Trisubstituted 2,5-Diketopiperazines
To this was added a solution of benzaldehyde 7 (1.06 g) in
methanol (0.5 mL) and t-butylisocyanide 9 (0.831 g). After 3 h
at -30 °C, the reaction was allowed to warm to room
temperature and was stirred for a further 72 h. The solvent
was removed in vacuo, and the residue purified using a column
(40 g, silica) eluting with cyclohexane/ethyl acetate (gradient
from 8:1 to 1:1). The required fractions were combined and
concentrated in vacuo to give methyl (2R)-2-{[2-(t-Butylamino)-
2-oxo-1-phenylethyl]amino}-4-methylpentanoate (15) as a col-
orless oil (2.27, 68%). The ratio of isomers was 8:1, and the
material was used without further purification.
(t, 2H, J ) 7 Hz), 1.26 (s, 9H), 0.90 (d, 3H, J ) 6.5 Hz), 0.89
(d, 3H, J ) 6.5 Hz); 13C NMR (d6-DMSO) 22.1, 23.1, 24.4, 28.3,
42.5, 49.9, 58.9, 65.6, 127.3, 128.2, 140.2, 170.6, 176.2; LCMS
m/z 321 (MH+) (tr 2.52 min); chiral HPLC 100% (tr 7.1 min);
Anal. calcd. for C18H28N2O3‚0.33 H2O: C, 66.24; H, 8.85; N,
8.58, found: C, 66.15; H, 8.62; N, 8.45.
(2R)-2-[[(1S)-2-(t-Butylamino)-2-oxo-1-phenylethyl]-
(formyl)amino]-4-methylpentanoic Acid (19). To a solu-
tion of acetic anhydride (0.102 g) in dichloromethane (3 mL)
was added formic acid (0.046 g) and pyridine (0.079 g), and
the reaction mixture was stirred under nitrogen at ambient
temperature for 20 min. To this was added (2R)-2-{[2-(t-
butylamino)-2-oxo-1-phenylethyl]amino}-4-methylpentanoic acid
(17) (0.10 g) and triethylamine (0.031 g). After 3 h, the reaction
mixture was separated between dichloromethane and 1 N
hydrochloric acid solution. The organic phase was dried using
a hydrophobic frit and evaporated in vacuo to give (2R)-2-
[[(1S)-2-(t-butylamino)-2-oxo-1-phenylethyl](formyl)amino]-4-
methylpentanoic acid (19) as an off-white solid (0.108 g, 100%).
1H NMR (d6-DMS0) 13.10 (s, 1H), 8.29 (s, 1H), 7.44 (m, 1H),
7.38 (m, 1H), 7.32 (m, 1H), 5.34 (s, 1H), 5.15 (dd, 1H, J ) 5,9
Hz), 1.70-1.51 (m, 3H), 1.31 (s, 9H), 0.87 (d, 3H, J ) 6 Hz),
0.86 (d, 3H, J ) 6 Hz); 13C NMR 20.2, 21.6, 22.5, 26.8, 36.9,
49.3, 50.6, 58.7, 126.4, 126.5, 127.2, 136.7, 162.6, 167.6, 171.6;
LCMS m/z 349 (MH+) (tr 3.13 min); HRMS calcd for C19H29N2O4
(MH+) 349.2127, found 349.2127; HPLC 99% (tr ) 12.0 min).
Methyl (2R)-2-[[(1S)-2-(t-Butylamino)-2-oxo-1-phenyl-
ethyl](formyl)amino]-4-methylpentanoate (16). To a solu-
tion of (2R)-2-[[(1S)-2-(t-butylamino)-2-oxo-1-phenylethyl]-
(formyl)amino]-4-methylpentanoic acid (19) (36 mg) in tetra-
hydrofuran (2 mL) was added a 2.0 M solution of trimethyl-
silyldiazomethane in hexanes (0.25 mL), and the reaction
mixture was stirred under nitrogen at ambient temperature
for 2 h. Methanol (2 mL) was added, and the reaction mixture
was stirred for a further 2 h. The solvent was removed in
vacuo, and the residue was purified by mass directed auto-
prep. This gave methyl (2R)-2-[[(1S)-2-(t-butylamino)-2-oxo-
1-phenylethyl](formyl)amino]-4-methylpentanoate (16) as an
off-white solid (30 mg, 80%).
Some of the mixture was purified to give the following
1
isomers: major isomer H NMR (CDCl3) 7.37-7.27 (m, 5H),
6.51 (s, 1H), 4.11 (s, 1H), 3.71 (s, 3H), 3.11 (t, 1H, J ) 7 Hz),
2.19 (broad signal, 1H), 1.70 (m, 1H), 1.48 (m, 2H), 1.31 (s,
9H), 0.87 (d, 3H, J ) 6.5 Hz), 0.77 (d, 3H, J ) 6.5 Hz); 13C
NMR (CDCl3) 22.0, 22.8, 24.8, 28.6, 42.5, 50.9, 51.8, 57.5, 66.3,
127.8, 128.3, 128.9, 138.9, 170.8, 175.4; LCMS m/z 335 (MH+)
(tr 3.38 min); HRMS calcd for C19H31N2O3 (MH+) 335.233468,
found 335.232462; chiral HPLC 99.5% (tr 14.1 min).
1
Minor isomer H NMR (CDCl3) 7.38-7.27 (m, 6H), 3.96 (s,
1H), 3.72 (s, 3H), 3.32 (dd, 1H, J ) 5, 8.5 Hz), 2.06 (broad
signal, 1H), 1.87 (m, 1H), 1.50-1.42 (m, 2H), 1.39 (s, 9H), 0.98
(d, 3H, J ) 6.5 Hz), 0.96 (d, 3H, J ) 6.5 Hz); 13C NMR (CDCl3)
22.2, 23.2, 24.9, 28.7, 43.3, 50.7, 52.0, 59.0, 66.9, 127.2, 128.1,
128.8, 139.5, 170.9, 175.9; LCMS m/z 335 (MH+) (tr 3.42 min);
HRMS calcd for C19H31N2O3 (MH+) 335.233468, found
335.232511; chiral HPLC 100% (tr 7.7 min)
Methyl (2R)-2-[[2-(t-Butylamino)-2-oxo-1-phenylethyl]-
(formyl)amino]-4-methylpentanoate (16). To a solution of
acetic anhydride (0.51 g) in dichloromethane (10 mL) was
added formic acid (0.23 g) and pyridine (0.39 g), and this was
stirred under nitrogen at ambient temperature for 1 h. To this
was added a solution of methyl (2R)-2-{[2-(t-butylamino)-2-
oxo-1-phenylethyl]amino}-4-methylpentanoate (15) (0.334 g)
in dichloromethane (2 mL) and triethylamine (0.101 g), and
the reaction mixture was left to stand under nitrogen at
ambient temperature for 20 h. The reaction mixture was
separated between dichloromethane and saturated sodium
bicarbonate solution. The organic phase was washed with 2
N hydrochloric acid solution and brine. The organic phase was
evaporated in vacuo to give methyl (2R)-2-[[2-(t-butylamino)-
2-oxo-1-phenylethyl](formyl)amino]-4-methylpentanoate (16)
(2S)-N-(t-Butyl)-2-[(3R,6S)-3-(2,3-dihydro-1H-inden-2-
yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-phenylethana-
mide (22). To a solution of (2R)-[(t-butoxycarbonyl)amino](2,3-
dihydro-1H-inden-2-yl)ethanoic acid (10) (58 mg) in dry
tetrahydrofuran (3 mL) under a nitrogen atmosphere at -25
°C was added N-methylmorpholine (20 mg) and a solution of
isopropylchloroformate in toluene (1.0 M, 0.2 mL). After 10
min, (2R)-2-{[2-(t-butylamino)-2-oxo-1-phenylethyl]amino}-4-
methylpentanoic acid (17) (70 mg) was added, and the result-
ant mixture was stirred at room temperature for 3 h. The
solvent was then removed in vacuo, and the residue was
treated with 4 N hydrochloric acid in dioxane (8 mL). After 4
h, methanol (15 mL) was added to the reaction mixture, and
this was left to stand for 18 h. The solvent was then removed
in vacuo, and the residue was purified on an SPE cartridge
(50 g, silica) eluting with cyclohexane/ethyl acetate (gradient
from 4:1 to neat ethyl acetate), which furnished (2S)-N-(t-
butyl)-2-[(3R,6S)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-
dioxopiperazin-1-yl]-2-phenylethanamide (22) as a white solid
1
as a white solid (0.274 g, 75%). H NMR (d6-DMSO) 8.24 (s,
1H), 7.99 (s, 1H), 7.49-7.27 (m, 6H), 5.24 (dd, 1H, J ) 5.6,8.8
Hz), 3.70 (s, 3H), 1.83-1.46 (m, 3H), 1.31-1.20 (m, 9H), 0.90-
0.75 (m, 6H); 13C NMR (d6-DMSO) 21.5, 22.9, 23.8, 28.1, 38.0,
50.7, 51.8, 52.1, 60.0, 127.8, 127.9, 128.7, 137.8, 163.9, 168.6,
171.7; LCMS m/z 363 (MH+) (tr 3.24 min); HRMS calcd for
C20H30N2O4 (MH+) 363.2284, found 363.2277; HPLC 93% (tr
) 13.0 min).
(2R)-2-{[2-(t-Butylamino)-2-oxo-1-phenylethyl]amino}-
4-methylpentanoic Acid (17). Methyl (2R)-2-[[2-(t-buty-
lamino)-2-oxo-1-phenylethyl]amino]-4-methylpentanoate (15)
(0.59 g) was dissolved in methanol (15 mL), and to this was
added lithium hydroxide (0.12 g) and water (2.5 mL). After
18 h, the methanol was removed in vacuo, and the residue
was dissolved in water. The pH was adjusted to 7 using 2 N
hydrochloric acid solution. This was applied to an OASIS
cartridge (6 g) and eluted twice with water and twice with
methanol. The methanol fractions were evaporated in vacuo
to give (2R)-2-{[2-(t-butylamino)-2-oxo-1-phenylethyl]amino}-
4-methylpentanoic acid (17) as a white solid (0.36 g, 64%).
Some of the mixture was purified to give the following
isomers: major isomer 1H NMR (d6-DMSO) 7.63 (s, 1H), 7.37-
7.21 (m, 5H), 4.12 (s, 1H), 2.80 (t, 1H, J ) 7 Hz), 1.73 (m, 1H),
1.36 (m, 2H), 1.21 (s, 9H), 0.82 (d, 3H, J ) 6.5 Hz), 0.70 (d,
3H, J ) 6.5 Hz); 13C NMR (d6-DMSO) 21.9, 22.9, 24.3, 28.3,
42.2, 50.0, 57.6, 64.7, 127.0, 127.4, 127.9, 140.4, 171.0, 176.5;
LCMS m/z 321 (MH+) (tr 2.46 min); chiral HPLC 100% (tr 9.2
min); Anal. calcd. for C18H28N2O3‚0.66 H2O: C, 65.06; H, 8.89;
N, 8.43, found: C, 65.16; H, 8.83; N, 8.36.
1
(54 mg, 57%) H NMR (CDCl3) d 7.42 (m, 5H), 7.20 (m, 2H),
7.17 (m, 2H), 5.64 (s, 1H), 5.59 (s, 1H), 5.48 (s, 1H), 4.23 (d,
1H, J ) 4 Hz), 4.00 (m, 1H), 3.39 (m, 2H), 3.13 (m, 1H), 2.91-
2.79 (m, 2H), 1.63-1.51 (m, 2H), 1.33 (s, 9H), 0.87 (m, 1H),
0.71 (d, 3H, J ) 6 Hz), 0.58 (d, 3H, J ) 6 Hz); 13C NMR (CDCl3)
20.9, 23.4, 24.2, 28.6, 34.1, 36.3, 38.6, 40.8, 51.8, 57.6, 58.7,
63.3, 124.5, 124.8, 126.7, 126.9, 129.17, 129.19, 129.9, 134.2,
141.4, 142.0, 167.5, 167.6, 169.5; LCMS m/z 476 (MH+) (tr 3.55
min); HRMS calcd for C29H37N3O3 (MH+) 476.2913, found
476.2908; HPLC 96% (tr ) 14.4).
(2S)-N-(t-Butyl)-2-[(3S,6S)-3-(2,3-dihydro-1H-inden-2-
yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-phenylethana-
mide (24). To a solution of (2S)-[(t-butoxycarbonyl)amino](2,3-
dihydro-1H-inden-2-yl)ethanoic acid (23) (58 mg) in dry
tetrahydrofuran (3 mL) under a nitrogen atmosphere at -25
°C was added N-methylmorpholine (20 mg) and a solution of
1
Minor isomer H NMR (d6-DMSO) 7.66 (s, 1H), 7.38-7.23
(m, 5H), 3.95 (s, 1H), 2.97 (t, 1H, J ) 7 Hz), 1.84 (m, 1H), 1.39
J. Org. Chem, Vol. 70, No. 12, 2005 4739