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was poured into 5% aqueous KHSO4 and extracted with ethyl acetate (9H, s), 2.30—2.56 (2H, m), 2.70—3.30 (5H, m), 3.65 (3H, s), 3.50—3.81
(EtOAc). The EtOAc extract was washed with saturated aqueous NaHCO3, (2H, m), 3.93 (2H, s), 4.55—4.82 (3H, m), 4.85 (1H, t, Jϭ5.0 Hz), 5.31 (1H,
dried over anhydrous MgSO4 and concentrated in vacuo. The residue was d, Jϭ8.4 Hz), 6.90 (2H, d, Jϭ8.4 Hz), 7.14 (2H, d, Jϭ8.4 Hz).
chromatographed on SiO2 (hexane–EtOAc, 3 : 7) to give 3h (0.84 g, 76%) as
Methyl 2-[(2S )-1-[(2S )-2-[(Benzyloxycarbonyl)amino]-3-(4-fluo-
rophenyl)propanoyl]-4-[2-(tert-butoxy)-2-oxoethyl]-3-oxopiperazinyl]ac-
etate (3s): A colorless oil (42%). IR (KBr) cmϪ1: 3310, 2978, 1741, 1640,
1507, 1438, 1366, 1220, 1154. 1H-NMR (CDCl3) d: 1.46 (9H, s), 2.50—
a colorless amorphous powder. IR (KBr) cmϪ1: 3287, 2978, 1738, 1651,
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1514, 1248, 1157. H-NMR (CDCl3) d: 1.45 (9H, s), 2.40—2.60 (1H, m),
2.66—3.22 (5H, m), 3.63 (3H, s), 3.78 (3H, s), 3.54—4.04 (4H, m), 4.70—
4.90 (1H, m), 4.97 (1H, t, Jϭ5.4 Hz), 5.10 (2H, s), 5.58 (1H, d, Jϭ8.8 Hz), 2.73 (1H, m), 2.64—3.24 (5H, m), 3.55—3.77 (2H, m), 3.63 (3H, s), 3.85
6.82 (2H, d, Jϭ8.8 Hz), 7.10 (2H, d, Jϭ8.8 Hz), 7.24—7.40 (5H, m). (1H, d, Jϭ17.4 Hz), 4.06 (1H, d, Jϭ17.4 Hz), 4.72—4.90 (1H, m), 4.96—
Compounds 3a—g and 3i—w were prepared in a manner similar to that 5.02 (1H, m), 5.09 (2H, d, Jϭ1.8 Hz), 5.58 (1H, d, Jϭ8.4 Hz), 6.86—7.04
described for 3h. Compounds 3b—g, 3m, 3q—3r and 3u were used for a (2H, m), 7.08—7.20 (2H, m), 7.28—7.42 (5H, m).
next reaction without purification.
Methyl 4-[(2S)-2-[(tert-Butoxycarbonyl)amino]-3-[(2S)-4-[2-(tert-bu-
Methyl 2-[(2S)-1-[(2S)-2-[(Benzyloxycarbonyl)amino]-3-(4-hydroxy- toxy)-2-oxoethyl]-2-(2-methoxy-2-oxoethyl)-3-oxopiperazinyl]-3-oxo-
phenyl)propanoyl]-4-[2-(tert-butoxy)-2-oxoethyl]-3-oxopiperazinyl]acetate
propyl]benzoate (3t): A colorless oil (51%). IR (KBr) cmϪ1: 3322, 2980,
1
(3a): A colorless amorphous powder (76%). IR (KBr) cmϪ1: 3300, 1738, 1719, 1649, 1525, 1435, 1367, 1281, 1152. H-NMR (CDCl3) d: 1.45 (9H,
1651, 1516, 1447, 1370, 1229, 1155. 1H-NMR (CDCl3) d: 1.46 (9H, s), s), 2.61—2.80 (1H, m), 2.80—3.25 (5H, m), 3.63 (3H, s), 3.40—4.05 (4H,
2.30—2.52 (1H, m), 2.68—3.24 (5H, m), 3.62 (3H, s), 3.36—3.84 (2H, m),
m), 3.90 (3H, s), 4.78—5.00 (1H, m), 4.98 (1H, t, Jϭ5.2 Hz), 5.08 (2H, d,
3.84 (1H, d, Jϭ17.2 Hz), 4.03 (1H, d, Jϭ17.2 Hz), 4.78 (1H, q, Jϭ7.6 Hz), Jϭ1.4 Hz), 5.61 (1H, d, Jϭ8.0 Hz), 7.16—7.46 (7H, m), 7.95 (2H, d, Jϭ8.0
4.96 (1H, t, Jϭ5.4 Hz), 5.10 (2H, s), 5.60 (1H, d, Jϭ9.2 Hz), 5.74—5.94
(1H, m), 6.75 (2H, d, Jϭ8.6 Hz), 7.02 (2H, d, Jϭ8.6 Hz), 7.20—7.50 (5H,
m).
Hz).
Methyl 2-[(2S )-1-[(2S )-2-[(tert-Butoxycarbonyl)amino]-3-(4-
vinylphenyl)propanoyl]-4-[2-(tert-butoxy)-2-oxoethyl]-3-oxopiperazinyl]ac-
etate (3v): A colorless crystalline powder (76%, EtOAc–petroleum ether),
Methyl 2-[(2S)-1-[(2S)-2-[(Benzyloxycarbonyl)amino]-3-(4-ethoxy-
phenyl)propanoyl]-4-[2-(tert-butoxy)-2-oxoethyl]-3-oxopiperazinyl]acetate
mp 148—152 °C. [a]D20 ϩ94.3° (cϭ0.47, CHCl3). IR (KBr) cmϪ1: 3446,
(3i): A colorless oil (65%). IR (KBr) cmϪ1: 3424, 2980, 1739, 1652, 1508, 1746, 1699, 1653, 1624, 1507, 1366, 1232, 1174, 1156. H-NMR (CDCl3)
1
1
1441, 1367, 1242, 1152. H-NMR (CDCl3) d: 1.39 (3H, t, Jϭ7.0 Hz), 1.45 d: 1.43 (9H, s), 1.44 (9H, s), 2.25—2.45 (1H, m), 2.70—3.25 (5H, m),
(9H, s), 2.36—2.58 (1H, m), 2.66—3.24 (5H, m), 3.56—3.86 (5H, m), 3.90
3.50—3.80 (2H, m), 3.65 (3H, s), 3.78 (1H, d, Jϭ17.2 Hz), 3.96 (1H, d,
(2H, d, Jϭ6.4 Hz), 3.99 (2H, q, Jϭ7.0 Hz), 4.70—4.90 (1H, m), 4.98 (1H, t, Jϭ17.2 Hz), 4.64—4.83 (1H, m), 4.99 (1H, t, Jϭ5.2 Hz), 5.22 (1H, d,
Jϭ5.4 Hz), 5.10 (2H, s), 5.59 (1H, d, Jϭ8.8 Hz), 6.80 (2H, d, Jϭ8.8 Hz), Jϭ10.8 Hz), 5.32 (1H, d, Jϭ8.6 Hz), 5.71 (1H, d, Jϭ17.6 Hz), 6.66 (1H, dd,
7.08 (2H, d, Jϭ8.8 Hz), 7.27—7.40 (5H, m).
Jϭ10.8, 17.6 Hz), 7.15 (2H, d, Jϭ8.2 Hz), 7.34 (2H, d, Jϭ8.2 Hz). Anal..
Calcd for C29H41N3O8: C, 62.24; H, 7.38; N, 7.51. Found: C, 62.01; H, 7.51;
N, 7.47.
Methyl 2-[(2S)-1-[(2S)-2-[(Benzyloxycarbonyl)amino]-3-(4-propoxy-
phenyl)propanoyl]-4-[2-(tert-butoxy)-2-oxoethyl]-3-oxopiperazinyl]acetate
(3j): A colorless oil (63%). IR (KBr) cmϪ1: 3304, 2970, 1737, 1655, 1510,
Methyl 2-[(2S)-1-[(2S)-2-[(tert-Butoxycarbonyl)amino]-3-(4-nitro-
1440, 1244, 1153. 1H-NMR (CDCl3) d: 1.02 (3H, t, Jϭ7.4 Hz), 1.45 (9H, s), phenyl)propanoyl]-4-[2-(tert-butoxy)-2-oxoethyl]-3-oxopiperazinyl]acetate
1.67—1.89 (2H, m), 2.36—2.58 (1H, m), 2.66—3.20 (5H, m), 3.56—3.79
(3w): A colorless crystalline powder (70%, CH2Cl2–hexane), mp 167—
(5H, m), 3.86 (2H, d, Jϭ6.2 Hz), 3.86 (1H, d, Jϭ17.2 Hz), 3.99 (1H, d, 170 °C. [a]D20 ϩ51.2° (cϭ0.60, CHCl3). IR (KBr) cmϪ1: 1736, 1700, 1654,
Jϭ17.2 Hz), 4.70—4.90 (1H, m), 5.02 (1H, t, Jϭ5.3 Hz), 5.09 (2H, s), 5.68 1518, 1347, 1232, 1158. 1H-NMR (CDCl3) d: 1.40 (9H, s), 1.45 (9H, s),
(1H, d, Jϭ8.8 Hz), 6.80 (2H, d, Jϭ8.8 Hz), 7.08 (2H, d, Jϭ8.8 Hz), 7.22— 2.70—3.30 (6H, m), 3.40—3.97 (3H, m), 3.66 (3H, s), 4.15—4.35 (1H, m),
7.43 (5H, m).
4.73—4.90 (1H, m), 5.00 (1H, t, Jϭ5.4 Hz), 5.32 (1H, d, Jϭ9.0 Hz), 7.30—
Methyl 2-[(2S)-1-[(2S)-2-[(Benzyloxycarbonyl)amino]-3-(4-isopropoxy- 7.60 (2H, m), 8.16 (2H, d, Jϭ8.8 Hz). Anal. Calcd for C27H38N4O10: C,
phenyl)propanoyl]-4-[2-(tert-butoxy)-2-oxoethyl]-3-oxopiperazinyl]acetate
(3k): A colorless oil (53%). IR (KBr) cmϪ1: 3304, 2980, 1740, 1657, 1508,
56.05; H, 6.62; N, 9.68. Found: C, 55.85; H, 6.36; N, 9.67.
General Synthetic Procedure (Method A). 2-[(3S)-4-[(2S)-2-(4-Amidi-
1445, 1368, 1242, 1154. 1H-NMR (CDCl3) d: 1.26—1.35 (6H, m), 1.45 nobenzoylamino)-3-(4-methoxyphenyl)propanoyl]-3-(2-methoxy-2-ox-
(9H, s), 2.32—2.54 (1H, m), 2.66—3.20 (5H, m), 3.54—3.84 (6H, m), 4.04
oethyl)-2-oxopiperazinyl]acetic Acid (4h) Under an H2 atmosphere, a
(1H, d, Jϭ17.4 Hz), 4.40—4.58 (1H, m), 4.72—4.88 (1H, m), 5.01 (1H, t, suspension of 3h (0.84 g, 1.41 mmol) and 10% Pd–C (0.14 g) in MeOH (4.2
Jϭ5.4 Hz), 5.09 (2H, s), 5.74 (1H, d, Jϭ8.8 Hz), 6.79 (2H, d, Jϭ8.8 Hz), ml) was stirred at room temperature for 40 min. The catalyst was removed
7.08 (2H, d, Jϭ8.8 Hz), 7.30—7.40 (5H, m).
by filtration, and the filtrate was concentrated in vacuo to give a colorless
syrup, which was dissolved in H2O (11.7 ml) and 1,4-dioxane (5.9 ml). To
this solution were added NaHCO3 (0.24 g, 2.81 mmol) and 4-amidinoben-
Methyl 2-[(2S)-1-[(2S)-2-[(Benzyloxycarbonyl)amino]-3-(4-decyloxy-
phenyl)propanoyl]-4-[2-(tert-butoxy)-2-oxoethyl]-3-oxopiperazinyl]acetate
(3l): A colorless oil (54%). IR (KBr) cmϪ1: 2926, 1740, 1657, 1510, 1436, zoylchloride hydrochloride (0.37 g, 1.69 mmol) at room temperature. After
1
1367, 1244, 1154. H-NMR (CDCl3) d: 0.88 (3H, t, Jϭ6.4 Hz), 1.09—1.54
being stirred for 1.5 h, the mixture was adjusted to pH 7 with 1 N HCl and
(23H, m), 1.65—1.85 (2H, m), 2.37—2.58 (1H, m), 2.65—3.35 (5H, m), concentrated in vacuo. Then, a mixture of the residue and toluene (5.9 ml)
3.63 (3H, s), 3.54—4.08 (6H, m), 4.68—4.89 (1H, m), 4.99 (1H, t, Jϭ5.2 was treated with trifluoroacetic acid (5.9 ml) and the mixture was stirred for
Hz), 5.09 (2H, s), 5.58 (1H, d, Jϭ8.4 Hz), 6.80 (2H, d, Jϭ8.4 Hz), 7.08 (2H, 1 h at room temperature. The mixture was concentrated in vacuo, and the
d, Jϭ8.4 Hz), 7.30—7.40 (5H, m). residue was chromatographed on MCI GEL CHP-20 (Mitsubishi Chemical
Methyl 2-[(2S )-1-[(2S )-2-[(tert-Butoxycarbonyl)amino]-3-(3,4- Industry, gradient elution: H2O to 15% aqueous MeCN) to give 4h (0.52 g,
dimethoxyphenyl)propanoyl]-4-[2-(tert-butoxy)-2-oxoethyl]-3-oxopiper-
60%) as a colorless crystalline powder (H2O–EtOH), mp 208—212 °C. [a]D20
azinyl]acetate (3n): A colorless oil (79%). IR (KBr) cmϪ1: 3426, 2978,
Ϫ76.7° (cϭ1.04, dimethyl sulfoxide (DMSO)). IR (KBr) cmϪ1: 1727, 1631,
1741, 1706, 1655, 1515, 1443, 1366, 1260, 1237, 1156, 1026. 1H-NMR 1484, 1452, 1383. H-NMR (D2O) d: 2.36—2.56 (1H, m), 2.76—3.02 (2H,
(CDCl3) d: 1.43 (9H, s), 1.45 (9H, s), 2.40—2.60 (1H, m), 2.66—3.10 (5H,
m), 3.65 (3H, s), 3.84 (3H, s), 3.85 (3H, s), 3.62—4.04 (4H, m), 4.64—4.88
1
m), 3.02—3.24 (3H, m), 3.59 (3H, s), 3.82 (3H, s), 3.44—4.20 (4H, m),
4.80—5.20 (2H, m), 6.95 (2H, d, Jϭ8.6 Hz), 7.24 (2H, d, Jϭ8.6 Hz), 7.80—
(1H, m), 5.02 (1H, t, Jϭ5.2 Hz), 5.34 (1H, d, Jϭ8.4 Hz), 6.62—6.95 (3H, 8.00 (4H, m). Anal. Calcd for C27H31N5O8·3H2O: C, 53.37; H, 6.14; N,
m).
Methyl 2-[(2S)-1-[(2S)-3-(4-Allyloxyphenyl)-2-[(tert-butoxycarbonyl)-
11.53. Found: C, 53.15; H, 6.14; N, 11.36.
General Synthetic Procedure (Method B). 2-[(3S)-4-[(2S)-2-(4-Amidi-
amino]propanoyl]-4-[2-(tert-butoxy)-2-oxoethyl]-3-oxopiperazinyl]acetate nobenzoylamino)-3-(4-nitrophenyl)propanoyl]-3-(2-methoxy-2-ox-
(3o): A colorless oil (72%). IR (KBr) cmϪ1: 2978, 2934, 1741, 1707, 1654,
oethyl)-2-oxopiperazinyl]acetic Acid (4w) To a solution of 3w (1.60 g,
1510, 1437, 1366, 1242, 1157. 1H-NMR (CDCl3) d: 1.43 (9H, s), 1.45 (9H, 2.77 mmol) in toluene (8.0 ml) was added trifluoroacetic acid (8.0 ml) at
s), 2.38—2.63 (1H, m), 2.65—3.30 (5H, m), 3.65 (3H, s), 3.45—3.82 (2H, room temperature. After being stirred for 1 h, the mixture was concentrated
m), 3.86 (1H, d, Jϭ18.0 Hz), 4.00 (1H, d, Jϭ18.0 Hz), 4.51 (2H, dt, Jϭ5.2,
1.5 Hz), 4.63-4.83 (1H, m), 4.99 (1H, t, Jϭ5.2 Hz), 5.22—5.48 (3H, m), (15 ml). To the solution were added NaHCO3 (0.93 g, 11.1 mmol) and 4-
5.90—6.18 (1H, m), 6.84 (2H, d, Jϭ8.6 Hz), 7.11 (2H, d, Jϭ8.6 Hz). amidinobenzoylchloride hydrochloride (0.79 g, 3.60 mmol) at room tempera-
Methyl 2-[(2S)-1-[(2S)-2-[(tert-Butoxycarbonyl)amino]-3-[4-(2-propyny- ture, and the mixture was stirred for 30 min. Then, the mixture was adjusted
in vacuo, and the resulting oil was dissolved in H2O (30 ml) and 1,4-dioxane
loxy)phenyl]propanoyl]-4-[2-(tert-butoxy)-2-oxoethyl]-3-oxopiperazinyl]ac-
to pH 2 with 1 N HCl and concentrated in vacuo. The residue was purified by
etate (3p): A colorless oil (75%). IR (KBr) cmϪ1: 2980, 2932, 1741, 1708, means of CHP-20 column chromatography (gradient elution: H2O to 25%
1651, 1510, 1442, 1368, 1220, 1156. 1H-NMR (CDCl3) d: 1.43 (9H, s), 1.45 aqueous MeCN) to give 4w (1.12 g, 68%) as a colorless crystalline powder