NoVobiocin Analogues as AntiproliferatiVe Agents
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24 6197
123.4, 122.4, 121.3, 113.5, 110.5, 110.0, 107.3, 102.9, 56.0, 55.7,
28.3, 25.8, 17.8, 8.2; IR (cm-1): 3366, 1692, 1677, 1636, 1601,
1572, 1536, 1495, 1370, 1249, 1110, 1024, 809, 759, 630; MS
(ES+) m/z 446 ([M + Na]+, 100); Anal. (C24H25NO6) C, H, N.
2,2-Dimethylchroman-6-carboxylic Acid (4,7-dihydroxy-8-
methyl-2-oxo-2H-chromen-3-yl)amide (Cyclonovobiocic Acid
6a).10 Aqueous chlorhydric acid (25 mL, 12 N) was added dropwise
to a reflux solution of monosodium novobiocin salt (4.0 g, 6.3
mmol) in absolute ethanol (50 mL). A white precipitate appeared;
the reaction mixture was stirred for 1 h at 78 °C. The solid formed
was collected, washed three times with absolute ethanol, and dried
under vacuum to give 99% of 6a (2.47 g, 6.24 mmol) as a beige
ethyl acetate was added and the organic layer washed with an
aqueous solution of 1 N HCl (pH ) 1-2), dried over Na2SO4,
filtered, and concentrated under vacuum. Further purification by
column chromatography on silica gel (cyclohexane/EtOAc: 6/4)
gave 98% of 6d (95 mg, 0.23 mmol) as a white solid. Rf
(cyclohexane/EtOAc: 6/4) 0.67; mp ) 207-209 °C; 1H NMR (400
MHz, CDCl3): δ 14.07 (s, 1H), 8.71 (s, 1H), 7.85 (d, J ) 8.8 Hz,
1H), 7.70 (m, 2H), 6.89 (m, 2H), 3.93 (s, 3H), 2.87 (t, J ) 6.6 Hz,
2H), 2.32 (s, 3H), 1.86 (t, J ) 6.6 Hz, 2H), 1.38 (s, 6H); 13C NMR
(100 MHz, CDCl3): δ 166.9, 161.8, 160.3, 158.6, 153.5, 148.2,
129.6, 127.1, 122.6, 122.4, 121.5, 117.9, 113.5, 110.6, 107.4, 102.9,
75.7, 56.0, 32.4, 26.9 (2C), 22.4, 8.0, IR (cm-1): 3286, 1673, 1596,
1493, 1367, 1255, 1115, 803; MS (ES-) m/z 408.0 ([M - H]-,
100); Anal. Calcd for C23H23NO6: C, 67.47; H, 5.66; N, 3.42.
Found: C, 66.71; H, 5.83; N, 3.40.
Toluene-4-sulfonic Acid 3-[(2,2-Dimethylchroman-6-carbo-
nyl)amino]-7-hydroxy-8-methyl-2-oxo-2H-chromen-4-yl Ester
(6e). A solution of pTsCl (530 mg, 2.78 mmol, 1.1 equiv) in
pyridine (5 mL) was added slowly to an ice-cooled suspension of
6a (1.0 g, 2.53 mmol, 1 equiv) in dry pyridine (10 mL). After the
mixture was stirred 24 h at room temperature, ethyl acetate (25
mL) was added and the organic layer washed with aqueous 1 N
HCl (pH ) 1-2), dried over Na2SO4, and concentrated under
vacuum. Further purification by column chromatography on silica
gel (cyclohexane/EtOAc: 6/4) gave 53% of 6e (743 mg, 1.35 mmol)
as a white solid. Rf (cyclohexane/EtOAc: 6/4) 0.20; mp ) 163-
165 °C; 1H NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 7.74 (d, J )
8.3 Hz, 2H), 7.68 (s, H+NH), 7.59 (d, J ) 8.5 Hz, 1H), 7.24 (d,
J ) 8.3 Hz, 2H), 6.85 (d, J ) 8.5 Hz, 1H), 6.53 (d, J ) 8.7 Hz,
1H), 6.49 (d, J ) 8.7 Hz, 1H), 2.86 (t, J ) 6.5 Hz, 2H), 2.40 (s,
3H), 2.13 (s, 3H), 1.88 (t, J ) 6.5 Hz, 2H), 1.40 (s, 6H); 13C NMR
(100 MHz, CDCl3): δ 167.2, 160.2, 159.5, 158.4, 152.2, 150.9,
146.5, 132.5, 130.2 (2C), 128.1 (3C), 127.3, 123.3, 121.4, 121.2,
117.5, 112.8, 112.5, 111.9, 108.1, 75.6, 32.5, 26.9 (2C), 22.4, 21.8,
8.0; IR (cm-1): 3250, 3100, 1696, 1592, 1363, 1256, 810, 761,
733, 656; MS (ES-) m/z 548.3 ([M - H]-, 100), 1097.2 ([2M -
H]-, 16); Anal. (C29H27NO8S) C, H, N.
Toluene-4-sulfonic Acid 3-[(2,2-Dimethylchroman-6-carbo-
nyl)amino]-4-hydroxy-8-methyl-2-oxo-2H-chromen-7-yl Ester
(6f). A solution of pTsCl (530 mg, 2.78 mmol, 1.1 equiv) in dry
THF (3 mL) was added slowly to an ice-cooled suspension of 6a
(1.0 g, 2.53 mmol, 1 equiv) and DMAP (309 mg, 2.53 mmol, 1
equiv) in a mixture of dry THF (30 mL) and TEA (5 mL). After
the mixture was stirred for 48 h at room temperature, ethyl acetate
(50 mL) was added and the organic layer washed with aqueous 1
N HCl, dried over Na2SO4, and concentrated under vacuum. Further
purification by column chromatography on silica gel (CH2Cl2) gave
54% of 6f (736 mg, 1.34 mmol) as a white solid. Rf (cyclohexane/
EtOAc: 6/4) 0.59; mp ) 197-198 °C; 1H NMR (400 MHz,
CDCl3): δ 14.16 (s, 1H), 8.70 (s, 1H), 7.74 (m, 5H), 7.35 (d, J )
8.0 Hz, 2H), 7.10 (d, J ) 8.6 Hz, 1H), 6.88 (d, J ) 8.6 Hz, 1H),
2.87 (t, J ) 6.7 Hz, 2H), 2.47 (s, 3H), 2.16 (s, 3H), 1.86 (t, J )
6.7 Hz, 2H), 1.38 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 167.3,
161.1, 159.0, 152.2, 150.1, 149.3, 145.9, 132.8, 130.0 (2C), 129.8,
128.5 (2C), 127.2, 122.2, 121.6 (2C), 120.3, 118.9, 118.0, 116.0,
104.8, 75.8, 32.4, 26.9 (2C), 22.4, 21.8, 9.5; IR (cm-1): 3360, 3100,
1697, 1596, 1536, 1489, 1484, 1374, 1074, 847, 811, 766, 733,
644, 616; MS (ES-) m/z 548 ([M - H]-, 100); Anal. (C29H27-
NO8S) C, H, N.
Toluene-4-sulfonic Acid 4-(4-Chlorophenyl)-3-[(2,2-dimeth-
ylchroman-6-carbonyl)amino]-8-methyl-2-oxo-2H-chromen-7-
yl Ester (6h). A solution 6e (50 mg, 91 µmol, 1 equiv),
4-chlorophenylboronic acid (18 mg, 0.12 mmol, 1.3 equiv), K3-
PO4 (58 mg, 0.27 mmol, 3 equiv), Bu4NBr (3 mg, 9.1 µmol, 10
mol %), and PdCl2(dppf) (4 mg, 4.5 µmol, 5 mol %) in CH3CN
was heated at 80 °C for 3 h. After the mixture was cooled to room
temperature, ethyl acetate was added. The organic layer was washed
with water, dried over Na2SO4, and concentrated under vacuum.
Further purification by column chromatography on silica gel
(cyclohexane/EtOAc: 6/4) gave 41% of 6h (24 mg, 37.0 µmol) as
a white solid. Rf (cyclohexane/EtOAc: 6/4) 0.35; mp ) 117-120
1
solid. Rf (cyclohexane/EtOAc: 6/4) 0.46; mp ) 286-287 °C; H
NMR (400 MHz, DMSO-d6): δ 11.80 (s, 1H), 10.40 (s, 1H), 9.20
(s, 1H), 7.80 (s, 1H), 7.73 (d, J ) 8.6 Hz, 1H), 7.57 (d, J ) 8.6
Hz, 1H), 6.88 (d, J ) 8.6 Hz, 1H), 6.79 (d, J ) 8.6 Hz, 1H), 2.88
(t, J ) 6.6 Hz, 2H), 2.19 (s, 3H), 1,80 (t, J ) 6.6 Hz, 2H), 1.30 (s,
6H); 13C NMR (100 MHz, DMSO-d6): δ 161.8, 161.1, 160.0,
159.4, 157.0, 151.6, 130.4, 127.8, 125.1, 121.8, 120.8, 116.8, 112.2,
110.8, 108.4, 100.8, 75.4, 32.3, 26.8 (2C), 22.1, 8.4; IR (cm-1):
3191, 2977, 1660, 1627, 1602, 1567, 1538, 1366, 1096, 823; MS
(TOF ES+) m/z 418 ([M + Na]+, 100); Anal. (C22H21NO6) C, H, N.
2,2-Dimethylchroman-6-carboxylic Acid (4,7-Dimethoxy-8-
methyl-2-oxo-2H-chromen-3-yl)amide (6b). To a suspension of
6a (600 mg, 1.52 mmol, 1 equiv) and K2CO3 (4.19 g, 30.3 mmol,
1.1 equiv) in DMF (12 mL) was added dropwise dimethyl sulfate
(2.88 mL, 30.3 mmol, 20 equiv). After the mixture was stirred 24
h at room temperature, ethyl acetate (40 mL) was added and the
organic layer washed with saturated aqueous NH4Cl, dried over
Na2SO4, and concentrated under vacuum. Further purification by
column chromatography on silica gel (cyclohexane/EtOAc: 6/4)
gave 61% of 6b (393 mg, 0.93 mmol) as a white solid. Rf
(cyclohexane/EtOAc: 6/4) 0.35; mp ) 237-238 °C; 1H NMR (200
MHz, CDCl3): δ 8.24 (s, 1H), 7.70 (s, 1H), 7.63 (m, 2H), 6.82 (d,
J ) 8.9 Hz, 1H), 6.70 (d, J ) 8.9 Hz, 1H), 4.12 (s, 3H), 3.89 (s,
3H), 2.73 (t, J ) 6.6 Hz, 2H), 2.25 (s, 3H), 1.77 (t, J ) 6.6 Hz,
2H), 1.33 (s, 6H); 13C NMR (50 MHz, CDCl3): δ 167.0, 163.6,
160.7, 160.3, 157.5, 152.0, 129.5, 127.1, 124.0, 122.0, 120.8, 117.1,
113.3, 111.0, 106.9, 102.9, 75.1, 59.3, 55.8, 32.4, 26.8 (2C), 22.2,
8.0; IR (cm-1): 3282, 1715, 1604, 1500, 1479, 1354, 1153, 881,
763; MS (ES+) m/z 446.3 ([M + Na]+, 100); Anal. (C24H25NO6)
C, H, N.
2,2-Dimethylchroman-6-carboxylic Acid (7-Hydroxy-4-meth-
oxy-8-methyl-2-oxo-2H-chromen-3-yl)amide (6c). To a suspen-
sion of 6a (200 mg, 0.51 mmol, 1 equiv) and K2CO3 (77 mg, 0.55
mmol, 1.1 equiv) in DMF (5 mL) was added dropwise dimethyl
sulfate (55 µL, 0.55 mmol, 1.1 equiv). After the mixture was stirred
48 h at room temperature, ethyl acetate was added to the solution.
The organic layer was washed with a saturated aqueous solution
of NH4Cl, dried over Na2SO4, filtered, and concentrated under
vacuum. Further purification by column chromatography on silica
gel (cyclohexane/EtOAc: 6/4) gave 20% of 6c (38 mg, 93 µmol)
as a white solid. Rf (cyclohexane/EtOAc: 6/4) 0.17; mp ) 223-
224 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.50 (s, 1H), 9.41 (s,
1H), 7.76 (s, 1H), 7.70 (d, J ) 8.6 Hz, 1H), 7.50 (d, J ) 8.8 Hz,
1H), 6.86 (d, J ) 8.8 Hz, 1H), 6.79 (d, J ) 8.6 Hz, 1H), 4.07 (s,
3H), 2.79 (t, J ) 6.6 Hz, 2H), 2.14 (s, 3H), 1.79 (t, J ) 6.6 Hz,
2H), 1.29 (s, 6H); 13C NMR (100 MHz, DMSO-d6): δ 166.5, 161.5,
161.3, 159.1, 156.8, 150.6, 129.8, 127.1, 124.7, 121.5, 120.7, 116.6,
112.0, 110.4, 108.4, 102.4, 75.1, 59.8, 31.8, 26.5 (2C), 21.7, 8.0;
IR (cm-1): 3284, 2935, 1673, 1595, 1570, 1537, 1491, 1366, 1254,
1114, 947, 759, 746; MS (ES+) m/z 432 ([M + Na]+, 25), 242.0
(100); Anal. Calcd for C23H23NO6: C, 67.47; H, 5.66; N, 3.42.
Found: C, 66.61; H, 5.75; N, 3.35.
2,2-Dimethylchroman-6-carboxylic Acid (4-Hydroxy-7-meth-
oxy-8-methyl-2-oxo-2H-chromen-3-yl)amide (6d). To a solution
of 6b (100 mg, 0.24 mmol, 1 equiv) in MeOH (4 mL) was added
morpholine (414 µL, 4.72 mmol, 20 equiv). The solution was heated
under reflux for 16 h, a second portion of morpholine (414 µL,
4.72 mmol, 20 equiv) was added, and the solution was heated under
reflux for 48 h. After the mixture was cooled to room temperature,