Six EKODE Isomers
crude product was purified by silica gel chromatography (eluent
hexanes-ether 3:1), affording 5 as a yellow oil (236 mg, 44%): 1H
NMR (trans isomer, 200 MHz, CDCl3) δ 1.22-1.52 (8H), 1.52-
1.70 (4H), 2.31 (t, 2H, J ) 7.3 Hz), 3.13 (dd, 1H, J ) 6.3 and 2.0
Hz), 3.23 (td, 1H, J ) 5.6 and 2.0 Hz), 3.67 (s, 3H), 9.02 (d, 1H,
J ) 6.3 Hz); 13C NMR (trans isomer, 50 MHz, CDCl3) δ 24.9 (+),
25.8 (+), 28.99 (+), 29.06 (+), 29.09 (+), 31.2 (+), 34.1 (+),
51.5 (-), 56.8 (-), 59.2 (-), 174.3 (+), 198.6 (-); HRMS (FAB)
calcd for C12H21O4 (MH+) 229.1440, found 229.1436. NMR
resonances for the minor cis isomer could not be readily ascertained.
Methyl 13-Oxo-trans(cis)-9,10-epoxy-11(E)-octadecenoate (8).13
n-Butyllithium (1.6 mL, 2.5 M in hexane, 3.8 mmol) was added to
a cooled (-70 °C) solution of 1-(triphenylphosphoranylidene)-2-
propanone (6) (1.0 g, 3.2 mmol) in THF (40 mL), causing a deep-
red color to develop. The mixture was stirred for 30 min, whereupon
n-butyl iodide (0.83 g, 4.5 mmol) was added dropwise, and the
mixture was then allowed to stir at room temperature for 18 h.
After evaporation of THF, the resulting red oil was dissolved in
EtOAc (20 mL) and washed with water. The dried (Na2SO4) organic
layer was evaporated to afford crude 1-(triphenylphosphora-
nylidene)-2-heptanone14 (7) as a viscous oil in essentially quantita-
tive yield (1.35 g). A solution of crude 7 (213 mg, 0.57 mmol) in
3 mL of anhydrous CH2Cl2 was added to a solution of methyl 9,-
10-epoxy-11-oxoundecanoate (5) (100 mg, 0.44 mmol) in 1 mL of
anhydrous CH2Cl2 at 0 °C. After stirring for 1 h, the mixture was
directly applied to a preparative silica gel TLC plate (0.5 mm),
which was eluted with hexanes-EtOAc 3:2. The band at Rf ) 0.59
was extracted with ether, and the extract was filtered and evaporated,
affording 8 as a yellow oil (99 mg, 70%): 1H NMR (trans isomer,
200 MHz, CDCl3) δ 0.88 (t, 3H, J ) 6.6 Hz), 1.22-1.70 (18H),
2.30 (t, 2H, J ) 7.3 Hz), 2.53 (t, 2H, J ) 7.2 Hz), 2.89 (td, 1H, J
) 5.3 and 2.0 Hz), 3.20 (dd, 1H, J ) 6.4 and 2.0 Hz), 3.66 (s,
3H), 6.38 (d, 1H, J ) 15.9 Hz), 6.51 (dd, 1H, J ) 15.9 and 6.4
Hz); 13C NMR (trans isomer, 50 MHz, CDCl3) δ 14.0 (-), 22.5
(+), 23.8 (+), 24.9 (+), 25.8 (+), 29.0 (+), 29.2 (2, +), 31.5 (+),
31.9 (+), 34.1 (+), 40.7 (+), 51.5 (-), 56.7 (-), 61.6 (-), 131.4
(-), 142.5 (-), 174.3 (+), 199.8 (+); HRMS (FAB) calcd for
C19H33O4 (MH+) 325.2379, found 325.2378. NMR resonances for
the minor cis isomer could not be readily ascertained.
13-Oxo-cis/trans-9,10-epoxy-11(E)-octadecenoic Acid (cis/
trans-EKODE-(E)-Ia). A solution of 8 (20 mg, 0.062 mmol) in
i-PrOH (1 mL) was treated with a solution of LiOH (2.7 mg, 0.11
mmol) in H2O (0.5 mL). After the solution was stirred at room
temperature for 1 h, saturated NH4Cl (400 µL) was added, and the
pH was adjusted to 4-5 with 0.1 N HCl. The aqueous layer was
extracted with EtOAc, and the combined organic extract was dried
(Na2SO4) and evaporated. The crude product was applied to a
preparative silica gel TLC plate (0.5 mm), which was eluted with
hexanes-ether-CH3COOH 30:50:1. The band at Rf ) 0.24 was
extracted with CH3OH, and the extract was filtered and evaporated,
affording trans-EKODE-(E)-Ia as a white solid (13 mg, 66%): 1H
NMR (200 MHz, CDCl3) δ 0.88 (t, 3H, J ) 6.4 Hz), 1.22-1.70
(18H), 2.35 (t, 2H, J ) 7.2 Hz), 2.53 (t, 2H, J ) 7.2 Hz), 2.89 (td,
1H, J ) 5.4 and 2.0 Hz), 3.20 (dd, 1H, J ) 6.4 and 2.0 Hz), 6.38
(d, 1H, J ) 15.9 Hz), 6.51 (dd, 1H, J ) 15.9 and 6.4 Hz); 13C
NMR (50 MHz, CDCl3) δ 14.0 (-), 22.5 (+), 23.8 (+), 24.7 (+),
25.8 (+), 29.0 (+), 29.1 (+), 29.2 (+), 31.5 (+), 31.9 (+), 34.0
(+), 40.7 (+), 56.7 (-), 61.6 (-), 131.4 (-), 142.5 (-), 179.7
(+), 199.9 (+); UV (ethanol) λmax ) 232 nm, ꢀ(λmax) ) 13 700
L‚mol-1‚cm-1; HRMS (FAB) calcd for C18H31O4 (MH+) 311.2222,
found 311.2214.
A second band at Rf ) 0.22 was extracted with CH3OH, and the
extract was filtered, purified by preparative HPLC, and evaporated,
affording cis-EKODE-(E)-Ia as an yellow oil (0.8 mg, 3%): 1H
NMR (200 MHz, CDCl3) δ 0.90 (t, 3H, J ) 6.7 Hz), 1.22-1.70
(18H), 2.36 (t, 2H, J ) 7.3 Hz), 2.55 (t, 2H, J ) 7.2 Hz), 3.20 (m,
1H), 3.53 (dd, 1H, J ) 6.4 and 3.5 Hz), 6.42 (d, 1H, J ) 15.9 Hz),
6.65 (dd, 1H, J ) 15.9 and 6.4 Hz); 13C NMR (150 MHz, CDCl3)
δ 13.9, 22.5, 23.8, 24.6, 26.2, 27.6, 28.8, 28.97, 29.03 (2), 31.4,
41.0, 55.5, 59.8, 132.9, 139.7, 199.7; UV (ethanol): λmax ) 232
nm; ꢀ(λmax) ) 11 000 L‚mol-1‚cm-1; HRMS (FAB) calcd for
C18H31O4 (MH+) 311.2222, found 311.2210.
9-Oxo-cis/trans-12,13-epoxy-10(E)-octadecenoic Acid (cis/
trans-EKODE-(E)-Ib). A solution of methyl 13-oxo-trans(cis)-
9,10-epoxy-11(E)-octadecenoate (13) (20 mg, 0.062 mmol) in
i-PrOH (1 mL) was treated with a solution of LiOH (2.7 mg, 0.11
mmol) in H2O (0.5 mL). After the solution was stirred at room
temperature for 1 h, saturated NH4Cl (400 µL) was added, and the
pH was adjusted to 4-5 with 0.1 N HCl. The aqueous solution
was extracted with EtOAc. The combined organic extract was dried
(Na2SO4) and evaporated. The crude product was applied to a
preparative silica gel TLC plate (0.5 mm), which was eluted with
hexanes-ether-CH3COOH 30:50:1. The band at Rf ) 0.24 was
extracted with CH3OH, and the extract was filtered and evaporated,
affording trans-EKODE-(E)-Ib as white solid (12 mg, 63%): mp
1
69 °C; H NMR (200 MHz, CDCl3) δ 0.90 (t, 3H, J ) 6.5 Hz),
1.22-1.70 (18H), 2.34 (t, 2H, J ) 7.4 Hz), 2.53 (t, 2H, J ) 7.4
Hz), 2.91 (td, 1H, J ) 5.3 and 2.1 Hz), 3.20 (dd, 1H, J ) 6.5 and
2.1 Hz), 6.38 (d, 1H, J ) 16.0 Hz), 6.51 (dd, 1H, J ) 16.0 and 6.5
Hz); 13C NMR (50 MHz, CDCl3) δ 14.0 (-), 22.6 (+), 24.0 (+),
24.6 (+), 25.6 (+), 28.9 (+), 29.0 (2, +), 31.6 (+), 32.0 (+), 34.0
(+), 40.6 (+), 56.7 (-), 61.7 (-), 131.4 (-), 142.7 (-), 179.5
(+), 199.7 (+); UV (ethanol): λmax ) 232 nm; ꢀ(λmax) ) 13 700
L‚mol-1‚cm-1; HRMS (FAB) calcd for C18H31O4 (MH+) 311.2222,
found 311.2227.
A second band at Rf ) 0.22 was extracted CH3OH, and the
extract was filtered and evaporated, affording cis-EKODE-(E)-Ib
as a yellow oil (0.8 mg, 4%): 1H NMR (200 MHz, CDCl3) δ 0.89
(t, 3H, J ) 6.8 Hz), 1.22-1.70 (18H), 2.35 (t, 2H, J ) 7.4 Hz),
2.54 (t, 2H, J ) 7.2 Hz), 3.20 (m, 1H), 3.52 (ddd, 1H, J ) 6.4,
4.4, and 0.8 Hz), 6.40 (dd, 1H, J ) 16.0 and 0.8 Hz), 6.65 (dd,
1H, J ) 16.0 and 6.4 Hz); 13C NMR (150 MHz, CDCl3) δ 14.2,
22.7, 24.2, 24.9, 26.2, 27.8, 29.1, 29.21, 29.24, 31.7, 41.1, 55.7,
60.1, 133.1, 140.0, 199.6 (one C signal missing and one apparently
overlapped); UV (ethanol): λmax ) 232 nm; ꢀ(λmax) ) 11 000
L‚mol-1‚cm-1; HRMS (FAB) calcd for C18H31O4 (MH+) 311.2222,
found 311.2230.
Methyl 9-Hydroxy-11-oxooctadec-12(E)-enoate (15). To a
precooled (-78 °C) solution of lithium diisopropylamide (2.0 mL,
2M in THF/n-heptane, 4.0 mmol) was added 3-nonen-2-one (14)
(560 mg, 4.0 mmol) slowly. The resulting solution was stirred at
-78 °C for 15 min before slowly adding methyl 9-oxononanoate
(3) (368 mg, 2.0 mmol) in anhydrous THF (2 mL). The reaction
mixture was stirred at -78 °C for a further 20 min and then
quenched by the addition of saturated aqueous NH4Cl (1 mL). The
resulting reaction mixture was allowed to warm to room temper-
ature. The mixture was further extracted with EtOAc and water,
and then the combined organic layers were dried (Na2SO4) and
evaporated. The crude product was purified by silica gel chroma-
tography (eluent hexanes-ether 1:1), affording 15 as slightly yellow
oil (246 mg, 38%): 1H NMR (400 MHz, CDCl3) δ 0.86 (t, 3H, J
) 7.2 Hz), 1.20-1.62 (18H), 2.19 (dtd, 2H, J ) 6.8, 6.8, and 1.6
Hz), 2.26 (t, 2H, J ) 7.6 Hz), 2.58 (dd, 1H, J ) 17.6 and 9.2 Hz),
2.71 (dd, 1H, J ) 17.6 and 2.8 Hz), 3.24 (d, 1H, J ) 3.2 Hz), 3.63
(s, 3H), 3.98-4.04 (1H), 6.05 (dt, 1H, J ) 16.0 and 1.6 Hz), 6.83
(dt, 1H, J ) 16.0 and 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ
14.2, 22.6, 25.1, 25.6, 27.9, 29.3, 29.4, 29.6, 31.5, 32.7, 34.3, 36.7,
46.2, 51.7, 67.9, 130.8, 149.2, 174.5, 201.5; HRMS (FAB) calcd
for C19H35O4 (MH+) 327.2535, found 327.2532.
(13) Hidalgo, F. J.; Zamora, R.; Vioque, E. Chem. Phys. Lipids 1992,
60, 225-233.
(14) Black, G. P.; Murphy, P. J.; Walshe, N. D. A. Tetrahedron 1998,
54, 9481-9488.
(15) Pelter, A.; Ward, R. S.; Whalley, J. L. Synthesis 1998, 12, 1793-
1802.
(16) Lin, J.; Fay, L. B.; Welti, D. H.; Blank, I. Lipids 1999, 34, 1117-
1126.
J. Org. Chem, Vol. 72, No. 25, 2007 9479