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A. Thomson et al. / Bioorg. Med. Chem. 22 (2014) 4602–4608
NMR spectra were collected on a Varian 500 MHz spectrometer.
Chemical shifts are reported in d (ppm) units relative to the solvent
peak. Thin Layer Chromatography (TLC) was conducted on pre-
coated silica gel plates. Column chromatography separations were
conducted on silica gel (230–450 mesh). RP-HPLC separations were
conduct on a Varian Prostar system with microsorb column
(4.6 ꢀ 25 mm) or (21 ꢀ 250 mm) eluting with a linear gradient
from 20%ACN/water/0.05%TFA to 100% ACN. SmAgD was overex-
pressed and purified as previously described.17
4.2.5. N-(5-Bromopentyl)phthalimide (5)
A solution of 5-phthalimido-1-pentanol (0.53 g, 2.3 mmol) and
triphenylphosphine (0.66 g, 2.5 mmol) in dichloromethane
(25 mL) was cooled to 0 °C. N-Bromosuccinimide (0.45 g,
2.5 mmol) was added portion-wise over 10 min and stirring was
continued at 0 °C for 3 h. The reaction mixture diluted with dichlo-
romethane (9 mL) and extracted with water (3 ꢀ 15 mL) and brine
(15 mL). The organics were dried over sodium sulfate and concen-
trated under reduced pressure. The residue was purified on silica
gel (30% ethyl acetate/hexane) to yield the product as a clear color-
less oil (0.54 g, 1.82 mmol, 80%). 1H NMR (500 MHz, CDCl3) d 7.82
(m, 2H), 7.71 (m, 2H), 3.68 (t, 2H, J = 7.5 Hz), 3.38 (t, 2H, J = 7 Hz),
1.88 (m, 2H), 1.69 (m, 2H), 1.46 (m, 2H); 13C NMR (125 MHz,
CDCl3) d 168.31, 133.86, 132.01, 123.13, 37.56, 33.34, 32.11,
27.65, 25.31.
4.2. Synthesis
4.2.1. N1-triphenylmethyl-1,4-diaminobutate (1)
1,4-Diaminobutane (1.59 g, 18.0 mmol) was treated with trityl
chloride (0.95 g, 3.4 mmol) as previously described to afford the
title compound as a clear colorless oil (1.01 g, 3.06 mmol, 90%).24
1H NMR (500 MHz, CDCl3) d 7.51 (m, 6H), 7.30 (m, 6H), 7.20 (t,
3H, J = 7.5 Hz), 2.67 (t, 2H, J = 6.5 Hz), 2.16 (t, 2H, J = 6.5 Hz), 1.51
(m, 4H); 13C NMR (125 MHz, CDCl3) d 146.15, 128.43, 127.68,
126.11, 70.77, 43.30, 41.87, 30.95, 28.07.
4.2.6. N-(5-Phthalimidopentyl)-N-[(4-triphenylmethylamino)-
butyl]-4-nitrobenzenesulfonamide (6)
Potassium carbonate (0.50 g, 3.6 mmol) was added to a solution
of
N-[(4-triphenylmethylamino)butyl]-4-nitrobenzenesulfona-
mide (0.93 g, 1.8 mmol) and N-(5-bromopentyl)phthalimide
(0.54 g, 1.8 mmol) in DMF (12 mL). The mixture was stirred at
95 °C and monitored by TLC (5% EtOAc in DCM). The reaction
was diluted with ethyl acetate (100 mL) and extracted with water
(4 ꢀ 100 mL) and brine (100 mL). The organics were dried over
sodium sulfate and concentrated under reduced pressure. The res-
idue was purified on silica gel (1:3:96 triethylamine/ethyl acetate/
dichloromethane) to yield the product as an off-white foam (1.03 g,
1.41 mmol, 78%). 1H NMR (500 MHz, DMSO) d 8.35 (d, 2H, J = 9 Hz),
8.02 (d, 2H, J = 9 Hz), 7.82 (m, 4H),7.35 (d, 6H, J = 8 Hz), 7.24 (t, 6H,
J = 7.5 Hz), 7.13 (t, 3H, J = 7.5 Hz), 3.51 (t, 2H, J = 7 Hz), 3.07 (m, 4H),
1.91 (m, 2H), 1.58 (m, 2H), 1.49 (m, 4H), 1.35 (m, 2H), 1.20 (m, 2H);
13C NMR (125 MHz, CDCl3) d 168.37, 149.78, 146.04, 145.92,
133.95, 132.01, 128.54, 128.16, 127.77, 126.22, 124.32,
123.20,70.79, 48.22, 47.98, 42.99, 37.47, 28.08, 27.99, 27.82,
26.44, 23.78; HRMS (C42H42N4O6S): calculated 730.2825, observed
730.2837.
4.2.2. N-[(4-Triphenylmethylamino)butyl]-4-nitrobenzenesulfon
amide (2)
Triethylamine (0.86 mL, 6.2 mmol) was added to a solution of
N1-tritylputrescine (1.03 mg, 3.1 mmol) and 4-nitrobenzenelsulfo-
nyl chloride (0.69 mg, 3.1 mmol) in dichloromethane (45 mL).
After stirring at ambient temperature for 1.25 h, the reaction was
diluted with dichloromethane (90 mL) and extracted with water
(5 ꢀ 75 mL). The organics were washed with brine (60 mL), dried
over anhydrous sodium sulfate, and concentrated under reduced
pressure to yield the title compound as an off-white foam
(1.41 g, 2.7 mmol, 88%). 1H NMR (500 MHz, CDCl3) d 8.33 (d, 2H,
J = 9.5 Hz), 7.99 (d, 2H, J = 9.5 Hz), 7.42 (m, 6H), 7.27 (m, 6H),
7.20 (m, 6H), 4.97 (br, 1 H), 3.01 (br, 2H), 3.11 (t, 2H, J = 7 Hz),
1.58 (m, 2H), 1.45 (m, 2H); 13C NMR (125 MHz, CDCl3) d 149.95,
146.03, 145.83, 128.54, 128.22, 127.83, 126.35, 124.36, 70.89,
43.31, 42.89, 27.73, 27.61; HRMS (C29H29N3O4S): calculated
515.1879, observed 515.1883.
4.2.7. N-(5-Phthalimidopentyl)-N-[(4-triphenylmethylamino)-
butyl]-(1,1-dimethyl)ethylcarbamate (7)
4.2.3. 5-Bromo-1-pentanol (3)
A solution of N-(5-phthalimidopentyl)-N-[(4-triphenylmethyla-
mino)butyl]-4-nitrobenzenesulfonamide (502 mg, 0.687 mmol) in
DMF (5 mL) was degassed with nitrogen for 20 min. Potassium car-
bonate (363 mg, 2.75 mmol) and thiophenol (0.14 mL, 1.37 mmol)
were added and the solution was stirred at ambient temperature
for 3 h. The reaction mixture was diluted with ethyl acetate
(60 mL) and extracted with water (2 ꢀ 20 mL), saturated sodium
bicarbonate (2 ꢀ 20 mL), water (2 ꢀ 20 mL), and brine (20 mL).
The organics were dried over sodium sulfate and concentrated
under reduced pressure. The residue was dissolved in dichloro-
methane (6 mL); Boc anhydride (0.247 mL, 0.763 mmol) and tri-
ethylamine (0.127 mL, 0.916 mmol) were added and the reaction
mixture was stirred at ambient temperature for 12 h. The reaction
mixture was diluted with dichloromethane (60 mL) and extracted
with water (2 ꢀ 50 mL) and brine (50 mL). The organics were dried
over sodium sulfate and concentrate under reduced pressure.
The product was purified on silica gel eluting with a gradient
(10–25%) of ethyl acetate in hexanes. Note: the elution solvents
contained 1% triethylamine. The product was isolated as a clear
colorless residue (300.3 mg, 0.466 mmol, 68%). 1H NMR
(500 MHz, CDCl3) d 7.83 (m, 2H), 7.69 (m, 2H), 7.46 (m, 6H), 7.26
(t, 6H, J = 7.5 Hz), 7.17 (t, 3H, J = 7.5 Hz), 3.67 (t, 2H, J = 7.5 Hz),
3.11 (br, 4H), 2.12 (t, 2H, J = 6.5 Hz), 1.69 (m, 2H), 1.52 (m, 4H)
1.44–1.38 (m, 11H), 1.30 (M, 2H); 13C NMR (125 MHz, CDCl3) d
168.17, 155.34, 146.06, 133.69, 131.91, 128.42, 127.56, 125.98,
122.96, 78.84, 70.64, 46.89, 46.70, 43.24, 37.65, 28.29, 28.17,
A round bottom flask, equipped with a Dean-Stark trap, was
charged with 1,5-pentanediol (3.71 g, 35.6 mmol), concentrated
hydrobromic acid (5 mL), and toluene (75 mL). The mixture was
stirred under refluxed for 15 h. After cooling, the reaction mixture
was extracted with 6 M sodium hydroxide (2 ꢀ 15 mL), 5% HCl
(2 ꢀ 15 mL), water (2 ꢀ 15 mL) and brine (20 mL). The organics
were dried over sodium sulfate and concentrated under reduced
pressure to yield the title compound as an orange/brown oil
(4.75 g, 2.84 mmol, 80%). 1H NMR (500 MHz, CDCl3) d 3.65 (t, 2H,
J = 6.5 Hz), 3.42 (t, 2H, J = 6.5 Hz), 1.91 (m, 2H), 1.59 (m, 2 H),
1.53 (m, 2H); 13C NMR (125 MHz, CDCl3) d 62.50, 33.68, 32.44,
31.70, 24.37.
4.2.4. 5-Phthalimido-1-pentanol (4)
Potassium phthalimide (3.0 g, 16.2 mmol) was added to a solu-
tion of 5-bromo-1-pentanol (2.0 g, 12.4 mmol) in DMF (60 mL) and
the mixture was stirred at 95 °C for 2 h. The reaction was diluted
with ethyl acetate (200 mL) and extracted with water
(4 ꢀ 100 mL) and brine (100 mL). The organics were dried over
sodium sulfate, and concentrated under reduced pressure to yield
the title compound as a colorless oil (2.06 g, 8.82 mmol, 71%). 1H
NMR (500 MHz, CDCl3) d 7.80 (m, 2H), 7.68 (m, 2H), 3.66 (t, 2H,
J = 7.5 Hz), 3.61 (t, 2H, J = 7 Hz), 1.68 (m, 2H), 1.58 (m, 2H), 1.39
(m, 2H); 13C NMR (125 MHz, CDCl3) d 168.43, 133.82, 131.98,
123.09, 62.42, 37.76, 32.07, 28.26, 22.94.