Total Synthesis of 17-isoLevuglandin E4
J . Org. Chem., Vol. 65, No. 17, 2000 5323
in H2O (50 mL) and then extracted with ether. The combined
organic layers were washed with H2O, 10% Na2S2O3 solution,
and brine and then dried. Solvent was removed by rotary
evaporation under reduced pressure. The crude product was
flash chromatographed on silica gel with 25% ethyl acetate in
hexanes (Rf ) 0.32) to deliver the desired product 4 (1.45 g,
68% based on phosphonium iodide). Meth od B: The Wittig
reaction was also carried out with by another method.22,27,28
To a solution of phosphonium iodide 2 (1.22 g, 2.87 mmol) in
anhydrous THF (40 mL) at -78 °C was added lithium
hexamethyldisilazide (2.58 mL of 1.0 M, 2.58 mmol, 0.90 equiv)
dropwise. Then, after 2 h of stirring at this temperature,
HMPA (6.5 mL) was added dropwise. After an additional 30
min of stirring at -78 °C, methyl 4-oxobutanoate (3, 433 mg,
3.73 mmol, 1.30 equiv) in THF (5 mL) was added into the red
reaction mixture over 45 min at -78 °C. The mixture was then
stirred for another 30 min at -78 °C and then allowed to warm
to 0 °C over 2 h. The reaction was quenched by addition of
saturated aqueous NH4Cl (20 mL). The workup and purifica-
tion were the same as for method A and gave 4 (423 mg, 55%
yield based on phosphonium iodide): 1H NMR (CDCl3, 300
MHz) δ 5.51-5.57 (2H, C7, C8-H), 5.35-5.38 (2H, C4, C5-
H), 4.61 (t, 1H, C2′-H), 4.25 (dd, 1H, J ) 6.0 Hz, J ) 12.4 Hz,
C9-Ha), 4.08 (dd, 1H, J ) 6.0 Hz, J ) 12.2 Hz, C9-Hb), 3.85
(1H, C6′-Ha), 3.65 (s, 3H, OCH3), 3.49 (1H, C6′-Hb), 2.82-
2.86 (dd, 2H, J ) 5.8 Hz, J ) 5.8 Hz, C6-H), 2.33-2.37 (4H,
C2, C3-H), 1.48-1.83 (6H, C3′, C4′, C5′-H); 13C NMR (CDCl3,
75 MHz) δ 173.49, 131.36, 128.85, 128.20, 126.35, 97.87, 62.61,
62.22, 51.56, 33.95, 30.66, 25.88, 25.48, 22.77, 19.51; HRMS
(20 eV) m/z calcd for C15H24O4 (M+) 268.1674, m/z found
268.1687.
Meth yl 9-Hyd r oxyn on a -4(Z),7(Z)-d ien oa te (5). A solu-
tion of THP ether 4 (795 mg, 2.97 mmol) and PPTS42 (74.8
mg, 0.297 mmol, 0.1 equiv) in methanol (24 mL) was stirred
at 38 °C for 11 h (monitored by TLC for the disappearance of
the THP ether). The solvent was removed by rotary evapora-
tion under reduced pressure, and the residue was chromato-
graphed on a silica gel column with 50% ethyl acetate in
hexanes to afford the pure alcohol 5 (536 mg, 98% yield); 1H
NMR (CDCl3, 300 MHz) δ 5.64 (dt, 1H, J ) 4.0 Hz, J ) 8.4
Hz, C8-H), 5.37-5.47 (3H, C7, C4, C5-H), 4.23 (d, 2H, J )
6.6 Hz, C9-H), 3.68 (s, 3H, OCH3), 2.84-2.87 (dd, 2H, J )
5.3 Hz, J ) 5.6 Hz, C6-H), 2.36-2.40 (4H, C2, C3-H), 1.67
(s, 1H, -OH); 13C NMR (CDCl3, 75 MHz) δ 173.75, 130.42,
128.84 (2C), 128.26, 58.37, 51.67, 33.86, 25.78, 22.79; HRMS
(20 eV) m/z calcd for C10H16O3 (M+) 184.1099, m/z found
268.1082.
Meth yl 9-Br om on on a -4(Z),7(Z)-d ien oa te (6). To a mag-
netically stirred solution of alcohol 5 (534 mg, 2.90 mmol) in
anhydrous CH2Cl2 (60 mL) at 0 °C was added CBr4 (1.16 g,
3.48 mmol, 1.2 equiv) and DIPHOS43 (1.39 g, 3.48 mmol, 1.2
equiv) portionwise over 15 min. The reaction mixture was
stirred at 0 °C for 1 h and then allowed to stir at room
temperature for another 1.5 h (monitoring disappearance of
alcohol by TLC). The solvent was removed by rotary evapora-
tion under reduced pressure. The residue was dissolved in
pentane. The suspension was filtered, washed with more
pentane, and concentrated by rotary evaporation to give the
crude product, which was purified by flash chromatography
on a silica gel column with 5% ethyl acetate in hexanes to give
the bromide 6 (688 mg, 96%): 1H NMR (CDCl3, 300 MHz) δ
5.73 (dt, 1H, J ) 4.0 Hz, J ) 8.6 Hz, C8-H), 5.55 (dt, 1H, J )
4.4 Hz, J ) 8.6 Hz, C7-H), 5.38-5.42 (2H, C4, C5-H), 4.01
(d, 2H, J ) 8.4 Hz, C9-H), 3.67 (s, 3H, OCH3), 2.88-2.91 (dd,
2H, J ) 5.2 Hz, J ) 5.4 Hz, C6-H), 2.36-2.43 (4H, C2, C3-
H); 13C NMR (CDCl3, 75 MHz) δ 173.46, 133.56, 128.95, 127.77,
125.67, 51.62, 33.89, 26.93, 25.27, 22.81; HRMS (20 eV) m/z
calcd for C10H15BrO2 (M+) 246.0255, m/z found 246.0254.
Met h yl 10-(Diet h ylp h osp h on o)-11-oxod od eca -4(Z),7-
(Z)-d ien oa te (8). Alkyl phosphonate 8 was prepared by
alkylation of diethyl phosphonoacetone (7).20,21,29 To a magneti-
cally stirred suspension of sodium hydride (138 mg, 95%
purity, 5.44 mmol, 2.0 equiv) in anhydrous THF (14 mL) was
added diethyl phosphonoacetone (7, 1.85 g, 9.52 mmol, 3.5
equiv) at 0 °C. After 1 h of stirring at 0 °C and 2 h at room
temperature, methyl 9-bromonona-4(Z),7(Z)-dienoate (6, 673
mg, 2.72 mmol) in THF (1 mL) was added dropwise at 0 °C.
The reaction mixture was warmed to room temperature and
allowed to stir in the dark for 24 h. The solvent was removed
by rotary evaporation, and water (5 mL) was added to the
residue. The aqueous mixture was extracted with ethyl
acetate. The combined ethyl acetate extracts were washed once
with brine, dried, and concentrated under reduced pressure.
The crude product was purified by chromatography on silica
gel with 75% ethyl acetate in hexanes giving 8 (882 mg, 90%
yield based on bromide 6): 1H NMR (CDCl3, 300 MHz) δ 5.43-
5.35 (3H, C5, C7, C8-H), 5.26 (dt, 1H, J ) 4.4 Hz, J ) 8.6 Hz,
C4-H), 4.08-4.19 (q, 4H, J ) 8.3 Hz, OCH2CH3), 3.67 (s, 3H,
OCH3), 3.19 (ddd, 1H, J ) 22.3 Hz, J ) 9.8 Hz, J ) 4.2 Hz,
C10-H), 2.72-2.85 (3H, C6, C9-Ha), 2.50 (1H, C9-Hb),
2.29-2.38 (7H, C2, C3, C12-H), 1.28-1.36 (t, 6H, J ) 7.0 Hz,
OCH2CH3); 13C NMR (CDCl3, 75 MHz) δ 203.09, 173.43,
130.38, 128.83, 128.32, 126.30 and 126.09 (split), 62.79 and
62.70 and 62.56 and 62.48 (split), 53.45 (d, J ) 123.1 Hz) 51.49,
33.92, 31.46, 25.52, 24.36, 24.31, 22.75, 16.39 and 16.32; HRMS
(20 eV) m/z calcd for C17H29O6P (M+) 360.1701, m/z found
360.1702.
Meth yl 10-Acetyl-12(S),13-isop r op ylid en ed ioxy-4(Z),7-
(Z),10(Z/E)-tr id eca tr ien oa tes (10E a n d 10Z). A magneti-
cally stirred suspension of sodium hydride (49 mg, 95%, 1.93
mmol, 1.30 equiv) in anhydrous THF (2.5 mL) was cooled to
-5 °C. The â-ketophosphonate 8 (534 mg, 1.48 mmol, 1.0
equiv) in anhydrous THF (2.5 mL) was added dropwise over
15 min. Stirring was continued at this temperature for 4 h.
Then freshly prepared isopropylidene-D-glyceraldehyde (9, 244
mg, 1.78 mmol, 1.20 equiv, 95% purity) in anhydrous THF (1.5
mL) was added over 10 min. The solution was allowed to warm
to room temperature, and stirring was continued for an
additional 12 h. Then the solvent was removed by rotary
evaporation, and water (5 mL) was added to the resulting
brown oily, gummy residue. The aqueous mixture was ex-
tracted with diethyl ether. The combined organic extracts were
washed with water, dried (anhydrous MgSO4), and filtered.
Solvent was removed under reduced pressure. The crude
product was flash chromatographed on a silica gel column,
eluting with 20% ethyl acetate in hexanes (v/v), furnishing a
mixture of enones 10E and 10Z (Rf ) 0.25, 324 mg, 65% based
on â-ketophosphonate 8). The 10Z and 10E isomers (1:8,
respectively) were used without separation for the next reac-
tion. Pure major isomer 10E and minor isomer 10Z were
isolated by the HPLC using 20% ethyl acetate in hexane as
eluant with a Whatman Partisil 10 column (4.6 mm ID × 25
cm) at a flow rate of 1.0 mL/min (retention time 18.6 min for
10Z, 21.0 min for 10E). 10Z (minor isomer): 1H NMR (CDCl3,
300 MHz) δ 5.78 (d, 1H, J ) 8.3 Hz, C11-H), 5.53 (1H, C8-
H), 5.32-5.44 (3H, C4, C5, C7-H), 4.90 (dd, 1H, J ) 6.4, 6.8
Hz, C12-H), 4.30 (dd, 1H, J ) 8.4, 6.8 Hz, C13-Ha), 3.67 (s,
3H, -OCH3), 3.56 (dd, 1H, J ) 8.4, 6.8 Hz, C13-Hb), 3.09 (d,
2H, J ) 7.2 Hz, C9-H), 2.83 (2H, C6-H), 2.33-2.41 (4H, C2,
C3-H), 2.26 (s, 3H, acetyl methyl), 1.44 (s, 3H, isopropylidene
methyl), 1.36 (s, 3H, isopropylidene methyl); 13C NMR (CDCl3,
75.4 MHz) δ 201.96 (acetyl carbonyl), 173.50 (C-1), 140.84 (C-
10), 137.45 (C-11), 130.80 (C-8), 128.58 (C-7), 128.42 (C-5),
125.75 (C-4), 109.54 (acetonide carbon, C(Me)2), 74.07, 69.65,
51.61, 33.92, 31.61, 29.26, 26.65, 25.65, 25.53, 22.85. 10E
(major isomer): 1H NMR (CDCl3, 300 MHz) δ 6.54 (d, 1H, J )
8.2 Hz, C11-H), 5.33-5.43 (3H, C5, C7, C8-H), 5.16 (1H, C4-
H), 4.93 (dd, 1H, J ) 6.4, 6.2 Hz, C12-H), 4.19 (dd, 1H, J )
8.2, 6.2 Hz, C13-Ha), 3.68 (s, 3H, -OCH3), 3.66 (dd, 1H, J )
8.2, 6.2 Hz, C13-Hb), 3.13 (dd, 1H, J ) 6.2, 13.8 Hz, C9-
Ha), 3.08 (dd, 1H, J ) 6.2, 13.8 Hz, C9-Hb), 2.91 (2H, C6-
H), 2.37-2.43 (4H, C2, C3-H), 2.35 (s, 3H, acetyl methyl), 1.48
(s, 3H, isopropylidene methyl), 1.42 (s, 3H, isopropylidene
methyl); 13C NMR (CDCl3, 75.4 MHz) δ 198.54 (acetyl carbo-
nyl), 173.51 (C-1), 142.61 (C-10), 140.03 (C-11), 128.86 (C-7,
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