Efficient total synthesis of 5-oxo-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid (5-oxo-ETE), a potent proinflammatory autacoid

Article abstract of DOI:10.1016/S0040-4039(01)00668-2

The title eicosanoid was prepared in good overall yield via a convergent aldol strategy that obviates the need for HPLC separation of olefinic isomers.

Full text of DOI:10.1016/S0040-4039(01)00668-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4109–4110
Efficient total synthesis of
5-oxo-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid (5-oxo-ETE),
a potent proinflammatory autacoid
Suchismita Mohapatra,a Jorge H. Capdevila,b Robert C. Murphy,c John M. Hevkoc and
J. R. Falcka,*
aDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
bDepartments of Medicine and Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
cDepartment of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206, USA
Received 5 April 2001; accepted 20 April 2001
Abstract—The title eicosanoid was prepared in good overall yield via a convergent aldol strategy that obviates the need for HPLC
separation of olefinic isomers. © 2001 Elsevier Science Ltd. All rights reserved.
Recent studies1,2 have established 5-oxo-6(E),8(Z),
11(Z),14(Z)-eicosatetraenoic acid (5-oxo-ETE, 1) as a
potent proinflammatory autacoid.3 It is derived from
the 5-LO pathway metabolite 5(S)-hydroxyeicosatetra-
enoic acid [5(S)-HETE] by a stereospecific NADP+-
dependent dehydrogenase.1 In neutrophils and
eosinophils, 1 induces calcium mobilization,4 degranu-
lation,5 actin polymerization,6,7 superoxide generation,6
considerable current interest (Fig. 1), including a novel,
bioactive 1,4-glutathione adduct12 (FOG7) reminiscent
of leukotriene C4. To expedite continuing efforts to
elucidate its pharmacology and metabolic fate, as well
its involvement in chronic pathology,1 e.g. asthma, we
report herein an efficient, stereospecific total synthesis
of 1.13 Our approach exploits a convergent aldol strat-
egy that obviates the need for HPLC separation of
olefinic isomers13 and is amenable to the introduction
of stable and/or radio-isotopes.14
chemotaxis,4,8
L
-selectin shedding,9 and expression of
adhesion molecules.7 Many of these effects are associ-
ated with G protein-linked receptors.4–6,10
The nucleophile for the aldol reaction, representing
C(1)ꢀC(6), was derived from commercial 4-acetylbu-
tyric acid (2) (Scheme 1). This was transformed
Although quite labile and prone to isomerization, 1 is
the precursor to a variety of secondary metabolites11 of
Figure 1. Metabolism of 1.
Scheme 1. Reaction conditions: (a) DCC, DMAP, MOX-OH, CH2Cl2, 0°C, 12 h. (b) BF3·Et2O (0.3 equiv.), CH2Cl2, 23°C, 8 h.
Keywords: eicosanoids; aldol reactions; biologically active compounds; hydrogenation; metabolites.
* Corresponding author. Tel.: 214-648-2406; fax: 214-648-6455; e-mail: j.falck@utsouthwestern.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00668-2

4110
S. Mohapatra et al. / Tetrahedron Letters 42 (2001) 4109–4110
Scheme 2. Reaction conditions: (a) TsCl, py, CH2Cl2, 23°C, 12 h. (b) 9, CuI, NaI, K2CO3, DMF, −40 to 23°C, 12 h. (c) Ni(P2),
H2, EtOH, 23°C, 2 h. (d) 4% oxalic acid, acetone/H2O (1:1), 0°C, 1 h. (e) 4, LDA, THF, −78°C, 2 h; product of step d, −78°C,
3 h. (f) 0.01% H2SO4, MeOH, 0°C, 0.5 h; K2CO3 (pH 10), 0°C, 1 h. (g) 1N LiOH, i-PrOH, 23°C, 12 h.
uneventfully into orthoester 415 via methyloxetane
Hashefi, M. J. Biol. Chem. 1993, 268, 9280–9286.
5. O’Flaherty, J. T.; Cordes, J.; Redman, J.; Thomas, M.
Biochem. Biophys. Res. Commun. 1993, 192, 129–134.
6. Norgauer, J.; Barbisch, M.; Czech, W.; Pareigis, J.;
Schwenk, U.; Schro¨der, J. M. Eur. J. Biochem. 1996, 236,
1003–1009.
7. Powell, W. S.; Gravel, S.; Halwani, F.; Hii, C. S.; Huang,
Z. H.; Tan, A. M.; Ferrante, A. J. Immunol. 1997, 159,
2952–2959.
8. Powell, W. S.; Chung, D.; Gravel, S. J. Immunol. 1995,
154, 4123–4132.
9. Powell, W. S.; Gravel, S.; Halwani, F. Am. J. Respir. Cell
Mol. Biol. 1999, 20, 163–170.
(MOX) ester 3 according to Corey and Raju.16
The electrophilic aldol acceptor (Scheme 2) was fash-
ioned from the readily available bis-acetylene 517 by
tosylation under conventional conditions and alkyla-
tion with propiolaldehyde diethyl acetal (9) in the pres-
ence of Cu(I).17 The resultant tris-acetylene adduct 6
contains all of the remaining carbons of the eicosanoid
backbone. Its partial hydrogenation utilizing P-2
nickel18 reproducibly afforded all-cis-triene 7 over a
wide scale (mmol–mmol) without the need for purifica-
tion beyond filtration and evaporation of the solvent.
Deuteration or tritiation could also be conveniently
achieved during this procedure using isotopic gas. Care-
fully controlled acetal hydrolysis using 4% oxalic acid
at 0°C gave rise to a labile cis-enal that was immedi-
ately condensed with the enolate of 4 in anhydrous
THF at −78°C. The adduct 8 was converted to 1 by
sequential acidic hydrolysis of the orthoester with
0.01% H2SO4, in situ transesterification to its methyl
ester, taking care not to exceed 0°C and pH 10, and
finally saponification in i-PrOH, as recommended by
Kerdesky et al.19 The use of MeOH or THF/H2O as
solvent induced significant, but variable, isomerization
to 8,9-trans-5-oxo-ETE.
10. O’Flaherty, J. T.; Taylor, J. S.; Thomas, M. J. J. Biol.
Chem. 1998, 273, 32535–32541.
11. Hevko, J. M.; Bowers, R. C.; Murphy, R. C. J. Pharm.
Exp. Ther. 2001, 296, 293–305.
12. Bowers, R. C.; Hevko, J.; Henson, P. M.; Murphy, R. C.
J. Biol. Chem. 2000, 275, 29931–29934.
13. The only total synthesis to date afforded 1 and its
8,9-trans-isomer in a 4:1 isolated ratio: Khanapure, S. P.;
Shi, X.-X.; Powell, S. P.; Rokach, J. J. Org. Chem. 1998,
63, 337–342.
14. Preparation of tritiated and deuterated 1: Khanapure, S.
P.; Shi, X.-X.; Powell, W. S.; Rokach, J. J. Org. Chem.
1998, 63, 4098–4102.
15. Orthoester 4: 1H NMR (CDCl3, 400 MHz) l 0.79 (s, 3H),
1.64–1.77 (m, 4H), 2.12 (s, 3H), 2.45 (t, 2H, J=7.0 Hz),
3.88 (s, 6H). Acetal 7: l 0.89 (t, 2H, J=7.0 Hz), 1.22 (t,
6H, J=7.0 Hz), 1.26–1.46 (m, 6H), 2.05 (q, 2H, J=7.3
Hz), 2.80 (t, 2H, J=6.7 Hz), 2.93 (t, 2H, J=6.7 Hz),
3.48–3.55 (m, 2H), 3.61–3.69 (m, 2H), 5.24 (d, 1H, J=6.4
Hz), 5.30–5.43 (m, 4H), 5.47–5.52 (m, 1H), 5.56–5.63 (m,
1H). Adduct 8: l 0.79 (s, 3H), 0.89 (t, 3H, J=6.7 Hz),
1.26–1.41 (m, 6H), 1.64–1.79 (m, 4H), 2.04 (q, 2H, J=7.3
Hz), 2.47 (t, 2H, J=7.3 Hz), 2.52–2.67 (m, 2H), 2.79 (t,
2H, J=6.7 Hz), 2.87 (q, 2H, J=7.9 Hz), 3.01 (d, 1H,
J=3.3 Hz), 3.87 (s, 6H), 4.87–4.93 (m, 1H), 5.28–5.49 (m,
6H). Synthetic 1 was identical by NMR, MS, and HPLC
with an authentic standard.
Acknowledgements
Supported financially by the USPHS NIH (GM31278,
DK38226), the Robert A. Welch Foundation, and an
unrestricted grant from Taisho Pharmaceutical Co.,
Ltd. We express our appreciation to Professor Joshua
Rokach (Florida Institute of Technology) for providing
extensive spectral data.
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