Asymmetric Synthesis of Phytosphingolipids
J . Org. Chem., Vol. 65, No. 22, 2000 7625
trated NH4OH 130:25:4 to collect the product. After concentra-
tion, the residue was purified by column chromatography
(elution with CHCl3/MeOH/concentrated NH4OH 130:25:4),
providing phytosphingosine 1a or 1b, or 4,5-dihydrosphin-
gosine 1c as white solids. The product was dissolved in a
minimum volume of CHCl3 and passed through a Cameo filter
to remove the dissolved silica gel.
30.64, 31.88, 36.36, 55.83, 56.10, 61.61, 73.70, 80.18, 97.13,
170.24, 174.59; HR-MS (FAB, MH+) calcd for m/z C38H76NO6
642.5672, found 642.5636.
Eth yl (2R,3S,4S)-2-p a lm itoyla m id o-3-h yd r oxy-4-(m eth -
oxym eth yloxy)octa d eca n oa te [(-)-11′]: mp 58.8-59.4 °C;
[R]25 -8.24° (c 1.93, CHCl3); IR 3510, 1742, 1652 cm-1 1H
;
D
NMR δ 0.86 (t, 6H, J ) 7.0 Hz), 1.20-1.42 (m, 49H), 1.60 (m,
3H), 1.74 (m, 1H), 2.22 (t, 2H, J ) 7.6 Hz), 2.65 (br s, 1H),
3.39 (s, 3H), 3.54 (m, 1H), 3.70 (dd, 1H, J ) 6.0, 3.8 Hz), 4.20
(m, 2H), 4.63 (d, 1H, J ) 6.8 Hz), 4.70 (dd, 1H, J ) 8.5, 3.7
Hz), 4.72 (d, 1H, J ) 6.9 Hz), 6.47 (d, 1H, J ) 8.4 Hz); 13C
NMR δ 14.11, 22.68, 25.20, 25.55, 29.23, 29.35, 29.48, 29.57,
29.61, 29.65, 29.68, 31.15, 31.91, 36.54, 54.22, 55.94, 61.52,
74.37, 82.40, 97.86, 170.35, 174.16; HR-MS (FAB, MH+) calcd
for m/z C38H76NO6 642.5672, found 642.5654.
D-r ibo-P h ytosp h in gosin e [(+)-1a ]: mp 98.5-101.5 °C
[lit.5h mp 95.4-98.5 °C]; [R]25D +9.7° (c 0.7, C5H5N) [lit.5h [R]27
D
+7.3° (c 1.0, C5H5N)]; IR (C5H5N) 3264, 2919, 2855, 1613, 1464,
1441, 1053 cm-1; 1H NMR (pyridine-d5) δ 0.85 (t, 3H, J ) 7.0
Hz), 1.20-1.50 (m, 22H), 1.71 (m, 1H), 1.91 (m, 2H), 2.26 (m,
1H), 3.52 (m, 1H), 3.98 (t, 1H, J ) 7.2 Hz), 4.23 (dd, 1H, J )
8.4, 2.8 Hz), 4.26 (dd, 1H, J ) 10.4, 6.0 Hz), 4.32 (dd, 1H, J )
10.4, 4.4 Hz), 4.94 (br s, 2H), 6.33 (br s, 2H); 13C NMR
(pyridine-d5) δ 14.27, 22.92, 26.17, 29.60, 29.91, 29.96, 30.00,
30.15, 30.40, 32.10, 34.70, 57.70, 65.08, 75.10, 75.76.
Eth yl
(2R,3R)-2-p a lm itoyla m id o-3-h yd r oxyocta d e-
ca n oa te [(-)-17]: mp 76.6-77.5 °C; [R]25 -23.51° (c 3.16,
D
1
D-r ibo-P h ytosp h in gosin e Tetr a a ceta te [(+)-10]. To a
solution of 20 mg (63.0 µmol) of phytosphingosine 14 in 2.0
mL of pyridine was added 120 µL (1.23 mmol) of Ac2O and 4.0
mg (32.0 µmol) of DMAP. The light brown solution was stirred
overnight at room temperature. After the solvent was removed
on a rotary evaporator, the residue was further dried under
high vacuum (0.7 Torr) for 20 min, dissolved in 2 mL of CH2-
Cl2, and filtered through a pad of silica gel in a buret. The
pad was rinsed with 50 mL of hexane/EtOAc 4:1. Concentra-
tion gave 29 mg (94%) of the desired phytosphingosine tet-
CHCl3); IR 3430, 1730, 1663, 1508 cm-1; H NMR δ 0.86 (t,
3H, J ) 7.1 Hz), 1.23-1.46 (m, 58H), 1.61 (m, 2H), 2.24 (t,
2H, J ) 7.7 Hz), 2.88 (br s, 1H), 3.92 (dt, 1H, J ) 8.4, 3.6 Hz),
4.22 (m, 2H), 4.65 (dd, 1H, J ) 6.6, 3.0 Hz), 6.42 (d, 1H, J )
6.6 Hz); 13C NMR δ 14.10, 14.12, 22.68, 25.58, 25.65, 29.20,
29.31, 29.35, 29.48, 29.57, 29.60, 29.65, 29.68, 31.91, 33.22,
36.40, 57.87, 61.90, 73.22, 170.44, 174.25; HR-MS (FAB, MH+)
calcd for m/z C36H72NO4 582.5461, found 582.5467.
Gen er a l P r oced u r e for Selective Red u ction of a n
Ester w ith Na BH4-LiBr in th e P r esen ce of a n Am id e.
To a heterogeneous mixture of 1.0 mmol of R-amido ester and
868 mg (10.0 mmol) of LiBr in 40 mL of freshly distilled THF
was added 454 mg (12.0 mmol) of NaBH4 at 0 °C. The
suspension was stirred vigorously at room temperature under
nitrogen until the full consumption of starting ester was
noticed (TLC). The reaction mixture was transferred to a
sintered glass funnel containing a pad of silica gel. The pad
was washed with 400 mL of CHCl3/MeOH 15:1 by gravity to
collect the product. The filtrate was concentrated, and the
residue was purified by column chromatography (elution with
CHCl3/MeOH 50:1). The product was dissolved in CHCl3 (15-
25 mL) and passed through a Cameo filter to remove the
dissolved silica gel.
raacetate 10 as a colorless syrup: [R]25 +27.8° (c 0.8, CHCl3)
D
[lit.5p [R]25 +26.2° (c 2.0, CHCl3), lit.5q [R]25 +26.3° (c 2.0,
D
D
CHCl3)]; IR 3324, 2937, 2865, 1742, 1665 cm-1; 1H NMR δ 0.85
(t, 3H, J ) 7.2 Hz), 1.22 (m, 24H), 1.6 (m, 2H), 2.00 (s, 3H),
2.02 (s, 6H), 2.05 (s, 3H), 3.97 (dd, 1H, J ) 11.6, 3.2 Hz), 4.26
(dd, 1H, J ) 12.0, 4.8 Hz), 4.44 (m, 1H), 4.90 (dt, 1H, J ) 9.6,
3.2 Hz), 5.07 (dd, 1H, J ) 8.4, 3.2 Hz), 5.95 (d, 1H, J ) 9.6
Hz); 13C NMR δ 14.11, 20.73, 20.76, 21.03, 22.67, 23.29, 25.49,
28.13, 29.28, 29.34, 29.47, 29.56, 29.61, 29.67, 31.90, 47.59,
62.81, 71.94, 72.94, 169.70, 170.07, 170.85, 171.14.
L-lyxo-P h ytosp h in gosin e [(+)-1b]: mp 104.8-106.0 °C
[lit.5g mp 96-98 °C]; [R]25 -7.4° (c 0.9, C5H5N) [lit.5g [R]20
D
D
-7.1° (c 1.0, C5H5N)]; IR (C5H5N) 3332, 2919, 2857, 1617, 1467,
1443, 1075 cm-1; 1H NMR (pyridine-d5) δ 0.85 (t, 3H, J ) 7.0
Hz), 1.20-1.50 (m, 22H), 1.58 (m, 1H), 1.77 (m, 1H), 1.92 (m,
1H), 2.00 (m, 1H), 3.63 (m, 1H), 3.96 (m, 1H), 4.17 (m, 1H),
4.29 (m, 2H); 13C NMR (pyridine-d5) δ 14.26, 22.92, 26.78,
29.60, 29.91, 29.97, 30.08, 30.27, 32.11, 34.60, 56.56, 65.15,
72.33, 75.12.
N-P alm itoyl-D-er yth r o-dih ydr osph in gosin e [(+)-2c]: mp
106.1-107.0 °C; [R]25 +6.67° (c 2.23, CHCl3/MeOH 9:1); IR
D
3422, 1653, 1506 cm-1; 1H NMR (CDCl3/CD3OD) δ 0.82 (t, 6H,
J ) 7.0 Hz), 1.19 (m, 49H), 1.44 (br s, 3H), 1.57 (m, 2H), 2.17
(t, 2H, J ) 7.8 Hz), 3.62 (dd, 2H, J ) 11.4, 3.4 Hz), 3.71 (m,
1H), 3.83 (dd, 1H, J ) 11.4, 3.95 Hz), 6.78 (d, 1H, J ) 7.9 Hz);
13C NMR (CDCl3/CD3OD) δ 14.00, 22.59, 25.70, 25.89, 29.21,
29.27, 29.43, 29.60, 31.83, 34.13, 36.63, 53.94, 61.82, 73.19,
174.05; HR-MS (FAB, MH+) calcd for m/z C34H70NO3 540.5356,
found 540.5356.
D-er yth r o-Sp h in ga n in e [(+)-1c]: mp 92.0-94.0 °C [lit.25e
mp 77-78 °C]; [R]25 +5.7° (c 2.74, CHCl3/MeOH 4:1) [lit.25e
D
[R]25 +5.5° (c 1.1, CHCl3/MeOH 10:1)]; IR 3618, 3422 cm-1
;
D
1H NMR δ 0.85 (t, 3H, J ) 7.0 Hz), 1.23 (m, 26H), 1.45 (m,
2H), 2.77 (br s, 4H), 2.57 (m, 1H), 3.67 (m, 2H); 13C NMR
(CDCl3/CD3OD) δ 14.11, 22.67, 26.09, 29.35, 29.65, 29.69,
31.91, 33.76, 55.67, 63.31, 74.48.
4-O-(Meth oxym eth yl)-N-p a lm itoyl-D-r ibo-p h ytosp h in -
gosin e [(-)-12]: mp 66.9-67.5 °C; [R]25 -11.46° (c 1.48,
D
CHCl3); IR 3422, 1658, 1501 cm-1; 1H NMR δ 0.86 (t, 6H, J )
7.0 Hz), 1.15-1.45 (m, 48H), 1.59 (m, 4H), 2.20 (t, 2H, J ) 7.7
Hz), 3.01 (br s, 2H), 3.41 (s, 3H), 3.62 (dt, 1H, J ) 8.26, 4.14
Hz), 3.73 (m, 2H), 3.89 (dd, 1H, J ) 11.5, 3.8 Hz), 4.11 (dt,
1H, J ) 4.15, 4.13 Hz), 4.61 (d, 1H, J ) 6.5 Hz), 4.72 (d, 1H,
J ) 6.5 Hz), 6.30 (d, 1H, J ) 8.4 Hz); 13C NMR δ 14.09, 22.67,
25.49, 25.74, 29.29, 29.34, 29.49, 29.59, 29.65, 29.68, 30.61,
31.91, 38.81, 51.65, 56.06, 62.59, 73.90, 82.00, 97.34, 173.85;
HR-MS (FAB, MH+) m/z calcd for C36H74NO5 600.5567, found
600.5567.
Gen er a l P r oced u r e for th e On e-P ot Con ver sion of a n
Azid o to a n Am id o Gr ou p . To a solution of 1.0 mmol of
R-azidoester and 944 mg (2.5 mmol) of p-nitrophenyl palmitate
in 30 mL of THF/H2O 9:1 was added 314 mg (1.2 mmol) of
Ph3P. The reaction mixture was stirred at room temperature
under nitrogen for 48 h (96 h for a phytoceramide precursor).
After the solvents were removed in vacuo (2-PrOH was used
to remove the residual H2O), the light yellow residue was
dissolved in 100 mL of Et2O and washed with 1% aqueous Na2-
CO3 solution (4 × 20 mL) to remove the 4-nitrophenol
byproduct. The organic phase was dried (Na2SO4) and con-
centrated. The residue was purified by column chromatogra-
phy (elution with hexane/EtOAc 5:1).
4-O-(Meth oxym eth yl)-N-p a lm itoyl-L-lyxo-p h ytosp h in -
gosin e [(+)-12′]: mp 65.0-65.8 °C; [R]25 +13.17° (c 1.4,
D
CHCl3); IR 3375, 1655, 1501 cm-1; 1H NMR δ 0.86 (t, 6H, J )
7.0 Hz), 1.23-1.41 (m, 48H), 1.56 (m, 4H), 2.19 (t, 2H, J ) 7.8
Hz), 3.29 (br s, 2H), 3.39 (s, 3H), 3.49 (m, 1H), 3.67 (m, 2H),
3.90 (dd, 1H, J ) 11.6, 3.6 Hz), 3.99 (dt, 1H, J ) 8.0, 4.2 Hz),
4.66 (d, 1H, J ) 6.6 Hz), 4.74 (d, 1H, J ) 6.6 Hz), 6.44 (d, 1H,
J ) 8.2 Hz); 13C NMR δ 14.08, 22.66, 25.19, 25.70, 29.26, 29.34,
29.48, 29.57, 29.63, 29.67, 31.27, 31.89, 36.81, 51.43, 55.94,
62.52, 74.43, 82.01, 97.79, 173.58.
Eth yl (2R,3S,4R)-2-palm itoylam ido-3-h ydr oxy-4-(m eth -
oxym eth yloxy)octa d eca n oa te [(-)-11]: mp 58.6-59.2 °C;
1
[R]25 -32.95° (c 1.39, CHCl3); IR 3537, 1738, 1654 cm-1; H
D
NMR δ 0.84 (t, 6H, J ) 7.0 Hz), 1.15-1.42 (m, 51H), 1.62 (m,
4H), 2.24 (t, 2H, J ) 7.6 Hz), 3.34 (s, 3H), 3.48 (m, 1H), 3.82
(br s, 1H), 4.01 (dd, 1H, J ) 7.1, 2.7 Hz), 4.16 (m, 2H), 4.51
(dd, 2H, J ) 12.3, 6.5 Hz), 4.67 (dd, 1H, J ) 6.7, 2.8 Hz), 6.67
(d, 1H, J ) 6.6 Hz); 13C NMR δ 13.96, 14.06, 22.64, 24.35,
25.52, 29.20, 29.28, 29.31, 29.43, 29.56, 29.61, 29.65, 29.83,
Gen er a l P r oced u r e for Rem ova l of th e MOM P r otect-
in g Gr ou p . The MOM protecting group was removed by acid
hydrolysis as follows. To 300 mg (0.50 mmol) of 2-palmitoyl-