The Journal of Organic Chemistry
ARTICLE
pressure yielding a yellow oil. Crude product was dissolved in Et2O, and
5% sodium bisulfite aqueous solution was added. After stirring over-
night, the layers were separated, and the aqueous layer was extracted
with Et2O. The combined organic layer were dried with MgSO4, filtered
over Celite, and concentrated under reduced pressure to yield 4.70 g of
alcohol S-3 as a yellowish oil.
To a stirred solution of the alcohol S-3 (4.70 g, 15.0 mmol) in DMF
(75 mL) were added imidazole (2.04 g, 30.0 mmol) and TBS-Cl (3.39 g,
22.5 mmol) at room temperature. After stirring for 48 h, the reaction
mixture wastransferredinto aseparationfunnelwithEt2O, and the organic
layer was washed with 1 N HCl, water, and brine, dried with MgSO4,
filtered, and concentrated under reduced pressure. Flash chromatography
of the brownish oily residue with EtOAc/hexanes (20/80) afforded 2.49 g
of metathesis precursor 15 (22%, 4 steps) as a light yellow oil.
5.82ꢀ5.64 (m, 2H), 5.40 (d, J = 8.0 Hz, 1H), 5.25ꢀ4.96 (m, 5H),
4.15ꢀ3.88 (m, 3H), 2.57 (dt, J = 44.0, 12.0 Hz, 1H), 2.30 (d, J = 20.0 Hz,
1H), 2.20ꢀ1.99 (m, 3H), 1.59 (d, J = 12.0 Hz, 1H), 1.12 (q, J = 12.0 Hz,
1H); 13C NMR (acetone-d6, 100 MHz) mixture of rotamers, major δ
155.1, 140.1, 137.6, 128.4, 127.7, 127.6, 126.9, 126.6, 114.0, 68.2, 66.4,
47.9, 45.0, 39.8, 39.1, 29.7, 29.6; FTIR (cmꢀ1) (neat) br 3443, 3027,
2923, 1682, 1427, 1261, 1120, 911; HRMS (ESI, Pos) calcd for
C19H23NO3 [M þ Na]þ: 336.1570 m/z, found 336.1569 m/z
Benzyl (3S,4aS,8aS)-3-Ethenyl-5-oxo-3,4,4a,5,6,8a-hexa-
hydroquinoline-1(2H)-carboxylate (13). To a stirred solution
of the alcohol S-4 (3.98 g, 12.7 mmol) were added DessꢀMartin
periodinane (8.08 g, 19.1 mmol) and a drop of water. The reaction
mixture was stirred for 4 h, diluted with Et2O, and poured into a
saturated NaHCO3 aqueous solution (100 mL) containing Na2S2O3
(25 g). This heterogeneous solution was stirred until the solid was
completely dissolved. The layers were separated, and the organic layer
was washed with saturated NaHCO3 aqueous solution and water, dried
over MgSO4, filtered over Celite, and concentrated under reduced
pressure. The resulting yellowish oil was dissolved in ethyl acetate
(127 mL), and alumina was added (20 g). The mixture was stirred
overnight, then filtered over Celite, and concentrated under reduced
pressure. The crude enone 13 was used to the next step without any
Benzyl (3S,4aS,8aS)-5-{[tert-Butyl(dimethyl)silyl]oxy}-3-
ethenyl-3,4,4a,5,6,8a-hexahydroquinoline-1(2H)-carboxy-
late (14). Metathesis precursor 15 (4.28 g, 10.0 mmol) was dissolved in
DCM (1000 mL), and Grubbs’ catalyst second generation (20) (0.170 g,
0.200 mmol) was added. After stirring 17 h, the reaction mixture was
quenched with the addition of ethyl vinyl ether (excess), and the solution
was concentrated under reduced pressure. Flash chromatography of the
brownish oil with EtOAc/hexane (20/80) afforded 3.48 g of metathesis
further purification. [R]20 = ꢀ41.1 (c 0.730, CHCl3); 1H NMR
product 14 (81%) as a colorless oil. (R)-diastereoisomer: [R]20
=
D
D
þ56.9 (c 0.520, CHCl3); 1H NMR (acetone-d6, 400 MHz) δ 7.45ꢀ7.29
(m, 5H), 5.85ꢀ5.71 (m, 2H), 5.39ꢀ5.29 (m, 1H), 5.23ꢀ4.98 (m, 4H),
4.91 (br s, 1H), 4.20ꢀ3.98 (m, 2H), 2.53 (dt, J = 44.0, 12.0 Hz, 1H),
2.32ꢀ2.19 (m, 1H), 2.19ꢀ1.98 (m, 3H), 1.88 (d, J = 12.0 Hz, 1H), 1.22
(q, J = 12.0 Hz, 1H), 0.92 (s, 9H), 0.12 (d, J = 8.0 Hz, 6H); 13C NMR
(acetone-d6, 100 MHz) mixture of rotamers, major δ 154.9, 140.3,
137.4, 128.4, 127.8, 127.7, 127.6, 127.3, 114.1, 69.1, 66.5, 51.7, 45.1, 39.8,
39.7, 31.0, 25.4, 24.8, 17.7, ꢀ5.4; FTIR (cmꢀ1) (neat) 3029, 2953, 2895,
2857, 1699, 1423, 1272, 1113, 837, 776; HRMS (ESI, Pos) calcd for
C25H37NO3Si [M þ Na]þ: 450.2435 m/z, found 450.2455 m/z.
(acetone-d6, 400 MHz) δ 7.48ꢀ7.28 (m, 5H), 7.13ꢀ7.01 (m, 1H),
6.03ꢀ5.93 (m, 1H), 5.88ꢀ5.71 (m, 1H), 5.24ꢀ5.02 (m, 4H),
4.82ꢀ4.72 (m, 1H), 4.13 (dd, J = 20.0, 16.0 Hz, 1H), 2.97ꢀ2.69 (m,
2H), 2.60ꢀ2.46 (m, 1H), 2.45ꢀ2.31 (m, 1H), 2.25 (br s, 1H),
1.79ꢀ1.68 (m, 1H), 1.49 (q, J = 12.0 Hz, 1H); 13C NMR (acetone-d6,
100 MHz) mixture of rotamers, major δ 199.3, 154.7. 148.4, 139.3, 137.2,
128.5, 128.3, 127.9, 127.8, 115.0, 66.8, 49.4, 47.6, 43.6, 39.3, 28.7, 24.5;
FTIR (cmꢀ1) (neat) 3063, 3033, 2930, 1681, 1498, 1417, 1263; HRMS
calcd for C19H21NO3 [M þ H]þ: 312.1594 m/z, found 312.1586 m/z.
Benzyl (3S,4aS,7S,8aS)-3-Ethenyl-7-methyl-5-oxooctahydro-
quinoline-1(2H)-carboxylate (21). To a stirred suspension of
copper iodide (7.26 g, 38.1 mmol) and THF (80 mL) was added
methyllithium (47.60 mL of a 1.0 M solution in Et2O, 47.60 mmol) at
0 °C. After the reaction mixture stirred for 30 min at 0 °C followed by an
additional 15 min at room temperature, the solution became colorless.
The reaction mixture was cooled to ꢀ78 °C and stirred 10 min. A
solution of enone 13 (12.7 mmol) in THF (80 mL) was added dropwise,
and the reaction mixture was stirred for 3 h at ꢀ78 °C. The reaction was
quenched at ꢀ78 °C by addition of saturated aqueous NH4Cl, removed
from the ice bath, and allowed to warm to room temperature. The
heterogeneous solution was diluted with water and extracted with Et2O.
The combined organic layers were dried over MgSO4, filtered over
Celite, and concentrated under reduced pressure. Flash chromatography
of the yellowish oil with EtOAc/hexanes (25/75) afforded 3.38 g of
ketone 21 (81%, 3 steps) as a light yellow oil. [R]20D = ꢀ52.2 (c 0.720,
CHCl3); 1H NMR (acetone-d6, 400 MHz) δ 7.47ꢀ7.27 (m, 5H),
5.87ꢀ5.70 (m, 1H), 5.28ꢀ5.00 (m, 4H), 4.78ꢀ4.62 (m, 1H),
4.18ꢀ4.00 (m, 1H), 2.76 (dd, J = 16.0, 4.0 Hz, 2H), 2.61ꢀ2.51 (m
1H), 2.46ꢀ2.32 (m, 2H), 2.25ꢀ2.12 (m, 1H), 2.01 (d, J = 12.0 Hz, 1H),
1.79 (q, J = 13.3 Hz, 1H), 1.71ꢀ1.61 (m, 1H), 1.50 (d, J = 12.0 Hz, 1H),
0.99 (d, J = 4.0 Hz, 3H); 13C NMR (acetone-d6, 100 MHz) δ 210.4,
154.5, 139.4, 137.3, 128.4, 127.8, 127.7, 114.9, 66.6, 51.3, 47.7, 43.3, 43.2,
39.4, 29.2, 28.1, 27.1, 18.6; FTIR (cmꢀ1) (neat) 2952, 2929, 2865, 1694,
1420, 1263, 1222; HRMS (ESI, Pos) calcd for C20H25NO3 [M þ H]þ:
328.1907 m/z, found 328.1902 m/z.
(S)-diastereoisomer: [R]20 = þ59.8 (c 0.660, CHCl3), 1H NMR
D
(acetone-d6, 400 MHz) δ 7.46ꢀ7.29 (m, 5H), 5.80ꢀ5.64 (m, 2H),
5.47ꢀ5.38 (m, 1H), 5.23ꢀ4.97 (m, 5H), 4.16ꢀ3.99 (m, 2H), 2.58 (dt, J
= 41.3, 13.0 Hz, 1H), 2.32 (d, J = 20 Hz, 1H), 2.15 (br s, 1H), 1.99 (d, J =
12.0 Hz, 2H), 1.62 (d, J = 12.0 Hz, 1H), 1.12 (q, J = 14.0 Hz, 1H),
0.94ꢀ0.88 (m, 9H), 0.14ꢀ0.10 (m, 6H); 13C NMR (acetone-d6, 100
MHz) δ 154.9, 140.0, 137.4, 128.4, 127.7, 127.6, 127.1, 126.2, 114.1, 69.7,
66.5, 48.0, 44.9, 39.9, 39.7, 30.2. 29.5, 25.4, 17.7, ꢀ5.4; FTIR (cmꢀ1
)
(neat) 3028, 2927, 2890, 2856, 1699, 1424, 1259, 1072, 951, 837, 775;
HRMS (ESI, Pos) calcd for C25H37NO3Si [M þ Na]þ: 450.2435 m/z,
found 450.2442 m/z.
Benzyl (3S,4aS,8aS)-3-Ethenyl-5-hydroxy-3,4,4a,5,6,8a-
hexahydroquinoline-1(2H)-carboxylate (S-4). To a stirred solu-
tion of metathesis product 14 (5.95 g, 13.9 mmol) in THF (27.8 mL)
was added TBAF (27.8 mL of a 1.0 M solution in THF, 27.8 mmol).
After stirring overnight, the mixture was extracted with DCM. The
combined organic extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. Flash chromatography
of the brownish oily solid with EtOAc/hexane (40/60) afforded 4.03 g
of the alcohol S-4 (92%) as a brownish oil. (R)-diastereoisomer: [R]20
D
= þ49.0 (c 0.300, CHCl3); 1H NMR (acetone-d6, 400 MHz) δ
7.45ꢀ7.29 (m 5H), 5.85ꢀ5.68 (m, 2H), 5.39ꢀ5.29 (m, 1H),
5.21ꢀ4.97 (m, 4H), 4.90ꢀ4.87 (m, 1H), 4.13ꢀ3.93 (m, 3H), 2.53
(dt, J = 44.0, 12.0 Hz, 1H), 2.34ꢀ2.21 (m, 1H), 2.18ꢀ1.95 (m, 3H),
1.89 (d, J = 16.0 Hz, 1H), 1.24ꢀ1.14 (m, 1H); 13C NMR (acetone-d6,
100 MHz) mixture of rotamers, major δ 155.0, 140.3, 137.4, 128.4,
127.8, 127.8, 127.7, 127.3, 114.0, 67.7, 66.5, 51.9, 45.1, 39.7, 39.5, 30.2,
24.6; FTIR (cmꢀ1) (neat) br 3438, 3029, 2923, 1697, 1427, 1274, 1116,
917; HRMS (ESI, Pos) calcdfor C19H23NO3 [M þ Na] þ: 336.1570 m/z,
Benzyl (3S,4aS,7S,8aS)-3-Acetyl-7-methyl-5-oxooctahydro-
quinoline-1(2H)-carboxylate (12). A stirred suspension of ketone
21 (4.83 g, 14.8 mmol), copper(II) chloride (0.146 g, 1.48 mmol), and
palladium(II) chloride (0.262 g, 1.48 mmol) in THF (118 mL) and
water (29.5 mL) was stirred under an oxygen atmosphere overnight.
Additional amounts of copper(II) chloride (0.146 g, 1.48 mmol) and
found 336.1568 m/z. (S)-diastereoisomer: [R]20 = þ58.5 (c 0.525,
D
CHCl3); 1H NMR (acetone-d6, 400 MHz) δ 7.47ꢀ7.27 (m, 5H),
5359
dx.doi.org/10.1021/jo200745n |J. Org. Chem. 2011, 76, 5354–5362