Total synthesis of the four enantiomerically pure diastereomers of 8-F2t-isoprostane

Article abstract of DOI:10.1021/jo001731k

Syntheses of the four enantiomerically pure diastereomers of 8-F_2t-isoprostane (5-8) are described. The key to this approach was to prepare the racemic alcohol 9 in high diastereomeric purity and then resolve 9 by lipase-mediated acetylation to yield the enantiomerically pure alcohols 39 and 32.

Full text of DOI:10.1021/jo001731k

1876
J . Org. Chem. 2001, 66, 1876-1884
Tota l Syn th esis of th e F ou r En a n tiom er ica lly P u r e Dia ster eom er s
of 8-F 2t-Isop r osta n e
Douglass F. Taber* and Qin J iang
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716
taberdf@udel.edu.
Received December 12, 2000
Syntheses of the four enantiomerically pure diastereomers of 8-F2t-isoprostane (5-8) are described.
The key to this approach was to prepare the racemic alcohol 9 in high diastereomeric purity and
then resolve 9 by lipase-mediated acetylation to yield the enantiomerically pure alcohols 30 and
32.
In tr od u ction
synthesis routes to each of them. We report herein the
first preparation of each of the four enantiomerically pure
diastereomers of 8-F2t-isoprostane (5-8).
In 1990, Roberts and Morrow reported that a series of
prostaglandin-like compounds are produced in abundance
in vivo independent of the cyclooxygenase enzymes, by
free radical-mediated oxidation of membrane-bound
arachidonic acid (1).1 These oxidation products have been
named the F2-isoprostanes,2 the D2-isoprostanes, and the
E2-isoprostanes.3 There are four different regioisomers
of each of these classes of isoprostanes. Thus 2 is 12-F2t-
isoprostane, 3 is 5-F2t-isoprostane, 4 is 15-F2t-isoprostane,
and 5 is 8-F2t-isoprostane. 15-F2t-Isoprostane (4), pre-
pared by total synthesis,4-11 has been shown to have
hormonal activity, with a receptor in the kidney vascu-
lature.12 To investigate the physiological activity4 of the
other isoprostanes, it has been necessary to devise
(1) (a) Morrow, J . D.; Hill, K. E.; Burk, R. F.; Nammour, T. M.; Badr,
K. F.; Roberts, L. J ., II Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 9383.
(2) (a) For a summary of isoprostane nomenclature, see: Taber, D.
F.; Morrow, J . D.; Roberts, L. J ., II. Prostaglandins 1997, 53, 63. (b)
For an alternative nomenclature system for the isoprostanes, see
Rokach, J .; Khanapure, S. P.; Hwang, S. W.; Adiyaman, M.; Lawson,
J . A.; FitzGerald, G. A. Prostaglandins 1997, 54, 853.
(3) Morrow, J . D.; Minton, T. A.; Mukundan, C. R.; Campell, M. D.;
Zackert, W. E.; Daniel, V. C.; Badr, K. F.; Blair, J . A.; Roberts, L. J .,
II. J . Biol. Chem. 1994, 269, 4317.
(4) Morrow, J . D.; Roberts, L. J ., II. Biochem. Pharmacol. 1996, 51,
1.
(5) For a previous synthetic route to 8-F2t-isoprostane, see: Adiya-
man, M.; Li, H.; Lawson, J . A.; Hwang, S. W.; Khanapure, S. P.;
FitzGerald, G. A.; Rokach, J . Tetrahedron Lett. 1997, 38, 3339.
(6) For synthetic routes to 15-F2t-isoprostane, see: (a) Corey, E. J .;
Shih, C.; Shih, N.-Y.; Shimoji, K. Tetrahedron Lett. 1984, 25, 5013. (b)
Hwang, S. W.; Adiyaman, M.; Khanapure, S.; Schio, L.; Rokach, J . J .
Am. Chem. Soc. 1994, 116, 10829. (c) Taber, D. F.; Herr, R. J .; Gleave,
D. M. J . Org. Chem. 1997, 62, 194. (d) Taber, D. F.; Kanai, K.
Tetrahedron 1998, 54, 11767.
(7) For synthetic routes to 15-F2c-isoprostane, see: (a) Larock, R.
C.; Lee, N. H. J . Am. Chem. Soc. 1991, 113, 7815. (b) Vionnet, J .-P.;
Renaud, P. Helv. Chim. Acta 1994, 77, 1781. (c) Hwang, S. W.;
Adiyaman, M.; Khanapure, S. P.; Rokach, J . Tetrahedron Lett. 1996,
37, 779.
(8) For a synthetic route to 15-E2t-isoprostane, see: (a) Taber, D.
F.; Hoerrner, R. S. J . Org. Chem. 1992, 57, 441. (b) Reference 6d.
(9) For synthetic routes to 5-F2t-isoprostane, see: (a) Adiyaman, M.;
Lawson, J . A.; Hwang, S. W.; Khanapure, S. P.; FitzGerald, G. A.;
Rokach, J . Tetrahedron Lett. 1996, 37, 4849. (b) Taber, D. F.; Kanai,
K.; Pina, R. J . Am. Chem. Soc. 1999, 121, 7773.
(10) For a synthetic route to 5-F2c-isoprostane, see: Adiyaman, M.;
Lawson, J . A.; FitzGerald, G. A.; Rokach, J . Tetrahedron Lett. 1998,
39, 7039.
Resu lts a n d Discu ssion
The 8-F2t-isoprostanes are produced in vivo as racemic
mixtures of C-8 diastereomers. To screen the bioactivity,
it was necessary to prepare each of the four enantiomeri-
cally pure diastereomers. We envisioned (Scheme 1) a
(12) (a) Morrow, J . D.; Minton, T. A.; Roberts, L. J ., II. Prostaglan-
dins 1992, 44, 155. (b) Fukunaga, M.; Makita, N.; Roberts, L. J ., II;
Morrow, J . D.; Takahashi, K.; Badr, K. F. Am. J . Physiol (Cell Physiol.
33) 1993, 264, C1619. (c) Takahashi, K.; Nammour, T. M.; Fukunaga,
M.; Ebert, J .; Morrow, J . D.; Roberts, L. J ., II; Hoover, R. L.; Badr, K.
F. J . Clin. Invest. 1992, 90, 136. (d) Longmire, A. W.; Roberts, L. J .,
II; Morrow, J . D. Prostaglandins 1994, 48, 247. (e) Fukunaga, M.;
Takahashi, K.; Badr, K. F. Biochem. Biophys. Res. Commun. 1993,
195, 507.
(11) For a synthetic route to 12-F2t-isoprostane, see: Pudukulathan,
Z.; Manna, S.; Hwang, S. W.; Khanapure, S. P.; Lawson, J . A.;
FitzGerald, G. A.; Rokach, J . J . Am. Chem. Soc. 1998, 120, 11953.
10.1021/jo001731k CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/10/2001

Synthesis of Diastereomers of 8-F2t-Isoprostane
J . Org. Chem., Vol. 66, No. 5, 2001 1877
Sch em e 1
Sch em e 2a
a
Key: (a) KHMDS, THF, -78 °C; ethyl 5-oxopentanoate, -78
°C to 0 °C; (b) 80% HOAc (aq.), rt; (c) NaIO4/SiO2, CH2Cl2/H2O,
rt; (d) 19, KHMDS, THF/CH2Cl2, -78 °C to room temperature;
(e) Dess-Martin periodinane, CH2Cl2, rt.
Sch em e 3a
a
Key: (a) K2CO3, toluene, TBAI (cat.), Cu, reflux; 1-bromopen-
stereodivergent synthetic route which would lead to each
of these four from a common intermediate, the racemic
alcohol 9. The diastereomerically pure alcohol 9 could be
prepared from the thioether 10, which could be produced
by kinetic opening of the activated cyclopropane of the
bicyclic ketone 11 with thiophenol and BF3‚OEt2. The
bicyclic ketone 11 could be assembled by a rhodium-
mediated cyclization of the diazoketone 12, the product
of aldol condensation between the diazoketone 14 and
the aldehyde 13. To establish this route, we had to
develop an efficient procedure for the resolution of 9, and
we had to develop a method for the preparation and
condensation of the unstable aldehyde 15.
tane, 50 °C; (b) p-NBSA, DBU, CH2Cl2, 0 °C.
Sch em e 4a
On the basis of the results we previously reported,13
we anticipated that rather than attempting purification
of the very reactive â,γ-unsaturated aldehyde 15, it would
be more sensible to prepare the precusor diol 18 (Scheme
2). To this end, Wittig reaction of the known phospho-
nium salt 1614 following a modification of the method of
Kobayashi15 with ethyl 5-oxopentanoate16 proceeded
smoothly to give the cis-alkene 17, which was hydrolyzed
by 80% acetic acid aqueous solution to furnish diol 18.
The key to this approach was the development of
conditions for the cleavage of diol 18 such that the very
unstable â,γ-aldehyde 15 would be generated in sufficient
purity that it could be used directly in the subsequent
Wittig condensation. In fact, the Vo-Quang17 periodate
cleavage (Scheme 2) gave a CH2Cl2 solution of 15 that
could be directly used in the following modified Wittig
a
Key: (a) KHMDS, toluene, -78 °C; 13, TESCl; (b) TBAF,
NH4Cl (solid), THF, 0 °C; (c) TBDPSCl, imidazole, DMAP (cat.),
CH2Cl2, rt; (d) Rh2(Oct)4, CH2Cl2, rt.
reaction15 with phosphonium salt 199b to give the trienol
20. Finally, oxidation of the trienol 20 with the Dess-
Martin periodinane18 produced the aldehyde 13.
The diazoketone 14 was prepared (Scheme 3) by the
approach we have previously reported.19 Thus, alkylation
of benzoylacetone (21) with 1-bromopentane gave the
diketone 22, which was smoothly converted to the diazo-
ketone 14 on exposure to p-nitrobenzenesulfonyl azide
(p-NBSA) and DBU.
(13) Taber, D. F.; You, K. J . Org. Chem. 1995, 60, 139.
(14) Mosset, P.; Pointeau, P.; Aubert, F.; Lellouche, J . P.; Beaucourt,
J . P.; Gre´e, R. Bull. Soc. Chim. Fr. 1990, 127, 298.
(15) Hosoda, A.; Taguchi, T.; Kobayashi, Y. Tetrahedron Lett. 1987,
28, 65.
Aldol condensation6d (Scheme 4) of the potassium
enolate of the diazoketone 14 with the aldehyde 13 in
the presence of triethylchlorosilane (TESCl) in toluene
(16) Ethyl 5-oxopentanoate was prepared by ethanolysis of δ-vale-
rolactone followed by PCC oxidation. For full characterization, see
Penn, J . H.; Liu, F. J . Org. Chem. 1994, 59, 2608.
(17) Daumas, M.; Vo-Quang, Y.; Vo-Quang, L.; Le Goffic, F. Syn-
thesis 1989, 64.
(18) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4156. (b)
Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(19) Taber, D. F.; Gleave, D. M.; Herr, R. J .; Moody, K.; Hennessy,
M. J . J . Org. Chem. 1995, 60, 2283.

1878 J . Org. Chem., Vol. 66, No. 5, 2001
Taber and J iang
Sch em e 5a
Sch em e 6a
a
Key: (a) TBDMSCl, imidazole, DMAP (cat.), CH2Cl2, rt; (b)
mCPBA, CH2Cl2, -78 °C; (MeO)3P, EtOH, -78 °C to room
temperature.
Sch em e 7a
a
Key: (a) PhSH, BF3‚OEt2, CH2Cl2, -30 °C; (b) NaBH4, MeOH,
0 °C; (c) Dess-Martin periodinane, CH2Cl2, rt.
gave the TES-protected aldol 23 together with a small
amount of the free aldol 24 (hydrolysis on workup). The
TES group of 23 does not survive under the conditions
for cyclopropane ring opening with thiophenol and BF3‚
OEt2, so it was necessary to change the protecting group
from TES to tert-butyldiphenylsilyl (TBDPS). The diazo-
ketone 12 was then cyclized with the Rh2(oct)4 catalyst
in CH2Cl2 to provide the desired bicyclic ketone 11 and
the diastereomer 25. The structures of the bicyclic
1
ketones 13 and 25 were assigned by comparing the H
and 13C NMR spectra to those for the analogous bicyclic
ketones that are intermediates in the synthesis of the
5-F2t-isoprostane.9b In particular, the oxygenated methine
1
of 11 (13C δ 69.3; H δ 4.46, d, J ) 4.9 Hz) is exactly
congruent with the analogous 5-F2t-isoprostane precusor
(13C δ 69.3; 1H δ 4.46, d, J ) 4.9 Hz), while the
1
oxygenated methine of 25 (13C δ 68.0; H δ 4.59, dt, J )
5.1 and 10.8 Hz) is quite different.
Kinetic cyclopropane ring opening of 11 (Scheme 5)
with thiophenol and BF3‚OEt2 in CH2Cl2 at -30 °C gave
the ketone 26 as a mixture of diastereomers. This was
immediately reduced with NaBH4 in methanol to produce
the alcohols 27, 28, and 10. Again, the relative configura-
tions of 28 (1H NMR δ 4.75, dt, J ) 2.1 and 5.8 Hz, 1H;
4.30, m, 1H) and 10 (1H NMR δ 4.48, dt, J ) 2.5 and 6.5
Hz, 1H; 4.05, m, 1H) were assigned by analogy to the
chemical shifts of the H’s at C-12 and C-14 in the
corresponding diastereomers of the 5-F2t-isoprostane
precusors (1H NMR δ 4.74, dt, J ) 2.6 and 6.2 Hz, 1H;
4.29, m, 1H) and (1H NMR δ 4.44, dt, J ) 3.6 and 6.6
Hz, 1H; 4.08, m, 1H).9b The undesired alcohol 28 was
recycled by oxidation with Dess-Martin periodinane,
followed by reduction with NaBH4.
a
Key: (a) Amano Lipase AK, vinyl acetate, 55 °C ∼ 60 °C; (b)
K2CO3, EtOH, rt; (c) Dess-Martin periodinane, CH2Cl2, rt; (d)
NaBH4, MeOH, 0 °C.
and reductive workup then gave the diastereromerically
pure alcohol 9.
With the racemic alcohol 9 in hand, we could proceed
with the separation of the two enantiomers. At first, we
tried the enzymatic resolution21 of alcohol 9 (Scheme 7)
with Amano lipase AK in neat vinyl acetate at room
temperature. Unfortunately, the reaction was too slow.
To speed up the reaction, the reaction temperature was
then raised to 55 °C to 60 °C, giving the alcohol 30 [(S)-
OH] and the acetate 31 after 13 days. The ee of the
alcohol 30 was determined to be >99% by chiral HPLC
Before establishing the side-chain hydroxyl of 9, we
first protected the ring hydroxyl in 10 (Scheme 6) with
TBDMSCl, to yield the disilyloxy thioether 29. Oxidation
of 29 with mCPBA followed by Mislow rearrangement20
(20) (a) Bickart, P.; Carson, F. W.; J acobus, J .; Miller, E. J .; Mislow,
K. J . Am. Chem. Soc. 1968, 90, 4869. (b) Tang, R.; Mislow, K. J . Am.
Chem. Soc. 1970, 92, 2100.
(21) Wong, C.-H.; Whitesides, G. M. Enzymes in Synthetic Organic
Chemistry; Pergamon Press: Oxford, U.K., 1994; and references
therein.

Synthesis of Diastereomers of 8-F2t-Isoprostane
J . Org. Chem., Vol. 66, No. 5, 2001 1879
Sch em e 8a
Sch em e 9a
a
Key: (a) TBAF, THF, rt; (b) LiOH‚H2O, THF/H2O (1:1, v/v),
rt.
Sch em e 10a
a
Key: (a) Dess-Martin periodinane, CH2Cl2, rt; (b) (S)-BINAL-
H, THF, -78 °C.
analysis.22 Deacetylation of the acetate 31 provided the
alcohol 32 [(R)-OH], the ee of which was determined to
be 80% by chiral HPLC analysis. Oxidation of the
alcohols 30 and 32, respectively, with Dess-Martin
periodinane followed by reduction with NaBH4 yielded
the epimeric alcohols 30, 33 (>99% ee) and 32, 34 (80%
ee).
To investigate the biological activity of the isopros-
tanes, it is necessary to prepare each of these in high
enantiomeric excess. Therefore, the enantiomerically
enriched alcohols 32 and 34 (80% ee) were again sub-
jected to the enzymatic resolution to give, respectively,
the alcohol 34, the ee of which was determined to be
>99% by chiral HPLC analysis, and, after deacetylation,
the alcohol 32, the ee of which was determined to be
>99% by chiral HPLC analysis.
a
Key: (a) TBAF, THF, rt; (b) LiOH‚H2O, THF/H2O (1:1, v/v),
rt.
The alcohols 30, 33, 32, and 34 were separately
desilylated (Schemes 9 and 10) with TBAF in THF
followed by hydrolysis with LiOH in THF/H2O (1:1) to
furnish 8-F2t-isoprostane (5), 8-epi-8-F2t-isoprostane (6),
ent-8-epi-8-F2t-isoprostane (7), and ent-8-F2t-isoprostane
(8). The H and 13C NMR data for 5 were identical with
1
those reported.5,23
The absolute configuration of the enzymatically re-
solved compounds was determined by comparison of the
chiral HPLC retention time of the alcohols 30 and 32
with the products 30 and 32 of enantioselective (S)-
BINAL-H reduction9b of the racemic ketone 35, which
was obtained by oxidation of the racemic alcohol 9
(Scheme 8). The ee’s of alcohols 30 and 32 which were
obtained from the (S)-BINAL-H reduction was deter-
mined to be 17% by chiral HPLC analysis. The major
enantiomer of the alcohols 30 and 32 had a retention time
of 9 min, and its minor enantiomer had a retention time
of 13 min. The alcohols 30 and 32 derived by the
enzymatic resolution had a retention time of 9 and 13
min, respectively. Thus, we established the absolute
configurations of the enzymatically resolved alcohols 30
and 32 to be as shown in Scheme 7.
Con clu sion
We have developed a practical synthesis of the four
enantiomerically pure diastereomers of 8-F2t-isoprostanes
(5-8) using rhodium-mediated intramolecular cyclopro-
panation and enzymatic resolution as the key steps. This
synthesis will make 5-8 available in sufficient quantity
to allow the detailed assessment of their physiological
activity.
Exp er im en ta l P r oced u r es.
Gen er a l. H NMR and 13C NMR spectra were obtained as
1
solutions in deuteriochloroform (CDCl3). 13C multiplicities were
determined with the aid of a J VERT pulse sequence, dif-
ferentiating the signals for methyl and methine carbons as
“down” from methylene and quaternary carbons as “up”. The
infrared (IR) spectra were determined as neat oils. Optical
rotations were determined as solutions in chloroform unless
(22) The ee’s were determined by HPLC analysis with a CHIRAL-
CEL OD column (Daicel Chemical Industries Ltd.): detector, UV (254
nm); flow rate, 1 mL/min; mobile phase, hexanes/2-PrOH ) 150/1.
Retention time: 30, 9 min; 32, 13 min; 33, 11 min; 34, 9 min.
(23) The previous report did not include [R]D, so no comparison could
be made.

1880 J . Org. Chem., Vol. 66, No. 5, 2001
Taber and J iang
otherwise noted. Rf values indicated refer to thin-layer chro-
matography (TLC) on 2.5 × 10 cm, 250 µm analytical plates
coated with silica gel GF and developed in the solvent system
indicated. Silica gel (60 Å) was used for flash column chroma-
tography. Tetrahydrofuran (THF) and diethyl ether were
distilled from sodium metal/benzophenone ketyl under dry
nitrogen. Dichloromethane (CH2Cl2) and toluene were distilled
from calcium hydride under dry nitrogen. All reaction mixtures
were stirred magnetically, unless otherwise noted.
63.2, 60.3, 33.6, 26.5, 26.0, 24.7; down 132.5, 130.1, 129.2,
128.2, 127.7, 125.9, 14.1; HRMS calcd for C14H20O2 (M - H2O)
220.1464, found 220.1466.
Ald eh yd e 13. To a stirred solution of trienol 20 (2.38 g,
10.00 mmol) in CH2Cl2 (100 mL) was added Dess-Martin
periodinane (6.30 g, 15.00 mmol). The reaction mixture was
stirred for 50 min at room temperature under N2 and was then
concentrated. The residue was filtered through a short pad of
silica gel. The filter cake was washed with Et2O (100 mL). The
filtrate was concentrated, and the residue was then chromato-
graphed to furnish the aldehyde 13 (2.28 g, 97% yield from
20) as a colorless oil, TLC Rf ) 0.70 (petroleum ether/MTBE
) 1/1); CI MS m/z (rel intensity) 236 (M+, 80), 191 (M+ - CH3-
CH2O, 65); IR (film) 2980, 2936, 2868, 1732, 1681, 1630, 1446,
1374, 1243, 1186, 1139, 1105, 1031, 964 cm-1; 1H NMR δ 9.63
(d, J ) 7.9 Hz, 1H), 7.45-7.53 (m, 1H), 6.25-6.31 (m, 1H),
6.12-6.19 (m, 1H), 5.91-5.98 (m, 1H), 5.39-5.49 (m, 2H),
4.09-4.16 (m, 2H), 3.09 (t, J ) 6.8 Hz, 2H), 2.29-2.38 (m, 2H),
2.14 (q, J ) 7.2 Hz, 2H), 1.67-1.76 (m, 2H), 1.26 (t, J ) 7.1
Hz, 3H); 13C NMR δ up 173.4, 60.2, 33.5, 26.6, 26.5, 24.6; down
193.9, 146.3, 141.0, 132.1, 130.6, 126.7, 126.5, 14.2; HRMS
calcd for C14H20O3 (M) 236.1413, found 236.1422.
Alk en e 17. To a stirred solution of the phosphonium salt
16 (24.40 g, 47.10 mmol) in THF (400 mL) was added a 0.55
M solution of KHMDS (81.70 mL, 44.90 mmol) in toluene at
-78 °C under N2. The reaction mixture was stirred for 1 h,
and then a solution of ethyl 5-oxopentanoate (6.17 g, 42.8
mmol) in THF (20 mL) was added. After an additional 10 min
at -78 °C, the reaction mixture was allowed to warm to room
temperature over 1.5 h. It was then partitioned between Et2O
and, sequentially, saturated aqueous NH4Cl and brine. The
combined organic extracts were dried (Na2SO4) and concen-
trated. The residue was chromatographed to produce the
alkene 17 (8.18 g, 75% yield from 16) as a colorless oil, TLC
Rf ) 0.78 (petroleum ether/MTBE ) 1/1); CI MS m/z (rel
intensity) 241 (M+ - CH3, 45); IR (film) 2984, 2936, 2872, 1735,
Dik eton e 22. To a stirred solution of benzoylacetone (21)
(16.20 g, 0.1 mol) in toluene (300 mL) were added K2CO3 (55.20
g, 0.4 mol), tert-butylammonium iodide (TBAI) (1.85 g, 5
mmol), and copper powder (0.32 g, 5 mmol). The reaction
mixture was heated to reflux for 3 h under N2 and was then
cooled to 50 °C. A solution of 1-bromopentane (15.10 g, 0.1 mol)
in toluene (60 mL) was then added over 40 min. The reaction
mixture was stirred at 50 °C for 43 h and was then cooled to
0 °C. The reaction mixture was filtered through a short pad
of silica gel, and the filter cake was washed with Et2O (300
mL). Concentration of the filtrate followed by chromatography
of the residue gave the diketone 22 (11.14 g, 48% yield from
21) as a colorless oil, TLC Rf ) 0.46 (petroleum ether/MTBE
) 9/1); FAB MS m/z (rel intensity) 233 (M+ + H, 100), 217
(M+ - CH3, 19); IR (film) 2956, 2929, 2859, 1723, 1677, 1596,
1456, 1370, 1244, 1214, 1157, 1062 cm-1 1H NMR δ 5.29-
;
5.44 (m, 2H), 4.00-4.06 (m, 3H), 3.93 (dd, J ) 6.0 and 7.9 Hz,
1H), 3.46 (dd, J ) 7.1 and 7.9 Hz, 1H), 2.15-2.35 (m, 4H),
2.01 (q, J ) 7.3 Hz, 2H), 1.61 (quint, J ) 7.4 Hz, 2H), 1.33 (s,
3H), 1.26 (s, 3H), 1.17 (t, J ) 7.2 Hz, 3H); 13C NMR δ up 173.2,
108.7, 68.8, 60.0, 33.4, 31.3, 26.5, 24.5; down 131.3, 124.9, 75.3,
26.7, 25.4, 14.0; HRMS calcd for C13H21O4 (M - CH3) 241.1440,
found 241.1442.
Diol 18. A solution of the alkene 17 (6.88 g, 26.88 mmol) in
80% aqueous HOAc (100 mL) was stirred for 42 h at room
temperature. The reaction mixture was then concentrated and
the residue was chromatographed to give the diol 18 (5.26 g,
91% yield from 17) as a colorless oil, TLC Rf ) 0.35 (petroleum
ether/EtOAc ) 1/3); CI MS m/z (rel intensity) 234 (M+ + NH4,
60), 217 (M+ + H, 100); IR (film) 3404, 2935, 1733, 1458, 1374,
1581, 1448, 1357, 1275, 1215, 1182, 971, 770, 694 cm-1 1H
;
1313, 1244, 1187, 1150, 1074, 1032 cm-1
;
1H NMR δ 5.35-
NMR δ 7.98-8.00 (m, 2H), 7.58-7.62 (m, 1H), 7.47-7.51 (m,
2H), 4.44 (t, J ) 7.0 Hz, 1H), 2.14 (s, 3H), 1.93-2.05 (m, 2H),
1.30 (brs, 6H), 0.86 (brs, 3H); 13C NMR δ up 204.5, 196.4, 136.4,
31.6, 29.0, 27.3, 22.3; down 133.6, 128.8, 128.6, 63.5, 27.7, 13.9;
HRMS calcd for C15H21O2 (M + H) 233.1542, found 233.1535.
Dia zok eton e 14. To a stirred solution of diketone 22 (2.32
g, 10 mmol) in CH2Cl2 (30 mL) was added a solution of DBU
(3.04 g, 20 mmol) in CH2Cl2 (3 mL) at 0 °C under N2. After 20
min, a solution of p-nitrobenzenesulfonyl azide (p-NBSA) (4.56
g, 20 mmol) in CH2Cl2 (20 mL) was added over 30 min. After
an additional 3 h at 0 °C, the reaction mixture was diluted
with CH2Cl2 (150 mL) and was then partitioned between CH2-
Cl2 and, sequentially, 10% aqueous NaOH, H2O, and brine.
The organic extract was dried (Na2SO4) and concentrated. The
residue was distilled bulb-to-bulb (100 °C/0.5 mmHg) to yield
the diazoketone 14 (1.12 g, 73% yield from 22) as a yellow oil,
TLC Rf ) 0.28 (petroleum ether/MTBE ) 9/1); IR (film) 2958,
2929, 2860, 2066, 1644, 1457, 1368, 1326, 1186, 1124, 963
5.45 (m, 2H), 4.06 (q, J ) 7.1 Hz, 2H), 3.65 (ddd, J ) 2.9, 7.1,
and 13.7 Hz, 1H), 3.62 (brs, 2H), 3.55 (dd, J ) 2.9 and 11.3
Hz, 1H), 3.38 (dd, J ) 7.3 and 11.3 Hz, 1H), 2.24 (t, J ) 7.4
Hz, 2H), 2.09-2.19 (m, 2H), 1.99-2.04 (m, 2H), 1.62 (quint, J
) 7.4 Hz, 2H), 1.87 (t, J ) 7.1 Hz, 3H); 13C NMR δ up 173.8,
66.0, 60.2, 33.5, 31.0, 26.4, 24.5; down 131.2, 125.7, 71.8, 14.0;
HRMS calcd for C11H21O4 (M + H) 217.1440, found 217.1436.
Tr ien ol 20. A stirred mixture of NaIO4 (3.98 g, 18.60 mmol)
and H2O (8 mL) was heated until the NaIO4 was dissolved,
and then SiO2 (20 g) was added with vigorous stirring. After
cooling to room temperature, CH2Cl2 (60 mL) was added,
followed by a solution of diol 18 (2.00 g, 9.30 mmol) in CH2Cl2
(20 mL). The reaction mixture was stirred for 20 min at room
temperature and was then filtered. The filter cake was washed
with CH2Cl2 (30 mL). The filtrate, which was a solution of the
aldehyde 15 in CH2Cl2, was used in the next step without
further purification.
1
To a stirred solution of the phosphonium salt 19 (4.22 g,
10.20 mmol) in THF (150 mL) was added a 0.51 M solution of
KHMDS in toluene (19.10 mL, 9.74 mmol) at -78 °C under
N2. After an additional 1 h at -78 °C, the solution of aldehyde
15 in CH2Cl2 was added, and the reaction mixture was then
allowed to warm slowly to room temperature over 4 h. The
reaction mixture was partitioned between Et2O and, sequen-
tially, saturated aqueous NH4Cl and brine. The combined
organic extracts were dried (Na2SO4) and concentrated. The
residue was chromatographed to yield the trienol 20 (1.19 g,
54% yield from 18) as a colorless oil, TLC Rf ) 0.41 (petroleum
ether/MTBE ) 1/1); CI MS m/z (rel intensity) 220 (M+ - H2O,
100); IR (film) 3435, 3009, 2934, 2866, 1734, 1458, 1374, 1313,
1244, 1188, 1156, 1087, 1029, 985, 952 cm-1; 1H NMR δ 6.51-
6.58 (m, 1H), 5.98 (t, J ) 10.9 Hz, 1H), 5.81 (dt, J ) 5.7 and
15.2 Hz, 1H), 5.32-5.41 (m, 3H), 4.18 (d, J ) 5.7 Hz, 2H), 4.09
(q, J ) 7.2 Hz, 2H), 2.90 (t, J ) 6.1 Hz, 2H), 2.28 (t, J ) 7.4
Hz, 2H), 2.23 (brs, 1H), 2.06-2.11 (m, 2H), 1.67 (quint, J )
7.3 Hz, 2H), 1.23 (t, J ) 7.2 Hz, 3H); 13C NMR δ up 173.8,
cm-1; H NMR δ 2.32 (t, J ) 7.3 Hz, 2H), 2.24 (s, 3H), 1.47
(brs, 2H), 1.32 (brs, 4H), 0.88 (brs, 3H); 13C NMR δ up 191.0,
30.8, 26.5, 22.2, 22.0; down 25.2, 13.8.
TES-P r otected Ald ol 23 a n d F r ee Ald ol 24. To a stirred
solution of diazoketone 14 (1.56 g, 10.13 mmol) in toluene (150
mL) was added a 0.59 M solution of KHMDS in toluene (18.00
mL, 10.62 mmol) at -78 °C under N2. The reaction mixture
was stirred for 10 min, and a solution of aldehyde 13 (2.28 g,
9.66 mmol) and triethylsilyl chloride (TESCl) (1.75 g, 11.61
mmol) in toluene (30 mL) was then added. After an additional
1 h, the reaction mixture was partitioned between EtOAc and,
sequentially, saturated aqueous NH4Cl and brine. The com-
bined organic extracts were dried (Na2SO4) and concentrated.
The residue was chromatographed to afford the TES-protected
aldol 23 (2.85 g, 58.5% yield from 13) as a pale yellow oil, TLC
Rf ) 0.85 (petroleum ether/MTBE ) 2/1); IR (film) 2956, 2934,
2875, 2069, 1736, 1630, 1458, 1369, 1239, 1176, 1097, 1069,
1006, 743 cm-1
1H), 5.94 (t, J ) 10.8 Hz, 1H), 5.65 (dd, J ) 6.4 and 15.0 Hz,
;
1H NMR δ 6.50 (dd, J ) 11.6 and 14.6 Hz,

Synthesis of Diastereomers of 8-F2t-Isoprostane
J . Org. Chem., Vol. 66, No. 5, 2001 1881
1
1H), 5.33-5.40 (m, 3H), 4.68 (brs, 1H), 4.11 (q, J ) 7.1 Hz,
2H), 2.89 (brs, 2H), 2.73 (dd, J ) 8.4 and 13.5 Hz, 1H), 2.45
(dd, J ) 4.0 and 13.5 Hz, 1H), 2.22-2.37 (m, 4H), 2.09 (q, J )
6.9 Hz, 2H), 1.69 (quint, J ) 7.4 Hz, 2H), 1.44 (brs, 2H), 1.30
(brs, 4H), 1.24 (t, J ) 7.1 Hz, 3H), 0.87-0.97 (m, 12H), 0.55
(q, J ) 7.9 Hz, 6H); 13C NMR δ up 191.7, 173.6, 68.8, 60.2,
46.7, 33.6, 30.9, 26.6, 26.5, 26.0, 24.7, 22.4, 22.3, 4.7; down
135.5, 130.4, 129.4, 128.2, 127.7, 124.8, 71.0, 14.2, 13.9, 6.7.
This was followed by the free aldol 24 (0.66 g, 17.5% yield from
13) as a pale yellow oil, TLC Rf ) 0.13 (petroleum ether/MTBE
) 2/1); 1H NMR δ 6.61 (dd, J ) 11.2 and 15.1 Hz, 1H), 5.98 (t,
J ) 11.0 Hz, 1H), 5.70 (dd, J ) 6.1 and 15.2 Hz, 1H), 5.35-
5.44 (m, 3H), 4.70 (dd, J ) 5.9 and 11.6 Hz, 1H), 4.12 (q, J )
7.1 Hz, 2H), 2.92 (t, J ) 6.1 Hz, 2H), 2.66-2.70 (m, 2H), 2.26-
2.36 (m, 4H), 2.11 (q, J ) 7.2 Hz, 2H), 1.70 (quint, J ) 7.4 Hz,
2H), 1.46-1.50 (m, 2H), 1.27-1.34 (m, 5H), 1.26 (t, J ) 7.1
Hz, 3H), 0.90 (t, J ) 6.8 Hz, 3H).
TBDP S-P r otected Ald ol 12. To a stirred mixture of TES-
protected aldol 23 (2.57 g, 5.09 mmol) and solid NH4Cl (1.36
g, 25.42 mmol) in THF (80 mL) was added a 1.0 M solution of
tetrabutylammonium fluoride (TBAF) in THF (7.64 mL, 7.64
mmol) at 0 °C. The reaction mixture was stirred for 1 h and
was then partitioned between EtOAc and, sequentially, satu-
rated aqueous NH4Cl and brine. The combined organic extracts
were dried (Na2SO4) and concentrated. The residue which
contained unpurified free aldol 24 was used in the next step
without further purification.
702 cm-1; H NMR δ 7.61-7.70 (m, 4H), 7.35-7.47 (m, 6H),
5.43-5.48 (m, 1H), 5.27-5.36 (m, 2H), 4.88-4.93 (m, 1H), 4.47
(d, J ) 4.9 Hz, 1H), 4.08 (q, J ) 7.1 Hz, 2H), 2.72 (t, J ) 7.0
Hz, 2H), 2.22-2.33 (m, 3H), 2.00-2.14 (m, 5H), 1.60-1.71 (m,
3H), 1.38-1.45 (m, 2H), 1.27-1.33 (m, 4H), 1.16-1.25 (m, 4H),
1.06 (s, 9H), 0.89 (t, J ) 7.0 Hz, 3H); 13C NMR δ up 212.9,
173.5, 133.7, 133.5, 60.2, 43.9, 42.9, 33.6, 31.7, 27.2, 26.5, 26.0,
24.7, 23.5, 22.6, 19.0; down 135.7, 131.7, 129.8, 129.5, 127.9,
127.8, 127.7, 125.1, 69.3, 41.5, 27.3, 26.9, 14.2, 14.0; HRMS
calcd for C38H52O4Si (M) 600.3635, found 600.3617.
Th ioeth er 26. To a stirred solution of bicyclic ketone 11
(1.47 g, 2.45 mmol) and thiophenol (0.81 g, 7.36 mmol) in CH2-
Cl2 (12 mL) was added BF3‚OEt2 (1.39 g, 9.79 mmol) dropwise
at -30 °C under N2. After an additional 5.5 h, the reaction
mixture was partitioned between CH2Cl2 and, sequentially,
saturated aqueous NaCO3 and brine. The combined organic
extracts were dried (Na2SO4) and concentrated. The residue
was chromatographed to recover the starting material 11 (0.29
g) and provide the thioether 26 (1.35 g, 96% yield from 11
based on 80% conversion) as a colorless oil, TLC Rf ) 0.46
(petroleum ether/CH2Cl2/MTBE ) 70/25/5); CI MS m/z (rel
intensity) 653 (M+ - C4H9, 15); IR (film) 2956, 2930, 2857,
1740, 1472, 1400, 1167, 1112, 1060, 1026, 822, 740, 702 cm-1
;
1H NMR δ 7.61-7.74 (m, 5H), 7.43-7.47 (m, 2H), 7.36-7.41
(m, 6H), 7.17-7.27 (m, 2H), 5.18-5.23 (m, 1H), 5.13 (t, J )
10.6 Hz, 1H), 5.01-5.06 (m, 1H), 4.79-4.86 (m, 1H), 4.62 (d,
J ) 5.8 Hz, 1H), 4.12 (q, J ) 7.1 Hz, 2H), 3.66 (dd, J ) 4.2
and 10.4 Hz, 1H), 2.81-2.86 (m, 1H), 2.68 (dd, J ) 3.7 and
7.6 Hz, 1H), 2.55 (dd, J ) 6.1 and 19.6 Hz, 1H), 2.34 (d, J )
19.6 Hz, 1H), 2.22 (t, J ) 7.5 Hz, 3H), 1.95-2.04 (m, 2H), 1.86
(q, J ) 7.2 Hz, 2H), 1.31-1.64 (m, 9H), 1.25 (t, J ) 7.1 Hz,
3H), 1.06 (s, 9H), 0.89 (t, J ) 6.9 Hz, 3H); 13C NMR δ up 217.3,
173.5, 135.2, 133.4, 133.3, 60.2, 46.9, 33.6, 31.9, 28.1, 26.4, 25.0,
24.6, 24.3, 22.5, 19.0; down 135.8, 135.7, 134.0, 129.9, 129.8,
129.3, 129.1, 128.8, 128.7, 127.8, 127.7, 127.6, 127.5, 70.4, 53.8,
52.6, 46.5, 26.9, 14.2, 14.1; HRMS calcd for C40H49O4SSi (M -
C4H9) 653.3121, found 653.3133.
To a stirred solution of the unpurified free aldol 24,
imidazole (1.04 g, 15.29 mmol), and DMAP (62 mg, 0.51 mmol)
in CH2Cl2 (80 mL) was added tert-butyldiphenylsilyl chloride
(TBDPSCl) (2.80 g, 10.18 mmol). The reaction mixture was
stirred for 12 h at room temperature and was then partitioned
between CH2Cl2 and, sequentially, saturated aqueous NH4Cl
and brine. The combined organic extracts were dried (Na2SO4)
and concentrated. The residue was chromatographed to give
the TBDPS-protected aldol 12 (2.43 g, 76% yield from 23) as
a pale yellow oil, TLC Rf ) 0.89 (petroleum ether/MTBE )
2/1); IR (film) 2929, 2856, 2066, 1735, 1636, 1458, 1427, 1370,
Alcoh ols 27, 28, a n d 10. To a stirred solution of thioether
26 (292 mg, 0.41 mmol) in MeOH (20 mL) was added NaBH4
(156 mg, 4.11 mmol) at 0 °C. The reaction mixture was stirred
for 30 min and was then partitioned between EtOAc and,
sequentially, 5% aqueous HCl and brine. The combined organic
extracts were dried (Na2SO4) and concentrated. The residue
was chromatographed to yield the alcohol 27 (35 mg, 12% yield
from 26) as a colorless oil, TLC Rf ) 0.40 (petroleum ether/
CH2Cl2/MTBE ) 70/25/5); CI MS m/z (rel intensity) 655 (M+
- C4H9, 8), 603 (M+ - PhS, 25); IR (film) 3532, 2930, 2857,
1733, 1588, 1472, 1428, 1373, 1310, 1188, 1153, 1112, 1037,
1
1155, 1112, 1063, 822, 739, 702 cm-1; H NMR δ 7.62-7.65
(m, 4H), 7.32-7.43 (m, 6H), 6.02 (dd, J ) 11.2 and 15.0 Hz,
1H), 5.74 (t, J ) 10.8 Hz, 1H), 5.53 (dd, J ) 7.3 and 15.0 Hz,
1H), 5.21-5.40 (m, 3H), 4.72 (dd, J ) 6.9 and 13.1 Hz, 1H),
4.12 (q, J ) 7.1 Hz, 2H), 2.80 (dd, J ) 7.5 and 13.7 Hz, 1H),
2.67 (t, J ) 7.1 Hz, 2H), 2.51 (dd, J ) 5.6 and 13.7 Hz, 1H),
2.20-2.37 (m, 4H), 2.05 (q, J ) 7.1 Hz, 2H), 1.68 (quint, J )
7.4 Hz, 2H), 1.38-1.43 (m, 2H), 1.26-1.30 (m, 4H), 1.25 (t, J
) 7.1 Hz, 3H), 1.03 (s, 9H), 0.88 (t, J ) 6.8 Hz, 3H); 13C NMR
δ up 191.3, 173.6, 133.8, 133.5, 68.6, 60.2, 46.3, 33.6, 30.9, 26.6,
26.5, 25.8, 24.7, 22.3, 19.3; down 135.9, 134.3, 130.4, 129.6,
129.5, 129.2, 128.2, 127.6, 127.4, 127.3, 125.9, 72.2, 26.9, 14.2,
13.9.
822, 739, 702 cm-1; H NMR δ 7.67-7.74 (m, 4H), 7.33-7.47
1
(m, 6H), 7.18-7.22 (m, 5H), 5.04-5.17 (m, 3H), 4.71-4.74 (m,
1H), 4.22 (brs, 1H), 4.19 (d, J ) 4.2 Hz, 1H), 4.10 (q, J ) 7.1
Hz, 2H), 3.52 (dd, J ) 5.7 and 10.3 Hz, 1H), 3.15 (d, J ) 10.5
Hz, 1H), 2.20 (t, J ) 7.4 Hz, 2H), 2.01-2.16 (m, 3H), 1.80-
1.93 (m, 5H), 1.54-1.67 (m, 5H), 1.34-1.37 (m, 5H), 1.24 (t, J
) 7.1 Hz, 3H), 1.07 (s, 9H), 0.90 (t, J ) 6.8 Hz, 3H); 13C NMR
δ up 173.4, 134.5, 133.0, 132.9, 60.2, 42.6, 33.5, 32.1, 30.8, 28.1,
26.3, 25.0, 24.6, 22.7, 18.9; down 136.0, 135.8, 133.6, 129.9,
129.8, 129.3, 129.0, 128.5, 128.3, 127.8, 127.7, 127.5, 127.3,
80.1, 75.3, 57.7, 49.3, 47.6, 26.9, 14.2, 14.1; HRMS calcd for
Bicyclic Keton e 11 a n d 25. To a stirred solution of
TBDPS-protected aldol 12 (5.90 g, 9.38 mmol) in CH2Cl2 (50
mL) was added a solution of Rh2(oct)4 (73 mg, 0.094 mmol) in
CH2Cl2 (170 mL) over a period of 2 h at room temperature.
After an additional 2 h, the reaction mixture was concentrated.
The residue was chromatographed to yield the bicyclic ketone
25 (1.97 g, 35% yield from 12) as a colorless oil, TLC Rf ) 0.41
(petroleum ether/MTBE ) 9/1); IR (film) 2956, 2930, 2858,
1728, 1463, 1428, 1372, 1156, 1112, 823, 742, 702 cm-1
;
1H
C40H51O4SSi (M - C4H9) 655.3277, found 655.3263. This was
NMR δ 7.63-7.73 (m, 4H), 7.37-7.47 (m, 6H), 5.57 (dt, J )
7.4 and 10.6 Hz, 1H), 5.40-5.47 (m, 2H), 5.38 (dd, J ) 9.1
and 10.6 Hz, 1H), 4.59 (dt, J ) 8.0 and 15.1 Hz, 1H), 4.12 (q,
J ) 7.1 Hz, 2H), 2.97 (t, J ) 7.0 Hz, 2H), 2.51 (dd, J ) 3.7 and
8.8 Hz, 1H), 2.21-2.36 (m, 4H), 2.13 (q, J ) 7.2 Hz, 2H), 1.80
(dd, J ) 4.2 and 4.9 Hz, 1H), 1.68-1.77 (m, 3H), 1.26 (t, J )
7.1 Hz, 3H), 1.07-1.22 (m, 7H), 1.05 (s, 9H), 0.80 (t, J ) 7.3
Hz, 3H); 13C NMR δ up 210.8, 173.6, 133.8, 133.4, 60.2, 46.8,
42.1, 33.7, 31.8, 26.8, 26.6, 26.1, 24.8, 24.0, 22.4, 19.1; down
135.7, 135.5, 131.6, 129.9, 129.8, 129.5, 128.1, 127.8, 127.7,
125.4, 68.1, 39.9, 26.7, 25.9, 14.2, 14.0; HRMS calcd for
followed by the alcohol 28 (101 mg, 35% yield from 26) as a
colorless oil, TLC Rf ) 0.30 (petroleum ether/CH2Cl2/MTBE
) 70/25/5); CI MS m/z (rel intensity) 603 (M+ - PhS, 15), 545
(M+ - PhSH - C4H9, 100); IR (film) 3460, 2957, 2929, 2856,
1736, 1588, 1472, 1428, 1373, 1188, 1155, 1112, 822, 740, 702
cm-1; 1H NMR δ 7.62-7.69 (m, 4H), 7.35-7.45 (m, 6H), 7.29-
7.33 (m, 2H), 7.19-7.24 (m, 3H), 5.16-5.24 (m, 2H), 4.98 (dt,
J ) 7.3 and 10.7 Hz, 1H), 4.83-4.91 (m, 1H), 4.74-4.76 (m,
1H), 4.29-4.31 (m, 1H), 4.11 (q, J ) 7.1 Hz, 2H), 3.90 (dd, J
) 6.4 and 10.7 Hz, 1H), 2.45-2.52 (m, 2H), 2.20-2.38 (m, 4H),
2.13 (ddd, J ) 2.3, 7.0 and 15.2 Hz, 1H), 1.85-1.94 (m, 4H),
1.55-1.63 (m, 3H), 1.41-1.53 (m, 2H), 1.26-1.32 (m, 5H), 1.25
(t, J ) 7.1 Hz, 3H), 1.05 (s, 9H), 0.89 (t, J ) 6.6 Hz, 3H); 13C
NMR δ up 173.7, 134.3, 134.0, 133.9, 60.2, 45.2, 33.7, 32.2,
28.5, 26.4, 25.5, 25.1, 24.7, 22.6, 19.1; down 135.9, 135.8, 134.6,
C
38H52O4Si (M) 600.3635, found 600.3628. This was followed
by the bicyclic ketone 11 (2.80 g, 50% yield from 12) as a
colorless oil, TLC Rf ) 0.28 (petroleum ether/MTBE ) 9/1);
IR (film) 2930,2858, 1727, 1428, 1156, 1113, 1063, 823, 740,

1882 J . Org. Chem., Vol. 66, No. 5, 2001
Taber and J iang
131.5, 129.6, 129.5, 128.8, 128.7, 128.3, 127.9, 127.5, 126.8,
76.1, 73.4, 54.9, 47.7, 46.3, 27.0, 14.2, 14.1; HRMS calcd for
organic extracts were dried (Na2SO4) and concentrated. The
residue was chromatographed to furnish the alcohol 9 (645
mg, 90% yield from 29) as a colorless oil, TLC Rf ) 0.30
(petroleum ether/MTBE ) 80/20); CI MS m/z (rel intensity)
677 (M+ - C4H9, 85), 659 (M+ - C4H9 - H2O, 100); IR (film)
3460, 2956, 2929, 2857, 1738, 1472, 1428, 1375, 1252, 1112,
1061, 836, 775, 702 cm-1; 1H NMR δ 7.63-7.66 (m, 4H), 7.34-
7.43 (m, 6H), 5.44-5.50 (m, 1H), 5.29-5.36 (m, 1H), 5.17-
5.22 (m, 2H), 4.12 (q, J ) 7.1 Hz, 2H), 3.96 (brs, 1H), 3.93
(quint, J ) 3.2 Hz, 1H), 3.72 (dd, J ) 7.4 and 13.3 Hz, 1H),
2.64 (brs, 1H), 2.29 (t, J ) 7.5 Hz, 2H), 2.10-2.22 (m, 4H),
2.04 (q, J ) 7.3 Hz, 2H), 1.58-1.72 (m, 3H), 1.46 (d, J ) 3.7
Hz, 1H), 1.19-1.29 (m, 11H), 1.05 (s, 9H), 0.89 (s, 9H), 0.87
(t, J ) 7.0 Hz, 3H), 0.01 (s, 3H), 0.00 (s, 3H); 13C NMR δ up
173.7, 134.4, 134.3, 60.3, 44.1, 35.1, 33.7, 32.1, 28.4, 27.5, 26.7,
24.7, 22.6, 19.1, 18.0; down 135.9, 135.8, 134.2, 131.2, 129.5,
129.1, 127.5, 125.8, 77.1, 76.5, 71.8, 52.7, 49.1, 26.9, 25.8, 14.2,
14.1, -4.4, -4.8; HRMS calcd for C40H61O5Si2 (M - C4H9)
677.4058, found 677.4047.
C
44H60O4SSiNa (M + Na) 735.3879, found 735.3896. This was
followed by the alcohol 10 (134 mg, 46% yield from 26) as a
colorless oil, TLC Rf ) 0.16 (petroleum ether/CH2Cl2/MTBE
) 70/25/5); CI MS m/z (rel intensity) 603 (M+ - PhS, 30), 545
(M+ - PhSH - C4H9, 100); IR (film) 3455, 2929, 2857, 1734,
1647, 1473, 1427, 1374, 1186, 1111, 1026, 822, 740, 702 cm-1
;
1H NMR δ 7.70-7.75 (m, 4H), 7.36-7.45 (m, 6H), 7.29-7.32
(m, 2H), 7.20-7.25 (m, 3H), 5.15-5.22 (m, 2H), 4.98 (dt, J )
7.4 and 10.7 Hz, 1H), 4.79-4.85 (m, 1H), 4.44-4.49 (m, 1H),
4.12 (q, J ) 7.1 Hz, 2H), 4.05 (brs, 1H), 3.71 (dd, J ) 6.9 and
10.6 Hz, 1H), 2.48-2.53 (m, 1H), 2.13-2.26 (m, 5H), 1.83-
1.92 (m, 3H), 1.77 (d, J ) 6.4 Hz, 1H), 1.48-1.67 (m, 4H),
1.20-1.30 (m, 7H), 1.25 (t, J ) 7.1 Hz, 3H), 1.08 (s, 9H), 0.86
(t, J ) 6.9 Hz, 3H); 13C NMR δ up 173.5, 134.6, 134.3, 133.8,
60.2, 43.7, 33.7, 32.1, 28.5, 27.8, 26.4, 25.1, 24.7, 22.6, 19.1;
down 136.1, 136.0, 134.8, 130.4, 129.6, 129.5, 129.0, 128.6,
128.5, 128.1, 127.7, 127.6, 127.5, 77.1, 76.4, 54.4, 50.6, 47.3,
27.1, 14.2, 14.1; HRMS calcd for C44H60O4SSiNa (M + Na)
735.3879, found 735.3907.
Alcoh ol 30 a n d Aceta te 31. To a stirred solution of the
racemic alcohol 9 (645 mg, 0.88 mmol) in vinyl acetate (15 mL)
was added Amano lipase AK (1935 mg, 3 mass eq.) at room
temperature. The reaction mixture was stirred at 55 °C to 60
°C for 13 days. The insoluble material was filtered, and the
filtrate was concentrated. The residue was chromatographed
to give the acetate 31 (374 mg, 55% yield from 9) as a colorless
oil, TLC Rf ) 0.65 (petroleum ether/MTBE ) 80/20); CI MS
m/z (rel intensity) 799 (M+ + Na, 25), 761 (M+ - CH3, 100),
719 (M+ - C4H9, 30); IR (film) 2929, 2857, 1737, 1472, 1428,
Alcoh ol 10 Obta in ed fr om Alcoh ol 28. To a stirred
solution of alcohol 28 (15.7 mg, 0.022 mmol) in CH2Cl2 (3 mL)
was added Dess-Martin periodinane (18.5 mg, 0.044 mmol)
at room temperature. The reaction mixture was stirred for 30
min and was then filtered through a short pad of silica gel.
The filter cake was washed with Et2O, and the filtrate was
concentrated. The residue was used in the next step without
further purification.
To a stirred solution of the residue in MeOH (2 mL) was
added NaBH4 (8.4 mg, 0.22 mmol) at 0 °C. The reaction
mixture was stirred for 30 min and was then partitioned
between EtOAc and, sequentially, 5% aqueous HCl and brine.
The combined organic extracts were dried (Na2SO4) and
concentrated. The residue was chromatographed to produce
the alcohol 28 (6 mg, 38% yield from 28) as a colorless oil,
followed by the alcohol 10 (8.5 mg, 54% yield from 28) as a
colorless oil.
1
1371, 1238, 1112, 1061, 835, 774, 740, 702 cm-1; H NMR δ
7.63-7.65 (m, 4H), 7.34-7.44 (m, 6H), 5.08-5.42 (m, 5H), 4.12
(q, J ) 7.1 Hz, 2H), 3.91 (quint, J ) 3.1 Hz, 1H), 3.69 (dd, J
) 7.5 and 13.5 Hz, 1H), 2.60-2.65 (m, 1H), 2.27-2.34 (m, 1H),
2.28 (t, J ) 7.5 Hz, 2H), 2.00-2.18 (m, 5H), 1.99 (s, 3H), 1.67
(quint, J ) 7.5 Hz, 2H), 1.60 (dt, J ) 4.6 and 14.2 Hz, 1H),
1.16-1.27 (m, 11H), 1.05 (s, 9H), 0.88 (s, 9H), 0.87 (t, J ) 7.1
Hz, 3H), 0.00 (s, 3H), -0.01 (s, 3H); 13C NMR δ up 173.5, 170.1,
134.3, 134.2, 60.2, 44.1, 33.6, 32.2, 32.0, 28.3, 27.4, 26.6, 24.7,
22.5, 19.1, 18.0; down 135.8, 132.8, 131.2, 129.6, 129.5, 127.5,
125.0, 76.9, 76.5, 74.1, 52.8, 49.2, 26.9, 25.8, 21.2, 14.2, 14.1,
-4.4, -4.8; HRMS calcd for C46H72O6Si2Na (M + Na) 799.4765,
found 799.4803. This was followed by the alcohol 30 (197 mg,
31% yield from 9) as a colorless oil, TLC Rf ) 0.30 (petroleum
Disilyloxy Th ioeth er 29. To a stirred solution of alcohol
10 (33.5 mg, 0.047 mmol), imidazole (9.6 mg, 0.14 mmol), and
a catalytic amount of DMAP in CH2Cl2 (5 mL) was added
TBDMSCl (14 mg, 0.093 mmol) at room temperature under
N2. The reaction mixture was stirred for 46 h and was then
partitioned between CH2Cl2 and, sequentially, saturated aque-
ous NH4Cl and brine. The combined organic extracts were
dried (Na2SO4) and concentrated. The residue was chromato-
graphed to give the disilyloxy thioether 29 (41 mg, 100% yield
from 10) as a colorless oil, TLC Rf ) 0.52 (petroleum ether/
CH2Cl2/MTBE ) 70/28/2); CI MS m/z (rel intensity) 769 (M+
- C4H9, 100), 716 (M+ - PhSH, 90); IR (film) 2956, 2929, 2856,
ether/MTBE ) 80/20); [R]20 ) -29.5° (c ) 3.94, CHCl3); ES
D
MS m/z (rel intensity) 757 (M+ + Na, 30); IR (film) 3456, 2956,
2929, 2857, 1737, 1472, 1428, 1374, 1252, 1112, 1060, 836, 775,
1
740, 702 cm-1; H NMR δ 7.64-7.68 (m, 4H), 7.34-7.44 (m,
6H), 5.44 (m, 1H), 5.29-5.37 (m, 1H), 5.21-5.24 (m, 2H), 4.12
(q, J ) 7.1 Hz, 2H), 3.93-3.99 (m, 2H), 3.74 (dd, J ) 7.4 and
13.4 Hz, 1H), 2.66 (brs, 1H), 2.30 (t, J ) 7.5 Hz, 2H), 2.12-
2.23 (m, 4H), 2.07 (q, J ) 7.3 Hz, 2H), 1.69 (quint, J ) 7.4 Hz,
2H), 1.63 (dt, J ) 4.6 and 14.3 Hz, 1H), 1.57 (brs, 1H), 1.21-
1.35 (m, 11H), 1.07 (s, 9H), 0.90 (s, 9H), 0.88 (t, J ) 7.1 Hz,
3H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR δ up 173.6, 134.4,
134.3, 60.2, 44.0, 35.1, 33.6, 32.0, 28.4, 27.5, 26.6, 24.7, 22.6,
19.1, 18.0; down 135.9, 135.8, 134.2, 131.5, 129.4, 129.0, 127.5,
127.4, 125.8, 77.1, 76.5, 71.8, 52.7, 49.1, 26.9, 25.8, 14.2, 14.1,
-4.4, -4.8; HRMS calcd for C44H70O5Si2Na (M + Na) 757.4660,
found 757.4683. The ee of the alcohol 30 was determined to
be >99% by HPLC with a CHIRALCEL OD column (Daicel
Chemical Industries Ltd.) using hexanes/2-propanol (150/1,
v/v) as a mobile phase; flow rate: 1 mL/min; monitoring at
254 nm. Alcohol 30 had a retention time of 9 min. Its
enantiomer, alcohol 32 (see below), had a retention time of 13
min.
1737, 1472, 1373, 1252, 1111, 1063, 836, 774, 740, 702 cm-1
;
1H NMR δ 7.69-7.79 (m, 4H), 7.33-7.44 (m, 8H), 7.22-7.25
(m, 3H), 5.17-5.26 (m, 2H), 4.99 (dt, J ) 7.2 and 10.7 Hz,
1H), 4.80-4.85 (m, 1H), 4.40 (quint, J ) 3.7 Hz, 1H), 4.12 (q,
J ) 7.1 Hz, 2H), 3.97 (dd, J ) 6.4 and 10.5 Hz, 1H), 3.81 (dd,
J ) 6.8 and 10.7 Hz, 1H), 2.49-2.50 (m, 1H), 2.27-2.32 (m,
1H), 2.23 (t, J ) 7.8 Hz, 2H), 2.12-2.17 (m, 1H), 1.93-2.04
(m, 2H), 1.88 (q, J ) 7.1 Hz, 2H), 1.57-1.68 (m, 2H), 1.53 (dt,
J ) 3.8 and 14.3 Hz, 1H), 1.16-1.43 (m, 8H), 1.26 (t, J ) 7.1
Hz, 3H), 1.08 (s, 9H), 0.89 (s, 9H), 0.86 (t, J ) 6.9 Hz, 3H),
0.00 (s, 3H), -0.03 (s, 3H); 13C NMR δ up 173.5, 134.9, 134.8,
134.2, 60.2, 44.3, 33.7, 32.1, 28.4, 27.2, 26.4, 25.1, 24.7, 22.6,
19.2, 18.0; down 136.2, 136.1, 134.8, 130.6, 129.4, 129.3, 128.9,
128.6, 128.3, 127.6, 127.4, 127.3, 127.2, 76.1, 75.7, 53.4, 50.0,
47.3, 27.1, 25.9, 14.2, 14.1, -4.4, -4.8; HRMS calcd for
C
46H65O4SSi2 (M - C4H9) 769.4142, found 769.4140.
Alcoh ol 9. To a stirred solution of disilyloxy thioether 29
Alcoh ol 32. To a stirred solution of the acetate 31 (271 mg,
0.35 mmol) in EtOH (35 mL) was added K2CO3 (240 mg, 1.74
mmol) at room temperature. The reaction mixture was stirred
for 16 h and was then concentrated. The residue was parti-
tioned between CH2Cl2 and, sequentially, 5% HCl aqeouse
solution and brine. The combined organic extracts were dried
(Na2SO4) and concentrated. The residue was chromatographed
to provide the alcohol 32 (231 mg, 90% yield from 31) as a
colorless oil. The data of TLC, MS, IR, 1H and 13C NMR of
alcohol 32 were the same as the alcohol 30. HRMS calcd for
(805 mg, 0.97 mmol) in CH2Cl2 (35 mL) was added a solution
of mCPBA (336 mg, 1.95 mmol) in CH2Cl2 (6 mL) at -78 °C
under N2. After an additional 1 h, a solution of P(OCH3)3 (1.21
g, 9.76 mmol) in EtOH (10 mL) was added. After an additional
15 min at -78 °C, the reaction mixture was allowed to warm
to room temperature and was then stirred for 30 min. The
reaction mixture was partitioned between EtOAc and, sequen-
tially, saturated aqueous NaCO3 and brine. The combined

Synthesis of Diastereomers of 8-F2t-Isoprostane
J . Org. Chem., Vol. 66, No. 5, 2001 1883
C44H70O5Si2Na (M + Na) 757.4660, found 757.4682. The ee of
the alcohol 32 was determined to be 80% by HPLC with a
CHIRALCEL OD column (see above).
oil, [R]20 ) +26.6° (c ) 2.50, CHCl3). The ee of the enantio-
D
merically pure alcohol 34 was determined to be >99% by
HPLC with a CHIRALCEL OD column (see above).
Alcoh ols 30 a n d 33. To a stirred solution of the alcohol 30
(197 mg, 0.27 mmol) in CH2Cl2 (20 mL) was added Dess-
Martin periodinane (225 mg, 0.54 mmol) at room temperature
under N2. The reaction mixture was stirred for 2 h and was
then concentrated. The residue was filtered through a short
pad of silica gel, and the filter cake was washed with petroleum
ether/MTBE (1/1, v/v). Concentration of the filtrate gave a
residue which was used in the next step without further
purification.
Ra cem ic Keton e 35 a n d (S)-BINAL-H Red u ction of 35.
To a stirred solution of racemic alcohol 9 (12.5 mg, 0.017 mmol)
in CH2Cl2 (3 mL) was added Dess-Martin periodinane (14 mg,
0.033 mmol) at room temperature under N2. After an ad-
ditional 1 h, the reaction mixture was filtered through a short
pad of silica gel and the filter cake was washed with petroleum
ether/MTBE (1/1, v/v). Concentration of the filtrate gave a
residue which was chromatographed to afford the racemic
ketone 35 (11 mg, 88% yield from 9).
To a stirred solution of the residue in MeOH (20 mL) was
added NaBH4 (103 mg, 2.71 mmol) at 0 °C. After an additional
30 min, the reaction mixture was partitioned between EtOAc
and, sequentially, 5% aqueous HCl and brine. The combined
organic extracts were dried (Na2SO4) and concentrated. The
residue was chromatographed to produce the alcohol 30 (82
mg, 42% yield from 30) as a colorless oil. This was followed by
the alcohol 33 (80 mg, 41% yield from 30) as a colorless oil,
To a stirred 1 M solution of LiAlH4 in THF (51 µL, 0.051
mmol) was added a 2 M solution of EtOH in THF (25.5 µL,
0.051 mmol) over a period of 5 min followed by a solution of
(S)-(-)-1,1′-bi-2-naphthol (14.6 mg, 0.051 mmol) in THF (0.5
mL) at room temperature under N2. After an additional 0.5 h,
a solution of the racemic ketone 35 (11 mg, 0.015 mmol) in
THF (0.5 mL) was added at -78 °C. After an additional 5 h at
-78 °C, the reaction mixture was partitioned between EtOAc
and, sequentially, saturated aqueous NH4Cl and brine. The
combined organic extracts were dried (Na2SO4) and concen-
trated. The residue was chromatographed to yield the alcohols
30 and 32 (3.7 mg, 30% yield from 35) as a inseparable
mixture. This was followed by the alcohols 33 and 34 (3 mg,
24% yield from 35) as a inseparable mixture. The ee of the
alcohols 30 and 32 was determined to be 17% by HPLC with
a CHIRALCEL OD column (see above).
Tr iol 36. To a stirred solution of the alcohol 30 (82 mg, 0.11
mmol) in THF (11 mL) was added a 1 M solution of tetrabu-
tylammonium fluoride (TBAF) in THF (0.56 mL, 0.56 mmol)
at room temperature under N2. After an additional 40 h, the
reaction mixture was partitioned between EtOAc and, sequen-
tially, saturated aqueous NH4Cl and brine. The combined
organic extracts were dried (Na2SO4) and concentrated. The
residue was chromatographed to furnish the triol 36 (35.5 mg,
83% yield from 30) as a colorless oil, TLC Rf ) 0.31 (petroleum
ether/acetone ) 1/1); [R]20D ) -8.2° (c ) 1.10, CHCl3); IR (film)
3355, 2926, 2856, 1735, 1459, 1375, 1153, 1033, 974 cm-1; 1H
NMR δ 5.57 (dd, J ) 6.1 and 15.4 Hz, 1H), 5.37-5.52 (m, 3H),
4.11 (q, J ) 7.1 Hz, 2H), 4.09-4.11 (m, 1H), 3.92-4.01 (m,
2H), 2.71-2.76 (m, 2H), 2.40 (quint, J ) 7.4 Hz, 2H), 2.03-
2.33 (m, 8H), 1.68 (quint, J ) 7.4 Hz, 2H), 1.62 (dt, J ) 3.3
and 14.7 Hz, 1H), 1.19-1.30 (m, 11H), 0.86 (t, J ) 7.0 Hz,
3H); 13C NMR δ up 173.9, 60.4, 42.4, 35.2, 33.7, 32.1, 29.0,
27.9, 26.7, 24.7, 22.6; down 134.7, 131.6, 128.9, 125.7, 76.8,
76.4, 71.9, 53.5, 50.4, 14.2, 14.1; HRMS calcd for C22H38O5Na
(M + Na) 405.2618, found 405.2607.
TLC Rf ) 0.29 (petroleum ether/MTBE ) 80/20); [R]20
)
D
-26.4° (c ) 3.48, CHCl3); IR (film) 3464, 2956, 2929, 2857,
1731, 1472, 1428, 1374, 1253, 1111, 1061, 836, 775, 740, 702
cm-1; 1H NMR δ 7.64-7.69 (m, 4H), 7.35-7.44 (m, 6H), 5.44-
5.50 (m, 1H), 5.30-5.36 (m, 1H), 5.13-5.24 (m, 2H), 4.12 (q,
J ) 7.1 Hz, 2H), 3.93-3.96 (m, 2H), 3.72 (dd, J ) 7.5 and 13.6
Hz, 1H), 2.64 (t, J ) 6.7 Hz, 1H), 2.30 (t, J ) 7.5 Hz, 2H),
2.12-2.25 (m, 4H), 2.05 (q, J ) 7.5 Hz, 2H), 1.69 (quint, J )
7.4 Hz, 2H), 1.64 (dt, J ) 4.9 and 14.3 Hz, 1H), 1.41 (d, J )
2.9 Hz, 1H), 1.23-1.28 (m, 11H), 1.07 (s, 9H), 0.90 (s, 9H),
0.88 (t, J ) 7.1 Hz, 3H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR δ
up 173.6, 134.4, 134.3, 60.2, 44.1, 35.1, 33.6, 32.0, 28.4, 27.4,
26.7, 24.7, 22.6, 19.1, 18.0; down 135.8, 134.3, 131.4, 129.7,
129.5, 129.4, 127.4, 125.8, 77.2, 76.5, 72.2, 52.8, 49.1, 26.9, 25.8,
14.2, 14.1, -4.4, -4.8; HRMS calcd for C44H70O5Si2Na (M +
Na) 757.4660, found 757.4675.
Alcoh ols 32 a n d 34. The reactions were performed with
the alcohol 32 (231 mg, 0.31 mmol), Dess-Martin periodinane
(264 mg, 0.63 mmol), CH2Cl2 (25 mL); NaBH4 (119 mg, 3.13
mmol), and MeOH (30 mL) in the same manner as described
for the preparation of the alcohols 30 and 33 to afford the
alcohol 32 (99 mg, 43% yield from 32) as a colorless oil and
the alcohol 34 (97 mg, 42% yield from 32) as a colorless oil.
1
The data of TLC, IR, H and 13C NMR of the alcohol 34 were
the same as the alcohol 33. HRMS calcd for C44H70O5Si2Na
(M + Na) 757.4660, found 757.4698. The ee of the alcohol 34
was determined to be 80% by HPLC with a CHIRALCEL OD
column (Daicel Chemical Industries Ltd.) using hexanes/2-
propanol (150/1, v/v) as a mobile phase; flow rate: 1 mL/min;
monitoring at 254 nm. Alcohol 34 had a retention time of 9
min. Its enantiomer, alcohol 33 (see above), had a retention
time of 11 min.
Tr iol 37. The reaction was performed with the alcohol 33
(80 mg, 0.11 mmol), a 1 M solution of TBAF in THF (0.55 mL,
0.55 mmol), and THF (11 mL) in the same manner as described
for the preparation of the triol 36 to give the triol 37 (36 mg,
87% yield from 33) as a colorless oil, TLC Rf ) 0.29 (petroleum
F u r th er Resolu tion of Alcoh ol 32. The reaction was
performed with the enantiomerically enriched alcohol 32 (99
mg, 0.14 mmol, 80% ee), Amano lipase AK (396 mg, 4 mass
equiv), and vinyl acetate (2.3 mL) in the same manner as
described for the preparation of the alcohol 30 and acetate 31
to provide the alcohol (35 mg, 35% yield from 32) and the
enantiomerically pure acetate 31 (65 mg, 62% yield from 32)
ether/acetone ) 1/1); [R]20 ) -23.1° (c ) 1.50, CHCl3); IR
D
(film) 3360, 2927, 2857, 1735, 1446, 1374, 1312, 1193, 1063,
972 cm-1; 1H NMR δ 5.55 (dd, J ) 6.9 and 15.2 Hz, 1H), 5.36-
5.51 (m, 3H), 4.11 (q, J ) 7.1 Hz, 2H), 4.06-4.10 (m, 1H), 3.93-
3.96 (m, 2H), 3.03 (brs, 3H), 2.72 (dd, J ) 8.8 and 12.5 Hz,
1H), 2.31-2.45 (m, 2H), 2.29 (t, J ) 7.5 Hz, 2H), 2.18-2.26
(m, 1H), 2.07 (q, J ) 7.2 Hz, 2H), 2.02-2.05 (m, 1H), 1.68
(quint, J ) 7.4 Hz, 2H), 1.61 (d, J ) 14.4 Hz, 1H), 1.16-1.30
(m, 11H), 0.86 (t, J ) 7.0 Hz, 3H); 13C NMR δ up 173.9, 60.4,
42.3, 35.3, 33.7, 32.1, 29.0, 27.9, 26.7, 24.7, 22.6; down 135.0,
131.5, 130.0, 125.7, 76.6, 76.3, 72.4, 53.5, 50.5, 14.2, 14.1;
as a colorless oil, [R]20 ) +42.1° (c ) 2.17, CHCl3). The
D
deacetylation was performed on the enantiomerically pure
acetate 31 (65 mg, 0.084 mmol), K2CO3 (58 mg, 0.42 mmol),
and EtOH (8 mL) in the same manner as described for the
preparation of the alcohol 32 to give the enantiomerically pure
alcohol 32 (56 mg, 91% yield from 31) as a colorless oil, [R]20
D
HRMS calcd for
405.2613.
C22H38O5Na (M + Na) 405.2618, found
) +30.2° (c ) 2.80, CHCl3). The ee of the enantiomerically
pure alcohol 32 was determined to be >99% by HPLC with a
CHIRALCEL OD column (see above).
Tr iol 38. The reaction was performed with the alcohol 32
(56 mg, 0.076 mmol), a 1 M solution of TBAF in THF (0.38
mL, 0.38 mmol), and THF (7.6 mL) in the same manner as
described for the preparation of the triol 36 to give the triol
38 (24.5 mg, 84% yield from 32) as a colorless oil, [R]20D ) +8.5°
(c ) 1.20, CHCl3). The data of TLC, IR, 1H and 13C NMR of
the triol 38 were the same as the triol 36. HRMS calcd for
F u r th er Resolu tion of Alcoh ol 34. The reaction was
performed with the enantiomerically rich alcohol 34 (97 mg,
0.13 mmol, 80% ee), Amano lipase AK (388 mg, 4 mass equiv),
and vinyl acetate (2.2 mL) in the same manner as described
for the preparation of the alcohol 30 and acetate 31 to furnish
the acetate (29 mg, 28% yield from 34) and the enantiomeri-
cally pure alcohol 34 (50 mg, 52% yield from 34) as a colorless
C
22H38O5Na (M + Na) 405.2618, found 405.2626.

1884 J . Org. Chem., Vol. 66, No. 5, 2001
Taber and J iang
Tr iol 39. The reaction was performed with the alcohol 34
(50 mg, 0.068 mmol), a 1 M solution of TBAF in THF (0.34
mL, 0.34 mmol), and THF (6.8 mL) in the same manner as
described for the preparation of the triol 36 to give the triol
(quint, J ) 7.7 Hz, 1H), 2.13-2.29 (m, 4H), 2.05 (q, J ) 7.1
Hz, 2H), 1.93-1.95 (m, 1H), 1.61 (quint, J ) 7.4 Hz, 2H), 1.47
(dt, J ) 5.0 and 14.1 Hz, 1H), 1.18-1.35 (m, 8H), 0.85 (t, J )
7.0 Hz, 3H); 13C NMR δ up 177.7, 43.8, 36.5, 34.5, 33.5, 30.0,
29.0, 28.0, 26.1, 23.9; down 136.1, 131.8, 131.1, 127.5, 77.0,
76.7, 73.8, 54.3, 50.6, 14.7; HRMS calcd for C20H34O5Na (M +
Na) 377.2305, found 377.2304.
39 (22.5 mg, 87% yield from 34) as a colorless oil, [R]20
)
D
+23.2° (c ) 1.13, CHCl3). The data of TLC, IR, 1H and 13C
NMR of the triol 39 were the same as the triol 37. HRMS calcd
for C22H38O5Na (M + Na) 405.2618, found 405.2637.
en t-8-epi-8-F 2t-Isop r osta n e (7). The reaction was per-
formed with the triol 39 (22.5 mg, 0.059 mmol), LiOH‚H2O
(25 mg, 0.59 mmol), and THF/H2O (1:1, 2.4 mL) in the same
manner as described for the preparation of 8-F2t-isoprostane
(5) to give ent-8-epi-8-F2t-isoprostane (7) (19 mg, 91% yield from
8-F 2t-Isop r osta n e (5). To a stirred solution of the triol 36
(22 mg, 0.058 mmol) in THF/H2O (1:1, 2.4 mL) was added
LiOH‚H2O (24 mg, 0.57 mmol) at room temperature. After an
additional 2 h, the reaction mixture was acidified to pH 4 by
adding 0.5% aqueous HCl at 0 °C. After addition of NaCl (1
g), the mixture was extracted with CHCl3. The combined
organic extracts were dried (Na2SO4) and concentrated. The
residue was chromatographed to afford 8-F2t-isoprostane (5)
(19.5 mg, 96% yield from 36) as a colorless oil, TLC Rf ) 0.33
39) as a colorless oil, [R]20 ) +14.5° (c ) 0.95, MeOH). The
D
data of TLC, IR, 1H and 13C NMR of ent-8-epi-8-F2t-isoprostane
(7) were the same as 8-epi-8-F2t-isoprostane (6). HRMS calcd
for C20H34O5Na (M + Na) 377.2305, found 377.2295.
en t-8-F 2t-Isop r osta n e (8). The reaction was performed
with the triol 38 (24.5 mg, 0.064 mmol), LiOH‚H2O (27 mg,
0.64 mmol), and THF/H2O (1:1, 2.6 mL) in the same manner
as described for the preparation of 8-F2t-isoprostane (5) to give
ent-8-F2t-isoprostane (8) (21 mg, 93% yield from 38) as a
colorless oil, [R]20D ) +9.3° (c ) 1.05, MeOH). The data of TLC,
IR, 1H and 13C NMR of ent-8-F2t-isoprostane (8) were the same
as 8-F2t-isoprostane (5). HRMS calcd for C20H34O5Na (M + Na)
377.2305, found 377.2302.
(EtOAc/MeOH/AcOH ) 80/20/0.1); [R]20 ) -9.2° (c ) 0.98,
D
MeOH); IR (film) 3338, 2927, 2856, 1708, 1407, 1247, 1064,
1
973 cm-1; H NMR (CD3OD) δ 5.48 (dd, J ) 5.8 and 15.4 Hz,
1H), 5.34-5.42 (m, 3H), 3.98 (q, J ) 6.1 Hz, 1H), 3.83 (dt, J )
4.2 and 6.7 Hz, 1H), 3.73-3.78 (m, 1H), 2.57 (dt, J ) 3.9 and
12.4 Hz, 1H), 2.39 (quint, J ) 7.0 Hz, 1H), 2.14-2.26 (m, 4H),
2.03 (q, J ) 7.2 Hz, 2H), 1.91-1.95 (m, 1H), 1.59 (quint, J )
7.4 Hz, 2H), 1.45 (dt, J ) 5.2 and 14.2 Hz, 1H), 1.18-1.35 (m,
8H), 0.83 (t, J ) 7.0 Hz, 3H); 13C NMR δ up 177.9, 43.9, 36.6,
34.6, 33.5, 29.8, 29.1, 28.0, 26.2, 23.9; down 136.0, 131.8, 130.1,
127.6, 76.9, 76.6, 73.3, 54.0, 50.6, 14.7; HRMS calcd for
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM42056) for support for this work.
We also thank Dr. L. J ackson Roberts, II and co-workers
at Vanderbilt University for collaborative efforts and
Amano Pharmaceutical Co., Ltd. for a gift of the lipase.
C
20H34O5Na (M + Na) 377.2305, found 377.2296.
8-epi-8-F 2t-Isop r osta n e (6). The reaction was performed
with the triol 37 (30 mg, 0.079 mmol), LiOH‚H2O (33 mg, 0.79
mmol), and THF/H2O (1:1, 3.2 mL) in the same manner as
described for the preparation of 8-F2t-isoprostane (5) to give
8-epi-8-F2t-isoprostane (6) (27 mg, 97% yield from 37) as a
colorless oil, [R]20D ) -14.4° (c ) 1.35, MeOH); IR (film) 3346,
2926, 2858, 1709, 1410, 1242, 1064, 972 cm-1; 1H NMR (CD3-
OD) δ 5.46 (dd, J ) 6.6 and 15.3 Hz, 1H), 5.34-5.41 (m, 3H),
3.97 (q, J ) 6.6 Hz, 1H), 3.85 (dt, J ) 4.3 and 6.6 Hz, 1H),
3.74-3.79 (m, 1H), 2.57 (dt, J ) 3.6 and 12.9 Hz, 1H), 2.40
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
13C NMR spectra for compounds 5-14, 17, 18, 20, 22, 23, 25-
1
34, 36-39 and a copy of the H NMR spectrum for compound
24. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O001731K