Synthesis of the eight enantiomerically pure diastereomers of the 12-F2-isoprostanes

Article abstract of DOI:10.1021/ja020816v

Syntheses of the eight enantiomerically pure diastereomers of the 12-F₂-isoprostanes (4-11) are described. The key steps included rhodium-mediated intramolecular cyclopropanation and enzymatic resolution of the racemic diol 12.

Full text of DOI:10.1021/ja020816v

Published on Web 10/11/2002
Synthesis of the Eight Enantiomerically Pure Diastereomers
of the 12-F2-Isoprostanes
Douglass F. Taber,* Ming Xu, and John C. Hartnett1
Contribution from the Department of Chemistry and Biochemistry, UniVersity of Delaware,
Newark, Delaware 19716
Received June 7, 2002
Abstract: Syntheses of the eight enantiomerically pure diastereomers of the 12-F2-isoprostanes (4-11)
are described. The key steps included rhodium-mediated intramolecular cyclopropanation and enzymatic
resolution of the racemic diol 12.
Introduction
report the preparation of all eight of the enantiomerically pure
diastereomers of the 12-F2-isoprostanes (4-11) from the racemic
diol 12 (Scheme 1). This is the first preparation of the 12-F2c
series.
The isoprostanes (e.g. 1-4), a new family of prostaglandin-
like compounds, were recently discovered to be produced in
vivo in humans, independent of the cyclooxygenase enzymes,
by free radical mediated oxidation of membrane-bound arachi-
donic acid.2 There are D-ring, E-ring, and F-ring isoprostanes.
Four different regioisomers of each of these classes of isopros-
tanes are formed.3 Interestingly, levels of F2-isoprostanes (1-
4) in normal human biological fluids exceed levels of prosta-
glandins. Several synthesis routes to particular isoprostanes have
been reported.4-10 Since we are interested in the physiological
activity of each of the isoprostanes,11 we thought it more
attractive to prepare, through a common advanced intermediate,
the several diastereomers of an isoprostane family. Herein, we
* To whom correspondence should be addressed. E-mail taberdf@udel.edu.
(1) Undergraduate research participant, University of Delaware.
(2) (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. (b) Morrow,
J. D.; Awad, J. A.; Kato. T.; Takahashi, K.; Badr, K. F.; Roberts, L. J., II;
Burk, R. F. J. Clin. InVest. 1992, 90, 2502. (c) Morrow, J. D.; Awad, J.
A.; Boss, H. J.; Blair, J. A.; Roberts, L. J., II. Proc. Natl. Acad. Sci. U.S.A.
1992, 89, 10721. (d) 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.
(3) 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.
(4) For synthetic routes to 5-F2t-isoprostane, see: (a) Taber, D. F.; Kanai, K.;
Pina, R. J. Am. Chem. Soc. 1999, 121, 7773. (b) Adiyaman, M.; Lawson,
J. A.; Hwang, S. W.; Khanapure, S. P.; FitzGerald, G. A.; Rokach, J.
Tetrahedron Lett. 1996, 37, 4849.
(5) For a synthetic route to 5-F2c-isoprostane, see: Adiyaman, M.; Lawson, J.
A.; Hwang, S. W.; FitzGerald, G. A.; Rokach, J. Tetrahedron Lett. 1998,
39, 7039.
(6) For synthetic routes to 8-F2t-isoprostane, see: (a) Taber, D. F.; Jiang, Q.
J. Org. Chem. 2001, 66, 1876. (b) Adiyaman, M.; Li, H.; Lawson, J. A.;
Hwang, S. W.; Khanapure, S. P.; FitzGerald, G. A.; Rokach, J. Tetrahedron
Lett. 1997, 38, 3339.
(7) 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. P.; 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. (e) Durand, T.; Guy, A.; Vidal, J.-F.; Rossi, J.-C. J. Org. Chem.
2002, 67, 3615.
(8) 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. (d) Lai, S.; Lee, D.; Sun
U, J. Cha, J. K. J. Org. Chem. 1999, 64, 7213.
Results and Discussion
The 12-F2-isoprostanes were first identified in human plasma
samples by Roberts.11 To screen the physiological activity of
the eight enantiomerically pure diastereomers of the 12-F2-
isoprostanes, it will be necessary to individually prepare each
of them. One synthesis, specifically of 12-F2t-isoprostane 4, was
reported by Rokach in 1998.9
It seemed more attractive to develop a stereodivergent
synthesis scheme toward these targets from a common inter-
mediate, rather than design different syntheses of each. We
envisioned (Scheme 1) that the eight target molecules could be
prepared from the same racemic intermediate 12. The two
enantiomers of 12, which could be obtained by enzymatic
resolution,12 could each be converted to two of the four
(9) For synthetic routes to 12-F2t-isoprostane, see: (a) 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. (b) Hwang, S. W.;
Adiyaman, M.; Lawson, J. A.; FitzGerald, G. A.; Rokach, J. Tetrahedron
Lett. 1999, 40, 6167.
(10) For a synthetic route to 15-E2t-isoprostane, see: Taber, D. F.; Hoerrner,
R. S. J. Org. Chem. 1992, 57, 441.
(11) Morrow, J. D.; Roberts, L. J., II. Biochem. Pharmacol. 1996, 51, 1.
(12) Wong, C.-H.; Whitesides, G. M. Enzymes in Synthetic Organic Chemistry;
Pergamon Press: Oxford, U.K., 1994; and references therein.
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J. AM. CHEM. SOC. 2002, 124, 13121-13126
13121

A R T I C L E S
Taber et al.
Scheme 1
Scheme 2
Scheme 3 a
enantiomerically pure diastereomers 4-7. Mitsunobu inversion13
of the enantiomers of 12 would lead to the four enantiomerically
pure cis isomers 8-11.
Pursuing the retrosynthetic analysis (Scheme 2), the key diol
12 could be generated by kinetic opening of the activated
bicyclic ketone 13 with thiophenol and BF3‚OEt2. The bicyclic
ketone 13 could be constructed by rhodium-mediated cyclo-
propanation of the diazoketone 14. The aldol condensation of
diazoketone 15 and aldehyde 16 would provide the desired
diazoketone 14.
The aldehyde 16, a natural odorant,14 was prepared from the
commercially available 1,2,4-butanetriol 17 (Scheme 3). On
exposure to acetone, 17 was converted to 18a and 18b (ratio
18a/18b ) 3:1) as a mixture, which was further transferred to
the mixture of p-toluenesulfonates 19a and 19b. These were
tedious to separate by column chromatography, especially on a
large scale. Fortunately, on exposure to NaI in acetone, both
19a and 19b were converted smoothly to 20. We also found
that the ratio of 18a to 18b increased when the mixture was
a Reagents and conditions: (a) acetone, TsOH; (b) TsCl, Et3N, CH2Cl2;
(c) NaI, Cu, acetone; (d) PPh3, NaHCO3, CH3CN; (e) KHMDS, THF, -78
°C, hexanal; (f) 80% HOAc (aq), room temp; (g) NaIO4/SiO2, CH2Cl2/
H2O, room temp; (h) HOCH2CHdCHCH2PPh3Br, KHMDS, THF/CH2Cl2,
-78 °C; (i) Dess-Martin periodinane, CH2Cl2, room temp.
stored at 5 °C for several weeks. Using this approach, substantial
quantities of the valuable phosphonium salt 2115 could be
conveniently prepared.
Wittig coupling of 21 with hexanal resulted in the cis-alkene
22, which was hydrolyzed with 80% aqueous acetic acid to
(13) (a) Mitsunobu, O. Synthesis 1981, 1 and references therein. (b) Martin, S.
F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(14) For alternative syntheses of 16, see: Blank, I.; Lin, J.; Vera, F. A.; Welti,
D. H.; Fay, L. B. J. Agric. Food. Chem. 2001, 49, 2959 and references
therein.
(15) Mosset, P.; Pointeau, P.; Aubert, F.; Lellouche, J. P.; Beaucourt, J. P.; Gree,
R. Bull. Soc. Chim. Fr. 1990, 127, 298.
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13122 J. AM. CHEM. SOC. VOL. 124, NO. 44, 2002

Eight Diastereomers of the 12-F -Ioprostanes
A R T I C L E S
2
Scheme 4 a
Scheme 5 a
a Reagents and conditions: (a) K2CO3, toluene, TBABr, ethyl 4-bromo-
butyrate, 60 °C; (b) p-NBSA, DBU, CH2Cl2, 0 °C; (c) KHMDS, toluene,
-78 °C, 16, (TES)Cl; (d) TBAF, THF, 0 °C; (e) (TBDPS)Cl, imidazole,
a Reagents and conditions: (a) PhSH, BF3‚OEt2, CH2Cl2, -30 °C, (b)
NaBH4, MeOH/ EtOH, 0 °C; (c) Dess-Martin periodinane, CH2Cl2, room
temp; (d) NaBH4, MeOH/EtOH, 0 °C; (e) TBAF, THF, 0 °C to room temp.
DMAP, CH2Cl2, room temp; (f) Rh2 (Oct) , toluene/ CH2Cl2, -20 °C.
4
Table 1. Rh2(Oct)4 Catalyzed Cyclization of Diazoketone 14a
Scheme 6 a
total yieldb
entry
solvent, concn (M)
temp (°C)
(13 and 30) (%) ratio 13/30
1
2
3
CH2Cl2, 0.01
CH2Cl2, 0.02
CH2Cl2, 0.03
0
0
0
0
0
rt
-78
-20
-20
48
52
63
36
58
56
61
72
62
53
80
73
40f
3.0:1
2.8:1
3.0:1
3.5:1
2.9:1
2.5:1
3.3:1
2.8:1
2.9:1
3.5:1
2.7:1
3.0:1
2.8:1
4c CH2Cl2, 0.03
5
6
7
8
9
CH2Cl2, 0.1
CH2Cl2, 0.03
CH2Cl2, 0.1
CH2Cl2, 0.06
toluene, 0.06
10 hexane/CH2Cl2, 0.05 -20
11 toluene/CH2Cl2, 0.05 -20
12d toluene/CH2Cl2, 0.05 -20
13e toluene/CH2Cl2, 0.05 -20 to room temp
a Unless otherwise indicated, all reactions were carried out with 1% of
Rh2(Oct)4. The solution of Rh2(Oct)4 (3 mL/mg in CH2Cl2) was added to
a solution of 14 over 1 h. b Isolated yield. c A solution of 14 in CH2Cl2
was added to a solution of Rh2(Oct)4 in CH2Cl2. d 0.5% of Rh2(Oct)4 was
used. e 0.2% of Rh2(Oct)4 was used. f With 75% conversion.
provide the diol 23. Expecting the â,γ-unsaturated aldehyde 24
to be unstable, we carried the crude product from the Vo-Quang
periodate cleavage16 directly into the modified Wittig reaction,17
to afford the trienol 25. Oxidation of the trienol 25 with the
Dess-Martin periodinane18 provided the aldehyde.
The diazoketone 1519 (Scheme 4) was prepared from the
commercially available diketone 26 following the procedure we
(16) Daumas, M.; Vo-Quang, Y.; Vo-Quang, L.; Le Goffic, F. Synthesis 1989,
64.
(17) Hosoda, A.; Taguchi, T.; Kobayashi, Y. Tetrahedron Lett. 1987, 28, 65.
(18) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Ireland, R.
E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(19) Shinada, T.; Kawakami, T.; Sakai, H.; Takada, I.; Ohfune, Y. Tetrahedron
Lett. 1998, 39, 3757. No preparation details or characterization data for
diazoketone 15 were found in this reference.
a Reagents and conditions: (a) Amano lipase AK, vinyl acetate, 45 °C,
48 h; (b) (TBDPS)Cl, imidazole, DMAP, CH2Cl2, room temp; (c) K2CO3,
EtOH, 60 °C.
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A R T I C L E S
Taber et al.
Scheme 7 a
Scheme 8 a
a Reagents and conditions: (a) Ac2O, pyr. CH2Cl2, room temp; (b) (i)
mCPBA, CH2Cl2, -78 °C; (ii) (MeO)3P, EtOH, -78 °C to room temp; (c)
(i)Dess-Martin periodinane, CH2Cl2, room temp; (ii) NaBH4, EtOH, 0 °C;
(d) LiOH, THF/H2O, room temp.
a Reagents and conditions: (a) Ac2O, pyr. CH2Cl2, room temp; (b) (i)
mCPBA, CH2Cl2, -78 °C; (ii) (MeO)3P, EtOH, -78 °C to room temp; (c)
(i)Dess-Martin periodinane, CH2Cl2, room temp; (ii) NaBH4, EtOH, 0 °C;
(d) LiOH, THF/H2O, room temp.
previously developed.20 Alkylation of benzoylacetone 26 with
ethyl 4-bromobutyrate gave the diketone 27. The diazo transfer
of 27 with p-nitrobenzenesulfonyl azide provided the diazo-
ketone 15.
Aldol condensation of the diazoketone 15 and the aldehyde
16 was carried out in toluene in the presence of triethylsilyl
(TES) chloride with potassium bis(trimethylsilyl)amide at -78
°C.7d Apart from the desired TES-protected aldol 28 (58%), a
small amount of the free aldol 29 (14%) was also found. Due
to the instability of the TES group under the conditions for
cyclopropane ring opening with thiophenol and BF3‚OEt2, we
changed the protecting group to t-butyldiphenylsilyl (TBDPS),
to give 14.
The rhodium catalyzed cyclopropanation of diazoketone 14
afforded the bicyclic ketone 13 and its diastereomer 30. To
optimize this intramolecular cyclopropanation, we screened
several variables of solvent, temperature, and catalyst loading.
The results are summarized in Table 1. We found that the
optimal concentration was around 0.05 M (entries 1-5). The
yield decreased dramatically when the solution of 14 was added
to the solution of Rh2(Oct)4 in CH2Cl2 (entry 4 vs 3).
Temperature had a modest affect on the ratio of 13 to 30. The
mixed solvent of toluene and dichloromethane gave the best
yield of 13 (58%) and 30 (22%) (entry 11). A catalyst loading
of 0.5 mol % also gave good results (entry 12). The reaction
did not go to completion with 0.2 mol % of Rh2(Oct)4, resulting
in a low chemical yield (entry 13).
The structures of the bicyclic ketones 13 and 30 were assigned
by comparing the 1H and 13C NMR spectra to those for
analogous bicyclic ketones that were intermediates in the
synthesis of the 5-F2t-isoprostanes4a and the 8-F2t-isoprostanes.6a
1
In particular, the oxygenated methine of 13 (13C δ 69.5; H δ
4.47, d, J ) 4.9 Hz) is congruent with the analogous 5-F2t-
1
isoprostane precursor (13C δ 69.3; H δ 4.46, d, J ) 4.9 Hz)
1
and 8-F2t-isoprostane precursor (13C δ 69.3; H δ 4.46, d, J )
4.9 Hz), while the oxygenated methine of 30 (13C δ 68.1; 1H δ
4.60, dt, J ) 5.1, 7.9 Hz) is quite different.
Initially, difficulties were encountered in the cyclopropane
ring opening of 13 (Scheme 5) with thiophenol and BF3‚OEt2.21
Low temperature (<-30 °C) or low concentration (<0.1 M)
resulted in incomplete reaction. Warmer temperatures (0 °C)
generated several side products. We found that treatment of 13
with 3 equiv of thiophenol and 4 equiv of BF3‚OEt2 in CH2Cl2
(0.2 M) at -30 to -20 °C for 6 h gave smooth conversion to
the ketone 31, which was used directly in the subsequent
reduction. We found that some deprotection of the TBDPS group
occurred when the reduction was carried out in MeOH or EtOH
over 1 h. Fortunately, this reaction could be finished in a mixed
solvent system of MeOH/EtOH (1:1) with NaBH4 within 20
min without causing silyl group deprotection.
The undesired alcohol 33 could be transferred to the mixture
of 33 and 34 by oxidation with Dess-Martin periodinane,18
(21) From ketone 13 on, all reactions (except for the enzymatic resolution and
the final hydrolysis steps) were run in the presence of a trace amount of
methylene blue to inhibit isomerization of the side chain. For the use of
methylene blue to stabilize 1,4-dienes, see: Taber, D. F.; Phillips, M. A.;
Hubbard, W. C. Prostaglandins 1981, 22, 349.
(20) Taber, D. F.; Gleave, D. M.; Herr, R. J.; Moody, K.; Hennessy, M. J. Org.
Chem. 1995, 60, 2283.
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Eight Diastereomers of the 12-F -Ioprostanes
A R T I C L E S
2
Scheme 9 a
Scheme 10 a
a Reagents and conditions: (a) K2CO3, EtOH, 60 °C, 1.5 h; (b) PPh3,
DEAD, p-NO2C6H4COOH, benzene; (c) mCPBA, CH2Cl2, -78 °C; (ii)
(MeO)3P, EtOH, -78 °C to room temp; (d) (i) Dess-Martin periodinane,
CH2Cl2, room temp; (ii) NaBH4, EtOH, 0 °C; (e) K2CO3, EtOH; (f) LiOH,
THF/H2O, room temp.
a Reagents and conditions: (a) K2CO3, EtOH, 60 °C, 1.5 h; (b) PPh3,
DEAD, p-NO2C6H4COOH, benzene; (c) mCPBA, CH2Cl2, -78 °C; (ii)
(MeO)3P, EtOH, -78 °C to room temp; (d) (i) Dess-Martin periodinane,
CH2Cl2, room temp; (ii) NaBH4, EtOH, 0 °C; (e) K2CO3, EtOH; (f) LiOH,
THF/H2O, room temp.
chiral HPLC.22 The enantiomerically enriched monoacetate (+)-
35 was hydrolyzed to diol 12 and subjected to enzyme resolution
again to give the monoacetate (+)-35 with >98% ee in 41%
overall yield (82% of theoretical) from the racemic diol 12.
followed by reduction. The relative configuration of 34 (1H
NMR δ 4.47, dt, J ) 2.5, 6.4 Hz, 1H, 4.08, m, 1H) was also
1
assigned by comparing the H and 13C NMR spectra to those
precursors for the 5-F2t-isoprostanes (1H NMR δ 4.44, dt, J )
3.6, 6.6 Hz, 1H, 4.08, m, 1H) and the 8-F2t-isoprostanes (1H
NMR δ 4.48, dt, J ) 2.5, 6.5 Hz, 1H, 4.05, m, 1H). Desilylation
of 34 with tetrabutylammonium fluoride (TBAF) in tetrahydro-
furan (THF) provided the key intermediate 12.
The racemic diol 12 (Scheme 6) when treated with Amano
lipase AK in neat vinyl acetate at 40 °C for 48 h provided
monoacetates (+)-35 (53% yield) and (-)-36 (34% yield) along
with the diacetate (-)-40 (8% yield with 86% ee). The
monoacetates (+)-35 and (-)-36 were converted to their
diacetates (+)-40 and (-)-40 in quantitative yield. Their ee
values were determined to be 85 and >98% respectively, by
The structure of the monoacetate (+)-35 was established by
conversion to 34 by protection followed by hydrolysis. The same
transformation converted the monoacetate (-)-36 to 39. Since
the same enzyme and a very similar substrate were employed
in this resolution, the absolute configurations of (+)-35 and (-)-
36 were assigned by analogy to our recent synthesis of the
enantiomerically pure diastereomers of 15-F2t-isoprostane.7d
(22) The ee’s were determined by HPLC analysis with a CHIRALCEL OD
column (Daicel Chemical Industries Ltd,): detector, UV (254 nm); flow
rate, 1 mL/ min; mobile phase, hexane/2-PrOH ) 9:1. Retention time: (+)-
40, 6.3 min; (-)-40, 8.0 min.
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A R T I C L E S
Taber et al.
With the requisite enantiomerically pure acetates (+)-35 and
(-)-36 in hand, the four enantiomerically pure trans isomers
of 12-F2t-isoprostane were prepared. The diacetate (+)-40
(Scheme 7) was obtained in quantitative yield by treating the
monoacetate (+)-35 with acetic anhydride. Oxidation and
Mislow rearrangement23 of (+)-40 provided the allylic alcohol
(-)-41, which on treatment with Dess-Martin periodinane,
followed by reduction with NaBH4, afforded the epimeric allylic
alcohol (-)-41 and (-)-42. These were readily separated by
column chromatography. They were separately hydrolyzed with
LiOH in THF-H2O (1:1) to furnish ent-12-F2t-isoprostane 6
and its 12-epimer 7 in 90 and 91% yields, respectively. The
same procedures were carried out (Scheme 8) with the mono-
acetate (-)-36 to complete the preparation of 12-F2t-isoprostane
the 13C NMR chemical shifts of the non-oxygenated methines
of 6 (δ 50.1, 54.2) with those of 8 (δ 46.9, 50.1).
Oxidation and Mislow rearrangement22 of (+)-43 provided
the allylic alcohol (+)-44. Oxidation of (+)-44 followed by
reduction gave an inseparable mixture of (+)-44 and 45.
Fortunately, transesterification of (+)-44 and 45 with K2CO3
at room temperature in EtOH gave (-)-46 and (-)-47, which
could be separated by column chromatography. Hydrolysis of
(-)-46 or (-)-47 individually with LiOH furnished the 12-F2c-
isoprostane diastereomers 8 and 9. The same strategy was
applied to the enantiomerically pure monoacetate (-)-36
(Scheme 10), leading to the two other 12-F2c-isoprostane
diastereomers 10 and 11. The 12-F2c diastereomers had never
previously been prepared.25
4 and its 12-epimer 5. The spectroscopic data for 4 (1H and 13
C
Conclusion
NMR) were consistent with those previously reported.9,24
A stereodivergent and practical synthesis of the eight enan-
tiomerically pure diastereomers of the 12-F2-isoprostanes has
been developed. The key steps include rhodium-mediated
intramolecular cyclopropanation and enzymatic resolution. This
approach has provided a sufficient quantity of 4-11 to assess
their physiological activity.
We thought that perhaps Mitsunobo inversion13 of 12 could
lead to the all-cis 12-F2-isoprostane derivatives. In fact, Mit-
sunobo coupling of the diol (+)-12 (Scheme 9) afforded the
12-F2c-isoprostane derivative (+)-43 in 45% yield, accompanied
by elimination products. That the reaction had proceeded with
inversion at each of the reacting stereogenic centers was
confirmed by comparing the 13C NMR chemical shifts of the
non-oxygenated methines of (+)-43 (δ 43.1, 44.6, 49.4) with
those of (+)-12 (δ 49.6, 50.5, 53.1). As can be seen by
comparing 33 (δ 46.3, 47.9, 55.2) with 34 (δ 47.3, 50.4, 54.6),
the methine adjacent to a cis OH resonates at higher field than
the methine adjacent to a trans OH. Since both the methines of
(+)-43 were shifted upfield, both of the reacting centers must
have inverted. This assignment was confirmed by comparing
Acknowledgment. We thank the National Institutes of Health
(Grant GM42056) for support for this work.
Note Added after Print Publication: Due to a production
error, Table 1 and Scheme 5 contained errors in the version
published on the Web 10/11/2002 (ASAP) and in the November
6, 2002 issue (Vol. 124, No. 44, pp 13121-13126); the correct
electronic version of the paper was published on 11/27/2002
and an Addition and Correction appears in the December 25,
2002 issue (Vol. 124, No. 51).
Supporting Information Available: Text giving detailed
experimental procedures and figures showing spectra for all new
compounds (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
(23) (a) Bickart, P.; Carson, F. W.; Jacobus, 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.
(24) The previous report did not include [R]D, so no comparison could be made.
(25) For a recent synthesis of each of the eight enantiomerically pure diaster-
eomers of the 15-F2-isoprostanes, see: Schrader, J. O.; Snapper, M. L. J.
Am. Chem. Soc. 2002, 124, 10998.
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