Synthesis of Enantiopure a-Alkylated Arylglycinesand Amides
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anal. calcd. for C10H14N2O: C 67.39, H 7.92, N, 15.72; found: C
67.15, H 7.96, N 15.71.
Enzymatic Hydrolysis of Racemic a-4-
Methoxyphenylalanine Amide (1b)
(S)-(À)-a-4-Methylphenylalanine (3d): Time 55 h; yield:
47%; mp>3008C; [a]2D5: À 64 (c 0.45, 2 N HCl); ee 89%
(HPLC, tR 16.68 min, tS 39.25 min); IR (KBr): n 2400
Thisafforded ( R)-()-a-4-methoxyphenylalanine amide (2b)
after 48 h; yield: 37%; mp 130 1318C; [a]2D5: 38 (c 0.5,
MeOH); ee 95% (HPLC, tR 6.12 min, tS 4.31 min); IR
3600 (NH3 ), 1614 cmÀ1 (COO-); 1H NMR (300 MHz, D2O
(KBr): n 3545, 3400, 3323, 3268 (NH2, CONH2), 1685, 1646
CF3CO2D): d 6.78 (d, J 8.1 Hz, 2H), 6.86 (d, J 8.1 Hz,
2H), 1.78 (s, 3H), 1.45 (s, 3H); 13C NMR (D2O CF3CO2D):
d ?173.8, 140.9, 132.4, 130.3, 125.9, 61.8, 21.2, 20.5; MS
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1608 cmÀ1 (C O); H NMR (300 MHz, DMSO-d6): d 7.41 (d,
J 8.1 Hz, 2H), 7.29 (br, s, 1H), 6.97 (br, s, 1H), 6.85 (d, J
8.1 Hz, 2H), 3.72 (s, 3H), 1.48 (s, 3H); 13C NMR (DMSO-d6):
d 179.1, 158.7, 139.4, 127.4, 114.0, 60.3, 55.9, 29.0; MS (EI): m/
(FAB): m/z 180 [M 1] ; anal. calcd. for C10H14NO2:
180.1024; HRMS (FAB) found for MH : 180.1020.
z (%) 150 [M CONH2] (2.7), 134 (63), 133 (53), 118 (100);
anal. calcd. for C10H15N2O2: 195.1127; HRMS (FAB) found for
MH : 195.1128.
Enzymatic Hydrolysis of Racemic a-3-
Methylphenylalanine Amide (1e)
(S)-(À)-a-4-Methoxyphenylalanine (3b): Time 36 h; yield:
35%; mp 256 2578C; [a]2D5: À 75.6 (c 0.45, 2 N HCl); ee 94%
(HPLC, tR 15.94 min, tS 39.26 min); IR (KBr): n 2400
Thisafforded (R)-( )-a-3-methylphenylalanine amide (2e)
after 56 h; yield: 46%; mp 101 101.58C; [a]2D5: 92 (c 0.5,
MeOH); ee 88% (HPLC, tR 12.31 min, tS 10.59 min); IR
3600 (NH3 ), 1612 cmÀ1 (COO-); 1H NMR (300 MHz, D2O
CF3CO2D): d 7.00 (d, J 9.0 Hz, 2H), 6.58 (d, J 7.2 Hz,
2H), 3.35 (s, 3H), 1.52 (s, 3H);13C NMR: d 173.6, 160.0, 127.5,
(KBr): n 2400 3500 (NH2, CONH2), 1683 cmÀ1 (C O);
114.9, 61.4, 55.6, 21.0; MS (FAB): m/z 196 [M 1] ; anal.
1H NMR (300 MHz, DMSO-d6): d 7.32 (br, s, 2H), 7.28 (s,
1H), 7.19 (t, J 7.7 Hz, 1H), 7.03 (d, J 7.8 Hz, 2H), 2.38 (br, s,
2H), 2.20 (s, 3H), 1.50 (s, 3H);13C NMR (DMSO-d6): d 178.8,
147.1, 137.5, 128. 6, 127.9, 126.9, 123.4, 60.8, 28.8, 22.1; MS (EI):
calcd. for C10H13NO3: C 61.53, H 6.71, N 7.17; found: C 61.34, H
7.00, N, 7.08.
m/z (%) 134 [M CONH2] (77), 133 (56), 118 (100); anal.
calcd. for C10H14N2O: C 67.39, H 7.92, N 15.72; found: C 67.53,
H 7.89, N 15.82.
Enzymatic Hydrolysis of Racemic a-3-
Methoxyphenylalanine Amide (1c)
(S)-(À)-a-3-Methylphenylalanine (3e): Time 56 h; yield:
50%; mp>3008C (hydrochloric acid salt); [a]2D5: À 42.5 (c 0.4,
2 N HCl); ee 73% (HPLC, tR 14.59 min, tS 21.27 min); IR
Thisafforded ( R)-()-a-3-methoxyphenylalanine amide (2c)
after 62 h; yield: 49%; mp 848C; [a]2D5: 31 (c 0.5, MeOH); ee
94% (HPLC, tR 12.10 min, tS 9.03 min); IR (KBr): n 3367,
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(KBr): n 2200 3600 (NH3 ), 1698 cmÀ1 (COO-); H NMR
(300 MHz, D2O CF3CO2D): d 6.98 7.08 (m, 4H, Ar), 2.03
(s, 3H), 1.70 (s, 3H); 13C NMR (D2O CF3CO2D): d 173.4,
140.0, 135.2, 130.8, 129.5, 126.3, 122.7, 61.9, 21.1, 20.6; MS
3300, 3200 (NH2, CONH2), 1670 cmÀ1 (C O); 1H NMR
(300 MHz, DMSO-d6): d 7.34 (br, s, 1H), 7.21 (t, J 7.7 Hz,
1H), 7.07 (s, 1H), 7.06 (d, J 8.2 Hz, 1H), 7.00 (br, s, 1H), 6.79
(d, J 7.2 Hz, 1H), 3.72 (s, 3H), 1.51 (s, 1H); 13C NMR
(DMSO-d6): d 178.8, 159.8, 149.0, 129.7, 118.6, 112.5, 112.4,
(FAB): m/z 180 [M 1] ; anal. calcd. for C10H13NO2 ¥ HCl: C
55.36, H 6.54, N 6.49; found: C 55.18, H 6.50, N 6.28.
60.9, 55.8, 28.9; MS (EI): m/z (%) 150 [M CONH2] (22),
149 (55), 134 (100); anal. calcd. for C9H14N2O2: C 61.84, H 7.27,
N 14.42; found: C 61.91, H 7.34, N 14.45.
Enzymatic Hydrolysis of Racemic a-2-
Methylphenylalanine Amide (1f)
(S)-(À)-a-3-Methoxyphenylalanine (3c): Time 62 h; yield:
50%; mp 258 2598C; [a]2D5: À 66 (c 0.5, 2 N HCl); ee 92%
(HPLC, tR 15.74 min, tS 22.97 min); IR (KBr): n 2400
Thisafforded ( R)-()-a-2-methylphenylalanine amide (2f):
Time 14 h; yield: 46%; mp 127 1298; [a]2D5: 51 (c 0.5,
MeOH); ee 99% (HPLC, tR 56.57 min, tS 53.60 min, flow
3600 (NH3 ), 1620, 1603 cmÀ1 (COO-); H NMR (300 MHz,
D2O CF3CO2D): d 6.80 (t, J 8.0 Hz, 1H), 6.41 6.51 (m,
3H), 3.19 (s, 3H), 1.39 (s, 3H);13C NMR: d 172.8, 159.4, 136.4,
130.6, 118.0, 115.0, 111.7, 61.6, 55.3, 20.8; MS (FAB): m/z 196
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rate 0.1 mL/min); IR (KBr): n 3362, 3160, (NH2, CONH2),
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1690 cmÀ1 (C O); H NMR (300 MHz, DMSO-d6): d 7.54 (s,
[M 1] ; anal. calcd. for C11H14NO3: 196.0970; HRMS (FAB)
1H), 7.50 (d, J 8.9 Hz, 1H), 7.09 7.19 (m, 3H), 7.05 (br, s,
1H), 2.30 (s, 3H), 2.18 (s, 2H), 1.55 (s, 3H);13C NMR (DMSO-
d6): d 179.4, 144.5, 136.5, 131.7, 126.9, 126.1, 125.7, 60.1, 28.3,
found for MH : 196.0968.
20.5; MS (EI): m/z (%) 179 [M 1] (58), 162 (50), 135 (31),
134 (100); anal. calcd for C10H14N2O: C 67.39, H 7.92, N 15.72;
found: C 67.05, H 7.87, N 15.71.
Enzymatic Hydrolysis of Racemic a-4-
Methylphenylalanine Amide (1d)
(S)-(À)-a-2-Methylphenylalanine (3f): Time 14 h; yield:
49%; mp 236 2388C; [a]2D5: À 74.4 (c 0.5, 2N HCl); ee 90%
(HPLC, tR 54.40 min, tS 67.30 min, flow rate 0.1 mL/min);
Thisafforded ( R)-()-a-4-methylphenylalanine amide (2d)
after 55 h; yield: 50%; mp 149 150.58C; [a]2D5: 33 (c 0.5,
MeOH); ee 82% (HPLC, tR 14.04 min, tS 8.79 min); IR
(KBr): n 3545, 3398, 3320, 3271 (NH2, CONH2), 1645 cmÀ1
IR (KBr): n 2200 3600 (NH3 ), 1635 cmÀ1 (COO-);
1H NMR (300 MHz, D2O CF3CO2D): d 7.32 (d, J
7.6 Hz, 1H), 7.04 7.18 (m, 3H), 2.12 (s, 3H), 1.90 (s, 3H);
13C NMR (D2O CF3CO2D): d 171.3, 134.7, 131.3, 130.6,
129.1, 125.5, 125.2, 60.4, 21.2, 17.6; MS (ESI): m/z 178 [M
(C O); 1H NMR (300 MHz, DMSO-d6): d 7.38 (d, J
8.1 Hz, 2H), 7.30 (s, 1H), 7.11 (d, J 8.1 Hz, 2H), 6.98 (s,
1H), 2.27 (s, Me), 1.49 (s, Me); 13C NMR (DMSO-d6): d
179.0, 144.3, 136.2, 129.6, 129.2, 126.2, 60.6, 28.9, 21.4; MS
1] ; anal. calcd. for C10H13NO2: C 67.02, H 7.31, N 7.82; found: C
(EI): m/z (%) 134 [M CONH2] (77), 113 (56), 118 (100);
67.12, H 7.34, N 7.87.
Adv. Synth. Catal. 2004, 346, 439 445
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¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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