4676 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 14
Rossiter et al.
(C), 159.8 (C), 158.0 (C), 130.6 (CH), 122.4 (CH), 115.6 (CH),
67.4 (CH2), 51.4 (CH), 42.5 (CH2), 39.1 (CH2), 30.9 (CH2); MS
(FAB+) found m/z 281.16180 (M + H), C13H20N4O3 M + H calcd
281.16136.
(S)-2-Amino-4-(N′,N′-dimethylguanidino)butanoic Acid
1
(25). Yield 31% (Method B). H NMR (CD3OD, 300 MHz): δ
4.01 (1H, t, J 6.3 Hz, NCH), 3.45 (2H, t, J 6.9 Hz, CH2), 2.98
(6H, s, N(CH3)2), 2.25-2.04 (2H, m, CH2); 13C NMR (75 MHz,
CD3OD, 27 °C) δ 171.8 (C), 158.1 (C), 51.9 (CH), 40.1 (CH2),
39.3 (CH3), 31.3 (CH2); MS (FAB+) found m/z 189.13494 (M
+ H), C7H16N4O2 M + H calcd 189.13514.
(S)-2-Amino-4-(N′-(2-isopropoxyethyl)guanidino)bu-
1
tanoic Acid (17). Yield 41% (Method A). H NMR (CD3OD,
300 MHz): δ 4.08 (1H, t, J 6.5 Hz, CH), 3.65 (1H, septet, J
6.1 Hz, OCH), 3.59 (2H, t, J 5.1 Hz, CH2), 3.50 (2H, t, J 7.1
Hz, CH2), 3.39 (2H, t, J 5.1 Hz, CH2), 2.30-2.11 (2H, m, CH2),
1.17 (5H, d, J 6.1 Hz, 2 × CH3); 13C NMR (75 MHz, CD3OD,
27 °C) δ 171.2 (C), 158.4 (C), 73.7 (CH), 51.4 (CH), 43.6 (CH2),
39.1 (CH2), 31.0 (CH2), 22.3 (CH3); MS (FAB+) found m/z
247.17699 (M + H), C10H22N4O3 M + H calcd 247.17701.
(S)-2-Amino-4-(N′-(2-methylthioethyl)guanidino)bu-
(S)-2-Amino-4-(N′,N′-diethylguanidino)butanoic Acid
1
(26). Yield 11% (Method B). H NMR (CD3OD, 300 MHz): δ
4.08 (1H, t, J 6.3 Hz, CH), 3.55 (2H, t, J 6.9 Hz, CH2), 3.43
(4H, q, J 7.1 Hz, 2 × NCH2), 2.32-2.14 (2H, m, CH2), 1.21
(6H, t, J 7.1 Hz, 2 × CH3), insufficient yield for 13C NMR (1024
scans); MS (FAB+) found m/z 217.16691 (M + H), C9H21N4O2
M + H calcd 217.16644.
1
(S)-2-Amino-4-[(piperidine-1-carboximidoyl)-amino]-
tanoic Acid (18). Yield 38% (Method A). H NMR (CD3OD,
1
butanoic Acid (27). Yield 32% (Method B). H NMR (CD3-
300 MHz): δ 4.09 (1H, t, J 6.6 Hz, CH), 3.51 (2H, t, J 7.1 Hz,
CH2), 3.46 (2H, t, J 6.7 Hz, CH2), 2.72 (2H, t, J 6.7 Hz, SCH2),
2.30-2.12 (2H, m, CH2), 2.13 (3H, s, SCH3); 13C NMR (75 MHz,
CD3OD, 27 °C) δ 171.2 (C), 157.6 (C), 51.4 (CH), 41.8 (CH2),
39.0 (CH2), 33.9 (CH2), 30.9 (CH2), 15.2 (CH3); MS (FAB+)
found m/z 235.12235 (M + H), C8H18N4O2S M + H calcd
235.12287.
OD, 300 MHz): δ 4.08 (1H, t, J 6.5 Hz, NCH), 3.54 (2H, t, J
7.1 Hz, CH2), 3.48-3.44 (4H, m, 2 × CH2), 2.31-2.13 (2H, m,
CH2), 1.68-1.59 (6H, m, 3 × CH2); 13C NMR (75 MHz, CD3-
OD, 27 °C) δ 171.7 (C), 157.5 (C), 51.9 (CH), 40.3 (CH2), 31.3
(CH2), 26.9 (CH2), 25.2 (CH2); MS (FAB+) found m/z 229.16582
(M + H), C10H20N4O2 M + H calcd 229.16644.
(S)-2-Amino-4-[(morpholine-4-carboximidoyl)-amino]-
(S)-2-Amino-4-(N′-(2-fluoroethyl)guanidino)butanoic
1
Acid (19). Yield 56% (Method A). 1H NMR (CD3OD, 300
butanoic Acid (28). Yield 30% (Method B). H NMR (CD3-
1
OD, 300 MHz): δ 4.09 (1H, t, J 6.2 Hz, CH), 3.74 (4H, t, J 4.9
Hz, 2 × CH2 morpholino), 3.55 (2H, t, J 6.8 Hz, CH2), 3.48
(4H, t, J 4.9 Hz, 2 × CH2 morpholino), 2.30-2.19 (2H, m, CH2);
13C NMR (75 MHz, CD3OD, 27 °C) δ 66.9 (CH2), 51.5 (CH),
47.6 (CH2), 39.9 (CH2), 30.8 (CH2); MS (FAB+) found m/z
231.14593 (M + H), C9H18N4O3 M + H calcd 231.14571.
(S)-2-Amino-4-[(pyrrolidine-1-carboximidoyl)-amino]-
MHz): δ 4.55 (2H, dt, JHF 47 Hz, JHH 4.7 Hz, CH2F), 4.09
(1H, t, J 6.4 Hz, CH), 3.62-3.50 (4H, m, 2 × NCH2), 2.29-
2.12 (2H, m, CH2); 13C NMR (75 MHz, CD3OD, 27 °C) δ 171.2
(C), 157.9 (C), 83.0 (d, 1JCF 168 Hz, CH2F), 51.4 (CH), 43.2 (d,
2JCF 20 Hz, CH2), 39.1 (CH2), 30.9 (CH2); MS (FAB+) found
m/z 207.12645 (M + H), C7H15FN4O2 M + H calcd 207.12572.
(S)-2-Amino-4-(N′-phenylguanidino)butanoic Acid (20).
1
1
butanoic Acid (29). Yield 23% (Method B). H NMR (CD3-
Yield 17% (Method B). H NMR (CD3OD, 300 MHz): δ 7.47
OD, 300 MHz): δ 4.11 (1H, t, J 6.2 Hz, CH), 3.54 (2H, t, J 6.8
Hz, CH2), 3.44 (4H, t, J 6.4 Hz, 2 × NCH2 pyrrolidino), 2.32-
2.05 (2H, m, CH2), 2.03 (4H, t, J 6.4 Hz, 2 × CH2); 13C NMR
(75 MHz, CD3OD, 27 °C) δ 171.4 (C), 155.0 (C), 51.5 (CH), 48.5
(CH2), 39.4 (CH2), 30.9 (CH2), 26.2 (CH2); MS (FAB+) found
m/z 215.15070 (M + H), C9H18N4O2 M + H calcd 215.15079.
General Method for Preparation of Esters. To a solu-
tion of the amino acid (typically 0.5 mmol) in the appropriate
alcohol (2 mL) at 0 °C was added thionyl chloride (1.1
equivalents), with stirring, The solution was stirred for 30 min
at 0 °C and then heated under reflux for 1 h and stirred at
room-temperature overnight. Solvent was then removed in
vacuo to give the ester (30-35, 37) as a white or yellow solid.
(S)-2-Amino-4-(N′-(2-methoxyethyl)guanidino)butano-
ic Acid Methyl Ester (30). Yield 83%. 1H NMR (CD3OD, 300
MHz): δ 4.15 (1H, t, J 6.5 Hz, CH), 3.86 (3H, s, OCH3), 3.54
(2H, t, J 4.9 Hz, CH2), 3.47 (2H, t, J 7.1 Hz, CH2), 3.42 (2H, t,
J 6.0 Hz, CH2), 3.38 (3H, s, OCH3), 2.29-2.11 (2H, m, CH2);
13C NMR (75 MHz, CD3OD, 27 °C) δ 170.3 (C), 157.5 (C), 72.1
(CH2), 59.2 (CH3), 54.0 (CH3), 51.5 (CH), 43.0 (CH2), 38.8 (CH2),
30.9 (CH2); MS (FAB+) found m/z 233.16097 (M + H),
C9H20N4O3 M + H calcd 233.16136.
(2H, t, J 7.3 Hz Ar C2H, C5H), 7.37 (1H, t, J 7.3 Hz, Ar C4H),
7.31 (2H, m, Ar C3H, C5H), 4.10 (1H, t, J 6.3 Hz, CH), 3.59
(2H, t, J 7.0 Hz, CH2), 2.33-2.14 (2H, m, CH2); 13C NMR (75
MHz, CD3OD, 27 °C) δ 171.5 (C), 131.5 (CH), 129.2 (CH), 127.1
(CH), 51.9 (CH), 39.8 (CH2), 31.4 (CH2); MS (FAB+) found m/z
237.13543 (M + H), C11H16N4O2 M + H calcd 237.13514.
(S)-2-Amino-4-(N′-benzylguanidino)butanoic Acid (21).
Yield 55% (Method A). 1H NMR (CD3OD, 300 MHz): δ 7.53-
7.22 (5H, m, ArH), 4.59 (2H, s, PhCH2), 4.15 (1H, t, J 6.7 Hz,
CH), 3.66 (2H, t, J 7.2 Hz, CH2), 2.41-2.24 (2H, m, CH2); 13
C
NMR (75 MHz, CD3OD, 27 °C) δ 171.5 (C), 158.0 (C), 137.9
(C), 130.3 (CH), 129.4 (CH), 128.8 (CH), 51.7 (CH), 46.5 (CH2),
39.5 (CH2), 31.4 (CH2); MS (FAB+) found m/z 251.15045
(MH+), C12H18N4O2 M + H calcd 251.15079.
(S)-2-Amino-4-(N′-allylguanidino)butanoic Acid (22).
Yield 50% (Method A). 1H NMR (CD3OD, 300 MHz): δ 5.99-
5.87 (1H, m, vinyl CH), 5.34 (1H, d, J 17.1 Hz, cis vinyl CH),
5.27 (1H, d, J 10.4 Hz, trans vinyl CH), 4.13 (1H, t, J 6.6 Hz,
NCH), 3.93 (2H, d, J 4.9 Hz. NCH2), 3.57 (2H, t, J 6.0 Hz,
CH2), 2.37-2.15 (2H, m, CH2); 13C NMR (75 MHz, CD3OD, 27
°C) δ 171.5 (C), 158.0 (C), 134.1 (CH), 117.9 (CH2), 51.8 (CH),
45.0 (CH2), 39.4 (CH2), 35.2 (CH2), 31.4 (CH2); MS (FAB+)
found m/z 201.13558 (M + H), C8H16N4O2 M + H calcd
201.13514.
(S)-2-Amino-4-(N′-(2-methoxyethyl)guanidino)butano-
1
ic Acid Ethyl Ester (31). Yield 84%. H NMR (CD3OD, 300
MHz): δ 4.33 (2H, q, J 7.1 Hz, CH2), 4.13 (1H, t, J 6.2 Hz,
CH), 3.55-3.39 (6H, m, 3 x CH2) 3.38 (3H, s, OCH3), 2.28-
2.20 (2H, m, CH2), 1.34 (3H, t, J 7.1 Hz, CH3); 13C NMR (75
MHz, CD3OD, 27 °C) δ 169.9 (C), 158.3 (C), 72.1 (CH2), 64.1
(CH2), 59.2 (CH3), 51.5 (CH), 43.1 (CH2), 38.9 (CH2), 30.9 (CH2),
14.4 (CH3); MS (FAB+) found m/z 247.17723 (M + H),
C10H22N4O3 M + H calcd 247.17701.
(S)-2-Amino-4-(N′-(2-methoxyethyl)guanidino)butano-
ic Acid Propyl Ester (32). Yield 80%. 1H NMR (CD3OD, 300
MHz): δ 4.25-4.15 (3H, m, CH, CH2), 3.56-3.39 (6H, m, 3 ×
CH2), 3.38 (3H, s, OCH3), 2.27-2.15 (2H, m, CH2), 1.73 (2H,
m, CH2), 0.98 (3H, t, J 7.1 Hz, CH3); 13C NMR (75 MHz, CD3-
OD, 27 °C) δ 170.0 (C), 158.1 (C), 72.1 (CH2), 69.5 (CH2), 59.3
(CH3), 51.6 (CH), 43.1 (CH2), 38.9 (CH2), 30.9 (CH2), 22.9 (CH2),
10.7 (CH3); MS (FAB+) found m/z 261.19258 (M + H),
C11H24N4O3 M + H calcd 261.19266.
(S)-2-Amino-4-(N′-(2′-dimethylaminoethyl)guanidino)-
butanoic Acid (23). Yield 0.29% (Method B). 1H NMR (CD3-
OD, 300 MHz): δ 4.15 (1H, t, J 6.7 Hz, CH), 3.73 (2H, t, J 6.2
Hz, NCH2), 3.56 (2H, t, J 7.1 Hz, NCH2), 3.43 (2H, t, J 6.2 Hz,
NCH2), 2.96 (6H, s, N(CH3)2), 2.32-2.19 (2H, m, CH2); 13C
NMR (75 MHz, CD3OD, 27 °C) δ 171.2 (C), 158.0 (C), 56.9
(CH2), 51.4 (CH), 43.9 (CH3), 39.2 (CH2), 37.9 (CH2), 30.8 (CH2);
MS (FAB+), found m/z 232.17283 (M + H), C9H21N5O2 M + H
calc 232.17734.
(S)-2-Amino-4-(N′-cyclopropylguanidino)butanoic Acid
1
(24). Yield 41% (Method B). H NMR (CD3OD, 300 MHz): δ
4.07 (1H, t, J 6.5 Hz, CH), 3.50 (2H, t, J 6.9 Hz, CH2), 2.52
(1H, m, NCH cyclopropyl), 2.27-2.11 (2H, br m, CH2), 0.89
(2H, m, 2 × CH cyclopropyl), 0.66 (2H, m, 2 × CH cyclopropyl);
13C NMR (75 MHz, CD3OD, 27 °C) δ 171.6 (C), 159.3 (C), 51.9
(CH), 39.4 (CH2), 31.4 (CH2), 23.9 (CH), 8.2 (CH2); MS (FAB+)
found m/z 201.13519 (M + H), C8H16N4O2 M + H calcd
201.13514.
(S)-2-Amino-4-(N′-(2-methoxyethyl)guanidino)butano-
1
ic Acid Butyl Ester (33). Yield 60%. H NMR (CD3OD, 300