Stereocontrolled access to isoprostanes via a bicyclo[3.3.0]octene framework

Article abstract of DOI:10.1021/ol802104z

(Chemical Equation Presented) We report a simple and highly stereocontrolled strategy toward the total synthesis of isoprostanes based on a bicyclic α,β-epoxy ketone Intermediate 6. Bicyclo[3.3.0]octene scaffold permitted stereodirection of reagents allowing stereoselective epoxidation, diastereoselective ketone reduction, and regioselective epoxide opening otherwise not accessible with a simple cyclopentene framework.

Full text of DOI:10.1021/ol802104z

ORGANIC
LETTERS
2008
Vol. 10, No. 21
5087-5090
Stereocontrolled Access to Isoprostanes
via a Bicyclo[3.3.0]octene Framework
Camille Oger, Yasmin Brinkmann, Samira Bouazzaoui, Thierry Durand, and
Jean-Marie Galano*
Institut des Biomole´cules Max Mousseron, IBMM, UMR CNRS 5247, UniVersite´
Montpellier I, UniVersite´ Montpellier II, Faculte´ de Pharmacie, 15. AV. Ch. Flahault,
F-34093 Montpellier cedex 05, France
jgalano@uniV-montp1.fr
Received September 9, 2008
ABSTRACT
We report a simple and highly stereocontrolled strategy toward the total synthesis of isoprostanes based on a bicyclic r,ꢀ-epoxy ketone
intermediate 6. Bicyclo[3.3.0]octene scaffold permitted stereodirection of reagents allowing stereoselective epoxidation, diastereoselective
ketone reduction, and regioselective epoxide opening otherwise not accessible with a simple cyclopentene framework.
Discovered in 1990 by Roberts, Morrow, et al., the nonenzy-
matic in vivo synthesis of isoprostanes (IsoPs) questioned the
apparently clear picture of cyclic polyunsaturated fatty acid
(PUFA) metabolites.1 Since then, joint efforts of biologists,
biochemists, and analytical and synthetic organic chemists has
revealed the multiple roles of a large variety of cyclic PUFA
metabolites.2 Isomeric to prostaglandins (lateral side chains are
cis in relation to the plane of the prostane ring), IsoPs are
produced by free-radical-catalyzed peroxidation of arachidonic
acid (AA) leading to four racemic isomers (5-, 8-, 12-, and 15-
series of IsoPs).3 The F-type of these compounds is used as
marker of oxidative stress in vivo.4 These lipid metabolites have
also been shown to be potent vasoconstrictors, to act as smooth
muscle growth factors, and to possess platelet aggregation
properties.5 From a synthetic point of view, efforts still have to
be made in developing divergent strategies which allow access
to the E- and D-types of IsoPs.6 These strategies should also
permit the synthesis of structurally related neuroprostanes
(NeuroPs)7 and phytoprostanes (PhytoPs)8 (Figure 1).
In this paper, we report our results concerning the synthesis
of E,D,F-IsoPs9 possessing syn-anti-syn stereochemistry
using a bicyclo[3.3.0]octane scaffold.
In the literature, other bicyclic synthetic intermediates
(bicyclo[4.3.0]nonane,9d bicyclo[3.2.0]heptane,9g and
bicyclo[3.1.0]hexane9c skeletons) have been used in the total
synthesis of IsoPs. The cis ring fusion of these systems
(1) 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) For a recent review, see: Jahn, U.; Galano, J.-M.; Durand, T. Angew.
Chem., Int. Ed. 2008, 47, 5894.
(5) (a) Morrow, J. D. Curr. Pharm. Des. 2006, 12, 895. (b) Cracowski,
J. L.; Durand, T. Fundam. Clin. Pharmacol. 2006, 20, 417.
(6) We recently reported a strategy to access E-type isoprostane isomers:
Pinot, E.; Guy, A.; Fournial, A.; Balas, L.; Rossi, J. C.; Durand, T. J. Org.
Chem. 2008, 73, 3063.
(3) Taber, D. F.; Morrow, J. D.; Roberts, L. J., II. Prostaglandins 1997,
53, 63.
(4) (a) Musiek, E. S.; Yin, H.; Milne, G. L.; Morrow, J. D. Lipids 2005,
40, 987. (b) Montuschi, P.; Barnes, P. J.; Roberts, L. J., II. FASEB J. 2004,
18, 1791.
(7) Nourooz-Zadeh, J.; Liu, E. H.; Angga¨rd, E.; Halliwell, B. Biochem.
Biophys. Res. Commun. 1998, 242, 338.
(8) Imbusch, R.; Mueller, M. J. Plant Physiol. 2000, 124, 1293.
10.1021/ol802104z CCC: $40.75
Published on Web 10/10/2008
2008 American Chemical Society

Scheme 1
.
Retrosynthetic Analysis of IsoPs Based on a
Bicyclo[3.3.0]octene Framework
Figure 1. Examples of different metabolites belonging to E,D-IsoPs,
NeuroPs, and PhytoPs.
permits adequate control over stereochemistry of isoprostane
side chains. However, a clear limitation of the previous
systems is the need for the early introduction of 1,3-diol or
1,3-ketohydroxyl functionalities prior to bicycle formations
impeding flexibility and leading to low diastereoselectivities
in bicycle formation and ketone reduction. We envisaged
that a bicyclic intermediate would not only serve to lock
side-chain stereochemistry but also solve the inherent
problem of introducing cis-1,3-hydroxyl groups on a cyclo-
pentane system.
Alcohol 4 was prepared following a previously described
two-step route from 1,3-cyclooctadiene (1,3-COD) 9 (Scheme
2).10 Monoepoxidation of 9 was achieved with peracetic acid
Scheme 2
.
Multigram-Scale Preparation of Enantiopure
Bicyclo[3.3.0]oct-7-en-2-ol 4
Bicyclo[3.3.0]octene systems are easily available by trans-
annular C-H insertion of cyclooctene oxide;10 therefore, we
considered that alcohol 4 may be used to address the above
issues and provide an attractive entry point to IsoPs (Scheme
1).
Precedent shows that the envelope shape of such systems
can efficiently bias the approach of reagents from the convex
face11 and that when this face is inaccessible, the more
accessible carbon from the concave face is the ꢀ carbon from
the fused ring.12 Therefore, we anticipated that epoxidation
of enone 5 obtained by oxidation of 4 should occur
selectively from the convex face. The newly introduced
epoxide functionality in 6 should then bias reduction of the
ketone from the concave face to afford exo-alcohol 7.
Moreover, the envelope shape of 7 should lead to regiose-
lective opening of the epoxide affording cis-1,3-diol 8. An
interesting feature of this approach is the possible chemose-
lective ketone reduction of 6, allowing orthogonal protection
of diol 8 in order to access to E- and D-series of IsoPs.
in CH2Cl2 at 0 °C for 3 h leading to the corresponding
monoepoxide. Subsequent treatment with Et2NLi in Et2O at
30 °C gave, after transannular C-H insertion, the bicyclic
alcohol 4 (40 g of 4 can be routinely prepared).
Ikegami et al. described an enzymatic resolution procedure
of 4 on a 5 g scale using a lipase from Pseudomonas
fluorescens (Amano AK) in the presence of vinyl acetate as
a solvent. Both enantiomers have been obtained with
excellent yields and ee’s >99% after only one enzymatic
resolution.13 Nevertheless, we wished to apply a procedure
that does not implicate purification by chromatography,
thereby allowing an easy scale-up of this step.14,15
(9) For leading strategies towards IsoPs, see: (a) Corey, E.; Shih, C.;
Shih, N.; Shimoji, K. Tetrahedron Lett. 1984, 25, 5013. (b) Larock, R. C.;
Lee, N. H. J. Am. Chem. Soc. 1991, 113, 7815. (c) Rondot, B.; Durand, T.;
Girard, J. P.; Rossi, J. C.; Schio, L.; Khanapure, S. P.; Rokach, J.
Tetrahedron Lett. 1993, 34, 8245. (d) Taber, D. F.; Herr, R. J.; Gleave,
D. M. J. Org. Chem. 1997, 62, 194. (e) 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. (f) Durand, T.; Guy, A.; Henry, O.; Vidal,
J.-P.; Rossi, J.-C.; Rivalta, C.; Valagussa, A.; Chiabrando, C. Eur. J. Org.
Chem. 2001, 809. (g) Zanoni, G.; Porta, A.; Vidari, G. J. Org. Chem. 2002,
67, 4346. (h) Schrader, T. O.; Snapper, M. L. J. Am. Chem. Soc. 2002,
124, 10998. (i) Quan, L. G.; Cha, J. K. J. Am. Chem. Soc. 2002, 124, 12424.
(j) Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2002, 43, 4575.
(10) Crandall, J. K.; Chang, L. H. J. Org. Chem. 1967, 32, 532.
(11) Hodgson, D. M.; Galano, J.-M.; Christlieb, M. Tetrahedron 2003,
59, 9719.
Best results were obtained by using Amano AK and
succinic anhydride in dry Et2O at room temperature (routinely
run on a 20 g scale of 4). At the stage of 50% of conversion,
unreacted (-)-(S)-alcohol 4 and monosuccinate 10 were
separated by basic (NaHCO3) aqueous-organic solvent
liquid-liquid extraction. Ester hydrolysis of 10 gave (+)-
(R)-alcohol 4. Both enantiomers were obtained in high yields
(12) Tanaka, M.; Tomioka, K.; Koga, K. Tetrahedron Lett. 1985, 26,
3035.
(13) Iimori, T.; Azumaya, I.; Hayashi, Y.; Ikegami, S. Chem. Pharm.
Bull. 1997, 45, 207.
5088
Org. Lett., Vol. 10, No. 21, 2008

and high ee’s ((S)-4 in 48% yield; ee >98%, (R)-4 in 47%
yield; ee >98%) with no need for any additional purifica-
tion.16
Indeed, chemoselective reduction of ketone 6 was achieved
with LiAlH4 (0.58 equiv) in THF at -78 °C for 20 min
providing R,ꢀ-epoxy alcohols 7 (95/5 dr in favor of the
desired compound 7). Protection of the alcohol functionality
was carried out by treatment of 7 with ethylvinyl ether (EVE)
in CH2Cl2 in the presence of a catalytic amount of PPTS at
rt providing 11 in 80% yield, after chromatographic separa-
tion of the undesired endo-epimer of 11. Subsequent epoxide
opening with LiAlH4 (1.0 equiv, -78 °C to rt) afforded
alcohol 8b as a single regioisomer. Formation of the tert-
butyldimethylsilyl (TBS) ether under classical conditions
gave rise to orthogonally protected diol 8c in 81% yield (two
steps), confirming the feasibility of our strategy for orthogo-
nal protection.
Recent studies by Nicolaou et al.17 led us to consider that
alcohol 4 might be oxidized in one step to enone 518 by
treatment with o-iodoxybenzoic acid (IBX). We were pleased
to find that reaction of alcohol (S)-4 (8 g) with IBX (3.0
equiv) in DMSO (0.8 M) at 90 °C for 15 h afforded enone
5 in 65% yield (Scheme 3). At this stage of the synthesis,
Scheme 3. Functionalization of Bicyclic Intermediate 5
Carrying on the synthesis toward 15-F2t-IsoP, 8a was
protected as its bis-TBS ether. Ozonolysis in CH2Cl2/MeOH
at -78 °C followed by NaBH4 reduction afforded diol 12 in
78% yield (two steps) (Scheme 4). We next investigated the
Scheme 4
.
Synthesis of Suitable Precursor 13 for Side-Chain
Introduction
nucleophilic epoxidation was investigated in order to intro-
duce the epoxide from the convex face of 5. After extensive
investigation, R,ꢀ-epoxy ketone 6 was reproducibly obtained
on a gram scale with complete exo-stereoselectivity in 82%
yield using t-BuOOH-15 mol % DBU19 in CH2Cl2 at 20
°C for 12 h. Treatment of 6 with LiAlH4 (1.9 equiv) in THF
or Et2O from -78 °C to rt led to ketone reduction and
subsequent epoxide ring opening in one pot. The desired cis-
1,3-diol 8a was obtained with high diastereoselectivity (75%,
dr ) 95/5). Easy separation from trans-8a20 was realized
by flash chromatography.
This six-step sequence from 1,3-COD is routinely per-
formed with only one column chromatography at the last
stage and affords up to 3 g of enantiopure cis-diol 8a starting
from 8 g of alcohol (S)-4.
In order to access to E,D-IsoPs, our strategy foresees
orthogonal protection of the 1,3-cis-diol functionality, al-
lowing at a later stage of the synthesis selective deprotection
of one of the two hydroxyls.
possibility of selective lactonization of diol 12 to 13a taking
advantage of the relative steric hindrance of primary alcohols.
Unfortunately, treatment of 12 with PDC or IBX (1.2 equiv)
only provided 20% of unseparable lactones 13a and 13b in
a 1:1 ratio and a separable mixture of the corresponding
lactols 15a and 15b in a 1:1 ratio in good yields.21 We next
turned our attention to a specifically designed reagent for
selective oxidation, Cp*Ir[OCH2C(C6H5)2NH].22 Ir catalysis
(0.8 mol %) in refluxing butanone afforded the corresponding
lactones 13 in 91% yield with an impressive 98/2 ratio in
favor of lactone 13a.23
Continuing the synthetic sequence toward our target
molecule, lactones 13 were reduced by DIBAL-H in CH2Cl2
at -78 °C to the corresponding lactols 15a and 15b. Desired
15a was obtained in 89% yield after flash chromatography
(Scheme 5). Introduction of the R-side chain was achieved
(14) ter Halle, R.; Bernet, Y.; Billard, S.; Bufferne, C.; Carlier, P.;
Delaitre, C.; Flouzat, C.; Humblot, G.; Laigle, J. C.; Lombard, F.; Wilmouth,
S. Org. Process Res. DeV. 2004, 8, 283.
(15) Bouzemi, N.; Debbeche, H.; Aribi-Zouioueche, L.; Fiaud, J. C.
Tetrahedron Lett. 2004, 45, 627.
(16) The ee’s were determined by converting alcohols into their
corresponding 2,4-dinitrobenzoate derivatives and by chiral HPLC analysis
(see the Supporting Information).
(17) Nicolaou, K. C.; Zhong, Y. L.; Baran, P. S. J. Am. Chem. Soc.
2000, 122, 7596.
(21) It is reported that oxidation of diols by IBX afforded only lactols.
For 1,4-diol to lactol oxidation by IBX, see: Corey, E. J.; Palani, A.
Tetrahedron Lett. 1995, 36, 3485.
(18) Enone 5 was previously obtained in three steps from 4 by palladium-
induced oxidation of the silyl enol ether obtained from the corresponding
ketone in 55% yield; see: Parkes, K. E. B.; Pattenden, G. J. Chem. Soc.,
Perkin Trans. 1988, 1119.
(22) Suzuki, T.; Morita, K.; Tsuchida, M.; Hiroi, K. Org. Lett. 2002, 4,
2361.
(19) Yadav, V. K.; Kapoor, K. K. Tetrahedron 1995, 51, 8573.
(20) The stereochemistry of cis- and trans-1,3-diols 8a was confirmed
by NMR experiments and by reported NMR data of trans-8a; see: Weinges,
K.; Haremsa, S. Liebigs Ann. Chem. 1987, 679.
(23) Lactone 13 has already been described in the total synthesis of
15-F2t-IsoP 1 based on an approach developed by Rokach; see: Hwang,
S. W.; Adiyaman, M.; Khanapure, S.; Schio, L.; Rokach, J. J. Am. Chem.
Soc. 1994, 116, 10829.
Org. Lett., Vol. 10, No. 21, 2008
5089

n-Bu4NF (TBAF) deprotection of the silyl groups in THF26
afforded triols in 91% yield.27 Finally, ester saponification
in the presence of LiOH in water/THF afforded 15-F2t-IsoP
1 and 15-epi-F2t-IsoP in 78% and 81% yields from 17a and
17b, respectively.
Scheme 5. Total Synthesis of 15-F2t-IsoP 1 and its 15-Epimer
In summary, the total synthesis of 15-F2t-IsoP 1 and its
15 epimer validated the feasibility of our strategy to access
isoprostane derivatives from a readily available bicyclo[3.3.0]-
octene scaffold. The bicyclic shape allowed an easy and
highly selective introduction of the four stereocenters of the
target compounds through a series of simple synthetic
transformations. Currently, the total syntheses of unreported
E, D-IsoPs and PhytoPs are in progress, and results will be
reported in due course.
Acknowledgment. We gratefully acknowledge the Min-
iste`re de l’Education Nationale et de la Recherche for a Ph.D.
fellowship (C.O.) and the Centre National de la Recherche
Scientifique for a postdoctoral fellowship (Y.B.). We are
deeply grateful to Pr. Jean-Yves Lallemand and the ICSN
for their generous financial support, and a part of this work
was supported by a University Montpellier I grant (BQR-
2008).
by Wittig reaction of 15a and (4-carboxybutyl)triphenylphos-
phonium bromide using t-BuOK as base in THF at 0 °C.
Esterification of the crude carboxylic acid (TMSCHN2 in
Et2O/MeOH) provided ester 16 in 65% yield.24 Introduction
of the ω-side chain was performed after Dess-Martin
periodinane oxidation into the aldehyde by Horner-
Wadsworth-Emmons (HWE) chain elongation in 82% yield
(only the E isomer was observed, within the limits of NMR
detection). Subsequent Luche reduction of the enone func-
tionality provided allylic alcohols epimers 17a and 17b as
an ∼1:1 mixture. These epimers were easily separated by
flash chromatography in 34% and 37% yields from 16.25
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL802104Z
(25) Absolute configurations were determinated after completion of the
synthesis to known 15-F2t-IsoP 1 and its 15-epimer and by NMR correlation
of known 17a (see ref 23).
(24) Two side products were also isolated; a coeluting compound with
16 attributed to the E isomer and a compound corresponding to a silyl
migration to the primary alcohol (see the Supporting Information).
(26) Kaburagi, Y.; Kishi, Y. Org. Lett. 2007, 9, 723.
(27) Yield given from a 1:1 mixture 17a and 17b after separation of
triol epimers (see the Supporting Information).
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Org. Lett., Vol. 10, No. 21, 2008