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T. Shinozuka et al. / Bioorg. Med. Chem. 14 (2006) 6807–6819
5.18.2.
N1-((1S)-1-{[(4-Methoxyphenyl)amino]meth-
5.20. tert-Butyl [(1S)-1-({[4-(benzyloxy)phenyl]ami-
no}methyl)propyl]carbamate (31)
yl}propyl)-N2-(2-oxo-6-phenyl-2H-pyran-4-yl)-L-leucina-
1
mide (28k). Yield: 90%; white solid; mp 170–173 ꢁC; H
NMR (400 MHz, CDCl3) d 0.89 (3H, d, J = 5.9 Hz);
0.95 (3H, d, J = 7.3 Hz), 0.96 (3H, d, J = 8.1 Hz),
1.62–1.74 (5H, m), 3.15 (1H, dd, J = 6.6, 12.5 Hz),
3.21 (1H, dd, J = 4.4, 12.5 Hz), 3.69 (3H, s), 3.98–4.11
(2H, m), 5.25 (1H, s), 6.34 (1H, d, J = 6.6 Hz), 6.20
(1H, s), 6.56 (2H, d, J = 8.8 Hz), 6.72 (2H, d,
J = 8.8 Hz), 7.37–7.45 (3H, m), 7.71–7.74 (2H, m); IR
(KBr): 3271, 3088, 2959, 1651, 1549, 1514, 1298, 1237,
Compound 31 was prepared according to the procedure
for 27, using appropriate starting materials. Yield: 82%;
mp 108–111 ꢁC; 1H NMR (400 MHz, CDCl3) d 0.97
(3H, t, J = 7.5 Hz), 1.45 (9H, s), 1.40–1.66 (2H, m),
3.01 (1H, dd, J = 7.6, 12.2 Hz), 3.17 (1H, dd, J = 4.6,
12.2 Hz), 3.65–3.80 (2H, m), 4.46 (1H, br s), 4.99 (2H,
s), 6.57 (2H, d, J = 8.9 Hz), 6.84 (2H, d, J = 8.9 Hz),
7.28–7.43 (5H, m); IR (KBr): 3375, 1683, 1514, 1245,
1175, 1018, 816 cmꢀ1; MS (FAB) m/z: 370 [M+], 223,
91, 57; Anal. Calcd for C22H30N2O3: C, 71.32; H,
8.16; N, 7.56. Found: C, 71.16; H, 7.93; N, 7.55.
820,
767,
693,
626 cmꢀ1
;
HRMS
found
[M+H]+ = 478.2711, calcd for C28H36N4O3: 478.2706.
5.18.3. N-((1S)-1-{[(4-Methoxyphenyl)amino]methyl}pro-
(28m).
pyl)-N2-(5-phenylisoxazol-3-yl)-L-leucinamide
5.21. General procedure for the preparation of amides 32
1
Yield: 67%; white powder; mp 165–167 ꢁC; H NMR
(400 MHz, CDCl3) d 0.92 (3H, d, J = 7.4 Hz), 0.97
(3H, d, J = 7.4 Hz), 1.43–1.55 (1H, m), 1.58–1.71 (2H,
m), 1.74–1.86 (2H, m), 3.01 (1H, dd, J = 8.3, 12.3 Hz),
3.19 (1H, dd, J = 4.3, 12.3 Hz), 3.70 (3H, s), 3.95–4.01
(1H, m), 4.03–4.12 (1H, m), 4.51 (1H, d, J = 6.3 Hz),
6.06 (1H, s), 6.49–6.55 (3H, m), 6.66–6.72 (2H, m),
7.34–7.41 (3H, m), 7.55–7.60 (2H, m);IR (KBr): 3278,
3065, 1649, 1556, 1512, 1235, 1039, 820, 761,
690 cmꢀ1; MS (FAB) m/z: 451.27 [M+H]+.
Compound 32 was prepared according to the procedure
for 28, using appropriate starting materials.
5.21.1.
N-[(1S)-1-({[4-(Benzyloxy)phenyl]amino}meth-
yl)propyl]-N2-biphenyl-3-yl-L-leucinamide (32b). Yield:
99%; colorless crystals; mp 117–119 ꢁC; 1H NMR
(400 MHz, CDCl3) d 0.93 (3H, t, J = 7.3 Hz), 0.94
(3H, d, J = 6.6 Hz), 1.01 (3H, d, J = 6.6 Hz), 1.39–1.92
(5H, m), 2.96 (1H, dd, J = 7.3, 12.5 Hz), 3.11 (1H, dd,
J = 4.4, 12.5 Hz), 3.40–3.55 (1H, br s), 3.74–3.82 (1H,
m), 3.92–3.95 (1H, m), 4.00–4.12 (1H, m), 4.93 (2H, s),
6.33 (2H, d, J = 9.5 Hz), 6.58 (1H, dd, J = 2.2, 8.1 Hz),
6.72 (2H, d, J = 9.5 Hz), 6.74–6.85 (2H, m), 7.03 (1H,
d, J = 8.1 Hz), 7.18 (1H, t, J = 8.1 Hz), 7.28–7.58
(10H, m); IR (KBr): 3324, 1624, 1511, 1231, 1214,
755 cmꢀ1; Anal. Calcd for C35H41N3O2: C, 78.47; H,
7.71; N, 7.84. Found: C, 78.47; H, 7.52; N, 7.78; MS
(FAB) m/z: 536 [M+H]+, 444, 238.
5.18.4. N-((1S)-1-{[(4-Methoxyphenyl)amino]methyl}pro-
pyl)-N2-(morpholin-4-ylcarbonyl)-L-leucinamide
(28n).
Yield: 73%; amorphous substance; 1H NMR
(400 MHz, CDCl3) d 0.91–0.96 (9H, m), 1.47–1.70
(5H, m), 3.09 (1H, dd, J = 7.3, 12.5 Hz), 3.19 (1H, dd,
J = 5.1, 12.5 Hz), 3.33–3.36 (4H, m), 3.66 (4H, t,
J = 4.4 Hz), 3.74 (3H, s), 3.99–4.02 (1H, m), 4.25–4.29
(1H, m), 4.84 (1H, d, J = 8.1 Hz), 6.17 (1H, d,
J = 8.1 Hz), 6.58 (2H, d, J = 8.8 Hz), 6.77 (2H, d,
J = 8.8 Hz); IR (KBr): 3284, 2957, 1623, 1515, 1239,
1119, 820 cmꢀ1; HRMS found [M+H]+ = 421.2801,
calcd for C22H37N4O4: 421.2815.
5.21.2.
N-[(1S)-1-({[4-(Benzyloxy)phenyl]amino}meth-
yl)propyl]-N2-(2-oxo-6-phenyl-2H-pyran-4-yl)-L-leucina-
mide (32k). Yield: 74%; colorless crystals; mp 142–
146 ꢁC; 1H NMR (400 MHz, CDCl3) d 0.87 (3H, d,
J = 5.9 Hz), 0.93 (3H, d, J = 5.9 Hz), 0.95 (3H, t,
J = 7.5 Hz), 1.52–1.72 (5H, m), 3.12–3.21 (2H, m),
4.03–4.09 (2H, m), 4.91 (2H, s), 5.33 (1H, d,
J = 1.6 Hz), 5.72 (1H, br s), 6.22 (1H, d, J = 1.6 Hz),
6.53 (2H, d, J = 9.0 Hz), 6.77 (2H, d, J = 9.0 Hz), 7.14
(1H, br s), 7.27–7.39 (8H, m), 7.66–7.68 (2H, m); IR
(KBr): 3269, 3088, 2959, 1650, 1549, 1512, 1298, 1232,
818, 767, 694 cmꢀ1; HRMS found [M+H]+ = 554.3012,
calcd for C34H40N3O4: 554.3024.
5.19. N-[4-(Benzyloxy)phenyl]-2-nitrobenzenesulfonamide
(29)
To a stirred solution of 4-(benzyloxy)aniline hydrochlo-
ride (11.79 g, 50 mmol) and 2-nitrobenzenesulfonyl
chloride (11.08 g, 50 mmol) in CH2Cl2 (150 mL) was
added Et3N (14.6 mL, 105 mmol) dropwise at 0 ꢁC.
After stirring for 4 h, water (200 mL) was added to the
reaction mixture. The organic layer was washed with
1 M HCl (100 mL) and saturated aqueous solution of
NaHCO3 (100 mL). The organic layer was dried
(Na2SO4) and concentrated. Recrystallization from
EtOH (350 mL) provided 2-nitrobenzenesulfonamide
29 (16.63 g, 87%). Mp 154–156 ꢁC; 1H NMR
(400 MHz, CDCl3) d 5.00 (2H, s), 6.85 (1H, d,
J = 8.9 Hz), 7.09 (1H, d, J = 8.9 Hz), 7.10 (1H, br s),
7.30–7.40 (5H, m), 7.55 (1H, dt, J = 1.2, 7.8 Hz), 7.68
(1H, dt, J = 1.4, 7.8 Hz), 7.75 (1H, dd, J = 1.4,
7.8 Hz), 7.85 (1H, dd, J = 1.2, 7.8 Hz); IR (KBr): 3312,
1540, 1507, 1166, 1005, 595 cmꢀ1; MS (FAB) m/z: 384
[M+]; Anal. Calcd for C19H16N2O5S: C, 59.37; H, 4.20;
N, 7.29; S, 8.34. Found: C, 59.21; H, 4.05; N, 7.27; S,
8.33.
5.21.3.
N-[(1S)-1-({[4-(Benzyloxy)phenyl]amino}meth-
yl)propyl]-N2-(5-phenylisoxazol-3-yl)-L-leucinamide (32m).
Yield: 81%; mp 184–186 ꢁC; 1H NMR (400 MHz,
CDCl3) d 0.93 (3H, t, J = 7.4 Hz), 0.95 (3H, d,
J = 6.1 Hz), 0.98 (3H, d, J = 6.1 Hz), 1.42–1.70 (3H,
m), 1.74–1.83 (2H, m), 3.00 (1H, dd, J = 8.5, 12.2 Hz),
3.19 (1H, dd, J = 4.2, 12.2 Hz), 3.54 (1H, br s), 3.80
(1H, br s), 3.92–3.99 (1H, m), 4.01–4.12 (1H, m), 4.31
(1H, d, J = 5.8 Hz), 4.92 (2H, s), 6.04 (1H, s), 6.41
(1H, d, J = 9.1 Hz), 6.50 (2H, d, J = 8.9 Hz), 6.75 (2H,
d, J = 8.9 Hz), 7.25–7.41 (8H, m), 7.53–7.58 (2H, m);
IR (KBr): 3279, 2960, 1645, 1511, 1231, 1025, 816,
762, 692 cmꢀ1; MS (FAB) m/z: 527.30 [M+H]+.