Zhao et al.
was stirred for 10 min, a solution of triethylamine (0.42 mL,
2.97 mmol) and 5a (1.47 g, 2.97 mmol) in DMF (20 mL) was
added dropwise. Stirring was continued at 0 °C for 4 h and
then at room temperature for 48 h. The solvent was removed
under reduced pressure and the resulting residue was tritu-
rated with dichloromethane (100 mL). The organic phase was
washed base free and dried over Na2SO4. After the solvent was
removed, the crude product was chromatographed (CH2Cl2/
for the preparation of 4. Mp 98-99 °C. [R]20 18.0 (c 0.91,
D
1
CHCl3). H NMR (CDCl3) δ 8.27 (s, 2 H), 7.31-7.28 (m, 5 H),
6.84 (d, J ) 7.2 Hz, 1 H), 5.05 (s, br, 3 H), 4.52-4.36 (m, 3 H),
3.73 (t, J ) 7.2 Hz, 2 H), 3.22 (s, br, 2 H), 1.69-1.52 (m, 4 H),
1.46 (s, 9 H), 1.33-1.26 (m, 12 H), 0.87 (t, J ) 6.3 Hz, 3 H).
MS (MALDI-tof) m/z 713 [M
37H46N4O9: C, 64.32; H, 6.72; N, 8.11. Found: C, 64.01; H,
6.81; N, 7.98.
+
Na]+. Anal. Calcd for
C
MeOH 20:1) to afford 7 as a white solid (2.60 g, 86%). Mp 149-
Com p ou n d 13 was prepared quantitatively from 12 ac-
cording to the procedure described for 5a , and used directly
for the next step without further purification. This compound
is unstable in the air.
Com p ou n d 10b. According to the procedure described for
the preparation of 4, 10a reacted with 13 to afford the
1
150 °C. [R]20 10.4 (c 1.03, CHCl3). H NMR (CDCl3) δ 7.96-
D
7.92 (m, 2 H), 7.82-7.78 (m, 2 H), 7.46-7.38 (m, 4 H), 7.36-
7.27 (m, 7 H), 6.85-6.71 (m, 5 H), 5.21 (s, br, 1 H), 5.06 (s, 2
H), 4.67-4.53 (m, 6 H), 4.12-4.07 (m, 4 H), 3.75 (s, 3 H), 3.37-
3.30 (m, 2 H), 3.19-3.14 (m, 2 H), 1.95-1.87 (m, 8 H), 1.75-
1.26 (m, 24 H), 0.90 (t, J ) 6.9 Hz, 6 H). MS (MALDI-tof) m/z
1041 [M + Na]+. Anal. Calcd for C59H78N4O11: C, 69.51; H,
7.73; N, 5.49. Found: C, 69.35; H, 8.16; N, 5.36.
Com p ou n d 5b was prepared quantitatively as a salt of
hydrochloric acid from 7 according to the procedure described
for 5a , and used directly for the next steps without further
purification.
corresponding dipeptide in 64% yield. White solid. Mp >213
1
°C dec. [R]20 9.81 (c 1.06, CHCl3). H NMR (CDCl3) δ 8.22 (s,
D
2 H), 8.18 (s, 2 H), 7.72 (d, J ) 7.8 Hz, 1 H), 7.13 (s, br, 1 H),
7.11 (s, br, 1 H), 4.57-4.39 (m, 6 H), 3.72 (t, J ) 7.2 Hz, 4 H),
3.41 (s, br, 1 H), 3.09 (s, br, 1 H), 1.84-1.59 (m, 11 H), 1.42 (s,
9 H), 1.31-1.25 (m, 20 H), 0.87-0.83 (m, 12 H). MS (MALDI-
tof) m/z 1061 [M + Na]+. Anal. Calcd for C55H71N7O13: C, 63.62;
H, 6.91; N, 9.44. Found: C, 63.43; H, 6.81; N, 9.18. A solution
of the above peptide (0.50 g, 0.72 mmol) in dichloromethane
(10 mL)-trifluoroacetic acid (5 mL) was stirred at room
temperature until the starting material was consumed (9 h).
The solvent was removed under reduced pressure and the
resulting residue was washed acid free with water, dried, and
subjected to column chromatography (CH2Cl2/MeOH 10:1) to
Com p ou n d 5c. A tripeptide was first prepared as a white
solid (68%) from the reaction of 5b and 12 according to the
procedure described for preparing compound 7. Mp 196-198
1
°C. [R]20 9.76 (c 0.84, CH2Cl2/MeOH 9:1). H NMR (CDCl3) δ
D
7.94-7.90 (m, 3 H), 7.79 (t, J ) 8.4 Hz, 3 H), 7.52-7.28 (m,
14 H), 7.02 (br, 2 H), 6.82-6.69 (m, 6 H), 5.24 (s, br, 1 H),
5.04 (s, 2 H), 4.63-4.52 (m, 9 H), 4.10-4.00 (m, 6 H), 3.70 (s,
3 H), 3.47-3.20 (br, 4 H), 1.92-1.26 (m, 48 H), 0.89 (t, J ) 6.3
Hz, 9H). MS (MALDI-tof) m/z 1468 [M + Na]+. Anal. Calcd
for C84H112N6O15: C, 69.77; H, 7.82; N, 5.81. Found: C, 69.75;
H, 7.73; N, 5.64. 5c was prepared quantitatively from the
peptide according to the procedure described for 5a , and used
directly for the next steps without further purification.
afford 10b (0.36 g, 74%) as a white solid. Mp 236-238 °C. [R]20
D
-7.56 (c 0.82, DMF). 1H NMR (DMSO-d6) δ 8.60 (d, J ) 7.8
Hz, 1 H), 8.45 (d, J ) 8.4 Hz, 1 H), 8.24 (s, 4 H), 8.00 (t, J )
5.7 Hz, 1 H), 4.35-4.22 (m, 6 H), 3.62 (t, J ) 7.2 Hz, 4 H),
3.08 (m, 2 H), 1.73-1.25 (m, 31 H), 0.91-0.84 (m, 12 H). MS
(ESI) m/z 981 [M]+. Anal. Calcd for C51H63N7O13: C, 62.36; H,
6.48; N, 9.98. Found: C, 62.40; H, 6.75; N, 9.54.
Com p ou n d 8. A solution of 1,2,4,5-benzenetetracarboxylic
anhydride (13.2 g, 20.0 mmol), glycine (4.50 g, 20.0 mmol), and
n-octylamine (9.90 mL, 60.0 mmol) in DMF (150 mL) was
stirred at 120 °C for 4 h. Upon cooling to room temperature,
the resulting solid was filtered off. Water (300 mL) was added
to the filtrate and the precipitate formed was filtered, washed
with water (30 mL), and then triturated with dichloromethane
(20 mL). The solid was filtered again, washed with acetone
(20 mL), and dried in vacuo to give 8 as a white solid (3.65 g,
16%). Mp 246-248 °C. 1H NMR (DMSO-d6) δ 13.39 (s, br, 1
H), 8.27 (s, 2 H), 4.39 (s, 2 H), 3.61 (t, J ) 6.9 Hz, 2 H), 1.62
(t, J ) 6.0 Hz, 2 H), 1.28-1.24 (m, 10 H), 0.85 (t, J ) 6.3 Hz,
3 H). MS (EI) m/z 386 [M]+. Anal. Calcd for C20H22N2O6: C,
62.16; H, 5.75; N, 7.25. Found: C, 62.19; H, 5.82; N, 7.12.
Com p ou n d 14 was prepared as a white solid (78%) from
12 according to the procedure described for the preparation
1
of 10b. Mp 146-148 °C. [R]20 12.9 (c 0.98, CHCl3). H NMR
D
(DMSO-d6) δ 8.61 (t, J ) 7.8 Hz, 1 H), 8.24 (s, 2 H), 7.40-7.29
(m, 5 H), 5.00 (s, 2 H), 4.32 (s, 2 H), 4.20 (m, 1 H), 3.61 (t, J )
6.6 Hz, 2 H), 3.00 (s, br, 2 H), 1.80-1.42 (m, 6 H), 1.39-1.24
(m, 10 H), 0.82 (t, J ) 6.6 Hz, 3 H). MS (ESI) m/z 657 [M +
Na]+. Anal. Calcd for C33H38N4O9: C, 62.44; H, 6.05; N, 8.83.
Found: C, 62.59; H, 6.01; N, 8.67.
Com p ou n d 15. Compound 13 reacted with 14 to afforded
the corresponding dipeptide as a white solid (74%) according
to the procedure as described for the preparation of 22. Mp
1
196 °C dec. [R]20 5.0 (c 1.08, CHCl3). H NMR (CDCl3) δ 8.24
D
(s, 4 H), 7.52 (d, J ) 7.8 Hz, 1 H), 7.31-7.25 (m, 5 H), 7.06 (d,
J ) 8.1 Hz, 1 H), 6.84 (t, J ) 5.4 Hz, 1 H), 5.26 (t, J ) 6.0 Hz,
1 H), 4.95 (s, 2 H), 4.53-4.36 (m, 6 H), 3.71 (t, J ) 7.5 Hz, 4
H), 3.34-3.14 (m, 4 H), 1.87 (m, 2 H), 1.74-1.50 (m, 10 H),
1.45 (s, 9 H), 1.32-1.26 (m, 20 H), 0.83 (t, J ) 6.6 Hz, 6 H).
Com p ou n d 10a . According to the reaction conditions
described for the preparation of 4, acid 8 reacted with amine
9 to afford the corresponding amide as a white solid (84%).
Mp 80-82 °C. [R]20 1.9 (c 0.93, CHCl3). 1H NMR (CDCl3) δ
D
8.29 (s, 2 H), 7.39-7.30 (m, 5 H), 6.29 (s, br, 1 H), 5.21 (s, 2
H), 4.73-4.66 (m, 1 H), 4.43 (d, J ) 7.8 Hz, 2 H), 3.74 (t, J )
6.6 Hz, 2 H), 1.70-1.54 (m, 5 H), 1.33-1.23 (m, 10 H), 0.93-
0.85 (m, 9 H). MS (EI) m/z 590 [M + H]+. Anal. Calcd for
MS (MALDI-tof) m/z 1172 [M]+. Anal. Calcd for C62H76N8O15
:
C, 63.46; H, 6.54; N, 9.55. Found: C, 63.26; H, 6.49; N, 9.37.
Compound 15 was prepared quantitatively from the peptide
according to the procedure as described for the preparation of
compound 10a and used for the next step without further
purification.
C
33H39N3O7: C, 67.21; H, 6.68; N, 7.13. Found: C, 67.26; H,
6.50; N, 7.05. A solution of the amide (3.60 g, 6.10 mmol) in
dichloromethane (30 mL)/methanol (30 mL) was stirred for 7
h at room temperature in the presence of Pd/C (10%, 0.40 g)
at 1 atm of hydrogen gas. The catalyst was then filtered off
and the solvent removed. The crude product was subjected to
flash chromatography (CH2Cl2/MeOH 10:1), to give 10a as a
Com p ou n d 10c. A tripeptide intermediate was first pre-
pared in 66% yield from the reaction of compounds 10a and
15 according to the procedure described for 7. Mp 260 °C dec.
[R]20 10.8 (c 0.51, CH2Cl2 (10% MeOH)). 1H NMR (DMSO-d6)
D
white solid (2.98 g, 98%). Mp 164-166 °C. [R]20 -2.0 (c 0.93,
δ 8.58-8.42 (m, 3 H), 8.22 (s, 6 H), 8.00 (s, br, 2 H), 4.40-4.05
(m, 9 H), 3.59 (s, br, 6 H), 3.05 (s, br, 4 H), 1.60-1.21 (m, 56
H), 0.73 (m, 15 H). MS (MALDI-tof) m/z 1519 [M]+, 1544 [M
+ Na]+. HRMS-MS (MALDI-tof) m/z 1520.7277. Calcd for
D
1
CHCl3). H NMR (DMSO-d6) δ 12.66 (s, 1 H), 8.58 (d, J ) 8.1
Hz, 1 H), 8.24 (s, 2 H), 4.30-4.21 (m, 3 H), 3.61 (t, J ) 6.3 Hz,
2 H), 1.66-1.50 (m, 5 H), 1.28-1.24 (m, 10 H), 0.91-0.82 (m,
9
C
H). MS (EI) m/z 455 [M -
CO2]+. Anal. Calcd for
C
80H101N11O19 1520.7207. The above compound was stirred in
dichloromethane/trifluoroacetic acid (2:1) at room temperature
26H33N3O7: C, 62.50; H, 6.67; N, 8.41. Found: C, 62.79; H,
6.67; N, 8.39.
Com p ou n d 12 was prepared as a white solid (83%) from
compounds 8 and 1129 according to the procedure described
(29) Kempton, R. J .; Black, A. M.; Anstead, G. M.; Kumar, A. A.;
Blankenship, D. T.; Freisheim, J . H. J . Med. Chem. 1982, 25, 475.
278 J . Org. Chem., Vol. 69, No. 2, 2004