1078 Bull. Chem. Soc. Jpn. Vol. 79, No. 7 (2006)
Asymmetric 1,3-Dipolar Cycloaddition of Nitrones
mp 116.5–117.5 ꢁC (from EtOH/hexane). IR (KBr) 3412, 3027,
2908, 1649, 1594, 1488, 1427, 1353, 1288, 1220, 1196, 1077,
extract was washed successively with water and brine, and then
dried over Na2SO4. Evaporation of the solvent and separation of
the residue by preparative TLC (hexane/AcOEt = 2/1, v/v) af-
forded the desired acetate of the cycloadduct 5Ae (36 mg) in 20%
1044, 1019, 960, 899, 817, 769, 751, 699 cmꢂ1 1H NMR (400
.
MHz, CDCl3) ꢂ 2.26 (1H, ddd, J ¼ 8:30, 9.27, 12.44 Hz), 2.83
(1H, ddd, J ¼ 1:95, 5.86, 12.44 Hz), 3.80–3.87 (1H, m), 3.82
(1H, brs), 4.02–4.08 (1H, m), 4.38–4.42 (1H, m), 4.49 (1H, d, J ¼
14:88 Hz), 4.50 (1H, d, J ¼ 17:32 Hz), 4.70 (1H, dd, J ¼ 1:95,
8.30 Hz), 4.80 (1H, d, J ¼ 17:32 Hz), 4.91 (1H, d, J ¼ 14:88 Hz),
6.91 (2H, d, J ¼ 8:30 Hz), 6.97 (1H, t, J ¼ 7:32 Hz), 7.19–7.42
(12H, m). 13C NMR (100 MHz, CDCl3) ꢂ 31.7, 49.5, 49.8, 62.0,
64.9, 78.7, 114.6, 122.7, 126.4, 127.6, 127.9, 128.2, 128.7, 128.9,
129.16, 129.22, 136.1, 136.6, 149.5, 171.7. Anal. Found: C, 74.59;
H, 6.56; N, 6.85%. Calcd for C25H26N2O3: C, 74.60; H, 6.51; N,
6.96%.
25
yield. ½ꢁꢃD ꢂ22 (c 0.20, EtOH; 78% ee). An oil. IR (neat) 2966,
2931, 1741, 1640, 1497, 1444, 1370, 1287, 1238, 1136, 1042, 734,
1
700 cmꢂ1. H NMR (300 MHz, CDCl3) ꢂ 0.83 (3H, brd, J ¼ 5:14
Hz), 1.04 (3H, d, J ¼ 6:42 Hz), 1.32 (3H, d, J ¼ 6:60 Hz), 1.33
(3H, d, J ¼ 6:79 Hz), 2.07 (3H, s), 2.53 (1H, ddd, J ¼ 8:07,
8.80, 12.47 Hz), 2.74 (1H, ddd, J ¼ 3:85, 5.50, 12.47 Hz), 3.23–
3.32 (1H, m), 3.52–3.72 (1H, m), 3.85 (1H, d, J ¼ 12:29 Hz),
3.97–4.02 (1H, m), 4.09 (1H, d, J ¼ 12:29 Hz), 4.27 (1H, dd, J ¼
7:70, 11.55 Hz), 4.40 (1H, dd, J ¼ 3:67, 11.55 Hz), 4.56–4.57 (1H,
m), 7.27–7.39 (5H, m). 13C NMR (100 MHz, CDCl3) ꢂ 20.2,
20.37, 20.42, 21.0, 29.7, 31.4, 46.1, 48.2, 61.3, 65.6, 66.0, 76.3,
127.9, 128.5, 129.8, 136.2, 167.5, 170.9. MS (EI) m=z 362 (Mþ,
4.61%), 347 (19.49), 235 (11.78), 234 (81.31), 174 (19.23), 149
(9.05), 128 (7.86), 91 (100.00), 86 (12.37).
trans-N,N-Dibenzyl-5-(hydroxymethyl)-2-phenylisoxazoli-
dine-3-carboxamide (4Ac):20 mp 124 ꢁC (from Et2O/hexane).
IR (KBr) 3457, 3056, 2926, 1642, 1596, 1494, 1473, 1451, 1429,
1362, 1298, 1271, 1205, 1077, 1039, 977, 961, 810, 764, 743,
698 cmꢂ1
.
1H NMR (400 MHz, C6D6) ꢂ 1.00 (1H, brs), 1.77
(3S,4R,5R)-5-(Hydroxymethyl)-N,N-diisopropyl-4-methyl-2-
25
(1H, dt, J ¼ 11:95, 7.32 Hz), 2.81 (1H, ddd, J ¼ 2:68, 7.32,
11.95 Hz), 3.28 (1H, dd, J ¼ 6:10, 11.95 Hz), 3.35 (1H, dd, J ¼
3:66, 11.95 Hz), 4.15 (1H, d, J ¼ 17:20 Hz), 4.25 (1H, d, J ¼
14:88 Hz), 4.51 (1H, dd, J ¼ 2:68, 7.32 Hz), 4.60 (1H, d, J ¼
17:20 Hz), 4.62–4.68 (1H, m), 4.96 (1H, d, J ¼ 14:88 Hz), 6.74–
6.80 (1H, m), 6.95–7.20 (14H, m). 13C NMR (100 MHz, CDCl3)
ꢂ 33.4, 49.2, 49.8, 64.0, 64.6, 80.8, 115.1, 122.8, 126.5, 127.5,
127.8, 128.3, 128.7, 129.0, 129.2, 136.4, 136.8, 150.1, 170.2.
Anal. Found: C, 74.50; H, 6.54; N, 6.83%. Calcd for C25H26N2O3:
C, 74.60; H, 6.51; N, 6.96%.
phenylisoxazolidine-3-carboxamide (5Bd):
3.02, EtOH; >99% ee). mp 91–92 ꢁC (from AcOEt/hexane). IR
(KBr) 3384, 2968, 2933, 2875, 1631, 1490, 1449, 1373, 1343,
½ꢁꢃD ꢂ98 (c
1245, 1210, 1138, 1093, 1042, 758, 695 cmꢂ1 1H NMR (400
.
MHz, CDCl3) ꢂ 1.11 (3H, d, J ¼ 6:83 Hz), 1.195 (3H, d, J ¼
6:59 Hz), 1.197 (3H, d, J ¼ 6:34 Hz), 1.426 (3H, d, J ¼ 6:83 Hz),
1.431 (3H, d, J ¼ 6:83 Hz), 2.97–3.06 (1H, m), 3.39–3.45 (1H,
m), 3.40 (1H, dd, J ¼ 1:95, 12.44 Hz), 3.70–3.95 (1H, br), 3.78
(1H, dd, J ¼ 3:66, 12.44 Hz), 3.88–3.91 (1H, m), 4.17 (1H, d, J ¼
5:37 Hz), 4.35–4.41 (1H, m), 6.94 (1H, t, J ¼ 7:32 Hz), 7.03 (2H,
d, J ¼ 8:54 Hz), 7.26 (2H, dd, J ¼ 7:34, 8.54 Hz). 13C NMR (100
MHz, CDCl3) ꢂ 17.2, 20.3, 20.5, 20.6, 20.9, 42.6, 46.6, 48.4, 61.0,
75.6, 85.7, 114.2, 122.0, 129.1, 151.0, 169.4. Anal. Found: C,
67.21; H, 8.87; N, 8.61%. Calcd for C18H28N2O3: C, 67.47; H,
8.81; N, 8.74%.
(3S,5R)-5-(Hydroxymethyl)-N,N-diisopropyl-2-phenylisoxa-
25
zolidine-3-carboxamide (5Ad): ½ꢁꢃD ꢂ135 (c 1.04, EtOH;
98% ee). mp 120.5–121.5 ꢁC (from AcOEt/hexane). IR (KBr)
3458, 1638, 1597, 1542, 1488, 1448, 1375, 1326, 1254, 1085,
1
1043, 891, 857 cmꢂ1. H NMR (300 MHz, CDCl3) ꢂ 1.18 (3H, d,
J ¼ 6:60 Hz), 1.23 (3H, d, J ¼ 6:97 Hz), 1.40 (3H, d, J ¼ 6:97
Hz), 1.50 (3H, d, J ¼ 6:60 Hz), 2.27 (1H, ddd, J ¼ 8:07, 9.17,
12.47 Hz), 2.72 (1H, ddd, J ¼ 2:20, 5.87, 12.47 Hz), 3.30–4.00
(1H, br), 3.40 (1H, hept, J ¼ 6:97 Hz), 3.76 (1H, dd, J ¼ 3:67,
12.47 Hz), 3.95 (1H, dd, J ¼ 2:20, 12.47 Hz), 4.20 (1H, hept,
J ¼ 6:60 Hz), 4.32 (1H, dddd, J ¼ 2:20, 3.67, 5.87, 9.17 Hz), 4.66
(1H, dd, J ¼ 2:20, 8.07 Hz), 6.97 (1H, t, J ¼ 7:34 Hz), 7.04 (2H,
d, J ¼ 7:70 Hz), 7.26 (2H, dd, J ¼ 7:34, 7.70 Hz). 13C NMR (100
MHz, CDCl3) ꢂ 20.3, 20.40, 20.44, 20.8, 31.3, 46.6, 48.8, 62.0,
66.0, 78.5, 114.6, 122.6, 129.3, 149.9, 169.5. Anal. Found: C,
66.38; H, 8.68; N, 9.06%. Calcd for C17H26N2O3: C, 66.64; H,
8.55; N, 9.14%.
(3S,5R)-5-(Acetoxymethyl)-2-benzyl-N,N-diisopropylisoxa-
zolidine-3-carboxamide (5Ae Acetate) (Table 2, Entry 5). Us-
ing 2-propen-1-ol (1A) (29 mg, 0.5 mmol), diethylzinc (1.0 M
solution in hexane, 0.8 mL, 0.8 mmol), diisopropyl (R,R)-tartrate
(23 mg, 0.1 mmol), iodine (178 mg, 0.7 mmol), pyridine N-oxide
(48 mg, 0.5 mmol), and N-[(diisopropylcarbamoyl)methylene]ben-
zylamine N-oxide (2e) (131 mg, 0.5 mmol), the isoxazolidine 5Ae
contaminated with by-products was obtained (91 mg) by TLC sep-
aration. However, since the impurity was not separable, 5Ae was
isolated as the corresponding acetate. To a CH2Cl2 (10 mL) solu-
tion of the crude product 5Ae obtained above, triethylamine
(0.058 mL, 0,42 mmol), a catalytic amount of 4-(dimethylamino)-
pyridine, and Ac2O (0.040 mL, 0.42 mmol) were added at rt under
N2. The resulting solution was kept at the same temperature over-
night with stirring. The solvent was removed in vacuo, and the
residue was partitioned between AcOEt and water. The organic
(3S,4R,5R)-5-(Acetoxymethyl)-N,N-diisopropyl-2-phenyl-4-
propylisoxazolidine-3-carboxamide (5Cd Acetate) (Table 2,
Entry 10). Using (E)-2-hexen-1-ol (1C) (210 mg, 2.1 mmol), di-
ethylzinc (1.0 M solution in hexane, 2.42 mL, 2.4 mmol), diisopro-
pyl (R,R)-tartrate (69 mg, 0.3 mmol), iodine (534 mg, 2.1 mmol),
pyridine N-oxide (144 mg, 1.5 mmol), and N-[(diisopropylcarba-
moyl)methylene]aniline N-oxide (2d) (372 mg, 1.5 mmol), the
crude isoxazolidine 5Cd was obtained after extraction. To a
CH2Cl2 (5 mL) solution of the crude cycloadduct 5Cd, triethyl-
amine (1.15 mL, 8.3 mmol), a catalytic amount of 4-(dimethyl-
amino)pyridine, and Ac2O (0.68 mL, 7.2 mmol) were added at
room temperature under N2. The resulting solution was kept at
the same temperature overnight with stirring. The solvent was re-
moved in vacuo, and the residue was partitioned between AcOEt
and water. The organic extract was washed successively with water
and brine, and then dried over Na2SO4. Evaporation of the solvent
and separation of the residue by flash column chromatography
(hexane/AcOEt = 2/1, v/v) afforded the desired cycloadduct
5Cd acetate (291 mg, 48%) as a colorless solid. Optical purity
was determined by HPLC analysis (Daicel Chiralcel OD-H, hex-
25
ane/iPrOH = 50/1, v/v). ½ꢁꢃD ꢂ90 (c 2.91, EtOH; >99% ee).
mp 81.9–83.5 ꢁC (from AcOEt/hexane). IR (KBr) 2960, 1748,
1636, 1599, 1490, 1444, 1371, 1308, 1224, 1032, 972, 892, 775,
696 cmꢂ1
.
1H NMR (400 MHz, CDCl3) ꢂ 0.86 (3H, t, J ¼ 7:07
Hz), 1.12 (3H, d, J ¼ 6:59 Hz), 1.16 (3H, d, J ¼ 6:59 Hz), 1.19–
1.50 (10H, m), 2.12 (3H, s), 2.88–2.95 (1H, m), 3.39 (1H, hept,
J ¼ 6:59 Hz), 4.01 (1H, dt, J ¼ 2:93, 7.07 Hz), 4.14 (1H, d, J ¼
5:86 Hz), 4.28 (1H, dd, J ¼ 7:07, 12.20 Hz), 4.38 (1H, hept, J ¼