Total synthesis of 4-F3t-neuroprostane and its 4-epimer

Article abstract of DOI:10.1016/j.tetlet.2009.01.075

The first synthesis of 4-F_3t-Neuroprostane 1a and its 4-epimer is described. This molecule presents an important contribution to the study of neuronal oxidative stress in DHA-ω3 depleted brain. The key step involves the introduction of two unsa

Full text of DOI:10.1016/j.tetlet.2009.01.075

Tetrahedron Letters 50 (2009) 1498–1500
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Tetrahedron Letters
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Total synthesis of 4-F -neuroprostane and its 4-epimer
3
t
Anne-Laure Auvinet , Barbara Eignerová , Alexandre Guy , Martin Kotora b,c, Thierry Durand a,
a
b,c
a
*
a
Institut des Biomolécules Max Mousseron, IBMM, UMR CNRS 5247, Université Montpellier 1, Université Montpellier 2, Faculté de Pharmacie, 15. Av. Ch. Flahault,
F-34093 Montpellier Cedex 05, France
b
Department of Organic and Nuclear Chemistry and Centre for New Antivirals and Antineoplastics, Faculty of Science, Charles University, Hlavova 8, 128 43 Praha 2, Czech Republic
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám eˇ stí 2, 166 10 Praha 6, Czech Republic
c
a r t i c l e i n f o
a b s t r a c t
Article history:
The first synthesis of 4-F3t-Neuroprostane 1a and its 4-epimer is described. This molecule presents an
Received 3 December 2008
Accepted 14 January 2009
Available online 19 January 2009
important contribution to the study of neuronal oxidative stress in DHA-
involves the introduction of two unsaturated side chains into the chiral polyfunctional cyclopentane 4 via
E selective HWE reaction and Z selective Wittig olefination for and chains, respectively.
x3 depleted brain. The key step
a
x
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
DPA
Oxidative stress
Neuroprostane
Total synthesis
Wittig
HWE
Polyunsaturated fatty acids (PUFAs) play an important role in
the defence of living organisms against the toxic effects of oxygen
due to their ability to transform the diradical to degradable organic
compounds. Neuroprostanes along with isoprostanes and phyto-
prostanes belong to a large family of prostaglandin-like com-
Our project focuses on one potential metabolite of peroxidation
of DPA—4-F3t-neuroprostane 1a—(Scheme 1), and it presents a first
total synthesis of compound 1a starting from the commercially
available (E)-3-(furan-2-yl)acrylic acid 2 (Scheme 2).
The first 12 steps leading to the substrate 3 were completed in
1
6
pounds, which are formed in vivo from these PUFAs.
9% overall yield via our previously reported procedure.
Neuroprostanes are created by the action of reactive oxygen spe-
cies (ROS) on the membrane phospoholipids via non-enzymatic,
Compound 4 was obtained in excellent yield and with well-de-
fined diastereoselectivity using diimide, by reduction of the tetra-
substituted double bond 3 (Scheme 3). These controlled conditions
afforded substrate 4 with the required syn–anti–syn orientation.6
Having the starting compound 4 in our hands we could switch
free-radical peroxidation of docosahexaenoic acid (DHA;
2
C22:6x3).
The formation of neuroprostanes increases dramatically under
conditions of an oxidative stress, therefore their measurement
could provide a unique marker of oxidative neuronal injury and
could mean an important advance in our ability to explore the role
to an introduction of
reduced by treatment of DIBAL-H. The adjunction of the
a
and
x
chains. Firstly, the ester function was
chain of
x
the neuroprostane was achieved by using (Z)-non-3-enyl triphen-
ylphosphonium iodide 6, which was prepared from commercially
3
of free radicals in the pathogenesis of human diseases. Investiga-
tion of rats depleted in long-chain polyunsaturated
3-depleted rats) showed a significant non-reciprocal increase
in a concentration of docosapentaenoic acid (DPA; C22:5 6) in
neuronal tissues. This experimental model represents an occiden-
x
3 fatty acid
available cis-non-3-en-1-ol by iodination and subsequent addition
7
(x
of PPh
3
. The presence of K
2
CO
3
was required to avoid epimeriza-
x
tion of the double bond (Scheme 4). The Wittig reaction between
aldehyde 5 and the ylide derived from the phosphonium salt 6 oc-
curred smoothly in the presence of NaHMDS, and afforded the pure
all cis dienic 7 in good 70% total yield after 2 steps (Scheme 4).
4
5
tal human being with a deficit of
est to confirm the formation of such lipids prompted us to prepare
these F -neuroprostanes by total chemical synthesis, which should
x3 PUFAs in nutrition. Our inter-
No traces of trans olefination could be detected by 13C or 1
H
3
broaden the knowledge concerning their role as mediators of oxi-
dative stress.
NMR analysis. Subsequently, the a-chain of the neuroprostane
was introduced by a Horner–Wadsworth–Emmons (HWE) reaction
8
using b-ketophosphonate 9, prepared in 2 steps (Scheme 4). Ace-
tal 7 was converted by acidic hydrolysis into aldehyde 8, and the
crude was directly applied in the next step. The olefination of alde-
hyde 8 underwent under same conditions as the previous Wittig
*
Corresponding author. Tel.: +33 4 67 54 86 22; fax: +33 4 67 54 86 25.
E-mail address: Thierry.Durand@univ-montp1.fr (T. Durand).
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.075

A.-L. Auvinet et al. / Tetrahedron Letters 50 (2009) 1498–1500
1499
O
O
CO2H
CO2H
CO2H
ROS
O2
CO2H
-
H
Docosapentaenoic acid
OOH
OH
HO
O
O
O
O
O2
CO2H
[red]
CO2H
HO 4-F3t-Neuroprostane 1a
Scheme 1. Possible pathway of free-radical cyclization of DPA.
O
P
O
MeO
MeO
OH
TBSO
TBSO
HO
CH(OMe)
2
2
CO Me
2
CO H
9
2
CO Me
O
2
CO H
3
IPh P
2
HO 4-F3t-Neuroprostane 1a
4
6
Scheme 2. Retrosynthesis of 4-F3t-Neuroprostane 1a.
TBSO
TBSO
TBSO
TBSO
TBSO
TBSO
a
CO
CH(OMe)2
Me
CO
2
Me
CH(OMe)
2
2
b
O
CO
2
H
CH(OMe)2
2
CO Me
2
3
4
Scheme 3. Reagents and conditions: (a) see Ref. 6; (b) dipotassium diazodicarboxylate salt, AcOH, MeOH, butanone, pyridine, reflux, 3 days, 72%.
TBSO
TBSO
TBSO
TBSO
CH(OMe)
2
CH(OMe)
CHO
2
a
TBSO
TBSO
2
CO Me
CH(OMe)
2
b
4
5
a',b'
7
HO
3
IPh P
6a
6
TBSO
CHO
c
7
O
TBSO
TBSO
TBSO
O
8
d
2
CO Me
O
P
O
P
O
MeO
MeO
MeO
MeO
c', d'
O
1
0
2
CO Me
O
9b
9a
9
Scheme 4. Reagents and conditions: (a) DIBAL-H, toluene, ꢀ78 °C, 1 h; (b) NaHMDS, THF, ꢀ78 °C to rt, 2 h, 70% (2 steps); (c) I
2
, PPh
3
, Im, CH
2
Cl
2
, 0 °C, 2 h, 94%; (d) PPh
3
,
toluene, K CO
2
3
, reflux, 24 h, 87%; (e) p-TsOH, acetone, reflux, 30 min; (f) NaHMDS, THF, ꢀ78 °C to rt, 4 h, 55% (2 steps); (g) n-BuLi, Et
2
O, ꢀ78 °C; (h) MeOH, H
2
SO , 2 h, 48%.
4
reaction affording the trans
a
,b-enone ester 10 in acceptable 55%
this procedure enabled to confirm the absolute stereochemistry
at C4. The technique usually used for such types of compound is re-
verse phase HPLC, but this method was not suitable in our case be-
cause of total decomposition of the substrate under acidic
conditions. Fortunately, after the deprotection of both TBS groups
in the presence of tetrabutylammonium fluoride (TBAF), the two
lactones 14a and 14b were obtained in high yield.13 We were
pleased to uncover the separability of the diastereoisomers using
an appropriate size of chromatographic column, although always
with approximately 30% of mixed fractions. Subsequently, the
opening of lactone occurred smoothly using LiOH, in THF and final
product 4(S)-F3t-neuroprostane 1a and its 4-epimer 1b were ob-
9
overall yield after 2 steps (Scheme 4). The prompt purification
of the resulting ketone allowed to avoid elimination or
epimerization.
Following reduction of the ketone under Luche conditions10
4 3
involving NaBH in the presence of CeCl afforded a diastereoiso-
meric mixture of alcohols 11 in high yield (Scheme 5). A separation
of both diastereoisomers was the final crucial issue of this synthe-
sis. First approach was based on the coupling of (R) or (S)-O-acetyl
mandelic acid with free alcohols 11.11 Unfortunately, the hydroxyl
group in 4-position close to carboxyl function is hindered and
unreactive, and this reaction occurred with poor results.
1
4
Afterwards, the stereospecific reduction using Noyori’s (S)-BI-
tained in quantitative yield (Scheme 5).
In conclusion, the first total synthesis of both optically pure dia-
stereoisomers of the 4(S)-F3t-neuroprostane 1a and 4(R)-F3t-neuro-
1
2
NAL-H was tried but this strategy failed as well because in our
case, it was carried out only selectively not specifically. Besides,

1
500
A.-L. Auvinet et al. / Tetrahedron Letters 50 (2009) 1498–1500
O
O
O
OH
O
O
TBSO
TBSO
TBSO
TBSO
HO
HO
a
b
CO
2
Me
CO
2
Me
C
5
H
11
5 11
C H
HO
HO
HO
HO
1
0
11
14a
14b
c
c
OH
OH
2
CO H
2
CO H
HO
HO
4
-(S)-F3t-Neuroprostane 1a
4-(R)-F3t-Neuroprostane 1b
3 4
Scheme 5. Reagents and conditions: (a) CeCl , NaBH , MeOH, 0 °C, 5 min, 87%; (b) TBAF in THF, 4 h, rt, 91%; (c) LiOH, THF, 4 h, quantitative yield.
prostane 1b was accomplished in 20 steps and 22% overall yield
after eight steps starting from cyclopentene 3. Our strategy which
50.7, 44.3, 35.1, 31.4, 29.2, 27.8, 27.2, 26.4, 25.7 (2C), 22.5, 17.9, 13.9, ꢀ4.5,
ꢀ
4.7, ꢀ4.8 (2C).
1
1
0. Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
1. Chataigner, I.; Lebreton, J.; Durand, D.; Guingant, A.; Villieras, J. Tetrahedron
Lett. 1998, 39, 1759–1762.
enables us to introduce the
x and a chains into the cyclopentane
ring 4 is based on the Wittig and HWE reactions. Further studies
regarding the biological activity of 4-F3t-neuroprostane 1a and its
1
2. Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J. Am. Chem. Soc. 1984, 106,
6717–6725.
4
-epimer 1b in order to profoundly understand their role in x3-de-
1
3. Hydrolysis of lactone 1a and selected physicochemical data for compound 14a: To
a solution of lactone 14a (0.07 mmol, 1.0 eq) in 1 mL of THF was added a 1 M
solution of aqueous LiOH (207 mL, 0.21 mmol, 3 eq) at room temperature
pleted organism are in progress and will be reported in due time.
under N
.1 M solution of NaHSO
were separated and the aqueous one extracted with 3 ꢁ 5 mL of EtOAc. The
combined organic layers were dried over MgSO , filtered and the solvents
evaporated. The triol-acid 1a was obtained as an yellow oil (25 mg, 100%).
NMR (300 MHz, CDCl ): d 5.64–5.61 (m, 2H), 5.42–5.24 (m, 4H), 4.93–4.86 (m,
1H), 4.05–3.95 (m, 2H), 2.87–2.77 (m, 1H), 2.75–2.68 (m, 2H), 2.54–2.48 (m,
2
atmosphere. After stirring for 4 h, the mixture was acidified with
Acknowledgements
0
4
(1 mL) and 10 mL of EtOAc were added. The layers
We gratefully acknowledge the Centre for New Antivirotics and
Antineoplastics No. 1M0508, the Grant No. MSM0021620857 from
the Ministry of Education of the Czech Republic (BE, MK) and the
University Montpellier I Grant BQR-2008 (ALA, AG, TD) for finan-
cial support. We thank Dr. Roger LEMA KISOKA for helpfull
discussions.
4
1
H
3
2
1
H), 2.45–2.40 (m, 2H), 2.23–2.12 (m, 1H), 2.05–1.89 (m, 7H), 1.65 (dt, J = 3.9,
4.5 Hz, 1H), 1.35–1.19 (m, 6H), 0.87 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl
53.4, 50.8, 42.4, 31.4, 29.2, 28.7, 28.4, 27.2, 26.9, 25.7, 22.5, 14.0; ½
.0, CDCl ); HR-MS (ES+) calcd for C22 [M+H] 363.2535, found 363.2542.
Selected physicochemical data for compound 14b: H NMR (300 MHz, CDCl
3
, 20 °C): d 176.7, 132.2, 130.7, 130.2, 129.8, 127.8, 127.2, 80.2, 76.3 (2C),
20
a
ꢂ
+44.4 (c
D
5
3
35 4
H O
1
3
): d
.63–5.61 (m, 2H), 5.42–5.25 (m, 4H), 4.91–4.88 (m, 1H), 4.10–4.02 (m, 1H),
References and notes
5
4
2
1
.00–3.95 (m, 1H), 2.87–2.79 (m, 1H), 2.75–2.71 (m, 2H), 2.56–2.49 (m, 2H),
1
.
Morrow, J. D.; Hill, K. E.; Burk, R. F.; Nammour, T. M.; Badr, K. F.; Roberts, L. J., II
Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 9383–9387; Jahn, U.; Galano, J.-M.; Durand,
T. Angew. Chem., Int. Ed. 2008, 47, 5894–5955.
.46–2.34 (m, 2H), 2.25–2.12 (m, 1H), 2.05–1.93 (m, 5H), 1.95–1.76 (br s, 2H),
13
.66 (dt, J = 3.9; 14.5 Hz, 1H), 1.36–1.24 (m, 6H), 0.86 (t, J = 6.8 Hz, 3H);
C
3
NMR (75 MHz, CDCl , 20 °C): d 176.7, 132.4, 130.6, 130.1, 129.7, 127.9, 127.2,
2
.
Nourooz-Zadeh, J.; Liu, E. H. C.; Änggard, E. E.; Halliwell, B. Biochem. Biophys.
Res. Commun. 1998, 242, 334–338.
8
1
0.3, 76.3, 76.1, 53.4, 50.7, 42.4, 31.4, 29.2, 28.7, 28.5, 27.2, 26.9, 25.7, 22.5,
20
4.0; ½a
ꢂ
3 35 4
ꢀ5.0 (c 5.0, CDCl ); HR-MS (ES+) calcd for C22H O [M+H] 363.2535,
D
3
4
.
.
Montine, T. J.; Morrow, J. D. Am. J. Pathol. 2005, 166, 1283–1289.
Greiner, R. S.; Catalan, J. N.; Moriguchi, T.; Salem, N., Jr. Lipids 2003, 38, 431–
found 363.2529.
4. Selected physicochemical data for compound 1a: 1H NMR (300 MHz, CD
1
3
OD): d
.56–5.51 (m, 2H), 5.46–5.27 (m, 4H), 4.08–4.01 (m, 1H), 3.98–3.92 (m, 1H),
.88–3.82 (m, 1H), 2.79–2.74 (m, 2H), 2.72–2.63 (m, 1H), 2.45 (dt, J = 7.2,
4.2 Hz, 1H), 2.33 (t, J = 7.5 Hz, 2H), 2.14–1.97 (m, 5H), 1.77 (q, J = 6.8 Hz, 2H),
.52 (dt, J = 5.1, 14.2 Hz, 1H), 1.41–1.22 (m, 6H), 0.88 (t, J = 6.9 Hz, 3H);
4
35.
5
3
1
1
5.
6.
7.
Delporte, C.; Malaisse, W. J.; Jurysta, C.; Portois, L.; Sener, A.; Carpentier, Y. A.
Eur. J. Oral. Sci. 2007, 115, 103–110; Zhang, Y.; Louchami, K.; Carpentier, Y. A.;
Malaisse, W. J.; Sener, A. Cell. Biochem. Funct. 2008, 26, 82–86.
13
C
Pinot, E.; Guy, A.; Fournial, A.; Balas, L.; Rossi, J. C.; Durand, T. J. Org. Chem. 2008,
3
NMR (75 MHz, CDCl , 20 °C): d 180.7, 134.7, 129.6, 129.0, 128.4, 128.1, 127.5,
73, 3063–3069; Pinot, E.; Guy, A.; Guyon, A. L.; Rossi, J. C.; Durand, T.
7
1
3
4.8, 74.7, 71.1, 52.1, 49.9, 42.1, 32.2, 31.2, 30.2, 29.0, 26.7, 25.9, 25.3, 22.1,
Tetrahedron: Asymmetry 2005, 16, 1893–1895.
Yadav, J. S.; Nanda, S.; Bhaskar Rao, A. Tetrahedron: Asymmetry 2001, 12, 2129–
20
2.9;
½
a
ꢂ
ꢀ0.8 (c 2.5, MeOH); HR-MS (ES+) calcd for
C
22
H
37
O
5
[M+H]
D
81.2641, found 381.2646.
2
135.
Selected physicochemical data for compound 1b: 1H NMR (300 MHz, CD
3
OD): d
8
9
.
.
Delamarche, I.; Mosset, P. J. Org. Chem. 1994, 59, 5453–5457.
Selected physicochemical data for compound 10: H NMR (300 MHz, CDCl
5
3
2
.61–5.52 (m, 2H), 5.44–5.28 (m, 4H), 4.10–4.06 (m, 1H), 4.01–3.96 (m, 1H),
.91–3.86 (m, 1H), 2.84–2.77 (m, 2H), 2.72–2.66 (m, 1H), 2.53–2.43 (m, 1H),
1
3
): d
6
.71 (dd, J = 9.9, 15.6 Hz, 1H), 6.16 (d, J = 15.6 Hz, 1H), 5.43–5.24 (m, 4H), 3.99
.30 (t, J = 7.4 Hz, 2H), 2.16–1.99 (m, 5H), 1.80 (q, J = 6.8 Hz, 2H), 1.54 (dt,
(
(
(
m, 1H), 3.86 (m, 1H), 3.66 (s, 3H), 2.86–2.77 (m, 3H), 2.74–2.66 (m, 2H), 2.61
t, J = 6.8 Hz, 2H), 2.36 (dt, J = 6.9, 13.8 Hz, 1H), 2.22–2.10 (m, 1H), 2.10–1.88
m, 4H), 1.57 (dt, J = 13.7 Hz, 4.8 Hz, 1H), 1.42–1.20 (m, 6H), 0.93–0.70 (m,
13
J = 14.1 Hz, 5.1 Hz, 1H), 1.40–1.22 (m, 6H), 0.91 (t, J = 6.9 Hz, 3H); C NMR
(
7
75 MHz, CDCl
4.8, 72.0, 52.3, 49.9, 42.0, 33.5 (2C), 31.2, 29.0, 26.7, 26.0, 25.3, 22.1, 12.9; ½
10.2 (c 5.0, MeOH); HR-MS (ES+) calcd for C22 [M+H] 381.2641, found
81.2649.
3
, 20 °C): d 180.7, 135.2, 129.6, 128.6, 128.4, 128.1, 127.5, 74.9,
20
aꢂ
D
1
3
2
3
4H), 0.02 (s, 6H), ꢀ0.01 (s, 3H), ꢀ0.02 (s, 3H); C NMR (75 MHz, CDCl , 20 °C):
ꢀ
37 5
H O
d 197.3, 173.2, 146.0, 130.9, 130.5, 129.2, 127.9, 127.3, 75.5, 75.3, 52.8, 51.7,
3