Novel Access to Amino Acids
3646 3652
by flash chromatography (hexanes/ethyl acetate 1:1). [a]D À17.3 (c 0.7
in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d 7.48 (m, 1H), 6.76/6.56
(dd, J 6.6, 2.2 Hz, each 2H), 4.52 (q, J 5.6 Hz, 1H), 4.04 (m, 3H), 4.01
(d, J 7.1 Hz, 1H), 3.74 (s, 3H), 3.52 (m, 3H), 2.49 (t, J 6.1 Hz, 2H), 1.46/
1.35 (s, each 3H), 1.17 (t, J 7.3 Hz, 1H); 13C NMR (75 MHz, CDCl3,
258C): d 171.8, 171.2, 153.3, 140.8, 115.0, 114.9, 109.8, 75.5, 66.8, 62.3, 60.6,
Reactions between secondary amines and azetidine-2,3-dione [()-1b].
General procedure for the synthesis of a-amino amides and dipeptides 8:
Method A: A solution of the appropriate amine (0.5 mmol) in THF
(0.1 mL) was added to a solution of the azetidine-2,3-dione ()-1b
(0.5 mmol) in THF (5 mL) and the solution was stirred at room temper-
ature for 20 72 h. The solvent was removed under reduced pressure and
after flash chromatography (hexanes/ethyl acetate or dichloromethane/
ethyl acetate), compounds 8 were obtained in analytically pure form.
Spectroscopic and analytical data for some representative pure forms of 8
are given below.
55.7, 34.7, 34.1, 26.5, 24.8, 14.0; IR (CHCl3): nÄ 3340, 3205, 1742, 1658 cmÀ1
;
MS (CI): m/z (%): 381 (100) [MH] , 380 (36) [M] ; elemental analysis
calcd (%) for C19H28N2O6 (380.4): C59.99, H 7.42, N 7.36; found: C60.07, H
7.44, N 7.35.
Peptide ()-2k: Method A: Azetidine-2,3-dione [()-1b, 48 mg,
0.164 mmol] gave ()-2k as a colorless oil (45 mg, 65%) after purification
by flash chromatography (hexanes/ethyl acetate 3:1). [a]D 11.0 (c 0.6
in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d 7.94 (d, J 6.8 Hz, 1H),
7.34 (m, 5H), 6.83/6.69 (dd, J 6.6, 2.4 Hz, each 2H), 5.53 (d, J 7.1 Hz,
1H), 4.53 (m, 1H), 4.30 (brs, 1H), 4.01 (m, 2H), 3.78 (m, 1H), 3.77 (s, 3H),
3.69 (s, 3H), 1.46/1.34 (s, each 3H); 13CNMR (75 MHz, CDCl 3, 258C): d
171.1, 170.7, 153.5, 141.1, 135.8, 128.9, 128.5, 127.1, 115.7, 114.9, 109.8, 75.5,
66.7, 62.6, 56.6, 55.7, 52.6, 26.5, 24.8; IR (CHCl3): nÄ 3338, 3204, 1740,
Method B: A solution of the appropriate amine (0.5 mmol) in THF (1 mL)
was added to a solution of the azetidine-2,3-dione ()-1b (0.5 mmol) in
THF (5 mL) and the solution was heated in a sealed tube at 908Cfor 2 h.
The reaction mixture was allowed to cool to room temperature, the solvent
was removed under reduced pressure and after flash chromatography
(hexanes/ethyl acetate or dichloromethane/ethyl acetate), compounds 8
were obtained in analytically pure form.
()-(2S)-2-(4-Methoxyphenylamino)-2-[(S)-2,2-dimethyl-1,3-dioxolan-4-
yl]-N-morpholinyl-methanecarboxamide [()-8c]: Method A: Azetidine-
2,3-dione [()-1b, 49 mg, 0.167 mmol] gave ()-8c as a colorless oil
(37 mg, 64%) after purification by flash chromatography (hexanes/ethyl
acetate 1:1). [a]D 13.8 (c 0.8 in CHCl3); 1H NMR (200 MHz, CDCl3,
258C): d 6.97 (brs, 1H), 6.76/6.51 (dd, J 6.6, 2.4 Hz, each 2H), 4.44 (m,
1H), 4.32 (d, J 5.1 Hz, 1H), 4.18 (dd, J 8.3, 7.1 Hz, 1H), 3.97 (dd, J 8.3,
6.6 Hz, 1H), 3.36 (m, 2H), 3.35 (s, 3H), 3.19 (m, 5H), 2.92 (m, 1H), 1.31/
1.23 (s, each 3H); 13CNMR (50 MHz, CDCl 3, 258C): d 169.2, 153.0,
140.6, 115.5, 114.9, 109.8, 75.9, 66.7, 65.9, 56.4, 55.7, 46.5, 42.6, 26.6, 25.1; IR
1657 cmÀ1; MS (CI): m/z (%): 429 (100) [MH] , 428 (44) [M] ; elemental
analysis calcd (%) for C23H28N2O6 (428.5): C64.47, H 6.59, N 6.54; found: C
64.40, H 6.60, N 6.52.
Peptide (À)-2l: Method A: Azetidine-2,3-dione [()-1b, 46 mg,
0.16 mmol] gave (À)-2l as a colorless solid (36 mg, 59%) after purification
by flash chromatography (dichloromethane/ethyl acetate 8:1). M.p. 117
1
1188C(hexanes/ethyl acetate). [ a]D À53.1 (c 0.7 in CHCl3); H NMR
(300 MHz, CDCl3, 258C): d 8.87 (brs, 1H), 6.86/6.81 (d, J 7.1 Hz, each
2H), 7.46/6.68 (dd, J 6.6, 2.4 Hz, each 2H), 4.66 (dd, J 11.2, 5.4 Hz, 1H),
4.14 (dd, J 8.8, 6.4 Hz, 1H), 4.02 (dd, J 8.8, 5.6 Hz, 1H), 3.79/3.76 (s,
each 3H), 3.71 (d, J 4.9 Hz, 1H), 1.49/1.38 (s, each 3H); 13CNMR
(75 MHz, CDCl3, 258C): d 169.0, 156.5, 153.7, 140.7, 130.2, 121.4, 115.6,
115.1, 114.1, 109.9, 75.5, 66.9, 63.2, 55.7, 55.5, 26.6, 24.8; IR (KBr): nÄ 3344,
(CHCl3): nÄ 3337, 1660 cmÀ1; MS (CI): m/z (%): 351 (100) [MH] , 350
(25) [M] ; elemental analysis calcd (%) for C18H26N2O5 (350.4): C61.70, H
7.48, N 7.99; found: C61.78, H 7.47, N 8.01.
(À)-(2S)-2-(4-Methoxyphenylamino)-2-[(S)-2,2-dimethyl-1,3-dioxolan-4-
yl]-N-(L-prolinyl methyl ester)-methanecarboxamide [(À)-8d]: Method A:
3203, 1743, 1670 cmÀ1; MS (CI): m/z (%): 387 (100) [MH] , 386 (48)
Azetidine-2,3-dione [()-1b, 121 mg, 0.414 mmol] gave (À)-8d as
a
[M] ; elemental analysis calcd (%) for C21H26N2O5 (386.5): C65.27, H 6.78,
colorless oil (75 mg, 46%) after purification by flash chromatography
(hexanes/ethyl acetate 1:1). [a]D À60.6 (c 0.8 in CHCl3); 1H NMR
(500 MHz, CDCl3, 258C): d 6.76/6.64 (dd, J 6.6, 2.4 Hz, each 2H), 4.45
(m, 1H), 4.26 (d, J 5.4 Hz, 1H), 4.08 (td, J 6.3, 1.7 Hz, 1H), 3.96 (dd,
J 8.5, 6.3 Hz, 1H), 3.73/3.72 (s, each 3H), 2.16 (m, 2H), 1.98 (m, 3H), 1.51/
1.37 (s, each 3H); 13CNMR 125 MHz, CDCl 3, 258C): d 172.1, 169.9,
152.9, 140.8, 115.7, 114.9, 109.6, 76.7, 66.1, 59.2, 59.1, 55.7, 52.1, 47.3, 28.8,
26.4, 25.2, 24.9; IR (CHCl3): nÄ 3337, 1735, 1660 cmÀ1; MS (CI): m/z (%):
N 7.25; found: C65.21, H 6.76, N 7.26.
(À)-(2S)-2-(Allylamino)-2-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-N-benzyl-
methanecarboxamide [(À)-2m]: Method A: Azetidine-2,3-dione [(À)-1c,
58 mg, 0.257 mmol] gave (À)-2m as a colorless oil (45 mg, 58%) after
purification by flash chromatography (hexanes/ethyl acetate 2:1). [a]D
À34.0 (c 0.8 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d 7.78 (brs,
1H), 7.29 (m, 5H), 5.80 (m, 1H), 5.11 (m, 2H), 4.45 (d, J 6.1 Hz, 1H), 4.21
(m, 1H), 4.09 (brs, 1H), 4.08 (d, J 6.6 Hz, 1H), 3.21 (m, 2H), 3.19 (d, J
6.8 Hz, 1H), 1.84 (brs, 1H), 1.42/1.34 (s, each 3H); 13CNMR (75 MHz,
CDCl3, 258C): d 171.3, 138.3, 135.7, 128.6, 127.5, 127.4, 116.7, 109.4, 76.2, 67.1,
64.8, 51.2, 42.9, 26.6, 25.2; IR (CHCl3): nÄ 3344, 3208, 1652 cmÀ1; MS (CI):
393 (100) [MH] , 392 (31) [M] ; elemental analysis calcd (%) for
C20H28N2O6 (392.5): C61.21, H 7.19, N 7.14; found: C61.13, H 7.18, N 7.16.
Reaction between sodium methoxide and azetidine-2,3-dione ()-1b.
Preparation of a-amino ester [()-9]: Sodium methoxide (12 mg,
0.22 mmol) was added in portions at room temperature to a solution of
the azetidine-2,3-dione ()-1b (43 mg, 0.15 mmol) in methanol (5 mL),
and the solution was heated at reflux temperature for 1 h. The reaction
mixture was allowed to cool to room temperature and then water was
added (2 mL). The methanol was removed under reduced pressure, the
aqueous residue was extracted with ethyl acetate (3 Â 10 mL), and the
organic layer was dried (MgSO4). The solvent was removed under reduced
pressure to give ()-9 (which contained ꢀ5% of its (1S)-epimer) as a
colorless oil (22 mg, 50%) after purification by flash chromatography
(dichloromethane/ethyl acetate 9:1).
m/z (%): 305 (100) [MH] , 304 (28) [M] ; elemental analysis calcd (%)
for C17H24N2O3 (304.4): C67.08, H 7.95, N 9.20; found: C67.16, H 7.93, N 9.21.
(À)-(2S)-2-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-(propargylamino)-N-
benzyl-methanecarboxamide [(À)-2o]: Method A: Azetidine-2,3-dione
[(À)-1d, 40 mg, 0.18 mmol] gave (À)-2o as a colorless oil (28 mg, 50%)
after purification by flash chromatography (hexanes/ethyl acetate 1:1).
[a]D À38.1 (c 1.8 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d
7.65 (m, 1H), 7.31 (m, 5H), 4.46 (d, J 6.1 Hz, 2H), 4.25 (m, 1H), 4.10 (m,
2H), 3.49/3.30 (td, J 17.3, 2.4 Hz, each 1H), 2.20 (t, J 2.4 Hz, 1H), 1.44/
1.34 (s, each 3H); 13CNMR (75 MHz, CDCl 3, 258C): d 170.8, 138.2,
128.6, 127.5, 127.4, 109.6, 80.9, 76.1, 72.2, 66.9, 64.0, 43.0, 37.2, 26.6, 25.0; IR
()-(2S)-2-(4-Methoxyphenylamino)-2-[(S)-2,2-dimethyl-1,3-dioxolan-4-
yl] methyl acetate [()-9]: [a]D 11.0 (c 0.6 in CHCl3); 1H NMR
(300 MHz, CDCl3, 258C): d 6.78/6.60 (dd, J 6.6, 2.4 Hz, each 2H), 4.54
(td, J 6.3, 3.2 Hz, 1H), 4.12 (dd, J 8.3, 6.6 Hz, 1H), 3.99 (m, 3H), 3.76/
3.75 (s, each 3H), 1.49/1.38 (s, each 3H); 13C NMR (75 MHz, CDCl3, 258C):
d 172.4, 153.0, 140.8, 115.3, 114.8, 110.1, 75.9, 66.3, 58.9, 55.7, 52.4, 26.3,
25.1; IR (CHCl3): nÄ 3332, 1738 cmÀ1; MS (CI): m/z (%): 280 (100)
(CHCl3): nÄ 3338, 3204, 1654 cmÀ1; MS (CI): m/z (%): 303 (100) [MH] ,
302 (19) [M] ; elemental analysis calcd (%) for C17H22N2O3 (302.4): C67.53,
H 7.33, N 9.26; found: C67.60, H 7.32, N 9.25.
Peptide (À)-2p: Method A: Azetidine-2,3-dione [(À)-1e, 96 mg,
0.43 mmol] gave (À)-2p as a colorless solid (69 mg, 43%) after purification
by flash chromatography (hexanes/ethyl acetate 1:1). [a]D À34.3 (c 0.6
in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d 8.04 (d, J 8.5 Hz, 1H),
7.31 (m, 5H), 4.59 (m, 1H), 4.00 (m, 5H), 3.76 (s, 3H), 3.20 (d, J 7.6 Hz,
1H), 2.48 (brs, 1H), 1.42 (d, J 7.3 Hz, 3H), 1.35/1.32 (s, each 3H);
13C NMR (75 MHz, CDCl3, 258C): d 173.1, 170.7, 128.5, 128.4, 127.4,
109.5, 76.0, 66.9, 64.9, 52.5, 52.4, 47.4, 26.7, 25.3, 18.3; IR (CHCl3): nÄ 3344,
[MH] , 279 (21) [M] ; elemental analysis calcd (%) for C15H21NO4
(279.3): C64.50, H 7.58, N 5.01; found: C64.58, H 7.56, N 5.00.
Cadmium-promoted reaction between azetidine-2,3-diones 1 and water.
General procedure for the synthesis of a-amino acids 10: A suspension of
the appropriate azetidine-2,3-dione 1 (0.5 mmol), granulated cadmium
(5 mmol), and solid ammonium chloride (3 mmol) in wet methanol (10 mL,
5% water) was stirred at room temperature for 2 4 d. The solvent was
removed under reduced pressure and after flash chromatography (hexanes/
3202, 1742, 1654 cmÀ1; MS (CI): m/z (%): 351 (100) [MH] , 350 (15)
[M] ; elemental analysis calcd (%) for C18H26N2O5 (350.4): C61.70, H 7.48,
N 7.99; found: C61.78, H 7.47, N 8.00.
Chem. Eur. J. 2002, 8, No. 16
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0816-3651 $ 20.00+.50/0
3651