F. Hong et al. / Bioorg. Med. Chem. 10 (2002) 3849–3858
3855
mg, 2.4 mmol) in DMSO (15 mL) was added Triton-B
(40% in MeOH, 1.5 mL). The solution was stirred at rt
for 72 h under N2, then poured into cold water, acidified
with 20% HCl to pH=4. Next, it was extracted with
ethyl acetate (3 ꢂ 30 mL). The combined extracts were
washed with water (50 mL), brine (50 mL), dried
(Na2SO4), and concentrated under reduced pressure.
The crude product was purified by column chromato-
graphy, eluting with 5% of methanol/chloroform, to
afford the desired product 16 (660 mg, 71%) as a light
88% yield as a light yellow oil; ꢀmax (neat)/cmꢃ1: 3329,
1723, 1634, 1159; H NMR (300 MHz, DCCl3) d 11.51
1
(s, 1H), 11.49 (s, 1H), 8.35 (t, J=4.9 Hz, 1H), 8.28 (t,
J=4.8 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.21 (d, J=8.3
Hz, 2H), 6.97 (d, J=8.3 Hz, 2H), 6.88 (d, J=7.7 Hz, 1H),
6.83–6.74 (m, 2H), 5.12 (s, 1H), 4.63–4.42 (m, 2H), 4.03 (t,
J=6.2 Hz, 2H), 3.55–3.45 (m, 2H), 3.44–3.35 (m, 2H),
3.23 (dd, J=5.1 and 13.5 Hz, 1H), 2.93 (dd, J=9.3 and
13.5 Hz, 1H), 2.02 (s, 3H), 1.95–1.30 (m, 71H); 13C
NMR (75.5 MHz, DCCl3) d 169.3, 163.6, 161.9, 157.4,
156.1, 156.0, 154.3, 153.3, 153.2, 139.4, 131.9, 130.0,
129.9, 124.4, 122.7, 120.4, 111.6, 105.1, 93.6, 83.0, 79.1,
78.4, 68.0, 55.1, 52.1, 44.4, 41.4, 40.9, 40.8, 38.5, 36.2,
30.3, 29.3, 29.0, 28.9, 28.8, 28.3, 28.0, 26.7, 23.5;LRMS
(ESI) 1198 (M+H+);HRMS (ESI) m/z calculated for
C65H100N9O12 (M+H+) 1198.7491, found 1198.7536.
yellow powder, mp 97.4–99.5 ꢀC; nmax (KBr)/cmꢃ1
:
1
3331, 3138 (br), 1723, 1634, 1138; H NMR (300 MHz,
DCCl3) d 11.49 (s, 1H), 8.37 (t, J=4.9 Hz, 1H), 8.31 (t,
J=5.0 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.37 (s, 1H),
6.80 (dd, J=1.9 and 8.7 Hz, 1H), 6.72 (s, 1H), 4.51 (t,
J=7.0 Hz, 2H), 4.02 (t, J=6.2 Hz, 2H), 3.49–3.34 (m,
4H), 1.92–1.30 (m, 50H); 13C NMR (75.5 MHz, DCCl3)
d 165.7, 163.4, 158.2, 156.1, 153.2, 140.4, 125.7, 123.5,
120.3, 112.2, 93.2, 83.0, 82.9, 79.2, 67.9, 44.3, 40.9, 40.8,
30.0, 28.9, 28.7, 28.2, 28.0, 26.5, 26.4, 23.4;LRMS (ESI)
N-[(2S)-1-(2-adamantylamino)-3-(4-tert-butyloxyphenyl)-
1-oxo-propan-2-yl] 1-{6-[N, N0-bis-(tert-butyloxycarbonyl)-
guanidino]hexyl}-6-{[5-(N, N0-bis-(tert-butyloxy-carbonyl)-
guanidino]pentyloxy}indole-2-carboxamide (19). This
was prepared similarly to the preparation of 17 in 97%
yield as a light yellow oil; nmax (neat)/cmꢃ1: 3329, 1723,
846 (M+H+);HRMS (ESI)
m/z calculated for
C42H68N7O11 (M+H+) 846.4976, found 846.5048.
1
N-{(2S)-1-[2-(tert-Butyloxycarbonyl)adamantyl-2-amino]-
3-(4-tert-butyloxyphenyl)-1-oxo-propan-2-yl} 1-{6-[N,N0-
bis-(tert-butyloxycarbonyl)guanidino]-hexyl}-6-{[5-(N,N0-
bis-(tert-butyloxycarbonyl)guanidino]pentyloxy}indole-2-
carboxamide (17). A solution of 16 (101 mg, 0.14 mmol),
1642, 1155, 1134; H NMR (300 MHz, DCCl3) d 11.51
(s, 1H), 11.49 (s, 1H), 8.34 (t, J=4.8 Hz, 1H), 8.27 (t,
J=4.7 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.21 (d, J=8.3
Hz, 2H), 6.95 (d, J=8.3 Hz, 2H), 6.83–6.72 (m, 3H),
6.18 (d, J=8.0 Hz, 1H), 4.80–4.70 (m, 1H), 4.56–4.48
(m, 2H), 4.08–3.95 (m, 3H), 3.53–3.42 (m, 2H), 3.42–
3.32 (m, 2H), 3.26 (dd, J=5.6 and 13.8 Hz, 1H), 3.05
(dd J=8.6 and 13.8 Hz, 1H), 1.95–1.31 (m, 73H); 13C
NMR (75.5 MHz, DCCl3) d 169.7, 163.6, 162.2, 157.5,
156.1, 154.4, 153.33, 153.3, 139.5, 131.7, 129.8, 124.4,
122.8, 120.3, 111.8, 105.2, 93.6, 83.0, 79.1, 78.4, 68.0, 54.8,
53.5, 44.5, 40.9, 40.8, 37.8, 37.4, 37.0, 36.95, 31.8, 31.7,
30.3, 29.0, 28.9, 28.8, 28.3, 28.1, 27.0, 26.7, 23.5;LRMS
(ESI) 1198 (M+H+);HRMS (ESI) m/z calculated for
C65H100N9O12 (M+H+) 1198.7491, found 1198.7546.
N-2-[(2-tert-butyloxycarbonyl)-2-adamantyl]
(2S)-2-
amino-3-(4-tert-butyloxyphenyl)propanamide (54 mg,
0.12 mmol), DCC (30 mg, 0.15 mmol) and HOBT (20
mg, 0.15 mmol) in DMF (8 mL) was stirred at room
temperature for 12 h under N2. The mixture was then
poured into cold water (30 mL), and then extracted with
EtOAc (3 ꢂ 30 mL). The combined extracts were
washed with H2O (40 mL), brine (40 mL), dried
(Na2SO4), and concentrated under reduced pressure.
The crude product was purified by column chromato-
graphy on silica gel, using 30% of ethyl acetate/hexanes
as eluent, to give 17 (105 mg, 67%) as a light yellow oil;
nmax (neat)/cmꢃ1: 3331, 1721, 1640, 1159; 1H NMR
(300 MHz, DCCl3) d 11.52 (s, 1H), 11.50 (s, 1H), 8.35 (t,
J=4.8 Hz, 1H), 8.28 (t, J=4.7 Hz, 1H), 7.45 (d, J=8.7
Hz, 1H), 7.26–7.23 (m, 2H), 6.96 (d, J=8.3 Hz, 2H),
6.79 (dd, J=1.8 and 8.7 Hz, 1H), 6.75–6.63 (m, 3H),
6.24 (s, 1H), 4.80–4.71 (m, 1H), 4.43 (t, J=7.8 Hz, 2H),
4.03 (t, J=6.2 Hz, 2H), 3.54–3.45 (m, 2H), 3.45–3.35
(m, 2H), 3.20 (d-d, J=5.9 and 13.9 Hz, 1H), 3.06 (dd,
J=8.2 and 13.9 Hz, 1H), 2.37 (s, 2H), 2.16–2.03 (m,
2H), 2.00–1.28 (m, 78H); 13C NMR (75.5 MHz, DCCl3) d
170.9, 169.3, 163.3, 162.2, 157.5, 156.1, 154.4, 153.3, 139.5,
131.7, 129.9, 129.5, 124.4, 122.8, 120.3, 111.8, 105.2, 93.6,
83.0, 80.5, 79.2, 78.4, 68.0, 63.9, 54.4, 49.1, 44.6, 40.9, 40.8,
37.8, 37.1, 33.9, 33.7, 33.0, 32.9, 32.7, 30.3, 29.0, 28.8,
28.3, 28.1, 27.9, 26.8, 26.7, 26.4, 25.6, 24.9, 23.5;LRMS
(ESI) 1298 (M+H+);HRMS (ESI) m/z calculated for
C70H108N9O14 (M+H+) 1298.8015, found 1298.8007.
1-[6-(N,N0-bis-benzyloxycarbonyl)guanidino]hexyl-7-{[5-
(N,N0-bis-benzyloxycarbonyl)guanidino]pentyloxy}indole-2-
carboxylic acid (21). This was prepared similarly to the
preparation of 16 in 47% yield as a light yellow oil; nmax
(neat)/cmꢃ1: 3337, 3130 (br), 1728, 1644, 1574, 1211; 1H
NMR (300 MHz, DCCl3) d 11.74 (s, 1H), 8.35 (t, J=5.1
Hz, 1H), 8.30 (t, J=5.0 Hz, 1H), 7.41–7.24 (m, 22H),
6.99 (t, J=7.9 Hz, 1H), 6.68 (d, J=7.7 Hz, 1H), 5.16 (s,
2H), 5.12 (s, 6H), 4.88 (t, J=7.4 Hz, 2H), 4.08 (t, J=6.3
Hz, 2H), 3.47 (q, J=6.3 Hz, 2H), 3.39 (q, J=.65 Hz, 2H),
1.95–1.50 (m, 10H), 1.45–1.30 (m, 4H); 13C NMR
(75.5 MHz, DCCl3) d 165.8, 163.6, 156.0, 155.9, 153.83,
153.8, 147.2, 136.7, 134.6, 129.7, 128.7, 126.6, 120.8,
115.1, 112.9, 105.8, 68.1, 68.0, 67.7, 67.1, 46.7, 41.1,
40.9, 32.0, 28.9, 28.8, 28.7, 26.5, 26.2, 23.5;LRMS (ESI)
982 (M+H+);HRMS (ESI) m/z calculated for 1/2 of
C54H61N7O11 (M+2H+) 491.7214, found 491.7200.
N-{(2S)-1-[2-(tert-butyloxycarbonyl)adamantyl-2-amino]-3-(4-
tert-butyloxyphenyl)-1-oxo-propan-2-yl}1-[6-(N,N0-bis-
benzyloxycarbonyl)guanidino]hexyl-7-{[5-(N,N0-bis-ben-
zyloxycarbonyl)guanidino]pentyloxy}indole-2-carboxa-
mide (22). This was prepared similarly to the
preparation of 17 in 88% yield as a light yellow oil; nmax
N-[(2S)-1-Adamantylamino-3-(4-tert-butyloxyphenyl)-
1-oxo-propan-2-yl] 1-{6-[N,N0-bis-(tert-butyloxycarbonyl)-
guanidino]hexyl}-6-{[5-(N,N0-bis-(tert-butyloxy-car-
bonyl)guanidino]pentyloxy}indole-2-carboxamide (18).
This was prepared similarly to the preparation of 17 in