2446 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 15
Kitamura et al.
amorphous powder: IR (neat) cm-1 3360, 2970, 1713, 1650,
1513, 1448, 1363, 1246, 1158; 1H NMR (CDCl3) δ 1.43 (9H, s),
1.46 (9H, s), 1.30-2.20 (4H, m), 3.02-4.80 (11H, m), 4.94-
5.08 (1H, m), 5.13 (2H, s), 5.64-5.86 (1H, m), 7.30-7.45 (5H,
m).
and N-(4-guanidinobenzoyloxy)-5-norbornene-2,3-dicarboxy-
imide hydrochloride (1.12 g, 3.0 mmol) at room temperature.
After being stirred for 1 h, the mixtute was adjusted to pH 3
with 1 N HCl and concentrated in vacuo. The residue was
purified by column chromatography (MCI GEL CHP-20 (Mit-
subishi Chemical Industry), gradient elution: H2O to 5%
aqueous CH3CN) to give 12c (0.48 g, 55%) as a colorless
amorphous powder, which was converted into a dihydrochlo-
ride and recrystallized from H2O-EtOH to afford a colorless
crystalline powder: mp 245-251.5 °C; [R]20D +61.8° (c ) 1.00,
H2O, on the anhydrous basis); IR (KBr) cm-1 3287, 1730, 1634,
Compounds 9a ,b and 9d were prepared by the same
procedure as that described for the synthesis of 9c.
ter t-Bu tyl 2-[(3S)-4-(2-[(Ben zyloxyca r bon yl)a m in o]-
acetyl)-3-[[(ter t-bu toxycar bon yl)am in o]m eth yl]-2-oxopip-
1
er a zin yl]a ceta te (9a ): colorless oil (yield 77% from 7a ); H
NMR (CDCl3) δ 1.38 (9H, s), 1.47 (9H, s), 3.20-4.40 (10H, m),
4.90-5.10 (2H, m), 5.13 (2H, s), 5.60-5.90 (1H, m), 7.36 (5H,
s).
1
1557, 1505, 1449, 1323, 1262, 1179; H NMR (D2O) δ 1.60-
2.25 (4H, m), 3.30-5.20 (11H, m), 7.30-7.48 (4H, m), 7.72-
7.94 (4H, m). Anal. (C27H34N10O6‚2HCl‚2H2O) C, H, N.
ter t-Bu tyl 2-[(3S)-4-(2-[(Ben zyloxyca r bon yl)a m in o]-
acetyl)-3-[2-[(ter t-bu toxycar bon yl)am in o]eth yl]-2-oxopip-
er a zin yl]a ceta te (9b): colorless oil (yield 95% from 8b); IR
(neat) cm-1 3450, 1705, 1655, 1640, 1500, 1450, 1360, 1240,
1160; 1H NMR (CDCl3) δ 1.43 (9H, s), 1.46 (9H, s), 2.05-2.33
(1H, m), 2.73-2.95 (1H, m), 3.15-4.20 (10H, m), 5.05 (1H, dd,
J ) 3.0 Hz), 5.13 (2H, s), 5.30 (1H, brs), 5.83 (1H, brs), 7.36
(5H, s).
2-[(3R)-4-[2-[(4-Gu a n id in oben zoyl)a m in o]a cetyl]-3-[3-
[(4-gu a n id in oben zoyl)a m in o]p r op yl]-2-oxop ip er a zin yl]-
a cetic Acid (R-12c). Compound R-12c was synthesized by
the same procedure as that described for the synthesis of 12c
using Z-D-Orn(Boc)-OH instead of Z-L-Orn(Boc)-OH: colorless
amorphous powder; [R]20 -45.1° (c ) 0.40, MeOH). Anal.
D
(C27H34N10O6‚HCl‚3H2O) C, H, N.
2-[(3S)-4-[2-[(4-Am id in ob en zoyl)a m in o]a cet yl]-3-[[(4-
a m id in ob en zoyl)a m in o]m et h yl]-2-oxop ip er a zin yl]a ce-
tic Acid (11a ). Compound 11a was synthesized by the same
procedure as that described for the synthesis of 12c using
4-amidinobenzoyl chloride hydrochloride instead of N-(4-
guanidinobenzoyloxy)-5-norbornene-2,3-dicarboxyimide hydro-
chloride: colorless amorphous powder (yield 11% from 9a );
ter t-Bu tyl 2-[(3S)-4-(2-[(Ben zyloxyca r bon yl)a m in o]-
acetyl)-3-[4-[(ter t-bu toxycar bon yl)am in o]bu tyl]-2-oxopip-
er a zin yl]a ceta te (9d ): colorless oil (yield 99% from 8d ); IR
(KBr) cm-1 3400, 2990, 2945, 1713, 1657, 1520, 1458, 1368,
1253, 1166; 1H NMR (CDCl3) δ 1.42 (9H, s), 1.46 (9H, s), 1.18-
2.12 (6H, m), 2.92-4.28 (10H, m), 4.48-4.84 (1H, m), 4.94-
5.10 (1H, m), 5.13 (2H, s), 5.60-5.88 (1H, m), 7.22-7.45 (5H,
m).
ter t-Bu tyl 2-[(3S)-4-[(2S)-2-[(Ben zyloxycar bon yl)am in o]-
3-(4-m et h oxyp h en yl)p r op a n oyl]-3-[3-[(ter t-b u t oxyca r -
bon yl)am in o]pr opyl]-2-oxopiper azin yl]acetate (10c). Com-
pound 10c was synthesized by the same procedure as that
described for the synthesis of 9c using Z-L-Tyr(Me)-OH instead
of Z-Gly-OH: colorless oil (yield 92% from 8c); IR (KBr) cm-1
3360, 2975, 1710, 1643, 1512, 1448, 1360, 1245, 1152, 1033;
1H NMR (CDCl3) δ 1.41 (9H, s), 1.44 (9H, s), 1.30-2.10 (4H,
m), 2.20-2.44 (1H, m), 2.80-3.84 (8H, m), 3.77 (3H, s), 4.23
(1H, d, J ) 17.2 Hz), 4.50-4.85 (2H, m), 4.85-5.00 (1H, m),
5.05 (1H, d, J ) 12.0 Hz), 5.14 (1H, d, J ) 12.0 Hz), 5.67 (1H,
d, J ) 8.8 Hz), 6.80 (2H, d, J ) 8.8 Hz), 7.09 (2H, d, J ) 8.8
Hz), 7.22-7.50 (5H, m).
ter t-Bu tyl 2-[(3S)-4-[(2S)-2-[(Ben zyloxycar bon yl)am in o]-
3-(4-m et h oxyp h en yl)p r op a n oyl]-3-[4-[(ter t-b u t oxyca r -
bon yl)a m in o]bu tyl]-2-oxop ip er a zin yl]a ceta te (10d ). Com-
pound 10d was synthesized by the same procedure as that
described for the synthesis of 9c using Z-L-Tyr(Me)-OH instead
of Z-Gly-OH: colorless oil (yield 99% from 8d ); IR (KBr) cm-1
2975, 1712, 1646, 1512, 1447, 1364, 1244, 1155; 1H NMR
(CDCl3) δ 1.43 (9H, s), 1.44 (9H, s), 1.00-2.45 (7H, m), 2.80-
3.90 (8H, m), 3.78 (3H, s), 4.23 (1H, d, J ) 17.4 Hz), 4.70-
5.10 (5H, m), 5.74 (1H, d, J ) 8.8 Hz), 6.81 (2H, d, J ) 8.6
Hz), 7.10 (2H, d, J ) 8.6 Hz), 7.25-7.50 (5H, m).
N-(4-Gu a n id in ob en zoyloxy)-5-n or b or n en e-2,3-d ica r -
boxyim id e Hyd r och lor id e. To a mixture of 4-guanidinoben-
zoic acid hydrochloride (5.0 g, 23 mmol), N-hydroxy-5-
norbornene-2,3-dicarboxyimide (5.0 g, 28 mmol), and DMF (46
mL) was added 1,3-dicyclohexylcarbodiimide (6.2 g, 30 mmol)
at room temperature. After being stirred for 2 h at room
temperature, the mixture was filtered, and the filtrate was
concentrated in vacuo to give the title compound (7.6 g, 87%)
as a colorless powder. This compound was used for a conden-
sation reaction without purification.
[R]20 +60.2° (c ) 0.54, MeOH); IR (KBr) cm-1 1640, 1550,
D
1
1490; H NMR (D2O) δ 3.30-4.55 (10H, m), 5.19 (1H, t, J )
6.8 Hz), 7.68 (2H, d, J ) 8.0 Hz), 7.78 (2H, d, J ) 8.0 Hz),
7.90 (4H, s). Anal. (C25H28N8O6‚HCl‚3H2O) C, H, N.
2-[(3S)-4-[2-[(4-Am id in oben zoyl)a m in o]a cetyl]-3-[2-[(4-
a m id in ob en zoyl)a m in o]et h yl]-2-oxop ip er a zin yl]a cet ic
Acid (11b). Compound 11b was synthesized by the same
procedure as that described for the synthesis of 12c using
4-amidinobenzoyl chloride hydrochloride instead of N-(4-
guanidinobenzoyloxy)-5-norbornene-2,3-dicarboxyimide hydro-
chloride: colorless amorphous powder (yield 30% from 9b);
1
[R]20 +30.3° (c ) 0.47, H2O); H NMR (CD3OD) δ 2.00-2.50
D
(2H, m), 3.20-3.50 (2H, m), 3.50-4.25 (6H, m), 4.25-4.70 (2H,
m), 4.80-5.10 (1H, m), 7.82 (2H, d, J ) 8.4 Hz), 7.88 (2H, d,
J ) 8.4 Hz), 7.98 (2H, d, J ) 8.4 Hz), 8.04 (2H, d, J ) 8.4 Hz).
Anal. (C26H30N8O6‚CF3CO2H‚3H2O) C, H, N.
2-[(3S)-4-[2-[(4-Am id in oben zoyl)a m in o]a cetyl]-3-[3-[(4-
a m id in ob en zoyl)a m in o]p r op yl]-2-oxop ip er a zin yl]a ce-
tic Acid (11c). Compound 11c was synthesized by the same
procedure as that described for the synthesis of 12c using
4-amidinobenzoyl chloride hydrochloride instead of N-(4-
guanidinobenzoyloxy)-5-norbornene-2,3-dicarboxyimide hydro-
chloride: colorless amorphous powder (yield 32% from 9c);
[R]20 +41.9° (c ) 0.73, MeOH); IR (KBr) cm-1 3280, 1630,
D
1
1545, 1480, 1380, 1290; H NMR (D2O) δ 1.50-2.20 (4H, m),
3.20-5.00 (11H, m), 7.70-8.00 (8H, m). Anal. (C27H32N8O6‚CF3-
CO2H‚2H2O) C, H, N.
2-[(3S)-4-[2-[(4-Am id in oben zoyl)a m in o]a cetyl]-3-[4-[(4-
a m id in ob en zoyl)a m in o]b u t yl]-2-oxop ip er a zin yl]a cet ic
Acid (11d ). Compound 11d was synthesized by the same
procedure as that described for the synthesis of 12c using
4-amidinobenzoyl chloride hydrochloride instead of N-(4-
guanidinobenzoyloxy)-5-norbornene-2,3-dicarboxyimide hydro-
chloride: colorless amorphous powder (yield 44% from 9d );
1
[R]20 +44.3° (c ) 1.01, H2O); H NMR (CD3OD) δ 1.34-2.20
D
(6H, m), 3.26-4.62 (10H, m), 4.76-5.04 (1H, m), 7.87 (2H, d,
J ) 8.6 Hz), 7.91 (2H, d, J ) 8.6 Hz), 8.02 (2H, d, J ) 8.4 Hz),
8.09 (2H, d, J ) 8.4 Hz). Anal. (C28H34N8O6‚CF3CO2H‚HCl‚
3H2O) C, H, N.
2-[(3S)-4-[2-[(4-Gu a n id in oben zoyl)a m in o]a cetyl]-3-[[(4-
gu a n id in oben zoyl)a m in o]m eth yl]-2-oxop ip er a zin yl]a ce-
tic Acid (12a ). Compound 12a was synthesized by the same
procedure as that described for the synthesis of 12c: colorless
amorphous powder (yield 16% from 9a ); [R]20D +44.2° (c ) 1.03,
H2O); IR (KBr) cm-1 1650, 1540, 1500; 1H NMR (D2O) δ 3.35-
4.55 (8H, m), 3.92 (2H, d, J ) 7.0 Hz), 5.20 (1H, t, J ) 7.0
2-[(3S)-4-[2-[(4-Gu a n id in oben zoyl)a m in o]a cetyl]-3-[3-
[(4-gu a n id in oben zoyl)a m in o]p r op yl]-2-oxop ip er a zin yl]-
a cetic Acid (12c). Under an H2 atmosphere, a suspension of
9c (0.70 g, 1.24 mmol) and 10% Pd-C (0.07 g) in MeOH (7.0
mL) was stirred for 30 min at room temperature. The catalyst
was removed by filtration, and the filtrate was concentrated
in vacuo. To a solution of the residual oil in toluene (7.0 mL)
was added TFA (7.0 mL) at 0 °C, and the mixture was stirred
for 2 h at room temperature and concentrated in vacuo. Then,
to a mixture of the residual oil, 1,4-dioxane (7.0 mL), and H2O
(14 mL) were added successively NaHCO3 (0.52 g, 6.2 mmol)