2604 J . Org. Chem., Vol. 67, No. 8, 2002
Chun et al.
(C6D6, 70 °C) δ 0.89 (t, 3H, J ) 6.2 Hz), 1.10-1.30 (m, 16H),
1.39 (s, 9H), 1.52 (s, 3H), 1.50-1.60 (m, 2H), 1.81 (s, 3H), 2.81
(m, 2H), 3.77 (m, 2H), 4.27 (br s, 1H), 5.13 (d, 1H, J ) 10.8
Hz), 5.50 (d, 1H, J ) 17.4 Hz), 6.13 (m, 2H).
dried (MgSO4). Purification by column chromatography (hex-
ane/EtOAc 3:2, Rf 0.72) gave 175 mg (50%) of 21 as a colorless
liquid: 1H NMR δ 0.83 (t, 3H, J ) 7.0 Hz), 1.10-1.40 (m, 18H),
1.87 (m, 2H), 2.35 (m, 2H), 3.08 (m, 2H), 5.22 (m, 1H), 5.41
(m, 1H), 7.51 (m, 2H), 7.61 (m, 1H), 7.86 (m, 2H); 13C NMR δ
14.0, 22.6, 25.8, 29.1, 29.2, 29.3, 29.47, 29.53, 31.8, 32.3, 56.0,
124.8, 128.0, 129.1, 133.5, 139.0.
N-ter t-Bu t oxyca r b on yl (4S)-4-[1′-H yd r oxy-(2′E,4′E)-
h exa d eca d ien yl]-2,2-d im eth yl-1,3-oxa zolid in e [(-)-23]. To
a solution dienone 13 (325 mg, 0.75 mmol) in 15 mL of dry
MeOH was added anhydrous CeCl3 (61.5 mg, 0.25 mmol) at
-15 °C. After the mixture was stirred for 10 min, NaBH4 (32
mg, 0.85 mmol) was added. The temperature was gradually
raised to 0 °C. After 2 h, water (20 mL) was added, and the
product was extracted with Et2O (3 × 25 mL), washed with
brine, and dried (MgSO4). Concentration and purification by
column chromatography (hexane/EtOAc 4:1, Rf 0.45) gave 235
N-ter t-Bu toxyca r bon yl (4S)-4-[1′-Oxo-2′-p h en ylsu lfo-
n yl-(4′E)-h exa d ecen yl]-2,2-d im eth yl-1,3-oxa zolid in e (18).
To a solution of â-ketosulfone 17 (383 mg, 1.0 mmol) in 10 mL
of benzene was added DBU (153 mg, 1.0 mmol) at rt. After
the mixture was stirred at rt for 1 h under nitrogen, a solution
of bromide 8 (275 mg, 1 mmol) in 5.0 mL of benzene was added
dropwise. The reaction mixture was stirred at rt for 3 h and
passed through a pad of silica gel to remove the precipitate
(DBU‚HBr). The pad was washed with benzene. Purification
by column chromatography (hexane/EtOAc 4:1, Rf 0.70) gave
428 mg (74%) of 18 as a colorless liquid: IR 1732, 1698, 1390,
1360, 1315, 1175, 1145 cm-1; 1H NMR (C6D6, 70 °C) δ 0.96 (t,
3H, J ) 7.0 Hz), 1.35 (m, 18H), 1.44 (s, 9H), 1.55 (s, 3H), 1.74
(s, 3H), 1.88 (m, 1H), 1.97 (m, 1H), 2.60-3.00 (m, 2H), 3.80-
4.19 (m, 1H), 4.01-4.30 (m, 1.5H), 4.78-4.90 (m, 1H), 5.39
(br s, 1H), 5.46-5.49 (m, 1.5H), 7.05-7.17 (m, 3H), 7.23 (m,
mg (72%) of 23 as a colorless oil: [R]25 -18.6° (c 1.5, CHCl3);
D
IR 1690, 1375 cm-1; H NMR (C6D6, 70 °C) δ 0.89 (t, 3H, J )
1
6.6 Hz), 1.28 (m, 18H), 1.38 (s, 9H), 1.43 (s, 3H), 1.61 (s, 3H),
2.02 (q, 2H, J ) 6.8 Hz), 3.65 (m, 1H), 3.79 (br s, 1H), 3.94 (br
s, 1H), 4.34 (m, 1H), 5.59-5.66 (m, 2H), 6.09 (m, 1H), 6.38
(m, 1H); 13C NMR (C6D6, 70 °C) δ 12.5, 14.1, 19.0, 22.9, 24.4,
26.8, 28.1, 28.4, 29.5, 29.59, 29.68, 29.71, 29.88, 29.99, 30.04,
32.3, 32.9, 33.1, 62.8, 65.0, 73.6, 80.2, 94.6, 128.7, 130.5, 131.78,
134.82; HR-MS (FAB, MNa+) calcd for m/z C26H47NO4Na
460.3403, found 460.3419.
1H), 8.04 (br s, 1H); HR-MS (FAB, MH+) calcd for m/z C32H52
-
NO6S 578.3515, found 578.3515.
(2S,3R)-(4E,6E)-2-Oct a n oyla m id ooct a d eca d ien e-1,3-
d iol [(-)-2]. A solution of 88 mg (0.2 mmol) of 23 in 4 mL of
1 M HCl and 4 mL of THF was heated at 70 °C with stirring
for 10 h under argon. The reaction mixture was cooled to rt
and neutralized with 1 M NaOH (4 mL). The product was
extracted with EtOAc (3 × 10 mL), and the combined organic
layers were washed with brine and dried (Na2SO4). Removal
of the solvent provided crude sphingosine analogue 25 as a
white solid, which was used in the next reaction without
further purification. To a solution of 25 in 6 mL of dry THF
was added 108 mg (0.40 mmol) of p-nitrophenyl octanoate at
rt. The mixture was stirred for 48 h and concentrated.
Purification by flash chromatography (CHCl3/MeOH 9:1) af-
forded 51 mg (61%, two steps) of ∆4,6-ceramide analogue 2 as
N-ter t-Bu t oxyca r b on yl (4S)-4-[1′-Oxo-(4′E)-h exa d ec-
en yl]-2,2-d im eth yl-1,3-oxa zolid in e [(-)-20]. To a solution
of ketosulfone 18 (290 mg, 0.50 mmol) in 25 mL of THF/H2O
20/1 was added Al(Hg) (freshly prepared from aluminum foil;
135 mg, 5 mmol, 2% aqueous HgCl2).20 After the mixture was
stirred at rt overnight, it was passed through a pad of silica
gel with suction, which was washed with EtOAc. Concentra-
tion and purification by flash column chromatography (hexane/
EtOAc 4:1, Rf 0.85) gave 186 mg (86%) of ketone 20 as a
colorless oil: [R]25 -5.6° (c 2.8, CHCl3); IR 1709, 1463, 1390,
D
1380, 1365, 1167 cm-1; 1H NMR (C6D6, 70 °C) δ 0.86 (t, 3H, J
) 7.0 Hz), 1.29 (m, 18H), 1.38 (m, 9H), 1.47 (s, 3H), 1.75 (s,
3H), 1.96 (m, 2H), 2.30 (m, 2H), 2.39 (m, 2H), 3.69 (m, 2H),
4.16 (br s, 1H), 5.43 (m, 2H); 13C NMR (C6D6, 70 °C) δ 14.1,
23.0, 26.7, 28.4, 29.6, 29.7, 29.9, 30.0, 30.1, 32.3, 32.9, 65.6,
65.7, 80.2, 129.1, 131.8, 206.2; HR-MS (FAB, MNa+) calcd for
m/z C26H47NO4Na 460.3403, found 460.3393.
a white solid: mp 69.0-71.0 °C; [R]25 -4.30° (c 2.2, CHCl3);
D
IR 1620, 1540, 1455 cm-1; 1H NMR δ 0.86 (t, 6H, J ) 6.6 Hz),
1.10-1.40 (m, 26H), 1.60 (m, 2H), 2.05 (q, 2H, J ) 7.1 Hz),
2.20 (t, 2H, J ) 7.4 Hz), 3.69 (m, 1H), 3.90 (m, 2H), 4.37 (br s,
1H), 5.60 (dd, 1H, J ) 15.3, 6.3 Hz), 5.73 (m, 1H), 6.00 (m,
1H), 6.27 (m, 2H); 13C NMR δ 14.05, 14.10, 22.6, 22.7, 25.8,
29.0, 29.15, 29.21, 29.3, 29.49, 29.59, 29.62, 29.65, 31.7, 31.9,
32.7, 36.8, 54.5, 62.5, 74.5, 128.9, 132.7, 136.7, 174.0; HR-MS
(FAB, MNa+) calcd for m/z C26H49NO3Na 446.3610, found
446.3598.
N-ter t-Bu toxyca r bon yl (4S)-4-[1′-Hyd r oxy-(4′E)-h exa -
d ecen yl]-2,2-d im eth yl-1,3-oxa zolid in e (26). To a solution
of ketone 20 (65 mg, 0.15 mmol) in 4 mL of dry MeOH was
added NaBH4 (6.4 mg, 0.17 mmol) at -15 °C. The temperature
was gradually raised to 0 °C. After 2 h, water (5 mL) was
added, and the product was extracted with Et2O (3 × 15 mL),
washed with brine, dried (MgSO4), and concentrated. Purifica-
tion by column chromatography (hexane/EtOAc 4:1, Rf 0.45)
gave 58 mg (88%) of 26 as a colorless oil: IR 1701, 1671, 1457,
1390, 1365 cm-1; 1H NMR (C6D6, 70 °C) δ 0.89 (t, 3H, J ) 6.9
Hz), 1.22 (m, 20H), 1.30 (s, 9H), 1.47 (s, 3H), 1.63 (s, 3H), 2.00
(m, 2H), 2.20 (m, 1H), 2.34 (m, 1H), 3.61-3.69 (m, 2H), 3.84
(br s, 2H), 5.46-5.55 (m, 2H); 13C NMR (C6D6, 70 °C) δ 14.1,
23.0, 27.2, 28.4, 29.1, 29.6, 29.7, 30.0, 30.1, 32.3, 33.0, 62.7,
65.1, 80.3, 94.4, 130.5, 131.2.
(2S,3R)-(6E)-2-Octa n oyla m id oocta d ecen e-1,3-d iol [(-)-
3]. A solution of 88 mg (0.2 mmol) of 26 in 4 mL of 1 M HCl
and 4 mL of THF was heated at 70 °C with stirring for 10 h
under argon. The reaction mixture was cooled to rt and
neutralized with 1 M NaOH (4 mL). The product was extracted
with EtOAc (3 × 10 mL), and the combined organic layers were
washed with brine and dried (Na2SO4). Removal of the solvent
provided crude sphingosine analogue 27 as a white solid, which
was used in the next reaction without further purification. To
a solution of 27 in 6 mL of dry THF was added 108 mg (0.40
mmol) of p-nitrophenyl octanoate at rt. The mixture was
stirred for 48 h and then concentrated under reduced pressure.
Purification by column chromatography (EtOAc) afforded 53
mg (63%, two steps) of ∆6-ceramide analogue 3 as a low-
melting white solid: [R]25D -2.39° (c 2.2, CHCl3); IR 1631, 1542
cm-1; 1H NMR δ 0.86 (t, 6H, J ) 7.1 Hz), 1.10-1.40 (m, 26H),
1.52 (m, 2H), 1.62 (m, 2H), 1.93 (m, 2H), 2.07 (m, 2H), 2.21 (t,
2H, J ) 7.7 Hz), 2.57 (br s, 2H), 3.78 (m, 2H), 3.88 (m, 1H),
N-ter t-Bu toxycar bon yl (4S)-4-[(P h en ylsu lfon yl)acetyl]-
2,2-d im eth yl-1,3-oxa zolid in e [(-)-17]. A solution of sulfone
16 (937 mg, 6.0 mmol) in 10 mL of THF was added 2.64 mL of
n-butyllithium (a 2.5 M solution in hexane, 6.6 mmol) at -15
°C under nitrogen. The reaction mixture was stirred at -15
°C for 30 min and then chilled to -78 °C. A solution of ester
9 (778 mg, 3.0 mmol) in 5 mL of THF was added dropwise.
The reaction mixture was stirred at -78 °C for 2 h and allowed
to warm to rt overnight. Saturated aqueous NH4Cl solution
(10 mL) was added, and the product was extracted with EtOAc,
washed with brine, and dried (MgSO4). Purification by column
chromatography (hexane/EtOAc 1:1, Rf 0.72) gave 817 mg
(71%) of 17 as a white solid: mp 105-106 °C; [R]25 -93.2° (c
D
2.2, CHCl3); 1H NMR (C6D6, 70 °C) δ 1.33 (s, 9H), 1.45 (s, 3H),
1.58 (s, 3H), 3.90 (br s, 2H), 3.99 (d, 1H, J ) 14.0 Hz), 4.15 (br
s, 1H), 4.53 (br s, 1H), 6.99 (m, 3H), 7.78 (m, 2H); HR-MS
(FAB, MH+) calcd for m/z C18H26NO6S 384.1481, found 384.1487.
(3E)-P en ta d ecen yl P h en yl Su lfon e (21). To a solution
of sulfone 16 (780 mg, 5.0 mmol) in 5 mL of THF was added
2.4 mL of n-butyllithium (a 2.5 M solution in hexane, 6.0 mmol)
at -78 °C under nitrogen. The solution was stirred at -78 °C
for 30 min. A solution of bromide 8 (140 mg, 5.0 mmol) in 5
mL of THF was added dropwise. The mixture was stirred at
-78 °C for 2 h and allowed to warm to rt overnight. After
saturated aqueous NH4Cl solution (10 mL) was added, the
product was extracted with EtOAc, washed with brine, and