Selective synthesis of ent-15-epi-F2t-isoprostane and a deuterated derivative

Article abstract of DOI:10.1055/s-2007-983768

Isoprostanes are an emerging class of lipid metabolites whose physiological properties are not well understood. The selective synthesis of ent-15-epi-F_2t-isoprostane, an isomer active in a preliminary screening assay is described. The synthesis features a regioselective cross-metathesis on an enantiomerically enriched divinyl cyclopentyl intermediate to selectively differentiate the side-chains of the target. The route provides the isoprostane, as well as a d₄-labeled analogue, in 14 steps from readily available starting materials. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983768

PAPER
2397
Selective Synthesis of ent-15-epi-F -Isoprostane and a Deuterated Derivative
2
t
S
M
ynthesis of ent-15-ep
a
n
2
t
Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College, 2609 Beacon Street, Chestnut Hill, MA 02467, USA
Fax +1(617)5521442; E-mail: marc.snapper@bc.edu
Received 8 March 2007
Dedicated to Professor Paul A. Wender on the occasion of his 60 birthday
th
O
Abstract: Isoprostanes are an emerging class of lipid metabolites
whose physiological properties are not well understood. The selec-
O
O
O
R
tive synthesis of ent-15-epi-F -isoprostane, an isomer active in a
O–
2
t
O
preliminary screening assay is described. The synthesis features a
regioselective cross-metathesis on an enantiomerically enriched di-
vinyl cyclopentyl intermediate to selectively differentiate the side-
chains of the target. The route provides the isoprostane, as well as a
d4-labeled analogue, in 14 steps from readily available starting
materials.
Me
P
OR'
O
arachidonyl phospholipid
O2 free radicals
HO
HO
O
O
Key words: asymmetric synthesis, metathesis, olefination, lipids
O
O
R
O
O
O–
OH
Me
P
Isoprostanes are produced upon non-enzymatic, free radi-
OR'
cal peroxidation of phosphatidyl arachidoniates
isoprostanyl phospholipid
PLA2
1
(
Scheme 1). In addition to possible activities within the
lipid bilayer, hydrolytic release of these soluble lipid oxi-
dation products may also lead to a variety of physiological
responses. The biological activities of the isoprostanes
that have been identified to date typically involve inflam-
matory responses, as well as activities related to smooth
HO
HO
CO2H
OH
Me
2
3
muscle growth factors, and platelet aggregation factors.
These lipid metabolites are also recognized as important
isoprostanes
+
lysophospholipid
4
indicators of oxidative stress, particularly in human mal- Scheme 1 Formation of the 15-F
adies such as Alzheimer’s disease, diabetes, and cancer.
-isoprostanes
2
5
6
7
While progress has been made in understanding the for-
mation and distribution of the isoprostanes, significant
questions remain regarding the physiological roles for
these endogenous metabolites.
prostane was more active than the known inhibitor, 15-
11
F -isoprostane. To further study this particular isopros-
2t
tane isomer, we modified our synthetic strategy toward
the 15-F -isoprostanes to provide access to any specific
2
isoprostane isomer. Herein, we describe how a regioselec-
tive olefin cross-metathesis of an enantiomerically en-
riched divinyl intermediate provides ent-15-epi-F2t-
isoprostane and a mass-labeled derivative in an enantiose-
lective manner.
Total synthesis has begun to provide useful quantities of
isoprostanes and derivatives required for their further
study. In this regard, we disclosed the preparation of all
8
eight 15-F -isoprostane isomers via a stereodivergent
2
9
strategy (Figure 1). The key intermediate in the synthesis
was obtained from a [2+2] photocycloaddition between a
functionalized cyclopentenone and acetylene, followed
Our synthesis of ent-15-epi-F -isoprostane begins with
enone 4, generated efficiently and selectively from an en-
2
t
1
0
by a ring-opening cross-metathesis. Subsequent resolu-
tion of the racemic diastereomers by an asymmetric CBS-
reduction provided the individual isoprostanes isomers in
an enantiomerically enriched manner. This sequence of-
fered simultaneous access to the complete library of 15-
F2-isoprostanes from a common synthetic precursor 1.
zymatic desymmetrization of meso-diol 2 (with pancreat-
12,13
in lipase).
Enone 4 can be accessed by functional
group manipulations from 3 in 80% overall yield
14
(
Scheme 2).
A photochemical [2+2] cycloaddition between enone 4
and acetylene generates a mixture of bicyclo[3.2.0]hep-
tenones 5 and 6 (5:6 = 2:1, Scheme 3). DIBAL-H reduc-
tion of the mixture yields isomers 7, 8, 9, and 10, which
are separable by silica gel chromatography. The reduction
favors the desired hydroxyl stereochemistry by an 84:16
ratio. The major product 7 could be isolated and the re-
maining fractions could be oxidized with PCC back to a
mixture of 5 and 6. Preliminary results show that the un-
Preliminary screening of the eight diastereomeric 15-F2-
isoprostanes in a whole blood platelet aggregation inhibi-
tion assay indicated that the unknown ent-15-epi-F -iso-
2t
SYNTHESIS 2007, No. 15, pp 2397–2403
x
x.
x
x
.
2
0
0
7
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-983768; Art ID: C01807SS
Georg Thieme Verlag Stuttgart · New York
©

2
398
M. Shizuka, M. L. Snapper
PAPER
HO 15-epi-F2c-isoprostane
CO2H
15-F -isoprostane
2t
HO
CO2H
Me
O
HO
HO
OH
ent-15-F2c-isoprostane
CO2H
Me
HO
HO
OH
(
± ±-1
TBSO
ent-15-epi-F2t-isoprostane
CO2H
3
steps
TBSO
TBSO
TBSO
ROCM
TBSO
+
TBSO
ROCM
HO
HO
OH
Me
HO
HO
OH
ent-15-F2t-isoprostane
CO2H
Me
ent-15-epi-F2c-isoprostane
CO2H
TBSO
TBSO
TBSO
(± ±
O
(± ±
O
Me
Me
HO
HO
Me
OH
HO
HO
OH
Me
1
5-F2c-isoprostane
1
5-epi-F2t-isoprostane
CO2H
Me
CO2H
HO
OH
HO
OH
Me
Figure 1 Stereodivergent synthesis of the 15-F -isoprostanes
2
HO
HO
HO
TBSO
O
d
a
b–d
TBSO
O
TBSO
O
TBSO
+
H
a
b
AcO
4
2
3
H
Scheme 2 Preparation of optically enriched enone 4. Reagents and
conditions: (a) pancreatin lipase, vinyl acetate, THF, >99% ee, 55%
yield after recryst.; (b) TBSCl, Et N, DMAP, CH Cl , 99%; (c)
O
4
5
6
c
3
2
2
K CO , MeOH, 90%; (d) PCC, Celite, CH Cl , 90%.
TBSO
+
TBSO
+
TBSO
+
2
3
2
2
TBSO
HO
H
H
H
H
desired syn-endo photoadduct 6 can be photoisomerized
using a Vycor filter to a 1:1 ratio of the desired syn-exo 5
isomer and the starting syn-endo 6. This isomerization be-
tween the two diastereomers is likely occurring through a
HO
HO
HO
7
(47%)
8 (13%)
9
(37%)
10 (3%)
c, b
1
5
1
,3-acyl migration. Given the reoxidation and isomer-
ization pathways, in principle, all undesired isomers can
be used to increase the overall yield of adduct 7; however,
in practice only cyclobutene 8 was routinely recycled.
Scheme 3 Preparation of metathesis precursor 7. Reagents and
conditions: (a) acetylene, acetone, Pyrex, hn, 65% (86% conversion),
5/6 = 2:1; (b) DIBAL-H, toluene, –78 °C, 98%; (c) PCC, Celite,
CH Cl , 98%; (d) hn, C H .
2
2
6
6
Ring-opening cross-metathesis (ROCM) of syn-exo com-
pound 7 in benzene using Grubbs’ catalyst 11 under an
ethylene atmosphere generates the divinyl species 13 in tionality may also play a role in dictating the selectivity of
7% yield (Scheme 4).10,16 High dilution is required to the reaction.
8
avoid ring-opening metathesis polymerization (ROMP).
In contrast, cross-metathesis (CM) of divinyl compound
When cyclobutene 7 was subjected to a direct ROCM
with oct-1-en-3-one using Hoveyda–Grubbs catalyst 12,
the desired compound 14 was not obtained; mainly
ROMP of the cyclobutene was observed. Furthermore,
Grubbs’ catalyst 11 was unreactive in a ROCM with oct-
1
3 with oct-1-en-3-one finds optimal conditions under
higher concentration in CH Cl at 40 °C with 5 mol%
2
2
Hoveyda–Grubbs catalyst 12. This leads to the desired
mono-CM product in high selectivity; none of the other
regioisomeric cross-metathesis product is observed and
only trace amount of the double cross-metathesis product
1
-en-3-one; only starting materials were recovered. Since
the two metatheses require different reaction conditions, it
was necessary to run these transformations in a stepwise
fashion.
1
7
is obtained. The newly formed enone in the desired
product is formed exclusively with E-stereoselectivity.
The high regioselectivity of the cross-metathesis could
arise through ruthenium coordination by the free hydroxyl
group on the cyclopentyl ring, although steric hindrance
of the silyl protecting group on the other hydroxyl func-
Silyl protection of the free hydroxyl group, followed by an
asymmetric catalytic reduction of enone 14 with (R)-2-
18
methyl-CBS-oxazaborolidine and catecholborane led to
alcohol 15 in high yield and diastereomeric excess (>95:5
Synthesis 2007, No. 15, 2397–2403 © Thieme Stuttgart · New York

PAPER
Synthesis of ent-15-epi-F -Isoprostane
2399
2
t
TBSO
O
O
D
D
a
MeO
Me
D
MeO
17
Me
D
b, c
D
D
O
MesN
Cl
NMes
7
PCy3
HO
HO
Cl
Cl
Ru
Ru
a
CO2H
Me
D
Ph Cl
D
PCy3
i-PrO
12
TBSO
Me
11
HO
D
D
OH
D
D
1
8
13
d -ent-15-epi-F -isoprostane
HO
4
2t
b
Scheme 6 Synthesis of cross-metathesis partner 18 for the internal
standard d -ent-15-epi-F2t-isoprostane. Reagents and conditions: (a)
TBSO
TBSO
4
TBSO
HO
D (1 atm), Pd/C, MeOH, 60%; (b) MeNH(OMe)·HCl, i-PrMgCl,
THF, –10 °C, 88%; (c) vinylmagnesium bromide, THF, 0 °C; 90%.
2
c, d
Me
OH
Me
O
lowed by vinyl group addition provided tetradeutero-
enone 18. Enone 18 was then used for the cross-metathe-
sis partner with 13 as described in Scheme 4. The rest of
the synthesis was carried out in an analogous manner to
1
5
14
Scheme 4 Installation of the isoprostanyl side-chains through a re-
gio- and stereoselective cross-metathesis. Reagents and conditions:
(
5
a) ethylene, 5 mol% 11, benzene (0.01 M), 87%; (b) oct-1-en-3-one,
mol% 12, CH Cl2 (0.2 M), 40 °C, 70–90%; (c) TBSCl, Et N,
that shown in Schemes 4 and 5 to yield d -ent-15-epi-F -
4
2t
2
3
DMAP, CH Cl , 99%; (d) (R)-2-methyl-CBS-oxazaborolidine, ca-
techolborane, toluene, –78 °C; 99%.
isoprostane.
2
2
d -ent-15-epi-F -Isoprostane was used as an internal stan-
4
2t
dard in a GC/MS assay to detect isoprostanes in human
dr) (Scheme 4).19 Hydroboration of the terminal olefin
with 9-BBN followed by an oxidative workup yields the
primary alcohol, which was oxidized with catalytic
TEMPO/NCS to generate aldehyde 16 (Scheme 5). Wit-
tig olefination forms the Z-olefin exclusively to complete
the overall isoprostane structure. Removal of the two silyl
protecting groups with TBAF delivered the desired ent-
23
urine. Four diastereomeric 15-F -isoprsotanes were sep-
2
24
arated on an achiral GC column. Although the known
1
5-F -isoprostane was not detected in this assay, prelimi-
2t
20
nary results revealed that the ent-15-epi-F -isoprostane
2
t
(
or its enantiomer) was present in the urine sample.
In summary, we have achieved a stereoselective synthesis
of ent-15-epi-F -isoprostane through a regio- and stereo-
2t
1
5-epi-F -isoprostane in nearly quantitative yield. Of par-
2t
selective ring-opening cross-metathesis/cross-metathesis
sequence. Enzymatic acylation generates the starting
enone 4 as a single enantiomer. Photocycloaddition with
acetylene followed by functional group manipulations
provides an enantiomerically enriched precursor for the
key metatheses. A catalyst-controlled asymmetric reduc-
ticular note, the efficiency of the synthetic route allows for
sufficient quantity of ent-15-epi-F -isoprostane to be
2
t
prepared for further biological and chemical studies (i.e.,
0.1 g).
>
TBSO
TBSO
TBSO
tion completes one of the 15-F -isoprostanyl side-chains
O
2
a, b
and allows for the installation of the second side-chain.
The overall sequence provides efficient access to ent-15-
TBSO
epi-F -isoprostane, as well as an isotopically labeled ent-
OH
Me
OH
Me
2t
15
16
1
5-epi-F -isoprostane to be used for in vivo studies.
2t
Moreover, it is expected that the synthetic strategy can be
readily modified to selectively access any of the 15-series
isoprostanes. Further biological and chemical studies of
ent-15-epi-F -isoprostane are underway.
HO
c, d
CO2H
2t
HO
ent-15-epi-F2t-isoprostane
OH
Me
Starting materials and reagents purchased from commercial suppli-
ers were used without further purification with the following excep-
tions: CH Cl , THF, benzene, Et O, and toluene were dried on
2
2
2
Scheme 5 Completion of ent-15-epi-F -isoprostane. Reagents and
conditions: (a) 9-BBN, THF; NaOH, H O , 80%; (b) TEMPO (cat.),
2
t
alumina columns using a solvent dispensing system. N-Chlorosuc-
2
2
cinimide was recrystallized from benzene/H O, and Bu NCl was re-
2
4
NCS, n-Bu NCl, CH Cl /H O, 84% (85% conv.); (c)
4
2
2
2
crystallized from acetone–Et O prior to use. 2,2,6,6-Tetramethyl-1-
[
Ph P(CH ) CO H]Br, t-BuOK, 93%; (d) TBAF, THF, 99%.
2
3
2 4
2
piperdinyloxy free radical (TEMPO) was purified by sublimation
prior to use. The Hoveyda–Grubbs catalyst was purified according
2
5
In addition, this route also allowed for the preparation of to published procedure.
a tetradeuterated analogue of ent-15-epi-F -isoprostane.
Exhaustive reduction of methyl sorbate under D gave 17
in 60% yield (Scheme 6). Weinreb amide formation, fol- (~0.5 mmHg) and purged with N prior to use. Air and/or moisture
2
1
2
t
Oxygen- and/or moisture-sensitive reactions were carried out under
N in Schlenk glassware that was flame dried under high vacuum
2
2
2
2
2
Synthesis 2007, No. 15, 2397–2403 © Thieme Stuttgart · New York

2
400
M. Shizuka, M. L. Snapper
PAPER
sensitive solids were transferred in a glove box. Unless otherwise
stated, reactions were stirred with a Teflon-covered stir bar. Con-
centration refers to the removal of solvent under reduced pressure
using a Büchi rotary evaporator. Silica gel column chromatography
was performed using Baxter brand silica gel 60 Å (230–400 mesh
ASTM). Cerium ammonium molybdate was used as the TLC stain-
ing reagent. IR spectra (FTIR) were recorded on a Nicolet 210 FT-
4-(tert-Butyldimethylsilyloxy)bicyclo[3.2.0]hept-6-en-2-ones (5,
6)
In a 3.0 L-photochemical vessel, enone 4 (2.40 g, 11.3 mmol) was
dissolved in acetone (2.80 L). A Pyrex immersion well containing a
Pyrex sleeve (~3.5 mm thickness) was placed into the vessel and the
solution was sparged with acetylene for 5 min. A 100 W medium-
pressure mercury vapor lamp was placed in the immersion well and
the stirred solution was irradiated with constant bubbling of acety-
lene for a total of 42 h (reaction progress monitored by GC). Solvent
was removed under reduced pressure and the residue was purified
–
1
1
IR spectrometer, and reported in wave numbers (cm ). H NMR
and 13C NMR spectra were measured on a Varian Gemini-400 in-
1
13
strument at 400 MHz ( H NMR) and 100 MHz ( C NMR). Chem-
ical shifts are reported with the solvent as the internal standard
by silica gel chromatography (hexanes–Et O, gradient 20:1, 10:1,
2
1
13
[
CDCl : d = 7.26 ( H NMR), d = 77.0 ( C NMR)]. Enantiomer ratio
5:1) to give a mixture of 5 and 6 [5:6 = 2:1, 86% conv., 1.73 g, 74%
3
1
was determined by chiral GLC analysis (Supelco Betadex 120 col-
umn (30 m × 0.25 mm). Optical rotations were measured on a Ru-
dolph Research Analytical Autopol IV polarimeter. High-resolution
mass spectral (HRMS) analyses were performed on a Micromass
LCT ESI-MS (positive mode) at the Mass Spectrometry Laboratory
at Boston College.
yield, based on recovered starting material (BRSM)]. The H NMR
1
3
9
and C NMR were identical to published results.
4-(tert-Butyldimethylsilyloxy)bicyclo[3.2.0]hept-6-en-2-ol (7)
In a flame-dried Schlenk flask, a mixture of 5 and 6 (1.00 g, 4.20
mmol) was dissolved in toluene (17.4 mL) and cooled to 78 °C.
DIBAL-H (823 mL, 4.62 mmol) was added to the mixture and
stirred for 3 h, after which the reaction was quenched carefully with
MeOH (3.0 mL). The solution was warmed to 23 °C and diluted
4
-(tert-Butyldimethylsilyloxy)cyclopent-2-enone (4)
2
6
Monoacetate compound 3 was obtained from literature procedure
after recrystallization with hexane–benzene as white needle-like
crystals (55% yield, >99% ee). The optical purity was established
by chiral GLC analysis. Acetate 3 (957 mg, 6.74 mmol) and DMAP
with Et O (10 mL). The reaction was opened to air and aq sat. solu-
tion of Rochelle’s salt (sodium potassium tartrate, 20 mL) was add-
ed to the mixture and stirred for 1 h. The solution was extracted with
2
(
411 mg, 3.37 mmol) were dissolved in CH Cl (67.0 mL) at 0 °C.
Et O (2 × 30 mL), and the combined organic layers were washed
2
2
2
Et N (2.80 mL, 20.2 mmol) and TBSCl (2.03 g, 13.5 mmol) were
with aq 1 M HCl (2 × 30 mL) and brine (1 × 30 mL). The combined
3
added to the mixture at 0 °C. The solution was warmed to 23 °C and
stirred for 12 h. The mixture was diluted with CH Cl (60 mL) and
organic layers were dried (MgSO ), filtered and concentrated. The
4
residue was purified by silica gel chromatography (hexanes–Et O;
2
2
2
washed with aq 0.5 M HCl (2 × 40 mL), aq sat. NaHCO (1 × 50
gradient, 10:1, 5:1, 3:1) to obtain 7, 8, 9, 10 (467 mg, 47%; 129 mg,
3
mL) and brine (1 × 50 mL). The organic layer was dried (MgSO ),
13%; 367 mg, 37%; 30 mg, 3% respectively; total yield: 993 mg,
4
2
0
filtered, and solvent was removed under reduced pressure to give
98% yield). Data shown only for cyclobutene 7; [a]D –0.74
TBS-protected cyclopentenyl acetate I (not shown) as a colorless
(c = 0.27, CHCl3).
1
oil, which was pure by H NMR spectroscopy (1.71 g, 99% yield).
IR (film): 3530 (b), 3040 (w), 2953 (s), 2929 (s), 2894 (m), 2855
An aqueous solution of 1 M K CO (6.37 mL, 6.37 mmol) was add-
2
3
(
(
1
m), 1469 (m), 1408 (m), 1253 (m), 1088 (s), 1053 (s), 1002 (s), 835
s), 773 (s), 697 cm (m).
ed to a stirred solution of I (1.63 g, 6.37 mmol) in MeOH (27.0 mL)
and was stirred for 3 h at 23 °C. The mixture was diluted with
CH Cl (20 mL) and washed with brine (2 × 50 mL). The aqueous
–1
H NMR (CDCl , 400 MHz): d = 6.05 (1 H, d, J = 2.8 Hz), 5.99, (1
3
2
2
H, d, J = 2.8 Hz), 4.18 (1 H, d, J = 3.6 Hz), 4.00 (1 H, dd, J = 11.2,
.4 Hz), 3.36 (1 H, s), 3.23, (1 H, s), 3.10 (1 H, d, J = 11.2 Hz), 2.31
1 H, dt, J = 14.0, 4.4 Hz), 1.87 (1 H, d, J = 14.4 Hz), 0.89 (9 H, s),
.09 (6 H, s).
layer was back-extracted with CH Cl (3 × 25 mL) and the com-
2
2
4
(
0
bined organic layers were dried (MgSO ) and filtered. The solvent
4
was removed under reduced pressure and the residue was purified
by silica gel chromatography (hexanes–EtOAc, 3:1) to give hy-
droxy cyclopentenyl compound II (not shown) as a colorless oil
13
C NMR (CDCl , 100 MHz): d = 140.3, 138.7, 73.8, 72.9, 57.2,
3
(
1.30 g, 96% yield). PCC (1.96 g, 9.11 mmol) and Celite (2.90 g)
5
6.5, 40.4, 26.2, 18.4, –4.38, –4.50.
were stirred in CH Cl (63.0 mL) at 23 °C. Intermediate II (1.30 g,
2
2
+
HRMS (ESI ): m/z calcd for C H O Si + Na (M + Na): 263.1443;
1
3
24
2
6
.07 mmol) in CH Cl (5.0 mL) was added to the mixture. After 2
2 2
found: 263.1445.
h, the solution was diluted with Et O (15 mL) and was filtered
2
through a pad of Celite (4 cm thick) over silica gel (4 cm thick) and
4
-(tert-Butyldimethylsilyloxy)-2,3-divinylcyclopentanol (13)
Grubbs catalyst 11 (74.0 mg, 89.8 mmol) was stirred in benzene
87.9 mL) and sparged with ethylene (balloon) for 5 min. Cy-
washed with hexanes–Et O (1:1, 50 mL). Solvent was removed un-
2
der reduced pressure and the residue was purified by silica gel chro-
(
matography (hexanes–Et O, 5:1) to give enone 4 as a colorless oil
2
2
0
clobutene 7 (432 mg, 1.80 mmol) in benzene (2.0 mL) was added
to the mixture and stirred under an ethylene atmosphere (balloon) at
2
(
1.18 g, 92%); [a]D +43.5 (c 1.08, CHCl3).
IR (film): 2954 (m), 2928 (m), 2887 (w), 2857 (m), 1742 (s), 1471
w), 1354 (m), 1182 (w), 1109 (m), 1071 (m), 900 (m), 838 (m), 777
3 °C for 15 h. The mixture was opened to air and ethyl vinyl ether
(
(1.0 mL) was added and stirred for 5 min. Silica gel (4.20 g) was
–
1
cm (m).
then added and stirred for another 15 min. The slurry was filtered
through a plug of silica gel and washed with hexanes–EtOAc (3:1,
3
chromatography (hexanes–Et O, 5:1) to obtain 13 as a clear yellow
oil (426 mg, 88%); [a]D +1.6 (c 0.37, CHCl3).
1
H NMR (CDCl , 400 MHz): d = 7.50 (1 H, dd, J = 6.0, 2.4 Hz),
3
0 mL). The filtrate was concentrated and purified by silica gel
6
.23 (1 H, dd, J = 5.6, 1.2 Hz), 5.04–5.02 (1 H, m), 2.75 (1 H, dd,
J = 18.0, 5.6 Hz), 2.29 (1 H, dd, J = 18.0, 2.0 Hz), 0.957 (9 H, s),
2
2
0
0
.17 (6 H, s).
1
3
IR (film): 3359 (b), 2955 (s), 2928 (s), 2857 (s), 1639 (w), 1471 (m),
C NMR (CDCl , 100 MHz): d = 206.3, 163.8, 134.5, 71.1, 45.3,
3
–
1
1
256 (s), 1089 (b), 912 (s), 836 (s), 775 cm (s).
2
6.1, 18.5, –4.27, –4.30.
1
+
H NMR (CDCl , 400 MHz): d = 5.66 (1 H, ddd, J = 17.1, 10.2, 8.8
HRMS (ESI ): m/z calcd for C H O Si + Na (M + Na): 235.1130;
found: 235.1126.
3
1
1
20
2
Hz), 5.60–5.51 (1 H, m), 5.14–5.06 (3 H, m), 5.03 (1 H, dd, J = 6.0,
1
2
2
.7 Hz), 4.06–4.01 (2 H, m), 2.84 (1 H, ddd, J = 8.5, 8.3, 5.4 Hz),
.77 (1 H, ddd, J = 8.8, 8.3, 3.1 Hz), 2.36 (1 H, dt, J = 14.1, 6.5 Hz),
.00 (1 H, d, J = 6.7 Hz), 1.69 (1 H, dt, J = 14.1, 4.0 Hz), 0.88 (9
H, s), 0.05 (6 H, s).
Synthesis 2007, No. 15, 2397–2403 © Thieme Stuttgart · New York

PAPER
Synthesis of ent-15-epi-F -Isoprostane
2401
2
t
1
3
13
C NMR (CDCl , 100 MHz): d = 137.3, 137.0, 116.8, 116.7, 77.4,
C NMR (CDCl , 100 MHz): d = 135.5, 129.5, 76.2, 72.9, 61.6,
3
3
7
6.7, 56.6, 55.7, 43.4, 26.2, 18.4, –4.1, –4.3.
53.5, 46.0, 44.4, 37.4, 32.4, 31.8, 25.9, 25.2, 22.7, 18.2, 18.1, 14.2,
–3.9, –4.4, –4.5.
+
HRMS (ESI ): m/z calcd for C H O Si + Na (M + Na): 291.1756;
found: 291.1753.
1
5
28
2
1
Diastereomeric ratio was determined by comparison of the H NMR
spectrum (C D ) with the authentic 1:1 diastereomeric mixture (es-
6
6
1
-[3-(tert-Butyldimethylsilyloxy)-5-hydroxy-2-vinylcyclopen-
timated detection limits of 20:1).
tyl]oct-1-en-3-one (14)
Divinyl compound 13 (425 mg, 1.58 mmol) and oct-1-en-3-one
ent-15-epi-F -Isoprostane
2
t
(
300 mg, 2.37 mmol) were dissolved in CH Cl (8.0 mL). Hoveyda–
9-BBN (0.5 M in THF, 1.0 mL, 0.50 mmol) was added to neat 15
2
2
Grubbs catalyst 12 (50.0 mg, 79.0 mmol) was added and the mixture
(111 mg, 0.23 mmol) at 0 °C under N and stirred for 5 min. The
2
was heated to 40 °C. The mixture was stirred for 5 h, then cooled to
mixture was warmed to 23 °C and stirred for 5.5 h. The reaction was
opened to air and diluted with EtOAc (1.5 mL). The solution was
cooled to 0 °C and aq 3 M NaOH (545 mL, 1.64 mmol) and 30%
H O (449 mL, 4.67 mmol) were added. After 1 h, the mixture was
2
3 °C and opened to air. Ethyl vinyl ether (2.0 mL) was added and
the mixture was stirred for 5 min. The solvent was removed under
reduced pressure and the residue was purified by silica gel chroma-
tography (hexanes–EtOAc, 5:1) to obtain 14 as a light brown oil
2
2
extracted with EtOAc (3 × 5 mL) and the combined organic layers
27
20
(
429 mg, 74% ); [a] –11 (c 0.30, CHCl3).
were washed with aq sat. NaHCO (2 × 10 mL) and brine (1 × 10
D
3
mL). The organic layer was dried (MgSO ), filtered, and solvent
4
IR (film): 3425 (b), 2956 (s), 2928 (s), 2857 (s), 1669 (m), 1625 (m),
–
1
was removed under reduced pressure. The residue was purified by
silica gel chromatography (hexanes–EtOAc, gradient 3:1, 1:1) to ob-
tain 1-[3,5-bis(tert-butyldimethylsilyloxy)-2-(2-hydroxyethyl)cy-
1
459 (m), 1359 (m), 1248 (m), 839 cm (s).
1
H NMR (CDCl , 400 MHz): d = 6.67 (1 H, dd, J = 15.8, 9.0 Hz),
3
6
.19 (1 H, dd, J = 15.8, 1.1 Hz), 5.49 (1 H, ddd, J = 16.4, 10.8, 9.6
Hz), 5.09–5.04 (2 H, m), 4.13 (1 H, tt, J = 7.3, 4.7 Hz), 4.08 (1 H,
dt, J = 5.9, 3.1 Hz), 3.01 (1 H, td, J = 8.3, 5.5 Hz), 2.88–2.83 (1 H,
m), 2.50 (2 H, t, J = 7.3 Hz), 2.39 (1 H, ddd, J = 14.3, 7.2, 5.7 Hz),
clopentyl]oct-1-en-3-ol (IV; not shown) as a colorless oil (96.4 mg,
20
8
5%); [a]D –15.6 (c 2.40, CHCl3).
IR (film): 3388 (b), 2956 (s), 2925 (s), 2857 (s), 1647 (m), 1468 (m),
–
1
1
363 (m), 1258 (m), 1061 (m), 851 (m), 770 (m), 666 cm (m).
2
.12 (1 H, d, J = 7.5 Hz), 1.74 (1 H, dt, J = 13.8, 3.3 Hz), 1.64–1.56
1
(
(
1
2 H, m), 1.35–1.24 (4 H, m), 0.91–0.87 (3 H, m), 0.89 (9 H, s), 0.06
6 H, s).
H NMR (CDCl , 400 MHz): d = 5.51 (1 H, dd, J = 15.3, 6.5 Hz),
3
5.37 (1 H, dd, J = 15.4, 9.9 Hz), 4.06 (1 H, q, J = 6.4 Hz), 3.90–3.84
(2 H, m), 3.72–3.60 (2 H, m), 2.56–2.51 (1 H, m), 2.35 (1 H, dt,
J = 13.7, 6.9 Hz), 2.24 (1 H, dt, J = 14.7, 8.1 Hz), 1.67–1.44 (6 H,
m), 1.39–1.24 (7 H, m), 0.91–0.89 (2 H, m), 0.89 (9 H, s), 0.88–0.86
3
C NMR (CDCl , 100 MHz): d = 200.3, 145.1, 135.9, 131.3, 117.8,
3
7
–
7.3, 76.6, 57.1, 54.2, 43.6, 41.0, 31.8, 26.2, 24.3, 22.8, 18.4, 14.3,
4.1, –4.2.
(
1 H, m), 0.87 (9 H, s), 0.07 (6 H, s), 0.02 (6 H, s).
+
HRMS (ESI ): m/z calcd for C H O Si + Na (M + Na): 389.2488;
2
1
38
3
13
C NMR (CDCl , 100 MHz): d = 135.5, 129.5, 76.7, 76.2, 72.9,
3
found: 389.2489.
6
1
1.7, 53.6, 46.0, 44.4, 37.4, 32.4, 31.9, 25.9, 25.2, 22.7, 18.2, 18.1,
4.2, –3.9, –4.4, –4.5.
1
-[3,5-Bis(tert-butyldimethylsilyloxy)-2-vinylcyclopentyl]oct-1-
+
en-3-ol (15)
HRMS (ESI ): m/z calcd for C H O Si + Na (M + Na): 523.3615;
2
7
56
4
2
Enone 14 (362 mg, 0.99 mmol) and DMAP (60.2 mg, 0.49 mmol)
were dissolved in CH Cl (9.9 mL). Et N (412 mL, 2.96 mmol) and
found: 523.3625.
2
2
3
Diol IV (232 mg, 0.463 mmol) and Bu NCl (25.7 mg, 92.6 mmol)
were stirred in CH Cl (3.8 mL) and H O (carbonate buffer, pH 8.6,
4
TBSCl (297 mg, 1.97 mmol) were added to the mixture. The solu-
tion was stirred at 23 °C for 12 h. The mixture was diluted with
CH Cl (40 mL) and washed with 0.5 M HCl (2 × 15 mL), aq sat.
2
2
2
3
.8 mL) at 23 °C. NCS (68.0 mg, 0.509 mmol) and TEMPO (14.5
2
2
mg, 92.6 mmol) was added to the mixture and stirred for 3 h. The
mixture was diluted with CH Cl (10 mL) and the CH Cl layer
NaHCO (1 × 20 mL), and brine (1 × 20 mL). The organic layer was
3
2
2
2
2
dried (MgSO ), filtered, and solvent was removed under reduced
4
washed with brine (2 × 15 mL). The aqueous layer was back-ex-
pressure. The residue was purified by silica gel chromatography
tracted with CH Cl (3 × 15 mL) and the combined organic layers
2
2
(
hexanes–Et O, 15:1) to obtain bis(TBS-protected) enone III (not
2
were dried (MgSO ), filtered, and concentrated. The residue was
4
shown) as a colorless oil (435 mg, 92%). To a flame-dried Schlenk
flask, intermediate III (300 mg, 0.62 mmol) and toluene (3.12 mL)
were added. The solution was cooled to –78 °C and (R)-methyl-
CBS-oxazoborilidine catalyst (1 M in toluene, 312 mL, 0.31 mmol)
was added followed by catecholborane (266 mL, 2.50 mmol). The
mixture was stirred at –78 °C for 15 h. MeOH (2.0 mL) was added
to quench the reaction and the mixture was gradually warmed to
purified by silica gel chromatography (hexanes–EtOAc, 4:1) to ob-
tain the aldehyde 16 as a thick orange oil (184 mg, 99%, BSRM)
and starting material (49 mg, 80% conv.). t-BuOK (329 mg, 2.94
mmol) in THF (4.9 mL) was added to a stirred solution of carboxy-
butyltriphenylphosphonium bromide (651 mg, 1.47 mmol) in THF
(
3.1 mL) at 23 °C. After this bright orange ylide solution was stirred
for 20 min, it was syringed into a stirred solution of the aldehyde
183 mg, 0.37 mmol) in THF (1.1 mL). After the reaction was
2
3 °C. The solution was diluted with EtOAc (20 mL) and the com-
(
bined organic layers were washed with aq 1 M NaOH (1 × 20 mL),
stirred for 3.5 h, aq sat. NH Cl (15 mL) and glacial AcOH (1 mL)
4
aq 1 M HCl (1 × 20 mL), and brine (1 × 20 mL). The organic layer
were added. The solution was extracted with EtOAc (3 × 10 mL),
was dried (MgSO ), filtered, and solvent was removed under reduce
4
dried (MgSO ), filtered, and concentrated. The residue was purified
4
pressure. The residue was purified by silica gel chromatography
by silica gel chromatography (hexanes–EtOAc–AcOH, 5:1:0.1) to
obtain TBS-protected-isoprostane V (not shown) as a colorless oil
(
[
hexanes–Et O, 8:1) to afford 15 as a colorless oil (303 mg, 99%);
a]D +1.9 (c 1.3, CHCl3).
2
20
(
200 mg, 93%). TBAF (1 M in THF, 2.69 mL, 2.69 mmol) was add-
IR (film): 3342 (b), 3070 (w), 2955 (s), 2925 (s), 2853 (s), 1638 (w),
ed to neat V (196 mg, 0.37 mmol) at 23 °C and stirred overnight.
The mixture was opened to air and diluted with EtOAc (5.0 mL) and
–
1
1
469 (m), 1361 (m), 1258 (s), 1095 (b), 835 (s), 775 cm (s).
1
washed with aq sat. NH Cl (2 × 5 mL) solution. The aqueous layer
4
H NMR (CDCl , 400 MHz): d = 5.63–5.41 (3 H, m), 5.06–5.04 (1
3
was back-extracted with EtOAc (3 × 10 mL) and the combined or-
ganic layers were washed with brine (1 × 25 mL). The solution was
H, m), 5.03–5.01 (1 H, m), 4.05 (1 H, qd, J = 10.2, 6.5 Hz), 3.95–
3
1
H, m), 0.91–0.86 (3 H, m), 0.87 (18 H, s), 0.018 (6 H, s), 0.013 (3
H, s), 0.007 (3 H, s).
.89 (2 H, m), 2.74–2.65 (2 H, m), 2.36 (1 H, dt, J = 14.0, 7.1 Hz),
.59 (1 H, dt, J = 13.7, 5.6 Hz), 1.54–1.43 (2 H, m), 1.36–1.25 (7
dried (MgSO ), filtered, and solvent was removed under reduced
4
pressure. The residue was purified by silica gel chromatography
(
EtOAc–MeOH–AcOH, 20:1:0.1) to obtain ent-15-epi-F -isopros-
2t
Synthesis 2007, No. 15, 2397–2403 © Thieme Stuttgart · New York

2
402
M. Shizuka, M. L. Snapper
PAPER
2
0
tane as a pale yellow oil (104 mg, 87%); [a]
–1.1 (c 0.55,
(3) (a) Leitinger, N.; Blazek, I.; Sinzinger, H. Thrombosis Res.
1997, 86, 337. (b) Cranshaw, J. H.; Evans, T. W.; Mitchell,
J. A. Brit. J. Pharm. 2001, 132, 1699. (c) For review, see:
Csiszar, A.; Stef, G.; Pacher, P.; Ungvari, Z. Prostaglandins,
Leukotrienes Essent. Fatty Acids 2002, 66, 557.
(4) (a) Morrow, J. D.; Zackert, W. E.; Van Der Ende, D. S.;
Reich, E. E.; Terry, E. S.; Cox, B.; Sanchez, S. C.; Montine,
T. J.; Roberts, L. J. Oxidative Stress Disease 2002, 8, 57.
D
MeOH).
IR (film): 3363 (b), 2999 (w), 2923 (m), 2847 (m), 1698 (s), 1405
–
1
(
w), 1235 (w), 1052 (m), 965 cm (m).
1
H NMR (CDCl , 400 MHz): d = 5.57 (1 H, dd, J = 15.3, 6.6 Hz),
.52–5.40 (3 H, m), 4.12 (1 H, q, J = 6.4 Hz), 4.04–4.00 (2 H, m),
.94–3.52 (3 H, br s), 2.78 (1 H, dq, J = 8.6, 3.9 Hz), 2.44 (1 H, dt,
J = 14.7, 6.9 Hz), 2.32 (2 H, t, J = 6.4 Hz), 2.21–2.04 (4 H, m),
.99–1.90 (1 H, m), 1.74–1.61 (3 H, m), 1.60–1.45 (2 H, m), 1.39–
3
5
3
(b) For a recent review, see: Milne, G. L.; Morrow, J. D.
1
1
Antioxid. Redox Signal. 2006, 8, 1379. (c) Yin, H.; Musiek,
E. S.; Morrow, J. D. J. Biol. Sci. 2006, 6, 469. (d) Morrow,
J. D. Curr. Pharmaceut. Design 2006, 12, 895.
.25 (6 H, m), 0.88 (3 H, t, J = 6.5 Hz).
1
3
C NMR (CDCl , 100 MHz): d = 176.5, 135.2, 129.7, 129.4, 129.2,
6.5, 76.4, 73.1, 53.8, 50.8, 42.3, 37.3, 32.6, 31.8, 27.0, 26.3, 25.2,
3
(
(
5) (a) Quinn, J. F.; Montine, K. S.; Moore, M.; Morrow, J. D.;
7
2
Kaye, J. A.; Montine, T. J. J. Alzheimer’s Dis. 2004, 6, 93.
4.4, 22.7, 14.2.
(
b) Nishio, T.; Miyadera, R.; Sakai, R.; Abe, K.; Kanazawa,
H.; Fukui, K.; Urano, S. J. Clin. Biochem. Nutr. 2006, 38,
61. (c) For a review, see: Montine, T. J.; Quinn, J. F.; Kaye,
+
HRMS (ESI ): m/z calcd for C H O + Na (M + Na): 377.2304;
2
0
34
5
found: 377.2290.
1
J. A.; Morrow, J. D. Oxidative Stress Disease 2006, 22, 147.
6) (a) For recent review, see: Giovanni, D.; Falco, A.; Patrono,
C. Chem. Phys. Lipids 2004, 128, 149. (b) See also: Boyne,
M. S.; Sargeant, L. A.; Bennett, F. I.; Wilks, R. J.; Cooper,
R. S.; Forrester, T. E. Diabetes Res. Clin. Pract. 2007, 76,
149.
d -ent-15-epi-F -Isoprostane
4
2t
The synthesis was carried out analogously as above, starting with
cross-metathesis of the appropriate d -oct-1-en-3-one and divinyl
4
cyclopentane 13;28 [a]D –0.6 (c 0.33, MeOH).
20
IR (film): 3420 (b), 2930 (m), 2873 (m), 1709 (s), 1413 (w), 1255
–
1
(
w), 1193 (w), 1060 (m), 966 cm (w).
(7) (a) Camphausen, K.; Menard, C.; Sproull, M.; Goley, E.;
1
Basu, S.; Coleman, C. N. Int. J. Radiat. Oncol. Biol. Phys.
H NMR (CDCl , 400 MHz): d = 5.56 (1 H, dd, J = 15.2, 6.8 Hz),
3
2
004, 58, 1536. (b) Rossner, P. Jr.; Gammon, M. D.; Terry,
5
4
2
.48–5.40 (3 H, m), 4.18 (1 H, br s), 4.14 (1 H, q, J = 6.0 Hz), 4.00–
.01 (2 H, m), 2.81–2.76 (1 H, m), 2.43 (1 H, dt, J = 14.8, 6.8 Hz),
.32 (2 H, t, J = 6.5 Hz), 2.21–2.04 (4 H, m), 1.98–1.93 (1 H,
M. B.; Agrawal, M.; Zhang, F. F.; Teitelbaum, S. L.; Eng, S.
M.; Gaudet, M. M.; Neugut, A. I.; Santella, R. M. Cancer
Epidem. Biomar. 2006, 15, 639.
m), 1.70–1.61 (3 H, m), 1.54–1.46 (2 H, m), 1.34–1.24 (4 H, m),
.89–0.84 (3 H, m).
(
8) For reviews, see: (a) Taber, D. F.; Hoerner, S. R.; Herr, J. R.;
Gleave, M. D.; Kanai, K.; Pina, R.; Jiang, Q.; Xu, M. Chem.
Phys. Lipids 2004, 128, 57. (b) Quan, L. G.; Cha, J. K.
Chem. Phys. Lipids 2004, 128, 3. (c) Rokach, J.; Kim, S.;
Bellone, S.; Lawson, J. A.; Pratico, D.; Powell, W. S.;
FitzGerald, G. A. Chem. Phys. Lipids 2004, 128, 35. For
early references, see: (d) Corey, E. J.; Shih, N. Y.; Shimoji,
K. Tetrahedron Lett. 1984, 25, 5013. (e) O’Connor, D. E.;
Mihelich, E. D.; Coleman, M. C. J. Am. Chem. Soc. 1984,
0
1
3
C NMR (CDCl , 100 MHz): d = 175.8, 135.6, 130.1, 129.7, 129.4,
3
7
6.6, 76.5, 73.2, 53.8, 50.9, 42.4, 32.7, 27.0, 26.4, 26.4, 24.5, 14.1.
+
HRMS (ESI ): m/z calcd for C H D O + Na (M + Na): 381.2550;
found: 381.2555.
2
0
30
4
5
Acknowledgment
1
06, 3577. (f) Rondot, B.; Durand, T.; Girard, J. P.; Rossi, J.
C.; Schio, L.; Khanapure, S. P.; Rokach, J. Tetrahedron Lett.
993, 34, 8245. (g) Hwang, S. W.; Adiyama, M.;
Khanapure, S.; Schio, L.; Rokach, J. J. Am. Chem. Soc.
994, 116, 10829. (h) Larock, R. C.; Lee, N. H. J. Am.
We thank the National Institutes of Health (R01-CA66617) for
financial support. We are also grateful to Materia for the gift of
metathesis catalyst.
1
1
Chem. Soc. 1991, 113, 7815. (i) See also: Roland, A.;
Durand, T.; Egron, D.; Vidal, J. P.; Rossi, J. C. J. Chem.
Soc., Perkin Trans. 1 2000, 245. (j) Durand, T.; Guy, A.;
Vidal, J. P.; Rossi, J. C. J. Org. Chem. 2002, 67, 3615.
(k) Jacobo, S. H.; Chang, C.-T.; Lee, G.-J.; Lawson, J. A.;
Powell, W. S.; Pratico, D.; FitzGerald, G. A.; Rokach, J. J.
Org. Chem. 2006, 71, 1370. (l) Jung, M. E.; Berliner, A.;
Angst, D.; Yue, D.; Koroniak, L.; Watson, A. D.; Li, R. Org.
Lett. 2005, 7, 3933. (m) Pinot, E.; Guy, A.; Guyon, A.-L.;
Rossi, J.-C.; Durand, T. Tetrahedron: Asymmetry 2005, 16,
1893.
References
(
1) For free radical peroxidation of arachidonic acid, see:
a) Morrow, J. D.; Hill, K. E.; Burk, R. F.; Nammour, T. M.;
Badr, K. F.; Roberts, L. J. II Proc. Nat. Acad. Sci. U.S.A.
990, 87, 9383. (b) Morrow, J. D.; Awad, J. A.; Boss, H. J.;
Blair, I. A.; Roberts, L. J. II Proc. Natl. Acad. Sci. U.S.A.
992, 89, 10721. (c) Morrow, J. D.; Minton, T. A.;
(
1
1
Mukundan, C. R.; Campbell, M. D.; Zackert, W. E.; Daniel,
V. C.; Badr, K. F.; Blair, I. A.; Roberts, L. J. II J. Biol. Chem.
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J. Biol. Chem. 1996, 271, 23185. (f) Basu, S.
(9) Schrader, T. O.; Snapper, M. L. J. Am. Chem. Soc. 2002,
124, 10998.
(10) (a) Schrader, T. O.; Snapper, M. L. Tetrahedron Lett. 2000,
41, 9685. For earlier studies on ring-opening cross-
metathesis of cyclobutenes, see: (b) Randall, M. L.;
Tallarico, J. A.; Snapper, M. L. J. Am. Chem. Soc. 1995, 117,
9610. (c) Tallarico, J. A.; Bonitatebus, P. J. Jr.; Snapper, M.
L. J. Am. Chem. Soc. 1997, 119, 7157. (d) Snapper, M. L.;
Tallarico, J. A.; Randall, M. L. J. Am. Chem. Soc. 1997, 119,
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Tetrahedron 1997, 53, 16511.
Prostaglandins, Leukotrienes Essent. Fatty Acids 1998, 58,
319. (g) Roberts, L. J.; Fessel, J. P. Chem. Phys. Lipids 2004,
128, 173. (h) See also: Wang, D.; DuBois, R. N. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 415.
(
2) (a) Natarajan, R.; Lanting, L.; Gonzales, N.; Nadler, J. Am.
J. Physiol. 1996, 271, E159. (b) Kunapuli, P.; Lawson, J.
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(11) Schrader, T. O. Ph.D. Thesis; Boston College: Chestnut Hill
Massachusetts, 2002.
Synthesis 2007, No. 15, 2397–2403 © Thieme Stuttgart · New York

PAPER
Synthesis of ent-15-epi-F -Isoprostane
2403
2
t
(
12) Theil, F.; Schick, H.; Winter, G.; Reck, G. Tetrahedron
991, 47, 7569.
(23) For selected examples of GC/MS studies for the analysis of
isoprostanes, see: (a) Roberts, L. J. II; Morrow, J. D. In
Methods in Biological Oxidative Stress; Hensley, K.; Floyd,
R. A., Eds.; Humana Press: Totawa NJ, 2003, Chap. 4, 33–
39. (b) Morrow, J. D.; Harris, T. M.; Roberts, L. J. II Anal.
Biochem. 1990, 184, 1. (c) Wang, Z.; Ciabattoni, G.;
Creminon, C.; Lawson, J.; FitzGerald, G. A.; Patrono, C.;
Maclouf, J. J. Pharmacol. Exp. Ther. 1995, 275, 94.
(d) Bachi, A.; Zuccato, E.; Baraldi, M.; Fanelli, R.;
Chiabrando, C. Free Radic. Biol. Med. 1996, 20, 619.
(e) Waugh, R. J.; Murphy, R. C. J. Am. Soc. Mass Spectrom.
1996, 7, 490. (f) Patrignani, P.; Santini, G.; Panara, M. R.;
Sciulli, M.; Greco, A.; Rotondo, M. T.; diGiamberardino,
M.; Maclouf, J.; Ciabattoni, G.; Patrono, C. Br. J.
Pharmacol. 1996, 118, 1285.
(24) More details on the setup and results of the GC/MS detection
assay may be obtained by contacting the authors.
(25) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168.
(26) Theil, F.; Schick, H.; Winter, G.; Reck, G. Tetrahedron
1991, 47, 7569.
1
(
(
13) Gosh, A. K.; Liu, W. J. Org. Chem. 1997, 62, 7908.
14) For a more recent and convenient approach to this
intermediate, see: Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.;
Snapper, M. L. Nature (London) 2006, 443, 67.
(
15) (a) Buchi, G.; Burgess, E. M. J. Am. Chem. Soc. 1960, 82,
4333. (b) Eaton, P. E. Tetrahedron Lett. 1964, 3695.
(c) Serebryakov, E. P.; Kulomzina-Pletneva, S. D.;
Margaryan, A. K. Tetrahedron 1979, 35, 77.
(
(
(
16) Cho, J. H.; Kim, B. M. Org. Lett. 2003, 5, 531.
17) Regioselectivity was determined by COSY NMR.
18) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37,
1
986.
1
(
19) Selectivity was determined by H NMR (estimated detection
limits of 20:1) by comparison with authentic samples of each
diastereomer.
(
(
20) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. J. Org.
Chem. 1996, 61, 7452.
21) This isotopically labeled isoprostane could be used as an
alternative standard for metabolic studies as shown in: Kim,
S.; Powell, W. S.; Lawson, J. A.; Jacobo, S. H.; Pratico, D.;
FitzGerald, G. A.; Maxey, K.; Rokach, J. Bioorg. Med.
Chem. Lett. 2005, 15, 1613.
(27) Data shown for a 74% yield reaction. Yields range from
70–90%, depending on catalyst purity.
(28) This compound is the major isomer; however, it is in a
mixture of isomers of lower deuterium incorporation.
(
22) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.;
Dolling, U.-J.; Grabowski, E. J. J. Tetrahedron Lett. 1995,
36, 5461.
Synthesis 2007, No. 15, 2397–2403 © Thieme Stuttgart · New York