Total Synthesis of (+)-Polyoxin J
J . Org. Chem., Vol. 64, No. 8, 1999 2793
3.34 (s, 3H), 1.49 (s, 3H), 1.31 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 132.4, 130.4, 112.3, 109.3, 87.4, 85.4, 84.5, 62.6, 54.7,
26.4, 24.9; MS (CI) m/z 230 (M+), 215, 198, 155, 141, 112, 93.
Anal. Calcd for C11H18O5: C, 57.38; H, 7.88. Found: C, 57.34;
H, 7.92.
3.33 (s, 3H), 1.48 (s, 3H), 1.32 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 168.7, 112.8, 110.2, 86.2, 85.0, 81.6, 63.3, 55.7, 52.7,
26.4, 24.9.
Meth yl (5-Azid o-5-d eoxy-1,2,3-tr i-O-a cetyl-D-a llofu r a -
n osid )u r on a te (17). To a stirred solution of the azide 16 (206
mg, 0.72 mmol) in MeOH (8 mL) was added Dowex 50 W H+
resin (1 g). The resulting mixture was heated at reflux at 65
°C for 12 h. The resin was filtered off, and the filter cake was
washed with MeOH. The filtrate was evaporated to give a
residue which was dissolved in CH2Cl2 (3 mL), and pyridine
(1 mL), DMAP (5 mg), and Ac2O (0.25 mL) were added. The
resulting mixture was stirred at 23 °C for for 4 h. After this
period, the mixture was diluted with CH2Cl2 (10 mL) and
washed with 1 M aqueous NaHSO4 solution and brine and
then dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure, and to a stirred solution of the residue
in CH2Cl2 (1 mL) at 0 °C were added AcOH (1 mL), Ac2O (0.5
mL), and 1 drop of concentrated H2SO4. The resulting mixture
was stirred at 0 °C for 1 h and then at 23 °C for an additional
1 h. The mixture was poured onto ice and allowed to stir for
30 min. The organic layer was separated. The aqueous layer
was extracted with CH2Cl2, and the combined organic layer
was washed with water and saturated aqueous NaHCO3 and
dried over anhydrous Na2SO4. Evaporation of the solvent
furnished a residue which was chromatographed over silica
gel (33% ethyl acetate/hexane) to afford the triacetate 17 (205
Met h yl (5S,6S)-5,6-E p oxy-2,3-O-isop r op ylid en e-â-D-
r ibo-h ep ta n ofu r a n osid e (8). To a stirred solution of alcohol
7 (1.29 g, 5.61 mmol) in CH2Cl2 (10 mL) were added m-CPBA
(1.21 g, 8.41 mmol) and NaHCO3 (700 mg, 8.33 mmol). The
resulting mixture was stirred at 23 °C for 12 h. After this
period, the solvent was removed under reduced pressure, and
the residue was diluted with ethyl acetate (20 mL) and water
(10 mL). The layers were separated, and the organic layer was
washed with aqueous NaHCO3 and brine and dried over
anhydrous Na2SO4. Evaporation of the solvents gave a residue
which was chromatographed over silica gel (40% ethyl acetate/
hexane) to furnish the epoxide 8 as a colorless oil (1.31 g,
95%): [R]23D -30.5 (c 1.16, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 5.01 (s, 1H), 4.67 (d, 1H, J ) 5.9 Hz), 4.58 (d, 1H, J ) 5.9
Hz), 4.04 (d, 1H, J ) 7.1 Hz), 3.91 (dd, 1H, J ) 2.4, 12.7 Hz),
3.64 (dd, 1H, J ) 4.2, 12.7 Hz), 3.39 (s, 3H), 3.11 (dd, 1H, J )
2.2, 7.1 Hz), 3.03 (ddd, 1H, J ) 2.2, 2.4, 4.2 Hz), 1.46 (s, 3H),
1.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 112.6, 109.3, 87.0,
85.1, 81.2, 60.8, 56.1, 55.7, 54.9, 26.3, 24.8; MS (CI) m/z 247
(M+ + H), 231, 215. Anal. Calcd for C11H18O6: C, 53.60; H,
7.37. Found: C, 53.21; H, 7.63.
Meth yl (5R,6R)-5-Azid o-5-d eoxy-2,3-O-isop r op ylid en e-
â-D-r ibo-h ep ta n ofu r a n osid e (9). To a stirred solution of Ti-
(OiPr)4 (0.37 mL, 1.23 mmol) in benzene (5 mL) was added
TMSN3 (0.33 mL, 2.46 mmol), and the resulting mixture was
heated at 75 °C for 5 h. After this period, a solution of 8 (202
mg, 0.82 mmol) in benzene (2 mL) was added at 75 °C. The
resulting mixture was stirred for 15 min, and then the mixture
was cooled to 23 °C. Benzene was removed under reduced
pressure, the residue was diluted with THF (10 mL), and 5%
aqueous citric acid (10 mL) was added. The resulting mixture
was stirred for 2 h, and the layers were separated. The aqueous
layer was extracted with ethyl acetate (3 × 20 mL), and the
combined organic layers were dried over anhydrous Na2SO4.
Evaporation of the solvent gave a residue which was chro-
matographed over silica gel (40% ethyl acetate/hexane) to
furnish the azido diols 9 (155 mg, 63%) and 10 (39 mg, 16%)
mg, 79%) as an oil (R/â ) 1/2, by 400 MHz 1H NMR):
â
anomer: 1H NMR (400 MHz, CDCl3) δ 6.15 (s, 1H), 5.53 (dd,
1H, J ) 4.8, 7.2 Hz), 5.36 (d, 1H, J ) 4.8 Hz), 4.60 (dd, 1H, J
) 4.4, 7.2 Hz), 4.33 (d, 1H, J ) 4.4 Hz), 3.80 (s, 3H), 2.12 (s,
6H), 2.08 (s, 3H); R anomer: 1H NMR (400 MHz, CDCl3) δ
6.44 (d, 1H, J ) 4.4 Hz), 5.33 (dd, 1H, J ) 4.8, 7.2 Hz), 5.22
(dd, 1H, J ) 4.8, 6.8 Hz), 4.62 (t, 1H, J ) 2.8 Hz), 4.40 (d, 1H,
J ) 3 Hz), 3.83 (s, 3H), 2.12 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H).
Meth yl 2,3-Di-O-a cetyl-5-a zid o-1,5-d id eoxy-1-(3,4-d ih y-
d r o-5-m eth yl-2,4-d ioxo-1(2H)-p yr im id in yl)-â-D-a llofu r a -
n u r on a te (18). To a stirred suspension of thymine (190 mg,
1.5 mmol) in hexamethyldisilazane (4.5 mL) at 23 °C was
added trimethylchlorosilane (0.3 mL) and the resulting mix-
ture was heated at 120 °C for 2 h under nitrogen atmosphere.
The reaction mixture was cooled to 23 °C, and the solvent was
removed under reduced pressure to give the crude bis-silylated
thymine. To the above residue, dry dichloroethane (4 mL)
followed by a solution of triacetate 17 (205 mg, 0.57 mmol) in
2 mL dichloroethane was added. TMSOTf (0.31 mL, 1.71
mmol) was then added, and the resulting mixture was heated
at 84 °C for 1 h. After this period, the reaction mixture was
cooled to 23 °C and quenched with saturated aqueous NaHCO3
(20 mL). The layers were separated, and the aqueous layer
was extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were washed with brine, dried over anhydrous Na2SO4,
and evaporated to a residue. Silica gel chromatography (2%
MeOH/CH2Cl2) of the residue furnished 18 as a pale brown
as colorless oils. Major azido diol 9: [R]23 -28.8 (c 0.57,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 5.02 (s, 1H), 4.83 (dd,
1H, J ) 1.4, 5.9 Hz), 4.61 (d, 1H, J ) 5.9 Hz), 4.18 (dd, 1H, J
) 1.4, 8.3 Hz), 3.92 (m, 1H), 3.75-3.85 (m, 2H), 3.61 (dd, 1H,
J ) 5.9, 8.3 Hz), 3.42 (s, 3H), 1.48 (s, 3H), 1.32 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 112.9, 110.3, 86.6, 84.7, 81.9, 72.2,
64.7, 62.7, 56.2, 26.4, 24.8. Anal. Calcd for C11H19N3O6: C,
45.67; H, 6.62. Found C, 45.61; H, 6.36. Minor azido diol 10:
1H NMR (200 MHz, CDCl3) δ 5.02 (s, 1H), 4.84 (d, 1H, J ) 6.0
Hz), 4.70 (s, 1H), 4.58 (d, 1H, J ) 6.0 Hz), 3.80-4.05 (m, 4H),
3.48 (s, 3H), 1.50 (s, 3H), 1.32 (s, 3H).
Meth yl (Meth yl 5-a zid o-5-d eoxy-2,3-O-isop r op ylid en e-
â-D-a llofu r a n osid )u r on a te (16). To a stirred solution of the
azido diol 9 (448 mg, 1.55 mmol) in a mixture (2:2:3) of MeCN-
CCl4-H2O (7 mL) were added H5IO6 (1.41 g, 6.2 mmol) and
RuCl3 (5 mg). The resulting suspension was stirred for 2 h at
23 °C. After this period, CH2Cl2 (10 mL) followed by water
(10 mL) was added, and the layers were separated. The
aqueous layer was extracted with CH2Cl2, and the combined
organic layers were dried over anhydrous Na2SO4. Evaporation
of the solvents gave the crude acid which was dissolved in DMF
(2 mL), and methyl iodide (0.2 mL, 3.1 mmol) followed by
KHCO3 (310 mg, 3.1 mmol) was added. The reaction mixture
was stirred at 23 °C for 12 h. The reaction mixture was then
diluted with ethyl acetate (100 mL), and the organic layer was
washed with saturated aqueous ammonium chloride and brine
and dried over anhydrous Na2SO4. Evaporation of the solvents
gave a residue which was chromatographed over silica gel (10%
ethyl acetate/hexane) to afford the ester 16 as a colorless oil
(356 mg, 80%): [R]23D -52.2 (c 1.62, CHCl3); lit.7d [R]23D -55.3
(c 0.89, CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.98 (s, 1H), 4.86
(dd, 1H, J ) 0.8, 5.9 Hz), 4.59 (d, 1H, J ) 5.9 Hz), 4.44 (dd,
1H, J ) 0.8, 8.8 Hz), 3.83 (s, 3H), 3.81 (d, 1H, J ) 8.8 Hz),
foam (221 mg, 91%): [R]23 -52.3 (c 0.82, CHCl3); 1H NMR
D
(400 MHz, CDCl3) δ 8.34 (s, 1H), 7.30 (s, 1H), 6.19 (d, 1H, J )
7.3 Hz), 5.38 (dd, 1H, J ) 2.9, 6.3 Hz), 5.30 (t, 1H, J ) 6.9
Hz), 4.51 (d, 1H, J ) 3.3 Hz), 4.45 (t, 1H, J ) 2.9 Hz), 3.87 (s,
3H), 2.11 (s, 3H), 2.08 (s, 3H), 1.96 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 169.5, 169.3, 167.1, 163.5, 150.7, 134.7, 112.2, 85.4,
81.5, 71.0, 69.8, 62.8, 53.2, 20.3, 20.2, 12.7; MS (CI) m/z 426
(M+ + H), 300, 212, 127. Anal. Calcd for C16H19N5O9: C, 45.18;
H, 4.50. Found: C, 45.31; H, 4.69.
(2R,3R,4R,5S)-6-[(ter t-Bu tyldim eth ylsilyl)oxy]-2,3-epoxy-
4,5-(isop r op ylid en ed ioxy)h exa n -1-ol (21). To a suspension
of powdered 4 Å molecular sieves (500 mg) in CH2Cl2 (8 mL)
at -23 °C were sequentially added Ti(OiPr)4 (72 µL, 0.24
mmol) and diethyl D-tartrate (50 µL, 0.29 mmol) under
nitrogen atmosphere. The resulting mixture was stirred for
15 min at -23 °C, and then a solution of alcohol 20 (715 mg,
2.32 mmol) in CH2Cl2 (2 mL) was added dropwise. The mixture
was stirred for 15 min, and tert-butyl hydroperoxide (1.5 mL,
5 M in n-decane) was added dropwise. The resulting mixture
was stirred at -23 °C for 0.5 h and was put into a freezer of
-23 °C for 24 h. After this period, aqueous NaOH solution (4
N) buffered with saturated aqueous NaCl (5 mL) was added,