Synthesis of R-Galactosyl Ceramide
J . Org. Chem., Vol. 67, No. 13, 2002 4563
21.02; 20.97; 17.85; 17.83; 17.80; 17.77; 11.72; 11.69. calcd
(C22H38O4SSiNa+) 449.2152, found 449.2158.
δ ) 7.33-7.25 (m, 10H); 5.57-5.33 (m, 2H); 4.69 (d, 1H, J )
11.4 Hz); 4.60 (m, 3H); 3.94 (m, 1H); 3.72 (m, 4H); 3.07 (d,
1H, J ) 4.8 Hz); 2.45 (dt, 1H, J ) 15.4, 7.0 Hz); 2.39 (dt, 1H,
J ) 15.2, 5.6 Hz); 1.99 (q, 2H, J ) 7.0 Hz); 1.33-1.20 (m, 19H);
1.12-0.99 (m, 21H); 0.86 (t, 3H, J ) 7.0 Hz). 13C NMR (CDCl3,
125 MHz): δ ) 138.29; 133.64; 132.33; 128.34; 128.30; 128.00;
127.77; 127.70; 127.57; 124.99; 80.06; 78.14; 73.69; 72.71;
71.30; 63.86; 31.91; 29.67; 29.64; 29.57; 29.38; 29.35; 29.01;
27.54; 22.68; 17.99; 14.10; 14.10; 11.87. HRMS calcd (C42H70O4-
SiNa+) 675.4779, found 675.4780.
p -Met h ylp h en yl 3,4-Di-O-b en zyl-2-d eoxy-1-t h io-6-O-
tr iisop r op ylsilyl-D-ga la ctop yr a n osid e (7). 6 (700 mg, 1.58
mmol) was dissolved in 10 mL of DMF. The reaction mixture
was cooled to -10 °C (ice bath/NaCl). Benzyl bromide (0.48
mL, 3.95 mmol, 2.5 equiv) was added, followed by 84 mg (3.32
mmol, 2.1 equiv) of sodium hydride (95%). The reaction was
monitored by TLC (hexanes:ethyl acetate 2:1) and completed
after 40 min at -10 °C. The reaction was quenched by addition
of solid NH4Cl, diluted with water, and the reaction mixture
was extracted with ethyl acetate (3×). The combined organic
layer was extracted with water (3×) and brine, dried over
sodium sulfate, and evaporated. The residue was subjected to
column chromatography (hexanes:ethyl acetate 15:1) to give
880 mg (89%) of 7. Ratio of the isomers after chromatogra-
phy: approx. 1:0.6. 1H NMR (CDCl3, 600 MHz): δ ) 7.45-
7.25 (m, 24.6H); 7.09 (d, 2H, J ) 8.3 Hz); 7.06 (d, 1.2H, J )
7.9 Hz); 5.68 (d, 1H, J ) 5.7 Hz); 4.99 (d, 1.6H, J ) 11.4 Hz);
4.72 (dd, 2.3H, J ) 11.8, 3.1 Hz); 4.69-4.58 (m, 4.2H); 4.29 (t,
1H, J ) 6.6 Hz); 4.05 (s, 1H); 3.97 (ddd, 1H, J ) 12.2, 4.1, 2.5
Hz); 3.93 (s, 0.6 H); 3.89-3.84 (m, 2.1H); 3.74 (dd, 1H, J )
9.7, 5.7 Hz); 3.62 (ddd, 0.6H, J ) 11.7, 4.3, 2.3 Hz); 3.44 (t,
0.6H, J ) 6.6 Hz); 2.63 (dt, 1H, J ) 12.7 Hz, 5.7 Hz); 2.33 (s,
3H); 2.325 (s, 2.1H); 2.20 (dd, 1H, J ) 12.9, 4.6 Hz); 1.16-
1.01 (m, 37H). 13C NMR (CDCl3, 125 MHz): δ ) 139.12; 138.94;
138.31; 138.20; 137.08; 136.94; 132.03; 131.57; 131.11; 130.55;
129.50; 129.39; 128.37; 128.32; 128.10; 127.98; 127.73; 127.69;
127.54; 127.33; 127.30; 127.24; 127.13; 84.88; 82.96; 79.71;
78.51; 75.43; 74.46; 74.03; 73.08; 72.35; 71.48; 70.40; 70.10;
62.36; 32.52; 31.86; 21.02; 17.96; 11.81. HRMS: calcd (C36H50O4-
SSiNa+) 629.3091, found 629.3075.
2-Azid o-3,4-d i-O-ben zyl-1-O-tr iisop r op ylsilyl-octa d ec-
6-en e (10). Sodium azide (6.5 g) was dispersed in 6.5 mL of
water and 40 mL of toluene. The suspension was cooled to
about 0 °C. Concentrated sulfuric acid (1.35 mL) was added
dropwise. While the internal temperature was kept below 10
°C, the reaction mixture was stirred slowly for another 30 min.
The toluene layer was decanted into a cooled conical flask (0
°C), dried over sodium sulfate, and stored in a freezer. To
determine the concentration, 0.3 mL of the solution and 0.3
mL of water were stirred in
a vial and one drop of a
phenolphthalein-solution (1% in MeOH) was added, and the
solution was titrated with 0.25 N NaOH. Triphenylphosphine
(482 mg, 1.84 mmol, 4 equiv) was dissolved in 15 mL of dry
THF under argon. The solution was cooled to -78 °C. DEAD
(0.29 mL, 320 mg, 1.84 mmol, 4 equiv) and 1.3 mL (c ) 1.4 M)
of the previously prepared HN3 solution were added. After
stirring for 1 min, a solution of 300 mg (0.46 mmol) of 9 in 7
mL of THF was added rapidly. The reaction was stirred
overnight. The reaction progress was checked by TLC (hex-
anes:ethyl acetate 9:1). The reaction was quenched by the
addition of methanol (color changes from orange to light
yellow), concentrated in vacuo, and chromatographed on silica
gel (hexanes:ethyl acetate 20:1) to yield 263 mg (84%) of 10.
1H NMR (CDCl3, 600 MHz): δ ) 7.37-7.26 (m, 10H); 5.55-
5.44 (m, 2H); 4.74-4.53 (m, 4H); 4.06 (dd, 1H, J ) 10.5, 3.1
Hz); 3.84 (dd, 1H, J ) 10.5, 7.9 Hz); 3.74-3.70 (m, 2H); 3.63
(dd, 1H, J ) 6.1, 4.2 Hz); 2.48 (t, 1H, J ) 5.5 Hz); 2.06 (m,
1H); 1.38-1.23 (m, 19H); 1.11-1.02 (m, 21H); 0.90 (t, 3H, J )
7.0 Hz). 13C NMR (CDCl3, 125 MHz): δ ) 138.32; 138.11;
132.34;128.30; 128.27; 127.90; 127.67; 127.51; 125.14; 79.48;
78.89; 73.59; 72.05; 64.65; 64.62; 31.92; 29.68; 29.65; 29.60;
29.57;29.40; 29.35; 27.90; 27.56; 22.68; 17.91; 14.11; 11.85.
HRMS calcd (C42H70N3O3Si+) 678.5024, found 678.5054.
3,4-Di-O-ben zyl-2-d eoxy-6-O-tr iisop r op ylsilyl-D-ga la c-
top yr a n osid e (8). 7 (820 mg, 1.35 mmol) was dissolved in 50
mL of acetone. The reaction mixture was cooled to 0 °C, and
NBS (281 mg, 1.59 mmol, 1.18 equiv) was added. The reaction
mixture turned orange immediately. After 10 min. the reaction
was quenched by addition of solid NH4Cl. The mixture was
diluted with water and ethyl acetate, and the aqueous layer
was extracted with ethyl acetate (3×). The combined organic
layer was extracted with brine, dried over sodium sulfate, and
evaporated. The residue was subjected to column chromatog-
raphy (hexanes:ethyl acetate 4:1) to give 520 mg (77%) of 8.
1
Ratio of R/â isomers: 1:0.4. H NMR (CDCl3, 600 MHz): δ )
2-Azid o-3,4-d i-O-ben zyl-octa d ec-6-en -1-ol (11). 10 (250
mg, 0.37 mmol) was dissolved in 5 mL of dry THF. The reaction
mixture was cooled to 0 °C, 1 mL of a 1 M TBAF solution was
added, and the reaction mixture was allowed to warm to room
temperature. After 10 min, the reaction was controlled by TLC
and found to be almost complete. After 20 min, the reaction
was stopped by addition of 5 mL saturated NaHCO3. The
aqueous layer was extracted with ethyl acetate (4×), and the
combined organic layer extracted with brine, dried, and
evaporated. The residue was chromatographed on silica gel
(hexanes:ethyl acetate 9:1) to yield 175 mg (91%) of 11.1H NMR
(CDCl3, 600 MHz): δ ) 7.39-7.26 (m, 10H); 5.51-5.48 (m,
1H); 5.48-5.38 (m, 1H); 4.70-4.61 (m, 3H), 4.56 (d, 1H, J )
11.4 Hz); 3.85 (dd, 1H, J ) 11.4, 4.8 Hz); 3.80-3.68 (m, 4H);
2.46 (m, 2H); 2.03 (m, 2H); 1.37-1.22 (m, 18H); 0.88 (t, 3H, J
) 7.0 Hz). 13C NMR (CDCl3, 150 MHz): δ ) 137.81; 137.58;
132.81; 128.44; 128.39; 127.97; 127.92; 127.88; 127.79; 124.40;
80.38; 78.57; 73.59; 72.26; 63.16; 62.24; 31.89; 29.65; 29.61;
29.54; 29.52; 29.36; 29.32; 28.11; 27.57; 22.66; 17.66; 14.09.
7.40-7.22 (m, 14H); 5.42 (d, 1H, J ) 2.2 Hz); 4.96 (d, 1.4H, J
) 11.4 Hz); 4.70 (dd, 1.8H, J ) 11.6, 5.5 Hz); 4.67-4.57 (m,
2.8H); 4.02-3.97 (m, 3H); 3.94 (s-b, 0.4 H); 3.90 (t, 0.4H, J )
9.2 Hz); 3.81 (dd, 1H, J ) 9.7, 7.5 Hz); 3.80 (m, 0.4H); 3.73
(dd, 1H, J ) 9.7, 5.7 Hz); 3.57 (ddd, 0.4H, J ) 12.1, 4.2, 2.6
Hz); 3.52 (s-b, 0.4H); 3.40 (dd, 0.4H, J ) 7.9, 5.7 Hz); 3.39
(s-b, 1H); 2.20 (dt, J ) 12.5, 3.5 Hz); 2.15 (dt, 0.4 Hz, J )
12.3, 2.1 Hz); 2.00 (m, 0.4H); 1.98 (dd, 1H, J ) 12.7, 4.0 Hz);
1.15-1.03 (m, 31H). 13C NMR (CDCl3, 125 MHz): δ ) 139.00;
138.89; 138.55; 138.21; 128.40; 128.34; 128.11; 128.04; 127.60;
127.36; 127.28; 94.82; 92.62; 77.14; 75.86; 74.53; 74.40; 74.26;
72.91; 71.76; 71.43; 70.36; 70.20; 62.38; 61.63; 34.90; 31.12;
17.98; 17.96; 14.14; 11.86; 11.84. HRMS calcd (C29H44O5SiNa+)
523.285, found 523.284.
3,4-Di-O-ben zyl-1-O-tr iisop r op ylsilyl-octa d ec-6-en e-2-
ol (9). Dodecyl triphenylphosphonium bromide (1.53 g, 3 mmol,
3 equiv) was suspended in 20 mL of dry THF. The mixture
was cooled to -10°. BuLi (1.75 mL, 2.8 mmol, 2.8 equiv) (1.6
M solution in hexanes) was added dropwise. The orange
solution was stirred for 30 min, and then the starting material
8 (510 mg, 0.99 mmol in 15 mL of dry THF) was added slowly.
The reaction was allowed to warm to room temperature and
stirred overnight. The reaction was monitored by TLC using
hexanes:ethyl acetate as a solvent system. For workup, the
reaction mixture was quenched with methanol. Afterward 80%
methanol in water was added and the reaction mixture was
extracted with hexanes (4×). The combined hexanes layer was
dried over sodium sulfate and evaporated, and the residue was
subjected to column chromatography (hexanes:ethyl acetate
+
HRMS calcd (C33H50N3O3 - N2): 494.3629, found 494.3643
2-Azid o-3,4-d i-O-ben zyl-1-O-(2,3,4,5-tetr a -O-ben zyl-r-D-
ga la ctop yr a n osyl)-D-r ibo-octa d eca -6-en -1-ol (13). A solu-
tion of thioglycoside 12 (73 mg, 0.11 mmol) and sphingosine
11 (50 mg, 0.096 mmol) in 1.5 mL of anhyd CH2Cl2 was added
over freshly dried powdered 4 Å molecular sieves and cooled
to 0 °C. Meanwhile, methyl disulfide (34.5 µL, 4 equiv) and
methyl trifluoromethanesulfonate (43.9 µL, 4 equiv) were
mixed in a separate vial to form solids. The solids in dry CH2-
Cl2 (0.5 mL) were added to the above solution, and the mixture
was stirred at 0 °C for 2.5 h. The reaction was quenched by
the addition of 3 drops of saturated aqueous Na2S2O3, diluted
1
10:1) to yield 610 mg (92%) of 9. H NMR (CDCl3, 600 MHz):