Polyamine-Vectored Iron Chelators
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 12 4133
of 8% NaHCO3, 0.5 M citric acid, H2O, and saturated NaCl.
Solvent removal and flash chromatography, eluting with 3%
CH3OH/CH2Cl2, afforded 1.20 g (92%) of 23 as an oil: 1H NMR
δ 1.40-1.85 (m, 35 H), 2.30 (s, 3 H), 3.04-3.30 (m, 10 H), 4.03
(t, 2 H, J ) 6.0), 5.28 (br s, 1 H), 7.35 (d, 2 H, J ) 8.1), 7.75 (d,
2 H, J ) 8.4); 13C NMR δ 21.28, 21.59, 22.86, 23.12, 25.81,
26.20, 26.82, 30.90, 31.18, 34.41, 37.00, 44.35, 53.53, 54.18,
80.19, 125.72, 125.83, 127.82, 128.84, 129.83, 133.06, 140.15,
141.98, 149.30. Anal. (C32H55N3O9S): C, H, N.
Ethyl (S)-2-(2,4-Dihydroxyphenyl)-4,5-dihydro-4-meth-
yl-4-thiazolecarboxylate (24). Iodoethane (7.02 g, 45.0
mmol) and DIEA (5.81 g, 45.0 mmol) were successively added
to 8 (6.33 g, 25.0 mmol) in DMF (290 mL), and the solution
was stirred at room temperature for 15 h. After solvent
removal under high vacuum, the residue was treated with 1:1
0.5 M citric acid/saturated NaCl (250 mL) and was extracted
with EtOAc (3 × 150 mL). The combined extracts were washed
with 250-mL portions of 0.25 M citric acid, 1% NaHSO3, H2O,
and saturated NaCl, and solvent was evaporated. Purification
by flash column chromatography using 1:3:6 EtOAc/hexanes/
CH2Cl2 furnished 6.72 g (96%) of 24 as a light yellow oil: [R]25
+50.8° (c 1.26, CHCl3); 1H NMR δ 1.30 (2 t, 3 H, J ) 7.1), 1.66
(s, 3 H), 3.19 (d, 1 H, J ) 11.3), 3.83 (d, 1 H, J ) 11.3), 4.25 (q,
2 H, J ) 7.1), 6.37 (dd, 1 H, J ) 8.6, 2.4), 6.44 (d, 1 H, J )
2.4), 7.27 (d, 1 H, J ) 8.6) 12.5 (br s, 1 H); 13C NMR δ 16.92,
27.32, 42.71, 64.88, 85.94, 105.95, 110.20, 112.89, 135.04,
163.20, 164.06, 175.88. Anal. (C13H15NO4S) C, H, N.
J ) 8.1), 3.06-3.22 (m, 6 H), 3.44 (d, 1 H, J ) 11.1), 3.84 (d,
1 H, J ) 11.7), 4.06-4.20 (m, 2 H), 6.45 (s, 1 H), 6.50 (d, 1 H,
J ) 8.7), 7.46 (d, 1 H, J ) 8.7); 13C NMR (D2O) δ 21.42, 21.55,
22.75, 24.31, 35.56, 37.60, 43.46, 46.46, 74.46, 100.33, 104.66,
108.48, 115.35 (J ) 290), 133.29, 159.71, 161.93 (q, J ) 35),
166.32, 173.59, 180.80; HRMS m/z calcd for C18H28N3O4S
382.1800 (M + H, free amine), found 382.1808.
N,N′-Bis(tert-butoxycarbonyl)-N-[4-(tosyloxy)butyl]-
1,3-diaminopropane (30). p-Toluenesulfonyl chloride (0.82
g, 4.3 mmol) in CH2Cl2 (5 mL) was added to 29 (1.0 g, 2.9
mmol) in CH2Cl2 (5 mL) at 0 °C, followed by NEt3 (0.82 mL,
5.9 mmol). The reaction mixture was stirred at room temper-
ature under N2 for 18 h and was concentrated in vacuo. The
residue was diluted with EtOAc (50 mL), followed by washing
with 50 mL portions of saturated NaHCO3, 0.5 M citric acid,
H2O, and saturated NaCl. After solvent removal in vacuo, flash
chromatography, eluting with 3% CH3OH/CH2Cl2, gave 1.15
g (80%) of 30 as a colorless viscous oil: 1H NMR (CD3OD) δ
1.30-1.70 (m, 6 H), 1.43 (s, 18 H), 2.46 (s, 3 H), 2.97-3.05 (m,
2 H), 3.15 (q, 4 H, J ) 6.6), 4.05 (t, 2 H, J ) 6.4), 6.57 (s, 1 H),
7.44 (d, 2 H, J ) 8.1), 7.78 (d, 2 H, J ) 8.4); 13C NMR δ 21.75,
24.44, 24.68, 26.35, 28.55, 37.53, 43.72, 44.31, 46.18, 70.20,
79.10, 79.86, 127.98, 129.98, 133.23, 144.90, 156.11. Anal.
(C24H40N2O7S): C, H, N.
Ethyl (S)-4,5-Dihydro-2-[2-hydroxy-4-[8-(tert-butoxy-
carbonylamino)-5-(tert-butoxycarbonyl)-5-azaoctyloxy]-
phenyl]-4-methyl-4-thiazolecarboxylate (31). Sodium (0.024
g, 1.0 mmol) was introduced to CH3CH2OH (10 mL) under N2,
and the solution was added to 24 (0.33 g, 1.2 mmol) and 30
(0.55 g, 1.1 mmol). The reaction mixture was heated to 80 °C
for 16 h and was concentrated in vacuo. The residue was taken
up in CHCl3 (30 mL), which was washed with H2O (20 mL)
and saturated NaCl (20 mL). After solvent was removed by
rotary evaporation, column chromatography on silica gel,
eluting with 5:1 hexanes/EtOAc, furnished 0.25 g (37%) of 31
a glass: [R]25 +31.9° (c 0.97, CHCl3); 1H NMR (CD3OD) δ 1.28
(t, 3 H, J ) 7.2), 1.43 (s, 9 H), 1.45 (s, 9 H), 1.64 (s, 3 H), 1.64-
1.80 (m, 6 H), 2.97-3.08 (m, 2 H), 3.20-3.32 (m, 5 H), 3.83 (d,
1 H, J ) 11.4), 4.03 (t, 2 H, J ) 6.0), 4.23 (q, 2 H, J ) 7.2),
6.46 (s, 1 H), 6.49 (d, 1 H, J ) 2.4), 6.59 (s, 1 H), 7.32 (d, 1 H,
J ) 9.0); 13C NMR δ 14.19, 24.57, 25.35, 26.51, 28.55, 37.46,
39.93, 43.88, 46.69, 61.98, 67.77, 79.76, 83.21, 101.37, 107.26,
109.82, 131.78, 156.22, 161.33, 163.28, 170.88, 172.92, 184.05.
Anal. (C30H47N3O8S): C, H, N.
(S)-4,5-Dihydro-2-[2-hydroxy-4-[8-(tert-butoxycarbonyl-
amino)-5-(tert-butoxycarbonyl)-5-azaoctyloxy]phenyl]-4-
methyl-4-thiazolecarboxylic Acid (32). Sodium hydroxide
(1 N, 1.2 mL, 1.2 mmol) was added to 31 (0.15 g, 0.25 mmol)
in CH3CH2OH (1.2 mL). The reaction was stirred at room
temperature for 16 h and was concentrated under reduced
pressure. The residue was treated with 1 N HCl (20 mL),
followed by extraction with EtOAc (3 × 20 mL). The combined
extracts were washed with H2O (30 mL) and saturated NaCl
(30 mL). Solvent removal in vacuo yielded 0.11 g (77%) of 32
a viscous tan oil: [R]25 +18.5° (c 0.96, CH3OH); 1H NMR δ 1.44
(s, 9 H), 1.46 (s, 9 H), 1.56-1.80 (m, 6 H), 1.72 (s, 3 H), 3.04-
3.30 (m, 6 H), 3.24 (d, 1 H, J ) 11.4), 3.86 (d, 1 H, J ) 11.4),
3.94-4.04 (m, 2 H), 5.34 (br s, 1 H), 6.42 (d, 1 H, J ) 8.4),
6.48 (s, 1 H), 7.29 (d, 1 H, J ) 8.4); 13C NMR (CD3OD) δ 25.34,
27.49, 28.74, 28.79, 38.97, 41.41, 68.74, 79.94, 80.99, 86.50,
102.44, 107.49, 111.40, 132.48, 157.44, 158.44, 162.82, 164.34,
169.75, 180.15; HRMS m/z calcd for C28H43N3NaO8S 604.2668
(M + Na), found 604.2687.
Ethyl (S)-4,5-Dihydro-2-[2-hydroxy-4-[12-(tert-butoxy-
carbonylamino)-5,9-bis(tert-butoxycarbonyl)-5,9-diaza-
dodecyloxy]phenyl]-4-methyl-4-thiazolecarboxylate (25).
A mixture of 23 (1.67 g, 2.54 mmol), 24 (0.751 g, 2.67 mmol),
and freshly prepared 0.20 M sodium ethoxide in CH3CH2OH
(8 mL, 1.6 mmol) was stirred at 60 °C for 15 h. After the white
solid was filtered, the filtrate was concentrated by rotary
evaporation. The residue was dissolved in CHCl3 (100 mL) and
was washed with H2O and saturated NaCl. Solvent removal
and column chromatography on silica gel, eluting with 5%
EtOAc/CH2Cl2, gave 1.31 g (67%) of 25 as a pale yellow oil:
1
[R]25 +17.0° (c 1.00, CHCl3); H NMR δ 1.30 (t, 3 H, J ) 7.2),
1.4-1.8 (s + m, 35 H), 3.02-3.33 (m + d, 11 H, J ) 11.4),
3.83 (d, 1 H, J ) 11.1), 3.98 (t, 2 H, J ) 5.8), 4.24 (2 q, 2 H, J
) 7.2), 6.41 (dd, 1 H, J ) 8.6, 2.4), 6.46 (d, 1 H, J ) 2.4), 7.28
(d, 1 H, J ) 6.6); 13C NMR δ 14.18, 24.57, 26.42, 26.50, 28.54,
28.56, 28.58, 29.81, 37.51, 39.92, 43.67, 44.97, 46.79, 61.91,
67.78, 79.52, 79.74, 83.21, 101.39, 107.24, 109.81, 131.77,
155.58, 156.10, 161.33, 163.29, 170.87, 172.91, 182.00. Anal.
(C38H62N4O10S): C, H, N.
(S)-4,5-Dihydro-2-[2-hydroxy-4-[12-(tert-butoxycarbon-
ylamino)-5,9-bis(tert-butoxycarbonyl)-5,9-diazadodecyl-
oxy]phenyl]-4-methyl-4-thiazolecarboxylic Acid (26).
Treatment of 25 (0.383 g, 0.499 mmol) with 1 M methanolic
NaOH (5 mL, 5 mmol) at room temperature for 15 h, acidifica-
tion with 1 N HCl, and solvent removal in vacuo gave a pink
solid. Purification using a short Sephadex LH-20 column,
eluting with CH3OH, gave an iron active band, which was
dried to provide 233 mg (63%) of 26 as a white solid: [R]26
1
+8.8° (c 1.02, CH3OH); H NMR δ 1.38-1.84 (s + m, 35 H),
3.02-3.32 (m + d, 11 H, J ) 11.4), 3.87 (d, 1 H, J ) 11.4),
3.98 (t, 2 H, J ) 5.6), 6.41 (d, 1 H, J ) 8.7), 6.48 (s, 1 H), 7.28
(d, 1 H, J ) 6.0); 13C NMR δ 24.64, 26.46, 28.57, 28.59, 28.62,
29.00, 37.34, 39.91, 45.03, 46.86, 67.79, 79.76, 79.91, 83.05,
101.48, 107.37, 109.71, 131.88, 155.74, 161.39, 162.23, 163.40,
174.85, 186.55; HRMS m/z calcd for C36H59N4O10S 739.3952
(M + H), found 739.3898. Anal. (C36H58N4O10S·0.5H2O): C, H,
N.
(S)-4,5-Dihydro-2-[2-hydroxy-4-(4-aminobutoxy)phenyl]-
4-methyl-4-thiazolecarboxylic Acid Trifluoroacetate (16).
Trifluoroacetic acid (5 mL) was added to 35 (0.505 g, 1.19
mmol) in CH2Cl2 (5 mL) with ice bath cooling, and the solution
was stirred for 1 h at 0 °C and for 1 h at room temperature.
Removal of volatiles in vacuo gave a white solid, which was
passed through a short Sephadex LH-20 column, eluting with
70:30 toluene/CH3OH. The iron active band was dried to
provide 0.331 g (63%) of 16 as a white solid: [R]26 +110.8° (c
0.48, H2O); 1H NMR (CD3OD) δ 1.74 (s, 3 H), 1.77-2.03 (m, 4
H), 3.46 (d, 1 H, J ) 12.0), 3.93 (d, 1 H, J ) 11.7), 4.10 (t, 2 H,
(S)-4,5-Dihydro-2-[2-hydroxy-4-(8-amino-5-azaoctyl-
oxy)phenyl]-4-methyl-4-thiazolecarboxylic Acid Bis(tri-
fluoroacetate) (15). Trifluoroacetic acid (2 mL) was added
to 32 (0.1 g, 0.17 mmol), and the solution was stirred for 1 h
at room temperature under N2. After TFA removal in vacuo,
the residue was treated with CH2Cl2 and CH3CH2OH. Solvent
removal in vacuo produced 15 (quantitatively) as tan crys-
1
tals: mp 122-124 °C; [R]25 +18.8° (c 0.85, CH3OH); HNMR
(D2O) δ 1.68 (s, 3 H), 1.80-1.92 (m, 4 H), 2.09 (quintet, 2 H,