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then stirred for 15 min. A solution of DCC (1.12 g, 5.4 mmol) in dry CH2Cl2 (10 mL) was added to the
suspension over 10 min and the mixture was slowly warmed to room temperature and stirred for 24 h.
The mixture was evaporated in vacuo to leave a solid and then taken up in ethyl acetate (50 mL),
filtered to remove DCU (by product). The filtrate was washed with saturated aqueous NaHCO3 (2×50
mL) and brine (50 mL). The organic layer was dried (MgSO4) and evaporated in vacuo to leave a
residue and then purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1)
20
to yield title compound 9 (1.56 g, 72.5%). [α] =+16.3°(c 1.0, CHCl3); IR (KBr): 2970, 2932, 1754,
D
1
1703, 1453, 1381, 1243, 1179, 1160, 1070, 746, 703cm-1; H-NMR (400 MHz, CDCl3) δ (rotamer):
7.14~7.32 (m, 10H), 5.30~5.32 (m, 1H), 5.08~5.15 (m, 2H), 3.91~4.05 (m, 2H), 3.10~3.18 (m,
2H), 2.79, 2.78 (s, 3H, rotamer), 1.26~1.46(m, 9H); 13C-NMR (100 MHz, CDCl3) δ (rotamer): 169.05,
168.64, 155.60, 154.95, 135.20, 135.13, 134.84, 129.16, 129.06, 128.31, 128.28, 128.26, 128.19,
128.09, 128.05, 126.81, 79.83, 79.77, 73.09, 73.01, 66.86, 50.39, 49.68, 36.98, 34.93, 28.06, 27.87.
2-{2-[(2-tert-Butoxycarbonylamino-3-methylpentanoyl)methylamino]acetoxy}-3-phenylpropionic acid
benzyl ester (3).
To a solution of 9 (1.70 g, 4.0 mmol) in dry CH2Cl2 (6 mL) was added TFA (2 mL, 26.0 mmol)
dropwise at 0°C with stirring. The mixture then was slowly warmed to room temperature and stirred
for 5 h. The reaction mixture was concentrated, the residue dried under high vacuum and dissolved in
dry CH2Cl2 (10 mL). A solution of N-Boc-Ile-OH 6 (1.01 g, 4.4 mmol) in dry CH2Cl2 (10 mL) was
added in one portion followed by HATU (99%) (1.84 g, 4.8 mmol). Triethylamine (5.6 mL, 39.8 mmol)
was added to the mixture dropwise under ice cooling. Then the mixture was warmed to room
temperature slowly and stirred for 12 h. The reaction was quenched by adding saturated aqueous
NH4Cl (2mL) dropwise and evaporated in vacuo followed by dissolving in ethyl acetate (150 mL). The
mixture was washed with saturated aqueous NaHCO3 (2×100 mL) and brine (100 mL), dried
(MgSO4), filtered and evaporated in vacuo to leave a residue which was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate, 5:1) to afford tridepsipeptide 3 (1.74 g,
20
80.9%). [α] =+6.3° (c 1.0 CHCl3); IR (KBr): 3409, 3316, 2969, 1753, 1708, 1652, 1497, 1402,
D
1377, 1246, 1176, 1075, 1031, 745, 703cm-1; 1H-NMR (400 MHz, CDCl3) δ (rotamer): 7.10~7.34 (m,
10H), 5.31 (dd, 1H, J1=5.2 Hz, J2=7.6 Hz), 5.04~5.17 (m, 3H), 4.51 (br, NH), 4.53 (d, 1H, J=17.6
Hz), 3.80 (d, 1H, J=17.6 Hz), 3.16(dd, 1H, J1=5.2 Hz, J2=14.4 Hz), 3.10 (dd, 1H, J1=7.6 Hz, J2=14.4
Hz), 3.00 (s, 3H), 1.66~1.71 (m, 1H), 1.40 (s, 9H), 0.88~0.96 (m, 8H); 13C-NMR (100 MHz, CDCl3)
δ (rotamer): 173.12, 168.95, 168.38, 155.83, 135.23, 134.97, 129.33, 128.56, 128.52, 128.49, 128.42,
128.36, 127.13, 79.48, 73.43, 67.23, 54.22, 49.16, 38.03, 37.15, 36.36, 28.32, 23.91, 15.55, 11.29.
2-(2-{[2-(2-{2-[(2-tert-Butoxycarbonylamino-3-methylpentanoyl)methylamino]acetoxy}-3-phenyl-
propionylamino)-3-methylpentanoyl]methylamino}acetoxy)-3-phenylpropionic acid benzyl ester (2).
A solution of 3 (0.26 g, 0.5 mmol) in ethyl acetate (30 mL) was treated with Pd-C (5%, 0.52 g), and
the black suspension was stirred at room temperature under an atmosphere of H2 for 12 h. The catalyst
was removed by filtration, and the filtrate was concentrated in vacuo to give crude 11 (used in the next
step without further purification). To a solution of 3 (0.20 g, 0.4 mmol) in dry CH2Cl2 (2 mL) was
added TFA (0.5 mL, 6.5 mmol) dropwise at 0°C with stirring. The mixture then was slowly warmed to