Journal of Medicinal Chemistry
ARTICLE
the general procedure afforded the title compound as a red solid
(0.067 g, 72%) that was used without further purification: mp
(20R,30R, 40R, 50R)- 5,6-Dihydro-6-(20, 30, 40, 50, 60-pentahydroxyhexyl)-
5,11-dioxo-11H-indeno[1,2-c]isoquinoline (17f).From lactone 16 (0.137 g,
0.550 mmol) and amine 15f (0.250 g, 1.38 mmol) in MeOH (45 mL), the
general procedure afforded the desired product as an orange solid (0.097 g,
43%) after washing with CHCl3 (∼500 mL): mp 244ꢀ246 °C. IR (KBr)
3450, 3302, 3235, 3071, 2969, 1713, 1654, 1634, 1610, 1549, 1504, 1414,
1317, 1200, 1075, 1012 cmꢀ1. 1H NMR (DMSO-d6) δ 8.61 (d, J = 8.0 Hz,
1 H), 8.22(d, J= 7.8 Hz, 1 H), 8.05 (d, J= 7.5 Hz, 1 H), 7.83 (t, J=7.6, 1H),
7.56ꢀ7.43 (m, 4 H), 5.02 (d, J = 5.7 Hz, 1 H), 4.80 (d, J = 6.9 Hz, 1 H),
4.75ꢀ4.45 (m, 2 H), 4.51 (d, J = 5.0 Hz, 1 H), 4.41 (t, J = 5.6 Hz, 1 H), 4.24
(d, J = 7.5 Hz, 1 H), 4.10ꢀ4.00 (br m, 1 H), 3.83 (t, J = 7.6 Hz, 1 H),
3.64ꢀ3.39 (m, 4 H). CIMS m/z (rel intensity) 248 ((MHþ ꢀ C6H12O5),
231ꢀ233 °C. IR (KBr) 3281, 2925, 1705, 1658, 1501, 1457, 1378 cmꢀ1
.
1H NMR (DMSO-d6) δ 8.61 (d, J = 8.1 Hz, 1 H), 8.20 (t, J = 7.4 Hz, 1 H),
7.81 (t, J = 7.4 Hz, 1 H), 7.54ꢀ7.44 (m, 4 H), 4.92 (d, J = 7.5 Hz, 1 H), 4.84
(d, J = 5.9 Hz, 1 H), 4.62ꢀ4.41 (m, 4 H), 4.32 (m, 1 H), 3.66 (t, J = 5.8 Hz,
1 H), 3.54ꢀ3.34 (m, 4 H). ESIMS m/z (rel intensity) 381 ((M ꢀ Hþ)ꢀ,
100). Anal. Calcd for C21H19NO6 0.5H2O: C, 64.61; H, 5.16; N, 3.39.
3
Found: C, 64.27; H, 5.10; N, 3.39.
(20S,30S,40R)-5,6-Dihydro-6-(20,30,40,50-tetrahydroxypentyl)-5,11-di-
oxo-11H-indeno[1,2-c]isoquinoline (17b). From lactone 16 (0.254 g,
1.02 mmol) and amine 15b (0.316 g, 2.05) in MeOH (125 mL), the
general procedure afforded the title compound as an orange solid (0.295
g, 75%) after flash column chromatography (SiO2, eluting with a
gradient of CHCl3 to 20% MeOH in CHCl3): mp 218ꢀ221 °C. IR
100), 412 (MHþ, 15). Anal. Calcd for C22H21NO7 0.8H2O: C, 62.05; H,
3
5.35; N, 3.29. Found: C, 61.73; H, 5.08; N, 3.19.
(20S,30R,40S,50R)-5,6-Dihydro-6-(20,30,40,50-tetrahydroxypentyl)-5,11-
dioxo-11H-indeno[1,2-c]isoquinoline (17g). From lactone 16 (0.319 g,
1.29 mmol) and amine 15g (0.797 g, 4.40 mmol), in MeOH (90 mL),
the general procedure afforded the desired product as an orange solid
(0.041 g, 8%): mp 261ꢀ265 °C. IR (KBr) 3419, 2951, 1971, 1697, 1610,
1573, 1547, 1501, 1458, 1421, 1320, 1268 cmꢀ1. 1H NMR (DMSO-d6)
δ 8.62 (d, J = 8.1 Hz, 1 H), 8.22 (d, J = 8.1 Hz, 2 H), 7.85 (t, J = 7.2 Hz,
1 H), 7.44ꢀ7.58 (m, 4 H), 4.88 (d, J = 3.9 Hz, 1 H), 4.78 (d, J = 6.1 Hz,
1 H), 4.66ꢀ4.62 (m, 1 H), 4.53ꢀ4.46 (m, 2 H), 4.37ꢀ4.33 (m, 1 H),
4.26 (d, J = 6.5 Hz, 1 H), 4.15ꢀ4.13 (m, 1 H), 3.81 (q, J = 6.2 Hz, 1 H),
3.58ꢀ3.42 (m, 4 H). EIMS m/z (rel intensity) 247 ((M ꢀ C6H12O5)þ,
100), 411 (Mþ, 2). Anal. Calcd for C22H21NO7: C, 64.23; H, 5.14; N,
3.40. Found: C, 63.91; H, 5.09; N, 3.43.
1
(KBr) 3476, 3380, 1691, 1656, 1504, 1069, and 761 cmꢀ1. H NMR
(DMSO-d6) δ 8.60 (d, J = 7.8 Hz, 1 H), 8.21ꢀ8.18 (m, 2 H), 7.83 (m,
1 H), 7.54ꢀ7.42 (m, 4 H), 5.19 (d, J = 5.0 Hz, 1 H), 4.98 (d, J = 5.5 Hz,
1 H), 4.77 (d, J = 4.5 Hz, 1 H), 4.68ꢀ4.62 (m, 3 H), 4.49 (t, J = 5.4 Hz,
1 H), 4.22ꢀ4.10 (m, 1 H), 3.67ꢀ3.61 (m, 3 H), 3.48ꢀ3.45 (m, 1 H).
ESIMS m/z (rel intensity) 382 (MHþ, 89), 364 [(MHþ ꢀ H2O)þ,
100]. Anal. Calcd for C21H19NO6 0.39H2O: C, 64.94; H, 5.13; N, 3.61.
3
Found: C, 64.56; H, 4.73; N, 4.00.
(20S,30R,40R,50R)-5,6-Dihydro-6-(20, 30, 40, 50, 60-pentahydroxyhexyl)-
5,11-dioxo-11H-indeno[1,2-c]isoquinoline (17c). From lactone 16
(0.200 g, 0.806 mmol) and amine 15c (0.363 g, 2.0 mmol) in MeOH
(60 mL), the general procedure afforded the title compound as an
orange solid (0.067 g, 20%) after flash column chromatography (SiO2,
eluting with a gradient of CHCl3 to 20% MeOH in CHCl3): mp
240ꢀ244 °C. IR (KBr) 3430, 2085, 1627, 1549, 1504, 1424, 1316,
1269, 1179 cmꢀ1. 1H NMR (DMSO-d6) δ 8.61 (d, J = 8.1 Hz, 1 H), 8.22
(t, J = 8.3 Hz, 2 H), 7.81 (t, J = 7.0 Hz, 1 H), 7.54ꢀ7.44 (m, 4 H), 5.13 (d,
J = 4.9 Hz, 1 H), 4.85 (d, J = 6.4 Hz, 1 H), 4.70ꢀ4.60 (m, 1 H),
4.60ꢀ4.54 (m, 3 H), 4.43 (t, J = 5.4 Hz, 1 H), 4.20ꢀ4.10 (br m, 1 H),
3.90ꢀ3.80 (br m, 1 H), 3.64ꢀ3.40 (m, 4 H). Negative ion ESIMS m/z
(rel. intensity) 821 (2(M ꢀ Hþ)ꢀ, þ Hþ, 100), 410 ((M ꢀ Hþ)ꢀ, 92).
(20S,30S,40R,50R)-5,6-Dihydro-6-(20,30,40,50,60-pentahydroxyhexyl)-
5,11-dioxo-11H-indeno[1,2-c]isoquinoline (17h). From lactone 16
(0.110 g, 0.440 mmol) and amine 15h (0.200 g, 1.10 mmol) in MeOH
(30 mL), the general procedure afforded the title compound as an
orange solid (0.045 g, 25%) after washing with H2O (10 mL) and
CHCl3 (∼200 mL): mp 201ꢀ205 °C. IR (KBr) 3373, 1703, 1639,
1019, 1548, 1504, 1425, 1316, 1263, 1062, 758 cmꢀ1 1H NMR
.
(DMSO-d6) δ 8.61 (d, J = 8.1 Hz, 1 H), 8.27 (d, J = 7.3 Hz, 1 H), 8.22
(d, J = 8.0 Hz, 1 H), 7.84 (t, J = 8.2 Hz, 1 H), 7.55ꢀ7.42 (m, 4 H), 5.27
(d, J = 5.1 Hz, 1 H), 4.97 (d, J = 5.3 Hz, 1 H), 4.84 (d, J = 4.4 Hz, 1 H),
4.67 (d, J = 5.8 Hz, 3 H), 4.47 (t, J = 5.6 Hz, 1 H), 4.27ꢀ4.20 (m, 1 H),
3.85ꢀ3.80 (m, 1 H), 3.67ꢀ3.42 (m, 4 H). Negative ion ESIMS m/z
Anal. Calcd for C22H21NO7 1H2O: C, 61.53; H, 5.40; N, 3.26. Found:
3
C, 61.78; H, 5.42; N, 3.47.
(20S,30R,40R)-5,6-Dihydro-6-(20,30,40,50-tetrahydroxypentyl)-5,11-di-
oxo-11H-indeno[1,2-c]isoquinoline (17d). From lactone 16 (0.100 g,
0.403 mmol) and amine 15d (0.251 g, 1.66 mmol) in MeOH (60 mL),
the general procedure afforded the title compound as a red solid (0.028 g,
18%) that was used without further purification: mp 220ꢀ224 °C. IR
(rel intensity) 410 ((M ꢀ Hþ)ꢀ, 36). Anal. Calcd for C22H21NO7
3
1H2O: C, 61.53; H, 5.40; N, 3.26. Found: C, 61.30; H, 5.25; N, 3.46.
(20S,30R,40R,50R)-5,6-Dihydro-6-(20,30,40,50,60-pentahydroxyhexyl)-3-
nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (19). From lactone 18
(0.040 g, 0.136 mmol) and amine 15c (0.062 g, 0.341 mmol) in MeOH
(15 mL), the general procedure afforded the title compound as an
orange solid (0.021 g, 34%) after concentrating, resuspending in CHCl3
(20 mL), filtering, and washing with CHCl3 (∼30 mL) and ether
(∼30 mL): mp 265ꢀ267 °C. IR (KBr) 3401, 2934, 1713, 1649, 1615,
1559, 1505, 1426, 1334, 1076 cmꢀ1. 1H NMR (DMSO-d6) δ 8.92 (d, J =
2.4 Hz, 1 H), 8.78 (d, J = 8.8 Hz, 1 H), 8.61ꢀ8.50 (m, 2 H), 7.64ꢀ7.56
(m, 4 H), 5.20 (d, J = 5.0 Hz, 1 H), 4.94 (d, J = 6.5 Hz, 1 H), 4.90ꢀ4.80
(m, 1 H), 4.62ꢀ4.58 (m, 3 H), 4.45 (t, J = 5.0 Hz, 1 H), 4.20ꢀ4.10 (m,
1 H), 3.90ꢀ3.80 (m, 1 H), 3.65ꢀ3.34 (m, 4 H). Negative ion ESIMS
m/z (rel intensity) 455 ((M ꢀ Hþ)ꢀ, 24), 291 ((M ꢀ Hþ) ꢀ
C6H12O5)ꢀ, 100). Anal. Calcd for C22H21NO7: C, 57.90 H, 4.42; N,
6.14. Found: C, 57.66; H, 4.66; N, 6.48.
1
(film) 3374, 1701, 1625, 1549, 1506, 1032, 884, 757 cmꢀ1. H NMR
(DMSO-d6) δ 8.63 (d, J = 7.8 Hz, 1 H), 8.25ꢀ8.22 (m, 2 H), 7.85
(t, J = 6.9 Hz, 1 H), 7.57ꢀ7.44 (m, 4 H), 5.05 (d, J = 5.1 Hz, 1 H), 4.87
(d, J = 6.2 Hz, 1 H), 4.79ꢀ4.53 (m, 4 H), 4.06ꢀ4.16 (br m, 1 H),
3.40ꢀ3.56 (m, 5 H). EIMS m/z (rel. intensity) 247 ((M ꢀ C5H10O4)þ,
100), 381 (Mþ, 5). Anal. Calcd for C21H19NO6 1.0H2O: C, 63.15; H,
3
5.30; N, 3.51. Found: C, 63.01; H, 5.03; N, 3.54.
(20R,30R,40R)-5,6-Dihydro-6-(20,30,40,50-tetrahydroxypentyl)-5,11-di-
oxo-11H-indeno[1,2-c]isoquinoline (17e). From lactone 16 (0.112 g,
0.450 mmol) and amine 15e (0.136 g, 0.900 mmol) in MeOH (30 mL),
the general procedure afforded the title compound as an orange solid
(0.024 g, 5%) after flash column chromatography (SiO2, eluting with a
gradient of CHCl3 to 20% MeOH in CHCl3): mp 183ꢀ185 °C. IR
(KBr) 3351, 2924, 1756, 1738, 1704, 1655, 1609, 1548, 1504, 1429,
(10S)-5,6-Dihydro-6-(10-hydroxy-20-methylethyl)-5,11-dioxo-11H-
indeno[1,2-c]isoquinoline (22a). From lactone 16 (0.100 g, 0.403
mmol) and alcohol 21a (0.108 g, 1.21 mmol) in CHCl3 (30 mL), the
general procedure afforded the desired product as a dark-red solid
(0.086 g, 71%) after extraction and washing with ether: mp 215ꢀ
217 °C. IR (KBr) 3061, 2980, 2937, 2890, 1658, 1575, 1457, 1418,
1262, 1171, 1017 cmꢀ1. 1H NMR (CDCl3) δ 8.67 (d, J = 8.1 Hz, 1 H),
8.27 (d, J = 8.1 Hz, 1 H), 7.75 (t, J = 7.0 Hz, 1 H), 7.65ꢀ7.58 (m, 2 H),
1
1316, 1267, 1197 cmꢀ1. H NMR (DMSO-d6) δ 8.61 (d, J = 8.1 Hz,
1 H), 8.22 (d, J = 8.1 Hz, 1 H), 8.08 (d, J = 7.6 Hz, 1 H), 7.83 (t, J =7.6,
1 H), 7.58ꢀ7.43 (m, 4 H), 5.08 (d, J = 5.7 Hz, 1 H), 4.82 (d, J = 6.9 Hz,
1 H), 4.72ꢀ4.53 (m, 3 H), 4.36 (d, J = 6.6 Hz, 1 H), 4.10ꢀ4.09
(br m, 1 H), 3.70ꢀ3.42 (m, 4 H). CIMS m/z (rel intensity) 382 (MHþ,
50), 364 ((MHþ ꢀ H2O)þ, 100). Anal. Calcd for C21H19NO6 1.1H2O:
3
C, 62.95; H, 5.32; N, 3.50. Found: C, 62.56; H, 4.91; N, 3.32.
4948
dx.doi.org/10.1021/jm101338z |J. Med. Chem. 2011, 54, 4937–4953