The handy use of brown's p2-ni catalyst for a skipped diyne deuteration: Application to the synthesis of a [D4]-labeled F4t- neuroprostane

Article abstract of DOI:10.1002/chem.201002304

Brown's P2-Ni does the job: An efficient synthesis of tetradeuterated neuroprostane (see structure) has been accomplished by using an ene-diyne stereoselective deuteration strategy.

Full text of DOI:10.1002/chem.201002304

DOI: 10.1002/chem.201002304
The Handy Use of Brownꢀs P2-Ni Catalyst for a Skipped Diyne Deuteration:
Application to the Synthesis of a [D4]-Labeled F4t-Neuroprostane
Camille Oger, Valꢁrie Bultel-Poncꢁ, Alexandre Guy, Laurence Balas, Jean-Claude Rossi,
Thierry Durand, and Jean-Marie Galano*[a]
In memory of Marc Julia
Since the discovery of isoprostanes (IsoPs), formed in
vivo by free radical peroxidation of arachidonic acid (AA,
C20:4 w6), in 1990, these compounds have been extensively
studied.[1] These metabolites have been shown to possess
several biological activities. They are potent vasoconstrictors
and produce vascular smooth muscle contraction as well as
platelet aggregation.[2] Furthermore, they are currently used
as an index of oxidative stress in numerous clinical trials.
Indeed, the [D4]-15-F2t-IsoP (also called [D4]-8-epi-PGF2a) is
used as a standard to quantify IsoP levels in blood, plasma,
and urine, as well as in various pathologies.[3] In 1998, new
lipid oxidation metabolites derived from docosahexaenoic
acid (DHA, C22:6 w3), named neuroprostanes (NeuroPs)
were discovered.[4] Since DHA is essentially located in the
brain,[5] NeuroPs have been speculated to be potential mark-
ers of oxidative stress processes in various neurodegenera-
tive disorders, including Alzheimerꢀs disease (AD). Indeed,
NeuroP levels are about two times higher in the temporal
lobe tissue of AD patients than in healthy control subjects.[6]
Consequently, the synthesis of deuterated NeuroP deriva-
tives is required. To the best of our knowledge, the synthesis
of such labeled compounds has rarely been studied. In fact,
only one example of a deuterated NeuroP has been synthe-
sized ([D4]-7-F4t-NeuroP).[7] Furthermore, Musiek et al.[6e]
reported the used of [18O2]-17-F4c-NeuroP as an internal
standard, although recent studies showed its limited use in
biological fluids (e.g., cerebrospinal fluid).[6h]
Taking into account that the fourth series of F4-NeuroPs
was reported as the most abundant series,[6e,8] an efficient
and convergent access for the syntheses of the 4-F4t-NeuroPs
and labeled analogues was needed (Scheme 1). In 2000, our
Scheme 1. Structures of compounds 4
ACHTUNGTRENNUNG
[D4]-4 ACHTNUGTRENNUNG
G
laboratory was the first to report the synthesis of 4-F4t-
NeuroP.[9] However, the strategy developed could not readi-
ly be used for the preparation of deuterated and tritiated
derivatives. Herein, as an extension of this work and in con-
nection with our ongoing program directed towards the
total synthesis of IsoP and NeuroP derivatives, a new and
flexible synthetic route to access both 1 and 2 is described.
From a retrosynthetic point of view, it is anticipated that
both 1 and 2 could be obtained from the regio- and stereo-
selective cis hydrogenation or deuteration reaction of the
key skipped diyne 4 (Scheme 2), which could be easily pre-
[a] C. Oger, Dr. V. Bultel-Poncꢁ, Dr. A. Guy, Dr. L. Balas,
Prof. J.-C. Rossi, Dr. T. Durand, Dr. J.-M. Galano
Institut des Biomolꢁcules Max Mousseron
UMR CNRS 5247, UM1 & UM2
15, avenue Charles Flahault, Facultꢁ de Pharmacie
Bꢂtiment D, 34093 Montpellier cedex 05 (France)
Fax : (+33)467548036
E-mail: jgalano@univ-montp1.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002304.
Scheme 2. Retrosynthetic analysis of 1 and 2.
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Chem. Eur. J. 2010, 16, 13976 – 13980

COMMUNICATION
pared from monoacetate
6
through successive olefination
reactions using b-ketophospho-
nate 5 and phosphonium salt 7.
Monoacetate derivative 6 could
arise from keto–epoxide inter-
mediate 8.[10]
The synthesis of the required
monoacetate 6 began from the
enantiomerically enriched bicy-
clic keto–epoxide 8 (>99% ee),
which was readily prepared in
five steps from 1,3-cycloocta-
diene
(1,3-COD)
Scheme 4. Synthesis of the methyl 5-(dimethoxyphosphory)-4-oxopentanoate 5 and the nona-3,6-diynyltriphe-
nylphosphonium iodide salt 7.
(Scheme 3).[10,11] Stereoselective
reduction of the ketone func-
the condensation reaction between succinic anhydride and
dimethyl methylphosphonate lithium carbanion, followed by
in situ esterification of the crude reaction mixture.[13] The
synthesis of phosphonium salt 7 involves a four-step se-
quence. The bromination reaction of pent-2-yn-1-ol gave
compound 11, which was subjected to a copper-catalyzed
cross-coupling reaction with but-3-yn-1-ol[14] under slightly
modified conditions.[15] The resulting alcohol 12 was then
converted to iodide 13 followed by a nucleophilic displace-
ment with PPh3 using Dawson and Vasser conditions[16] to
give the phosphonium salt 7 in 32% overall yield.
Having established a reliable and scalable access to the
three key intermediates 5, 6, and 7, we performed a Dess–
Martin oxidation[17] of alcohol 6, followed by the Horner–
Scheme 3. Synthesis of monoacetate 6.
tionality of compound 8 with LiAlH4 at low temperature led
to the formation of an epoxy alcohol intermediate that un-
derwent regioselective epoxide ring opening upon warming
the reaction mixture from À788C to RT. Under these condi-
tions, the cis-1,3-diol 9 was isolated in 75% yield with an ex-
cellent diastereomeric ratio (d.r.) (95:5 cis/trans). After tert-
butyldimethylsilyl (TBS) ether protection of the resulting
cis-1,3-diol, ozonolysis, and reduction, the pseudo-symmetri-
cal 1,5-diol 10 was acetylated
Wadsworth–Emmons (HWE)[18] reaction with 5, to intro-
duce the “upper” side chain (Scheme 5). Although some ep-
imerization occurs, diastereometrically pure enone 14 could
be isolated in good yield after flash column chromatography
(82%). It should be noted that no epimerization occurred
when Ba(OH)2 was used as a base, albeit enone 14 was ob-
tained with a significant decreased yield (60%). Subsequent
reduction of the enone 14 under Luche conditions[19] led to
by using the lipase B from Can-
dida antarctica (CALB) and
vinyl acetate, providing mono-
acetate 6 in excellent yield and
selectivity.[12] It should be noted
that this procedure is routinely
run on a multigram scale.
Then we focused on the syn-
thesis of the two lateral side-
chain intermediates, that is, the
nona-3,6-diynyltriphenylphos-
phonium iodide salt 7 and the
methyl
5-(dimethoxyphos-
phoryl)-4-oxopentanoate
5
(Scheme 4). The b-ketophosph-
onate 5 was easily obtained in a
Scheme 5. Synthesis of the skipped diyne precursor 4. DMAP=4-dimethylaminopyridine, DMP=Dess–Martin
one-pot, two-step procedure by periodinane, Im=imidazole.
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J.-M. Galano et al.
an equimolar epimeric mixture of the allylic alcohol, which
was then protected as a TBS ether (15). We next focused
our efforts on the installation of the “lower” side chain.
Thus, the skipped diyne 4 was readily obtained from com-
pound 15 in 45% overall yield through a three-step se-
quence involving deprotection of the acetate group, Dess–
Martin oxidation, and then Wittig reaction[20] between the
resulting aldehyde and the phosphonium salt 7.[21]
The next challenging issue was the regio- and stereoselec-
tive cis reduction of the alkyne functionalities of 4 to give
the desired tetraene 16b with E,Z,Z,Z-configured double
bonds. Although several approaches for such a transforma-
tion have already been described in the literature,[22] this re-
action proved to be more difficult than expected, and thus
extensive optimization was necessary to find appropriate
conditions. Based on a literature survey, Lindlarꢀs palladium
catalyst[23] (5% Pd/CaCO3 poisoned with lead) was revealed
to be a good candidate for the stereoselective semihydroge-
nation of skipped diynes as indicated in many successful
substrates.[24] The results of these experiments, summarized
in Table 1, clearly showed that the regio- and stereochemical
outcome of the reaction strongly depends on the solvent
and catalyst loading. No conversion was observed when
using 13% of Lindlarꢀs catalyst, irrespective of the solvents
employed (Table 1, entries 1–3).
duced product 16a[25] (Table 1, entries 4 and 5). Encouraging
results were obtained when the reaction was carried out in
cyclohexane in the presence 134% of catalyst, providing the
required triene product 16b in 80% yield, although it was
contaminated with 10% of both starting material 4 and the
partially reduced compound 16a (Table 1, entry 6). More-
over, increasing the reaction time from 7 to 45 h gave full
conversion, but led to the over-reduced product 16c
(Table 1, entry 7).
Since all attempts to isolate the required (Z,Z,Z)-triene
16b were unsuccessful, the appealing titanium(II)-based
methodology developed by Sato et al.[26] seemed promising,
in regard to its successful use by Kitching and Hungerford[27]
in the synthesis of deuterium-labeled linolenic acids. The
main feature of this convenient one-pot procedure is that
the alkoxytitanium–acetylene complex intermediate generat-
ed in situ from TiACHTNUGTRNEUNG(OiPr)4 (5.3 equiv) and iPrMgCl
(13.8 equiv) in diethyl ether at À788C could provide direct
access to both the reduced derivative 16b and the deuterat-
ed compound 17b by quenching with either H2O or D2O, re-
spectively (Scheme 6). Unfortunately, in our case, treatment
of compound 4 under the above reaction conditions resulted
in the formation of an inseparable mixture of unidentified
compounds.
Increasing the catalyst loading
from 13% to 33 and 77% (and
changing the solvent mixture)
led to 52 and 40% conversion,
respectively, affording essential-
ly the undesired, partially re-
Scheme 6. Titanium-based reduction of the skipped diyne 4.
Table 1. Lindlarꢀs catalyst reduction experiments with skipped diyne 4.[a,25]
A third approach was based
on the use of the P2-Ni catalyst,
pioneered by Brown and Ahuja
in the 1970s.[28] This catalytic
system is prepared by treating a
vigorously stirred solution of
nickel acetate tetrahydrate in
95% ethanol with a solution of
sodium borohydride in ethanol
in a hydrogen atmosphere. This
catalyst has previously been
used for the synthesis of
NeuroP derivatives.[29] In addi-
tion, this protocol has also been
employed for the deuteration of
skipped diyne intermediates for
the synthesis of [D8]-arachidon-
ic acid,[30a] and an intermediate
of leukotriene B4.[30b] To our de-
light, a clean conversion of the
skipped diyne 4 into the corre-
sponding (Z,Z,Z)-triene 16b
was obtained in 83% yield after
flash column chromatography,
Entry
Lindlarꢀs catalyst [wt%]
Solvents
t [h]
Ratio[b] 4/16a/16b/16c
1
2
3
4
5
6
7
13
13
13
33
77
cyclohexane
2
2
2
18
3
7
100:0:0:0
100:0:0:0
100:0:0:0
48:47:5:0
60:40:0:0
10:10:80:0
0:10:45:45
EtOAc/EtOH (1:1)
THF/Et3N (1:0.03)
EtOAc/EtOH/pyridine (13:6:1)
EtOAc/hexane/hexene (1:1:0.3)
cyclohexane
134
134
cyclohexane
45
[a] Reaction conditions: hydrogen atmosphere, substrate 4 (30 mg), Lindlarꢀs catalyst in solvent(s) (3 mL) at
208C. [b] Ratios were determined by GC/MS (EI) analysis.
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Brownꢀs Catalyst for Synthesis of Neuroprostane
COMMUNICATION
when the reaction was performed at 168C for 6 h. NMR
spectroscopy analysis as well as GC/MS (EI) analysis re-
vealed that the resulting sample was 98% pure with very
small amounts (2%) of the inseparable unwanted over-re-
duced product 16c (Scheme 7).
tive cis hydrogenation or deuteration of the advanced skip-
ped diyne intermediate 4 by Brownꢀs P2-Ni catalyst. This
strategy also permits us to envisage the synthesis of the tet-
ratritiated analogue 3. Finally, we hope that compound 2
will, in the near future, be used as a reliable internal stan-
dard for NeuroP quantification
in biological fluids.[32]
Experimental Section
P2-Ni deuteration procedure: com-
pound 17b: A solution of NaBH4 in
ethanol (1m, 30 mL, 0.030 mmol,
0.77 equiv) was added to a suspension
Scheme 7. P2-Ni-catalyzed regio- and stereoselective cis hydrogenation.
of
Ni
G
(3.0 mg,
0.012 mmol, 0.32 equiv) in ethanol (1.0 mL) in a D2 atmosphere. After
30 min ethylenediamine in ethanol (1m, 140 mL, 0.140 mmol, 3.70 equiv)
was added to the black suspension. After 30 min the skipped diyne 4
(28 mg, 0.038 mmol, 1.0 equiv) in ethanol (0.6 mL) was also added.
Before and after each addition, three cycles of vacuum/D2 were realized.
The reaction was then stirred for 6 h under D2. The mixture was then fil-
tered through a Celite pad, and rinsed
With this protocol in hand, and switching the hydrogen
gas for deuterium gas, the (Z,Z,Z)-compound 17b was iso-
lated in 75% yield after purification by flash chromatogra-
phy with 98% purity and only 2% of the unwanted com-
pound 17c (Scheme 8). Analysis by GC/MS of the reaction
with Et2O. The solvents were removed
under reduced pressure and the crude
mixture was purified by flash chroma-
tography (cyclohexane/Et2O 95:5).
The tetraene 17b was obtained as a
yellow oil (21 mg, 75%). Rf =0.86 (cy-
clohexane/Et2O
1:1);
1H NMR
(300 MHz, CDCl3): d=5.20–5.50 (m,
4H), 4.05–4.20 (m, 3H), 3.70–4.00 (m,
2H), 3.75 (m, 1H), 3.65 (s, 3H), 3.10–
3.65 (m, 3H), 3.50–3.70 (m, 1H), 2.15–
2.45 (m, 3H), 1.95–2.10 (m, 4H), 1.70–
2.00 (m, 3H), 1.40–1.60 (m, 2H), 0.97
(t, 3J
ACTHNUTRGNE(NUG H,H)=7.5 Hz, 3H), 0.70–0.90
(m, 27H), À0.15–0.10 ppm (m, 18H);
13C NMR (75 MHz, CDCl3): d=174.2
Scheme 8. P2-Ni-catalyzed regio- and stereoselective cis deuteration.[25]
(s, Cquat), 134.9 (s, CH), 134.8 (s,
CH), 129.1 (s, CH), 128.8 (s, CH),
128.7 (s, CH), 128.5 (s, CH), 128.4 (s, CH), 128.3 (s, CH), 76.2 (s, CH),
76.0 (s, CH), 72.0 (s, CH), 52.4 (s, CH), 51.4 (s, CH3), 50.0 (s, CH), 44.3
(s, CH2), 33.2 (s, CH2), 29.5 (s, CH2), 26.3 (s, CH2), 25.8 (s, CH3 ꢄ9), 25.6
(s , CH2), 25.3 (s, CH2), 20.4 (s, CH2), 18.1 (s, Cquat ꢄ3), 14.2 (s, CH3),
À4.4 (s, CH3 ꢄ2), À4.6 (s, CH3 ꢄ2), À4.7 (s, CH3), À4.8 ppm (s, CH3);
IR: n=2954, 2928, 2856, 1743, 1463, 1252, 1065 cmÀ1; HRMS (ESI+):
m/z: calcd for C41H83O5Si3: 739.5548 [M+H]+; found: 739.5549.
mixture showed a distribution in accordance with [D4] incor-
poration and without traces of [D3], [D2], [D1] or hydrogen
incorporation. The 2% impurities of [D4]-tetraene 17b com-
prised only the over-reduced product 17c.[31]
Finally, tetra-n-butylammonium fluoride (TBAF)-mediat-
ed removal of the TBS groups followed by saponification of
the methyl ester by using LiOH in THF/H2O provided the
4ACHTUNGTRENNUNG(R,S)-F4t-NeuroP 1 and its [D4]-labeled analogue 2 in 86
and 78% overall yields, respectively (Scheme 9).
Acknowledgements
In conclusion, the total syntheses of the 1 and 2 via the
pivotal intermediate 4 are reported. The key feature of our
synthetic strategy involves a highly regio- and stereoselec-
We thank the Ministꢅre de lꢀEducation Nationale et de la Recherche for
a doctoral fellowship (C.O.). We are deeply grateful to Prof. Jean-Yves
Lallemand and the ICSN for their generous funding. A part of this work
was also financially supported by the
Universitꢁ Montpellier I grants (BQR-
2008–2010), and by INRA (INRA-
AlimH-2008-2010). We also thank
Prof. FranÅoise Michel for her help
with GC/MS experiments and M. Sin-
gleton, H. C. Fisher, and S. Ortial for
proofreading.
Scheme 9. Synthesis of 1 and its [D4]-labeled analogue 2.
Chem. Eur. J. 2010, 16, 13976 – 13980
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J.-M. Galano et al.
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Keywords: hydrogenation
neuroprostanes · nickel · skipped diynes
·
isotopic
labeling
·
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Received: August 11, 2010
Published online: November 12, 2010
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Chem. Eur. J. 2010, 16, 13976 – 13980