E. Tayama et al. / Tetrahedron 69 (2013) 2745e2752
2751
6.8 Hz, 4-H), 5.27e5.14 (1H, m, 3-H), 4.13 (1H, br), 3.89 (1H, br), 3.49
(1H, br), 3.32e3.20 (1H, m), 2.80e2.50 (4H, m), 2.50e2.25 (2H, m),
1.64e1.49 (6H, br), 1.45 (5.85H, s, t-Bu), 1.44 (3.15H, s, t-Bu),
1.34e1.23 (1H, m); IR (film) 3449, 3062, 2933, 2863, 1687, 1661,
1604, 1470, 1449, 1421, 1366, 1314, 1272, 1163, 1063, 975, 914, 869,
13.0, 13.0, 4.2, 4.2 Hz, 6-H), 1.12 (1H, dddd, J¼13.0, 13.0, 11.6, 4.2 Hz,
5-H); 13C NMR (175 MHz, CDCl3)
153.4, 138.0, 119.4, 67.7, 59.9,
45.1, 39.7, 31.8, 25.9, 25.0, 23.7, 18.5; IR (KBr) 2932, 2857, 1676, 1478,
1443, 1390, 1364, 1347, 1320, 1304, 1262, 1229, 1177, 1137, 1104,
1049, 1010, 967, 951, 923, 853, 756 cmꢁ1; HRMSeESI (m/z): [MþH]þ
calcd for C12H20NO2: 210.1489. Found: 210.1486.
d
813, 745, 700 cmꢁ1
;
HRMSeESI (m/z): [MþNa]þ calcd for
C22H33NO3Na: 382.2353. Found: 382.2349.
3.5.3. (4S*,4aR*)-4-(40-Phenylbut-10-enyl)hexahydropyrido[1,2-c]
3.4.4. (2R*,20R*)-N-tert-Butoxycarbonyl-6-phenyl-2-(piperidin-20-yl)
[1,3]oxazin-1(3H)-one (major-5e). Yellow oil. E/Z¼65/35 mixture.
hex-3-en-1-ol (minor-4e). Colorless oil. 1H NMR (400 MHz, CDCl3)
1H NMR (700 MHz, CDCl3)
d 7.30e7.25 (2H, m, Ph), 7.22e7.13 (3H, m,
d
7.32e7.24 (2H, m, Ph), 7.22e7.13 (3H, m, Ph), 5.53 (2H, br, 3-H and
Ph), 5.66 (0.35H, dt, J¼10.5, 7.7 Hz, 20-H), 5.59 (0.65H, dt, J¼15.4,
7.0 Hz, 20-H), 5.27 (0.65H, dd, J¼15.4, 8.4 Hz, 10-H), 5.20 (0.35H, dt,
J¼10.5, 1.4 Hz, 10-H), 4.42e4.34 (1H, m, 8-H), 4.09e4.05 (1.3H, m, 3-
H), 3.90 (0.35H, dd, J¼10.7, 8.8 Hz, 3-H), 3.79 (0.35H, dd, J¼10.7,
3.5 Hz, 3-H), 3.24 (0.65H, ddd, J¼12.1, 6.2, 2.3 Hz, 4a-H), 2.96e2.90
(0.35H, m), 2.88 (0.35H, ddd, J¼11.6, 6.0, 2.5 Hz, 4a-H), 2.78e2.65
(2.65H, m), 2.65 (0.65H, ddd, J¼12.6, 12.6, 2.8 Hz), 2.58 (0.35H, ddd,
J¼13.0, 13.0, 2.8 Hz), 2.46e2.32 (2H, m), 1.89e1.81 (1H, m),
1.67e1.59 (1H, m), 1.47e1.21 (3.35H, m), 1.15 (0.65H, dddd, J¼12.5,
4-H), 4.15 (1H, br), 3.96 (1H, br), 3.55e3.20 (2H, br), 2.85e2.60 (3H,
m), 2.55e2.30 (3H, m), 1.75e1.20 (7H, m), 1.46 (9H, s, t-Bu); IR (film)
3440, 3062, 2933, 2859, 1687, 1656, 1476, 1423, 1366, 1317, 1275,
1252, 1161, 1075, 1033, 996, 974, 918, 867, 812, 746 cmꢁ1; HRMSeESI
(m/z): [MþNa]þ calcd for C22H33NO3Na: 382.2353. Found: 382.2349.
3.4.5. N-tert-Butoxycarbonyl-4-methyl-2-(10-(methylamino)-30-phe-
nylpropyl)pent-3-en-1-ol (4h). Colorless oil. (2S*,10R*)/(2R*,10R*)¼
85/15 mixture. 1H NMR (400 MHz, CDCl3, 80/20 mixture of
12.5, 12.5, 3.5 Hz); 13C NMR (175 MHz, CDCl3)
d 153.0, 152.9, 141.2,
rotamers)
d
7.32e7.25 (2H, m, Ph), 7.22e7.13 (3H, m, Ph), 5.19
141.1, 134.0, 133.3, 128.6, 128.4, 128.22, 128.16, 126.0, 125.7, 124.5,
123.3, 67.4, 67.0, 57.9, 57.5, 46.11, 46.09, 39.5, 35.32, 35.26, 34.22,
34.19, 29.7, 27.9, 27.5, 25.2, 25.1, 24.04, 23.98; IR (film) 3059, 3024,
2936, 2855,1693,1602,1475,1430,1371,1316,1296,1247,1176,1142,
1112, 1084, 1015, 974, 910, 855, 833, 819, 752, 700 cmꢁ1; HRMSeESI
(m/z): [MþH]þ calcd for C18H24NO2: 286.1802. Found: 286.1796.
(0.12H, d, J¼10.4 Hz, 3-H), 4.98 (0.03H, d, J¼10.4 Hz, 3-H), 4.89
(0.17H, d, J¼10.4 Hz, 3-H), 4.79 (0.68H, d, J¼10.8 Hz, 3-H), 4.35
(0.68H, br, 10-H), 4.20e3.85 (0.32H, br, 10-H), 3.60 (0.17H, dd, J¼11.0,
5.4 Hz), 3.48 (0.12H, dd, J¼11.4, 4.2 Hz), 3.43e3.27 (1.71H, m),
2.80e2.42 (1.64H, m), 2.71 (3H, s, NCH3), 2.57 (1.36H, t, J¼8.0 Hz, 30-
H), 1.94e1.57 (4.92H, m), 1.71 (2.04H, s, C(CH3)2), 1.64 (2.04H, s,
C(CH3)2),1.49 (7.2H, s, t-Bu),1.45 (1.8H, s, t-Bu); IR (film) 3440, 3061,
3026, 2972, 2928, 2866, 1689, 1666, 1603, 1480, 1452, 1394, 1365,
1346,1254, 1153,1057, 980, 874, 770, 749, 700 cmꢁ1; HRMSeESI (m/
z): [MþNa]þ calcd for C21H33NO3Na: 370.2353. Found: 370.2346.
3.5.4. (4R*,4aR*)-4-(40-Phenylbut-10-enyl)hexahydropyrido[1,2-c]
[1,3]oxazin-1(3H)-one (minor-5e). Colorless oil. E/Z¼85/15 mixture.
1H NMR (700 MHz, CDCl3)
d 7.30e7.26 (2H, m, Ph), 7.21e7.13 (3H, m,
Ph), 5.70e5.64 (0.15H, m, 20-H), 5.67 (0.85H, dt, J¼15.6, 7.2 Hz, 20-H),
5.11 (0.85H, dd, J¼15.6, 8.8 Hz, 10-H), 5.05 (0.15H, ddt, J¼10.2, 10.2,
1.4 Hz, 10-H), 4.47e4.41 (1H, m, 8-H), 4.00 (0.85H, dd, J¼11.0, 4.2 Hz,
3-H), 3.86 (0.85H, dd, J¼11.0, 11.0 Hz, 3-H), 3.73 (0.15H, dd, J¼10.9,
10.9 Hz, 3-H), 3.63 (0.15H, dd, J¼10.9, 4.6 Hz, 3-H), 2.90 (0.85H, ddd,
J¼11.6, 9.1, 2.5 Hz, 4a-H), 2.87 (0.15H, ddd, J¼11.2, 8.8, 2.8 Hz, 4a-H),
2.75e2.58 (2.15H, m), 2.63 (0.85H, ddd, J¼13.0, 13.0, 2.8 Hz),
2.46e2.33 (3H, m), 1.84e1.75 (2H, m), 1.70e1.63 (1H, m), 1.49e1.38
(0.15H, m), 1.45 (0.85H, ddddd, J¼13.2, 13.2, 13.2, 3.7, 3.7 Hz),
1.35e1.24 (0.15H, m), 1.31 (0.85H, ddddd, J¼13.2, 13.2, 13.2, 3.7,
3.7 Hz), 1.06 (0.85H, dddd, J¼13.2, 13.2, 11.8, 3.7 Hz), 0.97 (0.15H,
3.5. Representative procedure of the cyclization of 4
Sodium hydride (60 wt % in oil,17 mg, 0.43 mmol) in THF (1.8 mL)
was added to a solution of major-4a (101.7 mg, 0.359 mmol) at 0 ꢀC.
After stirring for 2 h at 0 ꢀC and 15 h at room temperature, the
resulting mixture was quenched with saturated aqueous ammo-
nium chloride at 0 ꢀC. Extractive workup and purification of the
residue by chromatography on silica gel (ethyl acetate as the eluent)
afforded major-5a (42.7 mg, 57% yield) as a white solid.
dddd, J¼13.2, 13.2, 11.8, 3.7 Hz); 13C NMR (175 MHz, CDCl3)
d 153.3,
3.5.1. (4S*,4aR*)-4-(20-Methylprop-10-enyl)hexahydropyrido[1,2-c]
153.2,141.2,141.0,134.9,134.4,128.5,128.4,128.3,128.2,126.1,125.9,
125.7, 125.0, 67.9, 67.4, 59.4, 59.1, 45.2, 45.0, 43.6, 38.8, 35.5, 35.4,
34.3, 31.6, 29.9, 24.91, 24.88, 23.63, 23.59; IR (film) 3059, 3025, 2935,
2855,1694,1602,1474,1432,1388,1368,1343,1313,1293,1251,1225,
1169,1124,1095,1050,1008, 971, 907, 849, 758, 700 cmꢁ1;HRMSeESI
(m/z): [MþNa]þ calcd for C18H23NO2Na: 308.1621. Found: 308.1617.
[1,3]oxazin-1(3H)-one (major-5a). White solid. 1H NMR (700 MHz,
CDCl3)
d
4.99 (1H, dqq, J¼9.8, 1.4, 1.4 Hz, 10-H), 4.45e4.41 (1H, m, 8-
H), 4.08 (1H, dd, J¼10.7, 9.3 Hz, 3-H), 4.02 (1H, dd, J¼10.7, 3.7 Hz, 3-
H), 3.30 (1H, ddd, J¼12.3, 5.6, 2.5 Hz, 4a-H), 3.05 (1H, dddd, J¼9.8,
9.3, 5.6, 3.7 Hz, 4-H), 2.68 (1H, ddd, J¼12.8, 12.8, 3.2 Hz, 8-H),
1.95e1.90 (1H, m, 6-H), 1.75 (3H, d, J¼1.4 Hz, C(CH3)2), 1.70e1.62
(2H, m, 5-H and 6-H), 1.69 (3H, d, J¼1.4 Hz, C(CH3)2), 1.52e1.40 (2H,
m, 7-H), 1.36 (1H, ddd, J¼12.3, 12.3, 3.9 Hz, 5-H); 13C NMR
3.5.5. (4R*,5S*)-3-Methyl-5-(20-methylprop-10-enyl)-4-phenethyl-
1,3-oxazinan-2-one (major-5h). Colorless oil. 1H NMR (700 MHz,
(100 MHz, CDCl3)
d
153.1, 137.0, 117.4, 67.5, 57.9, 46.3, 35.2, 27.7,
CDCl3)
d
7.31 (2H, dd, J¼7.7, 7.7 Hz, Ph), 7.22 (1H, t, J¼7.4 Hz, Ph), 7.16
25.9, 25.4, 24.2, 18.3; IR (KBr) 2948, 2859, 1705, 1691, 1479, 1448,
1383, 1355, 1339, 1302, 1258, 1223, 1198, 1175, 1157, 1133, 1092,
1049,1016, 953, 922, 858, 831, 745 cmꢁ1; HRMSeESI (m/z): [MþH]þ
calcd for C12H20NO2: 210.1489. Found: 210.1488.
(2H, d, J¼7.4 Hz, Ph), 4.94e4.90 (1H, m, 10-H), 4.15 (1H, dd, J¼10.9,
10.2 Hz, 6-H), 4.10 (1H, ddq, J¼10.9, 4.9, 1.1 Hz, 6-H), 3.24 (1H, td,
J¼5.8, 4.9 Hz, 4-H), 3.12 (1H, dddd, J¼10.2, 10.2, 4.9, 4.9 Hz, 5-H),
2.97 (3H, s, NCH3), 2.68 (2H, t, J¼8.4 Hz, CH2Ph), 1.97e1.85 (2H, m,
CH2CH2Ph), 1.77 (3H, s, C(CH3)2), 1.71 (3H, d, J¼1.4 Hz, C(CH3)2); 13
C
3.5.2. (4R*,4aR*)-4-(20-Methylprop-10-enyl)hexahydropyrido[1,2-c]
NMR (175 MHz, CDCl3) d 153.2, 140.8, 137.8,128.5,128.1, 126.2, 117.4,
[1,3]oxazin-1(3H)-one (minor-5a). White solid. 1H NMR (700 MHz,
67.7, 59.5, 36.8, 35.5, 33.4, 32.3, 25.9, 18.3; IR (film) 3060, 3025,
2929, 1709, 1684, 1602, 1482, 1452, 1406, 1385, 1318, 1243, 1226,
1177, 1145, 1080, 1040, 1033, 1002, 983, 930, 909, 841, 755,
701 cmꢁ1; HRMSeESI (m/z): [MþNa]þ calcd for C17H23NO2Na:
296.1621. Found: 296.1618.
CDCl3)
d
4.81 (1H, dqq, J¼9.5, 1.4, 1.4 Hz, 10-H), 4.49e4.44 (1H, m, 8-
H), 3.97 (1H, dd, J¼10.9, 4.6 Hz, 3-H), 3.84 (1H, dd, J¼10.9, 10.9 Hz,
3-H), 2.95 (1H, ddd, J¼11.6, 9.5, 2.5 Hz, 4a-H), 2.68 (1H, dddd,
J¼10.9, 9.5, 9.5, 4.6 Hz, 4-H), 2.66 (1H, ddd, J¼13.2, 13.2, 2.8 Hz, 8-
H), 1.88e1.81 (2H, m, 5-H and 7-H), 1.74 (3H, d, J¼1.4 Hz, C(CH3)2),
1.71e1.66 (1H, m, 6-H), 1.70 (3H, d, J¼1.4 Hz, C(CH3)2), 1.47 (1H,
ddddd, J¼13.0, 13.0, 13.0, 4.2, 4.2 Hz, 7-H), 1.35 (1H, ddddd, J¼13.0,
3.5.6. (4R*,5R*)-3-Methyl-5-(20-methylprop-10-enyl)-4-phenethyl-
1,3-oxazinan-2-one (minor-5h). Pale yellow solid. 1H NMR