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C. Marinzi et al. / Bioorg. Med. Chem. 12 (2004) 2749–2757
concentrated in vacuo. Flash column chromatography
of the residue (silica gel, 20% methanol in ethyl acetate)
afforded 4 (1.56 g, 91%). Compound 4: Rf ¼ 0:22 (silica
gel, 20% methanol in ethyl acetate); 1H NMR
(400 MHz, CDCl3): d 7.40–7.86 (m, 4H, Har), 4.65 (dd,
J1 ¼ 7:3, J2 ¼ 4:4 Hz, 1H, ArCH), 3.92 (dd, J1 ¼ 11:1,
J2 ¼ 4:4 Hz, 1H, CH2), 3.68 (dd, J1 ¼ 11:1, J2 ¼ 7:3 Hz,
1H, CH2), 2.1 (bs, 3H, NH2, OH).
(bs, 1H, ArCHNH), 5.25 (bs, 1H, NH), 3.20–3.40 (m,
2H, CH2SAc), 2.33 (s, 3H, CH3), 1.30 (s, 9H, t-Bu).
4.8. (N-tert-Butyloxycarbonyl)-2-amino-2-(o-nitrophenyl)
ethanethiol (8)
A solution of hydroxylamine (1 g, 14.4 mmol) in 50%
aqueous methanol (15 mL), pH 6.5, was added to a
solution of derivative 7 and the resulting mixture was
stirred for 2 h. Water (200 mL) was added and the
4.5. (N-tert-Butyloxycarbonyl)-2-amino-2-(o-nitrophenyl)
ethanol (5)
mixture
was
extracted
with
dichloromethane
(2 · 200 mL). The combined organic extracts were
washed with brine (400 mL), dried (Na2SO4) and evap-
orated. The crude product was used without further
purification. Compound 8: Rf ¼ 0:38 (silica gel, 10%
ethyl acetate in toluene).
Aminoalcohol 4 (1 g, 5.49 mmol) was dissolved in
methanol (20 mL) and di-tert-butylcarbonate (1.32 g,
6.04 mmol) and triethylamine (1.54 mL, 10.98 mmol)
were added at 0 ꢁC. The mixture was stirred for 2 h. The
solvent was evaporated and the residue was dissolved in
chloroform (150 mL). The organic layer was washed
with HCl (5% water solution, 2 · 200 mL), brine
(2 · 200 mL), dried (Na2SO4) and evaporated. Flash
column chromatography of the residue (silica gel, 50%
ethyl acetate in petroleum ether) afforded 5 (1.71 g,
99.6%). Compound 5: Rf ¼ 0:5 (silica gel, 50% ethyl
acetate in petroleum ether); 1H NMR (400 MHz,
CDCl3): d 7.40–7.90 (m, 4H, Har), 3.65 (m, 1H, ArCH),
2.05–2.30 (m, 2H, CH2OH), 1.40 (s, 9H, t-Bu), 3.30 (s,
1H, OH).
4.9. 2-Amino-2-(o-nitrophenyl) (S-trityl) ethanethiol (9)
N-Boc protected derivative 8 (313 mg, 1.05 mmol) was
dissolved in neat TFA (1 mL) and tritylalcohol (290 mg,
1.1 mmol) was added. After stirring for 30 min, the sol-
vent was evaporated and the residue was dissolved in
chloroform (200 mL). Aqueous NaOH (0.2 M, 200 mL)
was added and the mixture was extracted with chloro-
form (4 · 200 mL). The combined organic extracts were
washed with brine (2 · 200 mL), dried (Na2SO4) and
concentrated in vacuo. Flash column chromatography
of the residue (silica gel, 0.1% methanol in chloroform)
afforded 9 (425 mg, 95%). Compound 9: Rf ¼ 0:5 (silica
gel, 0.25% methanol in chloroform); (9) 1H NMR
(200 MHz, CDCl3): d 7.20–7.80 (m, 19H, Har), 4.25 (dd,
J1 ¼ 5:1, J2 ¼ 7:7 Hz, 1H, ArCHNH2), 2.75 (dd,
J1 ¼ 11:3, J2 ¼ 5:1 Hz, 1H, CH2STrt), 2.55 (dd,
J1 ¼ 11:3, J2 ¼ 7:7 Hz, 1H, CH2STrt), 1.70 (bs, 2H,
NH2).
4.6. (N-tert-Butyloxycarbonyl)-2-amino-2-(o-nitrophenyl)
ethyl p-toluenesulfonate (6)
To a stirred solution of 5 (1.54 g, 5.47 mmol) in pyridine
(7 mL), tosylchloride (1.3 g, 6.5 mmol) was added at 0 ꢁC
and the mixture was stirred for 8 h at room temperature.
Dichloromethane (200 mL) was added and the resulting
mixture was washed with HCl (5% aqueous solution,
4 · 200 mL), brine (2 · 200 mL) and evaporated. Crys-
tallization of the residue (10% ethyl acetate in petroleum
ether) afforded 6 (2.4 g, 98%). Compound 6: Rf ¼ 0:3
(silica gel, 20% ethyl acetate in toluene); 1H NMR
(400 MHz, CDCl3): d 7.4–8.0 (m, 8H, Har), 5.6 (m, 1H,
NH), 5.45 (bs, 1H, ArCHNH), 4.3–4.5 (m, 2H,
CH2OTs), 2.45 (s, 3H, CH3), 1.4 (s, 9H, t-Bu).
4.10. Synthesis of auxiliary 15. 2-Nitro-4,5-dimethoxy-
styrene (11)
To a suspension of triphenylphosphonium bromide
(22.1 g, 61.6 mmol) in THF (100 mL), a solution of
sodium hexamethyldisilazide (31 mL, 2 M in THF,
62 mmol) was added dropwise over 30 min at 0 ꢁC and
stirred for 1 h. A solution of o-nitroveratraldehyde (10 g,
47.4 mmol) in THF (120 mL) was then added dropwise
and the mixture was stirred at room temperature for an
additional 12 h. The solvent was evaporated and the
residue was dissolved in chloroform (300 mL). NH4Cl
(saturated aqueous solution, 300 mL) was added and the
layers were separated. The organic layer was washed
with NH4Cl (saturated aqueous solution, 2 · 300 mL),
brine (2 · 300 mL) dried (Na2SO4) and concentrated in
vacuo. Flash column chromatography of the residue
(silica gel, 10% ethyl acetate in petroleum ether) afforded
11 (6.2 g, 65%). Compound 11: Rf ¼ 0:42 (silica gel, 30%
4.7. (N-tert-Butyloxycarbonyl)-2-amino-2-(o-nitrophenyl)
(S-acetyl) ethanethiol (7)
A solution of caesium thiolacetate was prepared by
adding thiolacetic acid (1 mL, 14 mmol) to a suspension
of caesium carbonate (2.28 g, 7 mmol) in DMF (8 mL).
This solution was added dropwise to a solution of 6
(1.54 g, 3.54 mmol) in DMF (5 mL). After stirring for
24 h, the mixture was diluted with chloroform (200 mL)
and the organic layer was washed with brine
(3 · 200 mL), dried and evaporated. Flash column
chromatography of the residue (silica gel, 10% ethyl
acetate in toluene) afforded 7 (1.2 g, 98%). Compound 7:
1
ethyl acetate in petroleum ether); H NMR (200 MHz,
1
Rf ¼ 0:25 (silica gel, 10% ethyl acetate in toluene); H
CDCl3): d 7.58 (s, 1H, Har), 7.30 (dd, J ¼ 16:0, 8.9 Hz,
NMR (400 MHz, CDCl3): d 7.35–7.95 (m, 4H, Har), 5.55
1H, H2), 6.97 (s, 1H, Har), 5.63 (d, J ¼ 15:7 Hz, 1H,