The Journal of Organic Chemistry
Article
(
Z)-but-2-ene-1,4-diyl diacetate (437 mg, 2.542 mmol) followed by
EXPERIMENTAL SECTION
■
Grubbs−Hoveyda second-generation catalyst (20 mg, 0.0318 mmol).
The mixture was heated to reflux for 2 h, cooled, and filtered through a
Celite pad with a methylene chloride wash. After concentration under
reduced pressure, purification by radial PLC (SiO , 30−40% EtOAc/
1
clear oil. IR (neat) 3261, 3041, 2929, 1738, 1579, 1450, 1365, 1242,
1
Hz), 5.76 (m, 1H), 5.61 (m, 1H), 5.55 (bs, 1H), 4.94 (d, 1H, J = 7.0
Hz), 4.52, (d, 2H, J = 6.3 Hz), 3.29 (m, 1H), 2.29−2.14 (m, 3H), 2.07
(
NMR (75 MHz, CDCl ) δ 195.8, 171.0, 149.2, 134.6, 125.1, 97.1, 64.9,
5
(
2R*,3R*)-Phenyl 2-(But-3-enyl)-3-methyl-4-oxo-3,4-dihy-
dropyridine-1(2H)-carboxylate (9). To a solution of 8
15a
(460
mg, 1.70 mmol) in anhydrous THF (15 mL) at −78 °C was added a
THF solution of NaHMDS (1 M in THF, 1.87 mL, 1.87 mmol). The
mixture was stirred for 30 min at −78 °C. Methyl iodide (0.320 mL,
2
% methanol/1% Et N/hexanes) gave 130 mg (87% yield) of 4 as a
3
5
0
.10 mmol) was added dropwise, and then the solution was warmed to
−1 1
026, 970 cm ; H NMR (300 MHz, CDCl ) δ 7.11 (t, 1H, J = 7.0
3
°C over 1 h. The reaction mixture was quenched with a solution of
saturated aqueous NaHCO (20 mL). The resulting solution was
3
diluted with Et O (20 mL) and transferred to a separatory funnel, and
2
13
s, 3H), 1.84 (m, 1H), 1.66 (m, 1H), 1.18 (d, 3H, J = 7.2 Hz);
C
the phases were allowed to separate. The aqueous layer was extracted
3
with Et O (2 × 20 mL). The organic layers were combined, washed
2
8.1, 44.1, 31.0, 28.4, 21.0, 14.6; HRMS calcd for C H NO [(M +
13 20 3
with saturated NaHCO (30 mL) and brine (30 mL), dried over
3
+
H) ] 238.1438, found 238.1437.
3R*,5R*,8R*,8aR*)-8-Methyl-5-(2-methylallyl)-3-vinyl-
,2,3,5,8,8a-hexahydroindolizin-7-yl Trifluoromethanesulfo-
MgSO , filtered through Celite, and concentrated in vacuo. The crude
4
(
product was purified by PLC (SiO , 10% EtOAc/hexanes), affording
2
1
4
2
9
36 mg (90% yield) of 9 as a clear oil. IR (neat) 3076, 2974, 2931,
nate (20). To a stirred solution of 3 (250 mg, 1.41 mmol) in 8 mL
of anhydrous methylene chloride at −78 °C was added methallyl-
tributylstannane (973 mg, 2.82 mmol) followed by dropwise addition
of trifluoromethanesulfonic anhydride (0.33 mL, 1.97 mmol). The
mixture was stirred for 1 h at −78 °C, and then reaction mixture was
873, 1739, 1672, 1604, 1495, 1456, 1419, 1335, 1265, 1196, 1045,
−1 1
14, 752 cm ; H NMR (300 MHz, CDCl ) δ 7.85 (d, 1H, J = 8.3
3
Hz), 7.43 (m, 2H), 7.29 (m, 1H), 7.18 (m, 2H), 5.78 (m, 1H), 5.35
m, 1H), 5.03 (m, 2H), 4.44 (m, 1H), 2.50 (q, 1H, J = 7.2 Hz), 2.21
(
(
7
1
m, 1H), 2.11 (m, 1H), 1.89 (m, 1H), 1.76 (m, 1H), 1.28 (d, 3H, J =
quenched with a solution of saturated aqueous NaHCO (5 mL). The
.2 Hz); 1 C NMR (75 MHz, CDCl ) δ 197.4, 151.3, 150.4, 139.8,
3
3
3
resulting solution was diluted with methylene chloride (5 mL) and
transferred to a separatory funnel, and the phases were allowed to
separate. The aqueous layer was extracted with CH Cl (2 × 10 mL).
36.7, 129.6, 126.3, 121.2, 115.7, 105.9, 59.3, 43.6, 29.8, 17.0; HRMS
+
calcd for C H NO [(M + H) ] 286.1438, found 286.1444.
17
20
3
2
2
(
2R*,3R*)-Phenyl 2-((E)-5-Acetoxypent-3-enyl)-3-methyl-4-
The organic layers were combined, washed with saturated NaHCO3
20 mL) and brine (20 mL), dried over MgSO , filtered through
oxo-3,4-dihydropyridine-1(2H)-carboxylate (10). To a degassed
solution of alkene 9 (150 mg, 0.526 mmol) in 20 mL of anhydrous
methylene chloride was added (Z)-but-2-ene-1,4-diyl diacetate (271
mg, 1.580 mmol) followed by Grubbs−Hoveyda second-generation
catalyst (16.5 mg, 0.0263 mmol). The mixture was heated to reflux for
(
4
Celite, and concentrated in vacuo. The crude product was purified by
radial PLC (SiO , 10% EtOAc/hexanes) to give 334 mg (65% yield) of
triflate 20 as a clear oil. IR (neat) 3078, 2935, 1682, 1645, 1417, 1246,
1
2
−1 1
211, 1144, 993, 918, 862 cm ; H NMR (300 MHz, CDCl ) δ 5.79
3
2
h, cooled, and filtered through a Celite pad with a methylene
chloride wash. After concentration under reduced pressure,
(
(
dd, 1H, J = 1.9, 4.1 Hz), 5.61 (ddd, 1H, J = 8.3, 9.9, 17.3 Hz), 5.10
dd, 1H, J = 1.7, 17.3 Hz), 5.07 (dd, 1H, J = 1.7, 9.9 Hz), 4.78 (s, 1H),
purification by radial PLC (SiO , 30−50% EtOAc/1% methanol/1%
2
4
1
.69 (s, 1H), 3.53 (m, 1H), 3.14 (dd, 1H, J = 7.8, 15.2 Hz), 3.04 (dd,
H, J = 6.1, 8.8 Hz), 2.26−1.97 (m, 5H), 1.72 (s, 3H), 1.67−1.56 (m,
Et N/hexanes) gave 131 mg (70% yield) of 10 as a clear oil. IR (neat)
3
3
1
8
5
2
1
075, 2969, 2933, 1733, 1669, 1605, 1492, 1420, 1334, 1262, 1228,
13
−1
1
2H), 1.10 (d, 3H, J = 6.6 Hz); C NMR (75 MHz, CDCl ) δ 149.9,
1
5
3
198, 1026, 967 cm ; H NMR (300 MHz, CDCl ) δ 7.84 (d, 1H, J =
3
42.3, 141.3, 119.6, 118.5 (q, JC−F = 319 Hz), 116.6, 112.7, 65.6, 60.7,
1.6, 44.7, 32.1, 29.2, 28.1, 22.4, 14.6; HRMS calcd for C H F NO S
.0 Hz), 7.34 (m, 2H), 7.30 (m, 1H), 7.18 (m, 2H), 5.74 (m, 1H),
.61 (m, 1H), 5.35 (bs, 1H), 4.49 (d, 2H, J = 6.1 Hz), 4.44 (m, 1H),
.48 (q, 1H, J = 7.2 Hz), 2.21 (m, 1H), 2.12 (m, 1H), 2.03 (s, 3H),
1
6
23
3
3
+
[
(M + H) ] 366.1345, found 366.1341.
(3R,5R,8R,8aR)-8-Methyl-5-(2-methylallyl)-3-vinylhexahy-
droindolizin-7(1H)-one (21). To a stirred solution of enantiopure 3
56 mg, 0.316 mmol) in 4 mL of anhydrous methylene chloride at
13
.90 (m, 1H), 1.76 (m, 1H), 1.28 (d, 3H, J = 7.2 Hz); C NMR (75
MHz, CDCl ) 197.2, 170.7, 151.0, 150.4, 139.7, 133.9, 129.6, 126.4,
3
(
1
25.1, 121.1, 105.9, 64.7, 59.3, 43.7, 29.9, 28.3, 20.9, 16.9; HRMS calcd
+
−50 °C was added methallyltributylstannane (218 mg, 0.632 mmol)
followed by dropwise addition of trifluoroacetic anhydride (0.07 mL,
0
quenched with a solution of saturated aqueous NaHCO (5 mL). The
resulting mixture was diluted with methylene chloride (5 mL) and
transferred to a separatory funnel, and the phases were allowed to
separate. The aqueous layer was extracted with CH Cl (2 × 10 mL).
The organic layers were combined, washed with saturated NaHCO3
for C H NO Na [(M + Na) ] 380.1468, found 380.1462.
20
23
5
(
2R*,3R*)-2-((E)-5-Hydroxypent-3-enyl)-3-methyl-2,3-dihy-
dropyridin-4(1H)-one (11). To a solution of 10 (147 mg, 0.411
mmol) in 5 mL of methanol was added K CO (113 mg, 0.822 mmol).
After 12 h of stirring at rt, the solvent was removed in vacuo. To the
resulting solid was added EtOAc, and the mixture was filtered through
a Celite pad with an EtOAc wash. After concentration under reduced
pressure, purification by radial PLC (SiO , 25−30% EtOAc/1% Et N/
hexanes) gave 43 mg (54% yield) of vinylogous amide 11 as a clear oil.
This product was characterized as its acetate (4).
.474 mmol). The mixture was warmed to 0 °C over 1 h and then
3
2
3
2
2
2
3
(
20 mL) and brine (20 mL), dried over MgSO , filtered through
4
Celite, and concentrated in vacuo. The crude product was purified by
radial PLC (SiO , 5% EtOAc/hexanes) to afford 51 mg (69% yield) of
ketone 21 as a clear oil. [α]D +55.2 (c 0.92, MeOH); IR (neat) 3074,
(
2R*,3R*)-2-(But-3-enyl)-3-methyl-2,3-dihydropyridin-4(1H)-
one (12). To a solution of 9 (170 mg, 0.596 mmol) in 5 mL of
2
22
−
1
2
970, 2933, 1706, 1649, 1423, 1377, 1323, 1194, 993, 920, 887 cm ;
methanol was added K CO (164 mg, 1.192 mmol). After 12 h of
2
3
1
H NMR (300 MHz, CDCl ) δ 5.68 (ddd, 1H, J = 8.3, 9.9, 17.5 Hz),
stirring at rt, the solvent was removed in vacuo. To the resulting solid
was added EtOAc, and the mixture was filtered through a Celite pad
with an EtOAc wash. After concentration under reduced pressure,
3
5.18 (dd, 1H, J = 1.7, 17.5 Hz), 5.11 (dd, 1H, J = 1.7, 9.9 Hz), 4.76
(bs, 1H), 4.67 (bs, 1H), 3.62−3.51 (m, 2H), 3.19 (dd, 1H, J = 9.9, 6.1
Hz), 2.66 (dd, 1H, J = 12.7, 6.1 Hz), 2.24−2.10 (m, 6H), 1.78−1.64
(m, 2H), 1.68 (s, 3H), 0.97 (d, 3H, J = 6.3 Hz); 13C NMR (75 MHz,
CDCl ) δ 211.3, 142.6, 141.7, 116.2, 112.5, 64.6, 63.2, 54.2, 46.6, 42.6,
40.0, 30.0, 28.5, 22.1, 10.5; HRMS calcd for C15
234.1852, found 234.1855.
(3R*,5R*,8S*,8aR*)-8-Methyl-5-(2-methylallyl)-3-vinyl-
1,2,3,5,8,8a-hexahydroindolizine-7-carbaldehyde (26). A de-
purification by radial PLC (SiO , 20−30% EtOAc/1% methanol/1%
2
Et N/hexanes) gave 85 mg (86% yield) of vinylogous amide 12 as a
3
clear oil. IR (neat) 3257, 3041, 2972, 2929, 1576, 1452, 1408, 1346,
3
−1
1
+
1
1
1
1
246, 1205, 914, 791 cm ; H NMR (300 MHz, CDCl ) δ 7.10 (t,
H24NO [(M + H) ]
3
H, J = 6.9 Hz), 6.23 (bs, 1H), 5.75 (m, 1H), 4.99 (m, 2H) 4.85 (d,
H, J = 6.9 Hz), 3.27 (m, 1H), 2.19 (m, 1H), 2.11 (m, 2H), 1.78 (m,
H), 1.61 (m, 1H), 1.13 (d, 3H, J = 7.2 Hz); 13C NMR (75 MHz,
CDCl ) δ 196.0, 150.0, 137.3, 115.5, 95.8, 57.5, 43.8, 30.8, 29.5, 14.8;
gassed solution of flame-dried LiCl (74 mg, 1.75 mmol), Pd(PPh )
3 4
3
+
HRMS calcd for C H NO [(M + H) ] 166.1226, found 166.1226.
(51 mg, 0.0438 mmol), and triflate 20 (160 mg, 0.438 mmol) in
anhydrous THF (5 mL) was put under a carbon monoxide
atmosphere. The mixture was heated to 50 °C and treated with a
solution of tributyltin hydride (159 mg, 0.548 mmol) in THF (1 mL)
10
16
5
-((2R*,3R*)-3-Methyl-4-oxo-1,2,3,4-tetrahydropyridin-2-yl)-
pent-2-enyl Acetate (4). To a degassed solution of 12 (105 mg,
.635 mmol) in 20 mL of anhydrous methylene chloride was added
0
9
083
dx.doi.org/10.1021/jo501415r | J. Org. Chem. 2014, 79, 9074−9085