A R T I C L E S
Simpson and Widlanski
4.20 (d, J ) 6.8 Hz, 2H), 2.09 (m, 1H), 0.99 (d, J ) 6.8 Hz, 6H); 13
C
Experimental Section
NMR (100 MHz, CDCl3) δ 150.41, 130.06, 127.41, 121.15, 80.38,
28.19, 18.61; IR (neat) 2968, 2878, 1587, 1489, 1408, 1207, 1149,
973, 879; HRMS (CI) m/z calcd for C10H15O4S (M + H+) 231.0686,
found 231.0687.
General. Solvents were distilled under a dry nitrogen atmosphere
from potassium benzophenone ketyl (THF and Et2O) or calcium hydride
(triethylamine, pyridine, DMPU) or were fractionally distilled (metha-
nol, acetone, DMF). Other commercial reagents were used as received
unless otherwise noted. Sodium bis(trimethylsilyl)amide is com-
mercially available as a 1 M solution in THF. An accurate molarity of
this solution was determined by titration with the use of the 4-phenyl-
benzylidene benzylamine indicator.23 All reactions were carried out in
flame-dried flasks under a dry nitrogen or argon atmosphere and using
magnetic stirring. Flash column chromatography was performed with
60 Å 230-400 mesh silica gel. 1H and 13C NMR spectra were recorded
at 400 and 100 MHz, respectively. Fourier transformed infrared spectra
were recorded as neat liquids, solids, or thin films (obtained by
evaporation from chloroform). High-resolution mass spectra were
obtained by the methods indicated.
Synthesis of Neopentyl-Protected Sulfate Monester Esters. Rep-
resentative Example: Phenyl Neopentyl Sulfate (1). Phenol (0.3043
g, 3.23 mmol) was dissolved in 4 mL of THF and 3 mL of DMPU,
and the resulting solution was cooled to -75 °C. Sodium bis-
(trimethylsilyl)amide (0.93 M solution in THF, 3.8 mL, 3.53 mmol,
1.09 equiv) was added dropwise to the cooled solution and stirred for
10 min. Neat neopentyl chlorosulfate (0.56 mL, 3.52 mmol, 1.09 equiv)
was added quickly to the reaction mixture. After 10 min, the reaction
mixture was allowed to warm to room temperature. Upon completion
(TLC), ethyl acetate and saturated aqueous NaHCO3 were added. The
organic layer was separated and washed with saturated aqueous
NaHCO3, water and brine, and then dried over MgSO4 and concentrated
in vacuo. Purification by silica gel chromatography (10% ethyl acetate/
hexanes) gave 1 as clear liquid (0.750 g, 95%): 1H NMR (400 MHz,
CDCl3) δ 7.44-7.30 (m, 5H), 4.09 (s, 2H), 1.00 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 150.42, 130.10, 127.42, 121.17, 83.54, 32.05,
26.07; IR (neat) 2964, 2873, 1587, 1489, 1410, 1370, 1206, 1175, 1149,
962, 880; HRMS (EI) m/z calcd for C11H16O4S (M+) 244.0769, found
244.0776.
Synthesis of Isobutyl-Protected Sulfate Monester Esters. Rep-
resentative Example: Phenyl Isobutyl Sulfate (5). Phenol (0.2016
g, 2.14 mmol) was dissolved in 40 mL of THF, and the resulting
solution was cooled to -15 °C. Sodium bis(trimethylsilyl)amide (1.0
M solution in THF, 2.4 mL, 2.4 mmol, 1.1 equiv) was added dropwise
to the cooled solution and stirred for 10 min. Neat isobutyl chlorosulfate
(1.5 mL, 10.58 mmol, 4.9 equiv) was added quickly to the reaction
mixture. After 10 min, the reaction mixture was allowed to warm to
room temperature. Upon completion (TLC), ethyl acetate and saturated
aqueous NaHCO3 were added. The organic layer was separated and
washed with saturated aqueous NaHCO3, water and brine, and then
dried over MgSO4 and concentrated in vacuo. Purification by silica
gel chromatography (10% ethyl acetate/hexanes) gave 5 as a clear liquid
(0.392 g, 80%): 1H NMR (400 MHz, CDCl3) δ 7.44-7.30 (m, 5H),
Deblocking Neopentyl-Protected Sulfate Monester Esters. Rep-
resentative Example: Estrone Sulfate (16).10 In a flask fitted with a
reflux condenser, estrone neopentyl sulfate 2 (0.1011 g, 0.240 mmol)
was dissolved in 1 mL of DMF. Sodium azide (0.0213 g, 0.328 mmol,
1.4 equiv) was added, and the solution was stirred and heated to 70 °C
in an oil bath overnight. Removal of the solvent in vacuo and
purification of the crude product by silica gel chromatography (20%
ethanol/CH2Cl2) gave 16 as the sodium salt (0.088 g, 98%): 1H NMR
(400 MHz, MeOH-d4) δ 7.24 (d, J ) 8.4 Hz, 1H), 7.06-7.03 (m, 2H),
2.89-2.87 (m, 2H), 2.52-1.88 (m, 7H), 1.66-1.40 (m, 6H), 0.91 (s,
3H); 13C NMR (100 MHz, MeOH-d4) δ 151.76, 138.71, 137.51, 126.93,
122.48, 119.77, 45.46, 45.33, 39.59, 36.72, 32.79, 30.42, 27.52, 27.04,
22.52, 14.30, 14.21; IR (solid) 3453, 2930, 2867, 1724, 1493, 1227,
1049, 933; HRMS (ESI) m/z calcd for C18H21O5Na2S (M + 2Na+)
395.0900, found 395.0909.
Deblocking Isobutyl-Protected Aliphatic Sulfate Monester Esters.
Representative Example: D-Glucose 3-Sulfate (20).19 In a flask fitted
with a reflux condenser, D-glucose 3-isobutyl sulfate 12 (0.038 g, 0.120
mmol) was dissolved in 4 mL of acetone. Sodium iodide (0.0544 g,
0.363 mmol, 3.0 equiv) was added, and the solution was stirred and
heated to 55 °C in an oil bath for 5 h. The precipitated product was
washed several times with cold acetone to give 20 as a hydroscopic
solid (0.033 g, 97%): 1H NMR (400 MHz, D2O) δ (R-anomer, 45%)
5.30 (d, J ) 4.0 Hz, 1H), 4.51 (t, J ) 9.6 Hz, 1H), 3.45 (m, 1H);
(â-anomer, 55%) 4.77-4.74 (m, 1H), 4.33 (t, J ) 9.2 Hz, 1H), 3.58-
3.54 (m, 1H); (both anomers) 3.95-3.72 (m, 3H), 3.64 (t, J ) 9.6 Hz,
1H); 13C NMR (100 MHz, D2O) δ 96.45, 92.84, 85.11, 83.05, 76.22,
73.68, 71.99, 71.00, 69.13, 69.06, 61.48, 61.31; IR (solid) 3362, 1637,
1215, 1055, 999, 934, 816; HRMS (ESI) m/z calcd for C6H11O9Na2S
(M + 2Na+) 304.9914, found 304.9910.
Deblocking Isobutyl-Protected Aryl Sulfate Monester Esters.
Representative Example: Estrone Sulfate (22). In a flask fitted with
a reflux condenser, estrone isobutyl sulfate 6 (0.0420 g, 0.103 mmol)
was dissolved in 1 mL of acetone. Sodium thiocyanate (0.0177 g, 0.218
mmol, 2.1 equiv) and triethylamine (0.04 mL) were added, and the
solution was stirred and heated to 55 °C in an oil bath for 2 h. The
precipitated product was washed several times with cold acetone to
give 22 as a white solid (0.037 g, 96%): 1H NMR, 13C NMR, IR, and
HRMS identical to estrone sulfate 16.
Supporting Information Available: Complete experimental
procedures for the synthesis of all compounds, procedures for
protecting group reactivity and stability studies, and spectral
data. This material is available free of charge via the Internet
(23) Duhamel, L.; Plaquevent, J.-C. J. Organomet. Chem. 1993, 448, 1-3.
JA056086J
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1610 J. AM. CHEM. SOC. VOL. 128, NO. 5, 2006