T. Kambe et al. / Bioorg. Med. Chem. 20 (2012) 3502–3522
3515
preparation of 13a from 12 as a pale yellow solid (74 mg, 42% in two
5.1.51. 4-{[2-((2R)-2-{(1E,3S)-4-[3-(1,3-Dihydro-2H-isoindol-2-
steps). 1H NMR (300 MHz, CDCl3): d 8.03 (m, 1H), 7.96–7.82 (m, 3H),
7.73 (m, J = 8.5, 1.6 Hz, 1H), 7.67–7.37 (m, 5H), 7.30–7.17 (m, 1H),
5.81 (dd, J = 15.5, 5.9 Hz, 1H), 5.61–5.43 (m, 1H), 4.54–4.43 (m,
1H), 4.19–3.99 (m, 4H), 3.68–3.42 (m, 4H), 3.00–2.84 (m, 3H),
2.63–2.43 (m, 4H), 2.40–2.11 (m, 5H), 2.00 (m, 1H), 1.92–1.76 (m,
1H), 1.44–1.27 (m, 2H), 0.91 (t, J = 7.40 Hz, 3H).
yl)phenyl]-3-hydroxybut-1-enyl}-5-oxopyrrolidin-1-yl)ethyl]
sulfanyl}butanoic acid (3e)
Compound 3e was prepared from 13d according to the same
procedure as described for the preparation of 3b from 13a as col-
orless amorphous (39 mg, 65%). IR (film): 3389, 3043, 2925, 2861,
1913, 1723, 1714, 1660, 1605, 1580, 1497, 1469, 1455, 1418,
1374, 1305, 1260, 1225, 1163, 1096, 1036, 976, 910, 850, 775,
733, 699, 664, 647, 571, 462 cmꢀ1 1H NMR (300 MHz, CDCl3): d
;
5.1.47. 4-{[2-((2R)-2-{(1E,3S)-3-Hydroxy-4-[3-(2-naphthyl)
phenyl]but-1-enyl}-5-oxopyrrolidin-1-yl)ethyl]sulfanyl}
butanoic acid (3c)
7.33 (m, 6H), 6.57 (m, 2H), 5.81 (dd, J = 15.7, 5.5 Hz, 1H), 5.55
(dd, J = 15.7, 8.8 Hz, 1H), 4.78 (m, 4H), 4.49 (m, 1H), 4.12 (m,
1H), 3.59 (m, 1H), 2.72 (m, 13H), 1.79 (m, 3H); MS (FAB) m/z:
495 (M+H)+; HRMS-FAB (m/z): [M+H]+ calcd for C28H35N2O4S,
495.2318; found, 495.2330.
Compound 3c was prepared from 13b according to the same
procedure as described for the preparation of 3b from 13a as col-
orless amorphous (45 mg, 65%). IR (film): 3422, 3054, 2922, 1728,
1658, 1488, 1444, 1418, 1370, 1268, 1238, 1158, 1099, 1030, 973,
891, 859, 822, 791, 749, 706, 661, 625, 607, 570 cmꢀ1 1H NMR
;
5.1.52. Butyl 4-({2-[(2R)-2-{(1E,3S)-4-[3-(1H-indol-5-yl)phenyl]-
3-hydroxy-1-buten-1-yl}-5-oxo-1-pyrrolidinyl]ethyl}thio)
butanoate (13e)
(300 MHz, CDCl3): d 8.03 (s, 1H), 7.94–7.82 (m, 3H), 7.73 (dd,
J = 8.7, 2.1 Hz, 1H), 7.64–7.57 (m, 1H), 7.57–7.40 (m, 4H), 7.21
(d, J = 7.5 Hz, 1H), 5.79 (dd, J = 15.3, 6.0 Hz, 1H), 5.49 (ddd,
J = 15.3, 8.7, 1.2 Hz, 1H), 4.54–4.44 (m, 1H), 4.14–4.04 (m, 1H),
3.66–3.52 (m, 1H), 3.00–2.85 (m, 3H), 2.60–2.10 (m, 9H), 1.90–
1.60 (m, 3H); MS (FAB) m/z: 504 (M+H)+; HRMS-FAB (m/z):
[M+H]+ calcd for C30H34NO4S, 504.2209; found, 504.2199.
Compound 13e was prepared from 12 using the phosphonate
5g instead of 5b according to the same procedure as described
for the preparation of 13a from 12 as a colorless oil (74 mg,
46% in two steps). 1H NMR (300 MHz, CDCl3): d 8.42–8.21 (m,
1H), 7.84 (s, 1H), 7.61–7.21 (m, 6H), 7.19–7.10 (m, 1H), 6.67–
6.52 (m, 1H), 5.78 (dd, J = 15.5, 5.9 Hz, 1H), 5.48 (dd, J = 15.4,
8.8 Hz, 1H), 4.53–4.37 (m, 1H), 4.20–3.99 (m, 3H), 3.65–3.47 (m,
1H), 3.01–2.77 (m, 3H), 2.66–2.07 (m, 9H), 2.02–1.19 (m, 8H),
0.92 (t, J = 7.3 Hz, 3H).
5.1.48. Butyl 4-({2-[(2R)-2-{(1E,3S)-4-(3-pyridin-2-ylphenyl)-3-
hydroxy-1-buten-1-yl}-5-oxo-1-
pyrrolidinyl]ethyl}thio)butanoate (13c)
Compound 13c was prepared from 12 using the phosphonate 5r
instead of 5b according to the same procedure as described for the
preparation of 13a from 12 as a pale yellow solid (105 mg, 48% in
two steps). 1H NMR (300 MHz, CDCl3): d 8.69 (d, J = 4.8 Hz, 1H),
7.92–7.70 (m, 4H), 7.41 (t, J = 7.5 Hz, 1H), 7.38–7.20 (m, 2H), 5.79
(dd, J = 15.0, 5.7 Hz, 1H), 5.51 (dd, J = 15.0, 8.4 Hz, 1H), 4.48 (m,
1H), 4.18–4.00 (m, 3H), 3.60 (m, 1H), 3.00–2.83 (m, 3H), 2.63–2.10
(m, 10H), 2.03 (br s, 1H), 1.87 (m, 2H), 1.78–1.50 (m, 3H), 1.38 (m,
2H), 0.92 (t, J = 7.5 Hz, 3H).
5.1.53. 4-{[2-((2R)-2-{(1E,3S)-3-Hydroxy-4-[3-(1H-indol-5-
yl)phenyl]but-1-enyl}-5-oxopyrrolidin-1-yl)ethyl]sulfanyl}
butanoic acid (3f)
Compound 3f was prepared from 13e according to the same
procedure as described for the preparation of 3b from 13a as col-
orless amorphous (40 mg, 60%). IR (film): 3410, 3032, 2925, 1714,
1647, 1604, 1458, 1419, 1348, 1310, 1247, 1161, 1097, 1066,
1042, 1026, 975, 894, 882, 792, 768, 732, 704, 671, 665, 643,
610, 600, 571, 564, 540 cmꢀ1 1H NMR (300 MHz, CDCl3): d 8.35
;
(br s, 1H), 7.84 (m, 1H), 7.46–7.40 (m, 4H), 7.25 (m, 2H), 7.14
(m, 1H), 6.60 (m, 1H), 5.78 (dd, J = 15.4, 5.8 Hz, 1H), 5.46 (ddd,
J = 15.4, 8.8, 1.1 Hz, 1H), 4.48 (m, 1H), 4.07 (m, 1H), 3.54 (m,
1H), 2.90 (m, 3H), 2.09–1.80 (m, 13H); MS (FAB) m/z: 493
(M+H)+; HRMS-FAB (m/z): [M+H]+ calcd for C28H33N2O4S,
493.2161; found, 493.2170.
5.1.49. 4-[(2-{(2R)-2-[(1E,3S)-3-Hydroxy-4-(3-pyridin-2-
ylphenyl)but-1-enyl]-5-oxopyrrolidin-1-yl}ethyl)sulfanyl]
butanoic acid (3d)
Compound 3d was prepared from 13c according to the same
procedure as described for the preparation of 3b from 13a as col-
orless amorphous (60 mg, 65%). IR (film): 3366, 2924, 1715, 1666,
1590, 1566, 1462, 1436, 1418, 1217, 1155, 1101,1033, 975, 914,
5.1.54. Butyl 4-({2-[(2R)-2-{(1E,3S)-4-[3-(1,3-benzoxazol-2-
yl)phenyl]-3-hydroxy-1-buten-1-yl}-5-oxo-1-pyrrolidinyl]
ethyl}thio)butanoate (13f)
754, 666 cmꢀ1 1H NMR (300 MHz, CDCl3): d 8.74 (m, 1H), 7.93
;
(s, 1H), 7.84 (dt, J = 1.8, 7.8 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.65
(d, J = 8.1 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.37–7.23 (m, 2H),
5.88 (dd, J = 15.0, 4.5 Hz, 1H), 5.64 (ddd, J = 15.0, 9.0, 1.5 Hz,
1H), 5.45 (br s, 2H), 4.58 (m, 1H), 4.10 (m, 1H), 3.40 (m, 1H),
3.21 (m, 1H), 3.02–2.80 (m, 2H), 2.78–2.10 (m, 9H), 1.99–1.82
(m, 2H), 1.73 (m, 1H); MS (FAB) m/z: 455 (M+H)+; HRMS-FAB
(m/z): [M+H]+ calcd for C25H31N2O4S, 455.1992; found, 455.2005.
Compound 13f was prepared from 12 using the phosphonate
5h instead of 5b according to the same procedure as described
for the preparation of 13a from 12 as a colorless oil (80 mg,
45% in two steps). 1H NMR (300 MHz, CDCl3): d 8.20–8.08 (m,
2H), 7.77 (m, 1H), 7.60 (m, 1H), 7.54–7.32 (m, 4H), 5.81 (dd,
J = 15.1, 6.6 Hz, 1H), 5.60–5.48 (m, 1H), 4.49 (br s, 1H), 4.17–
4.01 (m, 3H), 3.68–3.53 (m, 1H), 3.49 (s, 1H), 3.01–2.89 (m, 3H),
2.69–2.47 (m, 5H), 2.45–2.30 (m, 5H), 2.10–2.05 (m, 1H), 1.93–
1.78 (m, 3H), 1.12–1.05 (m, 1H), 0.91 (t, J = 7.2 Hz, 3H).
5.1.50. Butyl 4-({2-[(2R)-2-{(1E,3S)-4-[3-(1,3-Dihydro-2H-
isoindol-2-yl)phenyl]-3-hydroxy-1-buten-1-yl}-5-oxo-1-
pyrrolidinyl]ethyl}thio)butanoate (13d)
5.1.55. 4-{[2-((2R)-2-{(1E,3S)-4-[3-(1,3-Benzoxazol-2-yl)phenyl]
-3-hydroxybut-1-enyl}-5-oxopyrrolidin-1-yl)ethyl]sulfanyl}
butanoic acid (3g)
Compound 3g was prepared from 13f according to the same
procedure as described for the preparation of 3b from 13a as col-
orless amorphous (45 mg, 60%). IR (film): 3423, 3060, 2923,
2854, 1945, 1899, 1727, 1660, 1552, 1491, 1473, 1454, 1421,
1359, 1244, 1175, 1109, 1032, 1002, 977, 930, 879, 803, 793,
Compound 13d was prepared from 12 using the phosphonate
5f instead of 5b according to the same procedure as described for
the preparation of 13a from 12 as a colorless oil (86 mg, 53% in
two steps). 1H NMR (300 MHz, CDCl3): d 7.43–7.17 (m, 6H),
6.65–6.46 (m, 2H), 5.81 (dd, J = 15.4, 5.8 Hz, 1H), 5.55 (ddd,
J = 15.4, 8.7, 1.1 Hz, 1H), 4.66 (s, 4H), 4.50–4.36 (m, 1H), 4.19–
4.01 (m, 3H), 3.73–3.52 (m, 1H), 3.07–2.73 (m, 3H), 2.71–2.13
(m, 10H), 2.01–1.21 (m, 8H), 0.93 (t, J = 7.3 Hz, 3H).