4206
Z.-D. Shi et al. / Bioorg. Med. Chem. 13 (2005) 4200–4208
(m, 3H). FABMS (+ve) m/z 356 [MH+]. HRMS calcd
recovered 16). H NMR (CDCl3) d 8.68 (br s, 1H), 8.13
(dd, 1H, J = 2.0 and 7.5 Hz), 7.49 (d, 1H, J = 8.6 Hz),
7.39 (t, 1H, J = 5.4 Hz), 7.30–7.23 (m, 3H), 7.14 (t, 1H,
J = 8.0 Hz), 7.03 (dd, 2H, J = 2.3 and 8.1 Hz), 6.79 (d,
2H, J = 8.0 Hz), 6.70 (d, 1H, J = 7.4 Hz), 6.50 (s, 1H),
6.26 (s, 1H), 5.87 (m, 1H), 5.54 (m, 1H), 5.41 (s, 1H),
5.11–5.04 (m, 2H), 4.96–4.88 (m, 2H), 4.55 (m, 1H), 3.34
(t, 1H, J = 9.5 Hz), 3.24 (m, 1H), 3.12–3.05 (m, 2H),
2.91 (d, 2H, J = 21.3 Hz), 2.85 (m, 1H), 2.71 (dd, 1H,
J = 6.5 and 15.1 Hz), 2.55 (dd, 1H, J = 4.8 and 15.1 Hz),
2.38 (dd, 1H, J = 9.5 and 17.7 Hz), 2.29 (dd, 1H, J = 3.6
and 17.7 Hz), 2.24–2.17 (m, 2H), 2.09–2.02 (m, 2H),
1.80–1.10 (m, 10H), 1.42 (s, 9H), 1.38 (s, 18H). FABMS
(+ve) m/z 960 [MH+], 998 [MK+].
for C20H26N3O3 [M+]: 356.1974. Found: 356.1968.
6.10. (2S)-2-[[(1-Aminocyclohexyl)carbonyl]amino]-N1-
[(2S)-2-(5-hydroxy-1-naphthalenylmethyl)-4-pentenyl]-
butanediamide (16)
To a solution of 15 (226 mg, 0.64 mmol) in DMF (4 mL)
was added an active ester solution prepared by the reac-
tion of N-Fmoc-1-amino-cyclohexenecarboxylic acid
(257 mg, 0.70 mmol), HOBt (95 mg, 0.70 mmol), and
DIPCDI (0.11 mL, 0.70 mmol) in DMF (3 mL) at room
temperature (10 min) and the resulting solution was stir-
red at room temperature (12 h). The solvent was evapo-
rated and the remaining residue was dissolved in EtOAc,
and washed with H2O, brine, and dried (Na2SO4). Sol-
vent was removed by evaporation and the remaining
residue was purified by silica gel flash chromatography
to provide crude N-Fmoc-protected intermediate as col-
orless oil (412 mg, 92% yield). [H NMR (CD3OD-d6) d
8.08 (m, 1H), 7.74 (dd, 2H, J = 2.3 and 7.6 Hz), 7.50
(d, 1H, J = 8.6 Hz), 7.42 (d, 1H, J = 7.4 Hz), 7.37–7.31
(m, 3H), 7.27–7.17 (m, 5H), 6.76 (d, 1H, J = 7.4 Hz),
5.79 (m, 1H), 5.03–4.96 (m, 2H), 4.61 (dd, 1H, J = 4.8
and 16.5 Hz), 4.26 (dd, 1H, J = 6.3 and 10.6 Hz), 4.12
(dd, 1H, J = 5.5 and 10.7 Hz), 4.00 (t, 1H, J = 6.0 Hz),
3.27 (dd, 1H, J = 7.3 and 13.3 Hz), 3.05 (dd, 1H,
J = 5.5 and 13.3 Hz), 2.97 (d, 2H, J = 6.7 Hz), 2.80
(dd, 1H, J = 6.7 and 15.7 Hz), 2.68 (dd, 1H, J = 4.8
and 15.7 Hz), 2.19–2.09 (m, 2H), 2.01 (m, 1H), 1.91–
1.63 (m, 3H), 1.55–1.23 (m, 7H). FABMS (+ve) m/z
703 [MH+].] To a solution of this intermediate
(371 mg, 0.53 mmol) in CH3CN (6 mL) was added
piperidine (0.6 mL) and the resulting solution was stir-
red at room temperature (2 h). Evaporation of solvent
gave a residue, which was purified by silica gel flash
chromatography to provide 16 as a white solid
(229 mg, 90% yield). H NMR (CD3OD) d 8.06 (m,
1H), 7.44 (d, 1H, J = 8.6 Hz), 7.28–7.24 (m, 3H), 6.76
(dd, 1H, J = 0.8 and 7.6 Hz), 5.81 (m, 1H), 5.06–5.00
(m, 2H), 4.61 (t, 1H, J = 6.3 Hz), 3.26 (m, 1H), 3.08
(dd, 1H, J = 5.3 and 13.5 Hz), 2.95–2.94 (m, 2H), 2.66
(dd, 1H, J = 6.6 and 15.4 Hz), 2.60 (dd, 1H, J = 5.9
and 15.4 Hz), 2.11–2.01 (m, 3H), 1.87–1.76 (m, 2H),
1.54–1.48 (m, 5H), 1.42–1.21 (m, 3H). FABMS (+ve)
m/z 481 [MH+]. HRMS calcd for C27H37N4O4 [MH+]:
481.2815. Found: 481.2834.
6.12. (9S,10S,11E,14S,18S)-18-(2-Amino-2-oxoethyl)-
10-[4-[[bis(1,1-dimethylethoxy)phosphinyl]methyl]phenyl]-
14-(1-(5-hydroxy)naphthalenylmethyl)-8,17,20-trioxo-
7,16,19-triazaspiro[5.14]eicos-11-ene-9-acetic acid 1,1-
dimethylethyl ester (20)
To a solution of 18 (87 mg, 0.091 mmol) in CH2Cl2
(40 mL) was added [((PCy3)(Im(Mes)2)Ru@CHPh)]
1925 (50 mg, 0.058 mmol) in CH2Cl2 (5 mL) under argon
and the reaction mixture was refluxed (48 h). The crude
reaction mixture was evaporated in vacuo, and the
remaining residue was purified by silica gel flash chro-
matography to give 20 as yellow oil (56 mg, 66% yield).
H NMR (CDCl3) d 9.34 (br s, 1H), 8.61 (d, 1H,
J = 8.2 Hz), 8.06 (d, 1H, J = 8.4 Hz), 7.77 (s, 1H), 7.50
(t, 1H, J = 5.9 Hz), 7.36 (d, 1H, J = 8.4 Hz), 7.21–7.16
(m, 5H), 7.07 (d, 1H, J = 6.8 Hz), 6.49–6.44 (m, 2H),
5.72 (dd, 1H, J = 10.0 and 14.1 Hz), 5.26–5.20 (m,
2H), 4.65 (m, 1H), 4.28 (d, 1H, J = 9.6 Hz), 3.69 (dd,
1H, J = 6.0 and 13.0 Hz), 3.30–3.23 (m, 2H), 3.05 (m,
1H), 2.96 (d, 2H, J = 21.3 Hz), 2.89 (dd, 1H, J = 11.9
and 17.2 Hz), 2.71 (m, 1H), 2.45 (dd, 1H, J = 4.3 and
15.0 Hz), 2.39–2.16 (m, 4H), 2.02 (m, 1H), 1.89–1.46
(m, 10H), 1.42 (s, 9H), 1.34 (s, 9H), 1.28 (s, 9H).
FABMS (+ve) m/z 931 [MH+].
6.13. (9S,10S,11E,14S,18S)-18-(2-Amino-2-oxoethyl)-
14-(1-naphthalenylmethyl)-8,17,20-trioxo-10-[4-(phos-
phonomethyl)phenyl]-7,16,19-triazaspiro[5.14]eicos-11-
ene-9-acetic acid (4)
A solution of 20 (16 mg, 0.017 mmol) in a mixture of
TFA–TES–H2O (2.0 mL, v/v, 3.7:0.1:0.2) was stirred
at room temperature (1 h). Solvent was evaporated in
vacuo and the remaining residue was purified by HPLC
using a linear gradient from 5% B to 95% B over 25 min.
Analytical retention time = 23.5 min; preparative reten-
tion time = 15.2 min. Lyophilization provided 4 as a
white solid (7.6 mg, 58% yield) in 96% purity as deter-
mined by HPLC. H NMR (DMSO-d6) d 9.98 (br s,
1H), 8.48 (s, 1H), 8.23 (d, 1H, J = 8.2 Hz), 8.01 (d,
1H, J = 8.0 Hz), 7.55 (d, 1H, J = 8.6 Hz), 7.46 (s, 1H),
7.38–7.24 (m, 5H), 7.15 (dd, 2H, J = 2.0 and 8.4 Hz),
7.03 (s, 1H), 6.86 (d, 1H, J = 7.4 Hz), 5.76 (dd, 1H,
J = 10.9 and 14.5 Hz), 5.45 (m, 1H), 4.28 (m, 1H), 4.06
(m, 1H), 3.60 (m, 1H), 3.55 (m, 1H), 3.10 (m, 1H),
2.87 (d, 2H, J = 21.3 Hz), 2.83–2.67 (m, 3H), 2.55 (m,
1H), 2.33 (dd, 1H, J = 4.8 and 15.5 Hz), 2.08–1.16 (m,
6.11. (bS,cS)-b-[[[1-[[[(1S)-3-Amino-1-[[[(2S)-2-(5-hydroxy-
1-naphthalenylmethyl)-4-pentenyl]amino]carbonyl]-3-oxo-
propyl]amino]carbonyl]cyclohexyl]amino]carbonyl]-
4-[[bis(1,1-dimethylethoxy)phosphinyl]methyl]-c-ethenyl-
benzenebutanoic acid 1,1-dimethylethyl ester (18)
To a solution of 16 (123 mg, 0.256 mmol) and protected
pTyr mimetic 1714 (127 mg, 0.256 mmol) in DMF
(4 mL) was added HOAt (0.512 mL, 0.256 mmol) and
EDCIÆHCl (60 mg, 0.256 mmol) at 0 ꢁC. The solution
was stirred at room temperature (1.5 h) then heated to
50 ꢁC and stirred (24 h). The crude reaction mixture was
evaporated in vacuo and the remaining residue was puri-
fied by silica gel flash chromatography to provide 18 as
yellow oil (48 mg, 65% effective yield based on 86 mg of