Total synthesis of 4(RS)-F(4t)-isoprostane methyl ester

Article abstract of DOI:10.1016/S0040-4039(00)00508-6

The first total synthesis of 4(RS)-F(₄t)-isoprostane methyl ester 1 is described using diacetone-D-glucose as starting material. This new isoprostane (neuroprostane) would be very useful in neurological studies as a potent lipid peroxidation in

Full text of DOI:10.1016/S0040-4039(00)00508-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3859–3862
Total synthesis of 4(RS)-F4t-isoprostane methyl ester
Thierry Durand,a,∗ Alexandre Guy,a Jean-Pierre Vidal,a Jacques Viala b and
Jean-Claude Rossi a
aUMR CNRS 5074, Université Montpellier I, Faculté de Pharmacie, 15 Av. Ch. Flahault, F-34060 Montpellier, France
bUMR CNRS 6516, Faculté des Sciences de St Jérôme, Boite D12, F-13397 Marseille cedex 20, France
Received 11 February 2000; accepted 22 March 2000
Abstract
The first total synthesis of 4(RS)-F4t-isoprostane methyl ester 1 is described using diacetone-D-glucose as starting
material. This new isoprostane (neuroprostane) would be very useful in neurological studies as a potent lipid
peroxidation index to obtain an integrated assessment of oxidative stress in the human brain. © 2000 Elsevier
Science Ltd. All rights reserved.
F2-Isoprostanes are prostaglandin-like compounds derived by free radical-catalyzed peroxidation from
arachidonic acid (AA)1 and are endowed with a powerful biological activity.2 During the last decade,
there has been a growing interest in the total synthesis of these optically active prostanoids.3 Free
radicals have been implicated in the pathogenesis of a wide variety of human disorders,4 specifically
in Alzheimer’s disease.5 The measurement of levels of endogenous unmetabolized F2-isoprostanes has
proven to be a valuable approach to assess oxidative stress in vivo.
Docosahexaenoic acid (DHA) is an essential requirement for the development of the brain and retina
ranges from 20 to 60% of the total fatty acid content, and is present esterified to phospholipids.6
Peroxidation of DHA produces F4-isoprostanes (neuroprostanes).7 Eight subfamilies of F4-isoprostanes
could be formed from DHA owing to free catalyzed attacks at positions C6, C9, C12, C15 and C18.
These different families of isoprostanes should be unique biomarkers of peroxidation of fatty acids and
would be very useful in neurological studies if they could be quantified in the human brain.
In connection with our program directed towards the synthesis of isoprostanes, we now report the first
total synthesis of 4(RS)-F4t-isoprostane methyl ester 1 from the alcoxyester 28 (Scheme 1).
Scheme 1.
∗
Corresponding author. Fax: 33-4-67-54-86-25; e-mail: thierry.durand@pharma.univ-montp1.fr (T. Durand)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00508-6
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The synthesis of 4(RS)-F4t-isoprostane methyl ester 1 from the commercially available diacetone-
D-glucose as starting material, is shown in Scheme 2. The first nine steps leading to cyclopentane
alcoxyester 2 were achieved in 27% overall yield by using the iodo pathway, according to our procedure.8
Scheme 2. (a) 1.1 equiv. DIBAL-H (1 M in toluene), toluene, –80°C, 30 min, 93%; (b) 4 equiv. [(Z,Z)-3,6-nonandiene-1-yl]
triphenylphosphonium iodide, 3.8 equiv. NaN(SiMe3)2, THF, –80°C to 20°C, 2 h, 68%; (c) NH4F, THF–MeOH, 4 h, 92%; (d)
4 equiv. BzCl, pyridine, 20°C, 1 h, 86%; (e) HCl 3% in MeOH, 20°C, overnight, 73%; (f) periodinane, CH2Cl2, rt, 2 h; (g) 1.2
equiv. diethyl[4-(methoxycarbonyl)-oxobutyl]phosphonate, 1.1 equiv. NaN(SiMe3)2, THF, 20°C, 30 min, 64%; (g) 1.1 equiv.
L-Selectride®, THF, –78°C, 20 min, 65%; (h) 1N NaOH, THF–MeOH, rt, 1 h, then CH2N2 63%
The alcoxyester 2 was converted into the aldehyde 3 by treatment with DIBAL-H in anhydrous toluene
(Scheme 2) with 93% yield.
The introduction of the ω chain of the neuroprostane was achieved by using a nine-carbon homolo-
gating agent, [(Z,Z)-3,6-nonadiene-1-yl]triphenylphosphonium iodide.9 The aldehyde 3 reacted with the

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ylide derived from this phosphonium salt and sodium hexamethyldisilyl amide as a base, in anhydrous
THF at −80°C, to afford the pure all-(Z) trienic ether 4 in 68% yield.10 No trace of the trans compound
1
could be detected by 13C and H NMR analysis. All the relative configurations were checked by
homonuclear 1H NOE experiments.
Deprotection of the triethylsilyl groups with ammonium fluoride in a mixture of MeOH:THF (2:1) at
60°C gave the diol 5 in 92% yield. The protection of the hydroxy functions of 5 with benzoyl chloride in
dry pyridine gave the colorless diesters 6 in 86% yield. The tert-butyldiphenylsilyl ether 6 was converted
into the alcohol 7 with a solution of 3% hydrogen chloride11 in methanol:diethyl ether (1:1, v/v), prepared
freshly from acetyl chloride and methanol, a method which proved to be much milder and to give
a higher yield (73%) than TBAF in THF. Dess–Martin oxidation12 of 7 with periodinane in CH2Cl2
gave the unstable aldehyde 8 which was immediately used in the next step without purification. It is
important to note that this Dess–Martin oxidation gave a higher yield avoiding any epimerization than
our first attempts using Swern conditions. The condensation of 8 with diethyl [4-(methoxycarbonyl)-2-
oxobutyl]phosphonate,13 in the presence of sodium hexamethyldisilyl amide, in anhydrous THF at room
temperature, afforded the trans-α,β enone ester 9 in 64% overall yield from the alcohol 7. Reduction of
the keto function of 9 with L-Selectride®14 furnished the mixture of epimeric lactones 10 in 65% yield,
which could not be separated by flash chromatography.
Finally, cleavage of the lactone and esters of 10 with 1N NaOH at room temperature, followed by
excess of CH2N2, afforded 115 in 63% yield.
In conclusion, we describe herein the first stereoselective synthesis of 4(RS)-F4t-neuroprostane methyl
ester 1 in nine steps from the alcoxyester 2. This neuroprostane should be very useful in neurological
studies as a potent lipid peroxidation index to obtain an integrated assessment of oxidative stress in the
human brain.
Acknowledgements
We wish to thank Dr. Paul Mosset for helpful discussion.
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1H), 3.94 (q, 1H, J=7.2 Hz), 3.6 (d, 2H, J=4.8 Hz), 2.61–2.84 (m, 4H), 1.98–2.43 (m, 7H), 1.47–1.59 (td, 1H, J=4 and 14
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129.1, 128.3, 128.1, 128, 127.6, 127.1, 76.3, 73.2, 62.6, 50.6, 48.2, 45.1, 26.8, 25.7, 25.5, 25.4, 19.1, 14.2, 6.8, 6.7, 4.9,
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1
15. Compound 1: UV (ethanol) λmax: 205 nm. H NMR (360 MHz, CDCl3) δ: 5.62–5.54 (m, 1H, H-5), 5.54–5.48 (m, 1H,
H-6), 5.47–5.23 (m, 6H, H-13, H-14, H-16, H-17, H-19, H-20), 4.19–4.10 (m, 1H, H-4), 4.07–3.96 (m, 1H, H-8), 4.01–3.93
(m, 1H, H-10), 3.66 (s, 3H, OMe), 2.81–2.75 (m, 5H, H-7, H-15, H-18), 2.45–2.37 (m, 3H, H-9, H-2), 2.22–2.13 (m, 1H,
H-11), 2.08–1.99 (m, 4H, H-12, H-21), 1.91 (dd, 1H, J=5 Hz, J=1 Hz, OH-8), 1.88–1.80 (m, 2H, H-3), 1.73 (dd, 1H, J=5
Hz, J=3 Hz, OH-10), 1.64 (td, 1H, J9,9 =15 Hz, J9 ,8=J9 ,10=4.5 Hz, H-90), 0.96 (t, 3H, J22,21=7.5 Hz, H-22). 13C NMR (90
MHz, CDCl3) δ: 172.2 (C-l), 135.2 (C-5), 132.1 (C-20), 129.3 (C-6, C-16), 128.7 (C-17), 128.4 (C-14), 127.6 (C-13),
126.9 (C-19), 76.4 (C-8, C-10), 71.5 (C-4), 53.6 (C-7), 51.7 (OMe), 50.8 (C-11), 42.4 (C-9), 32.0 (C-3), 30.0 (C-2), 27.1
(C-12), 25.7 (C-15, C-18), 20.5 (C-21), 14.2 (C-22). IR (NaCl) ν: 3520, 1720.
0
0
0