Synthesis of the two main urinary tetranor metabolites of 15-F2t-isoprostane

Article abstract of DOI:10.1016/S0040-4039(01)00754-7

The first synthesis of two main urinary tetranor metabolites of 15-F_2t-isoprostane methyl ester is described using L-glucose as starting material.

Full text of DOI:10.1016/S0040-4039(01)00754-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4333–4336
Synthesis of the two main urinary tetranor metabolites of
15-F2t-isoprostane
Thierry Durand,* Olivier Henry, Jean-Pierre Vidal and Jean-Claude Rossi
UMR CNRS 5074, Faculte´ de Pharmacie, Universite´ Montpellier I, 15, Av. Ch. Flahault, F-34060 Montpellier cedex 02, France
Received 27 March 2001; revised 30 April 2001; accepted 6 May 2001
Abstract—The first synthesis of two main urinary tetranor metabolites of 15-F2t-isoprostane methyl ester is described using
L
-glucose as starting material. © 2001 Elsevier Science Ltd. All rights reserved.
F2-isoprostanes (F2-isoP), a complex family of 32
stereoisomers to cyclooxygenase derived PGF2a, are
products o f non-enzymatic free radical-catalyzed peroxi-
dation of arachidonic acid.1–3 Since these compounds
are now widely used as indices of lipid peroxidation in
vivo,2–5 knowledge of their metabolic fate may be use-
ful, in general, to better define their overall formation.
In fact, the identification of major metabolites of F2-
isoP might help in finding new analytical targets to
monitor in addition to or instead of the parent com-
pounds. Moreover, given that selected F2-isoP isomers
have potent biological effects,2–5 it is important to
establish whether and how these isomers are specifically
degraded, in order to relate their levels in vivo to a
putative biological effect. To date, the only F2-isoP
metabolites identified and most studied were 2,3-dinor-
5,6-dihydro-15F2t-isoP6–8 and putative tetranor isomers
of 15-F2t-isoP.7,9
report the first total synthesis of two main urinary
tetranor metabolites of 15F2-isoP 1 and 2 from com-
mercially available L-glucose (Fig. 1).
The synthesis of 2,3,4,5-tetranor-15-oxo-5,6,13,14-tetra-
hydro-15F2t-isoP methyl ester 1, is shown in Schemes 1
and 2. The first six steps leading to iodo derivative 4
were assessed in 84% overall yield by using iodo path-
way, according to our procedure.10 Treatment of com-
pound 4 with ZnCl2 in ethanethiol at −15°C afforded
the diol–thioacetal 5 in 88% yield, which was protected
into dibenzoyl ether 6 in the presence of benzoyl chlo-
ride in pyridine at room temperature in 90% yield.
Removal of the thioacetal group under neutral condi-
tions (HgO/HgCl2) in acetone/water gave the unstable
aldehyde 7, which was immediately used in the follow-
ing steps without further purification. The aldehyde 7
reacted with the ylide derived from the 3-(tetra-
hydropyranyloxypropyl)triphenyl phosphonium bro-
mide 811 and KHMDS to afford the pure
cis-b,g-ethylenic derivative 9 in 74% yield. No trace of
In connection with our program directed towards the
synthesis of isoprostanes and neuroprostanes, we now
HO
CO2Me
O
BzO
OH
OH
CO2Me
OTBDPS
HO
O
1
2
+
HO
HO
HO
OH
L-Glucose
CO2Me
BzO
CO2Me
3
HO
O
Figure 1. Retrosynthesis scheme.
* Corresponding author. Fax: 33-4-67-54-86-25; e-mail: froxy@pharma.univ-montp1.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00754-7

4334
T. Durand et al. / Tetrahedron Letters 42 (2001) 4333–4336
O
O
O
O
I
SEt
SEt
OH
6 steps
OH
ZnCl2,
TBDPSO
I
HO
HO
EtSH, rt
88%
OH
I
(84%)
4
OH OH
CHO
5
TBDPSO
L-Glucose
I
SEt
SEt
HgO,HgCl2
BzCl, pyridine
8, KHMDS
TBDPSO
TBDPSO
acetone-H2O
100%
90%
74%
OBz OBz
OBz OBz
OBz OBz
7
6
I
I
1- "Jones Reagent"
CH2OTHP
CO2Me
TBDPSO
TBDPSO
2- CH2N2
86%
OBz OBz
10
CO2Me
OTBDPS
9
BzO
Bu3SnH, BEt3, O2
xylene, rt
3
BzO
72%
Scheme 1.
BzO
BzO
BzO
BzO
CO2Me
CO2Me
CO2Me
HCl, 3% MeOH
74%
periodinane, CH2Cl2
OH
11
OTBDPS
CHO
12
BzO
BzO
3
BzO
BzO
BzO
CO2Me
CO2Me
H2, 10% Pd/C
100%
13, HNa, THF, rt
89%
15
BzO
O
14
O
HO
CO2Me
1-NaOH 1N, 40°C
2-CH2N2
83%
HO
O
1
Scheme 2.
1
the trans compound could be detected by 13C and H
NMR analysis.
CH2Cl2 gave the unstable aldehyde 12, which was
immediately used in the next step without purification
to avoid any epimerization of the aldehyde. It is impor-
tant to note that this Dess–Martin oxidation gave a
higher yield avoiding any epimerization than our first
attempts using Swern conditions. The condensation of
12 with diethyl oxoheptyl–phosphonate 13, in the pres-
ence of NaH, in anhydrous THF, afforded the trans-
a,b-enone 14 in 89% overall yield from the alcohol 11.
Reduction of the trans double bond on the v chain, was
achieved using H2 on 10% Pd/C, giving the correspond-
ing oxo derivative 15 in 100% yield. Finally, cleavage of
the ester functions of 15 with 1N NaOH, followed by
treatment with diazomethane gave the 2,3,4,5-tetranor-
Oxidation of the protected primary alcohol 9 gave the
corresponding acid, which in the presence of an excess
of diazomethane was transformed in 86% yield into the
methyl ester 10. The radical precursor 10 was converted
to highly funtionalized hex-5-enyl radical then the
intramolecular cyclization was achieved12 to yield 72%
of the protected syn–anti–syn cyclopentane compound
3.13 The tert-butyldiphenylsilyl ether 3 was converted
into the alcohol 11 in 74% yield, with a solution of 3%
hydrogen chloride in methanol/ethyl ether (1:1, v/v).14
Dess–Martin oxidation15 of 11 with periodinane in

T. Durand et al. / Tetrahedron Letters 42 (2001) 4333–4336
4335
Supplementary material
15-oxo-5,6,13,14-tetrahydro-15F2t-isoP methyl ester 1
in 83% yield (Scheme 2).
Full experimental data for the compounds 3, 1 and 2.
The synthesis of 20-carboxy-2,3,4,5-tetranor-15-oxo-
5,6,13,14-tetrahydro-15F2t-isoP dimethyl esters 2 from
12 is shown in Scheme 3. The condensation of 12 with
diethyl [6-(methoxycarbonyl)-2-oxohexyl]phosphonate
16,16 in the presence of NaHMDS, in anhydrous THF
at −78°C, afforded the trans-a,b-enone 17 in 64% over-
all yield from the alcohol 11.
(1R,2S,3S,4S)-1,4-Bis-O-(benzoyl)-2-(tert-butyldiphenyl-
silyloxymethyl)-3-(methoxycarbonylethyl)cyclopentane-
1,4-diol (3):
1
IR: w=1715 cm−1. H NMR (CDCl3): l 1.09 (s, 9H),
1.94–1.70 (m, 2H), 1.90 (dq, 1H, J=15.7 Hz, J=4.15
Hz, J=2.82 Hz), 2.37 (t, 2H, J=8.62 Hz), 2.59–2.49
(m, 1H), 2.64–2.54 (m, 1H), 2.95 (dt, 1H, J=15.7 Hz,
J=7.4 Hz), 3.60 (s, 3H), 3.70 (dd, 1H, J=10.95 Hz,
J=5.14 Hz), 3.86 (dd, 1H, J=10.95 Hz, J=5.14 Hz),
5.31 (dq, 1H, J=6.14 Hz, J=4.15 Hz, J=7.4 Hz), 5.40
(dt, 1H, J=7.4 Hz, J=2.82 Hz), 7.38–7.31 (m, 4H),
7.45–7.35 (m, 2H), 7.45–7.36 (m, 4H), 7.57–7.49 (m,
2H), 7.71–7.63 (m, 4H), 8.06–7.95 (m, 4H). 13C NMR
(CDCl3): l 19.1, 23.2, 26.9, 32.7, 39.4, 45.0, 48.8, 51.5,
61.7, 77.4, 79.2, 127.8, 128.3, 129.6, 129.8, 130.3, 132.9,
132.9, 135.6, 135.7, 166.0, 166.1, 173.4. Anal. calcd for
C40H44O7Si: C, 72.26; H, 6.67. Found: C, 72.24; H,
6.68. [h]2D0=+11.5 (c=10−3, MeOH).
During the Horner–Wadsworth–Emons reaction, it was
not possible to avoid the formation of the compound
18 derived from the elimination of the benzoyl group at
C11 (Scheme 3). Reduction of the trans double bond on
the v chain, was achieved using H2 on 10% Pd/C,
giving the corresponding oxo derivative. Finally, cleav-
age of the ester functions with 1N NaOH, followed by
treatment with diazomethane gave the 20-carboxy-
2,3,4,5-tetranor-15-oxo-5,6,13,14-tetrahydro-15F2t-isoP
dimethyl esters 2 in 83% yield
In conclusion, we describe the first stereoselective syn-
thesis of 2,3,4,5-tetranor-15-oxo-5,6,13,14-tetrahydro-
15F2t-isoP methyl ester 1 in 17 steps and 20-carboxy-
2,3,4,5-tetranor-15-oxo-5,6,13,14-tetrahydro-15F2t-
isoP dimethyl esters 2 in 18 steps from commercially
20-Carboxy-2,3,4,5-tetranor-5,6,13,14-tetrahydro-15-oxo-
15-F2t-isoprostane dimethyl esters (2)
IR: w=3409,1732, 1713 cm−1. 1H NMR (CDCl3): l
1.31–1.44 (m, 1H), 1.35–1.48 (m, 1H), 1.51–1.60 (m,
1H), 1.53–1.60 (m, 2H), 1.54–1.64 (m, 2H), 1.59–1.71
(m, 1H), 1.65–1.77 (m, 1H), 1.94–2.02 (m, 1H), 1.97–
2.05 (m, 1H), 2.29 (t, 2H, J=7.13 Hz), 2.32–2.43 (m,
2H), 2.32–2.423 (m, 1H), 2.35–2.44 (m, 2H), 2.49 (t,
available
L-glucose. This route allows the enantiospe-
cific synthesis of two main urinary metabolites of 15F2t-
isoP, which provides the basis for the development of
methods of assay for its quantification in different
fluids. Such studies are currently being investigated.
BzO
CO2Me
CO2Me
BzO
BzO
CO2Me
17
89%
O
16, NaHMDS
THF, rt
CHO
BzO
CO2Me
BzO
12
CO2Me
O
9%
CO2Me
O
18
HO
1-H2, 10% Pd/C
17
CO2Me
2-NaOH 1N, 40°C
HO
3-CH2N2
2
83%
Scheme 3.

4336
T. Durand et al. / Tetrahedron Letters 42 (2001) 4333–4336
2H, J=7.30 Hz), 3.64 (s, 3H), 3.65 (s, 3H), 3.85–3.91
(m, 1H), 3.90–3.95 (m, 1H). 13C NMR (CDCl3): l 21.6,
23.1, 23.2, 24.4, 32.7, 33.8, 41.1, 42.4, 42.9, 48.8, 48.9,
51.5, 51.6, 76.0, 76.2, 174.0, 210.5. Anal. calcd for
C18H30O7: C, 60.32; H, 8.44. Found: C, 60.35; H, 8.42.
[h]2D0=+1.13 (c=10−3, MeOH).
4. Delanty, N.; Reilly, M.; Pratico, D.; FitzGerald, D. J.;
Lawson, J. A.; FitzGerald, G. A. Br. J. Clin. Pharmacol.
1996, 42, 15–19.
5. Pratico, D. Atherosclerosis 1999, 147, 1–10.
6. Roberts, II, L. J.; Moore, K. P.; Zackert, W. E.; Oates, J.
A.; Morrow, J. D. J. Biol. Chem. 1996, 271, 20617–20620.
7. Chiabrando, Ch.; Valagussa, A.; Rivalta, C.; Durand, T.;
Guy, A.; Zuccato, E.; Villa, P.; Rossi, J. C.; Fanelli, R. J.
Biol. Chem. 1999, 274, 1313–1319.
2,3,4,5-Tetranor-5,6,13,14-tetrahydro-15-oxo-15-F2t-iso-
prostane methyl ester (1)
8. (a) Guy, A.; Durand, T.; Cormenier, E.; Roland, A.;
Rossi, J. C. Tetrahedron Lett. 1998, 38, 6181–6184; (b)
Durand, T.; Guy, A.; Henry, O.; Vidal, J. P.; Rossi, J. C.;
Rivalta, C.; Valagussa, A.; Chiabrando, Ch. Eur. J. Org.
Chem. 2001, 4, 809–819; (c) Taber, D. F.; Kanai, K. J.
Org. Chem. 1999, 64, 7983–7987.
9. Basu, S. FEBS Lett. 1998, 428, 32–36 and references cited
therein.
10. Roland, A.; Durand, T.; Egron, D.; Vidal, J. P.; Rossi, J.
C. J. Chem. Soc., Perkin Trans. 1 2000, 245–251 and
references cited therein.
1
IR: w=3415, 1736, 1712 cm−1. H NMR (CDCl3): l
0.87 (t, 3H, J=6.97 Hz), 1.16–1.30 (m, 2H), 1.22–1.32
(m, 2H), 1.32–1.45 (m, 1H), 1.36–1.49 (m, 1H), 1.52–
1.61 (m, 1H), 1.50–1.60 (m, 2H), 1.59–1.72 (m, 1H),
1.66–1.79 (m, 1H), 1.95–2.03 (m, 1H), 1.98–2.07 (m,
1H), 2.33–2.44 (m, 3H), 2.35–2.43 (m, 2H), 2.49 (dd,
2H, J=7.3 Hz, J=7.8 Hz), 3.65 (s, 3H), 3.87–3.93 (m,
1H), 3.91–3.97 (m, 1H). 13C NMR (CDCl3): l 13.9,
21.7, 22.4, 23.1, 23.5, 31.4, 32.7, 41.1, 42.9, 48.9, 49.0,
51.6, 76.0, 76.3, 174.0, 211.3. Anal. calcd for C17H30O5:
C, 64.94; H, 9.62. Found: C, 64.97; H, 9.61. [h]2D0=+
1.34 (c=10−3, MeOH).
11. Bennett, III, R. B.; Cha, J. K. Tetrahedron Lett. 1990, 31,
5437–5440.
12. (a) Brown, H. C.; Midland, M. M. Angew. Chem., Int.
Ed. Engl. 1972, 11, 692–700; (b) Nokazaki, K.; Oshima,
K.; Utimoto, K. J. Am. Chem. Soc. 1987, 109, 2547–2549;
(c) Nokazaki, K.; Oshima, K.; Utimoto, K. Tetrahedron
Lett. 1988, 29, 6125–6126; (d) Barton, D. H. R.; Jang, D.
O.; Jaszberenyl, J. C. Tetrahedron Lett. 1990, 31, 4681–
4684.
13. We have determined and confirmed the relative configu-
rations of compound 3 by steady-state difference NOE
spectroscopy (DNOES) experiments, which have previ-
ously been employed by our group.10
Acknowledgements
The authors thank Professor Valdimir Bezuglov,
Moscow (Russia) and Dr. Chiara Chiabrando, Milan
(Italy) for helpful discussions.
References
14. Nashed, E.; Glaudemans, G. J. Org. Chem. 1987, 52,
5255–5260.
15. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48,
4155–4156; (b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993,
58, 2899.
1. Morrow, J. D.; Hill, K. E.; Burk, R. F.; Namour, T. M.;
Badr, K. F.; Roberts, II, L. J. Proc. Natl. Acad. Sci. USA
1990, 87, 9383–9387.
2. Roberts, II, L. J.; Morrow, J. D. Free Radical Biol. Med.
2000, 28, 505–513.
16. Demarche, I.; Mosset, P. J. Org. Chem. 1994, 59, 5453–
5457.
3. Lawson, J. A.; Rokach, J.; FitzGerald, G. A. J. Biol.
Chem. 1999, 274, 24441–24444.
.