Oxidative degradation of eicosapentaenoic acid into polyunsaturated aldehydes

Article abstract of DOI:10.1016/S0040-4020(03)01096-2

Eicosapentaenoic acid is converted in good overall yield to an α,β-ethylenic epoxide derivative. The oxidative cleavage of the epoxide ring with periodic acid in ether proceeded in part with acid-catalyzed rearrangement of the vinyl epoxide moiety prior to cleavage. Among the products were 2E- and 2Z, 5Z, 8Z, 11Z-tetradecatetraenal, 4-hydroxy-2E,6Z,9Z,12Z-pentadecatetraenal and (all-Z)-2-methoxy-3,6,9,12-pentadecatetraenal.

Full text of DOI:10.1016/S0040-4020(03)01096-2

Tetrahedron 59 (2003) 7157–7162
Oxidative degradation of eicosapentaenoic acid into
polyunsaturated aldehydes
*
Anne Kristin Holmeide and Lars Skattebøl
Department of Chemistry, University of Oslo, P.O. Box 1033 Blindern, 0315 Oslo, Norway
Received 11 February 2003; revised 6 June 2003; accepted 10 July 2003
Abstract—Eicosapentaenoic acid is converted in good overall yield to an a,b-ethylenic epoxide derivative. The oxidative cleavage of the
epoxide ring with periodic acid in ether proceeded in part with acid-catalyzed rearrangement of the vinyl epoxide moiety prior to cleavage.
Among the products were 2E- and 2Z, 5Z, 8Z, 11Z-tetradecatetraenal, 4-hydroxy-2E,6Z,9Z,12Z-pentadecatetraenal and (all-Z)-2-methoxy-
3,6,9,12-pentadecatetraenal.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
present paper describes a synthetic study with aldehyde 1 as
the primary target and the oxidative cleavage of an epoxide
with periodic acid as the key reaction.
Methylene interrupted double bonds as they are present in
naturally occurring polyunsaturated fatty acids are most
commonly constructed by semireduction of the correspond-
ing acetylenic compounds or by using Wittig type
reactions.1 The main problem with these methods is the
stereoselectivity of the double bond forming reactions.
Another approach to this class of compound involves the
selective degradation of abundantly available polyunsatu-
rated fatty acids to useful starting materials for further
synthesis, one of the advantages being the conservation in
the final product of some of the double bonds originally
present in the starting material. This ensures a regio- and
stereochemically pure product, provided the chemical
manipulations take place without isomerization. We have
used this approach starting from the naturally occurring
fatty acids eicosapentaenoic acid (EPA) and docosa-
hexaenoic acid for the successful syntheses of a variety of
polyunsaturated compounds.2–5 In connection with the
syntheses of some naturally occurring polyunsaturated
hydrocarbons we have recently reported5 a protocol for
the conversion of EPA into a mixture of 2E- and 2Z, 5Z, 8Z,
11Z-tetradecatetraenal (1) in 20% overall yield involving
the allylic alcohol 2 as an intermediate (Scheme 1). The
2. Results and discussion
Oxidation of the allylic alcohol 2 with tert-butyl hydro-
peroxide in the presence of vanadyl acetylacetonate
afforded a mixture of diastereomeric epoxy alcohols from
which the major isomer 3 was separated by flash
chromatography; the spectral data correponds to dia-
stereomer B in the previously published article.5 The H
1
NMR spectrum is practically identical with that of the
product obtained from the Sharpless oxidation of 2,6 in the
presence of (þ) diisopropyl tartrate; hence, the dia-
stereomers of the epoxy alcohol 3 have been assigned the
stereochemistry depicted in Scheme 2.7 The oxidative
cleavage of 3 with periodic acid5 in dry ether furnished a
mixture of the aldehydes 1 (36% yield), 4 (17%) and 5
(traces).8 The compounds were easily separated by flash
chromatography and the structural assignments are based on
spectral data. The 1H NMR spectrum showed by the
coupling constants that 1 was formed as an approximately
1:3 mixture of the 2Z- and 2E-isomers, the ratio being
Scheme 1.
Keywords: polyunsaturated aldehydes; epoxides; Payne type rearrangement.
*
Corresponding author. Tel.: þ47-22-85-55-30; fax: þ47-22-85-55-07; e-mail: larssk@kjemi.uio.no
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01096-2

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A. K. Holmeide, L. Skattebøl / Tetrahedron 59 (2003) 7157–7162
Scheme 2. Reagents and conditions: (i) H5IO6, ether, rt.
somewhat dependent on reaction time. On the other hand the
aldehyde 4 is formed exclusively as the 2E-isomer and the
aldehyde 5 as the all-Z isomer. The formation of 4 requires
the presence of water during the oxidation reaction and the
only source is periodic acid, which is used as the dihydrate
in stoichiometric amounts (Scheme 2).
assume that at least some of aldehyde 1 is formed directly
from the epoxide. Falck et al.10 has reported the acid
catalyzed ring opening of an a,b-unsaturated epoxide with a
result similar to ours.
Aiming at a procedure with improved selectivity and yield
of the desired aldehyde, the hydroxyl group of 3 was
protected. As already reported5 oxidation of the acetate 9
with periodic acid in ether furnished the aldehyde 1 as a
mixture of the 2E and 2Z isomers in 46% yield, the best
yield of this compound obtained so far. In addition, the
2-acetoxy aldehyde 10 was isolated in 10% yield. Variations
in the amount of periodic acid used as well as the reaction
temperature did not alter significantly the product compo-
sition. The formation of 10 is particularly interesting.
Apparently, periodic acid catalyzes epoxide migration prior
to the oxidative ring cleavage, although we cannot exclude
that the species actually being oxidized is the corresponding
vicinal diol. A similar reaction with the MOM protected
compound 11 led to the 2-methoxy derivative 12 as the only
aldehyde in 42% yield. A rearrangement similar to that
suggested for the acetate 9 can explain this result as well. A
proposed mechanism for this Payne type rearrangement is
depicted in Scheme 4.
Lead tetraacetate oxidation of a vicinal diol proceeds most
probably through a cyclic intermediate, and a similar
mechanism has been suggested for the oxidative cleavage
of an epoxide by periodic acid.9 Our results indicate that the
vinyl epoxide undergoes proton catalyzed ring opening to an
allylic cation, which reacts with water to give the triols 6
and 7 (Scheme 3). The triol 7 may also equilibrate under the
reaction conditions to the triol 8. Subsequent oxidative
cleavage of the glycolic C–C bonds of these triols provides
an explanation for the observed products. The E-configur-
ation has been assigned to the double bond adjacent to the
hydroxyl group for each of the triols; support for the
assignment has been obtained by the isolation of a
monomethylated derivative of the triol 7, for which an
E-configuration of this double bond has been established
(vide infra). The triol 8 is probably not the only precursor to
the aldehyde 5; a separate experiment revealed that the a,b-
unsaturated aldehyde 4 is converted slowly to 5 under the
reaction conditions, probably initiated by an acid catalyzed
Michael addition of water. Moreover, it is reasonable to
This type of epoxide migration11 usually takes place
under basic conditions, but examples of acid catalyzed
Scheme 3.

A. K. Holmeide, L. Skattebøl / Tetrahedron 59 (2003) 7157–7162
7159
Scheme 4. Reagents and conditions: (i) H5IO6, ether, rt; (ii) periodinane, CH2Cl2, rt.
rearrangement have been reported.12,13 We anticipated that
the reaction of the methoxy derivative 13 with periodic acid
would occur without migration, and the product consisted of
the aldehyde 1 (29%) in addition to 49% of an inseparable
diastereomeric mixture of the diol 14; the 7E configuration
of 14 was assigned based on a coupling constant of 15.6 Hz
for the pertinent olefinic protons. Formation of the diol is
explained by addition of water concurrent with double bond
migration and ring opening of the epoxide, as outlined in
Scheme 4. Being a mono methylated derivative of the triol
7, the presence of the diol 14 supports the proposed reaction
path to the 4-hydroxy aldehyde 4 (Scheme 3). We could not
detect any of this hydroxy aldehyde in the reaction mixture,
indicating that at least under our reaction conditions the diol
14 is not cleaved by periodic acid. Furthermore, oxidation of
the trimethylsilyl protected derivative 15 furnished a
mixture of the hydroxy aldehyde 4 (45%) and the aldehydes
1 (39%) and 5 (traces). It seems unlikely that the silyl ether
is hydrolyzed to 3 prior to oxidation, since the product from
the same reaction of 3 contained none of the aldehyde 5, and
the aldehydes 1 and 4 were formed in quite a different ratio
as well. Finally, Dess–Martin oxidation of 3 provided the
epoxy ketone 16 in high yield, but its oxidation by periodic
acid led only to a disappointingly low yield of aldehyde 1
(26%), admixed with aldehydes 4 (4%) and 5 (traces).
With regard to the yield of aldehyde 1, protection of the
hydroxyl function led only to a minor improvement. One
problem seemed to be the presence of water in the reaction
mixture, supplied by the periodic acid reagent. Hence, we
deliberately opened the epoxide 3 with formic acid–acetic
anhydride and oxidized the product with sodium metaper-
iodate. This reaction sequence furnished the aldehyde 4 in
40% overall yield, in addition to small amounts of aldehydes
1 and 5. Due to the anhydrous conditions of this reaction the
formate anion must be the nucleophile in the ring opening of
the epoxide and the formate ester formed is probably
hydrolyzed to 4 during the work-up procedure. By the same
protocol the methoxy derivative 13 afforded, besides traces
of aldehyde 1, a diastereomeric mixture of the diol 14 in
55% yield. We also tried to trap as the acetonide the vicinal
diol that might result from the aluminum chloride catalysed
ring opening of the epoxide 9; however, the reaction
conditions favored rearrangement of the epoxide to the

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A. K. Holmeide, L. Skattebøl / Tetrahedron 59 (2003) 7157–7162
Scheme 5. Reagents and conditions: (i) HCO2H, Ac2O rt; (ii) H5IO6, ether, rt; (iii) AlCl3, ether, rt.
ketone 17, which was isolated as the only product in 76%
yield (Scheme 5).
126.62, 126.90, 127.14, 127.58, 128.69, 129.02, 132.02,
134.76 (8£CHv), 173.70 (CO2CH3); m/z (CI, NH3) 410
([Mþ18]þ, 5), 343, 331, 175 (100%).
3. Conclusion
4.1.2. Methyl (all-Z)-5-methoxy-6,7-epoxy-8,11,14,17-
eicosatetraenoate (13). Epoxide 3 (major diastereomer;
840 mg, 2.4 mmol) and iodomethane (1.1 mL, 17.4 mmol)
in DMF (6 mL) was added to a stirred slurry of NaH
(104 mg, 4.4 mmol) in dry DMF (2 mL) at 08C. The mixture
was warmed to rt and stirred at this temperature over night.
A saturated aqueous NH4Cl solution was added and the
product was extracted with ether. The organic phase was
washed with water and dried (MgSO4). Evaporation of
solvents and purification of the residue by flash chroma-
tography (SiO2, 8:2 hexane/EtOAc) gave the epoxide 13
(470 mg, 54%) as an oil. nmax (film)/cm21 2990, 2940,
1725; dH (300 MHz) 0.94 (t, J¼7.5 Hz, 3H, CH3), 1.5–1.9
(m, 4H, H-3, H-4), 2.05 (m, 2H, H-19), 2.32 (t, J¼7.2 Hz,
2H, H-2), 2.7–3.1 (m, 8H, H-5, H-6, H-10, H-13, H-16),
3.36 (s, 3H, OCH3), 3.60 (dd, J¼9.0, 1.7 Hz, 1H, H-7), 3.64
(s, 3H, CO2CH3), 5.06 (m, 1H, H-8), 5.2–5.5 (m, 6H,
6£HCv), 5.68 (m, 1H, H-9); dC (50 MHz) 14.22 (CH3),
20.52, 20.56, 25.50, 25.59, 26.02, 31.82, 33.90 (7£CH2),
51.47 (CO2CH3), 52.93 (CH), 58.01 (OCH3), 60.60 (CH),
79.70 (C-5), 126.63, 126.86, 127.17, 127.51, 128.75,
129.02, 132.06, 134.74 (8£CHv), 173.78 (CO2CH3).
In conclusion, the synthetic effort so far has only provided
the aldehyde 1 in moderate yield. The aldehyde has already
served as starting material for the syntheses of laurencenyne
and trans-laurencenyne, two naturally occurring hydro-
carbons from a red alga.5 However, the aldehydes 4 and 10
are actually quite interesting as they may serve as starting
material for the syntheses of lipoxygenase derived EPA
metabolites. Further studies along this line are in progress.
4. Experimental
4.1. General
The NMR spectra were recorded in CDCl3, with a Bruker
Avance DPX 200 instrument or a Bruker Avance DPX 300
instrument. The IR spectra were obtained with a Perkin–
Elmer 1310 infrared spectrophotometer or a Nicolet Magna-
IR 550 spectrometer. Mass spectra were recorded at 70 eV
with a Fisons VG Pro spectrometer. All reactions were
performed under nitrogen or argon atmosphere.
4.1.3. Methyl (all-Z)-5-trimethylsilyloxy-6,7-epoxy-
8,11,14,17-eicosatetraenoate (15). To the epoxide 3
(major diastereomer; 600 mg, 1.72 mmol) in CH2Cl2
(20 mL) was added pyridine (380 ml, 4.71 mmol), tri-
methylchlorosilane (261 ml, 2.80 mmol) and DMAP
(20 mg, 0.16 mmol). The mixture was stirred for 2 h at rt.
Hexane was added and the organic layer was washed twice
with saturated aqueous NH4Cl solution, water and dried
(MgSO4). Evaporation of solvents and purification by flash
chromatography (SiO2, 9:1 hexane/EtOAc) gave the
epoxide 15 (611 mg, 84%) as an oil. nmax (film)/cm21
2990, 2940, 1725, 1240; dH (300 MHz) 0.01 (s, 9H, SiMe3)
0.92 (t, J¼7.5 Hz, 3H, CH3), 1.4–1.8 (m, 4H, H-3, H-4),
2.02 (m, 2H, H-19), 2.29 (m, 2H, H-2), 2.7–3.1 (m, 7H,
H-7, H-10, H-13, H-16), 3.4–3.6 (m, 2H, H-5, H-6), 3.61 (s,
3H, OCH3), 5.03 (m, 1H, H-8), 5.2–5.5 (m, 6H, 6£HCv),
5.62 (m, 1H, H-9); dC (75 MHz) 0.13 (SiMe3), 14.14 (CH3),
20.44, 20.62, 25.42, 25.52, 25.96, 33.81, 34.12 (7£CH2),
51.34 (CO2CH3), 51.94, 61.99, 70.90 (3£CH), 126.76,
126.83, 127.06, 127.48, 128.64, 128.94, 131.93, 134.38
(8£CHv), 173.66 (CO2CH3); m/z (EI) 420 (Mþ, 0.7), 203
4.1.1. Methyl (all-Z)-5-methoxymethylenoxy-6,7-epoxy-
8,11,14,17-eicosatetraenoate (11). To the epoxide 35
(major diastereomer; 1.0 g, 2.9 mmol) in CH2Cl2 (10 mL)
was added N-ethyldiisopropylamine (995 ml, 5.8 mmol) and
chloromethyl methyl ether (330 ml, 4.35 mmol) at 08C. The
mixture was stirred for 48 h at rt, diluted with hexane and
washed with saturated aqueous NH4Cl solution, water and
dried (MgSO4). Evaporation of solvents and purification of
the residue by flash chromatography (SiO2, 9:1 CH2Cl2/
ether) gave the epoxide 11 (720 mg, 63%) as an oil. nmax
(film)/cm21 2990, 2935, 1730; dH (300 MHz) 0.94 (t,
J¼7.5 Hz, 3H, CH3), 1.5–1.9 (m, 4H, H-3, H-4), 2.04 (m,
2H, H-19), 2.32 (m, 2H, H-2), 2.7–3.1 (m, 7H, H-6, H-10,
H-13, H-16), 3.31 (s, 3H, CH2OCH3), 3.3–3.5 (m, 1H, H-5),
3.59 (dd, J¼9.0, 2.0 Hz, 1H, H-7), 3.64 (s, 3H, CO2CH3),
4.62 (dd, J¼6.8 Hz, 2H, OCH2OCH3), 5.04 (m, 1H, H-8),
5.2–5.5 (m, 6H, 6£HCv), 5.66 (m, 1H, H-9); dC (75 MHz)
14.21 (CH3), 20.50, 20.59, 25.48, 25.57, 25.99, 32.18
(6£CH2), 33.82 (C-2), 51.45 (CO2CH3), 53.14 (C-7), 55.45
(OCH3), 60.70 (C-6), 75.91 (C-5), 96.03 (OCH2OCH3),

A. K. Holmeide, L. Skattebøl / Tetrahedron 59 (2003) 7157–7162
7161
(100), 73 (52%); (HRMS (EI): Mþ, found 420.2728.
C24H40O4Si requires 420.2696).
4.1.7. Reaction of epoxide 15 with periodic acid. By the
general procedure the reaction gave the aldehyde 1 (39%) as
a 7:1 mixture of the Z- and E-isomers, aldehyde 4 (45%),
and traces of aldehyde 5.
4.1.4. Reaction of epoxide 2a with periodic acid. General
procedure. A solution of epoxide 3 (1.2 g, 3.4 mmol) in dry
ether (7 mL) was added to periodic acid (1.5 g, 6.6 mmol) in
dry ether (200 mL) at rt. The mixture was stirred for 1 h at
this temperature. Hexane was added and the organic layer
was washed with a saturated aqueous NaHCO3 solution,
brine and dried (MgSO4). Evaporation of solvent under
reduced pressure and purification of the residue by flash
chromatography, using argon (SiO2, 95:5 CH2Cl2/ether)
gave the aldehyde 15 (250 mg, 36%) as a 3:1 mixture of the
E- and Z-isomers, traces of aldehyde 58 and 4-hydroxy-2E,
6Z, 9Z, 12Z-pentadecatetraenal (4, 17%): nmax (film)/cm21
3441, 3012, 2964, 1690, 1139, 1101; dH (200 MHz) 0.95 (t,
J¼7.5 Hz, 3H, CH3), 1.97 (d, J¼4.5 Hz, 1H, OH), 2.04 (m,
2H, H-14), 2.43 (m, 2H, H-5), 2.7–2.9 (m, 4H, H-8, H-11),
4.46 (m, 1H, H-4), 5.2–5.6 (m, 6H, 6£HCv), 6.32 (ddd,
J2,3¼15.7 Hz, J2,1¼7.8 Hz, J¼1.6 Hz, 1H, H-2), 6.81 (dd,
J3,2¼15.7 Hz, J3,4¼4.3 Hz, 1H, H-3), 9.57 (d, J1,2¼7.8 Hz,
1H, CHO); dC (50 MHz) 14.23 (CH3), 20.56, 25.55, 25.75,
34.52 (4£CH2), 70.37 (C-4), 123.41, 126.73, 127.09,
129.08, 131.00, 132.20, 132.92, 157.75 (8£CHv), 193.33
(CHO); m/z (EI) 149 ([M2C4H5O2]þ, 10), 93, 79 (100%);
(HRMS, (electrospray): [Mþ1]þ, found 235.1685.
C15H23O2 requires 235.1693).
4.1.8. Methyl (all-Z)-5-oxo-6,7-epoxy-8,11,14,17-eicosa-
tetraenoate (16). The epoxide 3 (770 mg, 2.2 mmol) was
added to a stirred solution of periodinane (1.16 g, 2.7 mmol)
in CH2Cl2 (60 mL) at rt. The mixture was stirred for 1 h and
then filtered through a silica plug with CH2Cl2. Evaporation
of solvent under reduced pressure and purification of the
residue by flash chromatography (SiO2, 9:1 hexane/EtOAc)
afforded the epoxy ketone 16 (700 mg, 92%) as an oil. nmax
(film)/cm21 3013, 2963, 1737, 1713, 1436, 1203; dH
(200 MHz) 0.92 (t, J¼7.5 Hz, 3H, CH3), 1.8–2.0 (m, 2H,
H-3), 2.02 (m, 2H, H-19), 2.2–2.6 (m, 4H, H-2, H-4), 2.7–
2.9 (m, 4H, H-13, H-16), 2.9–3.0 (m, 2H, H-10), 3.33 (d,
J¼1.9 Hz, 1H, H-6), 3.62 (s, 3H, OCH3), 3.71 (ddd, J¼8.6,
1.9, 0.8 Hz, 1H, H-7), 5.02 (ddt, J¼8.7, 10.9, 1.6 Hz, 1H,
H-8), 5.2–5.5 (m, 6H, 6£HCv), 5.74 (dtd, J¼10.9, 7.6,
0.7 Hz, 1H, H-9); dC (50 MHz) 14.15 (CH3), 18.11, 20.45,
25.43, 25.53, 26.00 (5£CH2), 32.71 (C-2), 36.31 (C-4),
51.48 (CO2CH3), 53.80 (C-7), 60.52 (C-6), 124.97, 126.51,
126.74, 127.29, 128.78, 129.38, 132.02, 136.54 (8£CHv),
173.27 (CO2CH3), 205.85 (CO); m/z (EI) 346 (Mþ, 0.1),
210, 129 (100), 101 (94%); (HRMS (EI): Mþ, found
346.2139 C21H30O4 requires 346.2144).
4.1.5. Reaction of epoxide 11 with periodic acid. By the
general procedure the reaction gave after flash chromato-
graphy, using argon (SiO2, 9:1 hexane/EtOAc) traces of
aldehyde 1 and (all-Z)-2-methoxy-3,6,9,12-pentadecatetrae-
nal (12, 42%): nmax (film)/cm21 3013, 2965, 2704, 1739,
1693, 1111; dH (200 MHz) 0.95 (t, J¼7.5 Hz, 3H, CH3),
2.05 (m, 2H, H-14), 2.7–3.0 (m, 6H, H-3, H-8, H-11), 3.39
(s, 3H, OCH3), 4.45 (br d, J¼8.4 Hz, 1H, H-2) 5.2–5.5 (m,
7H, 7£HCv), 5.84 (dtd, J¼10.8, 7.5, 1.3 Hz, 1H, H-4), 9.51
(d, J¼1.5 Hz, 1H, CHO); dC (75 MHz) 14.15 (CH3), 20.47,
25.46, 25.57, 26.60 (4£CH2), 56.76 (OCH3), 82.63 (C-2),
122.32, 126.44, 126.78, 127.36, 128.75, 129.27, 132.02,
136.32 (8£HCv), 198.52 (CHO).
4.1.9. Reaction of epoxy ketone 16 with periodic acid. A
solution of epoxy ketone 16 (330 mg, 0.95 mmol) in dry
ether (2 mL) was added to a solution periodic acid (260 mg,
1.14 mmol) in dry ether (7 mL) at rt. For completion more
periodic acid (390 mg, 1.71 mmol) was added and the
mixture was stirred for 4 h at rt. Hexane was added and the
solution was washed with a saturated aqueous NaHCO3
solution, brine and dried (MgSO4). Evaporation of solvents
under reduced pressure and purification of the residue by
flash chromatography, using argon (SiO2, CH2Cl2 to 9:1
CH2Cl2/ether) gave the aldehyde 1 (51 mg, 26%) as the
E-isomer, aldehyde 4 (6 mg, 4%) and traces of aldehyde 5.
4.1.10. Reaction of epoxide 3 with formic acid–acetic
anhydride followed by sodium metaperiodate. A solution
of epoxide 3 (550 mg, 1.58 mmol) in formic acid (5 mL)
and acetic anhydride (0.5 mL) was stirred at 08C for 2 h and
at rt for 1 h. Volatile compounds were evaporated under
reduced pressure. Ether was added to the residue and the
solution was washed with a saturated aqueous NaHCO3
solution and dried (MgSO4). The solvent was evaporated
under reduced pressure, the residue was dissolved in MeOH
(8 mL) and K2CO3 (640 mg) was added. The reaction
mixture was stirred for 1 h at rt, water was added and the
product extracted with ether. The extract was washed with
water and concentrated under reduced pressure. The residue
was dissolved in MeOH (6 mL), cooled to 08C and a
solution of sodium metaperiodate (507 mg, 2.37 mmol) in
water (2 mL) was added. The mixture was stirred for 1.5 h at
08C and 30 min at rt, diluted with water and extracted with
ether. The extract was washed with water and dried
(MgSO4). Evaporation of solvents under reduced pressure,
followed by flash chromatography (SiO2, 7:3 hexane/
EtOAc) gave the aldehyde 4 (146 mg, 40%) and traces of
aldehydes 1 and 5.
4.1.6. Reaction of epoxide 13 with periodic acid. Using
the general procedure, the reaction product consisted of the
aldehyde 1 (29%), as a 3:1 mixture of the E- and Z-isomers,
and methyl 5-methoxy-6,9-dihydroxy-7E, 11Z, 14Z, 17Z-
eicosatetraenoate (14, 49%), as a mixture of two dia-
stereomers: nmax (film)/cm21 3424, 3012, 2961, 1739, 1106;
dH (500 MHz) 0.95 (t, J¼7.5 Hz, 3H, CH3), 1.4–1.8 (m, 4H,
H-3, H-4), 2.05 (m, 2H, H-19), 2.2–2.4 (m, 4H, H-2, H-10),
2.7–2.9 (m, 4H, H-13, H-16), 3.1–3.2 (m, 1H, H-5), 3.40 (s,
3H, OCH3), 3.64 (s, 3H, CO2CH3), 4.1–4.2 (m, 1H, H-9),
4.3–4.4 (m, 1H, H-6), 5.3–5.5 (m, 5H, 5£HCv), 5.5–5.6
(m, 1H, HCv), 5.68 (dddd, J¼15.6, 6.0, 4.3, 1.1 Hz, 1H,
H-7), 5.80 (dddd, J¼15.6, 6.0, 3.0, 2.0, 1.2 Hz, 1H, H-8); dC
(126 MHz) 14.25 (CH3), 20.53, 21.02, 21.14, 25.53, 25.78,
28.36, 28.42, 33.88, 33.90, 35.11, 35.13, 51.56 (CO2CH3),
57.90 (OCH3), 57.94 (OCH3), 71.58 (CH), 71.67 (CH),
71.86 (CH), 71.89 (CH), 83.73 (C-5), 83.75 (C-5), 124.84,
126.92, 127.59, 127.60, 128.30, 128.72, 128.87, 128.97,
131.20, 131.24, 132.07, 134.64, 134.71, 173.99 (CO2CH3),
174.00 (CO2CH3); m/z (CI, NH3) 398 ([Mþ18]þ, 0.2), 380
(Mþ, 0.1), 345, 331, 145 (100%).

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4.1.11. Reaction of epoxide 13 with formic acid–acetic
anhydride followed by sodium metaperiodate. By the
above procedure the reaction gave the diol 14 (55%) as a
mixture of two diastereomers and traces of aldehyde 1.
References
1. Durand, S.; Parrain, J.-L.; Santelli, M. J. Chem. Soc., Perkin
Trans. 1 2000, 253–273.
2. Holmeide, A. K.; Skattebøl, L. J. Chem. Soc., Perkin Trans. 1
2000, 2271–2276.
4.1.12. Methyl (all-Z)-5-acetoxy-6-oxoeicosa-8,11,14,17-
tetraenoate (17). A mixture of the epoxide 95 (1.9 g,
4.9 mmol) and AlCl3 (33 mg, 0.2 mmol) in dry acetone
(20 mL) was stirred at rt for 2 days. A saturated solution of
NaHCO3 was added and the mixture was stirred for another
30 min before extraction with ether. The organic phase was
washed with water and dried (MgSO4). Evaporation of
solvents under reduced pressure followed by flash chroma-
tography (SiO2, 8:2 hexane/EtOAc) gave the ketone 17
(1.4 g, 76%) as an oil. nmax (film)/cm21 3010, 2963, 1740,
1437, 1235; dH (300 MHz) 0.92 (t, J¼7.5 Hz, 3H, CH3),
1.4–1.9 (m, 4H, H-3, H-4), 2.0–2.1 (m, 2H, H-19), 2.08 (s,
3H, C(O)CH3), 2.29 (t, J¼7 Hz, 2H, H-2), 2.6–2.9 (m, 6H,
H-10, H-13, H-16), 3.1–3.2 (m, 2H, H-7), 3.61 (s, 3H,
OCH3), 5.0–5.1 (m, 1H, H-5), 5.2–5.4 (m, 6H, 6£HCv),
5.5–5.6 (m, 2H, H-8, H-9); dC (75 MHz) 14.13 (CH3), 20.42
(CH2), 20.50 (CH2, CH3 overlapping signals), 25.40
(2£CH2), 29.49, 30.27, 33.17, 42.40 (4£CH2), 51.47
(CO2CH3), 77.42 (C-5), 121.19, 127.67, 128.44, 128.90,
131.88, 133.24 (6£CHv), 126.89 (2£CHv), 170.28,
173.19 (2£CvO), 205.08 (C-6); m/z (EI) 390 (Mþ 1.3),
174 (9.7), 131 (73), 43 (100%); (HRMS (EI): Mþ found
390.2388 C23H34O5 requires 390.2406).
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Acknowledgements
We are indebted to the Research Council of Norway for a
grant to A. K. H.