5846
E. W. Yue et al. / Bioorg. Med. Chem. 14 (2006) 5833–5849
169.2, 157.7, 153.6, 139.4, 137.6, 129.9, 129.5, 129.0,
128.0, 127.8, 127.3, 126.2, 125.8, 123.2, 113.4, 54.8,
53.7, 53.6, 41.0, 38.2, 37.7, 37.1, 28.4, 28.3, 20.6,
13.5; HRMS calcd for C35H40N4O7SNa (M+Na)+:
m/z = 683.2535.
2.97 (dd, J = 14.2, 5.9 Hz, 1H), 2.84 (dd, J = 14.2,
7.8 Hz, 1H), 1.66 (s, 9H), 1.42–1.34 (m, 2H), 1.33–
1.25 (m, 2H), 1.22–1.16 (m, 2H), 0.87 (t, J = 7.3 Hz,
3H); LC–MS calcd for C39H51N4O7S (M+H)+:
m/z = 719.3.
4.30. (2S)-3-[4-(2-tert-Butyl-1,1-dioxido-3-oxoisothiaz-
olidin-5-yl)phenyl]-2-[((2S)-2-{[(4-methoxyphenyl)ace-
tyl]amino}-3-phenylpropanoyl)amino]-N-pentylpropana-
mide (39)
Compound 41 (peak 2): 1H NMR (500 MHz,
CDCl3): d 7.29 (d, J = 8.3 Hz, 2H), 7.23–7.17 (m,
5H), 6.98–6.95 (m, 4H), 6.83 (d, J = 8.3 Hz, 2H),
6.40 (d, J = 8.3 Hz, 1H), 5.84 (dd, J = 5.9, 5.4 Hz,
1H), 5.78 (d, J = 6.8 Hz, 1 H), 4.75 (dd, J = 9.3,
8.8 Hz, 1H), 4.58 (dd, J = 15.1, 6.8 Hz, 1H), 4.50
(dd, J = 14.2, 6.3 Hz, 1H), 3.82 (s, 3H), 3.41 (d,
J = 16.1 Hz, 1H), 3.37 (d, J = 15.6 Hz, 1H), 3.23–
3.14 (m, 2H), 3.14–3.09 (m, 2H), 3.04 (dd, J = 6.8,
2.9 Hz, 2H), 2.97 (dd, J = 14.2, 5.9 Hz, 1H), 2.85
(dd, J = 14.2, 7.8 Hz, 1H), 1.65 (s, 9H), 1.40–1.34
(m, 2H), 1.31–1.25 (m, 2H), 1.23–1.17 (m, 2H), 0.88
(t, J = 7.3 Hz, 3H); LC–MS calcd for C39H51N4O7S
(M+H)+: m/z = 719.3.
Compound 39 was prepared from 24 according to the
procedure of 11a in 37% yield. 1H NMR (500 MHz,
CDCl3): d 7.29 (d, J = 7.8 Hz, 2H), 7.23–7.17 (m, 5H),
6.98–6.95 (m, 4H), 6.85–6.82 (m, 2H), 6.43 (dd,
J = 8.3, 4.9 Hz, 1H), 5.85–5.81 (m, 1H), 5.79–5.78 (m,
1H), 4.77–4.73 (m, 1H), 4.61–4.57 (m, 1H), 4.52–4.48
(m, 1 H), 3.82 (s, 3H), 3.43–3.35 (m, 2H), 3.23–3.18
(m, 2H), 3.16–3.09 (m, 2H), 3.06–3.02 (m, 2H), 3.00–
2.95 (m, 1H), 2.88–2.82 (m, 1H), 1.66 (s, 9H), 1.40–
1.33 (m, 2H), 1.32–1.25 (m, 2H), 1.23–1.15 (m, 2H),
0.88 (t, J = 7.1 Hz, 3H); LC–MS calcd for C39H51N4O7S
(M+H)+: m/z = 719.2.
Compound 43 was prepared from 40 (peak 1) accord-
ing to the procedure of 25 in 12% yield. Compound
43: 1H NMR (500 MHz, DMSO-d6 + 5 lL TFA-d,
30 ꢁC): d 8.08 (d, 2H), 7.79 (t, J = 5.4 Hz, 1H), 7.37
(d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 7.19
(m, 2 H), 7.16 (m, 1H), 7.15 (m, 2H), 6.97 (d,
J = 8.7 Hz, 2H), 6.75 (d, J = 8.4 Hz, 2H), 5.26 (dd,
J = 9.1, 9.1 Hz, 1 H), 4.47 (m, 1H), 4.44 (m, 1H),
3.69 (s, 3H), 3.38 (dd, J = 17.3, 9.8 Hz, 1H), 3.32 (d,
J = 14.4 Hz, 1H), 3.24 (d, J = 14.4 Hz, 1H), 3.20 (dd,
J = 17.6, 8.2 Hz, 1H), 2.99 (m, 2H), 2.98 (m, 1H),
2.93 (m, 1H), 2.84 (dd, J = 13.9, 8.3 Hz, 1H), 2.71
(dd, J = 14.0, 9.1 Hz, 1H), 1.32 (m, 2H), 1.24 (m,
2H), 1.18 (m, 2H), 0.84 (t, J = 7.1 Hz, 3H); 13C
NMR (125 MHz, DMSO-d6 + 5 lL TFA-d, 30 ꢁC): d
170.7, 170.2, 170.0, 168.3, 157.7, 138.9, 137.6, 129.8,
129.5, 129.0, 128.9, 127.9, 127.8, 126.9, 126.1, 113.4,
64.0, 54.8, 53.7, 53.5, 41.0, 38.3, 37.2, 37.1, 37.0,
28.4, 28.2, 21.5, 13.9; HRMS calcd for C35H42N4O7S-
Na (M+Na)+: m/z = 685.2686.
4.31. (2S)-3-[4-(1,1-Dioxido-3-oxoisothiazolidin-5-
yl)phenyl]-2-[((2S)-2-{[(4-methoxyphenyl)acetyl]amino}-
3-phenylpropanoyl)amino]-N-pentylpropanamide (42)
Compound 42 was prepared from 39 according to the
procedure of 25 in 39% yield. 1H NMR (500 MHz,
DMSO-d6, 30 ꢁC): d 8.08 (d, J = 8.2 Hz, 1H), 8.01 (d,
J = 8.2 Hz, 1H), 7.76 (t, J = 5.7 Hz, 1H), 7.22 (m, 2H),
7.21 (m, 2H), 7.16 (m, 3H), 7.15 (m, 2H), 6.97 (d,
J = 8.8 Hz, 2H), 6.75 (d, J = 8.6 Hz, 2H), 4.52 (dd,
J = 8.1, 8.1 Hz, 1H), 4.47 (m, 1H), 4.42 (m, 1H), 3.69
(s, 3H), 3.32 (d, J = 14.1 Hz, 1H), 3.25 (d, J = 14.1 Hz,
1H), 2.99 (m, 2H), 2.96 (m, 1H), 2.94 (m, 1H), 2.92
(m, 1H), 2.91 (m, 1H), 2.81 (dd, J = 13.8, 7.9 Hz, 1H),
2.71 (dd, J = 13.8, 10.0 Hz, 1H), 1.32 (m, 2H), 1.24
(m, 2H), 1.18 (m, 2H), 0.84 (t, J = 7.1 Hz, 3H); 13C
NMR (125 MHz, DMSO-d6, 30 ꢁC): d 173.3, 170.7,
170.3, 170.1, 157.7, 137.6, 137.0, 132.2, 129.8, 129.1,
128.9, 128.3, 128.2, 127.9, 126.1, 113.5, 64.5, 54.9,
53.7, 53.7, 41.4, 41.0, 38.3, 37.3, 37.0, 28.4, 28.2, 21.5,
13.8; HRMS calcd for C35H42N4O7SNa (M+Na)+:
m/z = 685.2659.
Compound 44 was prepared from 41 (peak 2)
according to the procedure of 25 in 21% yield. Com-
pound 44: 1H NMR (500 MHz, DMSO-d6 + 5 lL
TFA-d, 30 ꢁC): d 8.09 (m, 2H), 7.78 (t, J = 5.7 Hz,
1H), 7.36 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.0 Hz,
2H), 7.19 (m, 2 H), 7.16 (m, 1H), 7.15 (m, 2H),
6.98 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.5 Hz, 2H),
5.26 (dd, J = 9.4, 8.4 Hz, 1 H), 4.46 (m, 1H), 4.43
(m, 1H), 3.69 (s, 3H), 3.39 (dd, J = 17.0, 9.6 Hz,
1H), 3.32 (d, J = 14.5 Hz, 1H), 3.24 (d, J = 14.5 Hz,
1H), 3.20 (dd, J = 17.1, 8.0 Hz, 1H), 2.99 (m, 2H),
2.98 (m, 1H), 2.94 (dd, J = 14.4, 4.3 Hz, 1H), 2.84
(dd, J = 13.8, 8.3 Hz, 1H), 2.72 (dd, J = 14.0,
9.9 Hz, 1H), 1.31 (m, 2H), 1.24 (m, 2H), 1.18 (m,
2H), 0.84 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
4.32. Separation of diastereoisomeric mixture of 39
The diastereoisomeric mixture 39 was separated by
normal phase chiral HPLC (ChiralCel OD-H
[20 · 250 mm, 5 lm], 30% EtOH/70% hexane, 12 mL/
min, ambient temperature) to yield 40 (peak 1)
(21 mg, 28%) and 41 (peak 2) (27 mg, 36%). Com-
pound 40 (peak 1): 1H NMR (500 MHz, CDCl3): d
7.29 (d, J = 7.8 Hz, 2H), 7.22–7.17 (m, 5H), 6.98–
6.95 (m, 4H), 6.83 (d, J = 8.8 Hz, 2H), 6.50 (d,
J = 8.3 Hz, 1H), 5.90 (dd, J = 5.9, 5.4 Hz, 1H), 5.83
(d, J = 6.8 Hz, 1H), 4.75 (dd, J = 9.3, 8.8 Hz, 1H),
4.59 (dd, J = 15.1, 7.3 Hz, 1H), 4.51 (dd, J = 13.7,
6.3 Hz, 1H), 3.82 (s, 3H), 3.41 (d, J = 16.1 Hz, 1H),
3.37 (d, J = 16.1 Hz, 1H), 3.23–3.15 (m, 2H), 3.11
(dd, J = 15.1, 9.3 Hz, 2H), 3.04 (d, J = 6.8 Hz, 2H),
DMSO-d6 + 5 lL TFA-d, 30 ꢁC):
d 170.8, 170.2,
170.1, 168.4, 157.7, 138.9, 137.6, 129.8, 129.5, 129.0,
128.9, 128.0, 127.8, 126.9, 126.1, 113.3, 64.1, 54.8,
53.7, 53.5, 41.0, 38.2, 37.3, 37.1, 37.0, 28.4, 28.3,
21.5, 13.7; HRMS calcd for C35H42N4O7SNa
(M+Na)+: m/z = 685.2654.