Synthesis of Ephedra Alkaloid Analogues
J . Org. Chem., Vol. 61, No. 18, 1996 6187
Hz, 3H); 13C NMR (50.3 MHz, CDCl3) δ 154.3, 142.2, 128.5,
127.5, 127.2, 126.6, 110.0, 106.8, 69.1, 64.7, 40.1, 29.9, 23.2.
Anal. Calcd for C15H17NO: C, 74.05; H, 7.04; N, 5.76.
Found: C, 73.97; H, 6.86; N, 5.82.
8.66 (d, J ) 8.0 Hz, 1H), 7.95-7.49 (m, 7H), 7.36-7.28(m, 5H),
5.46 (d, J ) 2.0 Hz, 1H), 2.65 (q, J ) 6.4 Hz, 1H), 2.25 (d, J )
3.5 Hz, 1H), 2.18 (m, 1H), 1.46 (d, J ) 6.4 Hz, 3H), 1.42 (d, J
) 8.4 Hz, 1H); 13C NMR (50.3 MHz, CDCl3) δ 144.3, 128.9,
128.5, 127.3, 126.6, 126.5, 126.1, 125.7, 123.8, 123.3, 123.1,
122.9, 122.8, 122.4, 69.3, 66.7, 41.9, 30.3, 23.0. Anal. Calcd
for C25H23NO: C, 84.95; H, 6.52; N, 3.96. Found: C, 84.74;
H, 6.52; N, 3.94.
N-[(R)-r-Meth ylben zyl]-1′(S)-(3-m eth oxyp h en yl)a zir i-
d in e-2(S)-m eth a n ol (10g): mp 43-45 °C; [R]24 ) +116.9°
D
1
(c 0.80, CHCl3); H NMR (200 MHz, CDCl3) δ 7.38-7.18 (m,
5H), 7.18-7.10 (m, 1H), 6.79-6.65 (m, 3H), 4.21 (d, J ) 5.8
Hz, 1H), 3.73 (s, 3H), 2.52 (q, J ) 6.5 Hz, 1H), 1.79 (td, J )
6.3, 3.3 Hz, 1H), 1.57 (d, J ) 6.5 Hz, 1H), 1.45 (d, J ) 6.6 Hz,
3H); 13C NMR (75.4 MHz, CDCl3) δ 159,8, 144.4, 143.9, 129.3,
128.8, 127.7, 127.0, 118.1, 113.0, 111.3, 74.0, 69.2, 55.1, 44.6,
31.9, 22.2. Anal. Calcd for C18H21NO2: C, 76.30; H, 7.47; N,
4.94. Found: C, 76.28; H, 7.67; N, 5.02.
Rep r esen ta tive P r oced u r e of Azir id in e Rin g Red u c-
tion . To a solution of 10a (253 mg, 1.00 mmol) in 5.0 mL of
EtOAc was added 51 mg of Pd(OH)2. The mixture was stirred
under a balloon pressure of hydrogen for 4 h at room temper-
ature. The reaction mixture was filtered and concentrated in
vacuo. Purification by silica gel flash chromatography (EtOAc/
hexane, 50:50) gave 217 mg of 13a (85%) as a colorless oil.
1
N-[(R)-r-Meth ylben zyl]-1′(R)-(3-m eth oxyp h en yl)a zir i-
d in e-2(S)-m eth a n ol (12g): mp 68-70 °C; [R]25 ) +57.1° (c
D
13a : [R]25 ) +203.0° (c 0.66, CHCl3); H NMR (200 MHz,
D
1.00, CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.40-7.00 (m, 6H),
6.85-6.74 (m, 3H), 4.64 (d, J ) 3.2 Hz, 1H), 3.77 (s, 3H), 2.67
(q, J ) 6.5 Hz, 1H), 2.11(d, J ) 3.3 Hz, 1H), 1.83 (td, J ) 6.5,
3.3 Hz, 1H) ,1.43 (d, J ) 6.5 Hz, 3H), 1.42 (d, J ) 6.3 Hz, 1H);
13C NMR (75.4 MHz, CDCl3) δ 159,9, 144.5, 143.5, 129.4, 128.6,
127.3, 126.6, 118.5, 113.2, 111.6, 69.6, 68.9, 55.0, 42.6, 29.1,
23.0. Anal. Calcd for C18H21NO2: C, 76.30; H, 7.47; N, 4.94.
Found: C, 76.17; H, 7.46; N, 4.98.
CDCl3) δ 7.38-7.15 (m, 10H), 4.12 (d, J ) 8.4 Hz, 1H), 3.95
(q, J ) 6.6 Hz, 1H), 2.47 (m, 1H), 1.38 (d, J ) 6.6 Hz, 3H),
0.91 (d, J ) 6.3 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 144.8,
142.4, 129.1, 128.7, 128.1, 127.8, 127.5, 127.3, 78.4, 57.0, 55.2,
25.4, 16.1. Anal. Calcd for C17H21NO: C, 79.96; H, 8.29; N,
5.49. Found: C, 79.73; H, 8.52; N, 5.42.
(3S,4S)-2-[N-[(R)-r-Meth ylben zyl]a m in o]-2,2-d im eth yl-
1
3-p en ta n ol (13b): [R]25 ) +111.2° (c 1.0, CHCl3); H NMR
D
N-[(R)-r-Meth ylben zyl]-1′(S)-(4-ch lor oph en yl)azir idin e-
2(S)-m eth a n ol (10h ): mp 45-47 °C; [R]23D ) +126.0° (c 0.80,
CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.44-7.12 (m, 5H), 7.03
(d, J ) 5.5 Hz, 2H), 6.91 (d, J ) 8.3 Hz, 2H), 4.24 (d, J ) 4.4
Hz, 1H), 2.49 (q, J ) 6.6 Hz, 1H), 2.00 (d, J ) 3.6 Hz, 1H),
1.71 (m, 1H), 1.54 (d, J ) 6.3 Hz, 1H), 1.44 (d, J ) 6.6 Hz,
3H); 13C NMR (75.4 MHz, CDCl3) δ 144.1, 141.0, 133.0, 128.7,
128.3, 127.6, 127.1, 127.0, 72.5, 69.4, 44.2, 31.7, 22.2. Anal.
Calcd for C17H18ClNO: C, 70.95; H, 6.30; N, 4.87. Found: C,
70.96; H, 6.30; N, 4.72.
N-[(R)-r-Meth ylben zyl]-1′(R)-(4-ch lor oph en yl)azir idin e-
2(S)-m eth a n ol (12h ): mp 98-100 °C; [R]23D ) +60.0° (c 0.23,
CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.45-7.00 (m, 9H), 4.60
(d, J ) 3.6 Hz, 1H), 2.66 (q, J ) 6.6 Hz, 1H), 2.07 (d, J ) 3.6
Hz, 1H), 1.79 (m, 1H), 1.44 (d, J ) 6.6 Hz, 1H), 1.44 (d, J )
6.6 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 144.3, 140.3, 133.4,
128.6, 128.5, 127.5, 127.3, 126.6, 69.5, 69.0, 42.5, 29.2, 23.0.
Anal. Calcd for C17H18ClNO: C, 70.95; H, 6.30; N, 4.87.
Found: C, 70.89; H, 6.30; N, 4.73.
(200 MHz, CDCl3) δ 7.32-7.22 (m, 5H), 3.93 (q, J ) 6.5 Hz,
1H), 2.80 (d, J ) 5.9 Hz, 1H), 2.52-2.39 (m, 1H), 2.46 (m, 3H),
1.38 (d, J ) 6.5 Hz, 3H), 1.16 (d, J ) 6.5 Hz, 3H), 0.72 (s, 9H);
13C NMR (75.4 MHz, CDCl3) δ 144.6, 128.6, 127.3, 127.1, 81.0,
55.3, 49.8, 34.6, 25.9, 24.7, 21.0. Anal. Calcd for C15H25NO:
C, 76.55; H, 10.71; N, 5.95. Found: C, 76.47; H, 10.77; N, 5.93.
(1S,2S)-2-[N-[(R)-r-Meth ylben zyl]am in o]-1-(1-n aph th yl)-
1
1-p r op a n ol (13c): [R]23 ) +185.3° (c 1.0, CHCl3); H NMR
D
(200 MHz, CDCl3) δ 7.88 (d, J ) 8.4 Hz, 1H), 7.79 (d, J ) 8.0
Hz, 1H), 7.72 (dd, J ) 7.1, 2.2 Hz, 1H), 7.69-7.21 (m, 10H),
4.81 (d, J ) 8.5 Hz, 1H), 3.94 (q, J ) 6.6 Hz, 1H), 2.92 (m,
1H), 2.75 (br, 1H), 1.42 (d, J ) 6.6 Hz, 3H), 0.94 (d, J ) 6.3
Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 144.9, 137.6, 134.2,
131.3, 128.8, 128.4, 127.4, 127.1, 125.7, 125.4, 125.2, 124.4,
76.4, 55.4, 55.1, 24.9, 16.9. Anal. Calcd for C21H23NO: C,
82.59; H, 7.59; N, 4.59. Found: C, 82.23; H, 7.81; N, 4.55.
(1S,2S)-2-[N-[(R)-r-Meth ylben zyl]am in o]-1-(2-n aph th yl)-
1
1-p r op a n ol (13d ): [R]23 ) +191.0° (c 1.0, CHCl3); H NMR
D
N-[(R)-r-Meth ylben zyl]-1′(S)-(4-flu or oph en yl)azir idin e-
(200 MHz, CDCl3) δ 7.85-7.72(m, 4H), 7.68-7.27 (m, 8H), 4.36
(d, J ) 7.3 Hz, 1H), 4.01 (q, J ) 6.6 Hz, 1H), 3.09 (br, 2H),
2.66 (m, 1H), 1.44 (d, J ) 6.6 Hz, 3H), 0.99 (d, J ) 6.2 Hz,
3H); 13C NMR (75.4 MHz, CDCl3) δ 144.9, 139.8, 133.3, 128.8,
128.2, 128.1, 127.8, 127.4, 127.3, 127.0, 126.4, 126.1, 125.9,
125.0, 78.2, 56.3, 54.9, 25.2, 16.0. Anal. Calcd for C21H23NO:
C, 82.59; H, 7.59; N, 4.59. Found: C, 82.27; H, 7.82; N, 4.55.
2(S)-m eth a n ol (10i): [R]22 ) +113.3° (c 0.86, CHCl3); 1H
D
NMR (200 MHz, CDCl3) δ 7.29-7.26 (m, 5H), 7.02 (q, J ) 5.5
Hz, 2H), 6.83 (t, J ) 8.8 Hz, 2H), 4.24 (d, J ) 4.9 Hz, 1H),
2.51 (q, J ) 6.5 Hz, 1H), 2.00 (d, J ) 3.5 Hz, 1H), 1.75 (ddd,
J ) 6.5, 4.9, 3.5 Hz, 1H), 1.56 (d, J ) 6.5 Hz, 1H), 1.46 (d, J
) 6.5 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 163.9, 160.6,
144.3, 138.3, 128.8, 127.7, 127.6, 127.5, 127.1, 115.1, 114.9,
72.7, 69.3, 44.2, 31.5, 22.1. Anal. Calcd for C17H18FNO: C,
75.25; H, 6.69; N, 5.16. Found: C, 75.10; H, 6.80; N, 5.17.
N-[(R)-r-Meth ylben zyl]-1′(R)-(4-flu or oph en yl)azir idin e-
(1S,2S)-2-[N-[(R)-r-Met h ylb en zyl]a m in o]-1-(2-m et h -
ylp h en yl)-1-p r op a n ol (13e): mp 82-83 °C; [R]23D ) +189.0°
1
(c 0.93, CHCl3); H NMR (200 MHz, CDCl3) δ 7.33-7.23 (m,
5H), 7.14-7.07 (m, 4H), 4.46 (d, J ) 8.5 Hz, 1H), 3.97 (q, J )
6.6 Hz, 1H), 2.65-2.42 (m, 1H), 2.25 (s, 3H), 1.40 (d, J ) 6.3
Hz, 3H), 0.93 (d, J ) 6.3 Hz, 3H); 13C NMR (75.4 MHz, CDCl3)
δ 144.9, 140.2, 136.1, 130.5, 128.7, 127.3, 127.3, 127.0, 126.9,
74.1, 56.1, 54.8, 25.2, 19.3, 15.9. Anal. Calcd for C18H23NO:
C, 80.26.; H, 8.61; N, 5.20. Found: C, 80.16; H, 8.42; N, 5.26.
24
2(S)-m eth a n ol (12i): mp 86-88 °C; [R]D ) +54.5° (c 0.47,
CHCl3); 1H NMR (200 MHz, CDCl3) δ 7.49-7.03 (m, 7H), 6.94
(t, J ) 8.5 Hz, 2H), 4.61 (d, J ) 3.3 Hz, 1H), 2.66 (q, J ) 6.5
Hz, 1H), 2.11 (d, J ) 3.4 Hz, 1H), 1.80 (m, 1H), 1.44 (d, J )
6.5 Hz, 4H); 13C NMR (75.4 MHz, CDCl3) δ 164.1, 160.9, 144.4,
137.4, 128.6, 127.9, 127.8, 127.3, 126.6, 115.3, 115.0, 69.5, 69.0,
42.6, 29.2, 23.0. Anal. Calcd for C17H18FNO: C, 75.25; H,
6.69; N, 5.16. Found: C, 75.14; H, 6.82; N, 5.20.
(1S,2S)-2-[N-[(R)-r-Meth ylben zyl]a m in o]-1-(2-fu r yl)-1-
p r op a n ol (13f): mp 73-75 °C; [R]19D ) +143.0° (c 1.0, CHCl3);
1H NMR (200 MHz, CDCl3) δ 7.38-7.22 (m, 6H), 6.25 (m, 2H),
4.23 (d, J ) 8.4 Hz, 1H), 3.95 (q, J ) 6.6 Hz, 1H), 2.78 (m,
1H), 1.38 (d, J ) 6.3 Hz, 3H), 0.98 (d, J ) 6.4 Hz, 3H); 13C
NMR (50.3 MHz, CDCl3) δ 154.8, 144.8, 141.8, 128.5, 127.0,
126.6, 110.0, 107.3, 71.7, 54.9, 54.1, 25.2, 16.6. Anal. Calcd
for C15H17NO2: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.48;
H, 7.87; N, 5.75.
N-[(R)-r-Meth ylben zyl]-1′(S)-(9-p h en a n th r yl)a zir id in e-
2(S)-m eth a n ol (10j): mp 118-120 °C; [R]27 ) +9.9° (c 1.0,
D
CHCl3); 1H NMR (200 MHz, CDCl3) δ 8.69 (d, J ) 7.9 Hz, 1H),
8.59 (d, J ) 8.0 Hz, 1H), 8.03 (d, J ) 7.7 Hz, 1H), 7.67-7.52-
(m, 6H), 7.17-6.94(m, 5H), 5.15 (d, J ) 3.6 Hz, 1H), 2.53 (q,
J ) 6.4 Hz, 1H), 2.21 (d, J ) 3.5 Hz, 1H), 2.14(m, 1H), 1.65 (d,
J ) 6.3 Hz, 1H), 1.46 (d, J ) 6.5 Hz, 3H); 13C NMR (75.4 MHz,
CDCl3) δ 143.8, 136.2, 131.6, 130.9, 130.1, 129.9, 129.1, 128.4,
127.5, 126.8, 126.5, 126.1, 124.2, 124.0, 123.4, 122.3, 69.0, 68.9,
42.7, 32.0, 21.9. Anal. Calcd for C25H23NO: C, 84.95; H, 6.52;
N, 3.96. Found: C, 84.74; H, 6.52; N, 3.94.
(1S,2S)-2-[N-[(R)-r-Met h ylb en zyl]a m in o]-1-(3-m et h -
oxyph en yl)-1-pr opan ol (13g): mp 55-57 °C; [R]25D ) +224.0°
1
(c 0.93, CHCl3); H NMR (200 MHz, CDCl3) δ 7.38-7.11 (m,
6H), 6.92-6.74 (m, 3H), 4.17 (d, J ) 8.2 Hz, 1H), 3.97 (q, J )
6.6 Hz, 1H), 3.72 (s, 3H), 2.58-2.44 (m, 1H) 1.41 (d, J ) 6.6
Hz, 3H), 0.95 (d, J ) 6.3, Hz, 3H); 13C NMR (75.4 MHz, CDCl3)
δ 159.8, 145.0, 144.1, 129.2, 128.7, 127.3, 127.0, 120.0, 113.3,
N-[(R)-r-Meth ylben zyl]-1′(R)-(9-ph en an th r yl)azir idin e-
2(S)-m eth a n ol (12j): mp 83-85 °C.; [R]24 ) +0.7° (c 0.77,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.74 (d, J ) 8.0 Hz, 1H),