Oxygenated Metabolites of n-3 polyunsaturated fatty acids as potential oxidative stress biomarkers: Total synthesis of 8-F3t-IsoP, 10-F 4t-NeuroP and [D4]-10-F4t-NeuroP

Article abstract of DOI:10.1002/chem.201400380

A wide variety of metabolic products of polyunsaturated fatty acids is of paramount importance for improving our medical knowledge in the field of oxidized lipids. Two novel metabolites of n-3 polyunsaturated fatty acids, 8-F_3t-IsoP and 10-F_4t-NeuroP as well as a deuterated derivative thereof were synthesized based on an acetylenic intermediate. An original approach achieved lateral chain insertion of 8-F_3t-IsoP by a ring-closing alkyne metathesis/semi-reduction strategy together with a temporary tether. Three for the price of one! Two strategies, Caruso coupling or ring-closing alkyne metathesis (RCAM), enabled the synthesis of 8-F _3t-IsoP and 10-F_4t-NeuroP and its deuterated derivative from acetylenic intermediateA (see scheme). Such compounds represent potential biomarkers of neuronal oxidative stress.

Full text of DOI:10.1002/chem.201400380

DOI: 10.1002/chem.201400380
Full Paper
&
Organic Synthesis
Oxygenated Metabolites of n-3 Polyunsaturated Fatty Acids as
Potential Oxidative Stress Biomarkers: Total Synthesis of
8-F3t-IsoP, 10-F4t-NeuroP and [D4]-10-F4t-NeuroP
Alexandre Guy,[a] Camille Oger,[a] Johannes Heppekausen,[b] Cinzia Signorini,[c]
Claudio De Felice,[d] Alois Fꢀrstner,[b] Thierry Durand,[a] and Jean-Marie Galano*[a]
Abstract: A wide variety of metabolic products of polyunsa-
turated fatty acids is of paramount importance for improv-
ing our medical knowledge in the field of oxidized lipids.
Two novel metabolites of n-3 polyunsaturated fatty acids, 8-
F3t-IsoP and 10-F4t-NeuroP as well as a deuterated derivative
thereof were synthesized based on an acetylenic intermedi-
ate. An original approach achieved lateral chain insertion of
8-F3t-IsoP by a ring-closing alkyne metathesis/semi-reduction
strategy together with a temporary tether.
Omega-3 polyunsaturated fatty acids (n-3 PUFAs), especially
docosahexaenoic acid (DHA, C22:6 n-3), are highly prone to
peroxidation both in vitro and in vivo due to the presence of
skipped diene units. The H-atom abstraction at the bisallylic
position followed by oxygenation can either occur enzymati-
cally or by a free-radical mechanism, leading to neuroprotec-
tins[1] or neuroprostanes (NeuroPs), respectively.[2] Similar to
the NeuroPs, the F2-isoprostanes (F2-IsoPs) are isomers of pros-
taglandin PGF2a. These arachidonic acid (AA) derivatives,
which are formed by a non-enzymatic pathway, were con-
firmed as the most reliable markers for systemic oxidative
stress,[3] and possess relevant biological activities in humans.[4,5]
For these reasons, the formation of NeuroPs deserves attention
because it is the only pathway that can generate PG-like
isomer of DHA. Specifically, DHA is not a substrate for mamma-
lian cyclooxygenase (COX), and it actually inhibits cyclooxyge-
nation of arachidonic acid.
Although NeuroPs are increasingly explored in clinical set-
tings, only few applications yet exist. These compounds might
have paramount importance if one considers that the DHA
precursor is specifically distributed in the neuronal membrane.
In several pathologies, the availability of biochemical markers
would be advantageous to discriminate the damage of the
grey (concentrated with DHA) from that of white brain matter
(concentrated with adrenic acid). Peripheral biological fluids
are not universally considered to represent the biochemical ox-
idative events occurring in the brain.[6] However, our group has
demonstrated the relevance of changes of plasma levels of
NeuroPs in patients with Rett syndrome, a rare genetic cause
of autism in girls,[7] while other authors have confirmed the im-
portance of monitoring the plasma levels of NeuroPs in pa-
tients with Parkinson’s disease.[8]
Presently, it is largely unknown which NeuroP isomer is the
most abundant and/or most relevant in a given human or ex-
perimental condition or disease state. In this context, however,
we could previously show that 7-F2t-dihomo-IsoP is the most
abundant of the IsoP isomers in the early stage (stage 1) of
Rett syndrome.[9,10]
[a] Dr. A. Guy, Dr. C. Oger, Dr. T. Durand, Dr. J.-M. Galano
Institut des Biomolꢀcules Max Mousseron,UMR 5247 - CNRS - University
Montpellier I and II - ENSCM
Since the identification of NeuroPs,[2] several synthetic ap-
proaches to such compounds were reported,[11] but no consen-
sus has been reached as to which of these biomarkers is most
significant. A priori, one might expect that such a reference
molecule 1) would be the most abundant isomer, 2) must not
interfere with the products of oxidation deriving from other
PUFAs (such as F2-dihomo-IsoPs)[12] and 3) can be quantified
with sufficient sensitivity and reproducibility. To reach these
goals and to ameliorate our knowledge about the role of
NeuroP in human diseases, we describe herein the syntheses
of 10-F4t-NeuroP 1a and its deuterated derivative 2a, as well
as of 8-F3t-IsoP 3a (Scheme 1).
Faculty of Pharmacy, Montpellier (France)
Fax: (+33)411759553
E-mail: jgalano@univ-montp1.fr
[b] Dr. J. Heppekausen, Prof. A. Fꢁrstner
Max-Planck-Institut fꢁr Kohlenforschung
45470 Mꢁlheim/Ruhr (Germany)
[c] Dr. C. Signorini
Department of Molecular and Developmental Medicine
University of Siena
Siena (Italy)
[d] C. De Felice
Neonatal Intensive Care Unit, University Hospital
Azienda Ospedaliera Universitaria Senese (AOUS)
Siena (Italy)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201400380.
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figured a,b-unsaturated acylsi-
lane 6 in 85% yield. Reaction
with the zinc reagent derived
from 7-bromo-hept-5-ynoic acid
methyl ester in THF gave the de-
sired tertiary silanol derivative 7
in 73% yield. Unfortunately,
however, treatment with TBAF in
THF did not provide the desired
compound 8, but only cleaved
the TBS ethers while not affect-
Scheme 1. Retrosynthetic analysis of 10-F4t-NeuroP 1a and [D4]-10-F4t-NeuroP 2a and 8-F3t-IsoP 3a.
ing the C-TMS group. Formyla-
tion of the tertiary alcohol, as
Results and Discussion
described in the original paper,[15] followed by TBAF deprotec-
tion was not satisfactory either, resulting only in the loss of
material. Other fluorine sources or acidic conditions were
tested in the attempt to deprotect the TMS moiety, but in all
cases investigated only TBS cleavage was observed.
Therefore, we decided to explore another convergent strat-
egy by using a more advanced acetylenic intermediate 13 that
would then lead to NeuroP 1 and F3-IsoP 3.
We have recently reported the total synthesis of [D4]-4-F4t-
NeuroP to provide a deuterated internal standard for accurate
quantification of NeuroPs in vivo.[11f] In pursuit of this work, we
decided to focus our attention on another potentially interest-
ing isomer, that is, 10-F4t-NeuroP 1 and its deuterated variant
2. Its relative 8-F3t-IsoP 3 derived from eicosapentaenoic acid
(EPA, C20:5 n-3) possesses similar structural features. Since this
compound could, a priori, also be a b-oxidized metabolite of
10-F4t-NeuroP,[13] reference samples are essential for tracking
down the metabolisation of 10-F4t-NeuroP.
To this end, the unsaturated conjugated aldehyde 9 was pre-
pared by oxidation of 5 with the Dess–Martin reagent, fol-
lowed by reaction with methyl 2-(triphenylphosphoranylide-
ne)acetate, subsequent DIBAL-H reduction and Dess–Martin
periodinane oxidation (Scheme 3). An epimeric mixture of ho-
These targets possess the same short w-chain (lower part)
and share a common homoallylic unit on the a-chain, which
only differs by the number of carbon atoms and unsaturations
(Scheme 1). This led us envisage a convergent retrosynthetic
analysis, such that variations of a-chain would only be
a matter of late-stage modifications during the synthesis. Inter-
mediate A would be obtained from the previously described
pivotal lactol intermediate 4.[14]
Lactol 4, when treated with commercially available propyl
triphenyl phosphonium bromide and tBuOK in THF, afforded
alcohol 5 in good yield (Scheme 2). A tactic that was never
Scheme 3. a) Dess–Martin periodinane, RT; b) Ph3=CHCO2Me, THF, RT, 75%,
(over two steps); c) DIBAL-H, CH2Cl2, ꢀ788C; d) Dess–Martin periodinane, RT;
92%, (over two steps); e) BrMgCH2C2H5, Et2O, 08C, 80%; f) (S)-acetyl phenyl
acetic acid, EDCI, DMAP, CH2Cl2, 40% (11 a) and 48% (11 b); g) K2CO3, MeOH,
RT; h) TBSCl, imidazole, CH2Cl2, 79%, (over two steps); DIBAL-H = diisobutyl-
aluminium hydride; DMAP=4-dimethylaminopyridine; EDCI = N’-(3-dime-
thylaminopropyl)-N’-ethylcarbodiimide.
Scheme 2. a) BrꢀPh3P+CH2C2H5, tBuOK, THF, 08C, 94%; b) Dess–Martin peri-
odinane, CH2Cl2, RT; c) Me3SiCH2COSiMe3, LDA, ꢀ788C, 85% (over two
steps); d) BrCH2CCC2H4CO2Me, Zn dust, THF, 308C, 73%; e) TBAF, THF. LDA =
lithium diisopropylamide; TBAF=tetrabutylammonium fluoride.
mopropargyl alcohols 10 was easily obtained on treatment
with freshly prepared propargyl magnesium bromide in THF
(80%). Separation of the resulting epimers was accomplished
by the corresponding diastereomeric mandelic ester deriva-
tives 11 a and 11 b in 40 and 48% yields, respectively.[17] This
strategy not only allowed both epimers to be separated, which
used in IsoP synthesis is the regioselective propargylation or al-
lylation by using an acylsilane as the electrophile.[15] Com-
pound 5 was oxidized with Dess–Martin periodinane[16] and
the resulting aldehyde treated with [(trimethylsilyl)-acetyl]tri-
methylsilane and lithium diisopropylamine to give the E-con-
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are needed to access the full spectrum of IsoP/NeuroP isomers,
but also to establish the configuration of the stereocenter at
the allylic position. Saponification with K2CO3 in MeOH and
protection with TBSCl yielded the pivotal intermediates 13a
and 13b in 79 and 81% yields, respectively.
Starting from intermediate 13a, both IsoP 3 and NeuroPs
1 and 2 should be easily obtained by coupling with 2-(4-
bromo-butoxy)tetrahydropyran and the bromopropargyl part-
ner 15, respectively.
In the case of the 8-F3t-IsoP synthesis, we found that the
propargyl alcohol subunit of 13a could not be coupled with 2-
(4-bromo-butoxy)tetrahydropyran when using nBuLi in THF/
hexamethylphosphoramide (HMPA) as the reagent, whereas
a similar transformation was feasible in well reproducible yield
in a model study (Scheme 3). Indeed, the desired adduct 14a
could not be observed and the reaction mainly resulted in
OTBS elimination and/or OTBS deprotection. In contrast, intro-
duction of a skipped diyne unit following the Caruso condi-
tions[18] with the bromo propargyl partner 15 provided diyne
16a in 56% yield. The resulting diyne 16a was contaminated
with an approximately 5–10% of a mixture of allenic byprod-
ucts, and further purification was not successful at this stage
(Scheme 4).
Scheme 5. a) P2-Ni, EDA, EtOH, H2 or D2, RT; b) HCl (0.5m), MeOH/THF;
c) LiOH (0.5m), H2O, RT; d) semipreparative HPLC, 48% (1a) and 50% (2a);
P2-Ni=Ni(OAc)2·4H2O/NaBH4; EDA=ethylenediamine.
Scheme 6. Retrosynthetic analysis of 3 by using a RCAM/semi-reduction
strategy.
egy for the preparation of compound B with a lactone of at
least 11-ring atoms requires the use of compound C endowed
with a temporary tether.[23]
For this purpose, the synthesis of the acetylenic compound
19 was desired, but attempted homopropargylation of alde-
hyde 9 with the Grignard reagent of 1-bromo-but-2-yne gave
the allenic compound 20 as the main product (Scheme 7).
Scheme 4. Failure and success in accessing F4-NeuroP and F3-IsoP precursors
from 13a.
The use of the P2–Ni catalyst[19] for the simultaneous reduc-
tion of both alkyne units of 16a by using either hydrogen or
deuterium gas following our recent protocol[11f] gave com-
pounds 17a and 18a (Scheme 5). Deprotection of the hydroxyl
groups with HCl (0.5m) in MeOH/THF, followed by saponifica-
tion with LiOH (0.5m) gave 10-F4t-NeuroP 1a and [D4]-10-F4t-
NeuroP 2a. Final purification was performed by semi-prepara-
tive HPLC to obtain analytically pure compounds 1a and 2a
free of allenic and over-reduced byproducts in 48 and 50%
yields, respectively. The same procedure was applied for the
syntheses of the epimers 1b and 2b (not shown).
After having explored conventional routes to implement the
a-chain of 8-F3t-IsoP (see above), we turned our attention to
ring-closing metathesis reactions, in particular the powerful
ring-closing alkyne metathesis (RCAM)/semi-reductions strat-
egy.[20] RCAM has previously been used in the prostaglandin
series, for example for the synthesis of PGE2-lactone and hy-
bridalactone.[21,22] As seen in Scheme 6, a suitable RCAM strat-
Scheme 7. a) MgBrCH2CꢁCCH3, Et2O, 08C; b) ethylvinyl ether, PPTS, CH2Cl2,,
RT; c) LDA, MeI, DMPU, ꢀ788C, 71%; d) PPTS, propanol/CH2Cl2,, 71%.
PPTS=pyridinium p-toluenesulfonate.
Therefore, ethylether protection of 10a was necessary and ac-
complished under standard conditions in 77% yield, followed
by treatment with LDA and MeI in THF/1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) to access compound 21a in 71%
yield. Deprotection under mild acidic conditions afforded 19a
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Conclusion
Two novel metabolites of the free-radical peroxidation of DHA
and EPA were synthesized. Specifically, 10-F4t-NeuroP 1 and 8-
F3t-IsoP 3 together with their epimers and the novel tetra-deu-
terated derivative [D4]-10-F4t-NeuroP 2 have been obtained,
(the latter will serve as internal standard for the accurate quan-
tification of 10-F4t-NeuroP in vivo). While a classical Caruso-
type reaction allowed for the synthesis of F4-NeuroP 1, the
powerful RCAM/semi-reduction strategy gave access to F3-IsoP
derivatives for the first time. Further research is underway in
trying to explore the usefulness of these natural products as
potential biomarkers of neuronal oxidative stress.
Scheme 8. a) LDA, MeI, DMPU, ꢀ788C, 97%; b) 1,4-butan-diol, p-TsOH, hep-
tane, reflux, 91%; c) oxalyl chloride, DMSO, Et3N, CH2Cl2, ꢀ78!08C, 98%;
d) NaClO2, 2-methyl butene, KHPO4, 78%.
in good yield (71%). This compound was ready for coupling
with the appropriate appendage 22, which was prepared by
a four-step sequence (Scheme 8). Specifically, hexynoic acid
was treated with LDA followed by MeI in THF/1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) to access the
corresponding hept-5-ynoic acid in 97% yield. Esterification
with 1,4-butane diol and p-TsOH in refluxing heptane provided
ynoate 23 in 91% yield. Swern oxidation of 23 proceeded
smoothly, and the last oxidation step was performed with
NaClO2 by using the Pinnick protocol[24] to give the corre-
sponding acid 22 in 77% overall yield.
Experimental Section
Methyl 6-bromohex-4-ynoate (15)
2,4-Dihydropyran (12.35 mL, 243 mmol, 1.2 equiv) diluted in CH2Cl2
(20 mL) was added dropwise at room temperature to a solution of
the 4-pentynol (10 g, 119 mmol, 1 equiv) and p-toluene sulfonic
acid (565 mg, 2.9 mmol, 0.025 equiv) in CH2Cl2 (120 mL). The mix-
ture was stirred all the night and then a saturated solution of
NaHCO3 150 mL was added. The mixture was stirred for 15 min
and then the layers were separated. The aqueous layer was extract-
ed with 2ꢃ200 mL of Et2O. The combined organic layers were
washed with 100 mL of a saturated solution of NaHCO3 and 2ꢃ
100 mL of brine, dried over MgSO4, filtered and the solvents re-
moved under reduced pressure. The crude of the reaction was pu-
rified under silica gel chromatography (95:5 pentane/Et2O) and the
protected alcohol (18.9 g, 95%) was obtained. Rf =0.5 (8:2 cyclo-
hexane/AcOEt); 1H NMR (300 MHz, CDCl3): d=4.54 (lt, 3J(H,H)=
3.5 Hz, 1H); 3.84–3.73 (m, 2H); 3.48–3.38 (m, 2H); 2.24 (dt,
Coupling of precursors 19a and 22 in the presence of EDCI/
DMAP cleanly provided ester 24 ready for macrocyclization by
RCAM (Scheme 9). Treatment with 10 mol% of catalyst 25[25] in
3
3J(H,H)=4.2, 11.2 Hz, 2H); 1.88 (t, J(H,H)=2.7 Hz, 1H); 1.78 (quint,
3J(H,H)=5.1 Hz, 2H); 1.71–1.73 ppm (m, 6H); 13C NMR (75 MHz,
CDCl3): d=98.6 (CH(O-)2); 83.8 (Cꢁ); 68.3 (HCꢁ); 65.4 (CH2O); 62.0
(CH2O); 30.5 (CH2); 28.6 (CH2); 25.4 (CH2); 19.4 (CH2); 15.2 ppm
(CH2).
At room temperature, a commercial solution of methyl magnesium
bromide (3m in Et2O, 42 mL, 127 mmol, 2.0 equiv) was added drop-
wise in a solution of alkyne (10.7 g, 63.6 mmol, 1 equiv) in anhy-
drous THF (60 mL). The solution was refluxed for 1.5 h. The solu-
tion was cooled (08C) and p-formaldehyde (2.86 g, 95 mmol,
1.5 equiv) was added. The reaction was refluxed for 2 h and more
p-formaldehyde (2.4 g, 80 mmol, 1.5 equiv) was added. After reflux-
ing overnight, the solution was cooled at 08C, and Et2O (200 mL)
and a saturated solution of NaHCO3 (100 mL) were added drop-
wise. Celite (50 mL) was added and the mixture was filtered. The
solid was washed with Et2O (4ꢃ100 mL). The layers were separat-
ed. The aqueous one was extracted with 2ꢃ100 mL of Et2O. The
combined organic layers were washed with 2ꢃ100 mL of brine
and a saturated solution of NaHCO3 (50 mL), dried over MgSO4, fil-
tered and the solvents removed under reduced pressure. The
crude of the reaction was purified under silica gel chromatography
(8:2 to 1:1 pentane/Et2O) and the alcohol (9.65 g, 79%) was ob-
Scheme 9. a) EDCI, DMAP, CH2Cl2, 95% b) 25 (10 mol%), MS 5 ꢂ, toluene,
808C!RT; 69% c) P2-Ni, EDA, EtOH, H2, RT; d) HCl (0.5m), MeOH/THF; RT;
e) LiOH (0.5m), H2O, RT, 75% (over two steps).
the presence of MnCl2 and MS 5 ꢂ in toluene at 808C delivered
the desired 14-membered ring bislactone 26a. The stereoselec-
tive Z reduction of 26a was performed by P2–Ni in the pres-
ence of EDA with complete regio- and chemoselectivity. Fur-
ther treatment with HCl (0.5m) led to the clean deprotection
of the silyl ether groups. The final saponification to remove the
incremental tether was accomplished with LiOH (0.5m) and
provided 8-F3t-IsoP 3a in 76% yield (over two steps). The same
sequence was applied to the synthesis of the 3b, which is epi-
meric to 3a at the C8-position (not shown).
1
tained. Rf =0.5 (5:5 cyclohexane/AcOEt); H NMR (300 MHz, CDCl3):
3
3
d=4.55 (t, J(H,H)=3.4 Hz, 1H); 4.17 (dt, J(H,H)=2.1, 5.9 Hz, 2H);
3
3.82–3.73 (m, 2H); 3.48–3.39 (m, 2H); 2.46 (t, J(H,H)=5.8 Hz, 1H);
2.8 (tt, 3J(H,H)=5.8, 7.2 Hz, 2H); 1.74 (quint, 3J(H,H)=6.8 Hz, 2H);
1.67–1.45 ppm (m, 6H); 13C NMR (75 MHz, CDCl3): d=98.7 (CH(O-
)2); 85.4 (Cꢁ); 78.8 (Cꢁ); 65.8 (CH2O); 62.1 (CH2O); 51.0 (CH2O); 30.5
(CH2); 28.6 (CH2); 25.3 (CH2); 19.4 (CH2); 15.6 ppm (CH2).
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2
A solution of CBr4 (19.4 g, 58.5 mmol, 1.5 equiv) in CH2Br2 (35 mL)
was added to a solution of the propargyl alcohol (7.5 g, 39 mmol,
1 equiv), triphenylphosphine (17.2 g, 58.5 mmol, 1.5 equiv) and
triethylamine (0.54 mL, 3.9 mmol, 0.1 equiv) in CH2Br2 (35 mL) at
ꢀ108C. The mixture was stirred for 3 h at room temperature. The
mixture was then quenched with a 10% solution of Na2S2O3
(100 mL) and a saturated solution of NaHCO3 (100 mL). The layers
separated. The aqueous layer was then extracted with CH2Cl2 (3ꢃ
250 mL) and the combined organic layers were extracted with
Na2S2O3 (20 mL) and brine (20 mL), and finally dried over MgSO4,
filtered and the solvents removed in vacuo. The crude was diluted
in a mixture of pentane/Et2O 4:1 (250 mL) and filtered. After evapo-
ration, the crude of the reaction was purified under silica gel chro-
matography (100:0 to 80:20 pentane/Et2O) and protected alcohol
(4.2 g, 41%) was obtained. Rf =0.7 (5:5 cyclohexane/AcOEt);
2.10–1.86 (m, 5H); 1.50 (dt, J(H,H)=5.0, J(H,H)=13.7 Hz, 1H), 0.93
3
(t, J(H,H)=7.5 Hz, 3H); 0.88 (s, 9H); 0.86 (s, 9H); 0.84 (s, 9H); 0.07
(s, 3H); 0.03 (s, 3H); 0.01- ꢀ0.01 ppm (12H); 13C NMR (75 MHz,
CDCl3): d=173.0 (C quat); 1.33.0 (CH); 132.0 (CH); 129.1 (CH); 127.8
(CH); 78.3 (C quat); 77.7 (C quat); 76.0 (CHO-); 75.9 (CHO-); 75.6 (C
quat); 75.5 (C quat); 72.1 (CHO-); 52.1 (CH); 51.6 (OCH3); 50.0 (CH);
44.2 (CH2); 33.3 (CH2); 30.3 (CH2); 28.9 (CH2); 26.0 (CH2); 25.8 (CH3);
20.6 (CH2); 18.1 (C quat); 17.9 (C quat); 14.6 (CH3); 9.7 (CH2); ꢀ4.5
(CH3); ꢀ4.6 (CH3); ꢀ4.8 ppm (CH2).
(S,4Z,7Z,11E)-Methyl 12-{(1S,2R,3R,5S)-3,5-bis(tert-butyldime-
thylsilyloxy)-2-[(Z)-pent-2-enyl]cyclopentyl}-10-(tert-butyldi-
methylsilyloxy)dodeca-4,7,11-trienoate (17a)
NaBH4 in ethanol (0.5m, 139 mL, 0.07 mmol, 0.6 equiv) was added
to a suspension of Ni(OAc)2·4H2O (9.6 mg, 0.04 mmol, 0.33 equiv),
in ethanol with 0.01% BHT (3 mL) under a H2 atmosphere. The eth-
ylenediamine in solution in ethanol, (0.5m, 348 mL, 0.17 mmol,
1.5 equiv) was added after 10 min under the black suspension.
After a further 10 min, skipped diyne 16a (85 mg, 0.13 mmol,
1.0 equiv) in ethanol with 0.01% BHT (4 mL) was added. Before
and after each addition, three cycles of vacuum/H2 were realized.
The reaction was then stirred for 4 h under a H2 atmosphere (GC
control). The mixture was then quenched with 20 mL of a saturated
solution of NH4Cl and stirred for 30 min. The layers were extracted
with pentane/Et2O 1:1 (3ꢃ25 mL). The combined organic layers
were washed with water (10 mL), brine (2ꢃ10 mL) and dried over
MgSO4. The resulting mixture was then filtered and the solvents
were removed in vacuo. Compound 17a with allene, over-reduc-
tion byproducts and some solvents traces (98 mg) was obtained
and used directly. Rf =0.4 (9:1 cyclohexane/AcOEt).
3
1H NMR (300 MHz, CDCl3): d=4.56 (t, J(H,H)=2.8 Hz, 1H); 3.88 (t,
3J(H,H)=2.3 Hz, 2H); 3.82–3.75 (m, 2H); 3.49–3.41 (m, 2H); 2.36–
3
2.30 (m, 2H); 1.76 (quint, J(H,H)=6.5 Hz, 2H); 1.68–1.46 ppm (m,
6H); 13C NMR (75 MHz, CDCl3): d=98.7 (CH(Oꢀ)2); 87.4 (Cꢁ); 75.5
(Cꢁ); 65.7 (CH2O); 62.1 (CH2O); 30.6 (CH2); 28.5 (CH2); 25.4 (CH2);
19.4 (CH2); 15.8 (CH2); 15.5 ppm (CH2O).
A Jones’ solution (2.17m, 37 mL, 80 mmol, 5.0 equiv) was added
dropwise at 08C to a solution of protected alcohol (4.2 g, 16 mmol,
1.0 equiv) in acetone (320 mL). The solution was stirred 3 h at 08C
and 2 h at room temperature. Isopropanol (45 mL) was slowly
added. The mixture was filtered over Celite and rinsed with pen-
tane/Et2O 1:1 (3ꢃ500 mL). The organic layer was washed with 4ꢃ
250 mL of acidified brine, dried over MgSO4, filtered and the sol-
vents removed under reduced pressure. The crude was diluted in
anhydrous MeOH (65 mL) and BF3·Et2O (510 mL, 4 mmol,
0.25 equiv) was added. The solution was refluxed for 1 h and then
a saturated solution of NaHCO3 (250 mL) was added. The mixture
was extracted with 3ꢃ250 mL of pentane/Et2O 1:1. The organic
layers were washed with 3ꢃ100 mL of brine, dried over MgSO4, fil-
tered and the solvents removed. The crude of the reaction was pu-
rified under silica gel chromatography (95:5 pentane/Et2O) and 15
(2.65 g, 80%) was obtained. Rf =0.5 (8:2 cyclohexane/AcOEt); IR
10-F4t-NeuroP (1a)
At room temperature, a solution of HCl (0.5m in MeOH, 2.32 mL,
1.16 mmol, 10 equiv) was added to the crude of 17a (0.12 mmol,
1.0 equiv) in MeOH/THF (10:16 mL). The mixture was stirred for 2 h
and NaHCO3 solid was added. After 15 min, Celite was added and
the crude was filtered on Silica gel pad with AcOEt. The deprotect-
ed crude was directly used. The solution of crude (0.12 mmol) in
THF (5.8 mL) was stirred for 2 h with LiOH (0.5m in H2O, 5.8 mL,
2.4 mmol, 25 equiv). The base was neutralized with a solution of
NaHSO4 (1m in H2O, 2.4 mL, 2.4 mmol, 25 equiv) and NaCl solid
was added. The mixture was stirred for a further 2 h. The crude
was extracted with AcOEt (3ꢃ20 mL). The organic layers were
washed with 2ꢃ10 mL of brine, dried over MgSO4, filtered and the
solvents removed. The crude was purified by flash chromatography
(98:2 AcOEt/HCO2H). To eliminate over-reduction products and
allene, the mixture was purified by semi-preparative HPLC (250ꢃ
8 mm C18 column, 2.5 mLminꢀ1 (ACN/MeOH 95:5 with 0.1%
HCO2H)/H2O with 0.1% HCO2H 35:65, l=205 nm): a total of
21.4 mg, 48% of 10-F4t-NeuroP (1a) was collected. tr =27.5 min
(250ꢃ4 mm C18 Nucleodur, 0.4 mLminꢀ1, (ACN/MeOH 95:5 with
0.1% HCO2H)/H2O with 0.1% HCO2H 35:65, l=205 nm); [a]2D0 =ꢀ6
1
(neat): n˜ =1733 cmꢀ1 (C=O); H NMR (300 MHz, CDCl3): d=3.85 (t,
3J(H,H)=2.1 Hz, 2H); 3.65 (s, 3H); 2.56–2.49 ppm (m, 4H); 13C NMR
(75 MHz, CDCl3): d=172.0 (C quat); 85.7 (C quat); 76.0 (C quat);
51.7 (CH3); 32.9 (CH2); 15.0 (CH2); 14.8 ppm (CH2); HRMS (ESI+): m/
z: calcd for C7H10O2Br: 204.9864 [M+H]+; found: 204.9866.
(S,E)-Methyl 12-{(1S,2R,3R,5S)-3,5-bis(tert-butyldimethylsily-
loxy)-2-[(Z)-pent-2-enyl]cyclopentyl}-10-(tert-butyldimethylsi-
lyloxy)dodeca-11-en-4,7-diynoate (16a)
CsCO3 (120 mg, 0.28 mmol, 3 equiv), NaI (55 mg, 0.38 mmol,
3 equiv) and CuI (58 mg, 0.31 mmol, 2.5 equiv) were added succes-
sively at room temperature to
a solution of 13a (75 mg,
0.12 mmol, 1.0 equiv) and 15 (44 mg, 0.21 mmol, 1.75 equiv) in
DMF (4 mL). The reaction was stirred for 2 days. A solution of
NH4Cl 10% (25 mL) and NH4OH (0.5 mL) were then added. The mix-
ture was extracted with 3ꢃ25 mL of Et2O. The organic layers were
washed with 2ꢃ25 mL of brine, dried over MgSO4, filtered and the
solvents removed. The crude of the reaction was purified under
silica gel (30 nm, spherical) with pentane/Et2O (98:3 in presence of
butylated hydroxytoluene (BHT)) and 13a was obtained (46 mg,
56%) in the presence of allene. Rf =0.4 (8:2 cyclohexane/AcOEt);
1H NMR (300 MHz, CDCl3): d=5.55–5.45 (m, 2H); 5.36–5.27 (m, 2H);
4.18 (q, 3J(H,H)=5.9 Hz, 1H); 3.88 (dt, 3J(H,H)=4.3, 6.9 Hz, 1H);
3.79 (q, 3J(H,H)=6.9 Hz, 1H); 3.67 (s, 3H); 3.06 (t, 3J(H,H)=2 Hz,
2H); 2.64–2.53 (m, 1H); 2.52–2.42 (m, 4H); 2.38–2.21 (m, 3H);
1
(c=1 in MeOH); H NMR (300 MHz, MeOD): d=5.60–5.57 (m, 2H);
5.47–5.41 (m, 6H); 4.1 (q, J(H,H)=5 Hz, 1H); 4.0 (dt, J(H,H)=2.3,
7.0 Hz, 1H); 3.91–3.87 (m, 1H); 2.87 (t, J(H,H)=4.5 Hz, 2H); 2.76–
2.69 (m, 1H); 2.50 (dt, J(H,H)=7.1, 2J(H,H)=14.2 Hz, 1H); 2.44–2.29
(m, 6H); 2.16–2.04 (m, 5H); 1.56 (dt, J(H,H)=4.9, J(H,H)=14.2 Hz,
1H); 0.99 ppm (t, 3J(H,H)=7.4 Hz, 3H); 13C NMR (75 MHz, MeOD):
d=177.2 (C quat.); 133.0 (CH); 130.3 (CH); 127.7 (CH); 127.2 (CH);
127.1 (CH); 126.3 (CH); 125.8 (CH); 123.9 (CH); 73.2 (2ꢃHCOH);
70.2 (HCOH); 50.5 (CH); 48.5(CH); 40.7 (CH2); 33.4 (CH2); 24.2 (2ꢃ
3
3
3
3
3
2
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CH2); 23.8 (CH2); 21.1 (CH2); 18.7 (CH2); 11.7 ppm (CH3); HRMS (ESI+
BHT (10 mL) was added. Before and after each addition, three
cycles vacuum/H2 were realized. The reaction was then stirred for
48 h under a H2 atmosphere (GC control). The mixture was then
quenched with 20 mL of a saturated solution of NH4Cl and stirred
for 30 min. The layers were extracted with Et2O (3ꢃ20 mL). The
combined organic layers were washed with brine (3ꢃ10 mL) and
dried over MgSO4, filtered and the solvents were removed. The
crude of the reaction was purified by flash chromatography (97:3
pentane/Et2O) to obtain the ethylenic compound (88.3 mg, 70%).
Rf =0.29 (9:1 cyclohexane/AcOEt); [a]2D0 =ꢀ50.5 (c=10 in CHCl3):
n˜ =1737 cmꢀ1 (C=O); 1H NMR (400 MHz, CDCl3): d=5.58–5.56 (m,
): m/z: calcd for C22H34O5Na: 401.2304 [M+Na]+; found: 401.2308.
(S,E)-10-{(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyl)-2-[(Z)-
pent-2-enyl]cyclopentyl}-8-(4-hydroxybutanoyloxy)dec-9-en-
5-ynoate (26a)
MnCl2 was dried under vacuum at 1508C overnight and 5 ꢂ molec-
ular sieves powder was dried under vacuum at 4008C for 30 min
24a was dried by azeotropic evaporation with toluene. Catalyst 25
(50 mg, 0.04 mmol, 15% mol), MnCl2 (10.3 mg, 0.08 mmol, 30%
mol) and the molecular sieves powder (5 ꢂ, 1 g) in toluene (5 mL)
were heated at 808C over 30 min. 24a (191 mg, 0.27 mmol,
1 equiv) in toluene (10 mL) was added and the resulting reaction
mixture heated for 6 h at 808C and stirred overnight at room tem-
perature. For workup, the molecular sieves were filtered off
through a short pad of silica, the filtrate was evaporated and the
residue purified by flash chromatography (97:3 to 90:10, pentane/
Et2O). Compound 26a was obtained as a colourless syrup (126 mg,
69% with traces of silanol impurities). Rf =0.21 (9:1 cyclohexane/
AcOEt); 1H NMR (400 MHz, CDCl3): d=5.64 (dd, 3J(H,H)=9.5,
14.8 Hz, 1H); 5.49–5.28 (m, 4H); 4.19–4.07 (m, 2H); 3.91–3.87 (m,
1H); 3.83–3.78 (m, 1H); 2.68–2.57 (m, 2H); 2.47–2.24 (m, 9H);
2.06–1.81 (m, 7H); 1.74–1.65 (m, 1H); 1.53 (dt, 3J(H,H)=5.5,
2J(H,H)=13.6 Hz, 1H); 0.96 (t, 3J(H,H)=7.5 Hz, 3H); 0.88 (s, 9H);
0.86 (s, 9H); 0.03 (s, 6H); 0.01 (s, 3H); 0.00 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=173.3 (C=O); 172.2 (C=O); 134.3 (CH); 132.2
(CH); 129.2 (CH); 127.7 (CH); 79.8 (Cꢁ); 78.0 (Cꢁ); 75.8 (HCOꢀ); 75.5
(HCOꢀ); 73.3 (HCOꢀ); 63.9 (H2COꢀ); 52.2 (CH); 50.6 (CH); 44.2
(CH2); 31.9 (CH2); 31.6 (CH2); 26.0 (CH2); 25.8 (CH3); 25.1 (CH2); 23.3
(CH2); 22.1 (CH2); 20.6 (CH2); 18.0 (CH2); 17.9 (C quat); 17.6 (C
quat); 14.2 (CH3); ꢀ4.4 (CH3); ꢀ4.5 (CH3); ꢀ4.6 (CH3); ꢀ4.7 ppm
(CH3); HRMS (ESI+): m/z: calcd for C36H63O6Si2: 647.4163 [M+H]+;
found: 647.4154.
3
2
2H); 5.45–5.27 (m, 5H); 4.20 (dt, J(H,H)=4.4; J(H,H)=11 Hz, 1H);
3
2
4.03 (dt, J(H,H)=3.6; J(H,H)=11 Hz; 1H); 3.93–3.89 (m, 1H); 3.81
3
3
(q, J(H,H)=5.6 Hz; 1H); 2.69–2.65 (m, 1H); 2.54 (ddd, J(H,H)=4.4,
11.3, 15.6 Hz, 1H); 2.48–2.25 (m, 6H); 2.12–1.88 (m, 9H); 1.79
(quint., 3J(H,H)=5.6 Hz, 1H); 1.54 (dt, 3J(H,H)=5.5, 2J(H,H)=
3
13.7 Hz, 1H); 0.96 (t, J(H,H)=7.6 Hz, 3H); 0.88 (s, 9H); 0.86 (s, 9H);
0.03 (s, 6H); 0.02 (s, 3H); 0.01 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=173.7 (C=O); 172.0 (C=O); 132.8 (CH); 132.2 (CH); 131.8
(CH); 129.6 (CH); 127.7 (CH); 124.8 (CH); 75.9 (HCOꢀ); 75.5 (HCOꢀ);
73.7 (HCOꢀ); 62.1 (H2COꢀ); 52.4 (CH); 50.5 (CH); 44.2 (CH2); 33.7
(CH2); 32.8 (CH2); 30.3 (CH2); 26.4 (CH2); 26.1 (CH2); 25.8 (CH3); 24.9
(CH2); 23.3 (CH2); 20.6 (CH2); 18.0 (C quat); 17.9 (C quat); 14.2
(CH3); ꢀ4.4 (CH3); ꢀ4.5 (CH3); ꢀ4.6 (CH3); ꢀ4.7 ppm (CH3); HRMS
(ESI+): m/z: calcd for C36H65O6Si2: 649.4320 [M+H]+; found:
649.4333.
At room temperature, a HCl solution (0.5m in MeOH, 2.46 mL,
1.23 mmol, 10 equiv) was added to a solution of protected com-
pound (83 mg, 0.12 mmol, 1.0 equiv) in THF/MeOH (17:9 mL). The
reaction was stirred for 2 h and NaHCO3 powder was added. After
5 min of agitation, Celite was added and the solvent was evaporat-
ed. The crude of the reaction was purified by flash chromatogra-
phy (95:5 to 90:10 pentane/Et2O) to give free hydroxyl compound
(44 mg, 84%). Rf =0.3 (AcOEt); [a]2D0 =ꢀ51.9 (c=10 in CHCl3); IR
1
n˜ =3389 (OH); 1732 cmꢀ1 (C=O); H NMR (400 MHz, CDCl3): d=5.61
(dd, 3J(H,H)=6.4, 2J(H,H)=16 Hz, 1H); 5.53 (dd, 3J(H,H)=8.8,
2J(H,H)=16 Hz, 1H); 5.45–5.31 (m, 5H); 4.19 (dt, 3J(H,H)=3.6;
2J(H,H)=11.2 Hz, 1H); 4.07–3.95 (m, 3H); 2.81–2.76 (m, 1H); 2.54
(R,E)-10-{(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyl)-2-[(Z)-
pent-2-enyl]cyclopentyl}-8-(4-hydroxybutanoyloxy)dec-9-en-
5-ynoate (26b)
3
(ddd, J(H,H)=4.5, 11.1, 15.5 Hz, 1H); 2.46–2.37 (m, 4H); 3.31–2.24
Prepared in an analogous procedure to 26a from 24b (174 mg).
Product 26b was obtained as a colourless syrup (110 mg; 66%).
Rf =0.21 (9/1: cyclohexane/AcOEt); 1H NMR (400 MHz, CDCl3): d=
5.61 (dd, 3J(H,H)=9.6, 14.5 Hz, 1H); 5.47–5.25 (m, 4H); 4.19–4.06
(m, 2H); 3.92–3.87 (m, 1H); 3.80–3.76 (m, 1H); 2.62–2.55 (m, 2H);
2.44–2.18 (m, 9H); 2.05–1.80 (m, 7H); 1.74–1.65 (m, 1H); 1.52 (dt,
3J(H,H)=5.5, 2J(H,H)=13.6 Hz, 1H); 0.95 (t, 3J(H,H)=7.5 Hz, 3H);
0.87 (s, 9H); 0.85 (s, 9H); 0.02 (s, 6H); 0.00 (s, 3H); ꢀ0.01 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=173.3 (C=O); 172.2 (C=O); 134.0
(CH); 132.3 (CH); 129.3 (CH); 127.6 (CH); 79.8 (Cꢁ); 78.0 (Cꢁ); 75.7
(HCOꢀ); 75.5 (HCOꢀ); 73.2 (HCOꢀ); 63.8 (H2COꢀ); 52.3 (CH); 50.5
(CH); 44.2 (CH2); 32.0 (CH2); 31.7 (CH2); 26.1 (CH2); 25.8 (CH3); 25.2
(CH2); 23.3 (CH2); 22.2 (CH2); 20.7 (CH2); 18.0 (CH2); 17.9 (2ꢃC
quat); 14.2 (CH3); ꢀ4.4 (CH3); ꢀ4.6 (2ꢃCH3); ꢀ4.7 ppm (CH3);
HRMS (ESI+): calcd for C36H63O6Si2: 647.4163 [M+H]+; found:
647.4146.
(m, 2H); 2.21–2.16 (m, 1H); 2.12–1.90 (m, 8H); 1.78 (quint,
3J(H,H)=6.7 Hz, 2H); 1.66 (dt, 3J(H,H)=3.6, 2J(H,H)=14.4 Hz, 1H);
0.96 ppm (t, 3J(H,H)=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
173.7 (C=O); 172.2 (C=O); 133.1 (CH); 132.0 (CH); 131.2 (CH); 130.5
(CH); 127.2 (CH); 124.6 (CH); 76.4 (HCOH); 76.2 (HCOH); 73.6 (HCO-
); 62.2 (H2CO-); 53.6 (CH); 50.9 (CH); 42.3 (CH2); 33.6 (CH2); 32.8
(CH2); 30.4 (CH2); 26.9 (CH2); 26.4 (CH2); 24.7 (CH3); 23.4 (CH2); 20.7
(CH2); 14.2 ppm (CH3); HRMS (ESI+): m/z: calcd for C24H37O6:
421.2590 [M+H]+; found: 421.2588.
At room temperature, a solution of LiOH (0.5m, 5 mL, 2.5 mmol,
25 equiv) was added to a solution of lactone (44 mg, 0.1 mmol,
1.0 equiv) in THF (5 mL). The reaction was stirred 4 h and was acidi-
fied with a solution of NaHSO4 (1m) until pH 2 was reached. The
mixture was extracted with 3ꢃ20 mL of AcOEt. The combined or-
ganic layers were washed with brine (2ꢃ10 mL) and dried over
MgSO4, filtered and the solvents were removed. The crude of the
reaction was purified by flash chromatography (100:0 to 98:2
AcOEt/HCO2H) to obtain 3a (34.8 mg, 94%). Rf =0.27 (AcOEt/
HCO2H 95:5); [a]2D0 =ꢀ8.0 (c=5 in MeOH); 1H NMR (300 MHz,
MeOD): d=5.59–5.57 (m, 2H); 5.51–5.45 (m, 2H); 5.43–5.40 (m,
8-F3t-IsoP (3a)
NaBH4 in ethanol (0.5m, 339 mL, 0.17 mmol, 0.9 equiv) was added
under a H2 atmosphere to a suspension of Ni(OAc)2·4H2O (23.5 mg,
0.09 mmol, 0.5 equiv) in ethanol with 0.01% BHT (5 mL). After
10 min, the ethylenediamine in solution in ethanol, (0.5m, 1.7 mL,
0.85 mmol, 4.5 equiv) was added under the black suspension. After
10 min, 26a (126 mg, 0.19 mmol, 1.0 equiv) in ethanol with 0.01%
3
2H); 4.09 (q, J(H,H)=6.4 Hz, 1H); 4.03–3.97 (m, 1H); 3.91–3.87 (m,
1H); 2.74–2.69 (m, 1H); 2.50 (dt, 3J(H,H)=7.4, 2J(H,H)=14.2 Hz,
1H); 2.35–2.29 (m, 4H); 2.17–2.06 (m, 7H); 1.69 (quint., 3J(H,H)=
3
2
7.3 Hz, 1H); 1.56 (dt, J(H,H)=4.9, J(H,H)=14.2 Hz, 1H); 0.99 ppm
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3
(t, J(H,H)=7.5 Hz, 3H); 13C NMR (75 MHz, MeOD): d=175.0 (C=O);
124, 12424–12425; c) S. J. Kim, J. A. Lawson, D. Pratico, G. A. FitzGerald,
J. Rokach, Tetrahedron Lett. 2002, 43, 2801–2805; d) G. Zanoni, E. M.
Brunoldi, A. Porta, G. Vidari, J. Org. Chem. 2007, 72, 9698–9703; e) D. F.
Taber, P. G. Reddy, K. O. Arneson, J. Org. Chem. 2008, 73, 3467–3474;
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Galano, Chem. Eur. J. 2010, 16, 13976–13980; g) for IsoPs nomenclature;
D. F. Taber, J. D. Morrow, L. Jackson Roberts II, Prostaglandins 1997, 53,
63–67; h) for NeuroPs nomenclature; D. F. Taber, L. J. Roberts, Prosta-
glandins Other Lipid Mediators 2005, 78, 14–18.
133.0 (CH); 130.3 (CH); 128.7 (CH); 127.2 (CH); 125.8 (CH); 124.5
(CH); 73.2 (2 x HCOH); 70.3 (HCOH); 50.5 (CH); 48.5 (CH); 40.6
(CH2); 33.4 (CH2); 31.7 (CH2); 24.7 (CH3); 24.2 (CH2); 23.1 (CH2); 18.7
(CH2); 11.7 ppm (CH3); HRMS (ESI+): m/z: calcd for C20H32O5:
375.2147 [M+Na]+; found: 375.2150.
Acknowledgements
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We gratefully acknowledge the University of Montpellier I
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Received: January 29, 2014
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Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
7
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
&
Organic Synthesis
A. Guy, C. Oger, J. Heppekausen,
C. Signorini, C. De Felice, A. Fꢁrstner,
T. Durand, J.-M. Galano*
&& – &&
Three for the price of one! Two strat-
egies, Caruso coupling or RCAM, ena-
bled the synthesis of 8-F3t-IsoP and 10-
F4t-NeuroP and its deuterated derivative
from acetylenic intermediate A (see
scheme). Such compounds represent
potential biomarkers of neuronal oxida-
tive stress.
Oxygenated Metabolites of n-3
Polyunsaturated Fatty Acids as
Potential Oxidative Stress Biomarkers:
Total Synthesis of 8-F3t-IsoP, 10-F4t-
NeuroP and [D4]-10-F4t-NeuroP
&
&
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
8
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!