A cross-metathesis route to the 5-F2-isoprostanes

Article abstract of DOI:10.1021/jo702702s

(Chemical Equation Presented) A library of eight 5-F₂- isoprostanes was prepared through a ring-opening metathesis/cross-metathesis protocol between functionalized bicyclo[3.2.0]heptenes, ethylene, and α,β-unsaturated ketones. This sequence provided racemic enones in a regio- and stereoselective fashion that could be converted to enantiomerically enriched allylic alcohols through a catalyst-controlled asymmetric reduction. Completion of the sidechains, followed by global deprotection, resulted in a stereodivergent route to eight enantiomerically enriched 5-F₂ isoprostanes. Overall, the synthesis of this library of known and anticipated lipid oxidation metabolites was achieved in 10 steps from commercially available 4-hydroxy-2-cyclopentenone.

Full text of DOI:10.1021/jo702702s

A Cross-Metathesis Route to the 5-F2-Isoprostanes
Bhaumik A. Pandya and Marc L. Snapper*
Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College, 2609 Beacon Street,
Chestnut Hill, Massachusetts 02467-3860
marc.snapper@bc.edu
ReceiVed December 19, 2007
A library of eight 5-F2-isoprostanes was prepared through a ring-opening metathesis/cross-metathesis
protocol between functionalized bicyclo[3.2.0]heptenes, ethylene, and R,ꢀ-unsaturated ketones. This
sequence provided racemic enones in a regio- and stereoselective fashion that could be converted to
enantiomerically enriched allylic alcohols through a catalyst-controlled asymmetric reduction. Completion
of the sidechains, followed by global deprotection, resulted in a stereodivergent route to eight enan-
tiomerically enriched 5-F2 isoprostanes. Overall, the synthesis of this library of known and anticipated
lipid oxidation metabolites was achieved in 10 steps from commercially available 4-hydroxy-2-cyclopentenone.
Introduction
Reactive oxygen species have been implicated in a variety
of human diseases.1 These free radical intermediaries are
believed to be able to transform common lipid components into
a variety of potent secondary messengers. A well-known
example of this phenomenon is the conversion of arachidonic
acid into the prostaglandins (e.g., 2, Figure 1).2 A lesser known
example is the formation of the isoprostanes and isoprostanyl
esters3 from arachidonic esters (1).4 Since their discovery by
Morrow and Roberts,4 clinicians have used the levels of certain
isoprostanes in bodily fluids as quantitative markers of disease-
related oxidative stress.5 In addition, the isoprostanes have also
(1) For heptatorenal syndrome, see: (a) Morrow, J. D.; Moore, K. P.; Awad,
J. A.; Raveenscraft, M. D.; Marini, G.; Badr, K. F.; Williams, R.; Roberts, L. J,
II. Lipid Mediators 1993, 6, 417. For alcohol induced-liver disease, see: (b) Lands,
W. E. Alcohol.: Clin. Exp. Res. 1995, 19, 928. For pulmonary hypertension,
see: (c) Kang, H. K.; Morrow, J. D.; Roberts, L. J., II; Newman, J. H.; Banerjee,
M. J. Appl. Physiol. 1993, 74, 460. For myocardial infarction, see: (d) Sing, N.;
Dhalla, A. K.; Seneviratne, C.; Singal, P. K. Mol. Cell. Biochem. 1995, 147, 77.
For atherosclerosis, see: (e) Gopaul, N. K.; Nourooz-Zadeh, J.; Mallet, A. I.;
Anggard, E. E. Biochem. Biophys. Res. Commun. 1994, 200, 338. (f) Cracowski,
J.-L. Chem. Phys. Lipids 2004, 128, 75.
FIGURE 1. Arachidonic acid metabolites.
been linked to inflammatory events as well as smooth muscle
regulation.6 The role of these lipid metabolites in normal, as
(2) For example, see: (a) Prostaglandins, Leukotrienes and Essential Fatty
Acids; Horrobin, D. F., Manku, M. S., Sirois, P., Borgeat, P., Eds.; Churchill
Livingstone: Edinburgh, UK, 2002. (b) Prostaglandins, leukotrienes and other
eicosanoids: from biogenesis to clinical application, Marks, F., Furstenberger,
G., Eds.; Wiley-VCH: Weinheim, Germany, 1999. Also see: (c) Helmer, M. E.;
Lands, W. E. M. Lipids 1997, 12, 591. (d) Porter, N. A.; Funk, M. O. J. Org.
Chem. 1975, 40, 3614.
(3) Shizuka, M.; Schrader, T. O.; Snapper, M. L. J. Org. Chem. 2006, 71,
1330.
(4) 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.
3754 J. Org. Chem. 2008, 73, 3754–3758
10.1021/jo702702s CCC: $40.75 2008 American Chemical Society
Published on Web 04/17/2008

Cross-Metathesis Route to the 5-F2-Isoprostanes
well as disrupted, physiological processes may be critical to
uncovering relationships between radical-mediated oxidative
damage and human disease.7
Unlike the prostaglandins, the isoprostanes may be generated
in the absence of any initial enzymatic control.8 Depending on
the regioselectivity of the initial oxidation of the arachadonic
ester (1), four regioisomeric classes of the isoprostanes are
possible (Figure 1, 15-F2-isoprostane, 12-F2-isoprostane, 8-F2-
isoprostane, and 5-F2-isoprostane).9 Preliminary studies suggest
that each of these isoprostanoidal families may have unique
physiological activities.10
In an effort to learn more about the formation and physio-
logical functions of these lipid oxidation metabolites, we have
begun to develop concise, stereospecific entries into the specific
families of the isoprostanes. Previously, we reported the preparation
of a stereodefined library of 15-F2-isoprostanes using a ring-opening
cross-metathesis (ROCM)11 on a common cyclobutene precursor.12
Herein, we describe a modified metathesis strategy that allows for
the preparation of a stereodiverse library of the 5-F2-isoprostanes
(3-6, Figure 2).13 Although members of this class are among the
most abundant of the isoprostanes found in human urine, relatively
little is known about their biological activities and possible intra-
and extracellular interactions.14
FIGURE 2. Known and predicted 5-F2-isoprostanes.
isoprostanyl series. Given the low degree of olefin stereochemical
control observed in our earlier cross-metathesis studies, we were
particularly keen on using R,ꢀ-unsaturated ketones as reaction
partners to install the upper side chain of the 5-F2 isoprostanes.
Cross-metatheses of electron-deficient olefins are known to generate
E-disubstituted olefins, at times almost exclusively.15 Moreover,
the robust ruthenium benzylidenes 8 and 9 have shown to be
particularly useful in these transformations.16
Like the 15-F2-isoprostanes, a ROCM of functionalized
cyclobutenes was envisioned as an effective entry into the 5-F2-
(5) (a) Garret, A. F.; Rokach, J.; Lawson, J. A.; Patrico, D. Chem. Phys.
Lipids 2004, 128, 165. (b) Morrow, J. D.; Roberts, L. J., II. Cell. Mol. Life Sci.
2002, 59, 808. (c) Lawson, J. A.; Rokach, J.; Fitzgerald, G. A. J. Biol. Chem.
1999, 274, 2441. (d) Lawson, J. A.; Li, H.; Rokach, J.; Adiyaman, M.; Hwang,
S. W.; Khanapure, S. P.; Fitzgerald, G. A. J. Biol. Chem. 1998, 273, 29295. (e)
Kadiiska, M. B.; Morrow, J. D.; Awad, J. A.; Roberts, L. J., II; Mason, R. P.
Chem. Res. Toxicol. 1998, 11, 1516. (f) Morrow, J. D.; Minton, T. A.; Mukundan,
C. R.; Campbell, M. D.; Zackert, W. E.; Daniel, V. C.; Badr, K. F.; Blair, I. A.;
Roberts, L. J., II. J. Biol. Chem. 1994, 269, 4317.
(6) Hou, X.; Roberts, L. J., II; Gobeil, F., Jr.; Taber, D. F.; Kanai, K.; Abran,
D.; Brault, S.; Daniella, C.; Sennlaub, F.; LaChapelle, P.; Varma, D. R.; Chemtob,
S. Free Radical Bio. Med. 2004, 36, 163.
(7) Adiyaman, M.; Lawson, J. A.; Hwang, S.-W.; Khanapure, S. P.;
FitzGerald, G. A.; Rokach, J. Tetrahedron Lett. 1996, 37, 4849.
Results and Discussion
(8) (a) Morrow, J. D.; Awad, J. A.; Boss, H. J.; Blair, I. A.; Roberts, L. J.,
II. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 10721. (b) Kayganich-Harrison, K. A.;
Rose, D. M.; Murphy, R. C.; Morrow, J. D.; Roberts, L. J., II. J. Lipid Res.
1993, 34, 1229. A small percentage of isoprostane production may be attributed
to the action of the COX enzymes. (c) Practico´, D.; Lawson, J. A.; FitzGerald,
G. A. J. Biol. Chem. 1995, 270, 9800. (d) Practico´, D.; FitzGerald, G. A. J. Biol.
Chem. 1996, 271, 8919. (e) Patrignani, P.; Santini, G.; Panara, M. R.; Sciulli,
M.; Greco, A.; Rotondo, M. T.; Giamberardino, M.; Maclouf, J.; Ciabttoni, G.;
Patrono, C. Br. J. Pharmacol. 1996, 118, 1285.
In the retrosynthetic analysis of the 5-F2 isoprostanes, we
considered two metathesis-based strategies for elaborating the
functionalized cyclobutenes into the appropriate cis-dialkyl
substituted cyclopentandiols. These strategies are summarized
in Figure 3 (Pathways A and B). Pathway A involves a selective
ring-opening cross-metathesis of a bicyclo[3.2.0]heptene with
an suitably functionalized olefin. Given our experience with the
(9) (a) Patrono, C.; Davi, G.; Falco, A. Chem. Phys. Lipids 2004, 128, 149.
For a summary of isoprostane nomenclature, see: (b) Roberts, L. J., II; Taber,
D. F.; Morrow, J. D. Prostaglandins 1997, 53, 63. For an alternative nomenclature
system, see: (c) Rokach, J.; Khanapure, S. P.; Hwang, S. W.; Adiyaman, M.;
Lawson, J. A.; FitzGerald, G. A. Prostaglandins 1997, 54, 853.
(10) For a recent synopsis of the pharmacology of isoprostanes and other
lipid peroxidation products, see: Chem. Phys. Lipids 2004, 128, 1-193.
(11) (a) Randall, M. L.; Tallarico, J. A.; Snapper, M. L. J. Am. Chem. Soc.
1995, 117, 9610. For lead references on ring-opening cross-metathesis applica-
tions in total synthesis, see: (b) Grubbs, R. H., Ed.; Handbook of Metathesis;
Wiley-VCH: New York, 2003; Vol. 2, Sec. 2.6, and references therein.
(12) (a) Schrader, T. O.; Snapper, M. L. Tetrahedron Lett. 2000, 41, 9685.
(b) Schrader, T. O.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124, 10998.
(13) For lead references on the syntheses of 5-F2-isoprostanes, see: (a) Taber,
D. F.; Kanai, K.; Pina, R. J. Am. Chem. Soc. 1999, 121, 7773. (b) Adiyaman,
M.; Lawson, J. A.; Khanapure, S. P.; FitzGerald, G. A.; Rokach, J. Anal. Biochem.
1998, 262, 45. (c) Adiyaman, M.; Lawson, J. A.; FitzGerald, G. A.; Rokach, J.
Tetrahedron Lett. 1998, 39, 7039. (d) Durand, T.; Cracowski, J.-L.; Guy, A.;
Rossi, J.-C. Bioorg. Med. Chem. Lett. 2001, 11, 2495. (e) Also, see ref 7.
(14) For example, see: (a) Marliere, S.; Cracowski, J.-L.; Durband, T.;
Chavanon, O.; Bessard, J.; Guy, A.; Stank-Labesque, F.; Ross, J.-C.; Bessard,
G. Br. J. Pharmacol. 2002, 135, 1276. (b) Arnaud, C.; Cracowski, J.-L.; Hakim,
A.; Durand, T.; Guy, A.; Godin-Ribuot, D.; Bessard, G.; Ribuot, C. Clin. Exp.
Pharmacol. Physiol. 2005, 32, 350. (c) Hou, X.; Roberts, L. J.; Gobeil, F., Jr.;
Taber, D. F.; Kanai, K.; Abran, D.; Brault, S.; Checchin, D.; Sennlaub, F.;
Lachapelle, P.; Varma, D. R.; Chemtob, S. Free Radical Bio. Med. 2004, 36,
163.
FIGURE 3. ROM routes to the 5-F2-isoprostanes.
(15) Choi, T.-L.; Lee, C. W.; Chatterjee, A. K.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 10417.
(16) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168.
J. Org. Chem. Vol. 73, No. 10, 2008 3755

Pandya and Snapper
15-F2-isoprostanes, there were some concerns over establishing
the correct olefin stereochemistry in this cross-metathesis route.
Alternatively, as illustrated in pathway B, an intramolecular ring-
opening/ring-closing metathesis (RO/RCM) route could be used
to influence the stereochemistry of the newly established di-
substituted olefin. In this case, esterification of the bicyclo[3.2.0]-
heptene would provide an intermediate with an appended side
chain that contained a terminal olefin and appropriate substitu-
tion at the allylic position. Ring-opening/ring-closing metathesis
of this functionalized cyclobutene could generate a 10-membered
lactone with control over the newly formed olefin geometry.17
Hydrolysis of the lactone, followed installation of the lower side
chain, would then complete the synthesis of the 5-F2-isoprostane.
From the onset, we opted to examine both of these strategies
concurrently since the requisite starting materials were available
from known compounds in short order. Although multiple
precatalysts were evaluated for either approach, the most
productive were the Grubbs’ first generation complex 7 and
Hoveyda-Grubbs complex 9.
with enone 14 using the first generation Grubbs’ catalyst 7
provided intractable products that were ascribed to rapid ring-
opening polymerization of the cyclobutene. Despite modifica-
tions to the reaction conditions, such as changes to reaction
concentration, solvent, temperature, catalyst loading, and olefin
addition rates, this polymerization process could not be sup-
pressed. Initiation of ruthenium benzylidene with electron
deficient alkenes is not likely, and in our case, propagation with
the enone must be slower than reaction of the alkylidene with
another molecule of cylcobutene. Ring-opening of cyclobutene
13 with ethylene to provide the protected divinylcyclopentandiol
15, however, did proceed without incident (entry 2).19
TABLE 2. Ring-Opening Cross-Metatheses (ROCM)
Ring-Opening/Ring-Closing Metathesis (RO/RCM). Our
preliminary evaluation of the RO/RCM strategy using func-
tionalized cyclobutenes 10 and 12 is summarized in Table 1.
Cyclobutene 10 participated in a sequential ring-opening/ring-
closing metathesis with alkylidene 7 to provide lactone 11 as a
mixture of olefin isomers (3:1) in a modest 37% yield (entry
1). When the appended alkene contained an R,ꢀ-unsaturated
ketone at the terminus, such as 12, the ring-closed product was
not observed (Entry 2). The substrate did provide ring-opened
product under ethylene atmosphere in low yield, but further
reaction resulted only in homodimerization of the triene. Given
these shortcomings, attention was focused on the intermolecular
ROCM strategy (pathway A, Figure 3).
TABLE 1. Ring-Opening/Ring-Closing Metatheses
Interestingly, cyclobutene 16 was inert to reaction conditions
optimized for the diastereomeric cyclobutene 13 (entries 3 and
4). Rather than recover cyclobutene polymer when reacted with
enone 14, the major product obtained was the starting cy-
clobutene. This was peculiar considering the ring strain of these
molecules. Careful examination of the mass balance suggested
that the catalyst was being sequestered by the substrate thus
a Hoveyda-Grubbs catalyst 9 (5 mol%).
Ring-Opening Cross-Metathesis (ROCM). The results for
the ring-opening cross-metathesis studies on cyclobutenes 13,
16, and 17 with keto-ester 1418 and/or ethylene are summarized
in Table 2. As shown in entry 1, ROCM of cyclobutene 13
(18) (b) Fu¨rstner, A.; Schlede, M. AdV. Synth. Cat. 2002, 344, 657. (c)
Banwell, M. G.; Loong, D. T. J. Org. Biomol. Chem. 2004, 2, 2050. (d) Kaul,
R.; Surprenant, S.; Lubell, W. D. J. Org. Chem. 2005, 70, 3838. (e) Davoli, P.;
Fava, R.; Morandi, S.; Spaggiari, A.; Prati, F. Tetrahedron 2005, 61, 4427.
Milstein, D.; Stille, J. K. J. Org. Chem. 1979, 44, 1613.
(19) Yields for these reactions were dependent on the protocol used to
separate ruthenium byproducts from the desired material. For optimal results,
see: (a) Kim, B. M.; Cho, J. H. Org. Lett. 2003, 5, 531.
(17) (a) Fu¨rstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann,
C. W.; Mynott, R. J. Am. Chem. Soc. 2002, 124, 7061.
3756 J. Org. Chem. Vol. 73, No. 10, 2008

Cross-Metathesis Route to the 5-F2-Isoprostanes
preventing turnover.20 This problem was solved by silylation
of the free alcohol to provide meso-17. Ring-opening cross-
metathesis or polymerization activity was then restored with
fully protected cyclobutene 17 (entries 5 and 6).
SCHEME 2. Resolution of 5-F2t-Isoprostane Precursors
On the basis of these observations, a stepwise metathesis-
based functionalization of cyclobutenes 13 and 17 was examined
(Scheme 1). ROCM of cyclobutene 13 with ethylene, followed
by a cross-metathesis (CM) of the resulting diene 15 with enone
14, provided racemic ketone 19 as single regio- and (E)-
stereoisomer in 77% isolated yield in a single reaction vessel.21
SCHEME 1. ROCM/CM Entry into 5-F2-Isoprostanes
were also enhanced by recycling them through the oxidation/
asymmetric reduction sequence described above to give both
diols (-)-21 and (-)-22 in 96% ee.
Global protection of the secondary alcohols in (+)-21 and
(+)-22 as TBS ethers increased the selectivity of the subsequent
reactions (Scheme 3). Hydroboration of the terminal olefin was
accomplished with dicyclohexylborane to provide a primary
alcohol, which was then subjected to a one-pot oxidation-Wittig
olefination protocol.24 Fluoride-mediated deprotection of the
silyl groups and saponification of the ester yielded ent-5-epi-
F2t-isoprostane (+)-5 (from diol (+)-21) and 5-F2t-isoprostane
(-)-3 (from diol (+)-22) in overall yields of 18% and 14%,
respectively for the final four steps. Likewise, the final steps in
the synthesis (c-f, Scheme 3) were repeated to provide 5-epi-
F2t-isoprostane (-)-5 and ent-5-F2t-isoprostane (+)-3 in 17%
and 16% overall yield for the six-step sequence.
Although cyclobutene 17 undergoes a quantitative ROCM
with ethylene, the selectivity for the cross metathesis of the
resulting diene 18 with enone 14 was difficult to control. To
avoid consuming the desired ketone 20 to a second facile cross-
metathesis with enone 14, the reaction was run to partial
conversion and the recovered meso-diene 18 was recycled in
the cross-metathesis (3×) to provide the desired (E)-enone (()-
20 in an overall yield of 68%.
5-F2t-Isoprostane Syntheses. Having established a reliable
pathway to ketone (()-19, synthesis of the four trans 5-F2t-
isoprostanes proceeded with TMS protection of the secondary
alcohol and enantioselective reduction/resolution of the resulting
unsaturated ketone with catecholborane in the presence of the
(R)-CBS catalyst (Scheme 2).22 In situ removal of the TMS
ether provided the chromatographically distinct diastereomers
(+)-21 and (+)-22 in 82 and 78% ee, respectively, in an average
80% yield for the two steps. The optical purity of these diols
could be enhanced further by oxidation of these products to
the corresponding optically enriched R,ꢀ-unsaturated ketones
(+)- and (-)-19 and then resubjection of each enantiomerically
enriched ketone to the two-step TMS protection/enantioselective
reduction to provide diols (+)-21 and (+)-22 in 97% ee23 and
66% yield for the three-step sequence.
SCHEME 3. Preparation of 5-F2t-Isoprostanes
Alternatively, using the (S)-Methyl CBS catalyst and cat-
echolborane on racemic ketone 19 allowed access to the
diastereomeric diols (-)-21 (77% ee) and (-)-22 (78% ee) in
approximately 80% yield. The optical purity of these compounds
(20) For early examples of this type of interaction, see: (a) Snapper, M. L.;
Tallarico, J. A.; Randall, M. L. J. Am. Chem. Soc. 1997, 119, 1478. (b) Tallarico,
J. A.; Bonitatebus, P. J., Jr.; Snapper, M. L. J. Am. Chem. Soc. 1997, 1197157.
(21) For a related CM strategy to install a similar sidechain, see: (a) Jacobo,
S. H.; Chang, C.-T.; Lee, G.-J.; Lawson, J. A.; Powell, W. S.; Pratico´, D.;
FitzGerald, G. A.; Rokach, J. J. Org. Chem. 2006, 71, 1370. For a discussion of
selective issues in cross-metatheses, see: (b) Chatterjee, A. K.; Choi, T.-L.;
Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360. Catalyst 13
was inefficient in performing the CM either in tandem or separate operations.
Conversely, catalyst 15 provided only cyclobutene polymer when subjected to
optimal ring-opening under ethylene atmosphere.
5-F2c-Isoprostane Syntheses. Ketone ( ( )-20 provides the
launching point for the preparation of the cis 5-F2c-isoprostanes
(22) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1987.
(23) Enantiomeric excess determined by HPLC of corresponding ketone. See
Supporting Information for details.
(24) MacCoss, R. N.; Balskus, E. P.; Ley, S. V. Tetrahedron Lett. 2003, 44,
7779.
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Pandya and Snapper
SCHEME 4. Resolution of 5-F2c-Isoprostane Precursors
tionalized cyclobutenes with ethylene, followed by a cross-
metathesis with R,ꢀ-unsaturated ketone 14 provided isoprostane
precursors with high regio- and stereocontrol. Additional key
steps in the synthesis include an enantioselective reduction/
resolution strategy to generate enantiomerically enriched prod-
ucts and an oxidation/olefination protocol to complete the 5-F2-
isoprostane framework. These transformations offer in a longest
linear sequence of ten steps26 from commercially available
4-hydroxy-2-cyclopentenone, a concise, stereodivergent route
to eight enantiomerically enriched 5-F2-isoprostanes.
Experimental Section
Representative Procedure for the Cyclobutene Ring-Open-
ing Metathesis/Cross-Metathesis Sequence. (E)-Methyl-7-(-3-
(t-butyldimethylsilyloxy)-2-vinylcyclopentyl)-5-oxohept-6-no-
ate (()-19. To a solution of Grubbs’ catalyst 7 (131 mg, 0.159
mmol) in benzene (25 mL), ethylene gas was bubbled using a
balloon and outlet needle for 5 min. A violet-to-amber color change
of the catalyst solution was observed. To a solution of cyclobutene
13 (766 mg, 3.19 mmol) in benzene (70 mL) in a separate flask
was added this catalyst solution (25 mL, 0.006 M) by syringe with
continuous introduction of ethylene gas by balloon and outlet
needle. Saturation of the reaction medium with ethylene gas was
continued for an additional minute, after which the outlet needle
was removed and the balloon needle was raised from its immersion
in solvent. The balloon atmosphere of ethylene was maintained for
12 h, after which the reaction was judged to be complete by TLC
and GC with internal standard (decane). The ethylene balloon was
then replaced with a cold water condenser containing a nitrogen
inlet. The flask was charged with enone 14 (6.4 mmol) as a solution
in benzene (8 mL) followed by Hoveyda-Grubbs’ II catalyst 9 (200
mg, 0.320 mmol). The reaction was heated to a gentle reflux under
a N2 atmosphere for 18 h. The reaction was cooled to rt at which
time silica gel (10 g) was added to the dark solution along with
ethyl vinyl ether (3 mL). The suspension was stirred open to air
for 10 min before being loaded directly on to a silica gel column
prewet (10% EtOAc/hexanes). Enone (()-19 was obtained as a
yellow oil (969 mg, 2.45 mmol, 77% yield). TLC Rf 0.30 (33%
(Scheme 4). Reduction of the carbonyl with the (R)-CBS
catalyst, followed by protection and hydroboration yields the
primary alcohols (-)-23 and (+)-24, in approximately 50% ee
and 86% yield over three steps.25 Employing the opposite
antipode of the reduction-resolution catalyst, (S)-methyl-CBS,
gives alcohols (+)-23 and (-)-24 in similar yield and selectivity
after the analogous three-step sequence.
As shown in Scheme 5, the separable enantiomerically
enriched intermediates (+)-23 and (-)-24 were carried forward
to their respective isoprostanes (+)-6 and (-)-4 in a fashion
similar to the previously described isomers (Scheme 3). Using
this strategy, the four cis-isoprostanes, 5-epi-F2c-isoprostane (-)-
6, ent-5-F2c-isoprostane (+)-4, ent-5-epi-F2c-isoprostane (+)-
6, and 5-F2c-isoprostane (-)-4 were obtained in an average 26%
yield over 5 steps.
SCHEME 5. Preparation of 5-F2c-Isoprostanes
1
EtOAc/hexanes). H NMR (CDCl3, 400 MHz): δ 6.67 (dd, J )
15.6, 9.6 Hz, 1H), 6.13 (d, J ) 15.6 Hz, 1H), 5.48 (dt, J ) 16.4,
10.4 Hz, 1H), 5.08 (s, 1H), 5.05 (d, J ) 7.6 Hz, 1H), 4.12 (dt, J )
7.8, 4.8 Hz, 1H), 4.07 (dt, J ) 6.0, 3.2 Hz, 1H), 3.67 (s, 3H), 3.01
(dt, J ) 8.4, 5.6 Hz, 1H), 2.85 (t, J ) 8.0 Hz, 1H), 2.59 (t, J ) 7.2
Hz, 2H), 2.43-2.34 (m, 3H), 1.93 (qt, J ) 14.4, 7.2 Hz, 2H), 1.76
(t, J ) 3.4 Hz, 2H), 1.72 (t, J ) 3.4 Hz, 1H), 0.88 (s, 9H), 0.05 (s,
6H). 13C NMR (CDCl3, 100 MHz): δ 198.7, 173.4, 145.3, 135.6,
130.9, 117.6, 76.3, 56.8, 54.0, 51.6, 43.3, 39.5, 33.2, 25.9, 19.3,
18.1, -4.5, -4.6. IR (thin film, NaCl): 3444, 2955, 2926, 2852,
1741 (s), 1673, 1623, 1255, 1093 cm-1. Anal. Calcd for C20H34O5Si:
C, 62.79; H, 8.96; Found: C, 63.44; H, 9.38.
Acknowledgment. We thank the National Institutes of Health
(R01-CA66617) for support of this work. We acknowledge Thomas
O. Schrader and Manami Shizuka for helpful discussions. We are
also grateful to Materia for the gift of metathesis catalysts.
Supporting Information Available: Experimental proce-
dures and spectroscopic characterization for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO702702S
Conclusions
(25) Optical purity in this series was determined by 1H-NMR analysis of
the corresponding secondary alcohol Mosher esters. See Supporting Information
for details.
(26) The step count doesn’t include the recycling steps that were used to
enhance the optical purity of these isoprostanes.
Modifications to the ROCM strategy that was used to generate
the 15-F2-isoprostanes has allowed for a concise preparation of
a library of 5-F2-isoprostanes. ROCM of appropriately func-
3758 J. Org. Chem. Vol. 73, No. 10, 2008