Chemistry of C-2 Glyceryl Radicals
J. Am. Chem. Soc., Vol. 119, No. 12, 1997 2801
1,3-(Dibenzyloxy)-2-hydroxy-2-pivaloylpropane (16). To a sus-
pension of triol 11 (457 mg, 2.60 mmol) in dichloromethane (12 mL)
and cyclohexane (6 mL) was added benzyl 2,2,2-trichloroacetimidate
(1.45 mL, 1.96 g, 7.78 mmol, 1.5 equiv), followed by trifluoromethane-
sulfonic anhydride (15 drops). After 45 min the reaction mixture was
diluted with cyclohexane (10 mL) and filtered over Celite. The filtrate
was washed with concentrated sodium hydrogen carbonate (50 mL),
dried over magnesium sulfate, and chromatographed (silica gel, pentane/
diethyl ether, 9:1) after removal of the solvent. Compound 16 (758
mg, 2.13 mmol, 82%) was obtained as an oil: 1H NMR δ 7.4-7.2
(10H, m), 4.52 (4H, s), 3.74 (2H, d, J ) 9.4Hz), 3.53 (2H, d, J )
9.4Hz), 3.48 (1H, s), 1.25 (9H, s); 13C NMR δ 216.1, 137.6, 128.3,
127.7, 127.6, 84.7, 73.7, 73.6, 44.8, 26.7. Anal. Calcd for C22H28O4:
C, 74.13; H, 7.92. Found: C, 73.73; H, 7.78. The oil, which was
used in the next step, contained some trichloroamidate .
3-Acetoxy-2-methoxy-1-[(diphenoxyphosphoryl)oxy]-2-pivaloyl-
propane (22). A solution of alcohol 19 (118 mg, 510 µmol) in dry
dichloromethane (5 mL) was cooled to 0 °C under argon. After addition
of N-methylimidazole (0.16 mL, 165 mg, 2.01 mmol, 4 equiv) and
diphenoxyphosphoryl chloride (0.32 mL, 416 mg, 1.55 mmol, 3 equiv),
the reaction mixture was stirred for 1 h at 0 °C and 1 h at room
temperature and then separated on silica gel (pentane/diethyl ether, 1:1).
Phosphate 22 (196 mg, 422 µmol, 83%) was obtained as a yellow oil:
1H NMR δ 7.4-7.3 (2H, m), 7.25-7.15 (3H, m), 4.46 (1H, d, J )
11.8 Hz), 4.45 (2H, d, J ) 4.5 Hz), 4.09 (1H, d, J ) 11.8 Hz), 3.31
(3H, s), 2.02 (3H, s), 1.19 (9H, s); 13C NMR δ 213.3, 169.7, 150.1 (d,
J ) 7 Hz), 129.6 (2C, d, J ) 4 Hz), 125.4, 119.8 (d, J ) 5 Hz), 87.4
(d, J ) 9 Hz), 66.9 (d, J ) 6 Hz), 62.4, 50.7, 45.2, 26.3, 20.5; 31P
NMR δ -12.61 (m). Anal. Calcd for C23H29O8P: C, 59.48; H, 6.29.
Found: C, 59.35; H, 6.41.
1,3-(Dibenzyloxy)-2-methoxy-2-pivaloylpropane (17). To a solu-
tion of alcohol 16 (734 mg, 2.06 mmol) in dry dimethyl sulfoxide (2
mL) was added a suspension of pulverized potassium hydroxide (688
mg, 12.4 mmol, 6 equiv) in dimethyl sulfoxide (4 mL), followed by
methyl iodide (0.77 mL, 1.75 g, 12.4 mmol, 6 equiv). The reaction
mixture was stirred under argon for 75 min and excess methyl iodide
removed in Vacuo. After addition of dichloromethane (7 mL) and water
(40 mL) the aqueous phase was extracted with dichloromethane (100
mL) and the organic phase washed with concentrated sodium hydrogen
carbonate (10 mL) and dried over magnesium sulfate. Chromatography
(silica gel, pentane/dichloromethane, 1:1) yielded 17 (469 mg, 1.27
mmol, 61%) as a clear oil: 1H NMR δ 7.35-7.2 (10H, m), 4.48 (2H,
d, J ) 12.2 Hz), 4.43 (2H, d, J ) 12.2 Hz), 3.70 (2H, d, J ) 10.0 Hz),
3.66 (2H, d, J ) 10.0 Hz), 3.40 (3H, s), 1.23 (9H, s); 13C NMR δ
215.9, 138.0, 128.3, 127.5, 127.5, 89.5, 73.5, 70.3, 51.2, 45.2, 26.8.
1,3-Dihydroxy-2-methoxy-2-pivaloylpropane (18). Benzyl ether
17 (464 mg, 1.25 mmol) and palladium (10% on charcoal, 150 mg,
0.141 mmol, 0.11 equiv) were suspended in ethanol (50 mL) and shaken
at 3 bar of hydrogen in a Parr apparatus for 2 h at room temperature.
The reaction mixture was filtered over Celite to remove the catalyst
and concentrated in Vacuo. Chromatography (silica gel, pentane/tert-
butyl methyl ether, 1:1) yielded 18 (195 mg, 1.03 mmol, 82%) as a
1,3-Diacetoxy-2-methoxy-2-pivaloylpropane (20). Diol 18 (9.71
mg, 51.0 µmol), acetic anhydride (13.9 µL, 15.1 mg, 148 µmol, 3
equiv), triethylamine (21.0 µL, 15.2 mg, 150 µmol, 3 equiv), and
4-(dimethylamino)pyridine (0.15 mg, 1.22 µmol, 0.02 equiv) were
stirred under argon at room temperature for 1 h. Removal of solvent
and reagents at high vacuum yielded 20 (12.6 mg, 45.9 µmol, 90%) as
a slightly yellow oil, which crystallized at -20 °C: mp 37.5-40 °C;
1H NMR δ 4.50 (2H, d, J ) 11.9 Hz), 4.12 (1H, d, J ) 11.9 Hz), 3,34
(3H, s), 2.05 (6H, s), 1.25 (9H, s); 13C NMR δ 214.2, 170.1, 87.5,
62.8, 50.7, 45.4, 26.5, 20.8. Anal. Calcd for C13H22O6: C, 56.92; H,
8.08. Found: C, 57.19; H, 7.96.
Benzylidene Acetals 47 and 60 of 1,2,3-Trihydroxy-2-pivaloyl-
propane (11). Triol 11 (870 mg, 4.94 mmol), benzaldehyde (1 mL,
1.05 g, 9.87 mmol, 2 equiv), and a few crystals of p-toluenesulfonic
acid were suspended in 75 mL of toluene and heated to reflux under
argon with a Dean-Stark trap for 3 h. After cooling, triethylamine (2
mL) was added and the reaction mixture separated on silica gel (pentane,
100% f pentane/tert-butyl methyl ether, 1:1), yielding 1,3-acetal 47
(585 mg, 2.21 mmol, 45%) as a white solid and 1,2-acetal 60a,b (649
mg, 2.46 mmol, 50%) as a yellow oil. Data for 47: mp 122-125 °C;
1H NMR δ 7.55-7.45 (2H, m), 7.45-7.35 (3H, m), 5.57 (1, s), 4.26
(2H, dm, J ) 11.0 Hz), 3.99 (2H, dm, J ) 11.0 Hz), 3.57 (1H, s), 1.30
(9H, s); 13C NMR δ 213.8, 137.2, 129.3, 128.4, 125.9, 101.5, 78.3,
74.7, 45.6, 25.8. Anal. Calcd for C15H20O4: C, 68.16; H, 7.63.
Found: C, 68.14; H, 7.55. The diastereomeric 2:1 mixture of 60 could
be separated on silica gel (pentane/tert-butyl methyl ether, 5:1). Data
for 60a: mp 63-65.5 °C; 1H NMR δ 7.55-7.45 (2H, m), 7.45-7.35
(3H, m), 6.02 (1H, s), 4.33 (1H, d, J ) 9.3 Hz), 3.91 (1H, d, J ) 9.3
Hz), 3.87 (1H, dd, J ) 11.2 Hz, 7.6 Hz), 3.63 (1H, dd, J ) 11.2 Hz,
4.5 Hz), 2.29 (1H, dd, J ) 7.6 Hz, 4.5 Hz), 1.30 (9H, s); 13C NMR δ
217.1, 136.5, 129.6, 129.0, 126.3, 105.5, 90.4, 71.4, 67.4, 44.8, 25.0.
1
white powder: mp 82-83.5 °C; H NMR δ 3.89 (2H, dd, J ) 11.8
Hz, 7.9Hz), 3.83 (2H, dd, J ) 11.8 Hz, 5 Hz), 3.45 (3H, s) 2.52 (2H,
dd, J ) 7.9 Hz, 5 Hz), 1.24 (9H, s); 13C NMR δ 219.1, 89.2, 63.3,
51.4, 45.3, 26.6.
1-Acetoxy-3-hydroxy-2-methoxy-2-pivaloylpropane (19). To a
solution of diol 18 (423 mg, 2.22 mmol) and camphor-10-sulfonic acid
(9.65 mg, 41.5 µmol, 0.02 equiv) in dry dichloromethane (10 mL) was
added trimethyl orthoacetate (1.1 mL, 1.05 g, 8.90 mmol, 4 equiv),
and the resulting mixture was stirred for 8 h at room temperature under
argon. Hydrolysis was accomplished with acetic acid (10 mL, 50% in
water) with vigorous stirring for 2.5 h and was followed by the addition
of tert-butyl methyl ether (200 mL) and extraction with concentrated
sodium hydrogen carbonate (4 × 15 mL). The aqueous phases were
extracted with tert-butyl methyl ether (70 mL) and the combined organic
layers dried over magnesium sulfate. Removal of the solvent in Vacuo
1
Data for 60b: mp 43-45.5 °C; H NMR δ 7.6-7.5 (2H, m), 7.45-
7.35 (3H, m), 5.98 (1H, s), 4.22 (1H, d, J ) 9.0 Hz), 4,11 (1H, d, J )
9.0 Hz), 3.95 (1H, dd, J ) 11.5 Hz, 8.5 Hz), 3.82 (1H, dd, J ) 11.5
Hz, 5.0 Hz), 2.25 (1H, dd, J ) 8.5 Hz, 5.0 Hz), 1.19 (9H, s); 13C NMR
δ 216.5, 135.7, 129.3,128.3, 126.3, 104.4, 90.2, 71.8, 65.5, 44.9, 25.8.
Anal. Calcd for C15H20O4: C, 68.16; H, 7.63. Found: C, 68.46; H,
7.54.
1
yielded 19 (480 mg, 2.06 mmol, 93%) as a colorless oil: H NMR δ
4.49 (1H, d, J ) 12.1 Hz), 4.19 (1H, d, J ) 12.1 Hz), 3.82 (1H, dd, J
) 11.6 Hz, 7.8 Hz), 3.74 (1H, dd, J ) 11.6 Hz, 3.2 Hz), 3.39 (3H, s),
2.05 (3H, s), 2.05 (1H, dd, J ) 7.8 Hz, 3.2 Hz), 1.25 (9H, s); 13C
NMR δ 216.2, 170.3, 88.5, 62.9, 62.4, 50.7, 45.3, 26.5, 20.8.
Hydrolysis of Benzylidene Acetal 60. Acetal 60a,b (578 mg, 2.19
mmol) was dissolved in acetic acid (32 mL) and water (8 mL) and
heated to 60 °C for 3 h under argon. Removal of the solvents and
subsequent chromatography (silica gel, pentane/tert-butyl methyl ether,
1:1) yielded triol 11 (334 mg, 1.90 mmol, 87%).
3-Acetoxy-2-methoxy-1-[(diethoxyphosphoryl)oxy]-2-pivaloylpro-
pane (21). A solution of alcohol 19 (50.0 mg, 215 µmol) in dry
dichloromethane (2 mL) was cooled to 0 °C under argon. After addition
of N-methylimidazole (51 µL, 52.7 mg, 642 µmol, 3 equiv) and
diethoxyphosphoryl chloride (77 µL, 92.4 mg, 535 µmol, 2.5 equiv),
the reaction mixture was stirred for 1.5 h at 0 °C and 30 min at room
temperature and was then separated on silica gel (pentane/tert-butyl
methyl ether, 2:1). Phosphate 21 (60.1 mg, 163 µmol, 76%) was
obtained as a clear oil: 1H NMR δ 4.49 (1H, d, J ) 11.8 Hz), 4.26
(1H, dd, J ) 10.8 Hz, 4.6 Hz), 4.20 (1H, dd, J ) 10.8 Hz, 4.2 Hz),
4.15-4.05 (4H, m), 4.10 (1H, d, J ) 11.8 Hz), 3.43 (3H, s), 2.05 (3H,
s), 1.4-1.3 (6H, m), 1.25 (9H, s); 13C NMR δ 213.8, 170.0, 87.7 (d,
J ) 9 Hz), 65.8 (d, J ) 6 Hz), 64.0 (M), 62.5, 50.9, 45.3, 26.5, 20.7,
16.0 (d, J ) 7 Hz); 31P NMR δ -1.73 (m). Anal. Calcd for
C15H29O8P: C, 48.91; H, 7.94. Found: C, 48.99; H, 7.84.
5-(Benzyloxy)-2-phenyl-5-pivaloyl-1,3-dioxane (48). To a mixture
of alcohol 47 (585 mg, 2.21 mmol), sodium hydride (55% in oil, 195
mg, 4.42 mmol, 2 equiv), and tetrabutylammonium iodide (81.6 mg,
221 µmol, 0.1 equiv), cooled to -78 °C under argon, was added dry
tetrahydrofuran (20 mL), and the cooling bath was removed. After
the alcohol had completely dissolved, benzyl bromide (525 µL, 758
mg, 4.42 mmol, 2 equiv) was added dropwise, and the resulting mixture
was stirred for 16 h in the dark at room temperature. Quenching of
the reaction with methanol (1 mL) was followed by the addition of
concentrated sodium hydrogen carbonate (75 mL) and extraction with
tert-butyl methyl ether (5 × 100 mL). The combined organic phases
were dried over magnesium sulfate and chromatographed with 2 mL
of trimethylamine (silica gel, pentane/tert-butyl methyl ether, 20:1).
Removal of residual benzyl bromide in high vacuum at 120 °C yielded