Synthesis of Homoceramides
J . Org. Chem., Vol. 67, No. 3, 2002 995
and the solution was cooled to 0 °C (ice-bath). Cerium(III)
chloride (CeCl3‚7H2O, 713 mg, 1.91 mmol) was added until
complete dissolution, followed by addition of NaBH4 (265 mg,
7.01 mmol). The solution was stirred for 3 h at 0 °C, the solvent
was evaporated, and the residue was suspended in 1 N HCl
(69 mL). The aqueous phase was extracted with EtOAc. The
combined organic layers were dried over MgSO4 and concen-
trated in vacuo. Purification of the residue by flash chroma-
tography (silica, EtOAc/pentane 1:9) yielded an unseparable
mixture of epimeric alkynols 12 as an oil (1.55 g, 51%). Further
purification was achieved by HPLC (silica, EtOAc/hexane 2:8).
1H NMR (500 MHz, CDCl3): δ 0.06 (6 H, s), 0.86-0.90 (12 H,
m), 1.24-1.38 (8 H, m), 1.45-1.51 (2 H, quintet, J ) 7.3 Hz),
1.85-1.95 (2 H, m), 2.18 (2 H, td, J ) 1.9 and 7.1 Hz), 3.67-
3.77 (2 H, m), 3.88-3.92 (0.25 H, m, minor epimer), 3.95-
4.01 (1 H, m, major epimer), 4.42-4.47 (1 H, m), 5.10 (2 H, s),
5.44 (1 H, d, J ) 7.7 Hz), 7.34-7.36 (5 H, m) ppm; Exact mass
(ES): calculated for C27H45NO4Si [M + Na]+ 498.3015, found
498.3015.
Ben zyl (1S,2RS)-2-Hyd r oxy-1-(2-h yd r oxyleth yl)u n d ec-
3-yn ylca r ba m a te (13). To a solution of 12 (924 mg, 1.94
mmol) in MeOH (10 mL) was added 1.0 mL concentrated HCl
(37%). The reaction mixture was stirred at room-temperature
for 1.5 h and then neutralized with 25% aqueous ammonia.
Purification of the residue by flash chromatography (silica,
EtOAc/pentane 1:1) afforded an inseparable mixture of alkynols
13 as a white solid (541 mg, 77%). Further purification was
achieved by HPLC (silica, EtOAc/hexane 4:6). 1H NMR (500
MHz, CDCl3): δ 0.88 (3 H, t, J ) 6.8 Hz), 1.24-1.36 (8 H, m),
1.44-1.52 (2 H, m), 1.59-1.68 (1 H, m), 1.90-1.98 (1 H, m),
2.19 (2 H, t, J ) 7.1 Hz), 2.63 (2 H, br s), 3.64-3.75 (2 H, m),
3.95-3.99 (0.4 H, m, threo-epimer), 4.01-4.07 (1 H, m, erythro-
epimer), 4.41-4.44 (0.4 H, m, threo-epimer), 4.46-4.50 (1 H,
m, erythro-epimer), 5.09 (1 H, A of AB, J ) 12.1 Hz), 5.15 (1
H, B of AB, J ) 12.1 Hz), 5.25 (1 H, br s), 7.32-7.38 (5 H, m)
ppm; MS (ES, i-Prop/H2O): m/z (%) 384 ([M + H + Na]+, 100),
362 ([M + H]+, 27), 344 ([M + H - H2O]+, 26), 318 (26), 300
(28); Exact mass (ES): calculated for C21H32NO4 [M + H]+
362.2331, found 362.2366.
(3S,4R,5E)-3-Am in otr id ec-5-en e-1,4-d iol (14). A solution
of Li (249 mg, 0.036 mmol) in EtNH2 (10 mL) was stirred for
2 h at -78 °C, and a solution of 13 (866 mg, 2.40 mmol) in
THF (10 mL) was added dropwise. The reaction mixture was
stirred for 3 h at -78 °C, and the reaction was quenched by
adding a saturated NH4Cl-solution (8.5 mL). EtNH2 and THF
were removed under reduced pressure, and the residue was
diluted with water and extracted several times with EtOAc.
The organic layers were dried over MgSO4 and evaporated in
vacuo. The residue was subjected to flash chromatography
(silica, CH2Cl2/MeOH/2 M NH3 85:15:1). Both epimers could
be separated, but only the major erythro-epimer 14 was
obtained in pure form (313 mg, 57%). 1H NMR (500 MHz,
CD3OD): δ 0.87 (3 H, t, J ) 6.8 Hz), 1.20-1.38 (8 H, m), 1.40-
1.48 (2 H, m), 1.68-1.77 (1 H, m), 1.80-1.88 (1 H, m), 2.10 (2
H, q, J ) 7.0 Hz), 3.31 (1 H, quintet, J ) 1.6 Hz), 3.68-3.76
(2 H, m) 4.21 (1 H, br t), 5.48 (1 H, dd, J ) 6.7 and 15.4 Hz),
5.84 (1 H, dt, J ) 6.8 and 15.0 Hz) ppm; MS (ES): m/z (%)
252 ([M + Na]+, 16), 230 ([M + H]+, 50), 212 ([M + H - H2O]+,
100); exact mass (ES): calculated for C13H28NO2 [M + H]+
230.2120, found 230.2097.
Hz), 5.75 (1 H, dt, J ) 6.6 and 14.8 Hz), 6.25 (1 H, d, J ) 7.2
Hz) ppm; 13C NMR (75 MHz, CDCl3): δ 14.09, 22.65, 23.24,
29.11, 29.50, 29.69, 31.26, 31.79, 32.28, 50.94, 58.46, 74.42,
128.32, 134.19, 171.39; MS (ES): m/z (%) 294 ([M + Na]+, 54),
272 ([M + H]+, 40), 254 ([M + H - H2O]+, 100); exact mass
(ES): calculated for C15H30NO3 [M + H]+ 272.2226, found
272.2211.
N-[(1S,2R,3E)-2-H yd r oxy-1-(2-h yd r oxyet h yl)u n d ec-3-
en yl]h exa n a m id e (16). Compound 16 was synthesized from
amine 14 (124 mg, 0.54 mmol) and hexanoyl chloride (68 µl,
0.49 mmol) using the procedure described for the synthesis of
compound 15. Purification of the residue by flash chromatog-
raphy (silica, MeOH/CH2Cl2 6:94) yielded 16 as a white solid
(103 mg, 58%). Further purification was achieved by HPLC
(silica, EtOAc/hexane 8:2). [R]D ) -10.7 (c 0.43, CHCl3); 1H
NMR (200 MHz, CDCl3): δ 0.87-0.92 (6 H, m, 2 × CH3), 1.26-
1.38 (14 H, m, 7 × CH2), 1.46-1.53 (1 H, m, CH2CH2OH),
1.62-1.68 (2 H, quintet, J ) 7.3 Hz, NHC(O)CH2CH2), 1.83-
1.89 (1 H, m, CH2CH2OH), 2.06 (2 H, q, J ) 7.2 Hz, H-C(5)),
2.24 (2 H, t, J ) 7.6 Hz, NHC(O)CH2), 2.95 (2 H, br s, 2 ×
OH), 3.56 (1 H, td, J ) 2.9 and 11.7 Hz, CH2OH), 3.67 (1 H,
td, J ) 4.4 and 11.7 Hz, CH2OH), 4.10-4.15 (1 H, tt, J ) 2.9
and 8.8 Hz, H-C(1)), 4.24 (1 H, t, J ) 4.6 Hz, H-C(2)), 5.48
(1 H, dd, J ) 6.4 and 15.6 Hz, H-C(3)), 5.75 (1 H, dt, J ) 6.8
and 15.1 Hz, H-C(4)), 6.12 (1 H, d, J ) 8.3 Hz, NH) ppm; 13
C
NMR (75 MHz, CDCl3): δ 13.92 (CH3), 14.09 (CH3), 22.37,
22.64 (2 × CH2CH3), 25.53 (NHC(O)CH2CH2), 29.09, 29.12,
29.16 (C(6), C(7) and C(8)), 31.35, 31.40 (C(9) and NHC(O)-
CH2CH2CH2), 31.80 (CH2CH2OH), 32.30 (C(5)), 36.70 (NHC-
(O)CH2), 50.80 (C(1)), 58.46 (CH2OH), 74.46 (C(2)), 128.35
(C(4)), 134.12 (C(3)), 174.65 (CdO) ppm; MS (ES): m/z (%) 350
([M + Na]+, 39), 328 ([M + H]+, 39), 310 ([M + H - H2O]+,
100); Exact mass (ES): calculated for C19H38NO3 [M + H]+
328.2852, found 328.2866.
N-[(1S,2R,3E)-2-H yd r oxy-1-(2-h yd r oxyet h yl)u n d ec-3-
en yl]ben za m id e (17). Compound 17 was prepared by the
procedure described for the synthesis of 15 using 14 (110 mg,
0.48 mmol) and benzoyl chloride (50 µl, 0.43 mmol). Purifica-
tion of the residue by flash chromatography (silica, MeOH/
CH2Cl2 5:95) yielded 17 as a white solid (101 mg, 63%). For
identification purposes and biological testing, a small sample
was purified by HPLC (silica, EtOAc/hexane 7:3). [R]D ) -20.3
1
(c 0.48, CHCl3); H NMR (500 MHz, CDCl3): δ 0.88 (3 H, t, J
) 6.6 Hz), 1.23-1.31 (8 H, m), 1.35-1.40 (2 H, m), 1.60-1.67
(1 H, m), 1.95-2.01 (1 H, m), 2.07 (2 H, q, J ) 7.1 Hz), 2.74 (2
H, br s), 3.63-3.68 (1 H, m), 3.71-3.75 (1 H, m), 4.32-4.39 (2
H, m), 5.55 (1 H, dd, J ) 6.0 and 15.4 Hz), 5.80 (1 H, dt, J )
6.7 and 15.4 Hz), 6.87 (1 H, br s), 7.45 (2 H, t, J ) 7.6 Hz),
7.53 (1 H, t, J ) 7.3 Hz), 7.80 (2 H, d, J ) 8.0 Hz) ppm; 13C
NMR (75 MHz, CDCl3): δ 14.09, 22.65, 29.12, 29.16, 29.69,
31.52, 31.78, 32.33, 51.62, 58.72, 74.60, 127.03, 128.38, 128.66,
131.84, 133.80, 134.35, 168.51; MS (ES): m/z (%) 356 ([M +
Na]+, 37), 334 ([M + H]+, 28), 316 ([M + H - H2O]+, 100), 298
(8); exact mass (ES): calculated for C20H32NO3 [M + H]+
334.2382, found 334.2398.
(4S,5R)-4-(2-{[ter t-Bu t yl)d im et h yl)silyl]oxy}et h yl)-5-
(n on -1-yn yl)-1,3-oxa zolid in -2-on e (18). To a solution of 12
(106 mg, 0.22 mmol) in THF was added 100 µL (0.56 mmol) of
a 30% NaOMe solution in MeOH. The reaction mixture was
stirred at room-temperature for 4 h and diluted with Et2O and
water. The aqueous phase was extracted with EtOAc. The
combined organic layers were dried over MgSO4 and concen-
trated in vacuo. Purification of the residue by flash chroma-
tography (silica, EtOAc/hexane 15:85) gave the epimeric
mixture of oxazolidinones as an oil (30 mg, 37%). The major
isomer 18 could be obtained in pure form by HPLC (silica,
N-[(1S,2R,3E)-2-H yd r oxy-1-(2-h yd r oxyet h yl)u n d ec-3-
en yl]a ceta m id e (15). To a solution of amine 14 (94 mg, 0.41
mmol) in THF (4 mL) were added a 50% aqueous NaOAc
solution (4 mL) and acetyl chloride (26 µl, 0.37 mmol). After
completion of the reaction (6 h), THF and brine were added.
The organic phase was separated, washed with water, dried
over MgSO4, and concentrated in vacuo. Purification of the
residue by flash chromatography (silica, MeOH/CH2Cl2 7:93)
yielded 15 as a white solid (82 mg, 74%). Further purification
was achieved by HPLC (silica, MeOH/CH2Cl2 6:94). [R]D ) -7.9
1
EtOAc/hexane 2:8). H NMR (500 MHz, CDCl3): δ 0.09 (6 H,
s, 2 × Si-CH3), 0.88-0.92 (12 H, m, CH3 and tert-Bu), 1.25-
1.40 (8 H, m, 4 × CH2), 1.53 (2 H, quintet, J ) 7.3 Hz, Ct
C-CH2-CH2), 1.88-1.93 (2 H, m, CH2CH2OSi), 2.26 (2 H, dt,
J ) 2.0 and 7.1 Hz, CtC-CH2), 3.73-3.78 (1 H, m, CH2OSi),
3.85 (1 H, dt, J ) 4.7 and 10.6 Hz, CH2OSi), 3.98 (1 H, J ) 4.8
and 8.1 Hz, H-C(4)), 5.29 (1 H, dt, J ) 2.0 and 7.9 Hz,
H-C(5)), 5.58 (1 H, br s, NH) ppm. 13C NMR (50 MHz,
CDCl3): δ -5.52 (Si-CH3), -3.60 (Si-CH3), 14.02 (CH3), 18.73
1
(c 0.25, CHCl3); H NMR (500 MHz, CDCl3): δ 0.88 (3 H, t, J
) 6.9 Hz), 1.23-1.30 (10 H, m), 1.34-1.39 (1 H, m), 1.82-
1.88 (1 H, m), 2.00-2.07 (5 H, m), 2.69 (2 H, br s), 3.57 (1 H,
t, J ) 9.5 Hz), 3.66 (1 H, dd, J ) 4.1 and 11.6 Hz), 4.08-4.17
(1 H, m), 4.23-4.27 (1 H, m), 5.47 (1 H, dd, J ) 5.8 and 15.5