Amide Analogues of Trichostatin A
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 22 4675
Meth yl 5-(4-Dim eth ylam in oben zoyl)am in ovaler ate (6c).
Synthesized by method A from 4-dimethylaminobenzoic acid
(1.65 g, 10 mmol), TEA (1.39 mL, 1.01 g, 10 mmol), BOP-Cl
(2.80 g, 11 mmol), methyl 5-aminovalerate hydrochloride (1.68
g, 10 mmol), TEA (4.17 mL, 3.03 g, 30 mmol). The crude was
chromatographed using ethyl acetate/hexane (2:1, 1% diethyl-
amine): yield 1.28 g (46%); mp 79 °C; IR 1731, 1610; 1H NMR
(CDCl3) δ 7.71-7.67 and 6.69-6.63 (m, 2H), 6.32 (bs, 1H), 3.66
(s, 3H), 3.47-3.38 (m, 2H), 3.00 (s, 6H), 2.40-2.33 (m, 2H),
1.73-1.62 (m, 2H); 13C NMR (CDCl3) δ 174.02, 167.50, 152.45,
128.36, 121.65, 111.18, 51.51, 40.12, 39.35, 33.60, 29.28, 22.22;
MS(ESI) m/z 278 (M+).
1.51 mmol), 10% Pd on charcoal (60 mg): yield 360 mg (78%)
of white powder; mp 161 °C; IR 1665, 1595; 1H NMR (DMSO-
d6) δ 10.35 (s, 1H), 8.68 (s, 1H); 8.08-8.06 (m, 1H), 7.71-7.66
and 6.69-6.65 (m, 2H), 3.23-3.13 (m, 2H), 2.93 (s, 6H), 1.96-
1.88 (m, 2H), 1.52-1.40 (m, 4H), 1.24 (bs, 4H); 13C NMR
(DMSO-d6) δ 168.99, 165.87, 151.78, 128.20, 121.18, 110.54,
39.50, 39.06, 32.02, 29.02, 28.15, 26.02, 24.88; MS(ESI) m/z
307 (M+). Anal. (C16H25N3O3) C, H, N.
Meth yl 8-(4-Dim eth yla m in oben zoyl)a m in oocta n oa te
(6e). Synthesized by method A from 4-dimethylaminobenzoic
acid (1.65 g, 10 mmol), TEA (1.39 mL, 1.01 g, 10 mmol), BOP-
Cl (2.80 g, 11 mmol), methyl 8-aminooctanoate hydrochloride
(2.10 g, 10 mmol), TEA (4.17 mL, 3.03 g, 30 mmol). The crude
was chromatographed using ethyl acetate/hexane (2:1, 1%
diethylamine): yield 2.25 g (70%); mp 62 °C; IR 1738, 1618;
1H NMR (CDCl3) δ 7.71-7.67 and 6.67-6.63 (m, 2H), 6.21 (bs,
1H), 3.66 (s, 3H), 3.45-3.35 (m, 2H), 2.33-2.26 (m, 2H), 1.65-
1.55 (m, 4H), 1.34-1.32 (m, 6H); 13C NMR (CDCl3) δ 174.25,
167.45, 152.40, 128.33, 121.75, 111.12, 51.44, 40.14, 39.87,
34.07, 29.83, 29.06, 28.98, 26.84, 24.87; MS(ESI) m/z 320 (M+).
5-(4-Dim eth yla m in oben zoyl)a m in ova ler ic Acid (7c).
Synthesized by method C1 from 6c (1.11 g, 4 mmol): mp 138
3
°C; IR 1722, 1622; 1H NMR (DMSO-d6) δ 8.09 (t, J ) 5.5 Hz,
1H), 7.72-7.67 and 6.69-6.65 (m, 2H), 3.28-3.18 (m, 2H), 2.94
(s, 6H), 2.14-2.08 (m, 2H), 1.52-1.44 (m, 4H); 13C NMR
(DMSO-d6) δ 174.41, 165.99, 151.98, 128.39, 121.41, 110.74,
39.72, 33.40, 28.87, 22.05; MS(ESI) m/z 264 (M+).
N-Ben zyloxy-5-(4-d im et h yla m in ob en zoyl)a m in ova l-
er a m id e (8c). Synthesized by method A from crude 7c, TEA
(0.69 mL, 550 mg, 5 mmol), BOP-Cl (1.40 g, 5.5 mmol),
O-benzylhydroxylamine hydrochloride (770 mg, 5 mmol), TEA
(2.08 mL, 1.01 g, 15 mmol). The crude was chromatographed
using ethyl acetate/methanol (20:1, 1% diethylamine): yield
1.12 g (74% from 6c); mp 151 °C; IR 1675, 1607; 1H NMR
(DMSO-d6) δ 10.95 (s, 1H), 8.09 (bs, 1H), 7.72-7.68 and 6.69-
6.65 (m, 2H), 7.35 (s, 5H), 4.76 (s, 2H), 3.21-3.18 (m, 2H),
1.97-1.94 (m, 2H), 1.48-1.46 (m, 4H); 13C NMR (DMSO-d6) δ
168.93, 165.65, 151.62, 135.70, 128.33, 128.03, 127.85, 127.54,
121.13, 110.38, 76.41, 39.33, 38.30, 31.64, 28.53, 22.18; MS-
(ESI) m/z 369 (M+).
N -H yd r oxy-5-(4-d im e t h yla m in ob e n zoyl)a m in ova l-
er a m id e (5c). Synthesized by method D from 8c (260 mg, 0.71
mmol), 10% Pd on charcoal (30 mg): yield 160 mg (81%) of
white powder; mp 148 °C; IR 1660, 1595; 1H NMR (CD3OD) δ
7.73-7.66 and 6.74-6.67 (m, 2H), 3.38-3.28 (m, 2H), 2.16-
2.09 (m, 2H), 1.70-1.57 (m, 2H); 13C NMR (CD3OD) δ 172.74,
170.45, 154.25, 129.66, 122.21, 112.18, 40.26, 33.37, 30.09,
24.10; MS(ESI) m/z 279 (M+). Anal. (C15H23N3O3) C, H, N.
Meth yl 7-(4-Dim eth yla m in oben zoyl)a m in oh ep ta n oa te
(6d ). Synthesized by method A from 4-dimethylaminobenzoic
acid (1.65 g, 10 mmol), TEA (1.39 mL, 1.01 g, 10 mmol), BOP-
Cl (2.80 g, 11 mmol), methyl 7-aminoheptanoate hydrochloride
(1.96 g, 10 mmol), TEA (4.17 mL, 3.03 g, 30 mmol). The crude
was chromatographed using ethyl acetate/hexane (1:1, 1%
diethylamine): yield 1.64 g (56%); mp 68 °C; 1H NMR (CDCl3)
δ 7.70-7.65 and 6.68-6.64 (m, 2H), 6.12 (bs, 1H), 3.66 (s, 3H),
3.46-3.36 (m, 2H), 3.01 (s, 6H), 2.35-2.27 (m, 2H), 1.76-1.53
and 1.40-1.32 (m, 4H); 13C NMR (CDCl3) δ 174.17, 167.48,
152.49, 128.34, 121.83, 51.44, 40.15, 39.81, 34.03, 29.74, 28.86,
26.67, 24.87; MS(ESI) m/z 292 (M+).
8-(4-Dim eth yla m in oben zoyl)a m in oocta n oic Acid (7e).
Synthesized by method C1 from 6e (1.28 g, 4 mmol): mp 154
1
°C; IR 1708, 1604; H NMR (DMSO-d6) δ 8.09-8.03 (m, 1H),
7.71-7.67 and 6.69-6.65 (m, 2H), 3.28-3.13 (m, 2H), 2.94 (s,
6H), 2.21-2.13 (m, 2H), 1.50-1.40 (m, 4H), 1.39-1.26 (m, 6H);
13C NMR (DMSO-d6) δ 174.47, 165.96, 151.94, 128.38, 121.49,
110.73, 39.70, 38.97, 33.73, 29.30, 28.53, 28.51, 26.39, 24.48;
MS(ESI) m/z 306 (M+).
N -Be n zyloxy-8-(4-d im e t h yla m in ob e n zoyl)a m in ooc-
ta n a m id e (8e). Synthesized by method A from crude 7e, TEA
(0.69 mL, 550 mg, 5 mmol), BOP-Cl (1.40 g, 5.5 mmol),
O-benzylhydroxylamine hydrochloride (770 mg, 5 mmol), TEA
(2.08 mL, 1.01 g, 15 mmol). The product precipitated upon
evaporation of the organic layer and was collected by filtra-
tion: yield 770 mg (47% from 6e); mp 134 °C; IR 1670, 1607;
1H NMR (CD3OD) δ 7.72-7.67 (m, 2H), 7.40-7.31 (m, 5H),
6.73-6.68 (m, 2H), 4.86 (s, 2H), 3.35-3.28 (m, 2H), 2.99 (s,
6H), 2.07-2.00 (m, 2H), 1.61-1.51 (m, 4H), 1.34-1.28 (m, 4H);
13C NMR (CD3OD) δ 167.72, 152.53, 129.16, 128.56, 128.40,
121.65, 112.49, 111.24, 78.23, 40.16, 39.63, 32.83, 29.79, 28.77,
28.44, 26.49, 24.95; MS(ESI) m/z 411 (M+).
N -H y d r o x y -8-(4-d im e t h y la m in o b e n zo y l)a m in o o c -
ta n a m id e (5e). Synthesized by method D from 8e (300 mg,
0.73 mmol), 10% Pd on charcoal (30 mg): yield 140 mg (60%)
of white powder; mp 158 °C; IR 1610, 1555; 1H NMR (DMSO-
d6) δ 10.33 (s, 1H), 8.66 (s, 1H), 8.08-8.06 (m, 1H), 7.71-7.67
and 6.69-6.65 (m, 2H), 3.23-3.14 (m, 2H), 2.93 (s, 6H), 1.95-
1.88 (m, 2H), 1.50-1.43 (m, 4H) 1.41-1.25 (m, 6H); 13C
(DMSO-d6) δ 169.08, 165.95, 151.94, 128.38, 121.46, 110.72,
39.70, 38.95, 32.22, 29.31, 28.53, 28.47, 26.40, 25.05; MS(ESI)
m/z 321(M+). Anal. (C17H27N3O3) C, H, N.
Meth yl 4-(4-Dim eth yla m in oben zoyl)a m in op h en yla ce-
ta te (6f). Synthesized by method A from 4-dimethylaminoben-
zoic acid (1.65 g, 10 mmol), TEA (1.39 mL, 1.01 g, 10 mmol),
BOP-Cl (2.80 g, 11 mmol), methyl 4-aminophenylacetate
hydrochloride (3.49 g, 10 mmol), TEA (4.17 mL, 3.03 g, 30
mmol). The resulting suspension was extracted four times with
ethyl acetate (100 mL each) and the combined organic extracts
were evaporated after adding 1 g of silica. The powder was
subjected to chromatography using ethyl acetate/hexane (2:1,
1% diethylamine) and the main fraction was evaporated. The
resulting product was recrystallized form acetone/hexane:
yield 1.68 g (90%); mp 172 °C; IR 1729, 1646; 1H NMR
(acetone-d6) δ 9.24 (s, 1H), 7.92-7.87, 7.82-7.77, 7.26-7.22
and 6.78-6.73 (m, 2H), 3.64 (s, 3H), 3.61 (s, 2H), 3.03 (s, 6H);
13C NMR (acetone-d6) δ 172.40, 166.08, 153.71, 139.79, 130.24,
130.04, 129.76, 122.81, 120.82, 120.74, 111.82, 51.92, 40.81,
40.15; MS(ESI) m/z 312 (M+).
7-(4-Dim eth ylam in oben zoyl)am in oh eptan oic Acid (7d).
Synthesized by method C1 from 6d (1.17 g, 4 mmol): mp 124
°C; IR 1724, 1616; H NMR (CDCl3) δ 7.69-7.65 and 6.69-
1
6.62 (m, 2H), 6.16 (bs, 1H), 3.40-3.36 (m, 2H), 3.00 (s, 6H),
2.38-2.30 (m, 2H); 1.64-1.57 and 1.41-1.34 (m, 4H); 13C NMR
(CDCl3) δ 178.18, 167.94, 152.56, 128.41, 121.62, 111.25, 40.16,
39.88, 33.92, 29.68, 28.74, 26.61, 24.69; MS(ESI) m/z 292 (M+).
N-Ben zyloxy-7-(4-d im et h yla m in ob en zoyl)a m in oh ep -
ta n a m id e (8d ). Synthesized by method A from crude 7d , TEA
(0.69 mL, 550 mg, 5 mmol), BOP-Cl (1.40 g, 5.5 mmol),
O-benzylhydroxylamine hydrochloride (770 mg, 5 mmol), TEA
(2.08 mL, 1.01 g, 15 mmol). The crude was chromatographed
using ethyl acetate/methanol (20:1, 1% diethylamine): yield
1
990 mg (62% from 6d ); mp 136 °C; IR 1674, 1619; H NMR
(CD3OD) δ 7.72-7.67 (m, 2H), 7.40-7.31 (m, 5H); 6.73-6.68
(m, 2H), 4.86 (s, 2H), 3.35-3.28 (m, 2H), 2.99 (s, 6H), 2.07-
2.00 (m, 2H), 1.61-1.51 and 1.34-1.28 (m, 4H); 13C NMR (CD3-
OD) δ 172.89, 170.40, 154.19, 130.30, 129.64, 129.44, 122.22,
112.15, 78.91, 40.75, 40.27, 33.67, 30.51, 29.75, 27.67, 26.52;
MS(ESI) m/z 397 (M+).
4-(4-Dim eth yla m in oben zoyl)a m in op h en yla cetic Acid
(7f). Synthesized by method C1 from 6f (1.25 g, 4 mmol): mp
1
227 °C; IR 1716, 1611; H NMR (DMSO-d6) δ 12.2 (bs, 1H),
N -H yd r oxy-7-(4-d im e t h yla m in ob e n zoyl)a m in oh e p -
ta n a m id e (5d ). Synthesized by method D from 8d (600 mg,
9.84 (s, 1H), 7,88-7.83, 7.76-7.67, 7.21-7.16 and 6.77-6.72
(m, 2H), 3.51 (s, 2H), 2.98 (s, 6H); MS(ESI) m/z 298 (M+).