Total synthesis of phytoprostane F1 and its 16 epimer

Article abstract of DOI:10.1016/S0040-4039(03)00171-0

The first synthesis of the two enantiomers of phytoprostane F₁ methyl ester 1 and 2 is described using the syn-anti-syn alcoxy ester 3 as starting material.

Full text of DOI:10.1016/S0040-4039(03)00171-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2105–2108
Total synthesis of phytoprostane F1 and its 16 epimer
Siham El Fangour, Alexandre Guy, Jean-Pierre Vidal, Jean-Claude Rossi and Thierry Durand*
UMR CNRS 5074, Universite´ Montpellier I, Faculte´ de Pharmacie, 15. Av. Ch. Flahault, F-34093 Montpellier cedex 05, France
Received 10 January 2003; accepted 16 January 2003
Abstract—The first synthesis of the two enantiomers of phytoprostane F1 methyl ester 1 and 2 is described using the syn–anti–syn
alcoxy ester 3 as starting material. © 2003 Elsevier Science Ltd. All rights reserved.
Isoprostanes (IsoPs) are a complex family of com-
pounds produced, in vivo, from peroxidation of
polyunsaturated fatty acids (AA, DHA, EPA) via a
free-radical-catalyzed mechanism.1 Thus, quantification
of these IsoPs in the biological fluids and tissues as
markers of lipid peroxidation appears as an important
insight in the exploration of the role of the oxidative
stress in human pathology.2 Higher plants generally do
not synthesize the precursor arachidonate required for
isoPs formation, but rather utilize a-linolenic acid for
the formation of isoprostane F2-like compounds which
have been termed phytoprostanes F1.3 Jasmonates are
established plant signal compounds that induce defense
response.4 Preliminary data indicates that phyto-
prostanes also induce phytoalexins in a variety of plant
species suggesting a possible function of phytoprostanes
as mediators of plant defense reactions in response to
oxidative stress.5 During the last two years, Zanoni et
al. reported the first synthesis of phytoprostane A16 and
Spur et al. just published the synthesis of 15-E2-isoP
(PPE2).7
16-epimer 2 from the syn–anti–syn alcoxyester 39
(Scheme 1).
The synthesis of PPF1 type I 1 and its 16(R) epimer 2
from the commercially available diacetone-D-glucose as
starting material, is shown in Schemes 3 and 4. The first
nine steps leading to cyclopentane alcoxyester 3 were
achieved in 27% overall yield by using iodo pathway,
according to our procedure.9
Synthon 4 was selected and prepared using the follow-
ing procedure outlined in Scheme 2.
The commercially available o-caprolactone was trans-
formed to the corresponding hydroxy methyl ester 5
using acidic conditions in 97% yield. Halogenation with
PPh3/I2 in CH2Cl2 gave iodo ester 6 in good yield.
Phosphorylation of the iodide derivative 6 in the pres-
ence of PPh3 and 1% of K2CO3 in the reaction mixture
afforded the phophonium salt 7 in 98% yield.
The alcoxyester 3 was converted into the aldehyde 8 by
treatment with DIBAL-H in anhydrous toluene with
97% yield (Scheme 3). The introduction of the a-chain
of the phytoprostane was achieved by using the
In connection with our program directed towards the
synthesis of isoprostanes,8 we now report the first syn-
thesis of ent-phytoprostane F1 type I (PPF1) 1 and its
Scheme 1.
* Corresponding author. Tel.: +33-4-6754-8623; fax: +33-4-6754-8625; e-mail: thierry.durand@pharma.univ-montp1.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00171-0

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S. El Fangour et al. / Tetrahedron Letters 44 (2003) 2105–2108
Scheme 2. Reagents and conditions: (a) MeOH, H2SO4, rt, 30 min, 97%; (b) I2, PPh3, imidazole, CH2Cl2, −10°C, 2 h, 61%; (c)
PPh3, CH3CN, 1% K2CO3, 18 h, 98%.
Scheme 3. Reagents and conditions: (a) 1.1 equiv. DIBAL-H (1 M in toluene), toluene, −80°C, 30 min, 97%; (b) 2.25 equiv.
methoxycarbonylpentyltriphenylphosphonium iodide, 2.2 equiv. KN(SiMe3)2, THF, −80 to 20°C, 2 h, 70%; (c) H2, Pd/C 10%,
EtOH, 4 h, 98%; (d) 3 equiv. BzCl, pyridine, 20°C, 1 h, 77%; (e) HCl 3% in MeOH, 20°C, overnight, 80%; (f) periodinane,
CH2Cl2, rt, 2 h; (g) 3.3 equiv. dimethyl 2-oxobutylphosphonate, 3 equiv. NaN(SiMe3)2, THF, 20°C, 30 min, 60%.
methoxycarbonylpentyltriphenyl phosphonium iodide
7. The aldehyde 8 reacted with the ylide derived from
this phosphonium salt and potassium hexamethyldisilyl
amide as a base, in anhydrous THF at −80°C, to afford
the pure (Z) enic ether 9 in 70% yield. No trace of trans
compound could be detected by 13C and 1H NMR
analysis.
ride in dry pyridine gave the colorless diester 11 in
77% yield.
The tert-butyldiphenylsilyl ether 11 was converted into
the alcohol 12 with a solution of 3% hydrogen
chloride10 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 (80%) than TBAF in THF. Dess–Martin
oxidation11 of 12 in CH2Cl2 gave the unstable aldehyde
13 which was immediately used in the next step without
purification. The condensation of 13 with dimethyl
2-oxobutylphosphonate,12 in the presence of sodium
The cis double bond of 9 was reduced with H2 on 10%
Pd/C to give diol methyl ester 10 in 98% yield, Interest-
ingly, during this hydrogenation we could avoid
the deprotection of the triethylsilyl ethers. The protec-
tion of the hydroxy functions of 10 with benzoyl chlo-

S. El Fangour et al. / Tetrahedron Letters 44 (2003) 2105–2108
2107
Finally, deprotection of the benzoyl groups in 15 and
16, with 1N NaOH at room temperature, followed by
excess of CH2N2, afforded the desired ent-PPF1 type I
214 and its 16 epimer 115 in 91 and 93% yields,
respectively.
In conclusion, we have developed a practical synthesis
of phytoprostane F1 type I 2 and its 16 epimer 1 from
our intermediate, the syn–anti–syn alcoxyester 3 in nine
steps. The extension of this strategy towards type II
PPF1 and other phytoprostanes will be reported in due
course.
Figure 1. Observed NOEs resulting from irradiation of main
protons are indicated with solid.
Acknowledgements
hexamethyldisilyl amide, in anhydrous THF at room
temperature, afforded the trans-a,b enone ester 14 in
60% overall yield from the alcohol 12 (Scheme 3). We
confirmed the relative configurations of the chiral cen-
ters by homonuclear 1H steady-state-difference NOE
spectroscopy (DNOES) experiments, as shown in Fig-
ure 1.
We wish to thank the Ministe`re de l’Education
Nationale, de l’Enseignement Supe´rieur et de la
Recherche for financial support for one of us (S.E.).
References
The diastereoselective reduction of the C-16 keto group
in 14 with the chiral reducing agent13 (S)-BINAL-H
proceeded smoothly and gave the desired pure 16(S)
derivative 15 in 85% yield. Similarly, reduction of 14
using the (R)-BINAL-H gave the 16(R) epimer 16 in
87% yield (Scheme 4).
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Scheme 4. Reagents and conditions: (a) (S)-BINAL-H, −100°C, 2 h, 85%; (b) (R)-BINAL-H, −100°C, 2 h, 87%; (c) 1N NaOH,
THF–MeOH, rt, 1 h, then CH2N2, 93%.

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S. El Fangour et al. / Tetrahedron Letters 44 (2003) 2105–2108
3. Imbusch, R.; Mueller, M. J. Plant Physiol. 2000, 124,
1H, H-12), 3.97–3.90 (m, 1H, H-10), 3.66 (s, 3H, OCH3),
2.77–2.71 (m, 1H, H-13), 2.42 (dt, J11,10=J11,12=6.8 Hz,
J11,11%=14.5 Hz, 1H, H-11), 2.29 (t, J2,3=7.5 Hz, 2H,
H-2), 2.11–2.01 (m, 1H, H-9), 1.68–1.58 (m, 1H, H-11%),
1.66–1.55 (m, 2H, H-3), 1.65–1.45 (m, 2H, H-17), 1.33–
1.25 (m, 2H, H-4), 1.33–1.19 (m, 8H, H-5, H-6, H-7 and
H-8), 0.90 (t, J18,19=7.5 Hz, 3H, H-18); 13C NMR (100
MHz, CDCl3): l ppm 174.3 (C-1), 135.5 (C-15), 128.8
(C-14), 76.6 (C-10), 76.4 (C-12), 74.4 (C-16), 53.6 (C-13),
51.4 (OCH3), 50.4 (C-9), 42.5 (C-11), 34.0 (C-2), 30.1
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24.8 (C-3), 9.6 (C-18); IR (NaCl) w: 3520, 1720 cm−1
;
[h]2D0=−30 (c 1×10−2, MeOH).
1
15. Compound 1: UV (ethanol) umax: 203 nm; H NMR (400
MHz, CDCl3): l ppm 5.57 (dd, J15,16=6.2 Hz, J15,14
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15.4 Hz, 1H, H-15), 5.43 (dd, J14,13=5.4 Hz, J14,15=15.4
Hz, 1H, H-14), 4.05–3.96 (m, 1H, H-16), 4.04–3.99 (m,
1H, H-12), 3.98–3.93 (m, 1H, H-10), 3.66 (s, 3H, OCH3),
2.79–2.73 (m, 1H, H-13), 2.41 (dt, J11,10=J11,12=6.8 Hz,
J11,11%=14.5 Hz, 1H, H-11), 2.29 (t, J2,3=7.7 Hz, 2H,
H-2), 2.12–2.04 (m, 1H, H-9), 1.68–1.59 (m, 1H, H-11%),
1.66–1.55 (m, 2H, H-3), 1.60–1.48 (m, 2H, H-17), 1.33–
1.25 (m, 2H, H-4), 1.33–1.18 (m, 8H, H-5, H-6, H-7 and
H-8), 0.90 (t, J18,19=7.3 Hz, 3H, H-18); 13C NMR (100
MHz, CDCl3): l ppm 174.3 (C-1), 135.3 (C-15), 128.7
(C-14), 76.8 (C-10), 76.5 (C-12), 73.8 (C-16), 53.4 (C-13),
51.4 (OCH3), 50.3 (C-9), 42.5 (C-11), 34.0 (C-2), 30.1
(C-17), 29.4 (C-8), 29.0 (C-4, C-5 and C-7), 28.0 (C-6),
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1
14. Compound 2: UV (ethanol) umax: 203 nm; H NMR (400
MHz, CDCl3): l ppm 5.54 (dd, J15,16=7.1 Hz, J15,14
=
24.8 (C-3), 9.6 (C-18); IR (NaCl) w: 3520, 1720 cm−1
[h]2D0=−13 (c 1×10−2, MeOH).
;
15.2 Hz, 1H, H-15), 5.40 (dd, J14,13=9.7 Hz, J14,15=15.2
Hz, 1H, H-14), 4.02–3.93 (m, 1H, H-16), 4.03–3.95 (m,