2782 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
Grolla et al.
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.37-7.16 (m, 15-H), 6.72
137.3, 128.9, 128.7, 128.6, 126.8, 126.6, 126.5, 60.2, 56.9, 40.3,
35.4, 34.1, 34.0, 33.4, 30.9, 28.8, 28.7, 24.7, 24.6, 14.2; MS (ESI)
m/z 489 (M + Na)+.
(br t, 1-H), 4.88 (t, J ) 7.1 Hz, 1-H), 4.10 (q, J ) 7.1 Hz, 2-H),
3.55-3.15 (m, 6-H), 2.88-2.45 (m, 4-H), 2.27 (t, J ) 7.4 Hz, 2-H),
2.10 (m, 2-H), 1.61-1.40 (m, 4-H), 1.24 (m, 5-H); 13C NMR (75
MHz, CDCl3) δ 174.6, 173.7, 171.0, 138.9, 138.1, 137.5, 129.1,
129.0, 128.8, 128.6, 128.7, 128.5, 127.0, 126.8, 126.5, 60.3, 54.2,
48.5, 40.6, 35.8, 35.6, 34.5, 34.2, 33.4, 28.8, 24.9, 24.8, 14.3; MS
(ESI) m/z 565 (M + Na)+.
Heptanoic Acid, 7-Oxo-7-[[2-oxo-2-[(2-phenylethyl)amino]-1-
(phenylmethyl)ethyl](phenylmethyl)amino]-, Ethyl Ester (16). The
crude material is purified by column chromatography, using
petroleum ether/EtOAc 7:3 as eluant to give a yellow oil (18%).
IR (KBr) 2936, 1728, 1627, 1453, 1199, 1029, 731, 647 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.35-7.02 (m, 15-H), 6.53 (t, J ) 5.5
Hz, 1-H), 5.04 (t, J ) 7.7 Hz, 1-H), 4.53 (d, J ) 17.6 Hz, 1-H),
4.41 (d, J ) 17.6 Hz, 1-H), 4.08 (q, J ) 7.1 Hz, 2-H), 3.47-3.19
(m, 3-H), 2.99 (m, 1-H), 2.64 (m, 2-H), 2.21 (t, J ) 7.4 Hz, 2-H),
2.16 (t, J ) 7.4 Hz, 2-H), 1.61-1.45 (m, 4-H), 1.24-1.19 (m, 5-H);
13C NMR (75 MHz, CDCl3) δ 175.1, 173.7, 170.1, 138.9, 137.5,
137.4, 129.4, 129.1, 128.9, 128.6, 128.5, 128.4, 127.0, 126.8, 126.5,
60.3, 59.9, 49.3, 40.5, 35.5, 35.3, 34.1, 33.7, 28.7, 24.8, 24.7, 14.5;
MS (ESI) m/z 551 (M + Na)+.
Octanoic Acid, 8-[[1-([1,1′-Biphenyl]-4-ylmethyl)-2-oxo-2-[(2-
phenylethyl)amino]ethyl](phenylmethyl)amino]-8-oxo-, Ethyl Ester
(21). The crude material is purified by column chromatography,
using petroleum ether/EtOAc 8:2 as eluant to give a white solid
(43%). IR (KBr) 3266, 2943, 1731, 1674, 1618, 1192, 833, 768,
1
730 cm-1; H NMR (300 MHz, CDCl3) δ 7.55-7.05 (m, 19-H),
6.53 (br t, 1-H), 5.08 (br t, 1-H), 4.51 (m, 2-H), 4.09 (q, J ) 7.1
Hz, 2-H), 3.42-3.21 (m, 3-H), 3.04 (m, 1-H), 2.68 (m, 2-H), 2.23
(m, 4-H), 1.55 (m, 4-H), 1.23 (m, 7-H); 13C NMR (75 MHz, CDCl3)
δ 175.3, 173.7, 170.1, 140.8, 139.5, 138.9, 137.4, 136.6, 129.8,
128.9 (2C), 128.8, 128.5, 127.4, 127.3, 127.1, 127.0, 126.5, 126.3,
60.2, 59.9, 49.3, 40.5, 35.5, 34.5, 34.2, 33.8, 28.9 (2C), 25.0, 24.8,
14.4; MS (ESI) m/z 641 (M + Na)+; Mp ) 77-79 °C.
Octanoic Acid, 8-Oxo-8-[[1-[[(2-phenylethyl)amino]carbonyl]-
octyl](phenylmethyl)amino]-, Ethyl Ester (22). The crude material
is purified by column chromatography, using petroleum ether/EtOAc
7:3 as eluant to give a colorless oil (24%). IR (KBr) 2927, 2360,
1733, 1628, 1453, 1178, 1030, 749, 698 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.55-7.02 (m, 10-H), 6.78 (t, J ) 5.5 Hz, 1-H), 4.82 (t,
J ) 6.3 Hz, 1-H), 4.45 (m, 2-H), 3.97 (q, J ) 7.1 Hz, 2-H), 3.33
(m, 2-H), 2.67 (t, J ) 7.1 Hz, 2-H), 2.10 (m, 4-H), 1.77 (m, 1-H),
1.44 (m, 5-H), 1.09 (m, 17-H), 0.75 (t, J ) 6.9 Hz, 3-H); 13C NMR
(75 MHz, CDCl3) δ 175.4, 173.8, 170.9, 138.9, 137.8, 128.8, 128.7,
128.6, 127.3, 126.5, 126.0, 60.3, 57.9, 48.4, 40.3, 35.7, 34.3, 33.7,
31.8, 29.4, 29.1, 28.9 (2C), 28.3, 26.5, 25.1, 24.8, 22.6, 14.3, 14.2;
MS (ESI) m/z 573 (M + Na)+.
Heptanoic Acid, 7-[[1-[(Cyclohexylamino)carbonyl]heptyl](2-
phenylethyl)amino]-7-oxo-, Ethyl Ester (17). The crude material
is purified by column chromatography, using petroleum ether/EtOAc
8:2 as eluant to give a light yellow oil (22%). IR (KBr) 2929, 2855,
1734, 1625, 1534, 1452, 1255, 1179, 1030 cm-1; H NMR (300
1
MHz, CDCl3) δ 7.31-7.10 (m, 5-H), 6.54 (d, J ) 8.2 Hz, 1-H),
4.75 (t, J ) 7.7 Hz, 1-H), 4.10 (q, J ) 7.1 Hz, 2-H), 3.72 (m,
1-H), 3.45 (m, 2-H), 2.87 (m, 1-H), 2.74 (m, 1-H), 2.29 (m, 4-H),
2.03-1.54 (m, 12-H), 1.43-1.18 (m, 14-H), 0.85 (m, 6-H); 13C
NMR (75 MHz, CDCl3) δ 174.6, 173.7, 170.5, 138.3, 128.8 (2C),
126.8, 60.3, 58.0, 47.9, 47.1, 36.4, 34.2, 33.4, 32.9, 31.7, 29.2, 29.0,
28.2, 26.2, 25.6, 25.2, 24.8, 24.7, 22.6, 14.3, 14.1; MS (ESI) m/z
537 (M + Na)+.
General Procedure for the Saponification Reaction (23-31). The
ethyl ester (1 equiv) is dissolved in THF and water (2:1) and LiOH
(3 equiv) is added. The reaction is stirred at room temperature for
12 h. The volatile is evaporated and the crude material is purified
by column cromatography to give the carboxylic acid.
7-[[2-(Cyclohexylamino)-2-oxo-1-(phenylmethyl)ethyl](phenyl-
methyl)amino]-7-oxo-heptanoic Acid (23). The crude material is
purified by column chromatography, using petroleum ether/EtOAc
6:4 (+ formic acid 1%) as eluant to give a colorless oil (81%). IR
(KBr) 3260, 2931, 2360, 1721, 1608, 1288, 1190, 976, 733, 587
cm-1; 1H NMR (300 MHz, CDCl3) δ 10.39 (br s, 1-H), 7.28-7.01
(m, 10-H), 6.47 (d, J ) 8.0 Hz, 1-H), 5.07 (t, J ) 8.0 Hz, 1-H),
4.64 (d, J ) 17.6 Hz, 1-H), 4.48 (d, J ) 17.6 Hz, 1-H), 3.59 (m,
1-H), 3.18 (m, 1-H), 3.00 (m, 1-H), 2.22 (m, 4-H), 1.88-1.47 (m,
10-H), 1.34-1.05 (m, 6-H); 13C NMR (75 MHz, CDCl3) δ 178.1,
175.6, 169.2, 137.4 (2C), 129.3, 128.8, 128.5, 127.4, 126.7, 126.2,
60.2, 49.4, 48.1, 35.0 (2C), 32.6, 28.7, 25.3, 24.9, 24.6, 24.5 (2C);
MS (ESI) m/z 501 (M + Na)+.
Heptanoic Acid, 7-Oxo-7-[[2-oxo-1-(phenylmethyl)-2-[(phenyl-
methyl)amino]ethyl](2-phenylethyl)amino]-, Ethyl Ester (18). The
crude material is purified by column chromatography, using
petroleum ether/EtOAc 7:3 as eluant to give a yellow oil (17%).
IR (KBr) 1731, 1625, 1529, 1453, 1259, 1178, 1029, 748 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.36-7.04 (m, 15-H), 5.03 (t, J )
7.7 Hz, 1-H), 4.43 (d, J ) 5.8 Hz, 2-H), 4.09 (q, J ) 7.1 Hz, 2-H),
3.50-3.22 (m, 4-H), 2.68 (m, 2-H), 2.23 (t, J ) 7.4 Hz, 2-H), 2.13
(m, 2-H), 1.53 (m, 4-H), 1.21 (m, 5-H); 13C NMR (75 MHz, CDCl3)
δ 174.7, 173.6, 170.8, 138.2 (2C), 137.4, 129.3, 128.8, 128.7, 128.6
(2C), 127.7, 127.4, 126.8, 126.7, 60.5, 60.3, 48.4, 43.4, 36.0, 34.6,
34.1, 33.4, 28.8, 24.9, 24.7, 14.4; MS (ESI) m/z 551 (M + Na)+.
Octanoic Acid, 8-[[(2-Methylphenyl)methyl][2-oxo-2-[(2-phe-
nylethyl)amino]-1-(phenylmethyl)ethyl]amino]-8-oxo-, Ethyl Ester
(19). The crude material is purified by column chromatography,
using petroleum ether/EtOAc 7:3 as eluant to give a yellow oil
7-Oxo-7-[[2-oxo-2-[(2-phenylethyl)amino]-1-(phenylmethyl)ethyl](2-
phenylethyl)amino]-heptanoic Acid (24). The crude material is
purified by column chromatography, using petroleum ether/EtOAc
5:5 (+ formic acid 1%) as eluant to give a light yellow oil (92%).
(19%). IR (KBr) 1731, 1629, 1453, 1179, 1030, 730, 697 cm-1
;
IR (KBr) 2936, 1719, 1639, 1602, 1454, 1178, 1029, 896, 748 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.28-6.99 (m, 15-H), 6.71 (t, J )
5.5 Hz, 1-H), 5.06 (t, J ) 7.4 Hz, 1-H), 4.51 (d, J ) 17.6 Hz,
1-H), 4.35 (d, J ) 17.6 Hz, 1-H), 4.01 (q, J ) 7.1 Hz, 2-H),
3.39-3.12 (m, 3-H), 2.93 (m, 1-H), 2.56 (m, 2-H), 2.16 (t, J ) 7.1
Hz, 2-H), 2.09 (m, 2-H), 1.53 (m, 4-H), 1.48 (m, 4-H), 1.15 (m,
7-H); 13C NMR (75 MHz, CDCl3) δ 175.0, 173.6, 170.0, 139.0,
137.6 (2C), 129.3, 128.7, 128.6, 128.5, 128.4, 127.3, 126.6, 126.3,
126.2, 60.1, 59.7, 49.1, 40.5, 35.5, 35.0, 34.2, 33.7, 28.8 (2C), 25.0,
24.8, 14.3; MS (ESI) m/z 565 (M + Na)+.
1H NMR (300 MHz, CDCl3) δ 8.02 (s, 1-H), 7.38-7.12 (m, 15-
H), 4.92 (t, J ) 7.4 Hz, 1-H), 3.58-3.16 (m, 6-H), 2.78-2.49 (m,
4-H), 2.32 (t, J ) 7.4 Hz, 2-H), 2.10 (m, 2-H), 1.64-1.43 (m, 4-H),
1.25 (m, 2-H); 13C NMR (75 MHz, CDCl3) δ 178.2, 175.3, 171.2,
138.9, 138.0, 137.1, 129.1, 129.0, 128.9, 128.8, 128.6, 128.5, 127.0,
126.8, 126.5, 53.7, 48.9, 40.9, 35.8, 35.3, 34.6, 33.9, 33.4, 28.8,
24.9, 24.6; MS (ESI) m/z 537 (M + Na)+.
7-Oxo-7-[[2-oxo-2-[(2-phenylethyl)amino]-1-(phenylmethyl)eth-
yl](phenylmethyl)amino]-heptanoic Acid (25). The crude material
is purified by column chromatography, using petroleum ether/EtOAc
5:5 (+ formic acid 1%) as eluant to give a light yellow oil (75%).
IR (KBr) 1723, 1624, 1453, 1199, 1029, 973, 729 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.36-7.01 (m, 15-H), 6.57 (t, J ) 5.5, 1-H),
5.06 (t, J ) 7.9 Hz, 1-H), 4.48 (m, 2-H), 3.49-3.15 (m, 3-H), 2.98
(m, 1-H), 2.64 (m, 2-H), 2.26 (t, J ) 7.4 Hz, 2-H), 2.15 (t, J ) 7.4
Hz, 2-H), 1.53 (m, 4-H), 1.24 (m, 2-H); 13C NMR (75 MHz, CDCl3)
δ 175.3, 172.9, 170.1, 138.9, 137.5, 137.4, 129.4, 129.1, 128.9,
128.6, 128.5, 128.0, 127.0, 126.8, 126.5, 60.3, 49.3, 40.6, 35.5,
35.3 (2C), 33.7, 28.7, 24.8, 24.7; MS (ESI) m/z 523 (M + Na)+.
Octanoic Acid, 8-[Methyl[2-oxo-2-[(2-phenylethyl)amino]-1-
(phenylmethyl)ethyl]amino]-8-oxo-, Ethyl Ester (20). The crude
material is purified by column chromatography, using petroleum
ether/EtOAc 7:3 as eluant to give a colorless oil (18%). IR (KBr)
1
2933, 2361, 1731, 1630, 1454, 1259, 1177, 1030, 699 cm-1; H
NMR (300 MHz, CDCl3) δ 7.29-6.89 (m, 10-H), 6.19 (br t, 1-H),
5.28 (t, J ) 7.1 Hz, 1-H), 4.09 (q, J ) 7.1 Hz, 2-H), 3.44 (m,
2-H), 3.23 (m, 1-H), 2.75 (s, 3-H), 2.69 (m, 2-H), 2.23 (t, J ) 7.4
Hz, 2-H), 2.09 (m, 2-H), 1.54 (m, 2-H), 1.41 (m, 2-H), 1.19 (m,
7-H); 13C NMR (75 MHz, CDCl3) δ 174.0, 173.5, 170.1, 138.8,