Radical cyclization; towards the syntheses of tetranor metabolites of 15-F2t-isoprostane

Article abstract of DOI:10.1016/S0040-4020(03)00258-8

Radical cyclization of acyclic 1-substituted-2,4-dihydroxylated 5-hexenyl radicals produced functionalized cyclopentane derivatives. These cyclopentanic precursors after different protection/deprotection reactions followed by Wittig and Horner-Wadsworth-E

Full text of DOI:10.1016/S0040-4020(03)00258-8

Tetrahedron 59 (2003) 2485–2495
Radical cyclization; towards the syntheses of tetranor metabolites
of 15-F2t-isoprostane
*
Thierry Durand, Olivier Henry, Alexandre Guy, Arlene Roland, Jean-Pierre Vidal
`
and Jean-Claude Rossi
´ ´
Faculte de Pharmacie, Universite de Montpellier I., UMR CNRS 5074, 15, Av. Charles Flahault, BP 14491,
F34093 Montpellier cedex 05, France
Received 23 October 2002; revised 14 January 2003; accepted 17 February 2003
Abstract—Radical cyclization of acyclic 1-substituted-2,4-dihydroxylated 5-hexenyl radicals produced functionalized cyclopentane
derivatives. These cyclopentanic precursors after different protection/deprotection reactions followed by Wittig and Horner–Wadsworth–
Emmons coupling reactions led to the main urinary tetranor metabolites of 15-F2t-isoprostane (8-epi-PGF2a). q 2003 Elsevier Science Ltd.
All rights reserved.
1. Introduction
establish whether and how these isomers are specifically
degraded, in order to relate their levels in vivo to a putative
biological effect. To date, the only F2-isoP metabolites
identified were 2,3-dinor-15F2t-isoP, 2,3-dinor-5,6-dihydro-
15F2t-isoP9–11 and putative tetranor isomers of 15F2t-isoP.9,12
Isoprostanes are a complex family of compounds produced
from polyunsaturated fatty acids via a free radical-catalyzed
mechanism. In vitro generation of autoxidation products
derived from polyunsaturated fatty acids has been described
more than 30 years ago,1,2 but the first demonstration that
these compounds were produced in humans was shown in
1990 by Morrow et al.3 They reported the discovery of
prostaglandin F2-like compounds, termed F2-isoprostanes
(F2-isoP), generated by free radical-induced peroxidation of
arachidonic acid. Since that time, F2-isoprostanes have been
extensively used as clinical markers of lipid peroxidation in
human diseases,4 but knowledge of their metabolic fate may
be useful, to better define their overall formation.5 In fact,
the identification of major metabolites of F2-isoP might help
find new analytical targets to monitor in addition to the
parent compounds. Moreover, given that selected F2-isoP
isomers have potent biological effects,6–8 it is important to
As a consequence, and in connection with our program
directed toward the synthesis of isoprostanes, we report the
total synthesis of 2,3,4,5-tetranor-15-oxo-5,6,13,14-tetra-
hydro-15F2t-isoP methyl ester 1 and 20-carboxy-2,3,4,5-
tetranor-15-oxo-5,6,13,14-tetrahydro-15F2t-isoP dimethyl
ester 2,11d according to our general procedure shown in
Figure 1.
2. Results and discussion
The synthesis of 2,3,4,5-tetranor-15-oxo-5,6,13,14-tetra-
hydro-15F2t-isoP methyl ester 1 is shown in Schemes 1
Figure 1. Retrosynthetic scheme.
Keywords: radical cyclization; tetranor metabolites; 15-F26-isoprostane; cyclopentane precursors.
*
Corresponding author. Tel.: þ33-4-67-54-86-23; fax: þ33-4-67-54-86-25; e-mail: thierry.durand@pharma.univ-montp1.fr
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00258-8

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T. Durand et al. / Tetrahedron 59 (2003) 2485–2495
Scheme 1.
and 2. The first six steps leading to iodo derivative 4 were
achieved in 84% overall yield by using the iodo pathway,
according to our procedure.13 Treatment of compound 4
with ZnCl2 in ethanethiol at 2158C afforded the diol-
thioacetal 5 in 88% yield, which was converted into
dibenzoyl ester 6 in the presence of benzoyl chloride in
pyridine at room temperature in 90% yield. Removal of the
thioacetal group under neutral conditions (HgO/HgCl2) in
acetone/water gave the unstable aldehyde 7 which was
immediately used in the next steps without further
purification. The aldehyde 7 reacted with the ylide derived
from 3-(tetrahydropyranyloxypropyl)triphenyl phosphonium
Scheme 2.

T. Durand et al. / Tetrahedron 59 (2003) 2485–2495
2487
Scheme 3.
bromide 814 and KHMDS to afford the pure cis-b,g-
ethylenic derivative 9 in 74% yield. No trace of trans
compound could be detected by 13C and 1H NMR analysis.
with diazomethane gave the 2,3,4,5-tetranor-15-oxo-
5,6,13,14-tetrahydro-15F2t-isoP methyl ester 1 in 83%
yield (Scheme 2).
Oxidation of the protected primary alcohol from 9 gave the
corresponding acid, which in the presence of an excess of
diazomethane was transformed in 86% yield to the methyl
ester 10. The highly functionalized hex-5-enyl radical
derived from iodoester 10 underwent intramolecular
cyclization15 to yield 72% of the protected syn–anti–syn
cyclopentane 3 accompanied by a mixture of non isolated
cyclopentanic derivatives. The tert-butyldiphenylsilyl ether
in 3 was converted to the alcohol 11 in 74% yield with a
solution of 3% hydrogen chloride in methanol/ethyl ether
(1:1, v/v).16 Dess–Martin oxidation17 of 11 with period-
inane in CH2Cl2 gave the unstable aldehyde 12 which was
immediately used in the next step without purification to
avoid any epimerization of the aldehyde. It is important to
note that this Dess–Martin oxidation gave a higher yield in
avoiding any epimerization than our first attempts using
Swern conditions. The condensation of 12 with diethyl
oxoheptylphosphonate 13, in the presence of NaH, in
anhydrous THF, afforded the trans-a,b-enone 14 in 64%
overall yield from the alcohol 11. During the Horner–
Wadsworth–Emmons reaction, it was not possible to avoid
the formation of the compound 15 derived from the
elimination of the benzoyl group at C11 (Scheme 2).
Our synthesis of 20-carboxy-2,3,4,5-tetranor-15-oxo-
5,6,13,14-tetrahydro-15F2t-isoP dimethyl esters 2 from 12
is shown in Scheme 3. The condensation of 12 with diethyl
[6-(methoxycarbonyl)-2-oxohexyl]phosphonate 17,18 in the
presence of NaHMDS, in anhydrous THF at 2788C,
afforded the trans-a,b-enone 18 in 89% overall yield from
the alcohol 11.
Reduction of the trans double bond on the v chain, was
achieved using H2 on 10% Pd/C, giving the corresponding
oxo derivative 19. Finally, cleavage of the ester functions
with 1N NaOH, followed by treatment with diazomethane
gave the 20-carboxy-2,3,4,5-tetranor-15-oxo-5,6,13,14-
tetrahydro-15F2t-isoP dimethyl esters 2 in 83% yield.
The advantage of our strategy depicted in Schemes 1–3 was
demonstrated by several difficulties encountered in alterna-
tive routes during the course of this work and listed below:
(i) Our first goal was the introduction of the a chain of the
isoprostane by using a one-carbon homologation, starting
from our well-known cyclopentane precursor 20, leading to
the introduction of the a chain as shown in the following
Figure 2.
Reduction of the trans double bond on the v chain was
achieved using H2 on 10% Pd/C, giving the corresponding
oxo derivative 16 in 100% yield. Finally, cleavage of the
ester functions of 16 with 1N NaOH, followed by treatment
The first attempt was the Arndt–Eistert reaction, starting
from the cyclopentane 20,11b,13 using thionyl chloride
followed by addition of excess of CH2N2 then treatment
Figure 2. Original retrosynthetic scheme.

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T. Durand et al. / Tetrahedron 59 (2003) 2485–2495
ester 20 to the corresponding alcohol 23 in 95% yield using
a solution of LiBH4 (2 M in THF). Introduction of bromine
was achieved using PPh3/CBr4 in CH3CN leading to the
bromo diol 24 in 71% yield, then in the presence of KCN in
EtOH/H2O (2:1) the desired cyano derivative 25 was
obtained in 65% yield (Scheme 6). Unfortunately, once
more, we never obtained the desired methyl ester 30 derived
from manipulation of cyano function 25. In all experiments
we got back the starting material 25.
Scheme 4.
(ii) After all these above attempts, we found out that a better
alternative to this one-carbon homologation was the
introduction of the a chain before the cyclization reaction,
able to obtain directly the syn–anti–syn cyclopentane
compound 30 or analogs, depending of the function at C1
position.
Our first approach based on our earlier work, using a three-
carbon homologating agent: the (3,3-diisopropoxypropyl)-
triphenylphosphonium bromide19 is presented in Scheme 7.
Scheme 5.
As it is shown in the above scheme, if we obtained the
corresponding ylide in the presence of NaHMDS, we never
obtained the desired diol 27 and got back the starting
hemiacetal 26. The second difficulty were unexpected
reactions during the deprotection of the diisopropyl acetal
on compound 32 (Scheme 8).
of the crude product by Ag2O. Under these conditions we
never obtained the desired ester 30 and got only full
degradation of starting material (Scheme 4).
We have also tried a Wittig reaction using the methoxy-
methyltriphenylphosphonium chloride on aldehyde 20.11b,13
If we got the corresponding enolether 21 in 71% yield, all
our attempts to hydrolyse the enolether on 21 in the
presence of hydrogen fluoride in CH3CN or mild conditions
as oxalic acid in THF/H2O did not give the expected
carbaldehyde group on 22 (Scheme 5).
Treatment of iodo derivative 4 with ZnCl2 in ethanthiol at
2158C afforded diol-thioacetal 5 in 71% yield, which was
protected as disilyl ether 28 in 73% yield by use of
triethylsilyl chloride in pyridine at room temperature. The
introduction of the a chain of the isoprostane was achieved
by using as the three-carbon homologating agent (3,3-di-
isopropoxypropyl)triphenyl phosphonium bromide 30.19
The aldehyde 29 reacted with the ylide derived from this
phosphonium salt and NaHMDS to afford the pure cis-b-g-
ethylenic diisopropyl acetal 31 in 72% yield.
Finally, our last attempt was the full reduction of the methyl
The cyclization of 31 was achieved using Bu3SnH
(1.2 equiv.) and BEt3 (1 equiv.) in dry xylene at room
temperature, under a stream of air, to yield 72% of the
protected syn–anti–syn cyclopentane compound 32 and a
mixture of unseparated cyclopentane byproducts in 24%
yield. Finally, all our attempts to hydrolyse the diisopropyl
acetal on 32, with aqueous FeCl3 in acetone, or other acidic
conditions did not give the desired aldehyde 22, but only
different undesired byproducts (Scheme 8).
2.1. Structure determination of compound 3
1
We have shown that the NOE H NMR experiment is a
simple and efficient method for the determination of the
relative functional configuration of the tetrasubstituted
cyclopentane.13,20 Thus, the relative configuration in
Scheme 6.
Scheme 7.

T. Durand et al. / Tetrahedron 59 (2003) 2485–2495
2489
Scheme 8.
1
compound 3 was determined by homonuclear H steady-
state difference NOE spectroscopy (DNOES) experiments,
as shown in Figure 3. For compound 3 the relative cis
configuration of the protons 3-H, 5-H, 7-H, and 9-H was
determined by irradiation of 5-H, which induced NOEs of
1.5% on 3-H and 0.5% on 9-H, and by irradiation of 7-H,
which induced NOEs of 0.4% on 3-H and 1.6% on 9-H.
These observations allow one to check the relative syn
configuration of the side chains situated on C4 and C8, and
the relative anti configuration between the side chains and
the benzoyl groups situated on C5 and C7.
4. Experimental
4.1. General
Reagents were obtained from commercial suppliers and
were used as received, unless otherwise noted. All reactions
were conducted under nitrogen in distilled and dry solvents.
Methylene chloride (CH2Cl2) was distilled from CaH2. THF
and Et2O were distilled from sodium-benzophenone.
Pyridine was distilled from KOH. Xylene and MeOH
were distilled from Na. Acetone was dried with anhydrous
CaSO4. Reactions were monitored by thin-layer chroma-
tography (TLC) and judged complete when starting material
was no longer visible in the reaction mixture. Analytical
TLC was performed using precoated silicagel plates (Merck
silicagel, 0.25 mm, 60 F254) with p-anisaldehyde in ethanol
as indicator, and UV (254 nm) absorption. The extracts were
dried over anhydrous sodium sulfate and the solvent
removed under reduced pressure. The residue was purified
by flash silica gel chromatography with the eluting solvent
indicated. The structures of compounds were assigned on
the basis of their 1H NMR and 13C NMR spectra at 360 and
91 MHz, respectively, and by a combination of NMR
techniques which included 1H–1H COSY, HMBC and
HMQC. For unstable products, the NMR spectra were
obtained on Brucker 100 MHz.
Figure 3. Relative configuration observed by steady-state NOE difference
spectroscopy of compound 3.
3. Conclusion
´
In this study, we describe the first stereoselective synthesis
of 2,3,4,5-tetranor-15-oxo-5,6,13,14-tetrahydro-15F2t-isoP
methyl ester 1 in 17 steps and 20-carboxy-2,3,4,5-tetranor-
15-oxo-5,6,13,14-tetrahydro-15F2t-isoP dimethyl ester 2 in
18 steps from commercially available L-glucose. This route
allows the enantiospecific synthesis of two main urinary
metabolites of 15F2t-isoP which provides the basis for the
development of methods of assay for its quantification in
different fluids. Such studies are currently in progress.
4.1.1. (2S,4R,5R)-6-O-(tert-Butyldiphenylsilyl)-1,1-di-
ethylthio-5-iodo-hexan-2,4-diol (5). To the iodo derivative
4 (1 g, 1.81 mmol), in 5 mL of ethanethiol was added
anhydrous zinc chloride (0.98 g, 4.24 mmol) at 2208C.
After 0.5 h, the excess of ethanethiol was removed at 2208C
in vacuo. The foamy residue was deposed on a flash
chromatography column and was eluted (5–20% ethyl
acetate in cyclohexane). 0.79 g (71%) of 5 was obtained;
TLC Rf: 0.62 (cyclohexane/ethyl acetate, 7:3). IR (neat): n

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T. Durand et al. / Tetrahedron 59 (2003) 2485–2495
1
3465, 1732, 1425 cm21. H NMR (360 MHz, CDCl3): d
1.07 (9H, s, C(CH3)3), 1.19–1.34 (6H, m, CH3CH2S),
1.85–1.95 (1H, m, 3-H), 2.00–2.07 (1H, m, 30-H), 2.54–
2.80 (4H, m, CH3CH2S), 3.38 (2H, s, OH), 3.56–3.61 (1H,
m, 4-H), 3.80 (1H, d, J¼6.5 Hz, 1-H), 3.83–3.96 (1H, m,
2-H), 3.93–4.12 (2H, m, 6-H), 4.16–4.20 (1H, m, 5-H),
7.35–7.46 (6H, m, Ar-H), 7.64–7.75 (4H, m, Ar-H). 13C
H), 8.04–8.09 (2H, m, Ar-H), 9.60 (1H, s, CHO). 13C NMR
(91 MHz, CDCl3): d 15.3 (C(CH3)3), 26.6 (C(CH3)3), 34.8
(C-3), 36.0 (C-5), 65.7 (C-6), 68.0 (C-4), 75.6 (C-2), 127.6
(C-Ar), 127.8 (C-Ar), 128.5 (C-Ar), 129.8 (C-Ar), 129.9
(C-Ar), 130.0 (C-Ar), 132.4 (C-Ar), 132.7 (C-Ar), 133.4
(C-Ar), 133.6 (C-Ar), 135.5 (C-Ar), 165.1 (C(O)), 165.9
(C(O)), 197.2 (C-1).
NMR (91 MHz, CDCl3):
d 14.6 (CH3CH2S), 14.7
(CH3CH2S), 19.3 (C(CH3)3), 24.8 (CH3CH2S), 25.8
(CH3CH2S), 26.9 (C(CH3)3), 41.1 (C-3), 43.5 (C-5), 58.6
(C-1), 67.2 (C-6), 70.1 (C-4), 72.2 (C-2), 127.7 (C-Ar),
127.8 (C-Ar), 129.9 (C-Ar), 132.8 (C-Ar), 133.0 (C-Ar),
135.6 (C-Ar), 135.7 (C-Ar). Anal. calcd for C26H39IO3S2Si:
C, 50.47; H, 6.35. Found: C, 50.51; H, 6.33.
4.1.4. (5S,7R,8R)-9-O-(tert-Butyldiphenylsilyl)-5,7-di-O-
(benzoyl)-1-O-(tetrahydropyranyl)-8-iodo-3(Z)-nonene
(9). A 0.5 M toluene solution of KHMDS (604 mL,
314 mmol) was added to a suspension of 3-(tetrahydro-
pyranyl oxypropyl)triphenyl phosphonium bromide
(153 mg, 314 mmol) 8 in 1.6 mL of THF at 2808C. The
resulting orange solution of ylide was stirred 10 min. This
solution was added to aldehyde 7 solution in 1.6 mL of
THF. After slow warming to room temperature over 1 h, the
reaction mixture was hydrolyzed with 3 mL of water. The
aqueous layer was extracted with diethyl ether (3£3 mL),
and the combined extracts were washed with brine (5 mL).
All organic layers were dried with Na2SO4 and concen-
trated. The residue was purified by chromatography (10%
diethyl ether in cyclohexane) to give 76 mg (74%) of 9.
TLC Rf: 0.25 (cyclohexane/ethyl acetate, 9:1). IR (neat): n
4.1.2. (2S,4R,5R)-6-O-(tert-Butyldiphenylsilyl)-2,4-di-O-
(benzoyl)-1,1-diethylthio-5-iodo-hexane (6). To the diol 5
(400 mg, 647 mmol) in 5.5 mL of dry pyridine was added
benzoyl chloride (263 mL, 2.26 mmol). The reaction
mixture was stirred at room temperature overnight. The
pyridine was evaporated. The residue was purified by
chromatography (0–2% diethyl ether in cyclohexane) to
give 471 mg (88%) of 6. TLC Rf: 0,57 (cyclohexane/ethyl
acetate, 9:1). IR (neat): n 1721, 1451 cm21 1H NMR
.
1
(360 MHz, CDCl3): d 0.82 (9H, s, C(CH3)3), 1.19 (3H, t,
J¼7.5 Hz, CH3CH2S), 1.30 (3H, t, J¼7.5 Hz, CH3CH2S),
2.48–2.56 (1H,m, 3-H), 2.58–2.70 (1H, m, 30-H), 2.65 (2H,
q, J¼7.5 Hz, CH3CH2S), 2.77 (2H, q, J¼7.5 Hz,
CH3CH2S), 3.78–3.88 (2H, m, 6-H), 4.22 (1H, d, J¼
4.2 Hz, 1-H), 4.41–4.46 (1H, m, 5-H), 5.21 (1H, td, J¼2.5,
6.8 Hz, 4-H), 5.48 (1H, td, J¼4.2, 8.2 Hz, 2-H), 7.04 (2H, d,
J¼7.5 Hz, Ar-H), 7.15–7.24 (1H, m, Ar-H), 7.25–7.44 (7H,
m, Ar-H), 7.36–7.46 (2H, m, Ar-H), 7.43–7.58 (2H, m,
Ar-H), 7.50–7.60 (2H, m, Ar-H), 7.95–8.07 (4H, m, Ar-H).
13C NMR (91 MHz, CDCl3): d 14.4 (CH3CH2S), 14.6
(CH3CH2S), 18.9 (C(CH3)3), 26.1 (CH3CH2S), 26.2
(CH3CH2S), 26.4 (C(CH3)3), 36.5 (C-5), 36.6 (C-3), 53.9
(C-1), 65.7 (C-6), 68.7 (C-4), 72.9 (C-2), 127.5 (C-Ar),
127.8 (C-Ar), 128.4 (C-Ar), 129.6 (C-Ar), 129.7 (C-Ar),
129.8 (C-Ar), 130.0 (C-Ar), 132.5 (C-Ar), 132.7 (C-Ar),
133.1 (C-Ar), 135.4 (C-Ar), 135.5 (C-Ar), 165.2 (C(O)),
166.1 (C(O)). Anal. calcd for C40H47IO5S2Si: C, 58.10; H,
5.73 Found: C, 58.15; H, 5.74.
1720 cm21. H NMR (360 MHz, CDCl3): d 0.83 (9H, s,
C(CH3)3), 1.39–1.52 (1H, m, THP-H), 1.41–1.59 (2H, m,
THP-H), 1.49–1.60 (1H, m, THP-H), 1.60–1.73 (1H, m,
THP-H), 1.72–1.85 (1H, m, THP-H), 2.10–2.28 (1H, m,
6-H), 2.44–2.62 (1H, m, 60-H), 2.47–2.66 (2H, m, 2-H),
3.39–3.52 (1H0, m, 1-H), 3.40–3.52 (1H, m, THP-H), 3.71–
3.81 (1H, m, 1 -H), 3.76–3.87 (1H, m, THP-H), 3.81–3.90
(2H, m, 9-H), 4.48 (1H, ddd, J¼2.2, 6.5, 8.5 Hz, 8-H),
4.55–4.61 (1H, m, THP-H), 5.20–5.54 (2H, t, J¼6.5,
11.1 Hz, 4-H, 7-H), 5.64 (1H, td, J¼7.3, 11.1 Hz, 3-H), 5.91
(1H, ddd, J¼4.6, 9.0, 13.3 Hz, 5-H), 7.00–7.10 (2H, m,
Ar-H), 7.16–7.24 (1H, m, Ar-H), 7.26–7.47 (7H, m, Ar-H),
7.38–7.47 (2H, m, Ar-H), 7.45–7.61 (2H, m, Ar-H), 7.50–
7.60 (2H, m, Ar-H), 7.97–8.08 (4H, m, Ar-H). 13C NMR
(91 MHz, CDCl3): d 18.9 (C(CH3)3), 19.4 (C-THP), 25.5
(C-THP), 26.5 (C(CH3)3), 28.6 (C-2), 30.6 (C-THP), 36.6
(C-8), 39.7 (C-6), 62.1 (C-THP), 65.7 (C-9), 66.5 (C-1),
67.8 (C-5), 68.7 (C-7), 98.6 (C-THP), 127.6 (C-3), 127.7
(C-Ar), 128.3 (C-Ar), 128.4 (C-Ar), 128.5 (C-Ar), 129.6
(C-Ar), 129.8 (C-Ar), 130.1 (C-Ar), 131.4 (C-4), 132.5
(C-Ar), 132.9 (C-Ar), 133.1 (C-Ar), 135.4 (C-Ar), 135.5
(C-Ar), 165.1 (C(O)). Anal. calcd for C44H51IO7Si: C,
62.40; H, 6.07. Found: C, 62.44; H, 6.02.
4.1.3. (2S,4R,5R)-6-O-(tert-Butyldiphenylsilyl)-2,4-di-O-
(benzoyl)-5-iodo-hexanal (7). To the thioacetal 6 (100 mg,
2 mmol) in 4.6/0.46 mL of acetone/water, was added
mercuric oxide (243 mg, 1.12 mmol) and mercuric chloride
(105 mg, 387 mmol). The heterogeneous mixture was
refluxed overnight. 4 mL of saturated sodium bicarbonate
solution was added. The mixture was filtered through Celite,
extracted with 3£10 mL of methylene chloride. The organic
layers were washed with 3£5 mL of potassium iodide
solution and with 5 mL of brine. The extracts were dried
over Na2SO4 and evaporated. 87 mg (100%) of aldehyde 7
was obtained. TLC Rf: 0.82 (cyclohexane/ethyl acetate,
7:3). IR (neat): n 1722 cm21. 1H NMR (360 MHz, CDCl3):
d 0.94 (9H, s, C(CH3)3), 2.44–2.51 (1H, m, 3-H), 2.57–2.66
(1H, m, 30-H), 3.43–3.50 (2H, m, 6-H), 4.32 (1H, ddd,
J¼2.5, 5.8, 8.6 Hz, 5-H), 5.36–5.44 (2H, m, 2-H), 5.37–
5.47 (2H, m, 4-H), 7.12 (2H, q, J¼7.5 Hz, Ar-H), 7.22–7.27
(1H, m, Ar-H), 7.28–7.45 (7H, m, Ar-H), 7.46–7.50 (2H,
m, Ar-H), 7.51–7.61 (4H, m, Ar-H), 7.93–8.02 (2H, m, Ar-
4.1.5. Methyl (5S,7R,8R)-9-O-(tert-butyldiphenylsilyl)-
5,7-di-O-(benzoyl)-8-iodo-non-3(Z)-enoate (10). To a
stirred solution of 9 (500 mg, 0.59 mmol) in 12 mL of
freshly distilled acetone at 2108C was added Jones reagent
(1.15 mL, 2.95 mmol, 2.17 M). After slow warming to room
temperature over 2 h, the reaction was terminated using
propan-2-ol. The solution was filtered on Celite. 10 mL of
water was added and the aqueous phase was extracted with
3£10 mL of ethyl acetate. The organic layers were washed
with 10 mL of brine, dried with Na2SO4 and concentrated in
vacuo. An etheral solution of diazomethane was added.
After concentration, flash chromatography over silica gel
(cyclohexane/diethyl ether, 95:5), 401 mg of 10 was
obtained (86%). TLC Rf: 0.52 (cyclohexane/ethyl acetate,
8:2). IR (neat): n 1718 cm21. 1H NMR (360 MHz, CDCl3):

T. Durand et al. / Tetrahedron 59 (2003) 2485–2495
2491
d 0.84 (9H, s, C(CH3)3), 2.17 (1H,ddd, J¼4.8, 6.6, 14.4 Hz,
6-H), 2.5 (1H, ddd, J¼6.6, 8.9, 14.4 Hz, 6-H), 3.39 (2H, dt,
J¼1.8, 7.1 Hz, 2-H), 3.66 (3H, s, OCH3), 3.80–3.89 (2H, m,
9-H), 4.41 (1H, ddd, J¼2.1, 6.1, 8.6 Hz, 8-H), 5.20 (1H, td,
J¼2.1, 6.6 Hz, 7-H), 5.60 (1H, ddt, J¼1.8, 8.9, 10.8 Hz,
4-H), 5.78 (1H, td, J¼4.8, 8.9 Hz, 5-H), 5.86 (1H, dt, J¼7.1,
10.7 Hz, 3-H), 7.05 (2H, t, J¼7.3 Hz, Ar-H), 7.21 (1H, tt,
J¼1.5, 7.3 Hz, Ar-H), 7.27–7.35 (2H, m, Ar-H), 7.31–7.38
(2H, m, Ar-H), 7.28–7.39 (1H, m, Ar-H), 7.38–7.45 (2H,
m, Ar-H), 7.40–7.45 (2H, m, Ar-H), 7.49 (1H, tt, J¼1.5,
7.3 Hz, Ar-H), 7.52–7.57 (2H, m, Ar-H), 7.53–7.59 (1H,
m, Ar-H), 7.98–8.03 (2H, m, Ar-H), 7.99–8.04 (2H, m,
Ar-H). 13C NMR (91 MHz, CDCl3): d 18.9 (C(CH3)3), 26.4
(C(CH3)3), 33.1 (C-2), 36.6 (C-8), 39.6 (C-6), 51.9 (OCH3),
65.6 (C-9), 67.6 (C-5), 68.4 (C-7), 126.4 (C-3), 127.5
(C-Ar), 127.7 (C-Ar), 128.3 (C-Ar), 128.4 (C-Ar), 129.6
(C-Ar), 129.7 (C-Ar), 129.8 (C-Ar), 129.9 (C-4), 132.4
(C-Ar), 132.7 (C-Ar), 132.9 (C-Ar), 133.2 (C-Ar), 135.4
(C-Ar), 135.5 (C-Ar), 165.1 (C(O)), 165.6 (C(O)), 171.3
(C-1). Anal. calcd for C40H43IO7Si: C, 60.76; H, 5.48.
Found: C, 60.80; H, 5.50.
crude material. Flash chromatography over silica gel
(cyclohexane/ethyl acetate, 7:3) gave 216 mg of 11 (68%).
TLC Rf: 0.51 (cyclohexane/ethyl acetate, 1:1). IR (neat): n
1
3525, 1715 cm21. H NMR (360 MHz, CDCl3): d 1.57–
1.72 (1H, m, 3-H), 1.87–1.96 (1H, m, 30-H), 2.01 (1H, ddd,
J¼3.7, 7.5, 15.4 Hz, 6-H), 2.32 (1H, s, OH), 2.49 (2H, t,
J¼7.5 Hz, 2-H), 2.48–2.60 (1H, m, 4-H), 2.58–2.69 (1H,
m, 8-H), 2.92 (1H, dt, J¼7.5, 15.4 Hz, 60-H), 3.63 (3H, s,
OCH3), 3.72–3.80 (1H, m, 9-H), 3.85–3.92 (1H, m, 90-H),
5.21 (1H, ddd, J¼4.2, 5.3, 7.5 Hz, 5-H), 5.34 (1H, td, J¼3.7,
7.5 Hz, 7-H), 7.38–7.45 (4H, m, Ar-H), 7.52–7.58 (2H, m,
Ar-H), 7.99–8.05 (4H, m, Ar-H). 13C NMR (91 MHz,
CDCl3): d 22.6 (C-3), 32.5 (C-2), 38.0 (C-6), 45.2 (C-4),
49.2 (C-8), 51.7 (OCH3), 60.7 (C-9), 76.9 (C-7), 78.6 (C-5),
128.4 (C-Ar), 129.6 (C-Ar), 130.1 (C-Ar), 130.2 (C-Ar),
133.0 (C-Ar), 133.1 (C-Ar), 166.1 (C(O)), 166.7 (C(O)),
173.8 (C-1). Anal. calcd for C24H26O7: C, 67.59; H, 6.15.
Found: C, 67.60; H, 6.22.
4.1.8. (1R,2S,3S,4S)-1,4-Di-O-(benzoyl)-2-formyl-3-
(methoxycarbonylethyl) cyclopentane (12). To a solution
of 11 (108 mg, 0.253 mmol) in 18 mL of CH2Cl2 and 14 mL
of water at room temperature was added Dess–Martin
periodinane (322 mg, 0.76 mmol). The reaction mixture
was stirred for 30 min. The mixture was washed with a
solution of 1/1 NaHCO3 (10%)/Na2S2O3 (10%) (3£5 mL).
The aqueous layers were extracted with diethyl ether
(3£6 mL). The organic layer was washed with 6 mL of
brine, dried over Na2SO4 and concentrated. The crude
material 12 was used immediately for the next step. TLC Rf:
4.1.6. (1R,2S,3S,4S)-2-tert-Butyldiphenylsilyloxy methyl-
1,4-di-O-(benzoyl)-3-(methoxycarbonylethyl) cyclopen-
tane (3). To a solution of 10 (250 mg, 316 mmol) in 5 mL
of p-xylene was added tributyltin hydride (102 mL,
380 mmol) under a stream of dry argon. At room
temperature,
a 1N triethyl borane solution (63 mL,
63 mmol) was added under a stream of dry air. The mixture
was stirred 40 min. The solvent was removed and the
mixture was subjected to flash chromatography (0–10%
diethyl ether in cyclohexane) to give 151 mg (72%) of 3.
TLC Rf: 0.5 (cyclohexane/ethyl acetate, 8:2). IR (neat): n
1
0.7 (cyclohexane/ethyl acetate, 1:1). H NMR (100 MHz,
CDCl3): d 1.53–2.23 (3H, m, 3-H, 6-H), 2.37–3.06 (5H, m,
2-H, 4-H, 8-H, 60-H), 3.56 (3H, s, OCH3), 5.00–5.76 (2H,
m, 5-H, 7-H), 7.23–7.63 (6H, m, Ar-H), 7.83–8.01 (4H, m,
Ar-H), 9.93 (1H, s, 9-H).
1
1715 cm21. H NMR (360 MHz, CDCl3): d 1.09 (9H, s,
C(CH3)3), 1.70–1.85 (2H, m, 3-H), 1.90 (1H, dq, J¼2.8,
15.7 Hz, 6-H), 2.37 (2H, t, J¼8.6 Hz, 2-H), 2.49–2.59 (1H,
m, 8-H), 2.54–2.64 (1H, m, 4-H), 2.95 (1H, dt, J¼7.4,
15.7 Hz, 60-H), 3.60 (3H, s, OCH3), 3.70 (1H, dd, J¼5.1,
11.1 Hz, 9-H), 3.86 (1H, dd, J¼5.1, 11.1 Hz, 90-H), 5.31
(1H, m, 5-H), 5.40 (1H, dt, J¼2.8, 7.4 Hz, 1H, 7-H), 7.31–
7.38 (4H, m, Ar-H), 7.35–7.45 (2H, m, Ar-H), 7.36–7.45
(4H, m, Ar-H), 7.49–7.57 (2H, m, Ar-H), 7.63–7.71 (4H,
m, Ar-H), 7.95–8.06 (4H, m, Ar-H). 13C NMR (91 MHz,
CDCl3): d 19.1 (C(CH3)3), 23.2 (C-3), 26.9 (C(CH3)3), 32.7
(C-2), 38.8 (C-6), 45.0 (C-4), 48.8 (C-8), 51.5 (OCH3), 61.7
(C-9), 77.4 (C-7), 79.2 (C-5), 127.8 (C-Ar), 128.3 (C-Ar),
129.6 (C-Ar), 129.8 (C-Ar), 130.3 (C-Ar), 132.9 (C-Ar),
132.9 (C-Ar), 135.6 (C-Ar), 135.6 (C-Ar), 135.7 (C-Ar),
166.0 (C(O)), 166.1 (C(O)), 173.4 (C-1). Anal. calcd for
C40H44O7Si: C, 72.26; H, 6.67. Found: C, 72.24; H, 6.68.
[a]2D0¼þ11.5 (c¼1023, MeOH).
4.1.9. (1R,2S,3S,4S)-1,4-Di-O-(benzoyl)-3-(methoxy-
carbonyl ethyl)-2-((E) 3-oxo-oct-1-enyl) cyclo pentane
(14) and (1R,2S)-1-O-(benzoyl)-2-(2-methoxycarbonyl-
ethyl)-3-(methoxycarbonyl-3-oxo-oct-1E-enyl) cyclo-
pent-3E-ene (15). To a solution of 12 (0.253 mol) in
2 mL of THF was added dropwise a solution of ylide
prepared at room temperature from diethyl 2-oxoheptyl-
phosphonate (145 mL, 0.696 mmol) and NaH (10 mg,
0.633 mmol, 60% in oil) in 2 mL of THF. The reaction
was stirred for 10 min, neutralized with saturated NH4Cl
(2 mL) and extracted with diethyl ether (3£5 mL). The
organic layers were washed with brine (5 mL), dried with
Na2SO4 and evaporated in vacuo. The crude material was
purified by flash chromatography on silica gel (cyclo-
hexane/ethyl acetate, 8:2) to give 84 mg of 14 (64% in two
steps) and 9.1 mg of 15 (9% in two steps).
4.1.7. (1R,2S,3S,4S)-1,4-Di-O-(benzoyl)-2-hydroxy-
methyl-3-(methoxycarbonylethyl) cyclopentane (11).
Acetyl chloride (1 mL) was added dropwise to methanol
(17 mL), and the hydrogen chloride solution obtained was
cooled to 208C. A solution of 3 (500 mg, 0.8 mmol) in
freshly distilled diethyl ether (17 mL) was added and the
mixture was stirred at room temperature for 20 h. Then
neutralized with saturated NaHCO3. The aqueous layer was
extracted with ethyl acetate (3£10 mL), and the combined
extracts were washed with brine (10 mL). All organic
solution were dried with Na2SO4 and concentrated, giving a
Compound 14. TLC Rf: 0.79 (cyclohexane/ethyl acetate,
1:1). IR (neat): n 1717 cm21. 1H NMR (360 MHz, CDCl3):
d 0.87 (3H, t, J¼7.0 Hz, 16-H), 1.21–1.33 (2H, m, 14-H),
1.25–1.35 (2H, m, 15-H), 1.55–1.64 (2H, m, 13-H), 1.66–
1.85 (2H, m, 3-H), 2.03 (1H, ddd, J¼3.2, 6.5, 15.4 Hz, 6-H),
2.40–2.46 (2H, m, 2-H), 2.53 (2H, t, J¼7.5 Hz, 12-H),
2.59–2.68 (1H, m, 4-H), 2.98 (1H, td, J¼7.5, 15.4 Hz,
60-H), 3.23–3.29 (1H, m, 8-H), 3.61 (3H, s, OCH3), 5.21–
5.27 (1H, m, 5-H), 5.28–5.33 (1H, m, 7-H), 6.29 (1H, dd,
J¼0.8, 15.7 Hz, 10-H), 6.70 (1H, dd, J¼9.1, 15.8 Hz, 9-H),

2492
T. Durand et al. / Tetrahedron 59 (2003) 2485–2495
7.39–7.45 (4H, m, Ar-H), 7.45–7.58 (2H, m, Ar-H), 7.98–
8.04 (4H, m, Ar-H). 13C NMR (91 MHz, CDCl3): d 13.9
(C-16), 22.4 (C-15), 23.7 (C-13), 23.8 (C-3), 31.4 (C-14),
32.2 (C-2), 38.0 (C-6), 41.0 (C-12), 47.0 (C-4), 50.3 (C-8),
51.6 (OCH3), 77.3 (C-7), 78.0 (C-5), 128.4 (C-Ar), 129.6
(C-Ar), 129.9 (C-Ar), 130.0 (C-Ar), 132.8 (C-10), 133.2
(C-Ar), 140.9 (C-9), 165.9 (C(O)), 166.1 (C(O)), 173.2
(C-1), 199.8 (C-11). Anal. calcd for C31H36O7: C, 71.52; H,
6.97. Found: C, 71.55; H, 6.93.
crude product was purified by flash chromatography on
silica gel (cyclohexane/ethyl acetate, 1:1) to give 18.8 mg of
1 (83%). TLC Rf: 0.34 (ethyl acetate/acetic acid, 19:1). IR
(neat): n 3415, 1736, 1712 cm21 1H NMR (360 MHz,
.
CDCl3): d 0.87 (3H, t, J¼0.9 Hz, 16-H), 1.16–1.30 (2H, m,
14-H), 1.22–1.32 (2H, m, 15-H), 1.32–1.45 (1H, m, 9-H),
1.36–1.49 (1H, m, 3-H), 1.52–1.61 (1H, m, 6-H), 1.50–
1.60 (2H,0 m, 13-H), 1.59–1.72 (1H, m, 90-H), 1.66–1.79
(1H, m, 3 -H). 1.95–2.03 (1H, m, 4-H), 1.98–2.07 (1H, m,
8-H), 2.33–2.44 (3H, m, 60-H, 12-H), 2.35–2.43 (2H, m,
2-H), 2.49 (2H, dd, J¼7.3, 7.8 Hz, 10-H), 3.65 (3H, s,
OCH3), 3.87–3.93 (1H, m, 5-H), 3.91–3.97 (1H, m, 7-H).
13C NMR (91 MHz, CDCl3): d 13.9 (C-16), 21.7 (C-9), 22.4
(C-15), 23.1 (C-3), 23.5 (C-13), 31.4 (C-14), 32.7 (C-2),
41.1 (C-10), 42.9 (C-12), 42.9 (C-6), 48.9 (C-8), 49.0 (C-4),
51.6 (OCH3), 76.0 (C-7), 76.3 (C-5), 174.0 (C-1), 211.3
(C-11). Anal. calcd for C17H30O5: C, 64.97; H, 9.61. Found:
C, 64.97; H, 9.61. [a]2D0¼þ1.34 (c¼1023, MeOH).
Compound 15. TLC Rf: 0.85 (cyclohexane/ethyl acetate,
1:1). 1H NMR (360 MHz, CDCl3): d 0.87 (3H, t, J¼7.0 Hz,
16-H), 1.21–1.33 (2H, m, 14-H), 1.25–1.35 (2H, m, 15-H),
1.43–1.66 (3H, m, 3-H, 13-H), 2.01–2.12 (1H, m, 30-H),
2.40–2.73 (5H, m, 2-H, 6-H, 12-H), 2.86–3.00 (2H, m, 4-H,
60-H), 3.67 (3H, s, OCH3), 5.28–5.37 (1H, m, 5-H), 6.18–
6.20 (1H, m, 7-H), 6.27 (1H, d, J¼16.1 Hz, 10-H), 7.28 (1H,
d, J¼16.1 Hz, 9-H), 7.35–7.47 (2H, m, Ar-H), 7.49–7.53
(1H, m, Ar-H), 7.92–8.11 (2H, m, Ar-H). 13C NMR
(91 MHz, CDCl3): d 13.9 (C-16), 22.5 (C-15), 23.9 (C-13),
25.4 (C-3), 31.4 (C-2), 31.4 (C-14), 39.0 (C-6), 41.1 (C-12),
50.4 (C-4), 51.6 (OCH3), 78.8 (C-5), 127.2 (C-10), 128.3
(C-Ar), 129.6 (C-Ar), 130.2 (C-Ar), 133.0 (C-Ar), 136.4
(C-9), 137.3 (C-7), 143.0 (C-8), 166.2 (C(O)), 173.6 (C-1),
200.9 (C-11). Anal. calcd for C24H30O5: C, 72.34; H, 7.59.
Found: C, 72.40; H,7.63.
4.1.12. (1R,2S,3S,4S)-1,4-Di-O-(benzoyl)-3-(methoxy
carbonylethyl)-2-(methoxycarbonyl-3-oxo-oct-1E-enyl)
cyclopentane (18). To a solution of 12 (0.513 mol) in 4 mL
of THF was added dropwise a solution of ylide prepared at
room temperature from dimethyl [6 (methoxycarbonyl)-2-
oxohexyl] phosphonate (415 mL, 1.41 mmol) and NaH
(51 mg, 1.27 mmol, 60% in oil) in 4 mL of THF. The
reaction was stirred for 10 min, neutralized with saturated
NH4Cl (2 mL) and extracted with diethyl ether (3£2 mL).
The organic layers were washed with brine (2 mL), dried
with Na2SO4 and evaporated in vacuo. The crude material
was purified by flash chromatography on silica gel
(cyclohexane/ethyl acetate, 8:2) to give 258 mg of 18
(89% in two steps. TLC Rf: 0.68 (cyclohexane/ethyl acetate,
4.1.10. (1R,2S,3S,4S)-1,4-Di-O-(benzoyl)-3-(methoxycar-
bonylethyl)-2-(3-oxo-octanyl) cyclopentane (16). A mix-
ture of 14 (70 mg, 134 mmol) and 10% Pd/C (6 mg) in
absolute ethanol (2.7 mL) was hydrogenated at atmospheric
pressure for 4 h. The mixture was filtered through celite and
washed with ethyl acetate. The organic layer was concen-
trated to provide 70 mg of 16 (100%). TLC Rf: 0.79
(cyclohexane/ethyl acetate, 1:1). IR (neat): n 1735,
1
1:1). IR (neat): n 1733, 1710 cm21. H NMR (360 MHz,
CDCl3): d 1.58–1.69 (4H, m, 13-H, 14-H), 1.75–1.83 (2H,
m, 3-H), 2.03 (1H, td, J¼3.5, 15.9 Hz, 6-H), 2.32 (2H, t,
J¼7.1 Hz, 15-H), 2.35–2.52 (2H, m, 2-H), 2.56 (2H, t,
J¼7.1 Hz, 12-H), 2.57–2.68 (1H, m, 4-H), 2.98 (1H, td,
J¼7.5, 15.9 Hz, 60-H), 3.22–3.30 (1H, m, 8-H), 3.61 (3H, s,
OCH3), 3.64 (3H, s, OCH3), 5.24 (1H, ddd, J¼3.5, 5.3,
8.8 Hz, 5-H), 5.30 (1H, td, J¼3.5, 7.5 Hz, 7-H), 6.29 (1H,
dd, J¼1.0, 15.8 Hz, 10-H), 6.72 (1H, dd, J¼9.1, 15.8 Hz, 9-
H), 7.38–7.45 (4H, m, Ar-H), 7.52–7.58 (2H, m, Ar-H),
7.98–8.05 (4H, m, Ar-H). 13C NMR (91 MHz, CDCl3): d
23.3 (C-13), 23.8 (C-3), 24.5 (C-14), 32.2 (C-2), 33.8
(C-15), 38.0 (C-6), 40.5 (C-12), 47.1 (C-4), 50.3 (C-8), 51.5
(OCH3), 51.6 (OCH3), 77.3 (C-7), 78.0 (C-5), 128.4 (C-Ar),
129.6 (C-Ar), 129.9 (C-Ar), 130.0 (C-Ar), 132.6 (C-10),
133.2 (C-Ar), 141.3 (C-9), 165.9 (C(O)), 166.1 (C(O)),
173.2 (C-1), 173.8 (C-16), 199.0 (C-11). Anal. calcd for
C32H36O9: C, 68.07; H, 6.43. Found: C, 68.10; H, 6.45.
1
1715 cm21. H NMR (360 MHz, CDCl3): d 0.85 (3H, t,
J¼6.9 Hz, 16-H), 1.16–1.28 (2H, m, 14-H), 1.21–1.33 (2H,
m, 15-H), 1.40–1.51 (1H, m, 9-H), 1.49–1.60 (2H, m, 13-
H), 1.60–1.72 (1H, m, 3-H), 1.78–1.90 (1H, m, 90-H),
1.82–1.94 (1H, m, 30-H), 1.83–1.98 (1H, m, 6-H), 2.30–
2.41 (1H, m, 8-H), 2.34–2.45 (2H, m, 12-H), 2.41–2.51
(1H, m, 4-H), 2.42–2.58 (2H, m, 2-H), 2.53–2.69 (2H, m,
10-H), 2.91 (1H, td, J¼7.6, 15.6 Hz, 60-H), 3.62 (3H, s,
OCH3), 5.10–5.16 (1H, m, 7-H), 5.11–5.18 (1H, m, 5-H),
7.38–7.46 (4H, m, Ar-H), 7.50–7.58 (2H, m, Ar-H), 7.98–
8.06 (4H, m, Ar-H). 13C NMR (91 MHz, CDCl3): d 13.9
(C-16), 20.6 (C-9), 22.4 (C-15), 22.6 (C-3), 23.5 (C-13),
29.7 (C-14), 31.9 (C-2), 37.7 (C-6), 40.4 (C-10), 43.0
(C-12), 45.8 (C-4. C-8), 51.6 (OCH3), 78.2 (C-7), 78.4
(C-5), 128.4 (C-Ar), 129.6 (C-Ar), 130.2 (C-Ar), 133.0
(C-Ar), 166.2 (C(O)), 173.6 (C-1), 210.5 (C-11). Anal. calcd
for C31H38O7: C, 71.24, H, 7.34. Found: C, 71.30, H, 7.30.
4.1.13. (1R,2S,3S,4S)-1,4-Di-O-(benzoyl)-3-(methoxycar-
bonylethyl)-2-(methoxycarbonyl-3-oxo-octanyl) cyclo-
pentane (19). A mixture of 18 (20 mg, 35 mmol) and
10% Pd/C (1.6 mg) in absolute ethanol (0.7 mL) was
hydrogenated at atmospheric pressure for 4 h. The mixture
was filtered through celite and washed with ethyl acetate.
The organic layer was concentrated to provide 20 mg of 19
(100%). TLC Rf: 0.68 (cyclohexane/ethyl acetate, 1:1). IR
(neat): n 1733, 1710 cm21. 1H NMR (360 MHz, CDCl3): d
1.39–1.51 (1H, m, 9-H), 1.52–1.62 (4H, m, 13-H, 14-H),
1.62–1.73 (1H, m, 3-H), 1.77–1.89 (1H, m, 90-H),
4.1.11. 2,3,4,5-Tetranor-15-oxo-5,6,13,14-tetrahydro-
15F2t-isoP methyl ester (1). To the solution of 16
(38 mg, 72 mmol) in 580 mL of methanol and 380 mL of
THF was added 1N solution of NaOH (670 mL). The
mixture was stirred 2 h at 408C. 1N solution of NaHSO4
(710 mL) was then added for neutralization. The reaction
was diluted in water (1 mL) and extracted with ethyl acetate
(3£5 mL). The organic layers were dried with Na2SO4 and
evaporated. The residue was esterified with an etheral
solution of diazomethane. After evaporation of solvents, the

T. Durand et al. / Tetrahedron 59 (2003) 2485–2495
2493
1.80–1.92 (1H, m, 30-H), 1.83–1.98 (1H, m, 6-H), 2.22–
2.34 (2H, m, 15-H), 2.29–2.40 (1H, m, 8-H), 2.37–2.48
(2H, m, 12-H), 2.40–2.50 (1H, m, 4-H), 2.41–2.56 (2H, m,
2-H), 2.52–2.70 (2H, m, 10-H), 2.90 (1H, td, J¼7.6,
15.6 Hz, 60-H), 3.62 (3H, s, OCH3), 3.63 (3H, s, OCH3),
5.09–5.14 (1H, m, 7-H), 5.10–5.17 (1H, m, 5-H), 7.38–
7.45 (4H, m, Ar-H), 7.51–7,58 (2H, m, Ar-H), 7.98–8.05
(4H, m, Ar-H). 13C NMR (91 MHz, CDCl3): d 20.5 (C-9),
22.6 (C-3), 23.2 (C-13), 24.4 (C-14), 32.2 (C-2), 33.8 (C-
15), 37.6 (C-6), 40.4 (C-10), 42.5 (C-12), 45.7 (C-8), 45.8
(C-4), 51.5 (OCH3), 51.6 (OCH3), 78.1 (C-7), 78.3 (C-5),
128.4 (C-Ar), 129.6 (C-Ar), 130.2 (C-Ar), 133.0 (C-Ar),
166.2 (C(O)), 173.6 (C-16), 173.8 (C-1), 209.7 (C-11).
Anal. calcd for C32H38O9: C, 67.83; H, 6.76. Found: C,
67.90; H, 6.74.
1.90–2.60 (6H, m, 2-H, 3-H, 5-H, 7-H), 3.25–3.70 (5H, m,
6-H, OCH3), 3.80–4.40 (2H, m, 1-H, 4-H), 4.45–4.80 (1H,
m, 8-H), 6.06 (1H, d, J¼12.5 Hz, 9-H), 7.25–7.50 (6H, m,
Ar-H), 7.55–7.70 (4H, m, Ar-H). 13C NMR (25 MHz,
CDCl3): d 4.7 (SiCH2CH3), 4.9 (SiCH2CH3), 6.6 (SiCH2-
CH3), 19.1 (C(CH3)3), 26.9 (C(CH3)3), 48,6 (C-3 or C-7),
45.2 (C-3 or C-7), 50.4 (C-2), 59.2 (OCH3), 62.4 (C-6), 73.2
(C-1), 76.2 (C-4), 102.0 (C-8), 127.6 (C-Ar), 129.7 (C-Ar),
133.2 (C-Ar), 135.7 (C-Ar), 147.1 (C-9).
Z Isomer. 1H NMR (100 MHz, CDCl3): d 0.30–0.70 (12H,
m, SiCH2CH3), 0.70–1.00 (18H, m, 1.00 (9H, s, C(CH3)3),
1.90–2.60 (6H, m, 2-H, 3-H, 5-H, 7-H), 3.25–3.70 (5H, m,
6-H, OCH3), 3.80–4.40 (2H, m, 1-H, 4-H), 4.45–4.80 (1H,
m, 8-H), 5.80 (1H, d, J¼5.7 Hz, 9-H), 7.25–7.50 (6H, m,
Ar-H), 7.55–7.70 (4H, m, Ar-H). 13C NMR (25 MHz,
CDCl3): d 4.7 (SiCH2CH3), 4.9 (SiCH2CH3), 6.6 (SiCH2
CH3), 19.1 (C(CH3)3), 26.9 (C(CH3)3), 48,6 (C-3 or C-7),
45.2 (C-3 or C-7), 50.4 (C-2), 59.2 (OCH3), 62.4 (C-6), 72.3
(C-1), 76.5 (C-4), 105.9 (C-8), 127.6 (C-Ar), 129.7 (C-Ar),
133.2 (C-Ar), 135.7 (C-Ar), 146.2 (C-9). Anal. calcd for
C38H64O4Si3: C, 88.20; H, 9.64. Found: C, 88.24; H, 9.59.
4.1.14. 20-Carboxy-2,3,4,5-tetranor-15-oxo-5,6,13,14-
tetrahydro-15F2t-isoP dimethyl ester (2). To the solution
of 19 (38 mg, 67 mmol) in 580 mL of methanol and 380 mL
of THF was added 1N solution of NaOH (890 mL). The
mixture was stirred 2 h at 408C. 1N solution of NaHSO4
(945 mL) was then added for neutralization. The reaction
was diluted in water (1 mL) and extracted with ethyl acetate
(3£5 mL). The organic layers were dried with Na2SO4 and
evaporated. The residue was esterified with an etheral
solution of diazomethan. After evaporation of solvents, the
crude product was purified by flash chromatography on
silica gel (cyclohexane/ethyl acetate, 2:3) to give 20 mg of 2
(83%). TLC Rf: 0.46 (ethyl acetate/acetic acid, 19:1). IR
4.1.16. (1S,2R,3R,4R)-3-(Hydroxyethyl)-2-(tert-butyldi-
phenylsilyloxymethyl)-1,4-di-O-(triethylsilyl) cyclopen-
tane(23). To the (1S,2R,3R,4R)-3-(carbomethoxymethyl)-
2-(tert-butyldiphenylsilyloxymethyl)-1,4-di-O-(triethylsilyl)-
cyclopentane (544 mg, 0.81 mmol) in 1.2 mL of toluene,
was added 2 M THF solution of LiBH4 (446 mL,
0.89 mmol) at room temperature. The mixture was refluxed
3 h, and 3 mL of water were added. The solution was
neutralized with 2 M HCl solution and stirred 30 min. The
aqueous layer was saturated with K2CO3 and extract with
diethyl ether (3£5 mL). The organic layer was dried with
Na2SO4 and concentrated. The residue was purified by
chromatography (5–20% ethyl acetate in heptane) to give
494 mg of 23 (95%). TLC Rf: 0.65 (heptane/ethyl acetate,
70:30). IR (neat) 3370 cm21. 1H NMR (360 MHz, CDCl3):
d 0.45–0.63 (12H, m, SiCH2CH3), 0.85–0.97 (18H, m,
SiCH2CH3), 1.05 (9H, s, C(CH3)3), 1.50–1.73 (3H, m, 5-H,
7-H), 2.00 (1H, m, 2-H), 2.24–2.39 (2H, m, 50-H, 3-H), 2.75
(1H, bs, OH), 3.56–3.70 (4H, m, 6-H, 8-H), 4.00 (1H, q,
J¼8.6 Hz, 4-H), 4.10–4.12 (1H, m, 1-H), 7.24–7.42 (6H,
m, Ar-H), 7.61–7.64 (4H, m, Ar-H). 13C NMR (91 MHz,
CDCl3): d 4.7 (SiCH2CH3), 5.0 (SiCH2CH3), 6.8 (SiCH2-
CH3), 19.1 (C(CH3)3), 26.9 (C(CH3)3), 31.8 (C-7), 44.9
(C-5), 45.7 (C-3), 52.1 (C-2), 62.4, 62.6 (C-6 and C-8), 73.3
(C-1), 77.5 (C-4), 127.7 (C-Ar), 129.7 (C-Ar), 133.2 (C-Ar),
135.7 (C-Ar). Anal. calcd for C36H62O4Si3: C, 67.23; H,
9.72. Found: C, 67.21; H, 9.75.
(neat): n 3409, 1732, 1713 cm21 1H NMR (360 MHz,
.
CDCl3): d 1.31–1.44 (1H, m, 9-H), 1.35–1.48 (1H, m,
3-H), 1.51–1.60 (1H, m, 6-H), 1.53–1.60 (2H, m, 13-H),
1.54–1.64 (2H, m, 14-H), 1.59–1.71 (1H, m, 90-H), 1.65–
1.77 (1H, m, 30-H), 1.94–2.02 (1H, m, 4-H), 1.97–2.05 (1H,
m, 8-H), 2.29 (2H, t, J¼7.1 Hz, 15-H), 2.32–2.43 (3H, m,
2-H, 60-H), 2.35–2.44 (2H, m, 12-H), 2.49 (2H, t, J¼7.3 Hz,
10-H), 3.64 (3H, s, OCH3), 3.65 (3H, s, OCH3), 3.85–3.91
(1H, m, 5-H), 3.90–3.95 (1H, m, 7-H). 13C NMR (91 MHz,
CDCl3): d 21.6 (C-9), 23.1 (C-13), 23.2 (C-3), 24.4 (C-14),
32.7 (C-2), 33.8 (C-15), 41.1 (C-10), 42.4 (C-12), 42.9
(C-6), 48.8 (C-8), 48.9 (C-4), 51.5 (OCH3), 51.6 (OCH3),
76.0 (C-7), 76.2 (C-5), 173.9 (C-16), 174.0 (C-1), 210.5
(C-11). Anal. calcd for C32H36O9: C, 60.32; H, 8.44. Found:
C, 60.35; H, 8.42. [a]2D0¼þ1.13 (c¼1023, MeOH).
4.1.15. (1S,2R,3R,4R)-3-(30-Methoxyprop-20(E,Z)-enyl)-
2-(tert-butyldiphenylsilyloxymethyl)-1,4-di-O-(triethyl-
silyl) cyclopentane(21). A solution of tBuOK (44 mg,
0.4 mmol) in 1.2 mL of THF at 08C was added to
a suspension of (methoxymethyl)triphenylphosphonium
chloride (135 mg, 0.394 mmol) in 0.3 mL of THF at 08C.
The solution became red. The ylide was stirred 10 min and
added to a solution of aldehyde11b,13 (84 mg, 0.13 mmol) in
0.25 mL of THF at 08C. After 30 min, 0.9 mL of brine was
added. The mixture was extracted with diethyl ether
(3£5 mL). The organic layers were dried and evaporated
under reduce pressure. The residue was purified by
chromatography on silica gel (0–2% of ethyl acetate in
cyclohexane) to give 62 mg of 21 (71%) in ratio E/Z: 7:3.
TLC Rf: 0.72 (cyclohexane/ethyl acetate, 90:10).
4.1.17. (1S,2R,3R,4R)-3-(Bromoethyl)-2-(tert-butyldi-
phenylsilyloxymethyl) cyclopentan 1,4 diol (24). To a
solution of 23 (96 mg, 0.15 mmol) and triphenylphosphin
(62 mg, 0.239 mmol) in 0.9 mL of acetonitrile was added
carbon tetrabromide (79 mg, 0.239 mmol) at room tem-
perature and under N2 atmosphere. The mixture was stirred
50 min. The solution was concentrated in vacuo and was
purified by chromatography (20–70% ethyl acetate in
cyclohexane) to give 50.5 mg of 24 (71%). TLC Rf: 0.76
(ethyl acetate). 1H NMR (360 MHz, CDCl3): d 1.04 (9H, s,
C(CH3)3), 1.60 (1H, td, J¼4, 14.1 Hz, 5-H), 1.79–1.89 (2H,
m, 7-H), 2.24–2.30 (2H, m, 2-H, 3-H), 2.40 (1H, m, 50-H),
E Isomer. 1H NMR (100 MHz, CDCl3): d 0.30–0.70 (12H,
m, SiCH2CH3), 0.70–1.00 (18H, m), 1.00 (9H, s, C(CH3)3),

2494
T. Durand et al. / Tetrahedron 59 (2003) 2485–2495
3.32–3.42 (2H, m, 8-H), 3.53 (1H, d, J¼6.6 Hz, 6-H), 3.67
(1H, dd, J¼4.6, 10.5 Hz, 6-H), 3.92–3.99 (1H, m, 4-H),
4.18–4.20 (1H, m, 1-H), 7.24–7.44 (6H, m, Ar-H), 7.62–
7.65 (4H, m, Ar-H). 13C NMR (91 MHz, CDCl3): d 19.1
(C(CH3)3), 26.9 (C(CH3)3), 32.1 (C-7 and C-8), 43.1 (C-5),
47.2 (C-3), 51.2 (C-2), 62.8 (C-6), 74.8 (C-1), 76.8 (C-4),
127.8 (C-Ar), 129.9 (C-Ar), 133.0 (C-Ar), 135.5 (C-Ar).
Anal. calcd for C36H61BrO3Si3: C, 61.24; H, 8.71. Found: C,
61.25; H, 8.68.
was refluxed overnight. 4 mL of saturated sodium bicar-
bonate solution was added. The mixture was filtered through
Celite, extracted with 3£10 mL of methylene chloride. The
organic layers were washed with 3£5 mL of potassium
iodide solution and with 5 mL of brine. The extracts were
dried over Na2SO4 and evaporated. 87 mg (100%) of
aldehyde 30 was obtained. TLC Rf: 0.60 (cyclohexane/ethyl
1
acetate, 95:5). H NMR (100 MHz, CDCl3): d 0.40–0.77
(12H, m, SiCH2CH3), 0.83–0.97 (18H, m, SiCH2CH3), 1.10
(9H, s, C(CH3)3), 1.66–2.00 (1H, m, 3-H), 2.13–2.43 (1H,
m, 3-H), 3.33–4.36 (5H, m, 2-H, 4-H, 5-H, 6-H), 7.28–7.49
(6H, m, Ar-H), 7.52–7.81 (4H, m, Ar-H), 9.60 (1H, s,
CHO). 13C NMR (25 MHz, CDCl3): d 4.8 (SiCH2CH3), 5.2
(SiCH2CH3), 6.7 (SiCH2CH3), 6.8 (SiCH2CH3), 19.2
(C(CH3)3), 26.8 (C(CH3)3), 39.1 (C-3), 42.0 (C-5), 65.4
(C-2), 68.4 (C-4), 74.6 (C-6), 127.7 (C-Ar), 129.8 (C-Ar),
133.0 (C-Ar), 135.6 (C-Ar), 203.3 (C-1).
4.1.18. (1S,2R,3R,4R)-3-(Cyanoethyl)-2-(tert-butyldi-
phenylsilyloxymethyl) cyclopentan 1,4 diol (25). At
room temperature, potassium cyanide (7 mg, 94.2 mmol)
was added to 24 (100 mg, 31.4 mmol) in a solution of 51 mL
of ethanol/water: 2:1. After 5 min, the mixture was refluxed
1 day and evaporated under reduced pressure. The residue
was stirred vigorously with 50 mL of 2N KOH solution and
50 mL of diethyl ether. The aqueous layer was extracted
with ethyl acetate (3£1 mL). The organic layers were dried
with Na2SO4 and evaporated. The residue was purified by
chromatography on silica gel (50–100% of ethyl acetate in
cyclohexane) to give 9 mg of 25 (65%). TLC Rf: 0.70 (ethyl
acetate). IR (neat): 3420, 2930, 2250, 1440 cm21. 1H NMR
(100 MHz, CDCl3): d 1.0 (9H, s, C(CH3)3), 1.5–1.8 (3H, m,
5-H, 7-H), 2.1–2.6 (5H, m, 2-H, 3-H, 50-H, 8-H), 3.4–3.7
(2H, m, 6-H), 3.8–4.0 (1H, m, 4H), 4.1–4.3 (1H, m, 1-H),
7.2–7.5 (6H, m, Ar-H), 7.6–7.7 (4H, m, Ar-H). 13C NMR
(25 MHz, CDCl3): d 16.1 (C-8), 19.1 (C(CH3)3), 24.7 (C-7),
26.9 (C(CH3)3), 43.3 (C-5), 47.2 (C-3), 51.2 (C-2), 62.5
(C-6), 74.5 (C-1), 77.0 (C-4), 119.9 (CN), 127.8
(C-Ar), 129.9 (C-Ar), 132.8 (C-Ar), 135.5 (C-Ar). Anal.
calcd for C37H61NO3Si3: C, 68.14; H, 9.43. Found: C,
68.17; H, 9.41.
4.1.21. (5S,7R,8R)-9-O-(tert-Butyldiphenylsilyl)-1-(diiso-
propylacetal)-5,7-di-O-(triethylsilyl)-8-iodo-3(Z)-nonene
(31). A 1 M THF solution of NaHMDS (177 mL, 177 mmol)
was added to a suspension of (3,3-diisopropoxypropyl)tri-
phenylphosphonium bromide 30 (93 mg, 185 mmol) in
1 mL of THF at 2808C. The resulting orange solution of
ylide was stirred 10 min. This solution was added to
aldehyde 29 (46 mg, 62 mmol) solution in 0.75 mL of THF.
After slow warming to room temperature over 1 h, the
reaction mixture was hydrolyzed with 3 mL of water. The
aqueous layer was extracted with diethyl ether (3£3 mL),
and the combined extracts were washed with brine (5 mL).
All organic layers were dried with Na2SO4 and concen-
trated. The residue was purified by chromatography (10%
diethyl ether in cyclohexane) to give 49 mg of 31 (72%).
1
TLC Rf: 0.54 (cyclohexane/ethyl acetate, 95:5). H NMR
4.1.19. (2S,4R,5R)-6-O-(tert-Butyldiphenylsilyl)-2,4-di-
O-(triethylsilyl)-1,1-diethylthio-5-iodo-hexane (28). To
the diol 5 (259 mg, 420 mmol) in 3.5 mL of dry pyridine
was added chlorotriethylsilane (560 mL, 3.35 mmol). The
reaction mixture was stirred overnight at room temperature.
The mixture was evaporated. The residue was purified by
flash chromatography on silica gel (2% diethyl ether in
cyclohexane) to give 258 mg of 28 (73%). TLC Rf: 0.76
(cyclohexane/ethyl acetate, 95:5). 1H NMR (360 MHz,
CDCl3): d 0.43–0.69 (12H, m, SiCH2CH3), 0.83–1.00
(18H, m, SiCH2CH3), 1.07 (9H, s, C(CH3)3), 1.16–1.41
(6H, m, SCH2CH3), 1.82–1.92 (1H, m, 3-H), 2.13–2.22 (H,
m, 30-H), 2.58–2.80 (4H, m, SCH2CH3), 3.42–3.50 (1H, m,
4-H), 3.79–3.98 (3H, m, 1-H, 6-H), 4.01–4.07 (1H, m,
2-H), 4.22–4.29 (2H, m, 5-H), 7.35–7.40 (6H, m, Ar-H),
7.61–7.69 (4H, m, Ar-H). 13C NMR (91 MHz, CDCl3): d
5.2 (SiCH2CH3), 5.3 (SiCH2CH3), 6.9 (SiCH2CH3), 14.5
(SCH2CH3), 14.7 (SCH2CH3), 19.3 (C(CH3)3), 25.6
(SCH2CH3), 25.9 (SCH2CH3), 26.9 (C(CH3)3), 42.6 (C-3),
44.5 (C-5), 57.5 (C-1), 66.9 (C-6), 68.4 (C-4), 73.1 (C-2),
127.6 (C-Ar), 129.7 (C-Ar), 133.1 (C-Ar), 133.3 (C-Ar),
135.6 (C-Ar). Anal. calcd for C38H67IO3S2Si3: C, 53.87, H,
7.97. Found: C, 53.91, H, 7.95.
(100 MHz, CDCl3): d 0.43–0.66 (12H, m, SiCH2CH3),
0.80–0.97 (18H, m, SiCH2CH3), 1.00 (9H, s, C(CH3)3),
1.11–1.26 (12H, m, CH(CH3)2), 1.62–1.88 (2H, m, 6-H),
2.31–2.46 (2H, m, 2-H), 3.34–3.51 (1H, m, 7-H), 3.71–
4.00 (2H, m, 9-H), 3.80–3.83 (2H, m, OCH(CH3)2), 4.40–
4.63 (2H, m, 5-H, 8-H), 4.49 (1H, t, J¼5.5 Hz, 1-H), 5.34–
5.46 (2H, m, 3-H, 4-H), 7.28–7.43 (6H, m, Ar-H), 7.60–
7.71 (4H, m, Ar-H). 13C NMR (91 MHz, CDCl3): d 5.0
(SiCH2CH3), 5.3 (SiCH2CH3), 6.9 (SiCH2CH3), 19.2
(C(CH3)3), 22.5 (CH(CH3)2), 22.7 (CH(CH3)2), 23.3
(C(CH3)3), 34.1 (C-2), 45.5 (C-6), 46.5 (C-8), 65.9 (C-9),
67.1 (C-5), 67.1 (C-7), 67.9 (OCH(CH3)2), 99.5 (C-1), 124.3
(C-3), 127.6 (C-Ar), 129.7 (C-Ar), 133.1 (C-Ar), 133.4
(C-Ar), 134.8 (C-4), 135.6 (C-Ar). Anal. calcd for
C43H75IO5Si3: C, 58.48; H, 8.56. Found: C, 58.50; H, 8.55.
4.1.22. (1R,2S,3S,4S)-2-tert-Butyldiphenylsilyloxy
methyl-1,4-di-O-(triethylsilyl)-3-(diisopropylacetal propyl)
cyclopentane (32). To a solution of 31 (103 mg, 116 mmol)
in 1.6 mL of p-xylene was added tributyltin hydride (39 mL,
140 mmol) under a stream of dry argon. At room
temperature,
a 1N triethyl borane solution (23 mL,
23 mmol) was added under a stream of dry air. The mixture
was stirred 10 min. The solvent was removed and the
mixture was subjected to flash chromatography (cyclo-
hexane/diethyl ether, 95:5) to give 63 mg of 32 (72%). TLC
Rf: 0.55 (cyclohexane/ethyl acetate, 95:5). 1H NMR
(360 MHz, CDCl3): d 0.45 (6H, q, J¼8.0 Hz, (CH3CH2)3Si),
0.54 (6H, q, J¼8.0 Hz, (CH3CH2)3Si), 0.85 (9H,
4.1.20. (2S,4R,5R)-6-O-(tert-Butyldiphenylsilyl)-2,4-di-
O-(triethylsilyl)-5-iodo-hexanal (29). To the thioacetal
28 (100 mg, 118 mmol) in 7.6/0.8 mL of acetone/water, was
added mercuric oxide (243 mg, 1.12 mmol) and mercuric
chloride (105 mg, 387 mmol). The heterogeneous mixture

T. Durand et al. / Tetrahedron 59 (2003) 2485–2495
2495
Durand, T.; Guy, A.; Rossi, J.-P.; Fanelli, R. J. Lipid Res.
2002, 43, 495–509.
t, J¼8.0 Hz, (CH3CH2)3Si), 0.92 (9H, t, J¼8.0 Hz,
(CH3CH2)3Si), 1.04 (9H, s, C(CH3)3), 1.07 (3H, d, J¼
6.0 Hz, OCH(CH3)2), 1.09 (3H, d, J¼6.0 Hz, OCH(CH3)2),
1.14 (3H, d, J¼6.0 Hz, OCH(CH3)2), 1.15 (3H, d, J¼
6.0 Hz, OCH(CH3)2), 1.30–1.38 (2H, m, 3-H), 1.43–1.53
(1H, m, 6-H), 1.50–1.57 (2H, m, 2-H), 1.98–2.03 (1H, m,
8-H), 2.08–2.12 (1H, m, 4-H), 2.25–2.36 (1H, m, 60-H),
3.53–3.60 (2H, m, 9-H), 3.77–3.86 (2H, m, OCH(CH3)2),
3.90 (1H, dd, J¼7.3, 15.2 Hz, 5-H), 4.08–4.12 (1H, m,
7-H), 4.45 (1H, t, J¼5.3 Hz, 1-H), 7.30–7.43 (6H, m,
Ar-H), 7.59–7.67 (4H, m, Ar-H). 13C NMR (91 MHz,
CDCl3): d4.7 ((CH3CH2)3Si), 4.9 ((CH3CH2)3Si), 6.8
((CH3CH2)3Si), 6.9 ((CH3CH2)3Si), 19.1 (C(CH3)3), 22.5
(OCH(CH3)2), 22.7 (OCH(CH3)2), 23.1 (C-3), 23.2 (C-2),
23.4 (OCH(CH3)2), 26.9 (C(CH3)3), 45.3 (C-6), 47.6 (C-4),
50.8 (C-8), 62.4 (C-9), 67.4 (OCH(CH3)2), 67.5
(OCH(CH3)2), 73.4 (C-7), 77.2 (C-5), 100.5 (C-1), 127.6
(C-Ar), 129.6 (C-Ar). 135.7 (C-Ar). Anal. calcd for
C43H76O5Si3: C, 68.20; H, 10.12. Found: C, 68.15; H,
10.09. [a]2D0¼þ23.8 (c¼1023, MeOH).
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A.; Henry, O.; Vidal, J. P.; Rossi, J. C.; Rivalta, C.; Valagussa,
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Acknowledgements
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A part of this work was supported by University of
Montpellier I (funds BQR-2001). The authors are grateful
to Professor Andrew Kende for helpful discussion and for
carefully reading the manuscript.
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