Hydroxylated Polyamine Analogues as Antiproliferatives
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 15 2457
142.25; HRMS, m/z calcd for C16H27N2O2S 311.1793 (M + H),
room temperature, and the reaction mixture was stirred
overnight. The solvent was removed in vacuo, and the crude
product was purified by flash chromatography (CHCl3) to give
6.10 g of 13 (96%) as a colorless oil: 1H NMR δ 0.27 (m, 1 H),
0.35 (m, 1 H), 0.60 (m, 2 H), 1.04 (m, 1 H), 1.32 (s, 3 H), 1.40
(s, 3 H), 3.43 (m, 1 H), 3.51 (dd, 2 H, J ) 15.0, 7.2), 3.65 (dd,
1 H, J ) 8.7, 6.3), 3.69 (m, 1 H), 4.08 (dd, 1 H, J ) 8.7, 6.3),
4.31 (m, 1 H); 13C NMR δ 3.39, 4.58, 9.21, 25.25, 26.67, 54.22,
67.16, 75.26, 77.20, 110.06, 120.01 (q, J ) 328); HRMS, m/z
calcd for C11H19F3NO4S 318.0987 (M + H), found 318.0985;
found 311.1776.
N,N′-Bis(m esit ylen esu lfon yl)-N-cyclop r op ylm et h yl-
1,3-d ia m in op r op a n e (10). Mesitylenesulfonyl chloride (7.75
g, 35.4 mmol), 9 (10.0 g, 32.2 mmol), and 1 N NaOH (50 mL)
were reacted according to the method of 4. Flash chromatog-
raphy (8% acetone/toluene) generated 13.4 g of 10 (84%) as a
1
white solid: mp 92-94 °C; H NMR δ -0.06 to +0.05 (m, 2
H), 0.39-0.48 (m, 2 H), 0.67-0.80 (m, 1 H), 1.72 (quintet, 2
H, J ) 6.3), 2.30 (s, 6 H), 2.57 (s, 6 H), 2.62 (s, 6 H), 2.87-2.96
(m, 4 H), 3.45 (t, 2 H, J ) 6.3), 4.95 (t, 1 H, J ) 6.3), 6.93 (s,
2 H), 6.95 (s, 2 H); 13C NMR δ 3.85, 8.89, 20.94, 22.79, 22.87,
27.71, 39.24, 42.93, 50.01, 131.91, 132.00, 133.15, 134.02,
[R]25 -20.1 (c 2.33).
D
N-Cyclop r opylm eth yl-N-[(2S)-2,3-dih ydr oxyp r op yl]tr i-
flu or om eth a n esu lfon a m id e (14). A solution of 13 (5.91 g,
18.6 mmol) in acetone (40 mL) and 1 N HCl (80 mL) was
heated at reflux for 2 h. The solvent was removed in vacuo,
and the residue was purified by flash chromatography (15:1
CHCl3/CH3OH) to give 5.07 g of 14 (98%) as an oil: 1H NMR
δ 0.24 (m, 2 H), 0.57 (m, 2 H), 0.97 (m, 1 H), 2.60 (s, 2 H), 3.30
(s, 2 H), 3.52 (m, 3 H), 3.67 (dd, 1 H, J ) 11.7, 3.6), 3.93 (m,
1 H); 13C NMR δ 4.11, 9.42, 50.00, 54.69, 63.54, 70.03, 120.05
(q, J ) 323); HRMS, m/z calcd for C8H15F3NO4S 278.0674 (M
+ H), found 278.0673; [R]2D4 -4.94 (c 1.74).
138.87, 140.05, 141.97, 142.56; HRMS, m/z calcd for C25H37
N2O4S2 493.2195 (M + H), found 493.2132.
-
N1-Cyclop r op ylm eth yl-N11-eth yl-N1,N4,N8,N11-tetr a k is-
(m esitylen esu lfon yl)n or sp er m in e (11).31 Sodium hydride
(60%, 0.39 g, 9.8 mmol) was added to 10 (3.7 g, 7.5 mmol) in
DMF (50 mL) under ice-bath conditions. The mixture was
stirred for an additional 30 min each at 0 °C and at room
temperature and was added dropwise to 5b (5.3 g, 9.0 mmol)
in DMF (75 mL). The mixture was stirred overnight at room
temperature and was quenched under ice-bath conditions with
EtOH (10 mL) and H2O (10 mL). The solvents were removed
in vacuo, and the concentrate was taken up in CHCl3 (50 mL)
and H2O (50 mL). The chloroform layer was washed with brine
(50 mL); the solution was concentrated in vacuo. Flash
chromatography (3:1 hexane/EtOAc) gave 5.47 g of 10 (73%)
as a glassy white solid: 1H NMR δ -0.08 to -0.02 (m, 2 H),
0.38-0.45 (m, 2 H), 0.64-0.78 (m, 1 H), 0.95 (t, 3 H, J ) 7.2),
1.56-1.73 (m, 6 H), 2.29 (s, 12 H), 2.53 (s, 12 H), 2.54 (s, 12
H), 2.86 (d, 2 H, J ) 6.6), 2.91-3.17 (m, 14 H), 6.93 (s, 8 H);
13C NMR δ 3.77, 8.90, 12.61, 20.90, 22.68, 22.69, 22.74, 22.76,
25.08, 25.18, 25.28, 40.04, 42.49, 43.20, 49.92, 131.88, 131.96,
132.91, 132.96, 133.02, 133.10, 140.00, 140.02, 140.03, 142.32,
142.49, 142.52; HRMS, m/z calcd for C51H75N4O8S4 999.4468
(M + H), found 999.4382.
N-Cyclop r op ylm eth yl-N-[(2S)-2-h yd r oxy-3-(p-tolu en e-
su lfon a to)p r op yl]tr iflu or om eth a n esu lfon a m id e (15). p-
Toluenesulfonyl chloride (3.70 g, 19.4 mmol) in anhydrous
CH
2Cl2 (20 mL) was added dropwise to 14 (4.89 g, 17.7 mmol)
in anhydrous pyridine (25 mL) at 0 °C. After the reaction
mixture had been stirred at room temperature overnight, it
was poured into a slurry of 1 N HCl (300 mL) and ice and
then extracted with CHCl3 (300 mL). The organic layer was
washed with H2O (300 mL) and brine (300 mL), concentrated
under reduced pressure, and purified by flash chromatography
(40:1 CHCl3/CH3OH) to give 6.70 g of 15 (88%) as an oil: 1H
NMR δ 0.28 (m, 2 H), 0.61 (m, 2 H), 0.98 (m, 1 H), 2.44 (s, 3
H), 2.63 (br, 1 H), 3.33 (m, 2 H), 3.49 (dd, 1 H, J ) 15.3, 7.8),
3.58 (dd, 1 H, J ) 15.3, 4.2), 4.02 (m, 2 H), 4.14 (m, 1 H), 7.35
(d, 2 H, J ) 8.1), 7.78 (d, 2 H, J ) 8.1); 13C NMR δ 3.96, 4.27,
9.32, 21.65, 49.94, 54.90, 68.48, 71.03, 119.97 (q, J ) 323),
127.96, 130.06, 132.09, 145.47; HRMS, m/z calcd for C15H21F3-
NO6S2 432.0762 (M + H), found 432.0765; [R]2D2 -3.83 (c
1.07).
N1-Cyclop r op ylm eth yl-N11-eth yln or sp er m in e Tetr a h y-
d r och lor id e (1).31 Hydrogen bromide in HOAc (30%, 50 mL)
was added to 11 (5.3 g, 5.3 mmol) and phenol (19.9 g, 0.212
mol) in CH2Cl2 (50 mL) at 0 °C. The reaction mixture was
stirred overnight at room temperature and was quenched with
H2O (100 mL) under ice-bath conditions. The aqueous layer
was washed with CH2Cl2 (4 × 100 mL), and the former was
concentrated in vacuo. The residue was treated with 1 N
NaOH (20 mL) and 19 N NaOH (10 mL) under ice-bath cooling
and was extracted with CHCl3 (4 × 50 mL). After concentration
of the CHCl3 extracts, the oil was dissolved in EtOH (50 mL)
and acidified with concentrated HCl (10 mL). Solvent removal
in vacuo followed by recrystallization from aqueous EtOH gave
N-Cyclop r op ylm eth yl-N-[(2S)-2,3-ep oxyp r op yl]tr iflu o-
r om eth a n esu lfon a m id e (16). A suspension of 15 (6.59 g,
15.3 mmol) and K2CO3 (2.24 g, 16.2 mmol) in CH3OH (100 mL)
was stirred at room temperature for 4 h. Solids were filtered,
and brine (100 mL), water (150 mL), and CH2Cl2 (150 mL)
were added to the filtrate. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (2 × 100 mL). The
organic phase was evaporated under reduced pressure and
purified by flash chromatography (4:1 cyclohexane/EtOAc) to
give 2.93 g of 16 (74%) as an oil: 1H NMR δ 0.27 (m, 1 H),
0.35 (m, 1 H), 0.60 (m, 2 H), 1.07 (m, 1 H), 2.56 (dd, 1 H, J )
4.5, 2.4), 2.82 (t, 1 H, J ) 4.5), 3.16 (m, 1 H), 3.31 (m, 2 H),
3.43 (m, 1 H), 3.95 (dd, 1 H, J ) 15.0, 3.0); 13C NMR δ 3.49,
4.52, 9.45, 44.67, 50.54, 54.22, 119.99 (q, J ) 323); HRMS,
m/z calcd for C8H13F3NO3S (M + H), 260.0568, found 260.0560;
[R]2D2 -32.1 (c 1.00).
1
0.800 g of 1 (36%) as white flakes: mp >290 °C; H NMR δ
0.34-0.41 (m, 2 H), 0.66-0.74 (m, 2 H), 1.02-1.17 (m, 1 H),
1.30 (t, 3 H, J ) 7.5), 2.07-2.21 (m, 6 H), 2.98 (d, 2 H, J )
7.5), 3.08-3.26 (m, 14 H); 13C NMR δ 4.04, 7.22, 11.14, 23.34,
43.71, 44.47, 45.22, 45.31, 53.29; HRMS, m/z calcd for C15H35N4
271.2862 (M + H), found 271.2861. Anal. Calcd (C15H38Cl4N4)
C, H, N.
(2R)-N4,N7-Dib en zyl-N1-et h yl-2-h yd r oxy-N1-t r iflu or o-
m eth a n esu lfon yln or sp er m id in e (18). A solution of 17
(11.36 g, 50.89 mmol)30 and N,N′-dibenzyl-1,3-diaminopropane
(21.80 g, 85.70 mmol)42 in EtOH (200 mL) was heated at reflux
overnight, and the solvent was removed under reduced pres-
sure. The residue was purified using flash chromatography
(60:39.5:0.5 toluene/acetone/concentrated NH4OH) to afford
15.80 g of 18 (64%) as an oil: 1H NMR δ 1.13 (t, 3 H, J ) 7.2),
1.64 (m, 2 H), 2.37 (m, 2 H), 2.52 (m, 1 H), 2.65 (m, 3 H), 3.17
(m, 2 H), 3.40 (d, 1 H, J ) 13.5), 3.46 (m, 2 H), 3.64 (d, 1 H, J
) 13.5), 3.68 (s, 2 H), 3.73 (m, 1 H), 5.31 (br s, 1 H), 7.20 (m,
10 H); 13C NMR δ 13.49, 26.86, 44.80, 47.06, 51.19, 52.24,
53.97, 57.63, 59.46, 68.21, 120.00 (q, J ) 324), 127.03, 127.21,
128.28, 128.37, 128.41, 129.00, 138.64, 139.73; HRMS, m/z
calcd for C23H33F3N3O3S 488.2195 (M + H), found 488.2206;
[R]2D4 +12.6 (c 1.00).
N-Cyclop r op ylm et h ylt r iflu or om et h a n esu lfon a m id e
(12). Trifluoromethanesulfonic anhydride (27.00 g, 95.7 mmol)
in CH2Cl2 (50 mL) was added dropwise to 6 (10.30 g, 95.7
mmol) and Et3N (40 mL, 0.29 mol) in CH2Cl2 (100 mL) at -78
°C, and the reaction mixture was stirred overnight at room
temperature. The reaction solution was washed with 1 N HCl
(3 × 100 mL) and brine and was concentrated under reduced
pressure. Vacuum distillation afforded 9.74 g of 12 (50%): bp
1
81-84 °C at 2.6 mmHg; H NMR δ 0.27 (m, 2 H), 0.63 (m, 2
H), 1.08 (m, 1 H), 3.17 (t, 2 H, J ) 6.3), 4.91 (br, 1 H).
N-Cyclopr opylm eth yl-N-[(4S)-2,2-dim eth yl-1,3-dioxolan -
4-ylm eth yl]tr iflu or om eth a n esu lfon a m id e (13). (S)-(+)-
2,2-Dimethyl-1,3-dioxolane-4-methanol (2.64 g, 20.0 mmol) and
triphenylphosphine (6.29 g, 24.0 mmol) were added to 12 (4.06
g, 20.0 mmol) in THF (100 mL). Diisopropyl azodicarboxylate
(4.85 g, 24.0 mmol) in THF (40 mL) was added dropwise at