(NC᎐C), 78.63 (NC᎐C), 60.65 and 58.09 (2 × OCH Me), 51.53
3.09 (2H, t, J 7.6, CH C᎐S), 2.07 (2H, quintet, J 7.6, ring
᎐
2
᎐
᎐
2
(NCH), 45.88 (NCH ), 37.31 (CH C᎐O), 32.59 (CH C᎐),
CH2CH2CH2), 1.95–1.75, 1.7–1.5 and 1.4–1.1 (1H ϩ 3H ϩ 6H,
clusters of m, remaining CH2) and 0.88 [3H, br t, J ca. 6.5,
᎐
᎐
2
2
2
32.05, 31.35, 25.75 and 22.35 [(CH2)4Me], 20.95 (ring CH2-
CH2CH2), 14.61 and 13.97 (2 × OCH2Me) and 13.84 [(CH2)4-
Me]; m/z (EI) 325 (6%, Mϩ), 280 (29), 238 (100), 182 (78), 156
(53), 136 (30), 110 (71), 108 (46) and 55 (53) (Found: Mϩ,
325.2261. C18H31NO4 requires 325.2253).
(CH2)4Me]; δC (50 MHz; CDCl ; Me Si) 202.26 (C᎐S), 57.75
᎐
3
4
(CH OH), 53.06 (NCH), 48.55 (NCH ), 44.73 (CH C᎐S), 34.79
᎐
2
2
2
(CH2CH2OH), 32.67, 31.32, 25.67 and 22.31 [(CH2)4Me], 19.83
(ring CH2CH2CH2) and 13.84 [(CH2)4Me].
Ethyl (2E)-{1-[1-(2-hydroxyethyl)hexyl]pyrrolidin-2-
ylidene}acetate 8
( )-Ethyl (2E)-(1-{1-[2-(methylsulfonyloxy)ethyl]hexyl}-
pyrrolidin-2-ylidene)ethanoate 10
(a) Racemic compound. LiAlH4 (697 mg, 18.4 mmol) was
added slowly to a stirred solution of ( )-ethyl 3-[(2E)-2-
(ethoxycarbonylmethylene)pyrrolidin-1-yl]octanoate 7 (5.97 g,
18.4 mmol) in dry THF (100 cm3) at 0 ЊC. The reaction mixture
was stirred for 2 h at 0 ЊC and then allowed to warm to room
temperature and stirred for an additional 3 h. The reaction was
quenched by the sequential addition of H2O (0.7 cm3), NaOH
solution (15% w/v, 0.7 cm3) and H2O (2.1 cm3). The inorganic
salts were filtered off and washed with CH2Cl2. The organic
filtrate was dried (MgSO4), filtered and evaporated in vacuo.
The crude product was purified by column chromatography
(EtOAc–CH2Cl2 1:2), which gave the racemic hydroxy ester
( )-8 as a very pale yellow oil (4.709 g, 91%); Rf 0.52 (EtOAc);
νmax(film)/cmϪ1 3438 (m, br, OH), 2954 (s), 2932 (s), 2860 (s),
Freshly distilled methanesulfonyl chloride (0.08 cm3, 1 mmol)
was added dropwise to a solution of the hydroxy ester ( )-8
(303 mg, 1.07 mmol) and dry NEt3 (0.15 cm3, 1.1 mmol) in dry
CH2Cl2 (3 cm3) at Ϫ20 ЊC. The mixture was stirred for 2 h,
allowed to warm to room temperature and stirred for a further
1 h. The mixture was poured into saturated aqueous NaHCO3
solution (50 cm3) and extracted twice with CH2Cl2 (50 cm3, 25
cm3). The combined organic layers were dried (MgSO4), filtered
and evaporated in vacuo to afford an orange oil (310 mg).
Column chromatography (EtOAc–hexane 1:1) afforded the
methanesulfonate 10 as a colourless oil that subsequently
formed a low-melting (<25 ЊC) waxy white solid (177 mg, 46%);
Rf 0.63 (EtOAc–hexane 1:1); νmax(film)/cmϪ1 2990 (s), 2960 (s),
2892 (m), 1678 (s, C᎐O), 1590 (s, C᎐C), 1362 (s), 1160 (s) and
᎐
᎐
1682 (s, C᎐O), 1662 (s), 1582 (s, C᎐C), 1148 (s) and 1060 (s); δ
1062 (m); δ (200 MHz; CDCl ; Me Si) 4.63 (1H, s, ᎐CH), 4.22
᎐
H 3 4
᎐
᎐
H
(200 MHz; CDCl ; Me Si) 4.64 (1H, s, ᎐CH), 4.06 (2H, q, J 7.1,
OCH2Me), 3.76 (1H, quintet, J 7.0, NCH), 3.65–3.45 (2H, m,
CH2OH), 3.23 (2H, t, J 7.0, NCH2), 3.17 (2H, t with fine struc-
(1H, dt, J 10.0 and 4.5, MsOCHaHb), 4.15–4.0 and 4.07 (3H,
overlapping m and q, J 7.1, MsOCHaHb and OCH2Me), 3.74
(1H, br quintet, J ca. 7.2, NCH), 3.3–3.15 (4H, m, NCH2 and
᎐
3
4
ture, J 7.3 and <1, CH C᎐), 2.62 (1H, br s, OH; exchanges with
CH C᎐), 3.01 (s, 3H, MeSO O), 2.05–1.85 (4H, m, CH CH -
᎐
2 2 2 2
᎐
2
D2O), 1.90 (2H, quintet, J 7.3, ring CH2CH2CH2), 1.75 (2H, q,
J 6.7, CH2CH2OH), 1.6–1.45 (2H, m, CH2Bu), 1.35–1.2 and
1.24 (9H, m and t, J 7.1, remaining CH2 and OCH2Me) and
0.87 [3H, br t, J ca. 6.5, (CH2)4Me]; δC (50 MHz; CDCl3; Me4Si)
OMs and ring CH2CH2CH2), 1.65–1.45 (2H, m, CH2Bu), 1.4–
1.15 and 1.23 (9H, overlapping m and t, J 7.1, remaining CH2
and OCH2Me) and 0.88 [3H, br t, J ca. 6.5, (CH2)4Me]; δC (50
MHz; CDCl ; Me Si) 169.38 (C᎐O), 165.78 (NC᎐C), 78.25
᎐
᎐
3
4
169.86 (C᎐O), 166.05 (NC᎐C), 77.33 (NC᎐C), 59.20 (CH OH),
(NC᎐C), 66.70 (CH OMs), 58.12 (OCH Me), 50.89 (NCH),
᎐
2 2
᎐
᎐
᎐
2
58.13 (OCH2Me), 51.27 (NCH), 45.61 (NCH2), 34.77
(CH CH OH), 32.80 (CH C᎐), 32.32, 31.49, 25.82 and 22.35
45.49 (NCH ), 37.18 (MeSO O), 32.64 (CH C᎐), 31.71 (CH -
᎐
2 2 2 2
CH2OMs), 32.23, 31.38, 25.72 and 22.31 [(CH2)4Me], 20.90
(ring CH2CH2CH2), 14.59 (OCH2Me) and 13.82 [(CH2)4Me];
m/z (EI) 361 (16%, Mϩ), 316 (46), 291 (22), 282 (43), 274 (94),
266 (42), 238 (24), 220 (21), 195 (28), 194 (60), 192 (20), 182
(82), 156 (100), 122 (45), 120 (36), 110 (74), 108 (24), 69 (22), 67
(22) and 55 (35) (Found: Mϩ, 361.1938. C17H31NO5S requires
361.1923).
᎐
2
2
2
[(CH2)4Me], 20.84 (ring CH2CH2CH2), 14.56 (OCH2Me) and
13.83 [(CH2)4Me]; m/z (EI) 283 (6%, Mϩ), 212 (17), 197 (15),
196 (73), 182 (51), 156 (64), 152 (39), 128 (15), 110 (78), 108
(30), 82 (21), 70 (22), 55 (46), 45 (21) and 44 (100) (Found: Mϩ,
283.2146. C16H29NO3 requires 283.2147).
(b) (Ϫ)-Enantiomer. When the reaction was repeated with
LiAlH4 (34 mg, 0.90 mmol) and (ϩ)-tert-butyl (3R)-3-[(2E)-2-
(ethoxycarbonylmethylene)pyrrolidin-1-yl]octanoate 32 (see
below; 159 mg, 0.45 mmol) in dry THF (10 cm3) at room tem-
perature,chromatographicallypure(Ϫ)-ethyl(2E)-{1-[(1R)-1-
(2-hydroxyethyl)hexyl]pyrrolidin-2-ylidene}acetate (Ϫ)-8 was
obtained after work-up as a pale yellow oil (113 mg, 88%); [α]D26
Ϫ12.7 (c 1.10, absolute EtOH); δH within 0.05 ppm of the
values given above except for 2.27 (1H, br s, OH); δC within
0.20 ppm of the values given above.
Ethyl 5-pentyl-1,2,3,5,6,7-hexahydroindolizine-8-carboxylate 11
(a) Racemic compound. Dry NEt3 (0.46 cm3, 3.3 mmol) was
added dropwise to a stirred mixture of hydroxy ester ( )-8 (723
mg, 2.55 mmol), triphenylphosphine (870 mg, 3.32 mmol) and
tetrabromomethane (1.088 g, 3.28 mmol) in dry acetonitrile
(2.30 cm3) at 0 ЊC. After 5 min the mixture was allowed to warm
to room temperature and stirred for 13 h. Triethylammonium
bromide was filtered off, more dry acetonitrile (10 cm3) was
added and the diluted mixture was heated under reflux for 2 h.
The solvent was evaporated in vacuo. The residue was dissolved
in CH2Cl2 (50 cm3) and washed with H2O (50 cm3). The
aqueous layer was extracted with CH2Cl2 (4 × 30 cm3). The
combined organic layers were dried (MgSO4), filtered and
evaporated in vacuo. Purification of the crude material by
column chromatography (EtOAc–hexane 1:3) afforded the
racemic indolizine ester ( )-11 as an orange oil (573 mg, 85%);
Rf 0.52 (EtOAc–hexane 1:3); νmax(film)/cmϪ1 2932 (s), 2856 (m),
( )-1-[1-(2-Hydroxyethyl)hexyl]pyrrolidine-2-thione 9
LiAlH4 (66 mg, 1.8 mmol) was added to a solution of the
pyrrolidinethione 6 (237 mg, 0.87 mmol) in dry THF (10 cm3)
at 0 ЊC. The solution was then allowed to warm to room tem-
perature and stirred for 4 h. The reaction was quenched by the
sequential addition of H2O (0.1 cm3), aqueous NaOH solution
(15% w/v, 0.1 cm3) and H2O (0.3 cm3). The insoluble salts were
filtered off and washed with acetone. The organic filtrate
was dried (MgSO4), filtered and evaporated in vacuo to afford
the crude product (407 mg), which was purified by column
chromatography (hexane–EtOAc 1:2). ( )-1-[1-(2-Hydroxy-
ethyl)hexyl]pyrrolidine-2-thione 9 was obtained as a viscous,
colourless oil (147 mg, 73%); Rf 0.34 (hexane–EtOAc 1:2);
νmax(film)/cmϪ1 3396 (br s, OH), 2952 (s), 2928 (s), 2870 (s), 2860
(s), 1500 (s), 1464 (s), 1452 (s), 1426 (m), 1322 (s), 1312 (s), 1290
(s), 1108 (br s) and 736 (s); δH (200 MHz; CDCl3; Me4Si) 5.09
(1H, 11-line m, NCH), 3.65–3.25 (5H, m, NCH2 and CH2OH),
1676 (s, C᎐O), 1596 (vs, C᎐C), 1456 (m), 1368 (s), 1280 (s), 1196
᎐
᎐
(m), 1156 (m) and 1096 (s); δH (200 MHz; CDCl3; Me4Si) 4.11
(2H, q, J 7.1, OCH2Me), 3.51 (1H, dt, J 9.4 and 7.0, 3-Heq),
3.25–3.15 and 3.18 (2H, overlapping m and dt, J 9.3 and 7.0,
5-H and 3-Hax), 3.07 (2H, td, J 7.7 and 1.2, 1-H), 2.44 (1H, dt,
J 15.9 and 4.6, 6-Ha), 2.3–2.1 (1H, m, 6-Hb), 1.90 (2H, quintet,
J ca. 7.4, 2-H), 1.85–1.45 (4H, m, 7-H and CH2Bu), 1.45–1.10
and 1.26 (9H, overlapping m and t, J 7.1, remaining CH2 and
OCH2Me) and 0.89 [3H, br t, J ca. 6.5, (CH2)4Me]; δC (50 MHz;
J. Chem. Soc., Perkin Trans. 1, 2000, 1919–1928
1923