Preparation of Optically ActiVe Allylic Alcohols
J. Am. Chem. Soc., Vol. 122, No. 28, 2000 6615
2.60 (1H, m), 2.29-2-21 (1H, m), 1.86-1.62 (3H, m), 1.52-1.40
(1H, m) 1.46 and 1.33 (9H, each s), and 1.24-1.18 (1H, m); 13C NMR
(mixture of rotamers) δ 168.3, 168.1, 154.2, 152.6, 143.3, 142.9, 130.6,
130.5, 127.3, 127.1, 124.3, 124.1, 123.5, 123.4, 117.2, 116.8, 79.4,
79.3, 63.9, 63.8, 57.0, 55.6, 47.4, 47.3, 42.0, 41.4, 36.6, 34.0, 30.6,
30.4, 28.4, 28.2, 28.1, 28.0, 25.5, and 24.8; MS (EI) m/z (relative
intensity) 342 (M+, 12), 196 (16), 140 (100), 119 (42), 112 (17), and
96 (14). Anal. Calcd for C20H26N2O3‚0.7H2O: C, 67.66; H, 7.78; N,
7.89. Found: C, 67.74; H, 7.45; N, 7.13.
43.8, 43.2, 42.5, 34.8, 34.1, 30.5, 30.5, 29.9, 29.8, 28.5, 28.5, 21.7,
21.6, 20.5, and 20.5; GC-MS (EI) m/z (relative intensity) 236 (M+,
2), 219 (2), 140 (2), 112 (21), 96 (98), and 68 (100). Anal. Calcd for
C19H32N2O3: C, 67.82; H, 9.59; N, 8.33. Found: C, 67.69; H, 9.69; N,
8.18.
(1S,3R,4R)-3-[N-(cis-2,6-Dimethylpiperidinyl)]methyl-2-azabicyclo-
[2.2.1]heptane (1e). The procedure described for 1a was followed using
5e (0.23 g, 0.67 mmol), which gave 1e (0.14 g, 94%).
1e: Rf 0.48 (Al2O3, CH2Cl2/MeOH 9:1); [R]25 -8.8 (c ) 2.2,
D
1
CDCl3); IR (neat) 3185 and 2926 cm-1; H NMR δ 3.39-3.37 (1H,
(1S,3R,4R)-3-(N-Indolinyl)methyl-2-azabicyclo[2.2.1]heptane (1c).
The procedure described for 1a was followed using 5c (0.31 g, 0.91
mmol), which gave 1c (0.19 g, 96%) as a colorless oil.
m), 2.78 (1H, dd, J ) 8.9, 4.5 Hz), 2.54-2.44 (2H, m), 2.47 (1H, dd,
J ) 14.9, 8.9 Hz), 2.36-2.34 (1H, m), 2.23 (1H, dd, J ) 14.9, 4.5
Hz), 1.86 (1H, br s), 1.70-1.56 (3H, m), 1.50-1.42 (3H, m), 1.36-
1.20 (5H, m), 1.16 (1H, dt, J ) 10.2, 1.4 Hz), 1.12 (3H, d, J ) 2.2
Hz), and 1.10 (3H, d, J ) 2.2 Hz); 13C NMR δ 61.0, 58.3, 57.3, 55.4,
54.9, 39.7, 34.3, 33.3, 33.0, 32.6, 29.0, 24.5, 22.1, and 22.0; GC-MS
(EI) m/z (relative intensity) 220 (M+ - 2, 2), 205 (11), 126 (100), 112
(54), and 96 (16); HRMS calcd for C14H26N2 222.2096, found 222.2098.
(1S,3R,4R)-N-tert-Butoxycarbonyl-3-[N-((2S)-2-methoxymethyl)-
pyrrolidinyl]carbonyl-2-azabicyclo[2.2.1]heptane (5f). The procedure
described for 5a was followed, using amino acid 4 (1.05 g, 4.35 mmol)
and (S)-O-methylprolinol23 (0.58 g, 5.72 mmol), which gave 5f (1.5 g,
79%).
1c: Rf 0.40 (Al2O3, CH2Cl2/MeOH 9:1); [R]24 - 23.3 (c ) 0.9,
D
CH2Cl2); IR (neat) 3318, 3047, and 2953 cm-1; 1H NMR δ 7.10-6.98
(2H, m), 6.63 (1H, dt, J ) 7.5, 1.1 Hz), 6.45 (1H, td, J ) 7.5, 0.6 Hz),
3.62-3.48 (1H, m), 3.47-3.45 (1H, m), 3.39 (2H, t, J ) 8.4 Hz), 3.03-
2.88 (3H, m), 2.80 (1H, dd, J ) 12.8, 5.9 Hz), 2.35-2.32 (1H, m),
1.70-1.58 (4H, m), and 1.40-1.36 (2H, m); 13C NMR δ 152.5, 129.3,
127.0, 124.1, 117.0, 106.1, 59.8, 55.7, 55.3, 53.8, 39.3, 34.2, 32.2, 28.6,
and 28.4; MS (EI) m/z (relative intensity) 228 (M+, 3), 132 (82), 118
(8), 96 (6), and 68 (16). Anal. Calcd for C15H20N2‚CSA‚H2O: C, 63.00;
H, 7.61; N, 5.88. Found: C, 62.91; H, 7.32; N, 5.53.
(1S,3R,4R)-N-tert-Butoxycarbonyl-3-(N-isoindolinyl)carbonyl-2-
azabicyclo[2.2.1]heptane (5d). The procedure described for 5a was
followed using amino acid 4 (0.60 g, 2.48 mmol) and isoindoline22
(0.33 g, 2.73 mmol), which gave 5d (0.79 g, 93%) as an off-white
solid.
5f: Rf 0.25 (silica, pentane/EtOAc 1:2); [R]25 -10.8 (c ) 1.0,
D
1
CDCl3); IR (neat) 3566, 2971, 2361, 1697, and 1654 cm-1; H NMR
(mixture of rotamers) δ 4.24-4.22 and 4.11-4.09 (1H, each m), 4.16-
4.05 (1H, m), 3.91, 3.80, 3.76 and 3.69 (1H, each s), 3.65-3.40 (2H,
m), 3.35-3.14 (2H, m), 3.24 (1H, s), 3.22 and 3.20 (3H, each s), 2.42-
2.35 (1H, m), 2.53-2.41 and 2.22-2.10 (1H, each m), 2.02-1.69 (4H,
m), 1.67-1.46 (3H, m), 1.38-1.13 (1H, m), 1.33 (3H, s), and 1.28
(6H, t, J ) 11.6 Hz); 13C NMR (mixture of rotamers) δ 170.5, 168.8,
154.0, 152.9, 79.0, 75.2, 72.4, 71.8, 63.6, 62.0, 58.7, 58.6, 57.0, 56.8,
55.8, 55.7, 46.5, 46.4, 41.9, 41.3, 34.8, 34.7, 34.04, 33.98, 30.6, 30.3,
28.4, 28.2, 27.9, 27.1, 24.1, and 24.0; GC-MS (EI) m/z (relative
intensity) 338 (M+, 3), 196 (11), 140 (100), and 96 (29). Anal. Calcd
for C18H30N2O4‚H2O: C, 60.65; H, 9.05; N, 7.86. Found: C, 60.40; H,
8.85; N, 7.72.
5d: mp 185-190 °C; Rf 0.31 (silica, pentane/EtOAc 1:2); [R]25
D
+25.3 (c ) 1.1, CDCl3); IR (KBr) 3155, 2981, 1679, and 1657 cm-1
;
1H NMR (mixture of rotamers) δ 7.12 and 7.06 (4H, each s), 4.94 and
4.83 (1H, each d, J ) 13.3 Hz), 4.70-4.59 (2H, m), 4.66 and 4.52
(1H, each d, J ) 16.0 Hz), 4.22 and 4.09 (1H, each s), 3.86 and 3.78
(1H, each s), 2.43-2.40 (1H, m), 2.19 and 2.13 (1H, each d, J ) 9.8
Hz), 1.65-1.20 (4H, m), 1.28 and 1.17 (9H, each s), and 1.08 and
1.05 (1H, each d, J ) 9.8 Hz); 13C NMR (mixture of rotamers) δ
168.6, 168.4, 153.7, 152.2, 135.7, 135.6, 135.5, 135.4, 127.3, 127.04,
126.98, 126.8, 122.3, 122.2, 122.1, 122.0, 78.8, 78.6, 62.5, 62.4, 56.6,
55.2, 51.9, 51.8, 51.6, 51.5, 41.5, 41.0, 34.5, 33.7, 30.2, 30.0, 28.0,
27.9, 27.8, and 27.7; MS (EI) m/z (relative intensity) 342 (M+, <1),
242 (54), 140 (100), 118 (79), and 96 (46). Anal. Calcd for
C20H26N2O3: C, 70.15; H, 7.65; N, 8.18. Found: C, 69.97; H, 7.76; N,
8.17.
(1S,3R,4R)-3-[N-((2S)-2-Methoxymethyl)pyrrolidinyl]methyl-2-
azabicyclo[2.2.1]heptane (1f). The procedure described for 1a was
used to make 1f (0.58 g, 85%) from 5f (0.76 g, 2.26 mmol).
1f: Rf 0.39 (Al2O3, CH2Cl2/MeOH 9:1); [R]24 -28.4 (c ) 2.6,
D
1
CH2Cl2); IR (neat) 3360, 2922, and 2856 cm-1; H NMR δ 5.30 (1H,
(1S,3R,4R)-3-(N-Isoindolinyl)methyl-2-azabicyclo[2.2.1]heptane
(1d). The procedure described for 1a was followed, using 5d (2.53 g,
7.40 mmol), which gave 1d (1.4 g, 83%) as a white solid.
br s), 3.39-3.34 (1H, m), 3.30 (3H, s), 3.21 (1H, dt, J ) 11.5, 3.9
Hz), 3.17-3.10 (1H, m), 2.81-2.73 (1H, m), 2.59-2.49 (2H, m), 2.27
(1H, dt, J ) 11.5, 5.2), 2.20-2.12 (1H, m), 2.12-2.10 (1H, m), 1.87-
1.77 (1H, m), 1.72-1.62 (3H, m), 1.58-1.46 (3H, m), 1.42-1.20 (3H,
m), and 1.18-1.13 (1H, m); 13C NMR δ 76.9, 63.4, 61.4, 60.9, 58.9,
55.7, 54.8, 40.0, 35.2, 31.7, 28.6, 28.3, and 23.2; GC-MS (EI) m/z
(relative intensity) 225 (M+ + 1, 5), 209 (3), 193 (3), 179 (9), 128
(75), 110 (21), 96 (22), and 84 (100); HRMS calcd for C13H24N2O
224.1889, found 224.1892.
1d: Rf 0.39 (Al2O3, CH2Cl2/MeOH 9:1); [R]24 -34.0 (c ) 1.1,
D
CH2Cl2); IR (KBr) 3413, 3047, and 2958 cm-1; 1H NMR δ 7.15 (4H,
s), 3.92 (4H, s), 3.41 (1H, s), 2.88 (1H, t, J ) 7.2 Hz), 2.62 (1H, dd,
J ) 11.8, 7.2 Hz), 2.48 (1H, dd, J ) 11.8, 7.2 Hz), 2.32-2.29 (1H,
m), 1.98 (1H, br s), 1.67-1.55 (2H, m), 1.54-1.48 (1H, m), 1.42-
1.32 (2H, m), and 1.21-1.17 (1H, m); 13C NMR δ 140.0, 126.4, 122.0,
62.0, 60.5, 59.3, 55.7, 39.6, 34.8, 32.3, and 28.8; MS (EI) m/z (relative
intensity) 228 (M+, 2), 132 (100), 118 (13), 96 (16), and 68 (34). Anal.
Calcd for C15H20N2: C, 78.90; H, 8.83; N, 12.27. Found: C, 79.21; H,
8.52; N, 12.31.
(1R,3S,4S)-N-tert-Butoxycarbonyl-3-[N-((2S)-2-methoxymethyl)-
pyrrolidinyl]carbonyl-2-azabicyclo[2.2.1]heptane (5g). The procedure
described for 5a was followed, using ent-4 (0.50 g, 2.07 mmol) and
(S)-O-methylprolinol23 (0.28 g, 2.75 mmol), which gave amide 5g (0.37
g, 75%).
(1S,3R,4R)-N-tert-Butoxycarbonyl-3-[N-(cis-2,6-dimethylpiperidi-
nyl)]carbonyl-2-azabicyclo[2.2.1]heptane (5e). The procedure de-
scribed for 5a was followed, using 4 (0.50 g, 2.07 mmol) and cis-2,6-
dimethylpiperidine (0.33 mL, 2.48 mmol), which gave 5e as a gummy
solid (0.4 g, 57%).
5g: Rf 0.25 (silica, pentane/EtOAc 1:2); [R]25 -70.3 (c ) 1.4,
D
1
CDCl3); IR (neat) 2975, 1738, and 1653 cm-1; H NMR (mixture of
rotamers) δ 4.36-4.34 and 4.23-4.21 (1H, each m), 4.34-4.23 (1H,
m), 3.92, 3.88, 3.84, and 3.79 (1H, each s), 3.54-3.32 (3H, m), 3.36
(1H, d, J ) 2.2 Hz), 3.31 and 3.30 (3H, each s), 2.49-2.45 and 2.44-
2.40 (1H, each m), 2.22-2.13 (1H, m), 2.10-1.77 (4H, m), 1.76-
1.55 (3H, m), 1.50-1.30 (1H, m), 1.43 (6H, s), 1.38 and 1.35 (3H,
each s), 1.34 (1H, s), and 1.18 (1H, dd, J ) 10.5, 8.8 Hz); 13C NMR
(mixture of rotamers) δ 169.5, 168.7, 154.0, 153.6, 79.3, 79.2, 73.5,
72.2, 63.6, 63.2, 58.9, 57.2, 56.6, 56.5, 56.1, 55.8, 46.9, 46.8, 42.3,
41.7, 34.7, 34.1, 30.7, 30.5, 28.5, 28.33, 28.28, 28.0, 27.1, 26.9, 24.6,
5e: Rf 0.44 (silica, pentane/EtOAc 1:2); [R]25 + 15.0 (c ) 2.7,
D
1
CDCl3); IR (KBr) 2970, 1685, and 1625 cm-1; H NMR (mixture of
rotamers) δ 4.83-4.76 and 4.70-4.63 (1H, each m), 4.38-4.35 and
4.23-4.20 (1H, each m), 4.04-3.92 (1H, m), 3.95 and 3.82 (1H, each
s), 2.46-2.35 (1H, m), 2.11 and 1.99 (1H, each dt, J ) 9.5, 2.0 Hz),
1.86-1.27 (11 H, m), 1.42 and 1.37 (9H, each s), and 1.33 and 1.17
(6H, each d, J ) 7.1 Hz); 13C NMR (mixture of rotamers) δ 166.9,
166.6, 153.9, 152.6, 79.3, 78.9, 63.0, 62.8, 57.3, 56.2, 47.2, 46.9, 44.0,
(23) (a) Seebach, D.; Kalinowski, H.-O.; Bastani, B.; Crass, G.; Daum,
H.; Do¨rr, H.; DuPreez, N. P.; Ehrig, V.; Langer, W.; Nu¨ssler, C.; Oei, H.-
A.; Schmidt, M. HelV. Chim. Acta 1977, 60, 301-325.
(22) Gawley, R. E.; Chemburkar, S. R.; Smith, A. L.; Anklekar, T. V.
J. Org. Chem. 1988, 53, 5381-5383.