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yl)amino-5-phenyl-2-pentenoate23 was prepared from
N-Boc-L-Phe by a sequence of esterification (CH3I,
KHCO3, rt, 8 h, 94%), reduction (NaBH4, LiCl, THF,
EtOH, rt, 12 h, 89%), oxidation (pyridineÆSO3, DMSO,
Et3N, ꢀ10 ꢁC to rt, 1 h), and olefination [EtO2CCH2-
PO(OEt)2, NaN(TMS)2, THF, ꢀ78 ꢁC to rt, 2 h, 84%
for two steps], and then treated with HCl in 1,4-dioxane
to remove the Boc group. The resulting amine was react-
ed with N-Boc-L-Phe in the presence of EDCI, HOBt,
and 4-methylmorpholine, by a procedure similar to that
for compound 1a, to give the desired product 17 in 82%
overall yield.
4.2.5.2. Ethyl 4-[2-(4-nitrocinnamyl)amino-1-oxo-3-
phenyl]propylamino-5-phenyl-2-pentenoate (18b). Color-
less solid; mp 247–250 ꢁC; TLC (EtOAc/hexane, 1:1)
Rf = 0.27; IR (KBr) 3291, 1711, 1637, 1533, 1421,
1259 cmꢀ1 1H NMR (DMSO-d6, 400 MHz): d 8.49
;
(1H, d, J = 8.5 Hz), 8.38 (1H, d, J = 8.5 Hz), 8.25 (2H,
d, J = 8.7 Hz), 7.80 (2H, d, J = 8.7 Hz), 7.49 (1H, d,
J = 15.8 Hz), 7.29–7.14 (10H, m), 6.88 (1H, d,
J = 15.8 Hz), 6.78 (1H, dd, J = 15.8, 5.2 Hz), 5.66 (1H,
d, J = 15.8 Hz), 4.67–4.63 (2H, m), 4.09 (2H, q,
J = 7.1 Hz), 2.96–2.65 (4H, m), 1.19 (3H, t,
J = 7.1 Hz); 13C NMR (DMSO-d6, 100 MHz): d 171.8
(C), 165.9 (C), 164.3 (C), 148.5 (C), 147.9 (C), 141.9
(C), 138.1 (C), 137.9 (CH), 137.1 (CH), 129.7 (CH),
129.5 (CH), 129.0 (CH), 128.6 (CH, 2·), 128.5 (CH,
2·), 126.8 (CH, 2·), 126.7 (CH, 2·), 126.6 (CH, 2·),
124.6 (CH, 2·), 120.1 (CH), 60.4 (CH2), 54.7 (CH),
51.4 (CH), 39.3 (CH2), 31.2 (CH2), 14.6 (CH3); FAB-
MS m/z 542.23 (M++H); HRMS calcd for
C31H32N3N3O6, 542.2291 (M++H); found, 542.2289.
Anal. calcd for C31H31N3O6: C 68.75, H 5.77, N 7.76.
Found: C 68.77, H 5.56, N 7.76.
Compound 17: white solid; mp 129–131 ꢁC; TLC
(EtOAc/hexane, 3:7) Rf = 0.27; IR (KBr) 3214, 1711,
1
1645 cmꢀ1; H NMR (CDCl3, 400 MHz): d 7.30–7.15
(8H, m), 7.05 (2H, d, J = 6.7 Hz), 6.77 (1H, dd,
J = 15.5, 4.3 Hz), 6.00 (1H, d, J = 8.1 Hz), 5.59 (1H, d,
J = 15.5 Hz), 4.99–4.87 (2H, m), 4.29–4.25 (1H, m),
4.16 (2H, q, J = 7.1 Hz), 2.99–2.97 (2H, m), 2.81 (2H,
d, J = 6.7 Hz), 1.40 (9H, s), 1.27 (3H, t, J = 7.1 Hz);
13C NMR (CDCl3, 100 MHz): d 170.6 (C), 166.0 (C),
155.3 (C), 146.2 (C), 136.4 (C), 136.0 (CH), 129.3 (CH,
2·), 129.2 (CH, 2·), 128.8 (CH, 2·), 128.6 (CH, 2·),
127.1 (CH), 126.9 (CH), 121.5 (CH), 80.3 (C), 60.4
(CH2), 56.0 (CH), 50.6 (CH), 40.4 (CH2), 38.4 (CH2),
28.2 (CH3, 3·), 14.6 (CH3); FAB-MS 467.57 (M++H);
HRMS calcd for C27H35N2O5, 467.5771 (M++H);
found, 467.5775.
4.2.5.3. Ethyl 4-{2-[4-((dimethylamino)cinnaniyl]-
amino-1-oxo-3-phenyl}propylamino-5-phenyl-2-pentenoate
(18c). Colorless solid; mp 225–227 ꢁC; TLC (EtOAc/
hexane, 1:1) Rf = 0.24; IR (KBr) 3213, 1707, 1521,
1459, 1255 cmꢀ1 1H NMR (DMSO-d6, 400 MHz): d
;
8.32 (1H, d, J = 8.2 Hz), 8.16 (1H, d, J = 8.2 Hz), 7.36
(2H, d, J = 8.6 Hz), 7.29–7.14 (11H, m), 6.79 (1H, dd,
J = 15.8, 5.1 Hz), 6.70 (2H, d, J = 8.6 Hz), 6.41 (1H, d,
J = 15.7 Hz), 5.66 (1H, d, J = 15.7 Hz), 4.65–4.60 (2H,
m), 4.09 (2H, q, J = 7.1 Hz), 2.94 (6H, s), 2.90–2.64
(4H, m), 1.18 (3H, t, J = 7.1 Hz); 13C NMR (DMSO-
d6, 100 MHz): d 171.2 (C), 166.0 (C), 165.9 (C), 151.5
(C), 148.6 (C), 139.8 (C), 138.2 (C), 129.7 (CH, 2·),
129.5 (CH, 2·), 129.3 (CH, 2·), 128.6 (CH, 2·), 128.5
(CH, 2·), 126.7 (CH, 2·), 122.7 (CH), 126.8 (CH, 2·),
120.6 (CH), 116.8 (CH), 112.4 (CH), 60.4 (CH2), 54.6
(CH), 51.4 (CH), 40.5 (CH2, 2·), 38.4 (CH2, 2·), 14.6
(CH3); FAB-MS m/z 540.06 (M++H); HRMS calcd for
C33H38N3O4, 540.0641 (M++H); found, 540.0639. Anal.
calcd for C33H37N3O4: C 73.44, H 6.91, N 7.79. Found:
C 73.47, H 6.93, N 7.78.
4.2.5. Dipeptidomimetic a,b-unsaturated esters 18a–e. The
Phe-Phe dipeptide a,b-unsaturated ester 17 (235 mg,
0.5 mmol) was treated with HCl in 1,4-dioxane, by a
procedure similar to that for 14, to give the corre-
sponding aminium salt, which was then subjected to
coupling reactions with appropriate (substituted) cin-
namic acids (0.55 mmol) in DMF (10 mL) by promo-
tion of HBTU (0.6 mmol) and i-Pr2NEt (2.5 mmol),
by a procedure similar to that for 1a, to afford the
dipeptide conjugated esters 18a–e (69–83% yields).
4.2.5.1. Ethyl 5-phenyl-4-[2-(4-phenylcinnamyl)amino-
1-oxo-3-phenyl]propylamino-2-pentenoate (18a). Color-
less solid; mp 220–223 ꢁC; TLC (CH3OH/CH2Cl2,
1:19) Rf = 0.45; IR (KBr) 3211, 1709, 1629, 1521,
1259 cmꢀ1
;
1H NMR (DMSO-d6, 400 MHz): d 8.36
4.2.5.4. Ethyl 4-[2-(2,4-dimethoxycinnamyl)amino-1-
oxo-3-phenyl]propylamino-5-phenyl-2-pentenoate (18d).
Colorless solid; mp 203–205 ꢁC; TLC (EtOAc/hexane,
1:1) Rf = 0.27; IR (KBr) 3276, 2932, 1723, 1648, 1536,
(2H, d, J = 8.2 Hz), 7.73–7.69 (4H, m), 7.63 (2H, d,
J = 8.2 Hz), 7.46–7.42 (4H, m), 7.22–7.15 (10H, m),
6.78 (1H, dd, J = 15.7, 5.2 Hz), 6.75 (1H, d,
J = 15.7 Hz), 5.67 (1H, d, J = 15.7 Hz), 4.71–4.65 (2H,
m), 4.09 (2H, q, J = 7.1 Hz), 2.97–2.77 (4H, m), 1.19
(3H, t, J = 7.1 Hz); 13C NMR (DMSO-d6, 100 MHz):
d 171.0 (C), 165.9 (C), 165.1 (C), 148.5 (C), 141.4 (C),
139.8 (C), 138.9 (C), 138.1 (C), 138.0 (CH), 134.4
(CH), 129.7 (CH, 2·), 129.6 (CH, 2·), 129.5 (CH, 2·),
128.6 (CH, 2·), 128.5 (CH, 2·), 128.3 (CH, 2·), 127.6
(CH, 2·), 127.1 (CH, 2·), 126.8 (CH, 2·), 126.7 (CH),
122.4 (CH), 120.7 (CH), 60.4 (CH2), 54.9 (CH), 51.4
(CH), 38.4 (CH2, 2·), 14.6 (CH3); FAB-MS m/z 573.28
(M++H); HRMS calcd for C37H37N2O4, 573.2753
(M++H); found, 573.2755. Anal. calcd for
C37H36N2O4: C 77.60, H 6.34, N 4.89. Found: C
77.58, H 6.34, N 4.90.
1
1270, 1033 cmꢀ1; H NMR (CDCl3, 400 MHz): d 7.77
(1H, d, J = 15.7 Hz), 7.40 (2H, d, J = 8.5 Hz), 7.30–
7.14 (7H, m), 7.06 (2H, d, J = 8.5 Hz), 6.80 (1H, dd,
J = 15.7, 5.2 Hz), 6.50 (1H, d, J = 8.5 Hz), 6.47 (1H,
s), 6.38 (1H, d, J = 15.7 Hz), 6.37 (1H, br s), 6.05 (1H,
br s), 5.61 (1H, d, J = 15.7 Hz), 4.85–4.76 (2H, m),
4.18 (2H, q, J = 7.0 Hz), 3.88 (3H, s), 3.85 (3H, s),
3.12–3.06 (2H, m), 2.85–2.76 (2H, m), 1.30 (3H, t,
J = 7.0 Hz); 13C NMR (CDCl3, 100 MHz): d 170.6
(C), 166.9 (C), 166.1 (C), 162.4 (C), 159.8 (C), 146.3
(CH), 137.3 (C), 136.5 (C), 136.3 (CH), 130.7 (CH),
129.3 (CH), 129.2 (CH, 2·), 128.7 (CH, 2·), 128.5
(CH, 2·), 127.0 (CH, 2·), 126.7 (CH), 121.4 (CH),
118.2 (C), 116.6 (CH), 105.0 (CH), 98.4 (CH), 60.4