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tion using triphenylphosphine gave desired diene phosphoni-
um salt 20 with a 71% yield over the four last steps and
a 51% overall yield. Though this new synthesis offers the same
overall yield, it remained more convenient on a large scale and
less expensive. It is interesting to note that butylated hydroxy-
toluene (BHT) was added during the preparation and storage
of 20 for preservation of the “ÀCH À” in bis-allylic position.
2
Moreover, although most phosphonium salts are in solid state,
20 remained a sticky oil despite several crystallisation at-
tempts. Therefore phosphonium 20 was dried by three cycles
of dissolution in acetonitrile followed by desiccation at 1208C
under vacuum (10 mbar, for 15 min) before carrying out the
Scheme 4. a) PMBTCA, La(OTf)
imidazole, DMAP, CH Cl2, RT, quant.; d) DIBAl-H, CH
CH Cl
, RT; f) 13, NaHMDS, THF, À788C, 62% over 3 steps; g) CeCl
NaBH , MeOH, 08C, 95%; h) TBSCl, imidazole, DMAP, CH Cl , RT, 82%; i) DDQ,
8C, 86%. PMBTCA=para-methoxybenzyl trichloroacetimidate, Tf=trifluoro-
3
, RT, 87%; b) K
2
CO
3
, MeOH, RT, 79%; c) TBSCl,
Cl
, À788C; e) DMP,
·7H O,
2
2
2
À1
2
2
3
2
4
2
2
Wittig reaction.
0
From alcohol 15, the tandem oxidation-Wittig reaction pro-
ceeded, in 62% yield, to give the expected 5E,13Z,16Z,19Z-tet-
raene 21 (Scheme 6). TBAF-deprotection of silylated ethers af-
forded the five-membered ring lactone 22, which was saponi-
methanesulfonyl.
Thanks to our intermediate 6, the primary alcohol was first
protected using para-methoxybenzyl trichloroacetimidate and
5
fied using LiOH to achieve the synthesis of 4(RS)-SC-D -8-
La(OTf) in 87% yield before acetyl and benzoyl methanolysis
NeuroF (2).
3
to give methyl ester 11 in 79% yield (Scheme 4). Quantitative
silylation of secondary alcohols with TBSCl, imidazole and a cat-
alytic amount of DMAP afforded 12 in good yield. DIBAl-H re-
duction of methyl ester followed by oxidation of the resulting
aldehyde/alcohol mixture using Dess–Martin periodinane pro-
vided the desired aldehyde for Horner–Wadsworth–Emmons
olefination using previously described b-keto-phosphonate
[
18]
1
3. The resulting a,b-unsaturated ketone 14 (3 steps, 62%
yield) was reduced under Luche conditions and the resulting
allylic alcohol was protected into tert-butyldimethylsilyl ethers
prior to PMB deprotection. Alcohol 15 was then obtained after
Scheme 6. a) DMP, CH
steps; c) TBAF, THF, RT, 90%; d) LiOH, THF/H
2
Cl
2
, RT; b) 20, NaHMDS, THF, À788C, 62% over 2
O (1:1), RT, 87%.
3
steps in a 67% yield.
2
At this stage, the complex omega chain needed to be instal-
led. In 2000, our laboratory performed the synthesis of the 4-
F -NeuroP methyl ester containing the same omega chain, by
5
Consequently, the first total synthesis of 4(RS)-SC-D -8-
NeuroF (2) was completed after 13 steps and 14% yield start-
ing from alcohol 6 and without considering the preparation of
b-ketophosphonate 14 and phosphonium salt 20.
4t
[
19]
Wittig reaction using phosphonium salt 20. The latter was
obtained by a convergent strategy with a total of 8 steps and
[
20]
5
1% yield, in collaboration with Viala and Santelli. We decid-
5
ed to improve the synthesis of 20 (Scheme 5), because the pre-
To date, the specific type of NeuroFs, 4(RS)-ST-D -8-NeuroF 2
vious synthesis was costly and tricky.
described in this report has not been identified in biological
[9]
samples. Furthermore, in our previous report we have shown
1
5
the measurement of dihomo-IsoF, 17(RS)-10-epi-SC-D -11-
dihomo-IsoF 3 in prefrontal cortex of preterm pig brain and it
8
is unknown if the second type 7(RS)-ST-D -11-dihomo-IsoF 1, as
shown in the strategy herein, is measurable in biological sam-
5
ples. We now report the levels of 4(RS)-ST-D -8-NeuroF 2 and
8
7
(RS)-ST-D -11-dihomo-IsoF 1 in heart and brain samples from
Scheme 5. a) DHP, PPTS, CH
c) 17, NaHMDS, THF, À788C; d) PPTS MeOH, reflux; e) I
f) PPh , K CO (cat), BHT, CH CN, 71% (over 4 steps). DHP=dihydropyran,
2
Cl
2
, RT, 87%; b) DIBAl-H, Et
2
O, À788C, 82%;
adult rats. The levels are compared with IsoFs, 17(RS)-10-epi-
, PPh , Imidazole, RT;
3
15
2
SC-D -11-dihomo-IsoF 3 and total NeuroFs as well as the re-
spective isoprostanoids.
3
2
3
3
PPTS=pyridinium para-toluenesulfonate, BHT=butylated hydroxytoluene.
As expected the concentration of the PUFAs AA, AdA, and
DHA were higher in the brain tissues than the heart (Figure 1).
Interestingly, 4(RS)-4-F -NeuroP (from DHA) concentration was
Starting from 1-hydroxypropanenitrile, aldehyde 16 was ob-
tained in two steps and 71% yield by protecting the alcohol
into THP-ether and reducing the nitrile with DIBAl-H reagent. A
Wittig reaction between aldehyde 16 and previously described
4t
very high in both heart and brain tissues, and this also coin-
[9]
cides with our previous findings, in which it predominates
among the isoprostanoids. However, in this evaluation we also
found 5-F -IsoP from AA to be highly concentrated in both tis-
[
17]
phosphonium salt 17 gave diene 18. THP deprotection in
2t
acidic conditions prior to iodination and nucleophilic substitu-
sues. In comparison between the heart and the brain, the iso-
Chem. Eur. J. 2014, 20, 1 – 6
3
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