Total synthesis of isoprostanes derived from adrenic acid and EPA

Article abstract of DOI:10.1002/ejoc.201200070

Enantiomerically enriched F₂-dihomo-isoprostanes and F ₃-isoprostanes have been synthesized. Such compounds are derived from the action of reactive oxygen species on the phospholipid-bound polyunsaturated fatty acids (PUFA), adrenic

Full text of DOI:10.1002/ejoc.201200070

FULL PAPER
DOI: 10.1002/ejoc.201200070
Total Synthesis of Isoprostanes Derived from Adrenic Acid and EPA
Camille Oger,[a] Valérie Bultel-Poncé,[a] Alexandre Guy,[a] Thierry Durand,[a] and
Jean-Marie Galano*[a]
Keywords: Biomarkers / Oxidation / Total synthesis / Natural products
Enantiomerically enriched F2-dihomo-isoprostanes and F3-
isoprostanes have been synthesized. Such compounds are
derived from the action of reactive oxygen species on the
represent potential biomarkers for myelin damage as its main
PUFA constituent is adrenic acid. Our strategy, based on a
pivotal enantiomerically enriched intermediate, has allowed
phospholipid-bound polyunsaturated fatty acids (PUFA), ad- access to F2-dihomo-IsoP and both C5 epimers of 5-F3t-IsoP
renic acid and eicosapentaenoic acid, respectively. Of special
interest are the F2-dihomo-isoprostanes because they could
for the first time.
IsoP.[10] In addition, it was found that at least one F3-IsoP
could be generated from F4-NeuroP by a β-oxidation pro-
cess.[11]
The last family of IsoPs to be discovered was from adre-
nic acid (AdA, C22:4 ω6) peroxidation.[12] AdA is concen-
trated in the brain and especially in the myelin within the
white matter. VanRollins and co-workers also showed that
F2-dihomo-IsoPs are significantly increased in samples of
white matter taken from AD patients. Therefore, F4-NeuroP
and F2-dihomo-IsoP could represent oxidative stress bio-
markers for neuronal oxidative damage.
Having been interested for quite some time in the quanti-
fication of oxidative stress, we herein describe the syntheses
of the most abundant series of F2-dihomo-IsoP, ent-7-epi-
7-F2t-dihomo-IsoP (1) and both epimers of 17-F2t-dihomo-
IsoP (2; Figure 1). We also describe a novel access to both
epimers of 5-F3t-IsoP (3).
Introduction
Discovered in 1990 by Morrow and co-workers, isopros-
tanes (IsoPs) are generated in vivo during the oxidative
stress of phospholipid-bound arachidonic acid (AA,
C20:4 ω6) by a free-radical-catalyzed mechanism.[1] Oxidat-
ive stress has been implicated in a wide variety of human
disorders, for example, diabetes, cardiovascular, and neuro-
degenerative diseases. Furthermore, IsoPs are commonly
used in clinical trials as reliable oxidative stress biomarkers
for many diseases and pathologies.[2] But more than reliable
markers, IsoPs are also biologically active.[3]
In 1998, a novel class of IsoP, named neuroprostane
(NeuroP), was discovered independently by two teams.[4,5]
The name of neuroprostane was adopted because of their
polyunsaturated fatty acid source. Indeed, NeuroPs are gen-
erated from docosahexaenoic acid (DHA, C22:6 ω3), which
is among the most abundant fatty acids in both the brain
and retina and is essential for their development.[6] Levels
of F4-NeuroP are 2.1-fold higher in the temporal lobe of
Alzheimer’s disease (AD) patients than in a control sam-
ple[7] and are four-fold higher than F2-IsoP levels.[8] Re-
cently, a high level of F4-NeuroP in plasma was also found
in Rett (RTT) syndrome patients (one order of magnitude
higher than the control sample), thus providing a novel
RTT marker related to neurological symptoms, severity,
mutation type, and clinical presentation.[9]
Results and Discussion
We recently described the synthesis of 4-F4t-NeuroP and
D4-labeled 4-F4t-NeuroP by a NiP2 skipped diyne deuter-
iation strategy.[13] Such complex isoprostanoid syntheses
have been made easy by applying our previous approach,
which proceeds through an enantiomerically enriched bicy-
clo[3.3.0]octene keto-epoxide intermediate 4[14,15] to give
advanced intermediate 5[16] (up to 12 g in 10% overall yield
from 1,3-COD) ready for the introduction of lateral chains
(Scheme 1).
At the same time, novel IsoPs derived from eicosapenta-
enoic acid (EPA, C20:5 ω3) were discovered and named F3-
[a] Institut des Biomolécules Max Mousseron, UMR 5247 CNRS,
Universités Montpellier 1 & 2, Faculté de Pharmacie,
15 avenue Charles Flahault, Bâtiment D, 34093 Montpellier
Cedex 05, France
Synthesis of ent-7-epi-7-F2t-Dihomo-IsoP (1)
Fax: +33-4-11759553
The synthesis required the use of unreported β-keto
phosphonate 6, which was prepared in one step by conden-
sation of the lithium salt of dimethyl methylphosphonate
E-mail: jgalano@univ-montp1.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200070.
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Figure 1. Isoprostanes synthesized in this work.
With phosphonate 6 in hand, alcohol 5 was oxidized to
the corresponding aldehyde by using the Dess–Martin
periodinane reagent (DMP).[17] Subsequent Horner–
Wadsworth–Emmons (HWE) olefination in the presence of
Ba(OH)2 gave enone 8 in 38% yield (unoptimized condi-
tions, Scheme 3). The poor yield can be explained by the
presence of the dimethyl pimelate in the reaction medium.
Reduction of the keto group of 8 under Luche conditions[18]
led to a 1:1 epimeric mixture of the corresponding alcohol,
which was protected either as the silylated ether (compound
9) or the ethoxyethyl ether (EE, compound 10). Saponifica-
tion of the acetate group of 9 and 10 led to primary
alcohols 11 and 12, respectively. The ω chain was intro-
duced after oxidation followed by Wittig reaction[19] with
the hexylphosphonium bromide 13 in the presence of
NaHMDS to give compounds 14 and 15 in excellent to
moderate yields (94 and 63%, respectively). At no stage of
this procedure could the C7 epimeric mixture be separated
by flash column chromatography.
Scheme 1. Synthesis of bicyclo[3.3.0]octene keto-epoxide interme-
diate 4 and intermediate 5.
with dimethyl pimelate 7. Despite considerable effort, a
yield of only 28% of a 4:1 mixture of novel β-keto phos-
phonate 6 and dimethyl pimelate 7 was recovered after puri-
fication (Scheme 2).
Scheme 2. Synthesis of methyl 8-(dimethoxyphosphoryl)-7-oxooc-
tanoate (6).
Scheme 3. Lateral chain insertion towards ent-7-epi-7-F2t-dihomo-IsoP (1; Im = imidazole, EVE = ethyl vinyl ether, PPTS = pyridinium
p-toluenesulfonate).
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Total Synthesis of Isoprostanes
Therefore, a diastereoselective Noyori (S)-BINAL-H re- Luche reduction gave a 1:1 epimeric mixture of the allylic
duction[20] was performed on compound 8, but this gave alcohol 20, which was subsequently protected as the ethoxy-
low diastereoselectivity (approx. 2:1). The more advanced ethyl ether 21 in 91% yield over two steps. Acetate saponifi-
orthogonally protected compound 15 was then used to ac- cation led to primary alcohols (17RS)-22 in 88% yield.
cess enone 16 by a deprotection/oxidation two-step se- Chromatographic separation of the two epimers led to
quence (Scheme 4). (S)-BINAL-H reduction of 16 led to (17S)-22 and (17R)-22 in 47 and 48% yields, respectively.
the allylic alcohol (7S)-17 in 64% yield and with a good The α chain was then introduced after primary alcohol oxi-
diastereomeric ratio (Ͼ95:5). Finally, one-pot silyl ether de- dation by Wittig reaction with phosphonium salt 23 and
protection and methyl ester hydrolysis under acid condi- NaHMDS to give compounds (17S)-24 and (17R)-24 in 80
tions gave ent-7-epi-7-F2t-dihomo-IsoP (1) in 28% yield; and 25% yields, respectively.
ent-(7RS)-7-F2t-dihomo-IsoP [(RS)-1] could also be ob-
As the first total synthesis of 17-F2t-dihomo-IsoP, we
tained from compound 14 by similar acidic treatment in had to perform a diastereoselective reduction to assess the
58% yield.
absolute configuration at C17. We consistently observed a
low dr (2:1) after (S)-BINAL-H reduction to various enone
systems with the acetoxyethyl moiety as the second lateral
chain, and compound 19 suffered the same fate. Therefore,
racemic 24 was converted into enone 25 in a two-step se-
quence in good yield. (S)-BINAL-H reduction afforded
(17S)-26 in 81% yield and with a good diastereomeric ratio
(Ͼ95:5; Scheme 6). Finally, acid cleavage of the protecting
groups followed by ethyl ester saponification of (17S)-26
afforded 17-F2t-dihomo-IsoP (2) in 77% yield. Similarly,
(17S)-24 and (17R)-24 gave access to 17-F2t-dihomo-IsoP
(2) and 17-epi-17-F2t-dihomo-IsoP [(17R)-2] in good yields.
Synthesis of 5-F3t-IsoP (3)
Applying the same strategy, the α chain of 5-F3t-IsoP was
introduced after oxidation of the primary alcohol of ent-5
followed by HWE reaction with methyl 6-(diethoxyphos-
phoryl)-5-oxohexanoate (27)[21] and NaHMDS as base to
afford compound 28 (Scheme 7). Luche reduction and pro-
tection of the resulting allylic alcohol as a tert-butyldi-
methylsilyl ether furnished the protected compound (5RS)-
Scheme 4. Diastereoselective reduction and final deprotections in
the synthesis of 1.
Synthesis of 17-F2t-Dihomo-IsoP (2)
Starting from monoacetate 5, HWE reaction (to the cor- 29 in excellent yield over two steps. Saponification of the
responding aldehyde) with commercially available β-keto acetate functionality allowed separation of the epimeric
phosphonate 18 gave enone 19 in 57% yield (Scheme 5). mixture, and pure epimers (5R)-30 and (5S)-30 were reco-
Scheme 5. Lateral chain insertion towards 17-F2t-dihomo-IsoP (2).
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FULL PAPER
we had to perform a diastereoselective reduction to access
the corresponding diastereomerically enriched allylic
alcohol. As (S)-BINAL-H reduction of the enone 28 gave
poor diastereoselectivity, we had to resort to the previously
described lactol 32[14] to complete the diastereoselective
synthesis of 5-F3t-IsoP (3; Scheme 8).
Scheme 6. Diastereoselective reduction and final deprotections to
yield 17-F2t-dihomo-IsoP (2) and its epimer.
vered. The ω chain was inserted after oxidation of the pri-
mary alcohol functionality by Wittig reaction using phos-
phonium salt 31 and KHMDS in THF. Finally, one-pot
silyl ether cleavage and methyl ester hydrolysis under acidic
conditions led to 5-F3t-IsoP (3) and 5-epi-5-F3t-IsoP [(5R)-
3] in 17 and 3.5% overall yields, respectively.
Scheme 8. Synthesis of 5-F3t-IsoP (3) by using (S)-BINAL-H rea-
gent.
By applying a strategy similar to that of Rokach and co-
workers,[11] the upper chain was introduced into lactol 32
by Wittig reaction with phosphonium salt 31 and tBuOK
in THF to give diene 33 in 64% yield. The α chain was
subsequently attached by DMP oxidation followed by
HWE reaction with β-keto phosphonate 27 and NaHMDS
to give 34 in excellent yield. Diastereoselective reduction of
the enone 34 with the Noyori (S)-BINAL-H reagent led to
allylic alcohol 35 and lactone 36 in a 1:1 mixture with a
good diastereomeric ratio (Ͼ95%). Hydrolysis of the ter-
minal ester and TBS deprotection was achieved under
acidic conditions. A poor overall yield was observed for this
stereoselective synthesis of 5-F3t-IsoP (3). The unequivocal
determination of the C5 stereocenter was possible by com-
parison of the 13C NMR spectra.
Conclusions
We have described the enantioselective synthesis of the
two most abundant cyclic metabolites of the free-radical-
catalyzed peroxidation of adrenic acid, ent-7-epi-7-F2t-di-
homo-IsoP and 17-F2t-dihomo-IsoP. These metabolites are
of high interest in lipidomics as dihomo-IsoPs may repre-
sent very specific lipidic oxidative stress biomarkers of the
brain’s white matter. Validation of this hypothesis is un-
derway in our laboratory and will be reported in due course.
Experimental Section
Scheme 7. Synthesis of 5-F3t-IsoP (3) and its C5 epimer (5R)-3.
General: All reactions requiring anhydrous conditions were con-
ducted in oven-dried glassware with magnetic stirring under nitro-
gen unless mentioned otherwise. Syringes and needles for the trans-
To confirm the configuration of the stereogenic center at
C5, and because the 5-F3t-IsoP previously synthesized has
no reported 13C NMR data nor optical rotation value,[11] fer of reagents were dried at 120 °C and allowed to cool in a desic-
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Total Synthesis of Isoprostanes
cator over CaCl2 before use. THF and Et2O were redistilled from
sodium diphenylketyl and CH2Cl2 from CaH2. Other solvents and
reagents were used as obtained from the supplier unless otherwise
noted. Reactions were monitored by TLC using plates precoated
with silica gel 60 (Merck). Reaction components were visualized
by using a 254 nm UV lamp, treatment with acidic p-anisaldehyde
stain followed by gentle heating. Organic layers were dried with
MgSO4 unless otherwise stated. Column chromatography was per-
formed by using silica gel 40–63 μm, whereas spherical silica gel
30 μm was used for flash column chromatography. Concentrations
c reported for the optical rotation data are given in g/100 mL. In-
frared data are reported as wavenumbers (cm–1). ES-MS data were
obtained by ionization methods. 1H NMR spectra were obtained
at 300 or 400 MHz. The spectra were recorded in CDCl3 (internal
ture was extracted with Et2O (3ϫ 30 mL). The combined organic
layers were washed with brine, dried, and filtered. The solvent was
evaporated under reduced pressure. The residue was purified by
column chromatography (7:3 pentane/Et2O) to afford 115 mg of
the enone 8 as a colorless oil (38% over two steps). Rf = 0.55 (5:5
cyclohexane/Et2O). [α]2D0 = +20.6 (c = 1, CHCl ). IR: ν = 2955,
˜
3
2927, 2856, 1736, 1697, 1674, 1626, 1463, 1252, 1071 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 6.50–6.70 (m, 1 H), 6.10 (d, J =
15.6 Hz, 1 H), 3.80–4.20 (m, 4 H), 3.64 (s, 3 H), 2.65–2.85 (m, 1
H), 2.50 (t, J = 6.9 Hz, 2 H), 2.40 (m, 4 H), 2.00 (s, 3 H), 1.40–
1.75 (m, 7 H), 1.20–1.40 (m, 2 H), 0.75–0.90 (m, 18 H), –0.01 (d,
J = 13.0 Hz, 12 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 199.7
(1 C, Cq), 174.1 (1 C, Cq), 171.0 (1 C, Cq), 144.5 (1 C, CH), 131.5
(1 C, CH), 76.1 (1 C, CH), 75.4 (1 C, CH), 63.2 (1 C, CH2), 53.2
(1 C, CH), 51.5 (1 C, CH3), 46.6 (1 C, CH), 44.3 (1 C, CH2), 40.9
(1 C, CH2), 33.9 (1 C, CH2), 28.8 (1 C, CH2), 28.0 (1 C, CH2), 25.9
(6 C, CH3), 24.8 (1 C, CH2), 23.7 (1 C, CH2), 21.0 (1 C, CH3), 18.0
(2 C, Cq), –4.2 (1 C, CH3), –4.6 (2 C, CH3), –4.7 (1 C, CH3) ppm.
MS (ESI+): m/z = 541.4 [M + H – OAc]+, 409.3 [M – OTBS –
OAc]+. HRMS (ESI+): calcd. for C29H57O5Si2 [M + H – OAc]+
541.3745; found 541.3744.
1
reference at δ = 7.26 ppm) unless otherwise noted. The H NMR
spectra are reported as follows: chemical shift in ppm [multiplicity,
coupling constant(s) J in Hz, relative integral]. The multiplicities
are defined as follows: br. = broad, m = multiplet, AB = AB sys-
tem, s = singlet, d = doublet, t = triplet, or combinations thereof.
Selected 13C NMR spectra were recorded by using a J-modulated
sequence, and the central peak of the CDCl3 triplet was used as
the internal reference (δ = 77.16 ppm) and MeOD (fixed at δ =
49.0 ppm). The NMR spectra were assigned by homonuclear (1H–
1H) and heteronuclear (1H–13C) correlation spectroscopy
(COSY45, HMQC, HMBC) and are reported as follows: CH3,
CH2, CH, and Cq (for quaternary carbon atoms).
Methyl (E)-9-[(1S,2R,3R,5S)-2-(2-Acetoxyethyl)-3,5-bis(tert-butyl-
dimethylsilyloxy)cyclopentyl]-7-(tert-butyldimethylsilyloxy)non-8-en-
oate (9): CeCl3·7H2O (71 mg, 0.191 mmol) was added to a solution
of the enone 8 (115 mg, 0.19 mmol) in MeOH (12 mL). The mix-
ture was cooled to 0 °C and NaBH4 was added (6.0 mg,
0.159 mmol). After 10 min, the reaction was quenched with a Et2O/
H2O mixture (1:1, 20 mL). The reaction mixture was extracted with
Et2O (3ϫ 20 mL). The combined organic layers were washed with
brine, dried, and filtered. The solvent was evaporated under re-
duced pressure. The residue was purified by column chromatog-
raphy (7:3 pentane/Et2O) to afford 109 mg of the allylic alcohol as
Synthesis of Methyl 8-(Dimethoxyphosphoryl)-7-oxooctanoate (6):
nBuLi (2.4 mL, 2.5 m/hexanes, 6.0 mmol) was added dropwise to a
solution of dimethyl methylphosphonate (600 μL, 5.62 mmol) in
THF (50 mL) at –78 °C. After 30 min, the reaction mixture was
added through
a cannula to dimethyl pimelate 7 (1.5 mL,
8.3 mmol) in THF (50 mL) at –90 °C. After 3.5 h at –90 °C, AcOH
(1.0 mL) and Et2O (100 mL) were added, and the mixture was
warmed to room temp. The mixture was extracted with CH2Cl2
(3ϫ 40 mL). The combined organic layers were washed with brine,
dried, and filtered. The solvent was evaporated under reduced pres-
sure, and the residue was distilled under reduced pressure
(0.5 mbar, approx. 120 °C). The crude from the distillation was
purified by column chromatography (95:5 CH2Cl2/MeOH) to af-
ford 440 mg of the β-keto phosphonate 6 as an 8:2 mixture with
a colorless oil (95%). Rf = 0.37 (5:5 cyclohexane/Et2O). [α]2D0
=
+23.9 (c = 1, CHCl ). IR: ν = 3508, 2953, 2930, 1732, 1250,
˜
3
1056 cm–1. H NMR (300 MHz, CDCl3): δ = 5.45–5.55 (m, 1 H),
1
5.25–5.45 (m, 1 H), 4.15–4.40 (m, 0.5 H), 3.90–4.15 (m, 2 H), 3.70–
3.90 (m, 2.5 H), 3.64 (s, 3 H), 2.40–2.65 (m, 1 H), 2.15–2.40 (m, 3
H), 2.05–2.20 (m, 1 H), 2.00 (s, 3 H), 1.00–1.90 (m, 10 H), 0.80–
0.90 (m, 18 H), –0.10–0.10 (m, 12 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 174.2 (1 C, Cq), 171.3 (1 C, Cq), 136.1 (1 C, CH),
129.8 (1 C, CH), 76.4 (1 C, CH), 72.8 (1 C, CH), 72.4 (1 C, CH),
63.5 (1 C, CH2), 52.9 (1 C, CH), 51.5 (1 C, CH3), 45.8 (1 C, CH),
44.3 (1 C, CH2), 37.0 (1 C, CH2), 34.0 (1 C, CH2), 29.2 (1 C, CH2),
28.0 (1 C, CH2), 25.9 (6 C, CH3), 25.2 (1 C, CH2), 25.0 (1 C, CH2),
21.1 (1 C, CH3), 18.1 (2 C, Cq), –4.2 (1 C, CH3), –4.5 (1 C, CH3),
–4.6 (1 C, CH3), –4.7 (1 C, CH3) ppm. MS (ESI+): m/z = 583.3 [M
+ H – H2O]+, 451.2 [M + H – H2O – OTBS]+, 319.1 [M + H – H2O –
2 OTBS]+. HRMS (ESI+): calcd. for C31H59O6Si2 [M + H –
H2O]+ 583.3850; found 583.3849. Imidazole (50 mg, 0.73 mmol),
1
the dimethyl pimelate 7 (28%). H NMR (300 MHz, CDCl3): δ =
3.79 (d, J = 11.2 Hz, 6 H), 3.66 (s, 3 H), 3.09 (d, JPH = 22.0 Hz, 2
H), 2.50–2.70 (m, 2 H), 2.20–2.40 (m, 2 H), 1.50–1.80 (m, 4 H),
1.20–1.50 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 201.0
(1 C, Cq), 174.5 (1 C, Cq), 173.1 (1 C, Cq), 52.3 (1 C, CH3), 50.6
(2 C, CH3), 42.9 (1 C, CH2), 41.1 (1 C, CH2), 39.4 (1 C, CH2), 33.0
(1 C, CH2), 27.6 (1 C, CH2), 23.9 (1 C, CH2), 22.3 (1 C, CH2) ppm.
31P NMR (120 MHz, CDCl3): δ = 23.4 ppm.
Methyl (E)-9-[(1S,2R,3R,5S)-2-(2-Acetoxyethyl)-3,5-bis(tert-butyl-
dimethylsilyloxy)cyclopentyl]-7-oxonon-8-enoate (8): A Dess–Martin DMAP (10 mg, 0.076 mmol), and TBSCl (55 mg, 0.37 mmol) were
periodinane solution (1.5 mL of a 0.47 m solution in CH2Cl2,
0.70 mmol) was added dropwise to a solution of alcohol 5 (225 mg,
successively added to a solution of the allylic alcohol (147 mg,
0.25 mmol) in DMF (18 mL). After stirring overnight, the reaction
0.51 mmol) in CH2Cl2 (10 mL). After completion (TLC), 10% aq. was quenched with H2O (40 mL) and Et2O (30 mL). The mixture
NaHCO3/Na2S2O3 (1:1, 30 mL) was added. After stirring for 1.5 h,
the mixture was extracted with CH2Cl2 (3ϫ 30 mL). The combined
organic layers were washed with brine, dried, and filtered. The sol-
was extracted with Et2O (3ϫ 15 mL), and the combined organic
layers were washed with H2O (3ϫ 15 mL) and brine, dried, and
filtered. The solvent was evaporated under reduced pressure. The
vent was evaporated under reduced pressure. The material was di- residue was purified by column chromatography (9:1 pentane/Et2O)
rectly used in the next step without further purification. The β-
keto phosphonate 6 (440 mg, 1.11 mmol) was added dropwise to a
suspension of Ba(OH)2 (70 mg, 0.41 mmol) in THF (10 mL). After
1 h, the aldehyde in THF (20 mL) was added through a cannula to
the reaction mixture, which was stirred overnight. Then the reac-
tion was quenched with H2O (25 mL) and Et2O (25 mL). The mix-
to afford 206 mg of 9 as a colorless oil (quantitative yield). Rf =
0.47 (8:2 cyclohexane/Et2O). [α]2D0 = +24.0 (c = 1, CHCl ). IR: ν =
˜
3
2954, 2930, 1732, 1472, 1463, 1251, 1057 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 5.35–5.50 (m, 1 H), 5.20–5.35 (m, 1 H),
3.95–4.15 (m, 3 H), 3.75–3.90 (m, 2 H), 3.66 (s, 3 H), 2.40–2.60 (m,
1 H), 2.40 (m, 4 H), 2.02 (s, 3 H), 1.20–1.80 (m, 11 H), 0.75–1.00
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(m, 27 H), –0.10–0.10 (m, 18 H) ppm. 13C NMR (75 MHz, CDCl3): 53.7 (1 C, CH), 51.4 (1 C, CH3), 46.0 (1 C, CH), 44.4 (1 C, CH2),
δ = 174.3 (1 C, Cq), 171.2 (1 C, Cq), 136.3 (1 C, CH), 127.5 (1 C, 38.3 (1 C, CH2), 34.0 (1 C, CH2), 32.5 (1 C, CH2), 30.4 (1 C, CH2),
CH), 127.2 (1 C, CH), 76.3 (1 C, CH), 76.7 (1 C, CH), 73.1 (1 C, 29.1 (1 C, CH2), 25.8 (9 C, CH3), 24.9 (1 C, CH2), 18.2 (1 C, Cq),
CH), 63.5 (1 C, CH2), 53.0 (1 C, CH), 52.8 (1 C, CH), 51.5 (1 C, 18.0 (2 C, Cq), –4.1 (1 C, CH3), –4.3 (1 C, CH3), –4.4 (1 C, CH3),
CH3), 45.6 (1 C, CH), 44.3 (1 C, CH2), 38.4 (1 C, CH2), 34.2 (1 C, –4.6 (1 C, CH3), –4.7 (2 C, CH3) ppm. MS (ESI+): m/z = 673.5 [M
CH2), 29.3 (1 C, CH2), 27.8 (1 C, CH2), 25.8 (9 C, CH3), 25.0 (2 + H]+, 541.4 [M + H – OTBS]+, 409.3 [M + H – 2 OTBS]+, 277.2
C, CH2), 21.0 (1 C, CH3), 18.3 (1 C, Cq), 18.1 (2 C, Cq), –4.2 (1 [M + H – 3 OTBS]+. HRMS (ESI+): calcd. for C35H73O6Si3 [M +
C, CH3), –4.3 (1 C, CH3), –4.5 (1 C, CH3), –4.6 (2 C, CH3), –4.7
(1 C, CH3) ppm. MS (ESI+): m/z = 715.5 [M + H]+, 583.4 [M +
H – OTBS]+, 451.3 [M + H – 2 OTBS]+, 319.2 [M + H –
3 OTBS]+. HRMS (ESI+): calcd. for C37H75O7Si3 [M + H]+
715.4821; found 715.4827.
H]+ 673.4715; found 673.4720.
Methyl (E)-9-[(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2-
(2-hydroxyethyl)cyclopentyl]-7-(1-ethoxyethoxy)non-8-enoate (12):
K2CO3 (78 mg, 0.56 mmol) was added to a solution of 10 (109 mg,
0.16 mmol) in MeOH (11 mL). After 2 h, Et2O/H2O (1:1, 20 mL)
was added, and the mixture was stirred for 15 min. The mixture
was then extracted with pentane/Et2O (3ϫ 20 mL). The combined
organic layers were washed with brine, dried, and filtered. The sol-
vent was evaporated under reduced pressure. The residue was puri-
Methyl (E)-9-[(1S,2R,3R,5S)-2-(2-Acetoxyethyl)-3,5-bis(tert-butyl-
dimethylsilyloxy)cyclopentyl]-7-(1-ethoxyethyl)non-8-enoate
(10):
Ethyl vinyl ether (2 mL, 20.9 mmol) and PPTS (10 mg,
0.040 mmol) were successively added to a solution of the allylic
alcohol derived from enone 8 (109 mg, 0.18 mmol) in CH2Cl2 fied by column chromatography (1% Et3N deactivated SiO2, 7:3
(7 mL) at 0 °C. The reaction mixture was warmed to room temp.
overnight. Then 2 mL of a saturated aqueous solution of NaHCO3
was added, and the reaction mixture was extracted with CH2Cl2
(3ϫ 20 mL). The combined organic layers were washed with brine,
dried, and filtered. The solvent was evaporated under reduced pres-
sure. The residue was purified by column chromatography (1%
Et3N deactivated SiO2, 8:2 pentane/Et2O) to afford 109 mg of 10
pentane/Et2O) to afford 80 mg of 12 as a colorless oil (78%). Rf =
0.36 (5:5 cyclohexane/Et2O). [α]2D0 = +18.3 (c = 1, CHCl ). IR: ν =
˜
3
3484, 2930, 2857, 1739, 1253, 1055 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 5.15–5.60 (m, 2 H), 5.55–5.70 (m, 1 H), 3.75–4.00 (m,
3 H), 3.30–3.75 (m, 7 H), 2.45–2.60 (m, 1 H), 2.00–2.45 (m, 5 H),
1.00–1.85 (m, 16 H), 0.70–1.00 (m, 18 H), –0.10–0.10 (m, 12 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 174.3 (1 C, Cq), 134.2 (1
C, CH, diast.), 133.3 (1 C, CH, diast.), 131.9 (1 C, CH, diast.),
130.5 (1 C, CH, diast.), 130.2 (1 C, CH, diast.), 98.5 (1 C, CH,
as a colorless oil (89%). Rf = 0.65 (5:5 cyclohexane/Et2O). [α]2D0
+25.2 (c = 1, CHCl ). IR: ν = 2956, 2930, 2858, 1743, 1249,
=
˜
3
1056 cm–1. H NMR (300 MHz, CDCl3): δ = 5.20–5.60 (m, 2 H), diast.), 96.8 (1 C, CH, diast.), 96.7 (1 C, CH, diast.), 76.2–77.0 (3
1
5.55–5.70 (m, 1 H), 3.75–4.20 (m, 4 H), 3.66 (s, 3 H), 3.25–3.60 (m,
2 H), 2.45–2.60 (m, 1 H), 2.40 (m, 4 H), 2.02 (s, 3 H), 1.50–1.85
(m, 4 H), 1.00–1.45 (m, 14 H), 0.70–1.00 (m, 18 H), –0.10–0.10 (m,
C, CH), 61.8 (1 C, CH2), 61.1 (1 C, CH2), 59.0 (1 C, CH2), 54.0 (1
C, CH), 51.5 (1 C, CH3), 46.1 (1 C, CH), 44.9 (1 C, CH2), 35.2 (1
C, CH2), 34.9 (1 C, CH2), 34.1 (1 C, CH2), 29.2 (1 C, CH2), 26.0
12 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.2 (1 C, Cq), (6 C, CH3), 25.3 (1 C, CH2), 20.5 (1 C, CH3), 18.1 (2 C, Cq), 15.5
171.0 (1 C, Cq), 134.3 (1 C, CH, diast.), 133.6 (1 C, CH, diast.),
133.5 (1 C, CH, diast.), 131.5 (1 C, CH, diast.), 131.3 (1 C, CH,
(1 C, CH3), –4.0 (2 C, CH3), –4.5 (2 C, CH3) ppm. MS (ESI+): m/z
= 541.4 [M + H – C4H9O2]+, 409.3 [M + H – C4H9O2 – OTBS]+,
diast.), 129.9 (1 C, CH, diast.), 129.7 (1 C, CH, diast.), 98.7 (1 C, 277.2 [M + H – C4H9O2 – 2 OTBS]+. HRMS (ESI+): calcd. for
CH, diast.), 96.8 (1 C, CH, diast.), 96.7 (1 C, CH, diast.), 76.5 (3 C29H57O5Si2 [M + H – C4H9O2]+ 541.3745; found 541.3738.
C, CH), 63.5 (1 C, CH2), 61.3 (1 C, CH2), 59.0 (1 C, CH2), 53.1 (1
C, CH), 51.5 (1 C, CH3), 45.7 (1 C, CH), 44.3 (1 C, CH2), 35.9 (1
C, CH2), 34.1 (1 C, CH2), 29.2 (1 C, CH2), 28.0 (1 C, CH2), 25.9
(6 C, CH3), 25.3 (1 C, CH2), 20.0–21.0 (2 C, CH3, diast.), 18.0 (2
Methyl (E)-9-{(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2-
[(Z)-oct-2-enyl]cyclopentyl}-7-(tert-butyldimethylsilyloxy)non-8-eno-
ate (14): A Dess–Martin periodinane solution (600 μL of a 0.47 m
solution in CH2Cl2, 0.28 mmol) was added to a solution of 11
C, Cq), 15.5 (1 C, CH3), –4.2 (1 C, CH3), –4.6 (2 C, CH3), –4.7 (1
(110 mg, 0.16 mmol) in CH2Cl2 (11 mL). After 2 h and completion
C, CH3) ppm. MS (ESI+): m/z = 583.4 [M + H – C4H9O2]+,
of the reaction (TLC), a 10% aq. NaHCO3/Na2S2O3 solution (1:1,
451.3 [M + H – C4H9O2 – OTBS]+, 319.2 [M + H – C4H9O2
–
20 mL) was added. After stirring for 1.5 h, the mixture was ex-
tracted with CH2Cl2 (3ϫ 10 mL). The combined organic layers
were washed with brine, dried, and filtered. The solvent was evapo-
rated under reduced pressure. The material was directly used in the
2 OTBS]+, 259.2 [M + H – C4H9O2 – 2 OTBS – OAc]+. HRMS
(ESI+): calcd. for C31H59O6Si2 [M + H – C4H9O2]+ 583.3850; found
583.3844.
Methyl (E)-9-[(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2- next step without further purification. NaHMDS (600 μL, 2 m in
(2-hydroxyethyl)cyclopentyl]-7-(tert-butyldimethylsilyloxy)non-8-en-
oate (11): K2CO3 (110 mg, 0.8 mmol) was added to a solution of 9
toluene, 1.2 mmol) was added dropwise to a suspension of dried
phosphonium salt 13 (560 mg, 1.31 mmol) in degassed THF
(144 mg, 0.20 mmol) in MeOH (15 mL). After 2 h, a mixture of (10 mL) at 0 °C. After 1 h at 0 °C, the aldehyde in degassed THF
Et2O/H2O (1:1, 20 mL) was added and stirred for 15 min. The reac-
tion mixture was extracted with pentane/Et2O (1:1, 3ϫ 20 mL).
The combined organic layers were washed with brine, dried, and
filtered. The solvent was evaporated under reduced pressure and
the residue purified by column chromatography (7:3 pentane/Et2O)
to afford 125 mg of 11 as a colorless oil. Rf = 0.42 (5:5 cyclohexane/
(10 mL) was added by cannula to the reaction mixture. The reac-
tion mixture was warmed to room temp. overnight. After 1 h, the
reaction was quenched with a saturated aqueous solution of NH4Cl
(10 mL) and the mixture allowed to reach room temp. The mixture
was extracted with Et2O (3ϫ 20 mL). The combined organic layers
were washed with brine, dried, and filtered. The solvent was evapo-
rated under reduced pressure. The residue was purified by column
chromatography (95:5 pentane/Et2O) to afford 114 mg of 14 as a
colorless oil (94% over two steps). Rf = 0.79 (8:2 cyclohexane/
Et2O). [α]2D0 = +18.5 (c = 1, CHCl ). IR: ν = 3462, 2953, 2929,
˜
3
2857, 1741, 1252, 1055 cm–1. 1H NMR (300 MHz, CDCl3): δ =
5.15–5.60 (m, 2 H), 3.95–4.15 (m, 1 H), 3.75–3.95 (m, 2 H), 3.35–
3.75 (m, 5 H), 2.45–2.65 (m, 1 H), 2.15–2.45 (m, 4 H), 2.00–2.15
Et2O). [α]2D0 = +16.2 (c = 1, CHCl ). IR: ν = 2954, 2928, 2856,
˜
3
(m, 1 H), 1.50–1.70 (m, 4 H), 1.20–1.50 (m, 6 H), 0.70–1.00 (m, 27 1743, 1251, 1067 cm–1. 1H NMR (300 MHz, CDCl3): δ = 5.25–5.60
H), –0.2–0.2 (m, 18 H) ppm. 13C NMR (75 MHz, CDCl3): δ = (m, 4 H), 4.00–4.15 (m, 1 H), 3.85–4.00 (m, 1 H), 3.70–3.85 (m, 1
174.2 (1 C, Cq), 136.0 (1 C, CH), 127.7 (1 C, CH), 77.1 (1 C, CH),
H), 3.66 (s, 3 H), 2.50–270 (m, 1 H), 2.20–2.40 (m, 3 H), 1.85–2.15
76.3 (1 C, CH), 73.0 (1 C, CH), 61.9 (1 C, CH2), 54.0 (1 C, CH), (m, 4 H), 1.15–1.70 (m, 17 H), 0.70–1.00 (m, 30 H), –0.10–0.10 (m,
2626
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2621–2634

Total Synthesis of Isoprostanes
18 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.3 (1 C, Cq), H) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.9 (1 C, Cq), 135.4
135.8 (1 C, CH), 130.6 (1 C, CH), 128.7 (1 C, CH), 128.0 (1 C,
(1 C, CH), 130.4–130.7 (1 C, CH, epi), 130.2–130.4 (1 C, CH, epi),
CH), 76.3 (2 C, CH), 73.3 (1 C, CH), 52.5 (1 C, CH), 51.5 (1 C, 128.3–128.5 (1 C, CH, epi), 76.3 (1 C, CH), 76.0 (1 C, CH), 73.0
CH3), 50.3 (1 C, CH), 44.5 (1 C, CH2), 38.5 (1 C, CH2), 34.2 (1 C, (1 C, CH), 63.9 (1 C, CH2), 52.5 (1 C, CH2), 52.4 (1 C, CH3), 51.6
CH2), 31.7 (1 C, CH2), 29.5 (1 C, CH2), 29.3 (1 C, CH2), 27.5 (2 (1 C, CH), 44.4 (1 C, CH2), 37.3 (1 C, CH2), 34.4 (1 C, CH2), 31.6
C, CH2), 26.3 (1 C, CH2), 26.0 (9 C, CH3), 25.1 (1 C, CH2), 22.7
(1 C, CH2), 29.2 (2 C, CH2), 27.3 (1 C, CH2), 26.0 (6 C, CH3), 25.1
(1 C, CH2), 18.4 (2 C, Cq), 18.2 (1 C, Cq), 14.2 (1 C, CH3), –4.1 (2 C, CH2), 22.5 (1 C, CH2), 17.1 (2 C, Cq), 14.2 (1 C, CH3), –4.53
(1 C, CH3), –4.3 (1 C, CH3), –4.4 (2 C, CH3), –4.6 (2 C, Cq) ppm.
(1 C, CH3), –4.4 (2 C, CH3), –4.6 (1 C, CH3) ppm. MS (ESI+): m/z
= 625.5 [M + H]+, 607.5 [M + H – H2O]+, 475.4 [M + H – H2O –
OTBS]+, 343.3 [M + H – H2O – 2 OTBS]+. HRMS (ESI+): calcd.
for C35H69O5Si2 [M + H]+ 625.4684; found 625.4692. A Dess–Mar-
tin periodinane solution (150 μL of a 0.47 m solution in CH2Cl2,
0.071 mmol) was added to a solution of the previous allylic alcohol
(30 mg, 0.048 mmol) in CH2Cl2 (4 mL). After completion of the
reaction (TLC), a 10% aq. NaHCO3/Na2S2O3 solution (1:1, 5 mL)
was added. After stirring for 1.5 h, the mixture was extracted with
CH2Cl2 (3ϫ 15 mL). The combined organic layers were washed
with brine, dried, and filtered. The solvent was evaporated under
reduced pressure and the residue purified by column chromatog-
raphy (9:1 pentane/Et2O) to afford 17 mg of the enone 16 as a
colorless oil (57%). Rf = 0.55 (8:2 cyclohexane/Et2O). [α]2D0 = +0.8
Methyl (E)-9-{(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2-
[(Z)-oct-2-enyl]cyclopentyl}-7-(1-ethoxyethoxy)non-8-enoate (15): A
Dess–Martin periodinane solution (600 μL of a 0.47 m solution in
CH2Cl2, 0.28 mmol) was added to a solution of alcohol 12 (80 mg,
0.13 mmol) in CH2Cl2 (8 mL). After 2 h, Na2S2O3/NaHCO3
(20 mL, 1:1, v/v, 10%) was added, and the mixture was stirred for
1 h. The layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3ϫ 15 mL). The organic layers were washed with
brine (15 mL), dried with MgSO4, filtered, and the solvent was re-
moved under reduced pressure. The resulting aldehyde was used
directly in the next step without further purification. NaHMDS
(330 μL, 2 m in toluene, 0.66 mmol) was added dropwise to a sus-
pension of dried phosphonium salt 13 (296 mg, 0.69 mmol) in de-
gassed THF (5 mL) at 0 °C. After 1 h at 0 °C, the aldehyde in de-
gassed THF (4 mL) was added through a cannula to the ylide. The
reaction mixture was warmed to room temp. overnight. Then the
reaction was quenched with a saturated aqueous solution of NH4Cl
(10 mL), and the mixture was extracted with Et2O (3ϫ 20 mL).
The combined organic layers were washed with brine, dried, and
filtered. The solvent was evaporated under reduced pressure. The
residue was purified by column chromatography (1% Et3N deacti-
vated SiO2, 95:5 pentane/Et2O) to afford 56 mg of diene 15 as a
colorless oil (63% over two steps). Rf = 0.55 (8:2 cyclohexane/
(c = 1, CHCl ). IR: ν = 2955, 2927, 2856, 1736, 1697, 1674, 1626,
˜
3
1463, 1252, 1071 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.55–6.75
(m, 1 H), 6.15 (d, J = 15.2 Hz, 1 H), 5.15–5.50 (m, 2 H), 3.75–4.20
(m, 2 H), 3.65 (s, 3 H), 2.70–2.90 (m, 1 H), 2.20–2.70 (m, 5 H),
1.80–2.20 (m, 6 H), 1.50–1.80 (m, 6 H), 1.15–1.50 (m, 9 H), 0.70–
1.00 (m, 18 H), –0.10–0.10 (s, 12 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 200.0 (1 C, Cq), 174.2 (1 C, Cq), 145.8 (1 C, CH),
131.5 (1 C, CH), 131.3 (1 C, CH), 127.8 (1 C, CH), 75.8 (1 C, CH),
75.6 (1 C, CH), 52.9 (1 C, CH), 51.6 (1 C, CH3), 51.1 (1 C, CH),
44.5 (1 C, CH2), 40.6 (1 C, CH2), 34.0 (1 C, CH2), 31.7 (1 C, CH2),
30.3 (1 C, CH2), 29.4 (1 C, CH2), 27.6 (1 C, CH2), 26.6 (1 C, CH2),
25.9 (6 C, CH3), 24.9 (1 C, CH2), 23.9 (1 C, CH2), 22.7 (1 C, CH2),
18.1 (2 C, Cq), 14.2 (1 C, CH3), –4.3 (1 C, CH3), –4.4 (1 C, CH3),
–4.5 (1 C, CH3), –4.6 (1 C, Cq) ppm.
Et2O). [α]2D0 = +16.9 (c = 1, CHCl ). IR: ν = 2954, 2928, 2857,
˜
3
1740, 1251, 1059 cm–1. 1H NMR (300 MHz, CDCl3): δ = 5.15–5.60
(m, 4 H), 5.55–5.70 (m, 1 H), 4.00–4.15 (m, 1 H), 3.90–4.00 (m, 1
H), 3.75–3.90 (m, 1 H), 3.66 (s, 3 H), 3.30–3.65 (m, 2 H), 3.55–3.75
(m, 1 H), 2.15–2.45 (m, 3 H), 1.75–2.15 (m, 6 H), 1.00–1.75 (m, 23
H), 0.70–1.00 (m, 18 H), –0.10–0.10 (m, 12 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 174.3 (1 C, Cq), 133.5 (1 C, CH), 132.4 (1
C, CH), 131.0 (1 C, CH), 128.0 (1 C, CH), 97.1 (1 C, CH), 75.5 (3
C, CH), 63.7 (1 C, CH2), 61.3 (1 C, CH2), 59.0 (1 C, CH2), 52.3 (1
C, CH), 51.3 (1 C, CH3), 50.2 (1 C, CH), 38.1 (1 C, CH2), 35.8 (1
C, CH2), 32.5 (1 C, CH2), 29.6 (1 C, CH2), 28.6 (1 C, CH2), 27.1
(1 C, CH2), 26.0 (6 C, CH3), 25.1 (1 C, CH2), 23.5 (1 C, CH2), 22.5
(1 C, CH2), 20.3 (1 C, CH3), 17.9 (2 C, Cq), 15.3 (1 C, CH3), 14.0
(1 C, CH3), –4.5 (1 C, CH3), –4.6 (1 C, CH3), –4.7 (1 C, CH3), –4.8
(1 C, CH3) ppm. MS (ESI+): m/z = 607.5 [M + H – C4H9O2]+,
475.4 [M + H – C4H9O2 – OTBS]+. HRMS (ESI+): calcd. for
C35H67O4Si2 [M + H – C4H9O2]+ 607.4578; found 607.4575.
Methyl (S,E)-9-{(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-
2-[(Z)-oct-2-enyl]cyclopentyl}-7-hydroxynon-8-enoate (17): LiAlH4
(170 μL, 1 m in THF, 0.170 mmol) was added dropwise to a solu-
tion of dry (S)-binaphthol (49 mg, 0.171 mmol) in freshly distilled
dry THF at room temp. After 5 min, freshly distilled dried EtOH
(170 μL, 1 m in THF, 0.170 μL) was added dropwise. The reaction
mixture was cooled to –100 °C, and the enone 16 (17 mg,
0.0273 mmol) was added through a cannula to the reaction mixture.
The reaction mixture was slowly warmed to –30 °C. Then MeOH
(500 μL) and H2O (1.0 mL) were added, and the suspension was
filtered through a plug of Celite, which had previously been washed
with Et2O. The filtrate was washed with H2O (10 mL) and the mix-
ture was extracted with Et2O (3ϫ 15 mL). The combined organic
Methyl (E)-9-{(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2- layers were washed with brine, dried, and filtered. The solvent was
[(Z)-non-2-enyl]cyclopentyl}-7-oxonon-8-enoate (16): PPTS (4 mg,
0.016 mmol) was added to a solution of 15 (50 mg, 0.072 mmol) in
EtOH/CH2Cl2 (5:1, 4.8 mL). After 17 h at room temp., a saturated
aqueous solution of NaHCO3 (1 mL) was added, and the mixture
was extracted with CH2Cl2 (3ϫ 10 mL). The combined organic
layers were washed with brine, dried, and filtered. The solvent was
evaporated under reduced pressure. The residue was purified by
column chromatography (7:3 pentane/Et2O) to afford 35 mg of the
evaporated under reduced pressure. Excess binaphthol was precipi-
tated with hexanes, but traces of binaphthol remained. After con-
centration, the residue was purified by column chromatography
(8:2 heptane/Et2O) to afford the alcohol 17 as a colorless oil
(11 mg, 64% yield). Rf = 0.58 (5:5 cyclohexane/Et2O). [α]2D0 = +5.3
1
(c = 1, CHCl3). H NMR (300 MHz, CDCl3): δ = 5.20–5.70 (m, 4
H), 3.75–4.20 (m, 3 H), 3.66 (s, 3 H), 2.55–2.75 (m, 1 H), 2.15–2.50
(m, 4 H), 1.80–2.15 (m, 6 H), 1.10–1.80 (m, 17 H), 0.70–1.00 (m,
allylic alcohol as a colorless oil (78%). Rf = 0.49 (7:3 cyclohexane/ 18 H), –0.10–0.10 (s, 12 H) ppm. 13C NMR (75 MHz, CDCl3): δ
Et2O). [α]2D0 = +10.0 (c = 1, CHCl ). IR: ν = 34.82, 2954, 2928,
= 174.1 (1 C, Cq), 135.1 (1 C, CH), 130.5 (1 C, CH), 130.0 (1 C,
CH), 128.2 (1 C, CH), 76.0 (1 C, CH), 75.7 (1 C, CH), 72.8 (1 C,
˜
3
2856, 1739, 1463, 1252, 1069 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 5.15–5.60 (m, 4 H), 4.00–4.15 (m, 1 H), 3.75–4.00 (m, 2 H), CH), 52.3 (1 C, CH), 51.3 (1 C, CH3), 51.3 (1 C, CH), 44.2 (1 C,
3.66 (s, 3 H), 3.55–3.75 (m, 1 H), 2.15–2.45 (m, 3 H), 1.75–2.15 (m,
6 H), 1.00–1.75 (m, 18 H), 0.70–1.00 (m, 18 H), –0.10–0.10 (m, 12
CH2), 37.1 (1 C, CH2), 33.9 (1 C, CH2), 31.5 (1 C, CH2), 29.6 (1
C, CH2), 29.2 (1 C, CH2), 27.3 (1 C, CH2), 26.1 (1 C, CH2), 25.8
Eur. J. Org. Chem. 2012, 2621–2634
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2627

C. Oger, V. Bultel-Poncé, A. Guy, T. Durand, J.-M. Galano
FULL PAPER
(6 C, CH3), 25.0 (1 C, CH2), 24.8 (1 C, CH2), 22.5 (1 C, CH2), 18.0 1 C, CH2), 20.3–19.9 (d, JC-P = 0.4 Hz, 1 C, CH2), 13.7 (1 C, CH3)
(2 C, Cq), 14.0 (1 C, CH3), –4.5 (1 C, CH3), –4.6 (2 C, CH3), –4.8 ppm. 31P NMR (120 MHz, CDCl3): δ = 24.5 ppm.
(1 C, CH3) ppm.
2-{(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2-[(E)-3-
ent-7-epi-7-F2t-Dihomo-IsoP (1): HCl (1 m in THF, 1.0 mL,
oxooct-1-enyl]cyclopentyl}ethyl acetate (19): A Dess–Martin
1.0 mmol) was added to a solution of 17 (11 mg, 0.018 mmol) in
periodinane solution (1.5 mL of a 0.47 m solution in CH2Cl2,
THF (1 mL). After 2 d at room temp., brine (5 mL) was added, and
the mixture was extracted with EtOAc (3ϫ 10 mL). The combined
organic layers were washed with brine, dried, and filtered, and the
solvent was removed under reduced pressure. The residue was puri-
0.61 mmol) was added to a solution of alcohol 5 (225 mg,
0.51 mmol) in CH2Cl2 (10 mL). After completion of the reaction
(TLC), 10% aq. NaHCO3/Na2S2O3 (1:1, 50 mL) was added. After
stirring for 1.5 h, the mixture was extracted with CH2Cl2 (3 ϫ
30 mL). The combined organic layers were washed with brine,
dried, and filtered. The solvent was evaporated under reduced pres-
sure. The material was directly used in the next step without further
fied by column chromatography (9:1 EtOAc/MeOH) to afford
2.9 mg of ent-(7S)-F2t-dihomo-IsoP (1) as a colorless oil (28% over
two steps). Rf = 0.76 (9:1 EtOAc/MeOH + 1% AcOH). [α]2D0 = +2.4
(c = 0.166, MeOH). IR: ν = 3343, 2483, 2071, 1704, 1120 cm–1. 1H
˜
purification. β-Keto phosphonate 18 (440 mg, 1.11 mmol) was
added dropwise to a suspension of dry Ba(OH)2 (70 mg,
0.41 mmol) in THF (10 mL). After 1 h, the aldehyde in THF
(20 mL) was added through a cannula to the reaction mixture and
stirred overnight. Then the reaction was quenched with H2O
(25 mL) and Et2O (25 mL). The mixture was extracted with Et2O
(3ϫ 30 mL). The combined organic layers were washed with brine,
dried, and filtered. The solvent was evaporated under reduced pres-
sure. The residue was purified by column chromatography (9:1
pentane/Et2O) to afford 155 mg of enone 19 as a colorless oil (57%
NMR (300 MHz, [D4]MeOH): δ = 5.20–5.60 (m, 4 H), 3.60–4.10
(m, 3 H), 2.65–2.75 (m, 1 H), 2.35–2.55 (m, 1 H), 2.15–2.35 (m, 3
H), 1.90–2.00 (m, 4 H), 1.20–1.70 (m, 15 H), 0.80–1.00 (m, 3 H)
ppm. 13C NMR (75 MHz, [D4]MeOH): δ = 136.8 (1 C, CH), 131.7
(1 C, CH), 130.6 (1 C, CH), 129.3 (1 C, CH), 76.4 (1 C, CH), 76.3
(1 C, CH), 76.7 (1 C, CH), 54.8 (1 C, CH), 53.8 (1 C, CH), 51.5 (1
C, CH2), 43.6 (1 C, CH2), 38.4 (1 C, CH2), 35.4 (1 C, CH2), 32.7
(1 C, CH2), 30.5 (1 C, CH2), 30.3 (1 C, CH2), 28.4 (1 C, CH2), 27.4
(1 C, CH2), 26.3 (1 C, CH2), 23.7 (1 C, CH2), 14.4 (1 C, CH3) ppm.
MS (ESI+): m/z = 383.4 [M + H]+, 365.3 [M + H – H2O]+, 347.3
[M + H – 2 H2O]+, 329.3 [M + H – 3 H2O]+. HRMS (ESI+): calcd.
for C22H39O5 [M + H]+ 383.2797; found 383.2794.
over two steps). Rf = 0.50 (8:2 cyclohexane/Et2O). [α]2D0 = +23.4 (c
1
= 1, CHCl ). IR: ν = 2955, 2930, 2857, 1741, 1248, 1056 cm–1. H
˜
3
NMR (300 MHz, CDCl3): δ = 6.50 (dd, J = 10.5, 5.0 Hz, 1 H),
6.20 (d, J = 15.6 Hz, 1 H), 3.80–4.15 (m, 4 H), 2.65–2.90 (m, 1 H),
2.50 (t, J = 7.4 Hz, 2 H), 2.15–2.45 (m, 2 H), 2.03 (s, 3 H), 1.45–
1.80 (m, 7 H), 1.15–1.45 (m, 5 H), 0.70–1.00 (m, 18 H), –0.10–0.10
(m, 12 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 200.2 (1 C, Cq),
171.0 (1 C, Cq), 144.4 (1 C, CH), 131.6 (1 C, CH), 76.2 (1 C, CH),
75.4 (1 C, CH), 63.3 (1 C, CH2), 53.1 (1 C, CH), 46.4 (1 C, CH),
44.4 (1 C, CH2), 41.3 (1 C, CH2), 31.6 (1 C, CH2), 28.0 (1 C, CH2),
25.9 (6 C, CH3), 24.0 (1 C, CH2), 22.6 (1 C, CH2), 21.0 (1 C, CH3),
18.0 (2 C, Cq), 14.0 (1 C, CH3), –4.2 (1 C, CH3), –4.5 (2 C, CH3),
–4.7 (1 C, CH3) ppm. MS (ESI+): m/z = 599.4 [M + H]+, 467.3
[M – OTBS]+. HRMS (ESI+): calcd. for C31H59O7Si2 [M + H]+
599.3799; found 599.3791.
ent-(7RS)-7-F2t-dihomo-IsoP [RS-(1)]: HCl (1 m in THF, 1.0 mL,
1.0 mmol) was added to a solution of 14 (110 mg, 0.15 mmol) in
THF (5 mL). After 2 d at room temp., brine (10 mL) was added,
and the mixture was extracted with EtOAc (3ϫ 20 mL). The com-
bined organic layers were washed with brine, dried, and filtered,
and the solvent was removed under reduced. The residue was puri-
fied by column chromatography (9:1 EtOAc/MeOH) to afford
33 mg of ent-(7RS)-F2t-dihomo-IsoP [(RS)-1] as a colorless oil
(58%). Rf = 0.81 (9:1 EtOAc/MeOH + 1% AcOH). [α]2D0 = +6.7 (c
= 1ϫ10–2, MeOH). IR: ν = 3343, 2483, 2071, 1704, 1120 cm–1. 1H
˜
NMR (300 MHz, [D4]MeOH): δ = 5.25–5.60 (m, 4 H), 3.80–4.15
(m, 3 H), 2.60–2.80 (m, 1 H), 2.40–2.60 (m, 1 H), 2.30 (t, J =
7.0 Hz, 2 H), 1.90–2.15 (m, 5 H), 1.20–1.70 (m, 15 H), 0.80–1.00
(m, 3 H) ppm. 13C NMR (75 MHz, [D4]MeOH): δ = 177.7, (1 C,
Cq), 136.7 (1 C, CH), 131.76 (1 C, CH), 130.6 (1 C, CH), 129.6 (1
C, CH), 76.3 (1 C, CH), 73.6 (1 C, CH), 73.3 (1 C, CH), 54.6 (1
C, CH), 51.4 (1 C, CH), 43.6 (1 C, CH2), 38.3 (1 C, CH2), 35.0 (1
C, CH2), 32.7 (1 C, CH2), 30.5 (1 C, CH2), 30.2 (1 C, CH2), 28.4
(1 C, CH2), 27.4–26.3 (1 C, CH2), 23.6 (1 C, CH2), 14.4 (1 C, CH3)
ppm. MS (ESI+): m/z = 383.4 [M + H]+, 365.3 [M + H – H2O]+,
347.3 [M + H – 2 H2O]+, 329.3 [M + H – 3 H2O]+. HRMS (ESI+):
calcd. for C22H39O5 [M + H]+ 383.2797; found 383.2805.
2-{(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2-[(E)-3-
hydroxyoct-1-enyl]cyclopentyl}ethyl acetate (20): CeCl3·7H2O
(240 mg, 0.64 mmol) in MeOH (30 mL) was added to a solution of
enone 19 (350 mg, 0.65 mmol). The mixture was cooled to 0 °C,
and then NaBH4 was added (22.0 mg, 0.582 mmol). After 10 min,
the reaction was quenched with H2O (12 mL) and Et2O (5 mL).
The reaction mixture was extracted with Et2O (3ϫ 15 mL). The
combined organic layers were washed with brine, dried, and fil-
tered. The solvent was evaporated under reduced pressure. The resi-
due was purified by column chromatography (8:2 pentane/Et2O) to
afford 326 mg of 20 as a colorless oil (98%). Rf = 0.66 (5:5 cyclo-
(7-Ethoxy-7-oxoheptyl)triphenylphosphonium Bromide (23): Ph3P
(11.1 g, 42.2 mol) and a catalytic amount of K2CO3 were added to
a solution of ethyl 7-bromoheptanoate (5.0 g, 21.1 mol) in CH3CN
(100 mL) at room temp. The reaction mixture was heated at reflux
overnight, and the solvent was then removed under reduced pres-
sure. The residue was purified by column chromatography (solid
SiO2 deposit, 9:1 CH2Cl2/MeOH) to afford 21.0 g of 23 as a white
hexane/Et2O). [α]2D0 = +25.9 (c = 1, CHCl ). IR: ν = 3509, 2955,
˜
3
2929, 2857, 1732, 1250, 1056 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 5.20–5.60 (m, 2 H), 3.60–4.35 (m, 5 H), 2.40–2.55 (m 1 H),
1.85–2.40 (m, 7 H), 1.00–1.90 (m, 12 H), 0.70–1.00 (m, 18 H),
–0.10–0.10 (m, 12 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.3
(1 C, Cq), 136.2 (1 C, CH), 129.2 (1 C, CH), 76.4 (1 C, CH), 73.0
(1 C, CH), 72.6 (1 C, CH), 63.6 (1 C, CH2), 52.9 (1 C, CH), 45.8
(1 C, CH), 44.4 (1 C, CH2), 37.4 (1 C, CH2), 37.2 (1 C, CH2), 31.9
(1 C, CH2), 28.0 (1 C, CH2), 25.9 (6 C, CH3), 25.3 (1 C, CH2), 21.1
(1 C, CH3), 18.1 (2 C, Cq), 14.1 (1 C, CH3), –4.2 (1 C, CH3), –4.5
(1 C, CH3), –4.6 (1 C, CH3), –4.7 (1 C, CH3) ppm. MS (ESI+): m/z
powder (87%). R = 0.33 (9:1 EtOAc/MeOH). M.p. 130 °C. IR: ν
˜
f
= 3254, 2875, 1706, 1471, 1253, 1051 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 4.40 (q, J = 6.1 Hz, 1 H), 3.90 (m, 1 H), 3.50–3.80 (m,
3 H), 3.20 (s, 1 H), 1.80–2.25 (m, 3 H), 1.30–1.80 (m, 5 H), 0.89
(d, J = 2.8 Hz, 9 H), 0.08 (d, J = 2.9 Hz, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 135.0 (3 C, CH), 134.0 (3 C, Cq), 133.3 (6 = 543.4 [M + H]+, 525.4 [M + H – H2O]+, 393.3 [M + H – H2O –
C, CH), 130.4 (6 C, CH), 124.9 (1 C, CH), 124.7 (1 C, CH), 116.9–
118.0 (d, JC-P = 1.14 Hz, 1 C, CH2), 23.4–22.0 (d, JC-P = 0.65 Hz,
OTBS]+, 261.2 [M + H – H2O – 2 OTBS]+. HRMS (ESI+): calcd.
for C29H59O5Si2 [M + H – H2O]+ 543.3901; found 543.3910.
2628
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2621–2634

Total Synthesis of Isoprostanes
2-{(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2-[(E)-3-(1- CH2), 44.5 (1 C, CH2), 36.1 (1 C, CH2), 32.8 (1 C, CH2), 31.9 (1
ethoxyethoxy)oct-1-enyl]cyclopentyl}ethyl acetate (21): Ethyl vinyl
ether (2 mL, 20.9 mmol) and PPTS (10 mg, 0.053 mmol) were suc-
cessively added to a solution of 20 (140 mg, 0.27 mmol) in CH2Cl2
(7 mL) at 0 °C. The reaction mixture was allowed to warm to room
temp. overnight. Then a saturated aqueous solution of NaHCO3
(2 mL) was added, and the reaction mixture was extracted with
CH2Cl2 (3ϫ 20 mL). The combined organic layers were washed
with brine, dried, and filtered. The solvent was evaporated under
reduced pressure. The residue was purified by column chromatog-
raphy (1 % Et3N deactivated SiO2, 8:2 pentane/Et2O) to afford
145 mg of 21 as a colorless oil (91%). Rf = 0.61 (5:5 cyclohexane/
C, CH2), 25.8 (6 C, CH3), 25.3 (1 C, CH2), 22.7 (1 C, CH2), 20.7
(1 C, CH2), 18.1 (2 C, Cq), 15.5 (1 C, CH3), 14.2 (1 C, CH3), –3.9
(2 C, CH3), –4.5 (2 C, CH3) ppm. MS (ESI+): m/z = 483.4 [M +
H – C4H9O2]+, 351.3 [M + H – C4H9O2 – OTBS]+, 219.2 [M + H –
C4H9O2 – 2 OTBS]+. HRMS (ESI+): calcd. for C27H55O3Si2 [M +
H – C4H9O2]+ 483.3683; found 483.3690.
Ethyl (Z)-9-{(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2-
[(3R,E)-3-(1-ethoxyethoxy)oct-1-enyl]cyclopentyl}non-7-enoate
[(17R)-24]: A Dess–Martin periodinane solution (400 μL of a
0.47 m solution in CH2Cl2) was added to a solution of (17R)-22
(62 mg, 0.11 mmol) in CH2Cl2 (8 mL). After completion of the re-
action (TLC), 10% aq. NaHCO3/Na2S2O3 (1:1, 15 mL) was added.
After stirring for 1.5 h, the mixture was extracted with CH2Cl2 (3ϫ
20 mL). The combined organic layers were washed with brine,
dried, and filtered. The solvent was evaporated under reduced pres-
sure. The material was directly used in the next step without further
purification. NaHMDS (400 μL, 2 m THF, 0.8 mmol) was added
dropwise to a suspension of dried phosphonium salt 23 (433 mg,
0.87 mmol) in degassed THF (10 mL) at –50 °C. After 1 h, the mix-
ture was added through a cannula to the aldehyde in degassed THF
(7 mL) at –78 °C. After 3 h at –50 °C, the reaction mixture was
allowed to warm to room temp. overnight. The reaction was
quenched with a saturated aqueous solution of NH4Cl (20 mL).
The mixture was extracted with Et2O (3ϫ 10 mL). The combined
organic layers were washed with brine, dried, and filtered. The sol-
vent was evaporated under reduced pressure and the residue puri-
fied by column chromatography (1% Et3N deactivated SiO2, 95:5
pentane/Et2O) to afford 54 mg of (17R)-24 as a colorless oil (81%
Et2O). [α]2D0 = +26.4 (c = 1, CHCl ). IR: ν = 2953, 2930, 2858,
˜
3
1741, 1248, 1056 cm–1. 1H NMR (300 MHz, CDCl3): δ = 5.20–5.40
(m, 2 H), 4.55–4.80 (m, 1 H), 3.75–4.20 (m, 6 H), 3.25–3.75 (m, 4
H), 2.50–2.70 (m, 1 H), 2.50 (m, 2 H), 2.02 (s, 3 H), 1.40–1.90 (m,
7 H), 1.05–1.40 (m, 14 H), 0.70–1.00 (m, 18 H), 0.02 (m, 12 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 171.0 (1 C, Cq), 134.1 (1
C, CH), 130.5 (1 C, CH), 97.5 (1 C, CH), 76.5 (3 C, CH), 63.7 (1
C, CH2), 61.5 (1 C, CH2), 58.8 (1 C, CH2), 53.1 (1 C, CH), 45.7 (1
C, CH), 43.5 (1 C, CH2), 36.2 (1 C, CH2), 32.5 (1 C, CH2), 27.7 (1
C, CH2), 25.9 (6 C, CH3), 25.2 (1 C, CH2), 22.5 (1 C, CH2), 20.4–
20.9 (2 C, CH3), 18.0 (2 C, Cq), 15.5 (1 C, CH3), 14.0 (1 C, CH3),
–4.2 (1 C, CH3), –4.6 (2 C, CH3), –4.7 (1 C, CH3) ppm. MS (ESI+):
m/z = 525.4 [M + H – C4H9O2]+, 393.3 [M + H – C4H9O2
–
OTBS]+, 261.2 [M + H – C4H9O2 – 2 OTBS]+, 201.2 [M + H –
C4H9O2 – 2 OTBS – OAc]+. HRMS (ESI+): calcd. for C29H57O4Si2
[M + H – C4H9O2]+ 525.3795; found 525.3798.
2-{(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2-[(3S,E)-3-
(1-ethoxyethoxy)oct-1-enyl]cyclopentyl}ethanol [(17S)-22] and 2-
{(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2-[(3R,E)-3-(1-
ethoxyethoxy)oct-1-enyl]cyclopentyl}ethanol [(17R)-22]: K2CO3
(85 mg, 0.62 mmol) was added to a solution of 21 (140 mg,
0.23 mmol) in MeOH (15 mL). After 2 h, the reaction was
quenched with a solution of H2O/Et2O (20 mL). The mixture was
extracted with a mixture of Et2O/pentane (3ϫ 20 mL), washed with
brine, dried, and filtered. The solvent was evaporated under re-
duced pressure. The residue was purified by flash chromatography
(1% Et3N deactivated SiO2, 8:2 pentane/Et2O) to afford 61 mg of
(17S)-22 and 63 mg of (17R)-22 as colorless oils. (17S)-22: Rf =
over two steps). Rf = 0.51 (9:1 cyclohexane/Et2O). [α]2D0 = +35.2 (c
1
= 1, CHCl ). IR: ν = 2955, 2929, 2857, 1736, 1251, 1060 cm–1. H
˜
3
NMR (300 MHz, CDCl3): δ = 5.15–5.60 (m, 4 H), 4.55–4.80 (m, 1
H), 4.00–4.15 (m, 2 H), 3.75–4.00 (m, 2 H), 3.25–3.55 (m, 2 H),
2.50–2.75 (m, 1 H), 2.15–2.40 (m, 3 H), 1.90–2.15 (m, 4 H), 1.45–
1.90 (m, 6 H), 1.00–1.45 (m, 21 H), 0.70–1.00 (m, 20 H), –0.10–
0.10 (m, 12 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.8 (1 C,
Cq), 133.6 (1 C, CH), 132.3 (1 C, CH), 130.6 (1 C, CH), 128.6 (1
C, CH), 97.6 (1 C, CH), 77.1 (1 C, CH), 76.0 (1 C, CH), 76.3 (1
C, CH), 61.4 (1 C, CH2), 60.2 (1 C, CH2), 59.1 (1 C, CH2), 52.5 (1
C, CH), 50.4 (1 C, CH), 44.5 (1 C, CH2), 36.1 (1 C, CH2), 34.4 (1
C, CH2), 32.0 (1 C, CH2), 29.4 (1 C, CH2), 29.0 (1 C, CH2), 27.3
(1 C, CH2), 26.4 (1 C, CH2), 25.9 (6 C, CH3), 25.3 (1 C, CH2), 25.0
(1 C, CH2), 22.7 (1 C, CH2), 20.6 (1 C, CH3), 18.1 (2 C, Cq), 15.5
(1 C, CH3), 14.2 (1 C, CH3), –4.3 (1 C, CH3), –4.4 (1 C, CH3), –4.5
(1 C, CH3), –4.6 (1 C, CH3) ppm. MS (ESI+): m/z = 621.6 [M +
H – C4H9O2]+. HRMS (ESI+): calcd. for C36H69O4Si2 [M + H –
C4H9O2]+ 621.4734; found 621.4730.
0.56 (5:5 cyclohexane/Et2O). [α]2D0 = –2.2 (c = 1, CHCl ). IR: ν =
˜
3
3470, 2955, 2929, 2857, 1252, 1055 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 5.15–5.60 (m, 2 H), 4.60–4.90 (m, 1 H), 3.80–4.00 (m,
3 H), 3.75–3.90 (m, 2 H), 3.25–3.75 (m, 4 H), 2.45–2.65 (m, 1 H),
2.00–2.45 (m, 3 H), 1.50–1.75 (m, 4 H), 1.00–1.50 (m, 13 H), 0.60–
1.00 (m, 18 H), –0.20–0.20 (m, 12 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 134.0 (1 C, CH), 130.5 (1 C, CH), 97.0 (1 C, CH),
76.5 (3 C, CH), 61.9 (1 C, CH2), 60.9 (1 C, CH2), 59.0 (1 C, CH), Ethyl (Z)-9-{(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2-
46.1 (1 C, CH), 44.6 (1 C, CH2), 36.1 (1 C, CH2), 32.7 (1 C, CH2), [(3S,E)-3-(1-ethoxyethoxy)oct-1-enyl]cyclopentyl}non-7-enoate
31.9 (1 C, CH2), 26.0 (6 C, CH3), 25.3 (1 C, CH2), 22.7 (1 C, CH2), [(17S)-24]: The same procedure as described for the synthesis of
20.7 (1 C, CH2), 18.2 (2 C, Cq), 15.5 (1 C, CH3), 14.2 (1 C, CH3), (17R)-24 was applied to 35 mg of (17S)-22 to give 11 mg of (17S)-
–3.9 (2 C, CH3), –4.5 (2 C, CH3) ppm. MS (ESI+): m/z = 483.4 [M
24 (25% over two steps, non-optimized). Rf = 0.55 (8:2 cyclohex-
+ H – C4H9O2]+, 351.3 [M + H – C4H9O2 – OTBS]+, 219.2 [M +
ane/Et2O). [α]2D0 = +25.0 (c = 1, CHCl ). IR: ν = 2954, 2928, 2856,
˜
3
H – C4H9O2 – 2 OTBS]+. HRMS (ESI+): calcd. for C27H55O3Si2 1738, 1251, 1060 cm–1. 1H NMR (300 MHz, CDCl3): δ = 5.15–5.60
[M + H – C4H9O2]+ 483.3683; found 483.3690. (17R)-22: Rf = 0.46
(m, 4 H), 4.55–4.80 (m, 1 H), 4.00–4.15 (m, 2 H), 3.75–4.00 (m, 2
H), 3.25–3.55 (m, 2 H), 2.50–2.75 (m, 1 H), 2.15–2.40 (m, 3 H),
1.90–2.15 (m, 4 H), 1.45–1.90 (m, 6 H), 1.00–1.45 (m, 21 H), 0.70–
(5:5 cyclohexane/Et2O). [α]2D0 = +37.9 (c = 1, CHCl ). IR: ν = 3470,
˜
3
2955, 2929, 2857, 1252, 1055 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 5.15–5.60 (m, 2 H), 4.60–4.90 (m, 1 H), 3.80–4.00 (m, 3 H), 1.00 (m, 20 H), –0.10–0.10 (m, 12 H) ppm. 13C NMR (75 MHz,
3.75–3.90 (m, 2 H), 3.25–3.75 (m, 4 H), 2.45–2.65 (m, 1 H), 2.00–
2.45 (m, 3 H), 1.50–1.75 (m, 4 H), 1.00–1.50 (m, 13 H), 0.60–1.00
CDCl3): δ = 173.8 (1 C, Cq), 133.6 (1 C, CH), 132.1 (1 C, CH),
130.5 (1 C, CH), 128.6 (1 C, CH), 97.5 (1 C, CH), 77.0 (1 C, CH),
(m, 18 H), –0.20–0.20 (m, 12 H) ppm. 13C NMR (75 MHz, CDCl3): 76.3 (1 C, CH), 76.0 (1 C, CH), 61.4 (1 C, CH2), 60.2 (1 C, CH2),
δ = 134.0 (1 C, CH), 130.5 (1 C, CH), 97.7 (1 C, CH), 76.8 (3 C, 58.9 (1 C, CH2), 52.5 (1 C, CH), 50.3 (1 C, CH), 44.5 (1 C, CH2),
CH), 61.9 (1 C, CH2), 61.3 (1 C, CH2), 58.8 (1 C, CH), 46.2 (1 C, 36.1 (1 C, CH2), 34.4 (1 C, CH2), 31.9 (1 C, CH2), 29.4 (1 C, CH2),
Eur. J. Org. Chem. 2012, 2621–2634
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2629

C. Oger, V. Bultel-Poncé, A. Guy, T. Durand, J.-M. Galano
FULL PAPER
29.0 (1 C, CH2), 27.3 (1 C, CH2), 26.4 (1 C, CH2), 25.9 (6 C, CH3), tilled THF at room temp. After 5 min, a solution of freshly distilled
25.3 (1 C, CH2), 25.0 (1 C, CH2), 22.7 (1 C, CH2), 20.6 (1 C, CH3), dried EtOH (820 μL, 1 m in THF, 0.820 mmol) was added drop-
18.1 (2 C, Cq), 15.4–15.6 (1 C, CH3), 14.1–14.4 (1 C, CH3), –4.3
wise. The reaction mixture was cooled to –100 °C, and enone 25
(1 C, CH3), –4.4 (1 C, CH3), –4.5 (1 C, CH3), –4.6 (1 C, CH3) ppm. (85 mg, 0.134 mmol) was added through a cannula to the reaction
MS (ESI+): m/z = 621.6 [M + H – C4H9O2]+. HRMS (ESI+): calcd.
mixture. Then MeOH (1 mL) and H2O (2.5 mL) were added, and
the suspension was filtered through a plug of Celite that had been
previously washed with Et2O. The filtrate was washed with H2O
(10 mL). The mixture was extracted with Et2O (3ϫ 15 mL). The
combined organic layers were washed with brine, dried, and fil-
tered. The solvent was evaporated under reduced pressure. Excess
binaphthol was precipitated with hexanes. The crude residue was
purified by column chromatography (9:1 heptane/Et2O) to afford
69 mg of (17S)-26 as a colorless oil (81%). Rf = 0.60 (7:3 cyclohex-
for C36H69O4Si2 [M + H – C4H9O2]+ 621.4734; found 621.4725.
Ethyl (Z)-9-{(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2-
[(E)-3-oxooct-1-enyl]cyclopentyl}non-7-enoate (25): PPTS (5 mg,
0.02 mmol) was added to a solution of racemic 24 (142 mg,
0.2 mmol) in EtOH/CH2Cl2 (5:1, 12 mL). After 24 h at room temp.,
the reaction was quenched with a saturated aqueous solution of
NaHCO3 (5 mL), and the mixture was extracted with CH2Cl2 (3ϫ
10 mL). The combined organic layers were washed with brine,
dried, and filtered. The solvent was evaporated under reduced pres-
sure. The residue was purified by column chromatography (7:3
pentane/Et2O) to afford 90 mg of the corresponding allylic alcohol
ane/Et2O). [α]2D0 = +15.0 (c = 1, CHCl ). IR: ν = 3485, 2954, 2928,
˜
3
2856, 1738, 1251, 1065 cm–1. 1H NMR (300 MHz, CDCl3): δ =
5.25–5.70 (m, 4 H), 4.00–4.20 (m, 3 H), 3.70–4.00 (m, 2 H), 2.50–
2.80 (m, 1 H), 2.20–2.40 (m, 3 H), 1.80–2.15 (m, 5 H), 1.10–1.75
(m, 20 H), 0.70–1.00 (m, 18 H), –0.10–0.10 (m, 12 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 173.9 (1 C, Cq), 135.5 (1 C, CH),
130.2 (1 C, CH), 129.9 (1 C, CH), 128.8 (1 C, CH), 76.2 (1 C, CH),
76.0 (1 C, CH), 73.0 (1 C, CH), 60.3 (1 C, CH2), 52.6 (1 C, CH),
50.4 (1 C, CH), 44.4 (1 C, CH2), 37.6 (1 C, CH2), 34.5 (1 C, CH2),
31.9 (1 C, CH2), 29.4 (1 C, CH2), 29.0 (1 C, CH2), 27.3 (1 C, CH2),
26.4 (1 C, CH2), 26.0 (6 C, CH3), 25.3 (1 C, CH2), 25.0 (1 C, CH2),
22.7 (1 C, CH2), 18.1 (2 C, Cq), 14.4 (1 C, CH3), 14.1 (1 C, CH3),
–4.3 (1 C, CH3), –4.4 (2 C, CH3), –4.6 (1 C, CH3) ppm. MS (ESI+):
m/z = 639.5 [M + H]+, 621.6 [M + H – H2O]+, 489.5 [M + H –
OTBS]+, 357.4 [M + H – 2 OTBS]+. HRMS (ESI+): calcd. for
C36H71O5Si2 [M + H]+ 639.4840; found 639.4840.
as a colorless oil (80%). Rf = 0.78 (5:5 cyclohexane/Et2O). [α]2D0
=
+10.0 (c = 1, CHCl ). IR: ν = 3458, 2954, 2929, 2856, 1738, 1251,
˜
3
1066 cm–1. H NMR (300 MHz, CDCl3): δ = 5.20–5.70 (m, 4 H),
1
4.00–4.20 (m, 3 H), 3.70–4.00 (m, 2 H), 2.50–3.80 (m, 1 H), 2.20–
2.40 (m, 3 H), 1.80–2.15 (m, 5 H), 1.00–1.75 (m, 21 H), 0.70–1.00
(m, 18 H), –0.10–0.10 (m, 12 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 173.9 (1 C, Cq), 135.5 (1 C, CH), 130.2 (1 C, CH), 129.8 (1 C,
CH), 128.7 (1 C, CH), 76.2 (1 C, CH), 76.0 (1 C, CH), 73.0 (1 C,
CH), 60.3 (1 C, CH2), 52.4 (1 C, CH), 50.4 (1 C, CH), 44.4 (1 C,
CH2), 37.5 (1 C, CH2), 34.4 (1 C, CH2), 29.8 (1 C, CH2), 29.4 (1
C, CH2), 28.9 (1 C, CH2), 27.3 (1 C, CH2), 26.4 (2 C, CH2), 25.9
(6 C, CH3), 25.9 (1 C, CH2), 25.4 (1 C, CH2), 22.7 (1 C, CH2), 18.3
(2 C, Cq), 14.2 (1 C, CH3), –4.3 (1 C, CH3), –4.4 (2 C, CH3), –4.6
(1 C, CH3) ppm. MS (ESI+): m/z = 621.6 [M + H – H2O]+, 489.5
[M + H – OTBS]+, 357.4 [M + H – 2 OTBS]+. HRMS (ESI+):
17-F2t-Dihomo-IsoP (2): HCl (500 μL, 1 m in THF, 0.50 mmol) was
added to a solution of (17S)-24 (11 mg, 0.015 mmol) in THF
calcd. for C36H69O4Si2 [M + H – H2O]+ 621.4734; found 621.4738. (1 mL). After stirring at room temp. overnight, brine (5 mL) was
A Dess–Martin periodinane solution (500 μL of a 0.47 m solution
in CH2Cl2, 0.24 mmol) was added to a solution of the alcohol
(89 mg, 0.14 mmol) in CH2Cl2 (10 mL). After completion of the
reaction (TLC), 10 % aq. NaHCO3/Na2S2O3 (1:1, 15 mL) was
added. After stirring for 1.5 h, the mixture was extracted with
CH2Cl2 (3ϫ 15 mL). The combined organic layers were washed
with brine, dried, and filtered. The solvent was evaporated under
reduced pressure. The residue was purified by column chromatog-
raphy (9:1 pentane/Et2O) to afford 86 mg of the enone 25 as a
colorless oil (97%). Rf = 0.78 (5:5 cyclohexane/Et2O). [α]2D0 = +0.5
added and the mixture extracted with EtOAc (3ϫ 10 mL). The
combined organic layers were washed with brine, dried, and fil-
tered, and the solvent was removed under reduced pressure. The
residue was directly used in the next step without further purifica-
tion. LiOH (1.5 mg, 0.05 mmol) was added to a solution of the
previous material in THF/H2O (1:1, 1 mL). After stirring overnight
at room temp., the mixture was cooled to 0 °C, and a solution of
HCl (1 m) was added until pH = 1. The mixture was extracted with
EtOAc (3ϫ 10 mL). The combined organic layers were washed
with brine, dried, and filtered, the solvent was removed under re-
(c = 1, CHCl ). IR: ν = 2954, 2929, 2857, 1736, 1697, 1674, 1626, duced pressure, and the residue purified by flash chromatography
˜
3
1
1251, 1067 cm–1. H NMR (300 MHz, CDCl3): δ = 6.65 (dd, J = (9:1 EtOAc/MeOH) to afford 3.5 mg of 17-F2t-dihomo-IsoP (2) as
9.8, 5.7 Hz 1 H), 6.13 (d, J = 15.5 Hz, 1 H), 5.15–5.45 (m, 2 H),
4.10 (q, J = 7.0 Hz, 2 H), 3.90–4.00 (m, 1 H), 3.75–3.90 (m, 1 H),
2.70–2.90 (m, 1 H), 2.48 (t, J = 7.1 Hz, 2 H), 2.30–2.40 (m, 1 H),
2.26 (t, J = 7.3 Hz, 2 H), 1.80–2.20 (m, 5 H), 1.50–1.80 (m, 5 H),
a yellow oil (58% over two steps). Rf = 0.64 (9:1 EtOAc/MeOH +
1% AcOH). [α]2D0 = +12.0 (c = 1, MeOH). 1H NMR (300 MHz,
[D4]MeOH): δ = 5.25–5.65 (m, 4 H), 3.80–4.10 (m, 3 H), 2.55–2.80
(m, 1 H), 2.40–2.55 (m, 1 H), 2.27 (t, J = 7.0 Hz, 2 H), 1.90–2.20
1.15–1.50 (m, 14 H), 0.70–1.00 (m, 18 H), –0.10–0.10 (m, 12 H) (m, 5 H), 1.20–1.80 (m, 17 H), 0.80–1.00 (m, 3 H) ppm. 13C NMR
ppm. 13C NMR (75 MHz, CDCl3): δ = 200.3 (1 C, Cq), 173.8 (1
(75 MHz, [D4]MeOH): δ = 177.9 (1 C, Cq), 136.9 (1 C, CH), 131.3
C, Cq), 145.5 (1 C, CH), 131.5 (1 C, CH), 130.8 (1 C, CH), 128.1 (1 C, CH), 130.6 (1 C, CH), 129.5 (1 C, CH), 76.4 (1 C, CH), 76.3
(1 C, CH), 75.8 (1 C, CH), 75.5 (1 C, CH), 60.2 (1 C, CH2), 52.9 (1 C, CH), 73.8 (1 C, CH), 53.8 (1 C, CH), 51.4 (1 C, CH), 43.5 (1
(1 C, CH), 51.0 (1 C, CH), 44.5 (1 C, CH2), 40.9 (1 C, CH2), 34.4 C, CH2), 38.4 (1 C, CH2), 35.2 (1 C, CH2), 33.0 (1 C, CH2), 30.4
(1 C, CH2), 31.6 (1 C, CH2), 29.4 (1 C, CH2), 29.0 (1 C, CH2), 27.4 (1 C, CH2), 29.9 (1 C, CH2), 28.3 (1 C, CH2), 27.4 (1 C, CH2), 26.3
(1 C, CH2), 26.6 (1 C, CH2), 25.9 (6 C, CH3), 25.0 (1 C, CH2), 24.1 (1 C, CH2), 26.1 (1 C, CH2), 23.7 (1 C, CH2), 14.4 (1 C, CH3) ppm.
(1 C, CH2), 22.6 (1 C, CH2), 18.1 (2 C, Cq), 14.4 (1 C, CH3), 14.0 MS (ESI+): m/z = 365.3 [M + H – H2O]+, 347.3 [M + H –
(1 C, CH3), –4.3 (1 C, CH3), –4.5 (2 C, CH3), –4.6 (1 C, Cq) ppm.
MS (ESI+): m/z = 637.6 [M + H]+. HRMS (ESI+): calcd. for
C36H69O5Si2 [M + H]+ 637.4684; found 637.4692.
2 H2O]+, 329.3 [M + H – 3 H2O]+. HRMS (ESI+): calcd. for
C22H37O4 [M + H – H2O]+ 365.2692; found 365.2684.
17-epi-17-F2t-Dihomo-IsoP [(17R)-2]: The previous procedure as
Ethyl (Z)-9-{(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2- described for the synthesis of 17-F2t-dihomo-IsoP (2) was applied
[(E)-3-hydroxyoct-1-enyl]cyclopentyl}non-7-enoate [(17S)-26]: Li-
AlH4 (820 μL, 1 m in THF, 0.82 mmol) was added dropwise to a
solution of dry (S)-binaphthol (235 mg, 0.83 mmol) in freshly dis-
to 54 mg of (17R)-24 to give 17 mg of 17-epi-17-F2t-dihomo-IsoP
[(17R)-2] (58% over two steps). Rf = 0.71 (9:1 EtOAc/MeOH + 1%
AcOH). [α]2D0 = +4.4 (c = 1, MeOH). 1H NMR (300 MHz, [D4]-
2630
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2621–2634

Total Synthesis of Isoprostanes
MeOH): δ = 5.25–5.65 (m, 4 H), 3.80–4.20 (m, 3 H), 2.60–2.80 (m, at 0 °C, the reaction mixture was added through a cannula to the
1 H), 2.40–2.60 (m, 1 H), 2.27 (t, J = 7.0 Hz, 2 H), 1.90–2.20 (m,
5 H), 1.20–1.80 (m, 16 H), 0.80–1.00 (m, 3 H) ppm. 13C NMR
(75 MHz, [D4]MeOH): δ = 177.0 (1 C, Cq), 136.6 (1 C, CH), 131.4
aldehyde THF (15 mL) at –78 °C. The reaction mixture was al-
lowed to warm to room temp. overnight. Then the reaction was
quenched with H2O (10 mL) and Et2O (10 mL). The mixture was
(1 C, CH), 129.8 (1 C, CH), 129.6 (1 C, CH), 76.2 (2 C, CH), 73.4 extracted with Et2O (3ϫ 40 mL). The combined organic layers
(1 C, CH), 53.4 (1 C, CH), 51.4 (1 C, CH), 43.6 (1 C, CH2), 38.5 were washed with brine, dried, and filtered. The solvent was evapo-
(1 C, CH2), 35.2 (1 C, CH2), 33.0 (1 C, CH2), 30.5 (1 C, CH2), 29.9 rated under reduced pressure. The residue was purified by column
(1 C, CH2), 28.2 (1 C, CH2), 27.3 (1 C, CH2), 26.3 (1 C, CH2), 26.1 chromatography (7:3 pentane/Et2O) to afford 286 mg of the enone
(1 C, CH2), 23.7 (1 C, CH2), 14.4 (1 C, CH3) ppm. MS (ESI+): m/z
28 as a colorless oil (73% over two steps). Rf = 0.48 (5:5 cyclohex-
= 365.3 [M + H – H2O]+, 347.3 [M + H – 2 H2O]+, 329.3 [M + ane/Et2O). [α]2D0 = –23.0 (c = 1, CHCl ). IR: ν = 2929, 1737, 1247,
˜
3
H – 3 H2O]+. HRMS (ESI+): calcd. for C22H37O4 [M + H –
H2O]+ 365.2692; found 365.2700.
1055 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.60 (dd, J = 10.4,
5.0 Hz, 1 H), 6.10 (d, J = 15.6 Hz, 1 H), 3.95–4.10 (m, 2 H), 3.75–
3.95 (m, 2 H), 3.64 (s, 3 H), 2.65–2.80 (m, 1 H), 2.60 (t, J = 7.1 Hz,
2 H), 2.30–2.45 (m, 3 H), 2.30 (m, 1 H), 2.00 (s, 3 H), 1.80–2.00
(m, 2 H), 1.35–1.75 (m, 3 H), 0.83 (d, J = 7.4 Hz, 18 H), –0.01 (d,
J = 12.0 Hz, 12 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 199.0
(1 C, Cq), 173.7 (1 C, Cq), 171.1 (1 C, Cq), 144.9 (1 C, CH), 131.4
(1 C, CH), 76.1 (1 C, CH), 75.3 (1 C, CH), 63.2 (1 C, CH2), 53.2
(1 C, CH), 51.6 (1 C, CH3), 46.4 (1 C, CH), 44.3 (1 C, CH2), 39.8
(1 C, CH2), 33.1 (1 C, CH2), 28.0 (1 C, CH2), 25.8 (6 C, CH3), 21.1
(1 C, CH3), 19.2 (1 C, CH2), 18.0 (2 C, Cq), –4.3 (1 C, CH3), –4.3
(2 C, CH3), –4.8 (1 C, CH3) ppm. MS (ESI+): m/z = 571.4 [M +
H]+, 439.3 [M – OTBS]+, 307.2 [M – 2 OTBS]+. HRMS (ESI+):
calcd. for C29H55O7Si2 [M + H]+ 571.3486; found 571.3486.
17-F2t-Dihomo-IsoP (2) Derived from (17S)-26: The same procedure
described for the synthesis of (17S)-F2t-dihomo-IsoP (2) was ap-
plied to 69 mg of alcohol (17S)-26 to give 32 mg of 17-F2t-dihomo-
IsoP (2; 77% over two steps) with similar spectral data.
(Z)-Hex-3-enyltriphenylphosphonium Iodide (31): A solution of 3-
hexyn-1-ol (6.0 mL, 50.9 mol) in CH2Cl2 (100 mL) was added
through a cannula to a solution of Ph3P (19.8 g, 75.5 mol), imid-
azole (10.2 g, 150 mol), and iodine (19.0 g, 74.8 mol) in CH2Cl2
(200 mL) at 0 °C. The reaction mixture was warmed to room temp.
over 2.5 h, and a solution of Na2S2O3 (25%, 300 mL) was added.
After stirring for 15 min, the mixture was extracted with CH2Cl2
(3 ϫ 100 mL). The combined organic layers were washed with
brine, dried, and filtered. The solvent was evaporated under re-
duced pressure. The residue was purified by column chromatog-
raphy (100% pentane) to afford 10.7 g of the iodide as a colorless
Methyl (E)-7-[(1S,2R,3R,5S)-2-(2-Acetoxyethyl)-3,5-bis(tert-butyl-
dimethylsilyloxy)cyclopentyl]-5-(tert-butyldimethylsilyloxy)hept-6-
enoate [(5RS)-29]: CeCl3·7H2O (98 mg, 0.26 mmol) was added to a
solution of enone 28 (150 mg, 0.26 mmol) in MeOH (15 mL). The
mixture was cooled to 0 °C, and NaBH4 was added (7.6 mg,
0.20 mmol). After 10 min, the reaction was quenched with H2O
(12 mL) and Et2O (5 mL). The reaction mixture was extracted with
Et2O (3ϫ 20 mL). The combined organic layers were washed with
brine, dried, and filtered. The solvent was evaporated under re-
duced pressure. The residue was purified by column chromatog-
raphy (8:2 pentane/Et2O) to afford 145 mg of the allylic alcohol
(96%). Rf = 0.22 (5:5 cyclohexane/Et2O). [α]2D0 = –27.2 (c = 1,
oil (100%). R = 0.90 (5:5 cyclohexane/Et O). IR: ν = 2961, 1454,
˜
f
2
1
1238, 1168 cm–1. H NMR (300 MHz, CDCl3): δ = 5.40–5.65 (m,
1 H), 5.15–5.35 (m, 1 H), 3.12 (t, J = 7.3 Hz, 2 H), 2.60 (q, J =
7.2 Hz, 2 H), 1.90–2.20 (m, 2 H), 0.97 (t, J = 7.5 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 134.3 (1 C, CH), 127.2 (1 C, CH),
31.5 (1 C, CH2), 20.8 (1 C, CH2), 14.3 (1 C, CH3), 5.8 (1 C, CH2)
ppm. Ph3P (20.0 g, 76.3 mol) and a catalytic amount of K2CO3
were added to a solution of this iodide (10.7 g, 50.9 mol) in CH3CN
(300 mL). The reaction mixture was heated at reflux overnight,
then cooled, and the solvent was removed under reduced pressure.
The residue was purified by column chromatography (solid SiO2
deposit, 9:1 CH2Cl2/MeOH) to afford 21.0 g of the phosphonium
salt 31 as a white powder (87% yield over two steps). Rf = 0.30
CHCl ). IR: ν = 3480, 2929, 1738, 1248, 1056 cm–1 1H NMR
.
˜
3
(300 MHz, CDCl3): δ = 5.45–5.60 (m, 1 H), 5.25–5.45 (m, 1 H),
4.15–4.35 (m, 1 H), 3.90–4.15 (m, 2 H), 3.70–3.90 (m, 2 H), 3.64
(s, 3 H), 2.40–2.65 (m, 1 H), 2.20–2.40 (m, 3 H), 2.05–2.20 (m, 1
H), 2.00 (s, 3 H), 1.92 (s, 1 H), 1.60–1.80 (m, 3 H), 1.45–1.60 (m,
4 H), 0.85 (d, J = 6.0 Hz, 18 H), –0.00 (d, J = 8.8 Hz, 12 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 174.2 (1 C, Cq), 171.5 (1 C, Cq),
135.7 (1 C, CH), 130.0 (1 C, CH), 76.2 (1 C, CH), 72.6 (1 C, CH),
72.0 (1 C, CH), 63.5 (1 C, CH2), 52.8 (1 C, CH), 51.6 (1 C, CH3),
45.7 (1 C, CH), 44.3 (1 C, CH2), 36.6 (1 C, CH2), 33.9 (1 C, CH2),
28.0 (1 C, CH2), 25.9 (6 C, CH3), 21.2 (1 C, CH3), 21.0 (1 C, CH2),
18.1 (2 C, Cq), –4.2 (1 C, CH3), –4.5 (1 C, CH3), –4.6 (1 C, CH3),
–4.7 (1 C, CH3) ppm. MS (ESI+): m/z = 555.4 [M + H – H2O]+,
423.2 [M + H – H2 O – OTBS]+ , 291.2 [M + H – H2 O –
2 OTBS]+. HRMS (ESI+): calcd. for C29H55O6Si2 [M + H –
H2O]+ 555.3537; found 555.3534. Imidazole (70 mg, 1.0 mmol),
DMAP (10 mg, 0.08 mmol), and TBSCl (78 mg, 0.52 mmol) were
successively added to a solution of the allylic alcohol (197 mg,
0.34 mmol) in DMF (15 mL). After stirring overnight, the reaction
was quenched with H2O (30 mL) and Et2O (15 mL). The mixture
was extracted with Et2O (3ϫ 20 mL), and the combined organic
layers were washed with H2O (3ϫ20 mL) and brine, dried, and
filtered. The solvent was evaporated under reduced pressure. The
residue was purified by column chromatography (9:1 pentane/Et2O)
to afford 235 mg of 29 as a colorless oil (100%). Rf = 0.77 (5:5
(9:1 EtOAc/MeOH). M.p. 120 °C. IR: ν = 3254, 2875, 1706, 1471,
˜
1
1253, 1051 cm–1. H NMR (300 MHz, CDCl3): δ = 7.55–7.90 (m,
15 H), 5.20–5.50 (m, 2 H), 3.50–3.75 (m, 2 H), 2.25–2.55 (m, 2 H),
1.75–1.90 (m, 2 H), 0.80 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 135.0 (3 C, CH), 134.1 (3 C, Cq), 133.2 (6
C, CH), 130.3 (6 C, CH), 124.9 (1 C, CH), 124.7 (1 C, CH), 117.5
(d, JC-P = 85.4 Hz, 1 C, CH2), 22.9 (d, JC-P = 48.5 Hz, 1 C, CH2),
20.1 (d, JC-P = 30.0 Hz, 1 C, CH2), 13.7 (1 C, CH3) ppm. 31P NMR
(120 MHz, CDCl3): δ = 24.5 ppm.
Methyl (E)-7-[(1S,2R,3R,5S)-2-(2-Acetoxyethyl)-3,5-bis(tert-butyl-
dimethylsilyloxy)cyclopentyl]-5-oxohept-6-enoate (28): A Dess–
Martin periodinane solution (5.0 mL of a 0.47 m solution in
CH2Cl2, 2.35 mmol) was added dropwise to a solution of ent-5
(305 mg, 0.68 mmol) in CH2Cl2 (15 mL). After completion of the
reaction (TLC), 10 % aq. NaHCO3/Na2S2O3 (1:1, 40 mL) was
added. After stirring for 1.5 h, the mixture was extracted with
CH2Cl2 (3ϫ 20 mL). The combined organic layers were washed
with brine, dried, and filtered. The solvent was evaporated under
reduced pressure. The material was directly used in the next step
without further purification. NaHMDS (2.0 mL, 2 m in THF,
4.0 mmol) was added dropwise to a solution of the β-keto phos-
phonate 27 (1.15 g, 4.11 mmol) in THF (15 mL) at 0 °C. After 1 h
cyclohexane/Et2O). [α]2D0 = –29.4 (c = 1, CHCl ). IR: ν = 2952,
˜
3
2928, 2856, 1741, 1248, 1055 cm–1. 1H NMR (300 MHz, CDCl3):
Eur. J. Org. Chem. 2012, 2621–2634
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2631

C. Oger, V. Bultel-Poncé, A. Guy, T. Durand, J.-M. Galano
FULL PAPER
δ = 5.47 (dd, J = 10.0, 5.5 Hz, 1 H), 5.20–5.40 (m, 1 H), 3.95–4.20
ganic layers were washed with brine, dried, and filtered. The solvent
(m, 3 H), 3.75–3.95 (m, 2 H), 3.66 (s, 3 H), 2.45–2.60 (m, 1 H), was evaporated under reduced pressure. The material was directly
2.25–2.40 (m, 3 H), 2.20 (m, 1 H), 2.02 (s, 3 H), 1.30–1.85 (m, 7
used in the next step without further purification. KHMDS (1 mL,
0.5 m in toluene, 0.50 mmol) was added dropwise to a suspension
H), 0.70–1.00 (m, 27 H), 0.02 (d, J = 8.4 Hz, 18 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 174.1 (1 C, Cq), 171.2 (1 C, Cq), 135.8 (1 of the dried phosphonium salt 17 (238 mg, 0.51 mmol) in THF
C, CH), 127.9. (1 C, CH), 127.5. (1 C, CH), 76.6 (1 C, CH), 76.3 (8 mL) at –78 °C. After 1 h, the mixture was added through a can-
(1 C, CH), 72.8 (1 C, CH), 63.5 (1 C, CH2), 53.0 (1 C, CH), 52.8 nula to the aldehyde (0.158 mmol) in THF (8 mL) at –78 °C. The
(1 C, CH), 51.6 (1 C, CH3), 45.5 (1 C, CH), 44.3 (1 C, CH2), 37.8 reaction mixture was allowed to warm to room temp. overnight.
(1 C, CH2), 34.0 (1 C, CH2), 27.7 (1 C, CH2), 25.9 (9 C, CH3), 21.1 The reaction was then quenched with a saturated aqueous solution
(1 C, CH3), 20.8 (1 C, CH2), 18.3 (2 C, Cq), 18.1 (1 C, Cq), –4.2 of NH4Cl (15 mL) and the mixture warmed to room temp. The
(1 C, CH3), –4.3 (1 C, CH3), –4.4 (1 C, CH3), –4.5 (1 C, CH3), –4.6 mixture was extracted with Et2O (3ϫ 10 mL). The combined or-
(1 C, CH3), –4.7 (1 C, CH3) ppm. MS (ESI+): m/z = 788.6 [M + ganic layers were washed with brine, dried, and filtered. The solvent
H + Et3N]+, 555.4 [M – OTBS]+, [M – 2 OTBS]+, 291.2 [M – 3
OTBS]+. HRMS (ESI+): calcd. for C41H86NO7Si3 [M + H +
Et3N]+ 788.5712; found 788.5732.
was evaporated under reduced pressure. The residue was purified
by flash chromatography (95:5 cyclohexane/Et2O) to afford
66.3 mg of the triene as a colorless oil (59% over two steps). HCl
(370 μL, 1 m, 0.37 mmol) was added to a solution of the triene
(60 mg, 0.084 mmol) in THF (4 mL). After 2.5 d at room temp.,
brine (10 mL) was added, and the mixture was extracted with
EtOAc (3ϫ15 mL). The combined organic layers were washed with
brine, dried, and filtered. The solvent was evaporated under re-
duced pressure. The residue was purified by flash chromatography
(92:8 EtOAc/MeOH) to afford 8.5 mg of 5-F3t-IsoP (3) as a color-
Methyl (S,E)-7-[(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-
2-(2-hydroxyethyl)cyclopentyl]-5-(tert-butyldimethylsilyloxy)hept-
6-enoate [(5S)-30] and Methyl (R,E)-7-[(1S,2R,3R,5S)-3,5-Bis(tert-
butyldimethylsilyloxy)-2-(2-hydroxyethyl)cyclopentyl]-5-(tert-butyl-
dimethylsilyloxy)hept-6-enoate [(5R)-30]: K2CO3 (47 mg,
0.36 mmol) was added to a solution of acetate 29 (66 mg,
0.096 mmol) in MeOH (5 mL). After 2 h, the reaction was
quenched with a solution of H2O/Et2O (15 mL). The mixture was
extracted with pentane/Et2O (3ϫ 15 mL), washed with brine, dried,
and filtered. The solvent was evaporated under reduced pressure.
The residue was purified by flash chromatography (7:3 pentane/
Et2O) to afford 25 mg of (S)-30 and 12 mg of (R)-30 as colorless
oils, together with 22 mg of racemic 30. (5S)-30: Rf = 0.45 (5:5
less oil (29%). Rf = 0.55 (8:2 AcOEt/MeOH + 1% AcOH). [α]2D0
=
–6.8 (c = 0.5, MeOH). 1H NMR (300 MHz, [D4]MeOH): δ = 5.50–
5.70 (m, 2 H), 5.15–5.70 (m, 4 H), 3.80–4.10 (m, 3 H), 2.60–2.90
(m, 3 H), 2.40–2.60 (m, 1 H), 2.20–2.35 (m, 2 H), 1.90–2.20 (m, 5
H), 1.45–1.85 (m, 5 H), 0.97 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR
(75 MHz, [D4]MeOH): δ = 177.5 (1 C, Cq), 136.5 (1 C, CH), 132.7
(1 C, CH), 130.1 (1 C, CH), 129.9 (1 C, CH), 129.6 (1 C, CH),
128.4 (1 C, CH), 76.2 (1 C, CH), 76.1 (1 C, CH), 73.0 (1 C, CH),
53.5 (1 C, CH), 51.3 (1 C, CH), 43.6 (1 C, CH2), 37.8 (1 C, CH2),
34.8 (1 C, CH2), 27.3 (1 C, CH2), 26.6 (1 C, CH2), 22.3 (1 C, CH2),
21.5 (1 C, CH2), 14.7 (1 C, CH3) ppm. HRMS (ESI+): calcd. for
C20H31O4 [M – H2O]+ 335.2222; found 335.2213.
cyclohexane/Et2O). [α]2D0 = –14.8 (c = 1, CHCl ). IR: ν = 3289,
˜
3
2954, 2930, 2857, 1742, 1472, 1253, 1062 cm–1
.
1H NMR
(300 MHz, CDCl3): δ = 5.20–5.65 (m, 2 H), 4.00–4.20 (m, 1 H),
3.75–3.95 (m, 2 H), 3.50–3.75 (m, 5 H), 2.60 (m, 6 H), 1.30–1.75
(m, 7 H), 0.70–1.00 (m, 27 H), –0.20–0.20 (m, 18 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 174.2 (1 C, Cq), 135.2 (1 C, CH),
128.0 (1 C, CH), 76.8 (1 C, CH), 76.2 (1 C, CH), 72.2 (1 C, CH), 5-epi-5-F3t-IsoP 5R-(3): The same procedure as described for the
61.7 (1 C, CH2), 53.6 (1 C, CH), 51.5 (1 C, CH3), 45.9 (1 C, CH), synthesis of 5-F3t-IsoP (3) was applied to 47 mg of alcohol (5R)-30
44.3 (1 C, CH2), 37.4 (1 C, CH2), 33.9 (1 C, CH2), 32.4 (1 C, CH2), to give 7.4 mg of 5-epi-5-F3t-IsoP [(5R)-3] (25% over three steps).
25.8 (9 C, CH3), 20.4 (1 C, CH2), 18.1 (1 C, Cq), 18.0 (1 C, Cq), Rf = 0.50 (8:2 EtOAc/MeOH + 1% AcOH). [α]2D0 = –7.4 (c = 0.4,
17.9 (1 C, Cq), –4.2 (1 C, CH3), –4.6 (1 C, CH3), –4.7 (1 C, CH3), MeOH). 1H NMR (300 MHz, [D4]MeOH): δ = 5.50–5.70 (m, 2 H),
–4.8 (2 C, CH3), –4.9 (1 C, CH3) ppm. MS (ESI+): m/z = 645.3 [M
+ H]+, 513.2 [M + H – OTBS]+, 381.3 [M + H – 2 OTBS]+, 249.2
[M + H – 3 OTBS]+. HRMS (ESI+): calcd. for C33H69O6Si3 [M +
H]+ 645.4402; found 645.4408. (5R)-30: Rf = 0.49 (5:5 cyclohexane/
5.15–5.70 (m, 4 H), 3.80–4.10 (m, 3 H), 2.60–2.90 (m, 3 H), 2.40–
2.60 (m, 1 H), 2.20–2.35 (m, 2 H), 1.90–2.20 (m, 5 H), 1.45–1.85
(m, 5 H), 0.97 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, [D4]-
MeOH): δ = 177.5 (1 C, Cq), 136.6 (1 C, CH), 132.7 (1 C, CH),
130.6 (1 C, CH), 129.9 (1 C, CH), 129.6 (1 C, CH), 128.3 (1 C,
CH), 76.3 (1 C, CH), 76.2 (1 C, CH), 73.3 (1 C, CH), 53.8 (1 C,
CH), 51.4 (1 C, CH), 43.5 (1 C, CH2), 37.8 (1 C, CH2), 34.9 (1 C,
Et2O). [α]2D0 = –15.5 (c = 1, CHCl ). IR: ν = 3289, 2954, 2930, 2857,
˜
3
1742, 1472, 1253, 1062 cm–1. 1H NMR (300 MHz, CDCl3): δ =
5.35–5.50 (m, 1 H), 5.15–5.35 (m, 1 H), 4.00–4.15 (m, 1 H), 3.80–
3.95 (m, 2 H), 3.50–3.80 (m, 5 H), 2.60 (m, 6 H), 1.45–1.65 (m, 7 CH2), 27.4 (1 C, CH2), 26.6 (1 C, CH2), 22.2 (1 C, CH2), 21.5 (1
H), 0.70–1.00 (m, 27 H), –0.20–0.20 (m, 18 H) ppm. 13C NMR
C, CH2), 14.7 (1 C, CH3) ppm. HRMS (ESI+): calcd. for C20H31O4
(75 MHz, CDCl3): δ = 174.4 (1 C, Cq), 135.7 (1 C, CH), 128.3 (1 [M – H2O]+ 335.2222; found 335.2216.
C, CH), 76.2 (2 C, CH), 73.1 (1 C, CH), 61.9 (1 C, CH2), 54.1 (1
{(1R,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2-[(2Z,5Z)-
C, CH), 51.7 (1 C, CH3), 46.0 (1 C, CH), 44.5 (1 C, CH2), 37.8 (1
C, CH2), 34.0 (1 C, CH2), 32.7 (1 C, CH2), 26.0 (9 C, CH3), 20.8
(1 C, CH2), 18.3 (1 C, Cq), 18.1 (2 C, Cq), –4.0 (1 C, CH3), –4.1
(1 C, CH3), –4.6 (4 C, CH3) ppm. MS (ESI+): m/z = 645.3 [M +
H]+, 513.2 [M + H – OTBS]+, 381.3 [M + H – 2 OTBS]+, 249.2
[M + H – 3 OTBS]+. HRMS (ESI+): calcd. for C33H69O6Si3 [M +
H]+ 645.4402; found 645.4398.
octa-2,5-dienyl]cyclopentyl}methanol (33): tBuOK (68 mg,
0.606 mmol) was added to a suspension of the dried phosphonium
salt 31 (313 mg, 0.663 mmol) in THF (5 mL) at –78 °C. After 1 h
at –78 °C, the mixture was added through a cannula to the lactol
32 (40 mg, 0.0995 mmol) in THF (5 mL) at –78 °C. After 2.5 h at
–78 °C, the reaction mixture was allowed to warm to room temp.
overnight. The reaction was then quenched with a 10% NH4Cl
solution (20 mL) and the mixture stirred for 15 min. The mixture
was extracted with Et2O (3ϫ 20 mL). The combined organic layers
5-F3t-IsoP (3): A Dess–Martin periodinane solution (1.0 mL of a
0.47 m solution in CH2Cl2, 0.47 mmol) was added to a solution
of alcohol (5S)-30 (102 mg, 0.158 mmol) in CH2Cl2 (5 mL). After were washed with brine, dried, and filtered. The solvent was evapo-
completion of the reaction (TLC), a 10% aq. NaHCO3/Na2S2O3
solution (1:1, 20 mL) was added. After stirring for 1.5 h, the mix-
ture was extracted with CH2Cl2 (3ϫ 10 mL). The combined or-
rated under reduced pressure. The residue was purified by column
chromatography (9:1 cyclohexane/Et2O) to afford 30 mg of 33
(64%). Rf = 0.38 (8:2 cyclohexane/Et2O). [α]2D0 = –1.4 (c = 1,
2632
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Eur. J. Org. Chem. 2012, 2621–2634

Total Synthesis of Isoprostanes
CHCl ). IR: ν = 3495, 2957, 2930, 2857, 1472, 1253, 1069 cm–1. 1H
centration, the residue was purified by column chromatography
(8:2 heptane/Et2O). Unfortunately, the excess binaphthol could not
be completely removed. Therefore, the mixture of allylic alcohol
35, lactone 36, and binaphthol was used directly in the next step.
HCl (1 m, 140 μL, 0.14 mmol) was added to a solution of the pre-
˜
3
NMR (300 MHz, CDCl3): δ = 5.20–5.60 (m, 4 H), 3.90–4.20 (m, 1
H), 3.60–3.80 (m, 3 H), 2.70–2.90 (m, 2 H), 2.20–2.45 (m, 2 H),
1.90–2.20 (m, 5 H), 1.70–2.00 (m, 1 H), 0.98 (t, J = 7.4 Hz, 3 H),
0.88 (s, 18 H), 0.08 (d, J = 9.6 Hz, 12 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 132.2 (1 C, CH), 130.1 (1 C, CH), 129.3 (1 C, CH), vious material in THF (2 mL). After 2 d at room temp., brine
127.0 (1 C, CH), 75.7 (1 C, CH), 75.2 (1 C, CH), 62.8 (1 C, CH2), (10 mL) was added. The mixture was extracted with EtOAc (3ϫ
50.2 (1 C, CH2), 48.2 (1 C, CH), 44.6 (1 C, CH), 30.4 (1 C, CH2), 15 mL). The combined organic layers were washed with brine,
25.9 (6 C, CH3), 25.8 (1 C, CH2), 20.7 (1 C, CH2), 18.0 (2 C, Cq), dried, and filtered. The solvent was evaporated under reduced pres-
14.4 (1 C, CH3), –4.1 (1 C, CH3), –4.3 (1 C, CH3), –4.6 (1 C, CH3), sure. The residue was directly used in the next step without further
–4.7 (1 C, CH3) ppm. MS (ESI+): m/z = 469.4 [M + H]+. HRMS
purification. LiOH (5 mg) was added to a solution of the previous
material in THF/H2O (1:1; 5 mL). After 4 h, a solution of HCl
(1 m, 5 mL) was added until an acidic pH was obtained. The mix-
ture was extracted with EtOAc (3ϫ 10 mL). The combined organic
layers were washed with brine, dried, and filtered. The solvent was
evaporated under reduced pressure, and the residue was purified by
column chromatography (9:1 EtOAc/MeOH) to afford 1.2 mg of 5-
F3t-IsoP (3; 6.4% over three steps). The 13C NMR spectrum shows
characteristic peaks at δ = 130.1, 76.2, 73.0, and 53.5 ppm, similar
to the data obtained above for compound 3.
(ESI+): calcd. for C26H53O3Si2 [M + H]+ 469.3533; found 469.3538.
Methyl (E)-7-{(1S,2R,3R,5S)-3,5-Bis(tert-butyldimethylsilyloxy)-2-
[(2Z,5Z)-octa-2,5-dienyl]cyclopentyl}-5-oxohept-6-enoate (34): A
Dess–Martin periodinane solution (600 μL of a 0.47 m solution in
CH2Cl2, 0.28 mmol) was added dropwise to a solution of 33
(30 mg, 0.066 mmol) in CH2Cl2 (5 mL). After completion of the
reaction (TLC), 10 % aq. NaHCO3/Na2S2O3 (1:1, 10 mL) was
added. After stirring for 1.5 h, the mixture was extracted with
CH2Cl2 (3ϫ 15 mL). The combined organic layers were washed
with brine, dried, and filtered. The solvent was evaporated under
reduced pressure. The material was directly used in the next step
without further purification. NaHMDS (200 μL, 2 m in THF,
0.40 mmol) was added dropwise to a solution of the β-keto phos-
phonate 27 (200 mg, 0.71 mmol) in THF (5 mL) at 0 °C. After 1 h
at 0 °C, the mixture was added through a cannula to the aldehyde
in THF (5 mL) at –78 °C. Then the reaction mixture was allowed
to warm to room temp. overnight. The reaction was then quenched
with H2O (10 mL) and Et2O (10 mL). The mixture was extracted
with Et2O (3ϫ 20 mL). The combined organic layers were washed
with brine, dried, and filtered. The solvent was evaporated under
reduced pressure. The residue was purified by column chromatog-
raphy (9:1 pentane/Et2O) to afford 31.7 mg of enone 34 (83.5%
over two steps). Rf = 0.40 (8:2 cyclohexane/Et2O). [α]2D0 = –1.0 (c =
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all new products.
Acknowledgments
We thank the Ministère de l’Education Nationale et de la Recher-
che for a doctoral fellowship (C. O.). We are deeply grateful to Prof.
Jean-Yves Lallemand and the Institut de Chimie des Substances
Naturelles (ICSN) for generous funding. A part of this work was
also financially supported by the Université Montpellier I (grants
BQR-2008 and 2011), the Centre National de la Recherche Sci-
entifique (CNRS) for PEPII INSB-INC, and the Fédération pour
la Recherche Médicale (FRM) (DCM20111223047). We also thank
Prof. Françoise Michel for her help in GC–MS experiments.
1, CHCl ). IR: ν = 2955, 2930, 2857, 1738, 1253, 1064 cm–1. 1H
˜
3
NMR (300 MHz, CDCl3): δ = 6.60–6.80 (m, 1 H), 6.13 (d, J =
15.6 Hz, 1 H), 5.15–5.50 (m, 4 H), 3.95–4.05 (m, 1 H), 3.80–3.95
(m, 1 H), 3.66 (s, 3 H), 2.65–2.90 (m, 3 H), 2.58 (t, J = 7.1 Hz, 2
H), 1.80–2.25 (m, 8 H), 1.50–1.80 (m, 2 H), 0.96 (t, J = 7.5 Hz, 3
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Graham, C. E. Parker, A. Nyska, J. T. Wachsman, B. N. Ames,
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NMR (75 MHz, CDCl3): δ = 199.1 (1 C, Cq), 173.8 (1 C, Cq),
146.1 (1 C, CH), 132.2 (1 C, CH), 131.4 (1 C, CH), 129.3 (1 C,
CH), 128.1 (1 C, CH), 127.0 (1 C, CH), 75.7 (1 C, CH), 75.4 (1 C,
CH), 52.9 (1 C, CH), 51.7 (1 C, CH3), 50.9 (1 C, CH), 44.5 (1 C,
CH2), 39.6 (1 C, CH2), 33.2 (1 C, CH2), 26.6 (1 C, CH2), 25.9 (6
C, CH3), 25.8 (1 C, CH2), 19.3 (1 C, CH2), 18.1 (2 C, Cq), 14.4 (1
C, CH3), –4.3 (1 C, CH3), –4.4 (1 C, CH3), –4.5 (2 C, CH3), –4.6
(1 C, CH3) ppm. MS (ESI+): m/z = 593.4 [M + H]+. HRMS (ESI+):
calcd. for C33H61O5Si2 [M + H]+ 593.4058; found 593.4060.
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5-F3t-IsoP (3): LiAlH4 (330 μL, 1 m/THF, 0.330 mmol) was added
dropwise to a solution of dry (S)-binaphthol (96 mg, 0.335 mmol)
in freshly distilled dry THF (1.4 mL) at room temp. After 5 min,
freshly distilled dry EtOH (330 μL, 1 m in THF, 0.330 μL) was
added dropwise. The reaction mixture was cooled to –100 °C, and
the enone 34 (31.7 mg, 0.054 mmol) was added through a cannula.
The reaction mixture was slowly warmed to –30 °C. MeOH
(500 μL) and H2O (1.0 mL) were added, and the suspension was
filtered through a plug of Celite, which had previously been washed
with Et2O. The filtrate was washed with H2O (10 mL). The mixture
was extracted with Et2O (3ϫ 15 mL). The combined organic layers
were washed with brine, dried, and filtered. The solvent was evapo-
rated under reduced pressure. The excess of binaphthol was precipi-
tated with hexanes, but traces of binaphthol remained. After con-
Eur. J. Org. Chem. 2012, 2621–2634
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2633

C. Oger, V. Bultel-Poncé, A. Guy, T. Durand, J.-M. Galano
FULL PAPER
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Received: January 19, 2012
Published Online: March 15, 2012
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2621–2634