H), 1.58 (d, J )
6.8 Hz, 3 H), 1.55-1.72 (m, 1 H), 1.80-1.92 (m, 1 H), 2.43 (A
of ABX, J ) 16.1, 7.9 Hz, 1 H), 2.48 (B of ABX, J ) 16.1, 7.9
Hz, 1 H), 2.88 (sept, J ) 6.9 Hz, 1 H), 3.23-3.41 (m, 1 H),
3.41-3.55 (m, 1 H), 3.68-3.77 (m, 3 H), 3.80-3.94 (m, 1 H),
3.98-4.10 (m, 1 H), 4.39 (m: ddd, J ) 7.6, 7.6, 7.6 Hz, 1 H),
5.30 (q, J ) 6.7 Hz, 1 H), 6.78 (br s, 1 H), 7.05 (s, 1 H), 7.14 (s,
1 H); 13C NMR (75.5 MHz, CD3COCD3) δ 23.2 (CH3), 25.3
(CH3), 34.7 (CH), 36.3 (CH2), 37.3 (CH2), 60.1 (CH2), 61.6 (CH),
70.3 (CH), 73.1 (CH), 74.8 (CH), 121.5 (CH), 123.9 (CH), 133.0
(C), 146.9 (C), 148.5 (C), 149.5 (C), 173.9 (C); MS (DCI, NH3 +
isobutane) m/z 406 (MH+), 264, 231 (100), 176. More polar
1
1601, 1460 cm-1; H NMR (300 MHz) δ 1.10-1.35 (m, 36 H),
1.58 (d, J ) 6.8 Hz, 3 H), 1.77-1.87 (m, 2 H), 2.52 (m: ddd, J
) 7.7, 7.7, 7.7 Hz, 2 H), 2.79 (d, J ) 3.6 Hz, 1 H), 2.85 (sept,
J ) 6.9 Hz, 1 H), 2.92 (sept, J ) 6.9 Hz, 1 H), 3.13 (sept, J )
6.5 Hz, 1 H), 3.54 (m: ddd, J ) 7.8, 7.8, 7.8 Hz, 1 H), 3.76
(sept, J ) 6.9 Hz, 1 H), 4.04-4.25 (m, 5 H), 4.31 (dd, J ) 15.2,
7.6 Hz, 1 H), 5.15 (q, J ) 6.8 Hz, 1 H), 6.39 (s, 1 H), 6.97 (d,
J ) 1.6 Hz, 1 H), 7.05 (d, J ) 1.6 Hz, 1 H), 7.19 (s, 2 H); 13C
NMR (75.5 MHz) δ 23.4 (CH3), 23.7 (CH3), 24.0 (CH3), 24.4
(CH3), 24.9 (CH3), 25.0 (CH3), 28.4 (CH3), 29.3 (CH), 34.2 (CH2),
34.4 (CH), 37.4 (CH2), 60.8 (CH), 66.4 (CH2), 66.5 (CH), 71.8
(CH), 72.4 (CH), 121.1 (CH), 123.6 (CH), 124.0 (CH), 129.4 (C),
130.1 (C), 146.6 (C), 148.4 (C), 148.9 (C), 151.0 (C), 153.9 (C),
175.5 (C); MS (DCI, NH3 + isobutane) m/z 672 (MH+), 671
(M+), 340, 267, 232, 231 (100). Anal. Calcd for C39H61NO6S‚
H2O (mixture of diastereomers): C, 67.89; H, 9.20; N, 2.03.
Found: C, 67.93; H, 9.18; N, 2.00.
(1R,7aR)-7-Hydroxy-1-[(S)-1-(2,4,6-triisopropylphenyl)-
ethoxy]pyrrolizidine (19). Borane-dimethyl sulfide complex
(2.70 mL, 28.5 mmol) was added to a stirred solution of 2.15
g (3.20 mmol) of sulfonate 18b in 29 mL of THF. The mixture
was refluxed for 6 h, cooled at 0 °C, and treated carefully with
methanol. The solvent was evaporated under reduced pressure
and methanol was again added and evaporated (three times).
The resulting crude oil was dissolved in 14 mL of methanol
and stirred with 0.35 g of 10% palladium on carbon and 1.4
mL (9.8 mmol) of triethylamine for 12 h at 20 °C. The
palladium was removed by filtration and the filtrate concen-
trated. The resulting oil was then dissolved in ether, which
was washed with water, brine, and 10% NaOH, dried over Na2-
SO4, filtered, and concentrated under reduced pressure. The
resulting crude product was purified by silica gel (triethyl-
amine-deactivated) chromatography with 0-15% methanol
saturated with ammonia in dichloromethane to afford 1.05 g
(88%) of alcohol 19 as a white solid. Less polar diastereomer:
mp 105-106 °C (pentane); [R]25D -41.9 (c 0.5, CHCl3); IR (film)
3498, 2963, 2933, 2869 cm-1; 1H NMR (300 MHz) δ 1.10-1.35
(m, 18 H), 1.58 (d, J ) 6.9 Hz, 3 H), 1.95-2.10 (m, 3 H), 2.80-
3.05 (m, 4 H), 3.10-3.25 (m, 2 H), 3.36 (dd, J ) 7.7, 3.3 Hz, 1
H), 3.84 (sept, J ) 6.2 Hz, 1 H), 4.23 (dd, J ) 14.1, 6.4 Hz, 1
H), 4.30-4.40 (m, 2 H), 5.20 (q, J ) 6.9 Hz, 1 H), 6.97 (s, 1 H),
7.06 (s, 1 H); 13C NMR (75.5 MHz) δ 23.5 (CH3), 24.0 (CH3),
32.2 (CH2), 34.1 (CH), 36.1 (CH2), 52.7 (CH2), 53.7 (CH2), 70.5
(CH), 72.2 (CH), 73.9 (CH), 79.0 (CH), 120.9 (CH), 123.6 (CH),
131.6 (C), 148.0 (C); MS (CI) m/z 374 (MH+, 100), 373 (M+),
231. Anal. Calcd for C24H39NO2‚1/2H2O: C, 75.35; H, 10.54; N,
3.66. Found: C, 75.04; H, 10.52; N, 3.58. More polar diaste-
reomer: mp 115-116 °C (pentane); [R]25D -58.7 (c 0.5, CHCl3);
diastereomer: mp 200.5-201 °C (ethyl acetate); [R]25 -77.6
D
(c 0.4, CH3OH); IR (KBr) 3374, 3228, 2957, 2867, 1678 cm-1
;
1H NMR (300 MHz, CD3COCD3) δ 1.12-1.36 (m, 18 H), 1.53-
1.66 (m, 1 H), 1.58 (d, J ) 6.8 Hz, 3 H), 1.66-1.80 (m, 1 H),
2.39 (A of ABX, J ) 16.0, 8.0 Hz, 1 H), 2.54 (B of ABX, J )
16.0, 7.3 Hz, 1 H), 2.87 (sept, J ) 6.9 Hz, 1 H), 3.20-3.42 (m,
2 H), 3.56 (dd, J ) 7.4, 2.2, 1 H), 3.61-3.71 (m, 2 H), 3.88-
4.03 (m, 1 H), 4.12-4.22 (m, 1 H), 4.28 (m: ddd, J ) 7.7, 7.7,
7.7 Hz, 1 H), 5.25 (q, J ) 6.8 Hz, 1 H), 6.72 (br s, 1 H), 7.04 (s,
1 H), 7.13 (s, 1 H); 13C NMR (75.5 MHz, CD3OD) δ 23.5 (CH3),
24.4 (CH3), 25.5 (CH3), 29.4 (CH), 30.2 (CH), 35.4 (CH), 37.4
(CH2), 38.6 (CH2), 59.8 (CH2), 62.9 (CH), 67.9 (CH), 73.4 (CH),
74.2 (CH), 121.8 (CH), 124.3 (CH), 133.4 (C), 147.6 (C), 149.2
(C), 150.1 (C), 178.4 (C); MS (DCI, NH3 + isobutane) m/z 406
(MH+), 231, 176 (100). Anal. Calcd for C24H39NO4: C 71.08, H
9.70, N 3.46. Found: C 71.11, H 9.76, N 3.35.
2,4,6-Triisopropylbenzenesulfonic Acid 3-Hydroxy-3-
{(2S,3R)-5-oxo-3-[(S)-1-(2,4,6-triisopropylphenyl)ethoxy]-
pyrrolidin-2-yl}propyl Ester (18b). To a stirred solution of
0.755 g (1.86 mmol) of diol 18a in 9.0 mL of pyridine at 0 °C
were added dropwise 1.30 mL (9.33 mmol) of triethylamine,
0.230 g (1.88 mmol) of DMAP, and 1.130 g (3.73 mmol) of 2,4,6-
triisopropylbenzensulfonyl chloride. The resulting mixture was
stirred at 20 °C for 7 h and then treated at 0 °C with an
aqueous solution of NaHCO3. After being stirred for 30 min
at 0 °C, the mixture was extracted with ether. The organic
phase was washed with water, 5% HCl, saturated NaHCO3,
1
IR (film) 3361, 2962, 2961, 2868 cm-1; H NMR (300 MHz) δ
J. Org. Chem, Vol. 70, No. 21, 2005 8361