Total syntheses of four metabolites of 15-F2t-isoprostane

Article abstract of DOI:10.1002/1099-0690(200102)2001:4<809::AID-EJOC809>3.0.CO;2-6

Total syntheses are described of the methyl esters of enantiomers of two major urinary metabolites of 15F_2t-isoprostane - 2,3-dinor-5,6-dihydro-15F_2t-isoprostane 1 and 2,3-dinor15F_2t-isoprostane 2 - together with other, related, putative metabolites (15R)/(15S)-2,3-dinor-5,6,13,14-tetrahydro-15F_2tisoprostane 3 and 2,3-dinor-5,6,13,14-tetrahydro-15-oxo 15F_2t-isoprostane 4. The synthesis, starting from diacetone d-glucose, includes as its main steps a radical cyclization reaction of highly functionalized precursors, followed by Wittig and/or Horner-Wadsworth-Emmons elongation using phosphorus synthons. The compounds synthesized here have been used as reference compounds for studying the metabolism of 15F_2t-isoprostane and ent-15F_2t-isoprostane.

Full text of DOI:10.1002/1099-0690(200102)2001:4<809::AID-EJOC809>3.0.CO;2-6

FULL PAPER
Total Syntheses of Four Metabolites of 15-F2t-Isoprostane
Thierry Durand,*[a] Alexandre Guy,[a] Olivier Henry,[a] Jean-Pierre Vidal,[a]
Jean-Claude Rossi,[a] Claudia Rivalta,[b] Anna Valagussa,[b] and Chiara Chiabrando[b]
Keywords: Metabolism / Total synthesis / Wittig reactions
Total syntheses are described of the methyl esters of enanti-
omers of two major urinary metabolites of 15F2t-isoprostane
− 2,3-dinor-5,6-dihydro-15F2t-isoprostane 1 and 2,3-dinor-
15F2t-isoprostane 2 − together with other, related, putative
metabolites (15R)/(15S)-2,3-dinor-5,6,13,14-tetrahydro-15F2t-
glucose, includes as its main steps a radical cyclization reac-
tion of highly functionalized precursors, followed by Wittig
and/or Horner−Wadsworth−Emmons elongation using phos-
phorus synthons. The compounds synthesized here have
been used as reference compounds for studying the metabol-
ism of 15F2t-isoprostane and ent-15F2t-isoprostane.
isoprostane
3 and 2,3-dinor-5,6,13,14-tetrahydro-15-oxo-
15F2t-isoprostane 4. The synthesis, starting from diacetone d-
Introduction
parts of 15F2t-isoprostane metabolites; the metabolites
themselves should thus be accessible from -glucose.
Since the discovery of isoprostanes by Roberts et al.,[1]
there has been growing interest in the total synthesis[2] of
these optically active prostaglandin-like compounds, which
are formed in vivo by a free radical-catalyzed mechan-
ism.[1,3] The most studied compound of this family is 15F2t-
isoprostane[4] (also known as 8-epi-PGF2α or iPGF2α-III),[3]
an isomer endowed with powerful biological activity,[5] and
an extensively validated marker of oxidant stress in vivo.[5]
Because of their close similarity, it seems likely that cyclo-
oxygenase-derived PGF2α and 15F2t-isoprostane may un-
dergo metabolism through similar degradation pathways.
To date, two major metabolites have been identified in
humans: 2,3-dinor-5,6-dihydro-15F2t-isoprostane[6,7] and,
more recently, 2,3-dinor-15F2t-isoprostane.[7] We report
here the first enantiospecific chemical synthesis leading to
both compounds, and also to other putative related meta-
bolites. The availability of enantiomerically pure metabol-
ites is important from the viewpoint of the development of
enantioselective assays for these products (e.g. by the use
of immunoaffinity chromatography-GC-MS[7]). Such assays
might be useful for assessment of in vivo formation and
metabolism of 15F2t-isoprostane versus ent-15F2t-isopros-
tane. To date, it is not known to what proportion these en-
antiomers are formed in vivo and whether they can be sim-
ilarly degraded. We have developed our strategy by using
diacetone -glucose to provide the enantiomeric counter-
Results and Discussion
In connection with our program directed towards the
synthesis of isoprostanes, we have developed the first total
syntheses of ent-2,3-dinor-5,6-dihydro-15F2t-isoprostane
1a,[8] its 15 epimer 1b, ent-2,3-dinor-15F2t-isoprostane 2a,
its 15 epimer 2b, ent-(15R)/(15S)-2,3-dinor-5,6,13,14-tetra-
hydro-15F2t-isoprostane 3, and ent-2,3-dinor-5,6,13,14-
tetrahydro-15-oxo-15F2t-isoprostane 4, from the methyl es-
ter 5[9] (Scheme 1). Initially, 1a allowed us to confirm the
presence of endogenously produced 2,3-dinor-5,6-dihydro-
15F2t-isoprostane in human and rat urine and to identify its
∆5 unsaturated counterpart, 2,3-dinor-15F2t-isoprostane, as
another major endogenous metabolite.[7] Now, using direct
comparison with synthetic 2a, we have once again con-
firmed the identity of urinary and hepatocyte-derived 2,3-
dinor-15F2t-isoprostane.[7] The other putative metabolites
synthesized are being used as reference compounds to study
the in vitro metabolism of 15F2t-isoprostane and ent-15F2t-
isoprostane by isolated rat hepatocytes (Chiabrando et al.,
in preparation).
The synthesis of (1S,2S,3R,4R)-di-O-benzoyl-3-(meth-
oxycarbonylbutyl)-2-[(E)-3-oxo-1-octenyl)cyclopentane-1,4-
diol 14 Ϫ precursor of 1, 3, and 4 Ϫ from commercially
available diacetone--glucose, is shown in Scheme 2. The
first 9 steps leading to methyl cyclopentylacetate 5 were ac-
complished in 27% overall yield by using the iodo pathway,
according to our reported procedure.[9] The methyl ester 5
was converted into the aldehyde 6 by treatment with DI-
BAL-H (Scheme 2) in 93% yield.
[a]
´
Laboratoire de Chimie Biomoleculaire et Interactions
´
Biologiques, UMR CNRS 5074, Universite de Montpellier I,
´
Faculte de Pharmacie,
15, Av. Charles Flahault, 34060 Montpellier Cedex 2, France
E-mail: Thierry.Durand@pharma.univ-montp1.fr
Department of Environmental Health Sciences, Istituto di
Ricerche Farmacologiche ‘‘Mario Negri’’,
[b]
The introduction of the α chain of the isoprostane was
achieved by using a three-carbon homologating agent:
(3,3-diisopropoxypropyl)triphenylphosphonium bromide.[10]
The aldehyde 6 reacted with the ylide derived from this
Via Eritrea 62, 20157 Milano, Italy
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Eur. J. Org. Chem. 2001, 809Ϫ819
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809

T. Durand et al.
FULL PAPER
Scheme 1. Retrosynthesis of ent-15-F2t-isoP 1؊4
Scheme 2. Synthesis of compound 14; reagents and conditions:
(a) DIBAL-H, toluene, reflux, 93%; (b) BrϪ, Ph3PϩCH2CH2-
CH(OiPr)2, NaHMDS, THF, Ϫ80 °C, 83%; (c) H2, Pd/C 10%,
EtOH, 95%; (d) BzCl, pyridine, 91%; (e) FeCl3, acetone, reflux,
87%; (f) m-CPBA, THF, followed by CH2N2, 89%; (g) HCl 3%
methanolic solution, 83%; (h) (ClCO)2, DMSO, Et3N, CH2Cl2;
(i) (EtO)2P(O)CH2C(O)C5H11, NaH, THF, room temp., 89% over-
all yield for Swern oxidation and HWE
Figure 1. For compound 7: observed NOEs resulting from irradi-
ation of 1-H and 4-H (upper panel) and irradiation of 6-H and 7-
H (lower panel) are indicated with solid lines; 0% ϭ NOE not ob-
served
1
homonuclear H steady-state difference NOE spectroscopy
(DNOES) experiments,[2f] as shown in Figure 1.
phosphonium salt and NaHMDS to afford the pure cis-β,γ-
For compound 7, irradiation of 1-H induces a NOE of
ethylenic diisopropyl acetal 7 in 83% yield. No trace of the 0.5% on 6-H and of 1.6% on 5-H, while irradiation of 4-H
1
trans compound could be detected by 13C and H NMR induces a NOE of 0.6% on 7-H and of 1.1% on 5-H. Sim-
analysis. All the relative configurations were determined by ilarly, irradiation of 7Ј-H induces a NOE of 0.5% on 6-H
810
Eur. J. Org. Chem. 2001, 809Ϫ819

Total Syntheses of Four Metabolites of 15-F2t-Isoprostane
FULL PAPER
and of 0.8% on 4-H, while irradiation of 6-H induces a
NOE of 0.5% on 7Ј-H, of 0.6% on 1-H, and of 0.2% on 4-
H. These observations verify the relative cis configuration
of the protons 4-H, 1-H, 6-H, and 7Ј-H.
The cis double bond of 7 was reduced with H2 on 10%
Pd/C to give the diol diethyl acetal 8 in 95% yield. Interest-
ingly, during this hydrogenation we could not avoid the de-
protection of the triethylsilyl ethers and transacetalization
with the solvent. Protection of the hydroxy functions of 8
with benzoyl chloride gave the colorless diesters 9 in 91%
yield. Hydrolysis of the diethyl acetal 9 with aqueous FeCl3
in acetone afforded the aldehyde 10 in 87% yield. Oxidation
of 10 with m-CPBA and subsequent treatment with diazo-
methane gave the methyl ester 11 in 89% yield. The tert-
butyldiphenylsilyl ether 11 was converted into the alcohol
12 with a solution of 3% hydrogen chloride.[11] Swern oxida-
tion of 12 gave the unstable aldehyde 13, which was immedi-
ately used, without purification, in the next step to avoid
any epimerization of the aldehyde. The condensation of 13
with diethyl oxoheptylphosphonate, in the presence of
NaH, afforded the trans-α,β-enone 14 in 89% overall yield
from the alcohol 12.
The synthesis of ent-2,3-dinor-5,6-dihydro-15F2t-isopros-
tane 1a and its 15 epimer 1b from 14 is shown in Scheme 3.
Figure 2. For compounds 1a and 1b: observed NOEs resulting from
irradiation of 13-H are indicated with solid lines; 0% ϭ NOE not
observed
Synthetic 1a showed GC-NICIMS characteristics ident-
ical to its enantiomeric counterpart 2,3-dinor-5,6-dihydro-
15F2t-isoprostane, recently commercially available from the
Cayman Chemical Company (data not shown). Compound
1a had the same GC-NICIMS behavior as 2,3-dinor-5,6-
dihydro-15F2t-isoprostane derived from in vitro metabolism
of authentic 15F2t-isoprostane[7] and of endogenous 2,3-di-
nor-5,6-dihydro-15F2t-isoprostane isolated from urine using
an immobilized antibody stereo- and enantioselective to-
wards the 15F2t-isoprostane configuration.[7]
Scheme 3. Synthesis of ent-2,3-dinor-5,6-dihydro-15F2t-isoprostane
methyl ester 1a and its 15 epimer 1b; reagents and conditions: (a) -
Selectride , THF, Ϫ78 °C, 100%; (b) NaOH
1 , 40 °C;
(c) CH2N2 83%
Reduction of the oxo function of 14 with -Selectride
For compound 1b, the relative cis configuration of the
quantitatively afforded the epimeric allylic alcohols 15 as a protons 13-H, 15-H, 7-H, 11-H, 9-H, and 10-H was deter-
2:3 mixture that could not be separated by flash chromato- mined by irradiation of 13-H, which induced NOEs of 1.7%
graphy. Cleavage of the ester functions of 15 with 1  on 15-H, of 0.6% on 11-H, of 0.5% on 9-H, and of 0.2%
NaOH at 40 °C, followed by treatment with diazomethane, on 7-H. Also, irradiation of 10-H induced NOEs of 0.6%
gave a 3:2 mixture of methyl esters 1a and 1b in 83% yield. on 13-H, of 2.0% on 11-H, and of 2.3% on 9-H. Similar
These two epimers were easily separated by flash chromato- results were observed for compound 1a.
graphy on silica gel, using cyclohexane/ethyl acetate (30:70)
as solvent. We confirmed the relative configurations of the oxo-15F2t-isoprostane 4 from 14 is shown in Scheme 4.
chiral centers by homonuclear 1H steady-state difference
The first step is the reduction of the trans double bond
NOE spectroscopy (DNOES) experiments, as shown in Fig- on the ω chain; this was achieved using H2 on 10% Pd/C,
ure 2. giving the corresponding oxo derivative 16 in 100% yield.
The synthesis of ent-2,3-dinor-5,6,13,14-tetrahydro-15-
The two epimers (as their trimethylsilyl ether (TMS) pen- The last two steps were achieved using the same strategy
tafluorobenzyl ester (PFB) derivatives)[7] co-chromato- that we had developed for 1, and the 15-oxo metabolite 4
graphed on capillary GC-NICIMS ([M Ϫ PFB] at m/z ϭ was obtained in 70% yield.
543, tR ϭ 10.16 min, 25 m NB54 column, 1 min at 160 °C,
then to 300 °C at 10 °C/min).
Derivatization of 4 as TMS-methyloxime-PFB resulted in
equivalent amounts of syn/anti isomers, fully separable by
Eur. J. Org. Chem. 2001, 809Ϫ819
811

T. Durand et al.
FULL PAPER
Scheme 4. Synthesis of ent-2,3-dinor-5,6,13,14-tetrahydro-15-oxo-
15F2t-isoprostane methyl ester 4; reagents and conditions: (a) H2,
Pd/C 10%, EtOH, 100%; (b) NaOH 1 , 40 °C; (c) CH2N2 70%
GC-NICIMS ([M Ϫ PFB]Ϫ at m/z ϭ 500, tR ϭ 10.48 and
10.57 min). The TMS-PFB derivative gave a single peak at
m/z ϭ 471 ([M Ϫ PFB]Ϫ) and tR ϭ 10.72 min.
ent-(15R)/(15S)-2,3-Dinor-5,6,13,14-tetrahydro-15F2t-
isoprostane 3 was obtained in 50% overall yield from oxo
derivative 16 (Scheme 5). The first step was the reduction
of the carbonyl function by the action of NaBH4, which
afforded the racemic mixture of 17 in 71% yield. ent-(15R)/
Scheme 6. Synthesis of ent-2,3-dinor-15F2t-isoprostane methyl ester
2a and its 15 epimer 2b; reagents and conditions: (a) BrϪ,
Ph3PϩCH2CH2CH2OTHP, KHMDS, THF, Ϫ80 °C, 70%;
(b) NH4F, THF/MeOH, reflux, 88%; (c) BzCl, pyridine, 97%;
(d) Me2AlCl, CH2Cl2, Ϫ25 °C, 92%; (e) CrO3, H2SO4, acetone, fol-
lowed by CH2N2, 91%; (f) HCl 3% methanolic solution, 77%;
(g) periodinane, CH2Cl2; (h) (EtO)2P(O)CH2C(O)C5H11, NaH,
THF, room temp., 64% overall yield for DessϪMartin oxidation
and HWE; (i) -Selectride , THF, Ϫ78 °C, 83%; (j) NaOH 1 , 40
°C, then CH2N2 75%
(15S)-2,3-Dinor-5,6,13,14-tetrahydro-15F2t-isoprostane
3
was obtained using the same strategy that we have used
for the other metabolites: i.e., saponification of the ester
functions, followed by methylation of the carboxyl at C1. It
is important to note that we were not able to separate the
(15R)/(15S) epimers in this saturated series.
KHMDS to afford the pure cis-β,γ-ethylenic derivative 18
in 70% yield. No trace of trans compound could be detected
by 13C and 1H NMR analysis. Deprotection of the triethyl-
silyl groups with NH4F gave the alcohol 19 in 88% yield.
Protection using benzoyl chloride afforded the colorless di-
esters 20 in 97% yield. Selective deprotection of the THP
group was carried out in the presence of dimethylalumi-
nium chloride, affording the primary alcohol 21 in 92%
yield. Oxidation of the primary alcohol in the presence of
CrO3/H2SO4 in dry acetone at Ϫ10 °C gave the correspond-
ing acid, which in the presence of an excess of diazometh-
ane was transformed in 91% yield into the methyl ester 22.
The tert-butyldiphenylsilyl ether 22 was converted into
Scheme 5. Synthesis of ent-(15RS)-2,3-dinor-5,6,13,14-tetrahydro-
15F2t-isoprostane methyl ester 3; reagents and conditions: (a) N-
aBH4, EtOH, 0 °C, 71%; (b) NaOH 1 , 40 °C; (c) CH2N2 83%
The (R) and (S) epimers of 3 cochromatographed when the alcohol 23 in 77% yield, using a solution of 3% hydro-
analyzed by GC-NICIMS as their TMS-PFB derivatives gen chloride[11]. DessϪMartin oxidation[13] of 23 gave the
(tR ϭ 10.36 min, [M Ϫ PFB]Ϫ at m/z ϭ 545).
unstable aldehyde 24, which was used immediately, without
The synthesis, using a similar strategy, of ent-2,3-dinor- purification, in the next step, to avoid any epimerization of
15F2t-isoprostane 2a and its 15 epimer 2b from aldehyde 6 the aldehyde. It is important to note that this DessϪMartin
is shown in Scheme 6. Our first attempts at the introduction oxidation gave a higher yield, avoiding any epimerization,
of the upper chain, according to the first strategy, failed than our first attempts using Swern conditions. Condensa-
because of some silyloxyl migration during the hydrolysis tion of 24 with diethyl oxoheptylphosphonate in the pres-
of the diisopropyl acetal 7. The introduction of the α chain ence of NaH afforded the trans-α,β-enone 25 in 64% overall
to arrive at 2a and 2b was achieved by using a three-carbon yield from the alcohol 23. Reduction of the oxo function of
homologating agent: 3-(tetrahydropyranyloxypropyl)tri- 25 with -Selectride afforded the epimeric allylic alcohols
phenyl phosphonium bromide.[12] The aldehyde 6 reacted 26, in 83% yield, as a 2:3 mixture that we were unable to
with the ylide derived from this phosphonium salt and separate by flash chromatography. Cleavage of the ester
812
Eur. J. Org. Chem. 2001, 809Ϫ819

Total Syntheses of Four Metabolites of 15-F2t-Isoprostane
FULL PAPER
25 MHz respectively or on a Bruker AMX360 at 360 and 90 MHz
respectively. 2D NMR spectra were recorded on a Bruker AMX360
spectrometer. Chemical shifts (δ) are quoted in ppm, coupling con-
stants (J) are given in Hz. The residual hydrogenated solvent peak
was used as internal reference (for CHCl3: δH ϭ 7.27, δC ϭ 77.0).
Ϫ Infrared spectra were obtained on a Beckman AccuLab2 spec-
trophotometer and absorption bands (ν˜) are given in cmϪ1. Ϫ Ele-
mental analysis were performed at the ‘‘Service de Microanalyses
de l’ENSCN’’ at Montpellier (France), with the maximum error in
the range of Ϯ0.4% of calculated. Ϫ Analytical TLC was per-
functions of 27 with 1  NaOH, followed by treatment with
diazomethane, gave a 3:2 mixture of methyl esters 2a and
2b in 75% yield. These two epimers were easily separated
by flash chromatography on silica gel, using cyclohexane/
ethyl acetate (30:70) as solvent.
Like 1a and 1b, the 15-epimers 2a and 2b co-chromato-
graphed as their PFB-TMS derivatives (tR ϭ 10.0 min, [M
Ϫ PFB]Ϫ at m/z ϭ 541) under the conditions shown above.
Compound 2a had the same GC-NICIMS behavior as 2,3-
dinor-15F2t-isoprostane derived from in vitro metabolism formed on Merck silica gel 60 F254, aluminium sheets. Viewing
of authentic 15F2t-isoprostane[7] and of the endogenous 2,3-
methods included UV light, iodine vapors and anisaldehyde dip-
ping. Ϫ Column chromatography was performed with Merck silica
gel (Geduran 40 to 63 µm or 63 to 200 µm particle size). Ϫ All air-
dinor-15F2t-isoprostane obtained from urine by immunoaf-
finity extraction using an antibody stereo- and enantioselec-
sensitive experiments were carried out under nitrogen, with freshly
tive towards the 15F2t-isoprostane configuration.[7]
distilled, dried solvents. Methylene chloride (CH2Cl2) was distilled
from CaH2. THF was distilled from sodium-benzophenone. Trie-
thylamine (Et3N) was dried with KOH; benzene and diethyl ether
Conclusions
were dried by standing with sodium wire. Methanol was distilled
after treatment with sodium. Acetone was dried with anhydrous
CaSO4. DMSO was purchased anhydrous and kept over 4-A mo-
lecular sieves.
˚
In conclusion, we describe here the first stereoselective
syntheses of ent-2,3-dinor-5,6-dihydro-15F2t-isoprostane
1a, its 15 epimer 1b, ent-2,3-dinor-15F2t-isoprostane 2a, its
15 epimer 2b, ent-(15R)/(15S)-2,3-dinor-5,6,13,14-tetrahy-
dro-15F2t-isoprostane 3, and ent-2,3-dinor-5,6,13,14-tetra-
hydro-15-oxo-15F2t-isoprostane 4 from the methyl ester 5.
This route makes possible the enantiospecific synthesis of
two recently identified major urinary metabolites of 15F2t-
isoprostane and of other putative metabolites. In addition
to their proven use for such identification, these compounds
should provide the basis for development of quantitative
For DNOES experiments, 1H NMR spectra were recorded on a
Bruker AMX 360 spectrometer operating in the pulse mode. Com-
pounds were dissolved in the indicated solvent (Table 1). The
probe-head temperature was 32 °C. Solutions were degassed by ar-
gon bubbling. The NOE procedure was as follows: the standard
Bruker library microprogram was used to perform steady-state
NOE difference spectroscopy. The experiments were performed
with interleaving. Thirty-two scans (preceded by two dummy scans
to establish equilibrium: l1 ϭ 2) were measured for each irradiation
assays directed towards integrated and accurate determina- frequency, and the entire process was automatically repeated to
provide the requisite signal-to-noise ratio. The irradiation time was
typically 3 s. A 90° read pulse was employed in all cases. The de-
coupler power setting was chosen so as to minimize frequency
spillover to neighboring multiplets. NOE values were calculated by
comparing summed peak heights in the vertically expanded differ-
ence spectra with the control irradiation spectra. (3,3-Diisopro-
poxypropyl)-triphenylphosphonium bromide was prepared as pre-
viously reported by Viala et al.[10]
tion of oxidative stress status in humans.
Experimental Section
Melting points were determined on a Büchi Tottoli capillary appar-
atus and were not corrected. Ϫ 1H and 13C NMR spectra were
recorded either on a Bruker AC100 spectrometer at 100 and
Table 1. NOE values for compounds 1a, 1b
Eur. J. Org. Chem. 2001, 809Ϫ819
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T. Durand et al.
FULL PAPER
(1S,2R,3R,4R)-2-(tert-Butyldiphenylsilyloxymethyl)-3-
formylmethyl-1,4-di-O-(triethylsilyl)cyclopentane-1,4-diol
(6): To a solution of ester 5 (250 mg, 372 µmol, 1 equiv.) in dry
toluene (3 mL) at Ϫ78 °C, under nitrogen atmosphere, was added
dropwise DIBAL-H (1 /toluene, 410 µL, 410 µmol, 1.1 equiv.).
cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 1.03 [s, 9 H, C(CH3)3], 1.10Ϫ1.24
(m, 12 H, 3-H, 4-H, 5-H, OCH2CH3), 1.51Ϫ1.62 (m, 3 H, 2-H, 8-
H), 2.02Ϫ2.04 (m, 1 H, 6-H), 2.23Ϫ2.34 (m, 1 H, 10-H), 2.39 (dt,
J ϭ 4.5 and 6.9 Hz, 1 H, 8Ј-H), 3.42Ϫ3.45 (m, 2 H, OCH2CH3),
3.53Ϫ3.58 (m, 2 H, OCH2CH3), 3.73 (dd, J ϭ 5.2 and 10 Hz, 1 H,
The resulting mixture was stirred for 30 min at Ϫ78 °C, then hy- 11Ј-H), 3.94 (dt, J ϭ 4.5 and 6.6 Hz, 1 H, 7-H), 4.23 (dt, J ϭ 4.5
drolyzed with MeOH (500 µL). The reaction mixture was neutral-
ized with a solution of HCl (2 ); then the aqueous layers were
extracted three times with EtOAc. The organic layers were dried
with Na2SO4 and evaporated under reduced pressure before being
chromatographed on silica gel (cyclohexane/ethyl acetate, 97:3) to
and 6.7 Hz, 1 H, 9-H), 4.41 (t, J ϭ 5.8 Hz, 1 H, 1-H), 7.37Ϫ7.41
(m, 6 H, Ar-H), 7.62Ϫ7.65 (m, 4 H, Ar-H). Ϫ 13C NMR (CDCl3):
δ ϭ 15.3 (OCH2CH3), 19.1 [C(CH3)3], 24.9 (C-4), 26.9 [C(CH3)3],
28.1 (C-3), 28.3 (C-5), 33.5 (C-2), 42.9 (C-8), 48.7 (C-6), 51.2 (C-
10), 60.9 (OCH2CH3), 63.5 (C-11), 75.5 (C-9), 76.6 (C-7), 102.8
give the colorless oil 6 (221 mg, 93%): Rf 0.58 (cyclohexane/ ethyl (C-1), 127.8 (C-Ar), 129.8 (C-Ar), 133.1 (C-Ar), 135.6 (C-Ar). Ϫ
acetate, 90:10). Ϫ 1H NMR (CDCl3): δ ϭ 0.40Ϫ0.70 [m, 12 H,
(CH3CH2)3Si], 0.75Ϫ0.98 [m, 18 H, (CH3CH2)3Si], 1.04 [s, 9 H,
C(CH3)3], 2.12 (m, 2 H, 2-H, 5-H), 2.20Ϫ2.47 (m, 1 H, 3-H),
2.50Ϫ2.72 (m, 3 H, 5Ј-H, 7-H), 3.57 (m, 2 H, 6-H), 3.87 (q, J ϭ
7.7 Hz, 1 H, 4-H), 4.05 (m, 1 H, 1-H), 7.31Ϫ7.50 (m, 6 H, Ar-H),
7.51Ϫ7.67 (m, 4 H, Ar-H), 9.7 (s, 1 H, 8-H). Ϫ 13C NMR (CDCl3):
δ ϭ 4.5 [(CH3CH2)3Si], 4.7 [(CH3CH2)3Si], 6.5 [(CH3CH2)3Si], 6.6
[(CH3CH2)3Si], 18.9 [C(CH3)3], 26.7 [C(CH3)3], 42.7 (C-3), 43.1 (C-
7), 44.7 (C-5), 50.1 (C-2), 62.7 (C-6), 72.7 (C-1), 75.9 (C-4), 127.5
(C-Ar), 129.6 (C-Ar), 132.8 (C-Ar), 135.5 (C-Ar), 202.4 (C-8).
C31H48O5Si (528.8): calcd. C 70.41, H 9.15; found C 70.34, H 9.12
(1S,2R,3R,4R)-1,4-Di-O-benzoyl-2-(tert-butyldiphenyl-
silyloxymethyl)-3-(5,5-diethoxypentyl)cyclo pentane-
1,4-diol (9): To a solution of diol 8 (113 mg, 219 µmol, 1 equiv.) in
dry pyridine (1 mL) under nitrogen atmosphere, was added benzoyl
chloride (635 µL, 547 µmol, 2.5 equiv.). The reaction mixture was
stirred for 2 h at room temperature. The pyridine was evaporated
under reduced pressure and the residue was purified by flash chro-
matography on silica gel (cyclohexane/ethyl acetate, 95:5) to pro-
vide 9 (151 mg, 91%): Rf 0.51 (cyclohexane/ethyl acetate, 50:50). Ϫ
IR: ν˜ ϭ 1710 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 1.1 [s, 9 H,
C(CH3)3], 1.14Ϫ1.23 (m, 6 H, OCH2CH3), 1.27Ϫ1.36 (m, 2 H, 3-
H), 1.37Ϫ1.49 (m, 4 H, 4-H, 5-H), 1.51Ϫ1.59 (m, 2 H, 2-H), 1.91
(dt, J ϭ 3.2 and 15.6 Hz, 1 H, 8-H), 2.54Ϫ2.63 (m, 2 H, 6-H, 10-
H), 2.94 (dt, J ϭ 7.4 and 15.6 Hz, 1 H, 8Ј-H), 3.44Ϫ3.5 (m, 2 H,
OCH2CH3), 3.56Ϫ3.64 (m, 2 H, OCH2CH3), 3.68Ϫ3.72 (m, 1 H,
11-H), 3.84Ϫ3.88 (m, 1 H, 11Ј-H), 4.37Ϫ4.51 (m, 1 H, 1-H),
5.3Ϫ5.35 (m, 1 H, 7-H), 5.42Ϫ5.45 (m, 1 H, 9-H), 7.36Ϫ7.47 (m,
10 H, Ar-H), 7.54Ϫ7.59 (m, 2 H, Ar-H), 7.67Ϫ7.72 (m, 4 H, Ar-
H), 8.01Ϫ8.07 (m, 4 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 15.3
(OCH2CH3), 19.1 [C(CH3)3], 23.3 (C-3), 26.9 [C(CH3)3], 27.8 (C-
4), 28.2 (C-5), 33.5 (C-2), 38.8 (C-8), 45.5 (C-6), 48.8 (C-10), 60.9
(OCH2CH3), 61.8 (C-11), 77.2 (C-9), 79.5 (C-7), 102.9 (C-1), 127.7
(C-Ar), 128.3 (C-Ar), 129.6 (C-Ar), 129.7 (C-Ar), 130.5 (C-Ar),
132.8 (C-Ar), 133.1 (C-Ar), 135.7 (C-Ar), 166 [C(O)], 166.3 [C(O)].
Ϫ C45H56O7Si (737.0): calcd. C 73.33, H 7.66; found C, 73.45, H
7.59.
(1S,2R,3R,4R)-2-(tert-Butyldiphenylsilyloxymethyl)-3-[(Z)-
5,5-bis(isopropyloxy)pent-2-enyl]-1,4-di-O-(triethylsilyl)cyclo-
pentane-1,4-diol (7): To a suspension of (3,3-diisopropoxypropyl)-
triphenylphosphonium bromide[10] (345 mg, 686 µmol, 4 equiv.) in
dry THF (2 mL) at Ϫ80 °C, was added NaN(SiMe3)2 (1 /THF,
653 µL, 653 µmol, 3.8 equiv.). The orange solution of ylide was
stirred for 2 h at Ϫ80 °C. A solution of aldehyde 6 (210 mg, 172
µmol, 1 equiv.) in dry THF (750 µL) was added to the ylide. After
slow warming to room temperature over 2 h, the reaction mixture
was hydrolyzed with saturated, aqueous NH4Cl solution (10 mL)
and water (10 mL), diluted with diethyl ether (30 mL), and washed
with brine (5 mL). The aqueous layers were extracted with diethyl
ether (3ϫ 10 mL), and the combined extracts were washed with
brine (10 mL). All organic solutions were dried with Na2SO4 and
concentrated, giving crude product. Flash chromatography over sil-
ica gel, cyclohexane/ethyl acetate, 98:2) gave pure diisopropyl acetal
1
7 (233 mg, 83%): Rf 0.62 (cyclohexane/ethyl acetate, 90:10). Ϫ H
NMR (CDCl3): δ ϭ 0.46 [t, J ϭ 7.9 Hz, 6 H, (CH3CH2)3Si], 0.55
[t, J ϭ 7.9 Hz, 6 H, (CH3CH2)3Si], 0.85 [q, J ϭ 7.9 Hz, 9 H, (1S,2R,3R,4R)-1,4-Di-O-(benzoyl)-2-(tert-butyldiphenyl-
(CH3CH2)3Si], 0.93 [q, J ϭ 7.9 Hz, 9 H, (CH3CH2)3Si], 1.04 [s, 9 silyloxymethyl)-3-(formylbutyl)cyclopentane-1,4-diol (10): An aque-
H, C(CH3)3], 1.1Ϫ1.16 [m, 12 H, OCH(CH3)2], 1.5 (dt, J ϭ 5.2 ous solution of FeCl3 (0.02 , 125 µL, 2.5 µmol, 0.025 equiv.) was
and 13.5 Hz, 1 H, 8-H), 1.97Ϫ2.02 (m, 1 H, 5-H), 2.07Ϫ2.15 (m, added to a solution of acetal 9 (75 mg, 99.5 µmol, 1 equiv.) in 2
1 H, 10-H), 2.17Ϫ2.26 (m, 3 H, 2-H, 5Ј-H, 6-H), 2.27Ϫ2.36 (m, mL of dry acetone under nitrogen atmosphere. The resulting mix-
2 H, 2Ј-H, 8-H), 3.57Ϫ3.59 (m, 2 H, 11-H), 3.78Ϫ3.85 [m, 2 H, ture was stirred for 2 h at room temperature, and then quenched
OCH(CH3)2], 3.91 (q, J ϭ 6.8 Hz, 1 H, 7-H), 4.06 (dt, J ϭ 4.4 and
with brine (5 mL). The aqueous layer was extracted with diethyl
7.7 Hz, 1 H, 9-H), 4.49 (t, J ϭ 5.5 Hz, 1 H, 1-H), 5.37Ϫ5.42 (m, 2 ether (3ϫ 5 mL), and the combined extracts were washed with
H, 3-H, 4-H), 7.33Ϫ7.42 (m, 6 H, Ar-H), 7.6Ϫ7.63 (m, 4H, Ar-H). brine (5 mL). All organic solutions were dried with Na2SO4 and
Ϫ
13C NMR (CDCl3): δ ϭ 4.7 [(CH3CH2)3Si], 4.9 [(CH3CH2)3Si], concentrated, giving crude aldehyde 10 (57 mg, 87%), which was
6.8 [(CH3CH2)3Si], 6.8 [(CH3CH2)3Si], 19.2 [C(CH3)3], 22.6
[OCH(CH3)2], 23.3 [OCH(CH3)2], 25.9 (C-5), 26.9 [C(CH3)3], 33.8 hexane/ethyl acetate, 80:20). Ϫ IR: ν˜ ϭ 1710 cmϪ1. Ϫ 1H NMR
(C-2), 45.1 (C-8), 48.2 (C-6), 50.7 (C-10), 62.6 (C-11), 67.8 (CDCl3): δ ϭ 1.06 [s, 9 H, C(CH3)3], 1.46 (m, 6 H, 3-H, 4-H, 5-
[OCH(CH3)2], 73.2 (C-9), 76.4 (C-7), 100 (C-1), 124.9 (C-3), 127.6 H), 1.86 (m, 1 H, 8-H), 2.34 (m, 2 H, 2-H), 2.58 (m, 2 H, 6-H, 10-
(C-Ar), 129.6 (C-Ar), 130.7 (C-4), 133.5 (C-Ar), 135.7 (C-Ar). Ϫ H), 2.97 (dt, J ϭ 7.5 and 14 Hz, 1 H, 8Ј-H), 3.79 (m, 2 H, 11-H),
C45H78O5Si3 (783.4): calcd. C 69.00, H 10.04; found C 69.04, H 5.39 (m, 2 H, 7-H, 9-H), 7.43 (m, 10 H, Ar-H), 7.66 (m, 6 H, Ar-
used for the next steps without further purification. Rf 0.34 (cyclo-
10.08.
H), 8.05 (m, 4 H, Ar-H), 9.72 (s, 1 H, 1-H).
(1S,2R,3R,4R)-2-(tert-Butyldiphenylsilyloxymethyl)-3-
[5,5-bis(isopropyloxy)pentyl]cyclopentane-1,4-diol (8): A mixture of
7 (180 mg, 230 µmol, 1 equiv.) and 10% Pd/C (20 mg) in absolute
ethanol (5 mL) was hydrogenated at 40 psi for 4 h. The mixture
was filtered and the filtrate concentrated to provide 8 as a colorless
(1S,2R,3R,4R)-1,4-Bis-O-(benzoyl)-2-(tert-butyldiphenylsilyloxy-
methyl)-3-(methoxycarbonylbutyl)cyclopentane-1,4-diol (11): To a
solution of aldehyde 10 (57 mg, 86 µmol, 1 equiv.) in THF (2 mL)
at room temperature, was added m-CPBA (59 mg, 344 µmol, 4
equiv.). The resulting mixture was stirred for 12 h; then excess m-
oil (113 mg, 95%): Rf 0.45 (CH2Cl2/MeOH 90:10). Ϫ IR: ν˜ ϭ 3360 CPBA was destroyed using Me2S (25 µL, 344 µmol, 4 equiv.). Stir-
814 Eur. J. Org. Chem. 2001, 809Ϫ819

Total Syntheses of Four Metabolites of 15-F2t-Isoprostane
ring was continued for an additional 30 min. The solvent was re- (316 µL, 885 µmol, 2.5 equiv.) and NaH (60% suspension in oil, 39
FULL PAPER
moved under reduced pressure; then the crude material was diluted
with diethyl ether and esterified by addition of diazomethane. After
concentration, flash chromatography on silica gel (cyclohexane/
mg, 974 µmol) in THF (2 mL). The reaction was stirred for 10
minutes, neutralized with saturated NaCl, and extracted with di-
ethyl ether (3ϫ 10 mL). Organic phases were washed with brine,
ethyl acetate, 95:5) gave 11 (53 mg, 89%): Rf 0.73 (cyclohexane/ dried with Na2SO4, filtered, and evaporated under reduced pressure
ethyl acetate, 70:30). Ϫ IR: ν˜ ϭ 1720, 1710 cmϪ1. Ϫ 1H NMR to give 173 mg of 14 (89%) after purification by flash chromato-
(CDCl3): δ ϭ 1.08 [s, 9 H, C(CH3)3], 1.35Ϫ1.46 (m, 4 H, 4-H, 5- graphy on silica gel (cyclohexane/ethyl acetate, 90:10): Rf 0.21
H), 1.49Ϫ1.5 (m, 2 H, 3-H), 1.89 (dt, J ϭ 3.3 and 15.6 Hz, 1 H, 8-
(cyclohexane/ethyl acetate, 70:30). Ϫ IR: ν˜ ϭ 1720, 1710, 1670
1
H), 2.22 (t, J ϭ 6.6 Hz, 2 H, 2-H), 2.47Ϫ2.57 (m, 2 H, 6-H, 10-H), cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 0.88 (t, J ϭ 7.9 Hz, 3 H, 18-H),
2.92 (dt, J ϭ 5.7 and 7.4 Hz, 1 H, 8Ј-H), 3.6 (s, 3 H, OCH3), 3.66 1.26Ϫ1.31 (m, 4 H, 16-H, 17-H), 1.37Ϫ1.43 (m, 4 H, 4-H, 5-H),
(dd, J ϭ 4.9 and 10.7 Hz, 1 H, 11-H), 3.84 (dd, J ϭ 4.7 and
10.7 Hz, 1 H, 11Ј-H), 5.29 (m, 1 H, 7-H), 5.40 (m, 1 H, 9-H), 7.38
1.55Ϫ1.62 (m, 4 H, 3-H, 15-H), 2.00 (dt, J ϭ 3.1 and 15.9 Hz, 1
H, 8-H), 2.27 (t, J ϭ 7.4 Hz, 2 H, 2-H), 2.53 (t, J ϭ 7.5 Hz, 2 H,
(m, 10 H, Ar-H), 7.54 (m, 2 H, Ar-H), 7.64Ϫ7.68 (m, 4 H, Ar-H), 14-H), 2.56Ϫ2.62 (m, 1 H, 6-H), 2.95 (dt, J ϭ 7.5 and 15.9 Hz, 1
8 (t, J ϭ 8.3 Hz, 4 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 19.1
H, 8Ј-H), 3.23Ϫ3.29 (m, 1 H, 10-H), 3.62 (s, 3 H, OCH3),
(C(CH3)3), 25 (C-3), 26.9 (C(CH3)3), 27.5 (C-5), 27.8 (C-4), 33.9 5.22Ϫ5.26 (m, 1 H, 7-H), 5.28Ϫ5.33 (m, 1 H, 9-H), 6.27 (dd, J ϭ
(C-2), 38.8 (C-8), 45.4 (C-6), 48.7 (C-10), 51.4 (OCH3), 61.7 (C-
11), 77.6 (C-9), 79.5 (C-7), 127.7 (C-Ar), 128.3 (C-Ar), 129.6 (C-
1 and 15.8 Hz, 1 H, 12-H), 6.71 (dd, J ϭ 9.1 and 15.8 Hz, 1 H, 11-
H), 7.35 (t, J ϭ 7.7 Hz, 4 H, Ar-H), 7.54 (t, J ϭ 7.4 Hz, 2 H, Ar-
Ar), 129.8 (C-Ar), 130.5 (C-Ar), 132.8 (C-Ar), 135.7 (C-Ar), 166.2 H), 8.02 (t, J ϭ 7.8 Hz, 4 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ
[C(O)], 166.8 [C(O)], 174 (C-1). Ϫ C42H48O7Si (692.9): calcd. C
72.8, H 6.98; found C, 72.65, H 7.06.
13.9 (C-18), 22.5 (C-16), 23.8 (C-15), 24.9 (C-3), 27.5 (C-5), 28.3
(C-4), 31.4 (C-17), 33.8 (C-2), 38 (C-8), 40.9 (C-14), 47.7 (C-6), 50.2
(C-10), 51.5 (OCH3), 77.4 (C-9), 78.4 (C-7), 128.4 (C-Ar), 129.6 (C-
Ar), 132.4 (C-12), 133.2 (C-Ar), 141.5 (C-11), 165.9 [C(O)], 166.1
[C(O)], 173.8 (C-1), 199.8 (C-13). Ϫ C33H40O7 (548.7): calcd. C
72.24, H 7.35; found C, 72.31, H 7.40.
(1S,2R,3R,4R)-1,4-Di-O-benzoyl-3-(methoxycarbonylbutyl)-2-
(hydroxymethyl)cyclopentane-1,4-diol (12): Acetyl chloride (770 µL)
was added dropwise to methanol (18 mL), and the hydrogen chlor-
ide solution obtained was cooled to 20 °C. A solution of the silyl
derivative 11 (400 mg, 577 µmol) in diethyl ether (18 mL) was ad-
ded, and the mixture was stirred at room temperature overnight,
and then neutralized with saturated NaHCO3 (10 mL) and ex-
tracted with diethyl ether (3ϫ 50 mL). The organic layers were
dried with Na2SO4 and concentrated under reduced pressure, and
the crude material was purified by flash chromatography on silica
gel (cyclohexane/ethyl acetate, 85:15) to provide alcohol 12 (261
mg, 83%): Rf 0.21 (cyclohexane/ethyl acetate, 70:30). Ϫ IR: ν˜ ϭ
(1S,2S,3R,4R)-1,4-Di-O-benzoyl-3-(methoxycarbonylbutyl)-2-
[(3RS,E)-3-hydroxyoct-1-enyl]cyclopentane-1,4-diol (15): To a co-
oled (Ϫ78 °C) solution of 14 (20 mg, 36.4 µmol) in dry THF (400
µL) was added a solution of -Selectride (1  in THF, 40 µL, 40
µmol). The mixture was stirred at Ϫ78 °C for 20 minutes, quenched
with MeOH (10 µL), and diluted with diethyl ether (5 mL). The
organic layer was washed with 1  NH4Cl (5 mL), dried with
Na2SO4, filtered, evaporated, and chromatographed (cyclohexane/
ethyl acetate, 90:10) to give a mixture of isomers of 15 (20 mg,
100%) as a colorless oil. Rf 0.37 (cyclohexane/ethyl acetate, 70:30).
1
3520, 1720, 1710 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.2Ϫ1.57 (m, 4
H, 4-H, 5-H), 1.65Ϫ1.73 (m, 2 H, 3-H), 2.05 (dt, J ϭ 3 and
15.6 Hz, 1 H, 8-H), 2.34 (t, J ϭ 7.5 Hz, 2 H, 2-H), 2.53Ϫ2.67 (m,
2 H, 6-H, 10-H), 2.91 (dt, J ϭ 7.5 and 15.1 Hz, 1 H, 8Ј-H), 3.66
(s, 3 H, OCH3), 3.74 (dd, J ϭ 7.2 and 10.8 Hz, 1 H, 11-H), 3.88
(dd, J ϭ 5 and 10.8 Hz, 1 H, 11Ј-H), 5.23Ϫ5.27 (m, 1 H, 7-H),
5.40 (dt, J ϭ 3.4 and 7.4 Hz, 1 H, 9-H), 7.44 (q, J ϭ 7.4 Hz, 4 H,
Ar-H), 7.56 (t, J ϭ 7.5 Hz, 2 H, Ar-H), 8.06 (t, J ϭ 8.5 Hz, 4 H,
Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 25 (C-3), 27.3 (C-5), 27.7 (C-4),
33.8 (C-2), 38 (C-8), 45.7 (C-6), 49.2 (C-10), 51.5 (OCH3), 60.7(C-
11), 77.2 (C-9), 78.9 (C-7), 128.4 (C-Ar), 129.6 (C-Ar), 130.1 (C-
Ar), 130.4 (C-Ar), 133 (C-Ar), 133.1 (C-Ar), 166.2 [C(O)], 166.8
[C(O)], 174 (C-1). Ϫ C26H30O7 (454.5): calcd. C 68.71, H 6.65;
found C, 68.79, H 6.57.
Ϫ IR: ν˜ ϭ 3530, 1720, 1710 cmϪ1
.
1
Minor Isomer: H NMR (CDCl3): δ ϭ 0.85Ϫ0.92 (m, 3 H, 18-H),
1.23Ϫ1.28 (m, 4 H, 16-H, 17-H), 1.41Ϫ1.46 (m, 8 H, 4-H, 5-H, 14-
H, 15-H), 1.57Ϫ1.65 (m, 2 H, 3-H), 1.92Ϫ1.97 (m, 1 H, 8-H), 2.27
(t, J ϭ 7.3 Hz, 2 H, 2-H), 2.47Ϫ2.52 (m, 1 H, 6-H), 2.84Ϫ2.93 (m,
1 H, 8Ј-H), 3.06Ϫ3.11 (m, 1 H, 10-H), 3.62 (s, 3 H, OCH3), 4.63
(q, J ϭ 6.1 Hz, 1 H, 13-H), 5.14Ϫ5.23 (m, 2 H, 7-H, 9-H), 5.42Ϫ5.5
(m, 1 H, 11-H), 5.61Ϫ5.65 (m, 1 H, 12-H), 7.39 (t, J ϭ 7.6 Hz, 4
H, Ar-H), 7.54 (t, J ϭ 7.6 Hz, 2 H, Ar-H), 8.02 (d, J ϭ 8.3 Hz, 4
H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 14 (C-18), 22.6 (C-16), 25
(C-3), 26.9 (C-15), 27.3 (C-5), 28.3 (C-4), 31.7 (C-17), 33.7 (C-2),
37.2 (C-14), 38 (C-8), 47.1 (C-6), 50.2 (C-10), 51.4 (OCH3), 72.6
(C-13), 78.7 (C-7), 78.8 (C-9), 126.3 (C-11), 128.3 (C-Ar), 129.6 (C-
Ar), 130.3 (C-Ar), 133 (C-Ar), 137.3 (C-12), 166 [C(O)], 166.3
[C(O)], 174.2 (C-1). Ϫ C33H42O7 (550.7): calcd. C 71.97, H 7.69;
found C, 72.21, H 7.80.
(1S,2S,3R,4R)-1,4-Di-O-benzoyl-3-(methoxycarbonylbutyl)-2-[(E)-
3-oxooct-1-enyl]cyclopentane-1,4-diol (14): To a solution of oxalyl
chloride (77 µL, 885 µmol, 2.5 equiv.) in dry CH2Cl2 (2.8 mL) at
Ϫ60 °C was added dropwise under N2 a solution of DMSO (125
µL, 1.17 mmol, 5 equiv.) in CH2Cl2 (400 µL). After 15 minutes, the
solution of 12 (161 mg, 354 mmol, 1 equiv.) in CH2Cl2 (800 µL)
was added dropwise and the reaction mixture was stirred for 40
minutes at Ϫ60 °C. Then triethylamine (197 µL, 1.41 µmol, 4
equiv.) was added and the reaction mixture was kept for 10 minutes
at Ϫ60 °C before being allowed to cool to room temperature. The
mixture was diluted with water (2 mL) and extracted three times
with diethyl ether (15 mL). Organic layers were washed with brine,
dried with Na2SO4, filtered, and evaporated under reduced pres-
sure, and the crude product was used immediately for the next step.
To a cooled (Ϫ10 °C) solution of aldehyde (previous crude product)
in dry THF (2 mL) was added dropwise a solution of ylide pre-
pared at room temperature from diethyl 2-oxoheptylphosphonate
1
Major Isomer: H NMR (CDCl3): δ ϭ 0.85Ϫ0.92 (m, 3 H, 18-H),
1.23Ϫ1.28 (m, 4 H, 16-H, 17-H), 1.41Ϫ1.46 (m, 8 H, 4-H, 5-H, 14-
H, 15-H), 1.57Ϫ1.65 (m, 2 H, 3-H), 1.92Ϫ1.97 (m, 1 H, 8-H), 2.27
(t, J ϭ 7.3 Hz, 2 H, 2-H), 2.47Ϫ2.52 (m, 1 H, 6-H), 2.84Ϫ2.93 (m,
1 H, 8Ј-H), 3.06Ϫ3.11 (m, 1 H, 10-H), 3.62 (s, 3 H, OCH3), 4.09
(q, J ϭ 6.5 Hz, 1 H, 13-H), 5.14Ϫ5.23 (m, 2 H, 7-H, 9-H), 5.46
(dd, J ϭ 8.6 and 15.4 Hz, 1 H, 11-H), 5.63 (m, 1 H, 12-H), 7.39 (t,
J ϭ 7.6 Hz, 4 H, Ar-H), 7.54 (t, J ϭ 7.6 Hz, 2 H, Ar-H), 8.02 (d,
J ϭ 8.3 Hz, 4 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 14 (C-18), 22.6
(C-16), 25 (C-3), 26.9 (C-15), 27.4 (C-5), 28.3 (C-4), 31.7 (C-17),
33.8 (C-2), 376 (C-14), 37.9 (C-8), 47.1 (C-6), 50.2 (C-10), 51.4
(OCH3), 72.6 (C-13), 78.7 (C-7), 78.8 (C-9), 126.3 (C-11), 128.3 (C-
Eur. J. Org. Chem. 2001, 809Ϫ819
815

T. Durand et al.
FULL PAPER
Ar), 129.6 (C-Ar), 130.3 (C-Ar), 133 (C-Ar), 137.5 (C-12), 166 270 µL). The same procedure as for 1 was used to give 4 (8 mg,
[C(O)], 166.3 [C(O)], 174.2 (C-1). Ϫ C33H42O7 (550.7): calcd. C 70%): Rf 0.66 (ethyl acetate/acetic acid, 95:5). Ϫ IR: ν˜ ϭ 3510,
1
71.97, H 7.69; found C 72.21, H 7.80.
1720, 1710 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 0.87 (t, J ϭ 7.1 Hz, 3
H, 18-H), 1.23Ϫ1.39 (m, 7 H, 4-H, 11-H, 16-H, 17-H), 1.53Ϫ1.65
(m, 8 H, 3-H, 5-H, 8-H, 11Ј-H, 15-H), 1.93Ϫ2.03 (m, 2 H, 6-H,
10-H), 2.30 (t, J ϭ 7.3 Hz, 2 H, 2-H), 2.31Ϫ2.39 (m, 1 H, 8Ј-H),
2.38 (t, J ϭ 7.5 Hz, 2 H, 14-H), 2.47 (q, J ϭ 8.2 Hz, 2 H, 12-H),
3.64 (s, 3 H, OCH3), 3.89 (dt, J ϭ 3.7 and 7.1 Hz, 1 H, 7-H), 3.95
(dt, J ϭ 3.2 and 6.7 Hz, 1 H, 9-H). Ϫ 13C NMR (CDCl3): δ ϭ 13.9
(C-18), 21.8 (C-11), 22.4 (C-16), 23.5 (C-15), 24.9 (C-3), 27.4 (C-
5), 27.7 (C-4), 31.4 (C-17), 33.9 (C-2), 41.3 (C-14), 42.9 (C-8, C-
12), 49 (C-6), 49.5 (C-10), 51.5 (OCH3), 76.3 (C-9), 76.5 (C-7),
174.1 (C-1), 211.3 (C-13). Ϫ [α]2D0 ϭ Ϫ10 (c ϭ 10Ϫ3, MeOH). Ϫ
NICI-MS of PFB-TMS derivative, carboxylate anion [M Ϫ PFB]Ϫ
at m/z ϭ 471; NICI of PFB-MO-TMS derivatives (syn/anti iso-
mers), carboxylate anion at m/z ϭ 500.
ent-15(RS)-2,3-Dinor-5,6-dihydro-15-F2t-isoprostane Methyl Ester
(1a and 1b): To a solution of 15 (24 mg, 53.2 µmol) in methanol
(350 µL) and THF (230 µL) was added NaOH (1  solution, 400
µL). The mixture was stirred for two hours at 40 °C. NaHSO4 (1
 solution, 710 µL) was then added for neutralization. The reaction
was diluted in water (1 mL) and extracted with ethyl acetate (3ϫ 5
mL). The organic layers were dried with Na2SO4 and evaporated.
The residue was esterified with diazomethane. After neutralization
of excess with acetic acid and evaporation of solvents, the crude
product was purified by flash chromatography on silica gel (cyclo-
hexane/ethyl acetate, 30:70) to give 15 mg of 1a and 1b in a ratio
of 3:2.
ent-(15R)-2,3-Dinor-5,6-dihydro-15-F2t-isoprostane Methyl Ester
(1a): Rf 0.51 (ethyl acetate/acetic acid, 95:5). Ϫ IR: ν˜ ϭ 3520, 1720
(1S,2S,3R,4R)-1,4-Di-O-benzoyl-3-(methoxycarbonylbutyl)-2-
[(3RS)-octanol]cyclopentane-1,4-diol (17): To a cooled (0 °C) solu-
tion of 16 (30 mg, 66.5 µmol, 1 equiv.) in distilled ethanol (140 µL)
was added NaBH4 (1 mg, 26.4 µmol, 0.4 equiv.), diluted in the
same solvent (140 µL). The reaction was stirred for 4 hours at room
temperature. The mixture was hydrolyzed with 1 mL of brine and
extracted with 3ϫ 2 mL of ether. The organic layers were dried and
evaporated with Na2SO4 and evaporated under reduced pressure to
give 21.4 mg of 17 (71%), after purification by flash chromato-
graphy on silica gel (cyclohexane/ethyl acetate, 90:10): Rf 0.47
(cyclohexane/ethyl acetate, 70:30). Ϫ IR: ν˜ ϭ 3520, 1720 cmϪ1. Ϫ
1H NMR (CDCl3): δ ϭ 0.86 (t, J ϭ 7.2 Hz, 3 H, 18-H), 1.22Ϫ1.29
(m, 8 H, 4-H, 11-H, 16-H, 17-H), 1.4Ϫ1.66 (m, 9 H, 3-H, 5-H, 12-
H, 14-H, 15-H), 1.89 (d, J ϭ 16 Hz, 1 H, 8-H), 2.3 (q, J ϭ 6.9 Hz,
2 H, 2-H), 2.39Ϫ2.47 (m, 3 H, 6-H, 10-H, 12Ј-H), 2.85 (dt, J ϭ 8.1
and 16 Hz, 1 H, 8Ј-H), 3.58Ϫ3.63 (m, 1 H, 13-H), 3.63 (s, 3 H,
OCH3), 5.15Ϫ5.22 (m, 2 H, 7-H, 9-H), 7.39Ϫ7.43 (m, 4 H, Ar-H),
7.52Ϫ7.56 (m, 2 H, Ar-H), 8.01Ϫ8.03 (m, 4 H, Ar-H). Ϫ 13C NMR
(CDCl3): δ ϭ 14 (C-18), 22.6 (C-16), 22.9 (C-11), 25.1 (C-3), 25.3
(C-4), 26.9 (C-15), 27.5 (C-5), 31.8 (C-17), 33.8 (C-2), 34.1 (C-12),
35.5 (C-14), 35.9 (C-14Ј), 39.9 (C-8), 46.3 (C-6), 46.5 (C-10), 51.5
(OCH3), 71.6 (C-13), 72.1 (C-7), 78.8 (C-9), 128.3 (C-Ar), 129.6
(C-Ar), 130.4 (C-Ar), 132.9 (C-Ar), 166.3 [C(O)], 174 (C-1). Ϫ
C33H44O7 (552.7): calcd. C 71.71, H 8.02; found C 71.61, H 7.97.
1
cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 0.87 (t, J ϭ 6.5 Hz, 3 H, 18-H),
1.24Ϫ1.41 (m, 10 H, 4-H, 5-H, 15-H, 16-H, 17-H), 1.56Ϫ1.65 (m,
5 H, 3-H, 8-H, 14-H), 1.97 (brs, 1 H, OH), 2.10 (t, J ϭ 4.5 Hz, 1
H, 6-H), 2.29 (t, J ϭ 7.3 Hz, 2 H, 2-H), 2.38 (dt, J ϭ 6.9 and
14 Hz, 1 H, 8Ј-H), 2.70Ϫ2.76 (m, 1 H, 10-H), 3.64 (s, 3 H, OCH3),
3.93Ϫ3.96 (m, 1 H, 7-H), 3.98Ϫ4 (m, 1 H, 9-H), 4.01Ϫ4.07 (m, 1
H, 13-H), 5.35 (dd, J ϭ 9.7 and 15.3 Hz, 1 H, 11-H), 5.55 (dd, J ϭ
6.7 and 15.3 Hz, 1 H, 12-H). Ϫ [α]2D0 ϭ Ϫ5.9 (c ϭ 0.76·10Ϫ3
,
MeOH). Ϫ NICI-MS of PFB-TMS derivative: carboxylate anion
[M Ϫ PFB]Ϫ at m/z ϭ 543.
ent-(15S)-2,3-Dinor-5,6-dihydro-15-F2t-isoprostane Methyl Ester
(1b): Rf 0.6 (ethyl acetate/acetic acid, 95:5). Ϫ IR: ν˜ ϭ 3520, 1720
1
cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 0.86 (t, J ϭ 6.7 Hz, 3 H, 18-H),
1.24Ϫ1.37 (m, 10 H, 4-H, 5-H, 15-H, 16-H, 17-H), 1.56Ϫ1.62 (m,
5 H, 3-H, 8-H, 14-H), 1.88 (brs, 1 H, OH), 2.08 (m, 1 H, 6-H),
2.27Ϫ2.39 (m, 3 H, 2-H, 8Ј-H), 2.71Ϫ2.75 (m, 1 H, 10-H), 3.65 (s,
3 H, OCH3), 3.91Ϫ4 (m, 2 H, 7-H, 9-H), 4.04 (q, J ϭ 6.7 Hz, 1 H,
13-H), 5.36 (dd, J ϭ 9.8 and 15.3 Hz, 1 H, 11-H), 5.55 (dd, J ϭ
6.7 and 15.3 Hz, 1 H, 12-H). Ϫ [α]2D0 ϭ Ϫ16 (c ϭ 10Ϫ3, MeOH).
Ϫ NICI-MS of PFB-TMS derivative: carboxylate anion [M Ϫ
PFB]Ϫ at m/z ϭ 543.
(1S,2S,3R,4R)-1,4-Di-O-benzoyl-3-(methoxycarbonylbutyl)-2-(3-
oxooctanyl)cyclopentane-1,4-diol (16): A solution of 14 (45.3 mg,
0.1 mmol) was hydrogenated with Pd/C (4.5 mg) in ethanol (2 mL)
for 4 hours at atmospheric pressure. The mixture was filtered
through Celite and evaporated under reduced pressure to give 45.4
mg of 16 (100%): Rf 0.37 (cyclohexane/ethyl acetate, 70:30). Ϫ IR:
ν˜ ϭ 1720, 1710 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 0.85 (t, J ϭ
6.9 Hz, 3 H, 18-H), 1.22Ϫ1.58 (m, 6 H, 4-H, 16-H, 17-H),
1.60Ϫ1.72 (m, 7 H, 3-H, 5-H, 15-H, 11-H), 1.76Ϫ1.85 (m, 1 H,
11Ј-H), 1.86Ϫ1.94 (m, 1 H, 8-H), 2.30 (t, J ϭ 7.4 Hz, 2 H, 2-H),
2.39 (m, 4 H, 6-H, 10-H, 14-H), 2.57 (t, J ϭ 7 Hz, 2 H, 12-H), 2.86
(dt, J ϭ 7.3 and 16 Hz, 1 H, 8Ј-H), 3.62 (s, 3 H, OCH3), 5.11Ϫ5.18
(m, 2 H, 7-H, 9-H), 7.38Ϫ7.44 (m, 4 H, Ar-H), 7.5Ϫ7.58 (m, 2 H,
Ar-H), 7.99Ϫ8.04 (m, 4 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 13.9
(C-18), 20.7 (C-11), 22.4 (C-16), 23.5 (C-15), 25.1 (C-3), 27.1 (C-
4), 27.5 (C-5), 31.4 (C-17), 33.9 (C-2), 37.7 (C-8), 40.6 (C-14), 43
(C-12), 45.9 (C-6), 46.3 (C-10), 51.4 (OCH3), 78.4 (C-9), 78.7 (C-
7), 128.3 (C-Ar), 129.5 (C-Ar), 130.3 (C-Ar), 133 (C-Ar), 166.3
[C(O)], 174 (C-1), 210.9 (C-13). Ϫ C33H42O7 (550.7): calcd. C
71.97, H 7.69; found C 72.18, H 7.75.
ent-(15RS)-2,3-Dinor-5,6,13,14-tetrahydro-15-F2t-isoprostane
Methyl Ester (3): To 17 (19.9 mg, 43.9 µmol) in methanol (395 µL)
and THF (295 µL) was added NaOH solution (1 , 350 µL). The
same procedure as for 1 was used to give a mixture of (15R)/(15S)
isomers of 3 (13.5 mg, 83%): Rf 0.55 (ethyl acetate/acetic acid,
95:5). Ϫ IR: ν˜ ϭ 3520, 1720 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 0.88
(t, J ϭ 6.8 Hz, 3 H, 18-H), 1.24Ϫ1.47 (m, 10 H, 4-H, 5-H, 11-H,
16-H, 17-H), 1.54Ϫ1.67 (m, 8 H, 3-H, 8-H, 12-H, 14-H, 15-H),
1.99Ϫ2.07 (m, 3 H, 6-H, 8Ј-H, 10-H), 2.30 (t, J ϭ 7.4 Hz, 2 H, 2-
H), 2.34Ϫ2.40 (m, 1 H, 12Ј-H), 3.56Ϫ3.61 (m, 1 H, 13-H), 3.65 (s,
3 H, OCH3), 3.93Ϫ3.96 (m, 2 H, 7-H, 9-H). Ϫ 13C NMR (CDCl3):
δ ϭ 14 (C-18), 22.6 (C-16), 24.1 (C-11), 25 (C-3), 25.3 (C-4), 27.2
(C-15), 27.7 (C-5), 29.7 (C-12), 31.8 (C-17), 33.9 (C-2), 35.9 (C-14),
37.5 (C-8), 42.8 (C-6), 49.5 (C-10), 51.5 (OCH3), 72 (C-13), 72.2
(C-7), 76.2 (C-9), 173.6 (C-1). Ϫ NICI-MS of PFB-TMS derivative,
carboxylate anion at m/z ϭ 545.
(1S,2R,3R,4R)-2-(tert-Butyldiphenylsilyloxymethyl)-3-[(Z)-5-tetra-
hydropyranyloxypent-2-enyl]-1,4-bis(triethylsilyl)cyclopentane-1,4-
diol (18): To a suspension of 3-(tetrahydropyranyloxypropyl)tri-
phenylphosphonium bromide[12] (1.4 g, 2.9 mmol, 3 equiv.), in dry
THF (10 mL) at Ϫ80 °C, was added KN(SiMe3)2 (5.4 mL, 2.85
ent-2,3-Dinor-5,6,13,14-tetrahydro-15-oxo-15-F2t-isoprostane
Methyl Ester (4): To a solution of 16 (15.1 mg, 33.5 µmol) in meth-
anol (300 µL) and THF (195 µL) was added NaOH (1  solution, equiv, 0.5  in toluene). The orange solution of ylide was stirred
816 Eur. J. Org. Chem. 2001, 809Ϫ819

Total Syntheses of Four Metabolites of 15-F2t-Isoprostane
for 10 min. A solution of aldehyde 6 (611 mg, 9.5 mmol, 1 equiv.) C(CH3)3], 1.41Ϫ1.55 (m, 4 H, THP-H), 1.62Ϫ1.69 (m, 1 H, THP-
FULL PAPER
in dry THF (8 mL) was added to the ylide. After slow warming to
room temperature over 1 h, the reaction mixture was hydrolyzed
with water (10 mL). The aqueous layer was extracted with diethyl
ether (3ϫ 10 mL), and the combined extracts were washed with
brine (10 mL). All organic solutions were dried with Na2SO4 and
concentrated, giving a crude material. Flash chromatography over
silica gel (cyclohexane/diethyl ether 96:4) gave pure 18 (511 mg,
70%): Rf 0.65 (cyclohexane/ethyl acetate, 90:10). Ϫ 1H NMR
H), 1.72Ϫ1.81 (m, 1 H, THP-H), 1.91 (d, J ϭ 15.6 Hz, 1 H, 8-H),
2.19Ϫ2.25 (m, 4 H, 2-H, 5-H), 2.60Ϫ2.64 (m, 2 H, 6-H, 10-H),
2.91 (dt, J ϭ 7.4 and 15.6 Hz, 1 H, 8Ј-H), 3.31Ϫ3.34 (m, 1 H, 1-
H), 3.42Ϫ3.48 (m, 1 H, THP-H), 3.66Ϫ3.89 (m, 4 H, 1Ј-H, 11-H,
THP-H), 4.53Ϫ4.54 (m, 1 H, THP-H), 5.30Ϫ5.32 (m, 1 H, 4-H),
5.36Ϫ5.44 (m, 3 H, 3-H, 7-H, 9-H), 7.34Ϫ7.41 (m, 10 H, Ar-H),
7.50Ϫ7.57 (m, 2 H, Ar-H), 7.63Ϫ7.68 (m, 4 H, Ar-H), 7.93Ϫ8.03
(m, 4 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 19.1 [C(CH3)3], 19.5
(CDCl3): δ ϭ 0.45 [q, J ϭ 7.9 Hz, 6 H, (CH3CH2)3Si], 0.55 [q, J ϭ (C-THP), 25.5 (C-THP), 25.7 (C-2), 26.9 [C(CH3)3], 28.1 (C-5),
7.9 Hz, 6 H, (CH3CH2)3Si], 0.85 [t, J ϭ 7.9 Hz, 9 H, (CH3CH2)3Si], 30.6 (C-THP), 38.6 (C-8), 45.9 (C-6), 48.7 (C-10), 61.9 (C-11), 62.1
0.93 [t, J ϭ 7.9 Hz, 9 H, (CH3CH2)3Si], 1.05 [s, 9 H, C(CH3)3],
(C-THP), 66.8 (C-1), 77.2 (C-9), 79.2 (C-7), 98.7 (C-THP), 127.5
1.42Ϫ1.59 (m, 5 H, 8-H, THP-H), 1.62Ϫ1.72 (m, 1 H, THP-H), (C-4), 127.7 (C-Ar), 128.3 (C-Ar), 129.1 (C-3), 129.6 (C-Ar), 129.7
1.75Ϫ1.85 (m, 1 H, THP-H), 1.98Ϫ2.14 (m, 2 H, 5-H, 10-H), (C-Ar), 132.8 (C-Ar), 135.7 (C-Ar), 166.1 [C(O)]. Ϫ C46H54O7Si
2.15Ϫ2.37 (m, 5 H, 2-H, 5Ј-H, 6-H, 8Ј-H), 3.33 (td, J ϭ 6.9 and
9.6 Hz, 1 H, 1-H), 3.41Ϫ3.51 (m, 1 H, THP-H) 3.58 (d, J ϭ 5.1 Hz,
2 H, 11-H), 3.61Ϫ3.72 (m, 1 H, 1Ј-H), 3.81Ϫ3.85 (m, 1 H, THP-
H), 3.91 (q, J ϭ 7.4 Hz, 1 H, 7-H), 4.07 (m, 1 H, 9-H), 4.53Ϫ4.56
(m, 1 H, THP-H), 5.29Ϫ5.47 (m, 2 H, 3-H, 4-H), 7.30Ϫ7.44 (m, 6
H, Ar-H), 7.58Ϫ7.67 (m, 4 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ
4.7 [(CH3CH2)3Si], 4.9 [(CH3CH2)3Si], 6.7 [(CH3CH2)3Si], 6.8
[(CH3CH2)3Si], 19.1 [C(CH3)3], 19.5 (C-THP), 25.5 (C-THP), 25.7
(C-5), 26.9 [C(CH3)3], 28.1 (C-2), 30.7 (C-THP), 45.2 (C-8), 48.2
(C-6), 50.7 (C-10), 62.1 (C-THP), 62.6 (C-11), 66.9 (C-1), 73.2 (C-
9), 76.4 (C-7), 98.7 (C-THP), 126.1 (C-3), 127.6 (C-Ar), 129.6 (C-
Ar), 130.6 (C-4), 133.5 (C-Ar), 135.7 (C-Ar). Ϫ C44H74O5Si3
(767.3): calcd. C 68.87, H 9.72; found C, 68.89, H 9.80.
(747.0): calcd. C 73.96, H 7.29; found C 74.12, H 7.36.
(1S,2R,3R,4R)-1,4-Bis-O-(benzoyl)-2-(tert-butyldiphenylsilyloxy-
methyl)-3-[(Z)-5-hydroxypent-2-enyl]cyclopentane-1,4-
diol (21): To a stirred solution of 20 (735 mg, 1 mmol, 1equiv.) in
dry CH2Cl2 (8.4 mL) at Ϫ25 °C under nitrogen atmosphere was
added (CH3)2AlCl (3.9 mL, 3.9 mmol, 4 equiv, 1  in hexane).
After slow warming to room temperature over 2 h, the reaction
mixture was hydrolyzed with a solution of Na2CO3 in water (5 mL)
and washed with brine (5 mL). The aqueous layers were extracted
with ethyl acetate (3ϫ 5 mL) and the combined extracts were
washed with brine (5 mL). All organic solutions were dried with
Na2SO4 and concentrated, giving a crude material. Flash chroma-
tography over silica gel (cyclohexane/ethyl acetate, 80:20) gave pure
(1S,2R,3R,4R)-2-(tert-Butyldiphenylsilyloxymethyl)-3-[(Z)-5-tetra- 21 (602 mg, 92%): Rf 0.29 (cyclohexane/ethyl acetate, 80:20). Ϫ IR:
hydropyranyloxypent-2-enyl]cyclopentane-1,4-diol (19): A mixture of
18 (952 mg, 1.2 mmol, 1 equiv.) and NH4F (9.9 mL, 4 equiv, 0.5 
in MeOH) in 14 mL of MeOH/THF (7:3) was stirred for 2 h at
ν˜ ϭ 3426 cmϪ1, 1717 cmϪ1 Ϫ 1H NMR (CDCl3): δ ϭ 1.07 [s, 9 H,
C(CH3)3], 1.87Ϫ1.95 (m, 1 H, 8-H), 2.09Ϫ2.26 (m, 4 H, 2-H, 5-H),
2.56Ϫ2.69 (m, 2 H, 6-H, 10-H), 2.92 (dt, J ϭ 7.8 and 15.7 Hz, 1
reflux. The reaction mixture was diluted with brine (5 mL) and H, 8Ј-H), 3.56 (t, J ϭ 6.4 Hz, 2 H, 1-H), 3.73 (dd, J ϭ 5.3 and
ethyl acetate (10 mL). The aqueous layers were extracted with ethyl
acetate (3ϫ 10 mL), and the combined extracts were washed with
brine (10 mL). All organic solutions were dried with Na2SO4 and
concentrated, giving a crude material. Flash chromatography over
silica gel (cyclohexane/ethyl acetate, 60:40) gave pure 19 (589 mg,
10.8 Hz, 1 H, 11-H), 3.87 (dd, J ϭ 5.3 and 10.8 Hz, 1 H, 11Ј-
H), 5.33Ϫ5.42 (m, 3 H, 3-H, 7-H, 9-H), 5.48Ϫ5.56 (m, 1 H, 4-H),
7.31Ϫ7.43 (m, 10 H, Ar-H), 7.51Ϫ7.56 (m, 2 H, Ar-H), 7.63Ϫ7.68
(m, 4 H, Ar-H), 7.97Ϫ8.01 (m, 4 H, Ar-H). Ϫ 13C NMR (CDCl3):
δ ϭ 19.1 [C(CH3)3], 25.8 (C-5), 26.9 [C(CH3)3], 31 (C-2), 38.6 (C-
88%): Rf 0.4 (cyclohexane/ethyl acetate, 50:50). Ϫ IR: ν˜ ϭ 3360 8), 46 (C-6), 48.8 (C-10), 61.9 (C-11), 62.1 (C-1), 77.2 (C-9), 79.1
cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 1.04 [s, 9 H, C(CH3)3], 1.45Ϫ1.70 (C-7), 127 (C-3), 127.7 (C-Ar), 128.3 (C-Ar), 129.6 (C-Ar), 129.8
(m, 6 H, 8-H, THP-H), 1.73Ϫ1.81 (m, 1 H, THP-H), 1.92Ϫ2.03
(C-Ar), 130.5 (C-Ar), 132.9 (C-4), 133.2 (C-Ar), 135.7 (C-Ar),
(m, 4 H, 5-H, OH), 2.11Ϫ2.23 (m, 3 H, 2-H, 6-H), 2.25Ϫ2.43 (m, 166.1 [C(O)], 166.2 [C(O)]. Ϫ C41H46O6Si (662.9): calcd. C 74.29,
2 H, 8Ј-H, 10-H), 3.30Ϫ3.35 (m, 1 H, 1-H), 3.43Ϫ3.49 (m, 1 H, H 6.99; found C 74.22, H 6.96.
THP-H), 3.54Ϫ3.84 (m, 4 H, 1Ј-H, 11-H, THP-H), 3.92Ϫ4.02 (m,
(1S,2R,3R,4R)-1,4-Bis-O-(benzoyl)-2-(tert-butyldiphenylsilyloxy-
1 H, 7-H), 4.19Ϫ4.23 (m, 1 H, 9-H), 4.51Ϫ4.57 (m, 1 H, THP-H),
methyl)-3-[(Z)-methoxycarbonylbut-2-enyl]cyclopentane-1,4-
5.34Ϫ5.44 (m, 2 H, 4-H, 3-H), 7.37Ϫ7.40 (m, 6 H, Ar-H),
diol (22): To a stirred solution of 21 (602 mg, 0.91 mmol, 1 equiv.)
7.62Ϫ7.65 (m, 4 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 19.1
in freshly distilled acetone (15 mL) at Ϫ10 °C was added JonesЈ
[C(CH3)3], 19.6 (C-THP), 25.4 (C-THP), 26.4 (C-5), 26.9
reagent (627 µL, 1.36 mmol, 1.5 equiv, 2.17 ). After slow warming
[C(CH3)3], 28 (C-2), 30.6 (C-THP), 42.5 (C-8), 48.6 (C-6), 51.3 (C-
to room temperature over 2 h, the reaction was terminated using
2-propanol. The crude material was filtered on Celite; then a solu-
10), 62.4 (C-THP), 63.7 (C-11), 66.9 (C-1), 75.2, (C-9), 76.6 (C-7),
98.8 (C-THP), 127.4 (C-4), 127.7 (C-Ar), 129.8 (C-Ar), 130 (C-3),
tion of CH2N2 in diethyl ether was added. After concentration,
133.1 (C-Ar), 133.2 (C-Ar), 135.6 (C-Ar). Ϫ C32H46O5Si (538.8):
flash chromatography over silica gel (cyclohexane/ethyl acetate,
calcd. C 71.33, H 8.61; found C 71.40, H 8.70.
90:10) gave pure 22 (570 mg, 91%): Rf 0.64 (cyclohexane/ethyl acet-
1
(1S,2R,3R,4R)-1,4-Bis-O-(benzoyl)-2-(tert-butyldiphenylsilyloxy-
methyl)-3-[(Z)-5-tetrahydropyranyloxypent-2-enyl]cyclopentane-
1,4-diol (20): To a stirred solution of diol 19 (546 mg, 1 mmol, 1
equiv.) in dry pyridine (7 mL) under nitrogen atmosphere, was ad-
ded benzoyl chloride (411 µL, 3.5 mmol, 3.5 equiv.). The reaction
mixture was stirred for 20 min at room temperature. MeOH (1 mL)
was added to the reaction mixture; then the pyridine was evapor-
ated under reduced pressure and the residue purified by flash chro-
matography on silica gel (cyclohexane/ethyl acetate, 95:5) to pro-
ate, 50:50). Ϫ IR: ν˜ ϭ 1718 cmϪ1 Ϫ H NMR (CDCl3): δ ϭ 1.08
[s, 9H C(CH3)3], 1.87Ϫ1.95 (m, 1 H, 8-H), 2.19Ϫ2.24 (m, 2 H, 5-
H), 2.56Ϫ2.67 (m, 2 H, 6-H, 10-H), 2.88Ϫ3.01 (m, 3 H, 2-H, 8Ј-
H), 3.63 (s, 3 H, OCH3), 3.71 (dd, J ϭ 5.3 and 10.8 Hz, 1 H, 11-
H), 3.86 (dd, J ϭ 5.3 and 10.8 Hz, 1 H, 11Ј-H), 5.29Ϫ5.33 (m, 1
H, 7-H), 5.38Ϫ5.40 (m, 1 H, 9-H), 5.54Ϫ5.57 (m, 2 H, 3-H, 4-H),
7.35Ϫ7.42 (m, 10 H, Ar-H), 7.5Ϫ7.55 (m, 2 H, Ar-H), 7.63Ϫ7.66
(m, 4 H, Ar-H), 7.97Ϫ8.03 (m, 4 H, Ar-H). Ϫ 13C NMR (CDCl3):
δ ϭ 19.1 [C(CH3)3], 25.8 (C-5), 26.9 [C(CH3)3], 32.8 (C-2), 38.6 (C-
vide 20 (735 mg, 97%): Rf 0.62 (cyclohexane/ethyl acetate, 80:20). 8), 45.7 (C-6), 48.7 (C-10), 51.8 (OCH3), 61.9 (C-11), 77.1 (C-9),
IR: ν˜ ϭ 1715 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 1.07 [s, 9 H,
79.1 (C-7), 122.3 (C-3), 127.8 (C-Ar), 128.3 (C-Ar), 129.6 (C-Ar),
817
Eur. J. Org. Chem. 2001, 809Ϫ819

T. Durand et al.
FULL PAPER
129.8 (C-Ar), 130.4 (C-Ar), 130.9 (C-4), 132.9 (C-Ar), 133.1 (C- (C-6), 50 (C-10), 51.9 (OCH3), 77.2 (C-9), 78.1 (C-7), 123.1 (C-3),
Ar), 135.7 (C-Ar), 166.1 [C(O)], 166.2 [C(O)], 171.9 (C-1). Ϫ 128.4 (C-Ar), 129.6 (C-Ar), 130.1 (C-4), 132.5 (C-12), 133.2 (C-
C42H46O7Si (690.9): calcd. C 73.01, H 6.71; found C 73.15, H 6.86.
Ar), 141.3 (C-11), 165.9 [C(O)], 166 [C(O)], 172 (C-1), 199.8 (C-
13). Ϫ C33H38O7 (546.7): calcd. C 72.51, H 7.01; found C 72.65,
H 7.16.
(1S,2R,3R,4R)-1,4-Di-O-benzoyl-3-[(Z)-methoxycarbonylbut-2-
enyl]-2-(hydroxymethyl)cyclopentane-1,4-diol (23): Acetyl chloride
(1.07 mL) was added dropwise to methanol (18 mL), and the hy-
drogen chloride solution obtained was cooled to 20 °C. A solution
of 22 (560 mg, 0.8 mmol, 1 equiv.) in freshly distilled diethyl ether
(18 mL) was added, and the mixture was stirred at room temper-
ature for 20 h, then neutralized with saturated NaHCO3. The aque-
ous layer was extracted with ethyl acetate (3ϫ10 mL), and the com-
bined extracts were washed with brine (10 mL). All organic solu-
tions were dried with Na2SO4 and concentrated, giving a crude
material. Flash chromatography over silica gel (cyclohexane/ethyl
acetate, 80:20) gave pure 23 (282 mg, 77%): Rf 0.54 (cyclohexane/
ethyl acetate, 50:50). Ϫ IR: ν˜ ϭ 3520 cmϪ1, 1711 cmϪ1. Ϫ 1H NMR
(CDCl3): δ ϭ 1.75 (s, 1 H, OH), 2.05 (dt, J ϭ 3.7 and 5.2 Hz, 1 H,
8-H), 2.16Ϫ2.22 (m, 1 H, 5-H), 2.28Ϫ2.33 (m, 1 H, 5Ј-H), 2.64 (m,
2 H, 6-H, 10-H), 2.87 (dt, J ϭ 7.4 and 15.2 Hz, 1 H, 8Ј-H), 3.1 (d,
J ϭ 5.4 Hz, 2 H, 2-H), 3.66 (s, 3 H, OCH3), 3.77 (dd, J ϭ 6 and
11 Hz, 1 H, 11-H), 3.85 (dt, J ϭ 5.1 and 11 Hz, 1 H, 11Ј-H),
5.21Ϫ5.24 (m, 1 H, 7-H), 5.37Ϫ5.41 (m, 1 H, 9-H), 5.62Ϫ5.68 (m,
2 H, 3-H, 4-H), 7.37Ϫ7.44 (m, 4 H, Ar-H), 7.53Ϫ7.55 (m, 2 H, Ar-
H), 7.99Ϫ8.04 (m, 4 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 25.7 (C-
5), 33 (C-2), 37.8 (C-8), 46 (C-6), 49.1 (C-10), 60.8 (C-11), 77 (C-
9), 78.7 (C-7), 122.6 (C-3), 128.4 (C-Ar), 129.6 (C-Ar), 131 (C-4),
133 (C-Ar), 133.2 (C-Ar), 165.9 (C(O)), 166 (C(O)), 173.2 (C-1). Ϫ
C26H28O7: calcd. C 69.01, H 6.24; found C 69.12, H 6.34.
(1S,2S,3R,4R)-1,4-Di-O-benzoyl-3-[(Z)-methoxycarbonylbut-2-
enyl]-2-[(3RS,E)--hydroxyoct-1-enyl]cyclopentane-1,4-diol (26): To a
cooled (Ϫ78 °C) solution of 25 (83 mg, 0.2 mmol, 1 equiv.) in dry
THF (1.6 mL) was added dropwise a solution of -Selectride (200
µL, 0.2 mmol, 1 eq, 1  in THF). The reaction was stirred at Ϫ78
°C for 20 min, quenched with methanol (40 µL), then diluted with
diethyl ether (5 mL), washed with brine (5 mL) and extracted with
diethyl ether (3ϫ 5 mL). The combined extracts were washed with
brine (5 mL). All organic solutions were dried with Na2SO4 and
concentrated, giving a crude material. Flash chromatography over
silica gel (cyclohexane/ethyl acetate, 92:8) gave pure 26 (69 mg,
83%): Rf 0.52 (cyclohexane/ethyl acetate, 50:50). Ϫ 1H NMR
(CDCl3): δ ϭ 0.85Ϫ0.88 (m, 3 H, 18-H), 1.22Ϫ1.26 (m, 6 H, 15-
H, 16-H, 17-H), 1.43Ϫ1.54 (m, 2 H, 14-H), 1.75 (s, 1 H, OH), 1.96
(d, J ϭ 15.9 Hz, 1 H, 8-H), 2.18Ϫ2.20 (m, 2 H, 5-H), 2.55Ϫ2.63
(m, 1 H, 6-H), 2.91 (dt, J ϭ 8.2 and 15.9 Hz, 1 H, 8Ј-H), 3.07 (d,
J ϭ 5.3 Hz, 2 H, 2-H), 3.11Ϫ3.16 (m, 1 H, 10-H), 3.65 (s, 3 H,
OCH3), 4.07Ϫ4.11 (m, 1 H, 13-H), 5.19Ϫ5.27 (m, 2 H, 7-H, 9-H),
5.51Ϫ5.62 (m, 3 H, 3-H, 4-H, 11-H), 5.66Ϫ5.73 (m, 1 H, 12-H),
7.39Ϫ7.44 (m, 4 H, Ar-H), 7.52Ϫ7.57 (m, 2 H, Ar-H), 8Ϫ8.03 (m,
4 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 14 (C-18), 22.5 (C-17), 25
(C-15), 26.5 (C-5), 31.7 (C-16), 33.1 (C-2), 37.2 (C-14), 38.9 (C-8),
47.6 (C-6), 50 (C-10), 51.9 (OCH3), 72.4 (C-13), 78.4 (C-7, C-9),
122.4 (C-3), 126.2 (C-11), 128.4 (C-Ar), 129.6 (C-Ar), 130.2 (C-
Ar), 130.8 (C-4), 133 (C-Ar), 137.5 (C-12), 166 [C(O)], 166.1 [C(O)],
171.9 (C-1). Ϫ C33H40O7 (548.7): calcd. C 72.24, H 7.35; found C
72.32, H 7.39.
(1S,2S,3R,4R)-1,4-Dis-O-benzoyl-3-[(Z)-methoxycarbonylbut-2-
enyl]-2-[(E)-3-oxooct-1-enyl]cyclopentane-1,4-diol (25): To a stirred
solution of 23 (47 mg, 0.1 mmol, 1 equiv.) in freshly distilled
CH2Cl2 (2.5 mL) and water (2.5 µL) at room temperature was ad-
ded DessϪMartin periodinane (53 mg, 1.2 equiv.). The reaction
mixture was stirred for 2 h, diluted with diethyl ether (3 mL), and
washed with 1:1 NaHCO3 (10%)/Na2S2O3 (10%) (3ϫ 2 mL). The
aqueous layers were extracted with diethyl ether (3ϫ 3 mL), and
the combined extracts were washed with brine (6 mL). All organic
solutions were dried with Na2SO4 and concentrated, giving a crude
material 24. This was used immediately for the next step: Rf 0.6
(cyclohexane/ethyl acetate, 50:50).
ent-(15RS)-2,3-Dinor-15-F2t-isoprostane Methyl Ester (2a and 2b):
To a stirred solution of 26 (30 mg, 65 µmol) in THF (285 µL) and
MeOH (435 µL) at 40 °C was added NaOH (520 mL, 1  solution).
The same procedure as for 1 was used, to give a mixture of 2a and
2b [16.5 mg, 75%; 9.9 mg/6.6 mg (R)/(S)].
ent-(15R)-2,3-Dinor-15-F2t-isoprostane Methyl Ester (2a): Rf 0.46
(ethyl acetate/acetic acid, 95:5). Ϫ IR (15S): ν˜ ϭ 3363 cmϪ1, 1737
1
cmϪ1. Ϫ UV (CH3CN): 197 nm. Ϫ H NMR (CDCl3): δ ϭ 0.86
(t, J ϭ 6.7 Hz, 3 H, 18-H), 1.23Ϫ1.27 (m, 6 H, 15-H, 16-H, 17-H),
1.45Ϫ1.5 (m, 2 H, 14-H), 1.63 (dt, J ϭ 4.0 and 14.5 Hz, 1 H, 8-
H), 1.98Ϫ2.03 (m, 2 H, 5-H), 2.14Ϫ2.17 (m, 1 H, 6-H), 2.25Ϫ2.46
(m, 4 H, 8Ј-H, OH), 2.71Ϫ2.77 (m, 1 H, 10-H), 3.06 (t, J ϭ 5.7 Hz,
2 H, 2-H), 3.67 (s, 3 H, OCH3), 3.92Ϫ4.05 (m, 3 H, 7-H, 9-H, 13-
H), 5.43 (dd, J ϭ 9.4 and 15.3 Hz, 1 H, 11-H), 5.52Ϫ5.62 (m, 3 H,
3-H, 4-H, 12-H). Ϫ 13C NMR (CDCl3): δ ϭ 14 (C-18), 22.6 (C-
17), 25.1 (C-16), 27.2 (C-5), 29.7 (C-15), 31.7 (C-14), 33 (C-2), 42.5
(C-8), 50.3 (C-6), 52 (OCH3), 53.5 (C-10), 72.5 (C-13), 76.2 (C-7,
C-9), 121.8 (C-11), 129 (C-12), 132.1 (C-3), 136.4 (C-4), 172.4 (C-
1). Ϫ [α]2D0 ϭ Ϫ11.8 (c ϭ 2·10Ϫ3, MeOH). Ϫ NICI-MS of PFB-
TMS derivative, carboxylate anion at m/z ϭ 541.
To a solution of 24 (previous crude product, 0.31 mmol, 1 equiv.)
in dry THF (0.8 mL) was added dropwise a solution of ylide pre-
pared at room temperature from diethyl 2-oxoheptylphosphonate
(178 µL, 0.9 mmol, 2.75 equiv.) and NaH (10 mg, 2.5 equiv, 60%
suspension in oil) in THF (0.8 mL). The reaction was stirred for
10 min, neutralized with saturated NH4Cl (2 mL), extracted with
diethyl ether (3ϫ 2 mL), and the combined extracts washed with
brine (2 mL). All organic solutions were dried with Na2SO4 and
concentrated, giving a crude material. Flash chromatography over
silica gel (cyclohexane/ethyl acetate, 80:20) gave pure 25 (31 mg,
54%): Rf 0.34 (cyclohexane/ethyl acetate, 80:20). Ϫ IR: ν˜ ϭ 1715
1
cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 0.87 (t, J ϭ 6.8 Hz, 3 H, 18-H),
1.23Ϫ1.31 (m, 4 H, 16-H, 17-H), 1.56Ϫ1.64 (m, 2 H, 15-H), 2.03
(dt, J ϭ 3.3 and 16 Hz, 1 H, 8-H), 2.18 (t, J ϭ 6.7 Hz, 2 H, 5-H),
ent-(15S)-2,3-Dinor-15-F2t-isoprostane Methyl Ester (2b): Rf 0.35
(ethyl acetate/acetic acid, 95:5). Ϫ IR (15R): ν˜ ϭ 3351 cmϪ1, 1739
2.52 (t, J ϭ 7.4 Hz, 2 H, 14-H), 2.66Ϫ2.71 (m, 1 H, 6-H), 2.97 (m, cmϪ1. Ϫ UV (CH3CN): 199 nm. Ϫ 1H NMR (CDCl3): δ ϭ
1 H, 8Ј-H), 3.04Ϫ3.06 (m, 2 H, 2-H), 3.27Ϫ3.33 (m, 1 H, 10-H),
0.84Ϫ0.89 (m, 3 H, 18-H), 1.23Ϫ1.27 (m, 6 H, 17-H, 16-H, 15-H),
3.65 (s, 3 H, OCH3), 5.21Ϫ5.26 (m, 1 H, 7-H), 5.33Ϫ5.37 (m, 1 H, 1.43Ϫ1.51 (m, 2 H, 14-H), 1.62 (dt, J ϭ 3.9 and 14.4 Hz, 1 H, 8-
9-H), 5.56Ϫ5.69 (m, 2 H, 3-H, 4-H), 6.27 (dd, J ϭ 1 and 15.7 Hz,
1 H, 12-H), 6.74 (dd, J ϭ 9 and 15.7 Hz, 1 H, 11-H), 7.39Ϫ7.44
(m, 4 H, Ar-H), 7.53Ϫ7.58 (m, 2 H, Ar-H), 8Ϫ8.04 (m, 4 H, Ar-
H), 2Ϫ2.07 (m, 5 H, 5-H, OH), 2.13Ϫ2.18 (m, 1 H, 6-H),
2.39Ϫ2.45 (m, 1 H, 8Ј-H), 2.71Ϫ2.77 (m, 1 H, 10-H), 3.06 (d, J ϭ
6.1 Hz, 2 H, 2-H), 3.67 (s, 3 H, OCH3), 3.93Ϫ4.05 (m, 3 H, 7-H,
H). Ϫ 13C NMR (CDCl3): δ ϭ 13.9 (C-18), 22.4 (C-17), 23.7 (C- 9-H, 13-H), 5.40 (dd, J ϭ 9.4 and 15.9 Hz, 1 H, 11-H), 5.54Ϫ5.64
15), 26.5 (C-5), 31.4 (C-16), 32.9 (C-2), 37.9 (C-8), 40.9 (C-14), 48 (m, 3 H, 12-H, 3-H, 4-H). Ϫ 13C NMR (CDCl3): δ ϭ 14 (C-18),
818
Eur. J. Org. Chem. 2001, 809Ϫ819

Total Syntheses of Four Metabolites of 15-F2t-Isoprostane
FULL PAPER
J. A. Lawson, J. Rokach, G. A.
FitzGerald, J. Biol. Chem. 1999, 274, 2441Ϫ2444.
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Rev. 1999, 31, 117Ϫ139. Ϫ
22.6 (C-17), 25.1 (C-16), 27.2 (C-5), 29.7 (C-15), 31.7 (C-14), 33
(C-2), 42.5 (C-8), 50.3 (C-6), 52 (OCH3), 53.5 (C-10), 72.7 (C-13),
76.4 (C-7, C-9), 121.8 (C-11), 128.3 (C-12), 132.2 (C-3), 136.4 (C-
4), 172.5 [C(O)]. Ϫ [α]2D0 ϭ Ϫ2.3 (c ϭ 10Ϫ3, MeOH). Ϫ NICI-MS
of PFB-TMS derivative, carboxylate anion at m/z ϭ 541.
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819