Hydrolysis of the Endogenous Sleep-Inducing Lipid
J. Am. Chem. Soc., Vol. 118, No. 25, 1996 5943
31.9, 29.7, 29.6, 29.5, 29.3(2), 29.2, 29.0, 28.9, 27.2, 27.1, 22.9, 22.7,
1,1,1-Trifluoro-10(E)-nonadecen-2-one (14). A solution of elaidic
acid (204 mg, 0.72 mmol, 1 equiv) in anhydrous CH2Cl2 (3.5 mL) was
cooled to 0 °C under N2 and treated with oxalyl chloride (2 M in CH2-
Cl2, 1.1 mL, 2.2 mmol, 3 equiv). The reaction mixture was warmed
to 25 °C and stirred for 3 h before the solvent was removed in vacuo.
Anhydrous Et2O (5 mL), trifluoroacetic anhydride (0.6 mL, 4.3 mmol,
6 equiv), and anhydrous pyridine (0.23 mL, 2.8 mmol, 4 equiv) were
added at 25 °C, and the solution was stirred for 1 h before being cooled
to 0 °C. The mixture was treated with H2O (30 mL), and the aqueous
layer was extracted with EtOAc (3 × 30 mL). The organic layers were
dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography
(SiO2, 2 × 13 cm, 1% Et3N in 5-10% EtOAc-hexane gradient elution)
afforded 14 (190 mg, 79%) as a clear oil: 1H NMR (CDCl3, 400 MHz)
δ 5.41-5.31 (m, 2H), 2.68 (t, 2H, J ) 7.3 Hz), 1.94 (m, 4H), 1.65 (p,
2H, J ) 6.9 Hz), 1.28-1.24 (m, 20H), 0.86 (t, 3H, J ) 6.6 Hz); 13C
NMR (CDCl3, 100 MHz) δ 191.5 (q, J ) 35 Hz), 130.6, 130.1, 115.6
(q, J ) 291 Hz), 36.3, 32.6, 32.5, 31.9, 29.7, 29.5(2), 29.3, 29.2, 29.1,
28.8, 28.7, 22.7, 22.4, 14.0; IR (film) νmax 2925, 2855, 1765, 1466,
1208, 1152, 967, 709 cm-1; FABHRMS (NBA-NaI) m/z 334.2475
(C19H33OF3 - H+ requires 334.2484).
14.1, 14.0; IR (film) νmax 2925, 2854, 1730, 1465, 1260, 1059 cm-1
;
FABHRMS (NBA-CsI) m/z 471.1875 (C21H38O3 + Cs+ requires
471.1888).
Ethyl 2-Oxo-nonadecanoate (10). A solution of stearic acid (101
mg, 0.36 mmol, 1 equiv) in anhydrous THF (0.2 mL) at 25 °C under
Ar was treated with DMAP (4 mg, 0.03 mmol, 0.1 equiv), anhydrous
pyridine (85 µL, 1.1 mmol, 3 equiv), and ethyl oxalyl chloride (79 µL,
0.71 mmol, 2 equiv). The reaction mixture was stirred for 24 h before
the solvent was concentrated in vacuo. Chromatography (SiO2, 2 ×
13 cm, 5-10% EtOAc-hexane) afforded 10 (35 mg, 30%) as a white
solid: mp 43-44 °C; 1H NMR (CDCl3, 400 MHz) δ 4.29 (q, 2H, J )
7.2 Hz), 2.80 (t, 2H, J ) 7.4 Hz), 1.60 (p, 2H, J ) 7.2 Hz), 1.35 (t,
3H, J ) 7.1 Hz), 1.33-1.23 (m, 28H), 0.86 (t, 3H, J ) 6.8 Hz); 13C
NMR (CDCl3, 100 MHz) δ 194.8, 161.2, 62.4, 39.3, 31.9, 29.7(7),
29.6, 29.40, 29.35, 29.28, 28.9, 23.0, 22.7, 14.1, 14.0; IR (film) νmax
2916, 2848, 1733, 1472, 1463, 723 cm-1; FABHRMS (NBA-NaI)
m/z 363.2885 (C21H40O3 + Na+ requires 363.2875).
tert-Butyl 3-Oxo-2,2-dihydroxyoctadecanoate (11). A solution of
28 (161 mg, 0.26 mmol, 1 equiv) in THF-H2O (2:1; 3 mL) was treated
with Oxone (249 mg, 0.41 mmol, 1.6 equiv), and the reaction mixture
was stirred at 25 °C for 7 h. Water (30 mL) was added, and the aqueous
layer was extracted with EtOAc (3 × 30 mL). The organic layers were
combined, dried (Na2SO4), filtered, and concentrated in vacuo. Chro-
matography (SiO2, 2 × 15 cm, 10-20% EtOAc-hexane gradient
elution) afforded 11 (65 mg, 64%) as a white solid: mp 49-51 °C; 1H
NMR (DMSO-d6, 400 MHz) δ 6.96 (s, 2H), 2.17 (t, 2H, J ) 7.4 Hz),
1.49-1.38 (m, 11H), 1.22 (s, 24H), 0.84 (t, 3H, J ) 6.8 Hz); 13C NMR
(DMSO-d6, 100 MHz) δ 205.6, 174.5, 94.2, 81.5, 35.6, 33.6, 31.3,
29.0(3), 28.9, 28.8, 28.72, 28.70, 28.53, 28.46, 27.4(2), 24.5, 22.9, 22.1,
13.9; IR (film) νmax 3440, 2914, 2849, 1728, 1471, 1371, 1260, 1122,
831, 718 cm-1; FABHRMS (NBA-NaI) m/z 409.2925 (C22H42O5 +
Na+ requires 409.2930).
1,1,1-Trifluoro-10(Z)-nonadecen-2-one (12). Oleic acid (100 µL,
0.32 mmol, 1 equiv) was dissolved in anhydrous CH2Cl2 (1.5 mL) and
cooled to 0 °C under N2. Oxalyl chloride (2 M in CH2Cl2, 0.47 mL,
0.94 mmol, 3 equiv) was added slowly. The reaction mixture was
warmed to 25 °C and was stirred in the dark for 3 h before the solvent
was removed in vacuo. Anhydrous Et2O (2.2 mL), trifluoroacetic
anhydride (270 µL, 1.9 mmol, 6 equiv), and pyridine (0.2 mL, 2.5
mmol, 8 equiv) were added at 25 °C, and the solution was stirred for
45 min before being cooled to 0 °C. The reaction was quenched with
the addition of H2O (30 mL), and the aqueous layer was extracted with
CH2Cl2 (3 × 30 mL). The organic layers were dried (Na2SO4), filtered,
and concentrated in vacuo. Chromatography (SiO2, 1.5 × 13 cm, 1%
Et3N in 5% EtOAc-hexane) afforded 8 (75 mg, 71%) as a clear oil:
1H NMR (CDCl3, 400 MHz) δ 5.37-5.28 (m, 2H), 2.68 (t, 2H, J )
7.3 Hz), 1.98 (m, 4H), 1.65 (p, 2H, J ) 7.1 Hz), 1.29-1.25 (m, 20H),
0.86 (t, 3H, J ) 6.9 Hz); 13C NMR (CDCl3, 100 MHz) δ 191.6 (d, J
) 17 Hz), 130.0, 129.5, 115.6 (q, J ) 145 Hz), 36.3, 31.9, 29.8, 29.6,
29.5, 29.3(2), 29.1, 29.0, 28.7, 27.2, 27.1, 22.7, 22.4, 14.1; IR (film)
2-Hydroxy-9(Z)-octadecenamide (17). A solution of 18 (52 mg,
0.18 mmol, 1 equiv) in anhydrous CH2Cl2 (0.7 mL) cooled to 0 °C
under N2 was treated with oxalyl chloride (2 M in CH2Cl2, 0.22 mL,
0.44 mmol, 3 equiv). The solution was allowed to warm to 25 °C and
stirred for 3 h in the dark. The solvent was removed in vacuo, and the
acid chloride was cooled to 0 °C. The sample was treated with excess
concentrated aqueous NH4OH. Chromatography (SiO2, 1.5 × 10 cm,
66-100% EtOAc-hexane gradient elution) afforded 17 (31 mg, 60%)
1
as a white solid: mp 103-104 °C; H NMR (CDCl3, 400 MHz) δ
6.37 (br, 1H), 5.64 (br, 1H), 5.36-5.28 (m, 2H), 4.12 (t, 1H, J ) 3.8
Hz), 2.66 (br, 1H), 2.02-1.94 (m, 4H), 1.86-1.77 (m, 1H), 1.68-
1.59 (m, 1H), 1.43-1.24 (m, 20H), 0.86 (t, 3H, J ) 6.8 Hz); 13C NMR
(CDCl3, 100 MHz) δ 176.6, 130.0, 129.7, 71.9, 34.8, 31.9, 29.7, 29.6,
29.5, 29.3(2), 29.2, 29.1, 27.2, 27.1, 24.9, 22.7, 14.1; IR (film) νmax
3381, 3289, 2917, 2848, 1637, 1461, 1417, 1331, 1074 cm-1
;
FABHRMS (NBA) m/z 298.2760 (C18H35NO2 + H+ requires 298.2746).
2-Chloro-9(Z)-octadecenamide (19). A solution of 20 (48 mg, 0.15
mmol, 1 equiv) in anhydrous CH2Cl2 (0.7 mL) cooled to 0 °C under
N2 was treated with oxalyl chloride (2 M in CH2Cl2, 0.23 mL, 0.46
mmol, 3 equiv). The solution was allowed to warm to 25 °C and was
stirred for 3 h in the dark before the solvent was removed in vacuo.
The crude acid chloride was cooled to 0 °C and treated with excess
concentrated aqueous NH4OH. Chromatography (SiO2, 1.5 × 10 cm,
20-33% EtOAc-hexane gradient elution) afforded 19 (37 mg, 78%)
as a yellow solid: mp 49-50 °C; 1H NMR (CDCl3, 400 MHz) δ 6.49
(br, 1H), 5.92 (br, 1H), 5.36-5.27 (m, 2H), 4.29 (m, 1H), 2.12-1.86
(m, 6H), 1.53-1.16 (m, 20H), 0.85 (t, 3H, J ) 6.9 Hz); 13C NMR
(CDCl3, 100 MHz) δ 171.9, 130.1, 129.6, 60.6, 35.5, 31.9, 29.7, 29.6,
29.5, 29.3(2), 29.0, 28.7, 27.2, 27.1, 25.8, 22.7, 14.1; IR (film) νmax
3383, 3183, 3001, 2921, 2850, 1657, 1465, 1412, 1240, 1100 cm-1
;
ν
max 2926, 2855, 1766, 1467, 1404, 1261, 1208, 1153, 1039, 802, 709
FABHRMS (NBA) m/z 316.2415 (C18H34NOCl + H+ requires 316.2407).
cm-1; ESIMS m/z (M+) 334.
1-Diazo-10(Z)-nonadecen-2-one (21). Oleic acid (1.0 mL, 3.2
mmol, 1 equiv) was dissolved in anhydrous CH2Cl2 (15 mL) under
N2. The solution was cooled to 0 °C, and oxalyl chloride (2 M in
CH2Cl2, 4.8 mL, 9.6 mmol, 3 equiv) was added. The reaction mixture
was allowed to warm to 25 °C and was stirred for 3 h in the dark. The
solvent was removed in vacuo before the acid chloride was transferred
to a flask with no ground glass joints and cooled to 0 °C. Excess
diazomethane in Et2O (prepared from N-nitrosomethylurea in 50%
aqueous KOH and drying over KOH pellets) was added. The reaction
was stirred at 0 °C for 1 h before warming to 25 °C overnight. The
solution was diluted with EtOAc (60 mL) and washed with saturated
aqueous NaHCO3 (60 mL) and saturated aqueous NaCl (60 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated in vacuo.
Chromatography (SiO2, 4.0 × 16 cm, 5-10% EtOAc-hexane gradient
elution) afforded 21 (0.89 g, 92%) as a yellow oil: 1H NMR (CD3OD,
400 MHz) δ 5.72 (br, 1H), 5.29-5.21 (m, 2H), 2.23 (m, 2H), 1.94 (m,
4H), 1.50 (p, 2H, J ) 6.9 Hz), 1.23-1.20 (m, 20H), 0.81 (t, 3H, J )
6.9 Hz); 13C NMR (CD3OD, 100 MHz) δ 198.8, 130.9, 130.8, 41.6,
33.1, 30.9, 30.8(2), 30.6, 30.5, 30.4(2), 30.3, 30.2, 28.1(2), 26.5, 23.8,
1,1,1-Trifluoro-9(Z)-octadecen-2-one (13). A solution of 27 (101
mg, 0.38 mmol, 1 equiv) in anhydrous CH2Cl2 (1.8 mL) was cooled to
0 °C under N2 and treated dropwise with oxalyl chloride (2 M in CH2-
Cl2, 0.56 mL, 1.1 mmol, 3 equiv). The reaction mixture was warmed
to 25 °C and stirred for 3 h before the solvent was removed in vacuo.
Anhydrous Et2O (2.5 mL), trifluoroacetic anhydride (0.32 mL, 2.3
mmol, 6 equiv), and anhydrous pyridine (0.12 mL, 1.5 mmol, 4 equiv)
were added at 25 °C, and the solution was stirred for 2 h before being
cooled to 0 °C. The reaction mixture was treated with H2O (30 mL),
and the aqueous layer was extracted with EtOAc (3 × 30 mL). The
organic layers were dried (Na2SO4), filtered, and concentrated in vacuo.
Chromatography (SiO2, 2 × 15 cm, 1% Et3N in 10% EtOAc-hexane)
afforded 13 (65.5 mg, 54%) as a clear oil: 1H NMR (CDCl3, 400 MHz)
δ 5.39-5.26 (m, 2H), 2.69 (t, 2H, J ) 7.2 Hz), 1.99 (m, 4H), 1.66 (m,
2H), 1.35-1.24 (m, 18H), 0.86 (t, 3H, J ) 6.9 Hz); 13C NMR (CDCl3,
100 MHz) δ 191.4, 130.5, 129.1, 115.6 (q, J ) 146 Hz), 36.3, 31.9,
29.7, 29.5, 29.3(3), 29.2, 28.3, 27.2, 26.8, 22.7, 22.3, 14.1; IR (film)
ν
max 2926, 2855, 1765, 1462, 1209, 1154, 1024 cm-1; ESIMS m/z (M
+ Na+) 343.