A bicyclo[3.2.0]hept-3-en-6-one approach to prostaglandin intermediates

Article abstract of DOI:10.1021/ol006664v

(equation presented) The substituted cyclopentanic structures, 6-benzyloxymethyl-7-hydroxy-2-oxabicyclo[3.3.0]octan-3-one (1), a Corey lactone derivative, and 6-exobenzyloxymethyl-2-oxabicyclo[3.3.0]oct-7-en-3-one (2), have been obtained stereoselectively

Full text of DOI:10.1021/ol006664v

ORGANIC
LETTERS
2000
Vol. 2, No. 26
4145-4148
A Bicyclo[3.2.0]hept-3-en-6-one
Approach to Prostaglandin
Intermediates
Emanuela Marotta, Paolo Righi, and Goffredo Rosini*
Dipartimento di Chimica Organica “A. Mangini” dell’UniVersita` di Bologna,
Viale Risorgimento no. 4, 40136 Bologna, Italy
rosini@ms.fci.unibo.it
Received September 27, 2000
ABSTRACT
The substituted cyclopentanic structures, 6-benzyloxymethyl-7-hydroxy-2-oxabicyclo[3.3.0]octan-3-one (1), a Corey lactone derivative, and 6-exo-
benzyloxymethyl-2-oxabicyclo[3.3.0]oct-7-en-3-one (2), have been obtained stereoselectively through the bicyclo[3.2.0]hept-3-en-6-one approach
via 5-benzyloxymethyl-3-hydroxy-6-heptenoic acid, easily accessible from the inexpensive monoprotected cis-2-butene-1,4-diol.
Prostaglandins (PGs) constitute a part of a large class of
natural products, the eicosanoids, biosynthesized in mammals
mainly from arachidonic acid. Their complex structures play
key roles in the process of inflammation, in tissue repair,
and in immune response. From their initial isolation and
characterization,1 they have acquired immense biochemical
importance2 and have inspired and challenged synthetic
chemists for decades.3,4 Recently, much attention has been
devoted to antineoplastic and antiviral prostaglandins5 and
to isoprostanes,6 epimeric prostaglandins with cis-dialkyl
stereochemistry at the five-membered ring. Access to pros-
taglandin analogues (prostanoids) with improved pharma-
cological profiles has been and continues to be a main target
in organic and medicinal chemistry. In attempting to achieve
molecular diversity in this field, Ellman7 and Janda8 have
reported, respectively, the solid-phase synthesis of a variety
of E- and F-prostaglandins and the soluble-polymer supported
synthesis of a prostanoid library, of which some components
have shown an interesting antiviral activity.8b
To better exploit the potentialities of the “toolbox”
(cyclopentenone, R-chain, ω-chain) and with the linear/
multistep Corey-type plan9 to assembly the prostaglandin
(1) von Euler, U. S. Arch. Exp. Pathol. Pharmakol. 1934, 175, 78.
(2) Collins, P. W.; Djuric, S. W. Chem. ReV. 1993, 93, 1533.
(3) (a) Bindra, J. S.; Bindra, R. Prostaglandin Synthesis; Academic
Press: New York, 1977. (b) Mitra, A. The Synthesis of Prostaglandins;
Wiley: New York, 1977. (c) New Synthetic Routes to Prostaglandins and
Tromboxanes; Roberts, S. M., Scheinmann, F., Eds.; Academic Press: New
York, 1982. (d) Newton, R. F.; Roberts, S. M. Prostaglandins and
Tromboxanes; Butterworth: London, 1982. (e) Corey, E. J.; Cheng, X.-M.
The Logic of Chemical Synthesis; John Wiley and Sons: New York, 1989.
(f) Nicolaou, K. C.; Sorensen, E. J. In Classics in Total Synthesis- Targets,
Strategies, Methods; VCH: Weinheim, 1996; p 65. (g) Nicolaou, K. C.;
Vourlomis, D.; Wissinger, N.; Baran, P. S. Angew. Chem., Int. Ed. 2000,
39, 45.
(4) For recent general syntheses of these molecules, see: (a) Sannigrahi,
M.; Mayhew, D. L.; Clive, D. L. J. J. Org. Chem. 1999, 64, 2776. (b)
Fleming, I.; Winter, B. D. Tetrahedron Lett. 1995, 36, 1733. (c) Lipshutz,
B. H.; Wood, M. R. J. Am. Chem. Soc. 1994, 116, 11689. (d) Johnson, C.
R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014. (e) Gooding, O. W.
J. Org. Chem. 1990, 55, 4209. (f) Noyori, R.; Suzuki, M. Chemtracts: Org.
Chem. 1990, 173. (g) Johnson, C. R.; Penning, T. D. J. Am. Chem. Soc.
1988, 110, 4726. (h) Suzuki, M.; Yangisawa, A.; Noyori, R. J. Am. Chem.
Soc. 1988, 110, 4718.
(5) Suzuki, M.; Kiho, T.; Tomokiyo, K.; Furuta, K.; Fukushima, S.;
Takeuchi, Y.; Nakanishi, M.; Noyori, R. J. Med. Chem. 1998, 41, 3084
and literature cited therein.
(6) (a) Lai, S.; Lee, D.; U, J. S.; Cha, J. K. J. Org. Chem. 1999, 64,
7213 and literature cited therein. (b) Taber, D. F.; Green, J. H.; Zhang, W.;
Song, R. J. Org. Chem. 2000, 65, 5436 and literature cited therein.
(7) Thompson, L. A.; Moore, F. L.; Moon, Y.-C.; Ellman, J. A. J. Org.
Chem. 1998, 63, 2066.
(8) (a) Chen, S.; Janda, K. D. J. Am. Chem. Soc. 1997, 119, 8724;
Tetrahedron Lett. 1998, 39, 3943. (b) Lee, K. J.; Angulo, A.; Ghazal, P.;
Janda, K. D. Org. Lett. 1999, 1, 1859.
10.1021/ol006664v CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/28/2000

framework in mind, we needed an efficient and versatile
synthesis of important cyclopentanic scaffolds with func-
tionalized sites for the elongation of R- and ω-chains.
Some years ago we devised an efficient, general, and
convenient approach10 to bicyclo[3.2.0]hept-3-en-6-ones
which were shown to be useful intermediates in the stereo-
selective synthesis of a variety of natural products11 and
valuable precursors12 of some relevant synthetic targets.
Here we report the extension of this new methodology to
the synthesis of racemic important prostaglandin building
blocks: 13,13 and 2,3,14 well-known as key intermediates for
the synthesis of all primary prostaglandins. Our efforts were
aimed at devising a procedure that was practical and general
enough to be applied to the preparation of several alkyl-
substituted compounds of type 1 and 2 amenable as precur-
sors for a variety of prostanoids.
synthetic approach uses 5-benzyloxymethyl-3-hydroxy-6-
heptenoic acid (4) as the central precursor, which incorporates
all the carbon atoms of the bicyclic core of the target
compounds. In addition, the wedge-shaped molecular struc-
ture of bicyclo[3.2.0]hept-3-en-6-ones made us confident of
the possibility of achieving chemo-, regio-, and stereoselec-
tive manipulations of the key intermediate 3.
Scheme 2 depicts the more direct route and the main
features of our approach. For the purpose of merging with
Scheme 2. The General Synthetic Route to Compounds 1 and 2
through the Bicyclo[3.2.0]hept-3-en-6-one Approacha
Scheme 1 summarizes our retrosynthetic analysis that
stems from two main chemical events: (i) the preparation
Scheme 1. Retrosynthetic Analysis for the Preparation of
Compounds 1 and 2, Key Intermediates in Prostaglandin
Synthesis
a (a) NaH, (E)-(carboxyvinyl)trimethlylammonium betaine, re-
fluxing THF; H3O+, 92%; (b) 180 °C/0,1 mmHg, -CO2, 85%; (c)
Mg, tert-butyl bromoacetate, MeI, Et2O, 84%; (d) KOH, methanol,
24 h, H3O+, quantitative; (f) CH3COOK, Ac2O, rt (2 h); ∆ (3 h);
cooling, n-hexane/water, 93%; (g) H2O2, CH3COOH; 10% aq.
Na2S2O6, 90%; (h) NBS, DME/water 1:1, 70%; (i) 1-ethylpiperidine
hypophosphite/AIBN, dioxane, 4, 85-90%.
of protected bicyclo[3.2.0]hept-3-en-6-one 3 and (ii) its
manipulation to obtain the target compounds 1 and 2. This
(9) Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am.
Chem. Soc. 1969, 91, 5675.
(10) (a) Rosini, G.; Confalonieri, G.; Marotta, E.; Rama, F.; Righi, P.
Org. Synth. 1997, 74, 158. (b) Rosini, G.; Serra, R.; Rama, F.; Confalonieri,
G. ENICHEM S.p.A.- Istituto G. Donegani S.p.A.- Eurp. Patent Spec. N.
922001957.5- Pub. N. 0521 571 B1 (September 13, 1995). For an account
on this topic, see: Marotta, E.; Righi, P.; Rosini, G. Org. Process Res.
DeV. 1999, 3, 206.
(11) (a) Monoterpenes grandisol and lineatin: Confalonieri, G.; Marotta,
E.; Rama, F.; Righi, P.; Serra, R.; Venturelli, F. Tetrahedron 1994, 50,
3235. (b) filifolone: Marotta, E.; Righi, P.; Rosini, G. Tetrahedron Lett.
1994, 35, 2949. (c) Sesquiterpene raikovenal: Rosini, G.; Laffi, F.; Marotta,
E.; Pagani, I.; Righi, P. J. Org. Chem. 1998, 63, 2389.
(12) Marotta, E.; Pagani, I.; Righi, P.; Rosini, G. Tetrahedron 1994, 50,
7645. The unsaturated lactones, easy available from bicyclo[3.2.0]hept-3-
en-6-ones, are crucial precursors in the synthesis of condensed triquinane
sesquiterpenes by the “tandem radical cyclization” devised by Curran
(Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. ReV. 1991, 91, 1237)
and can be used efficiently in the synthesis of several functionalized
carbocyclic nucleosides (see: Johansen, S.; Korno, H. T.; Lundt, I. Synthesis
1999, 171.)
(13) Among the more important approaches to the core structure of 1,
see: (a) Corey, E. J.; Imai, N.; Pikul, S. Tetrahedron Lett. 1991, 51, 7517
and literature cited therein. (b) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini,
G. P.; Simoni, D.; Zanirato, V. Tetrahedron 1987, 43, 4669. (c). Takano,
S.; Kubodera, N.; Ogasawara, K. J. Org. Chem. 1977, 42, 786. (d)
To¨mo¨sko¨zi, I.; Gruber, L.; Kova´cs, G.; Szekely, I.; Simonidesz Tetrahedron
Lett. 1976, 4639. Bindra, J. S.; Grodski, A.; Schaaf, T. K.; Corey. E. J. J.
Am. Chem. Soc. 1973, 95, 7522.
previous prostaglandin syntheses, the commercially available
monobenzyl ether of cis-1,4-but-2-enediol (6) was chosen
as starting material.15
The sodium salt of alcohol 6 was reacted with (E)-
(carboxyvinyl)trimethylammonium betaine according to a
procedure developed by Bu¨chi and Vogel16 and gave adduct
7, following trimethylamine elimination when heated to
reflux in THF. The carboxylic acid 7, with an allyl vinyl
ether moiety, underwent a clean thermal Claisen rearrange-
ment17 with CO2 elimination to give the functionalized
aldehyde 5 in 78% yield from alcohol 6.
(15) For a preparation, see: Roush, W. R.; Straub, J. A.; VanNieuwenhze
J. Org. Chem. 1991, 56, 1636.
(16) Vogel, D. E.; Bu¨chi, G. Org. Synth. 1987, 66, 29.
(17) Claisen, L. Ber. Dtsch. Chem. Ges. 1912, 45, 3157. For recent
reviews on the Claisen rearrangement, see: (a) Ito, H.; Taguchi, T. Chem.
Soc. ReV. 1999, 28, 43. (b) Enders, D.; Knopp, M.; Schiffers, R.
Tetrahedron: Asymmetry 1996, 7, 1847. (c) Wipf, P. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
U.K., 1991; Vol. 5, Chapter 7.2, p 827.
(14) (a) Corey, E. J.; Grieco, P. A. Tetrahedron Lett. 1972, 107. (b)
Crabbe´, P.; Guzma´n, A. Tetrahedron Lett. 1972, 115. (c) Hodgson, D. M.;
Gibbs, A. R. Synlett 1997, 657. (d) Dow, R. L.; Kelly, R. C.; Schletter, T.;
Wierenga, W. Synth. Commun. 1981, 11, 43.
4146
Org. Lett., Vol. 2, No. 26, 2000

Although this strategy for the synthesis of aldehyde 5
proved to be direct and reasonably efficient, the preparation
of large amounts of (E)-(carboxyvinyl)trimethylammonium
betaine can be tedious, time-consuming, and expensive. To
circumvent these drawbacks, particularly relevant in large
scale preparations of the desired aldehyde 5, an alternative
procedure was devised that, although less direct, resulted in
a more practical and useful preparation of compound 5 on a
25-100 g scale.
With aldehyde 5 in hand, we turned our attention to the
two-carbon chain-elongation needed to prepare the corre-
sponding 3-hydroxy acid 4. The Reformatsky reaction,21
when performed according to the Rathke and Lindert9a,22
modification, gave yields ranging from 20% to 85% and
frequently the reaction was difficult to start. This drawback
occurred in a nonpredictable fashion even when zinc dust
was activated.23 More reliable and predictable results were
obtained when the more hindered tert-butyl R-bromoacetate
was reacted with magnesium, activated by methyl iodide,24
instead of zinc. This practical modification was revealed to
be very effective and gave ester 8 in a satisfying and
reproducible yield (Scheme 2).
The alternative procedure (Scheme 3), based on the
Johnson orthoester variant18 of the Claisen rearrangement,
Similar good results in terms of yield and practicality were
achieved also when aldehyde 5 was treated with ethyl
diazoacetate in the presence of tin(II) chloride as a catalyst25
(Scheme 5). The â-ketoester 12 so obtained underwent a
chemoselective reduction to 3-hydroxyester 13 when treated
with sodium borohydride in ethanol.
Scheme 3
Scheme 5. The Diazoacetate Route to 3-Hydroxyester 13
takes advantage of a very efficient reaction of the mono-
protected diol 6 with ethyl orthoacetate (EOA) at 140-150
°C that give rise to a protected allyl ketene acetal prone to
undergo thermal rearrangement to the unsaturated ester 10.19
The careful and continuous ethanol removal by distillation
is crucial to achieving good results. The distillation of the
excess of ethyl orthoacetate gave a residual crude mixture
from which compound 10 was finally obtained pure by
distillation at reduced pressure. The chemoselective reduction
of 10 with DIBAL was carried out at -78 °C (Scheme 4)
and allowed for the conversion into aldehyde 5.
Both tert-butyl (8) and ethyl esters (13) were easily
hydrolyzed with a methanol solution of KOH at room
temperature to give the desired acid 4, as a mixture of
isomers, in an almost quantitative yield.
After having assembled all the carbon atoms necessary
for the target compounds 1 and 2, we tackled the key step
by which the linear structure of 4 became a bicyclic scaffold
with some preference for one of the possible diastereoiso-
mers. Taking into account our previous results, the bicy-
clization reaction of hydroxy acid 4 was performed with
potassium acetate in acetic anhydride at room temperature
for 2 h and then in refluxing conditions for 3 h. The workup
of the reaction gave a diastereoisomeric mixture of exo- and
endo-2-benzyloxymethylbicyclo[3.2.0]hept-3-en-6-one (exo-3
and endo-3, respectively) in 93% yield and a 3:1 ratio
(Scheme 2).26 The chemo- and regioselective Baeyer-
Villiger reaction27 with an in situ generated peroxyacetic acid
(Scheme 2) converted (90% yield) this mixture into a
mixture, with the same 3:1 composition, of the corresponding
lactones 2.
Scheme 4. An Alternative Route to Aldehyde 5
This reduction works well also on a 0.3 mol scale reaction
when performed in dichloromethane solution at that low
temperature for almost half an hour, followed by warming
to 0 °C. In any case, to avoid the limitation of the very low
temperature, the reduction of the ester group of compound
9 was carried out with lithium aluminum hydride in THF at
room temperature to obtain in high yield the unsaturated
alcohol 11, which was converted into aldehyde 5 by a
straightforward oxidation.20
The mixture of isomers was carried through to the
bromohydrin derivatives as a 3:1 mixture (GC) of the
(21) Reformatsky, S. N. Ber. Dtsch. Chem. Ges 1887, 20, 1210. For
reviews, see: (a) Erdik, E. Organozinc Reagents in Organic Synthesis; CRC
Press: London, 1996. (b) Rathke, M. W.; Weipert, P. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds; Pergamon Press: New
York, 1991; Vol 2, p 277. (c) Furstner, A. Synthesis 1989, 571. (d) Rathke,
M. W. Org. React. 1975, 22, 423.
(22) Rathke, M. W.; Lindert, A. J. Org. Chem. 1970, 35, 3966.
(23) Newman, M. S.; Evans, F. J. J. Am. Chem. Soc. 1955, 77, 946.
(24) Moriwake, T. J. Org. Chem. 1966, 31, 983.
(18) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.;
Li, T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92, 741.
(19) This procedure has been already used directly on a variety of trans-
2-alkene-1,4-diols (Kondo, K.; Mori, F. Chem. Lett. 1974, 741).
(20) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974.
(25) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258.
Org. Lett., Vol. 2, No. 26, 2000
4147

epimers; it could not be efficiently separated at this stage.
However, the formation of the endo-isomer as a minor
component may not be detrimental. In fact, in pursuing the
elongation of the ω-chain the primary hydroxy group of
isomers 2, after deprotection, must be oxidized to aldehyde.
Facile enolization should result in equilibration to the more
stable exo-isomer.28
hydrins 9 was performed according to the Barton procedure,32
which uses hypophosphorous acid salts in a radical chain
reaction initiated by AIBN. The 1-ethylpiperidine hypophos-
phite-AIBN method was found to be very efficient and
allowed us to convert each bromohydrins 9 into the corre-
sponding dehalogenated alcohols 1. It is worthy of note that
racemic compounds 1 may be deprotected under hydrogen
on palladium to obtain free diols, while the unsaturated
lactones 2 have been already converted into the correspond-
ing acetates by treatment with BF3 etherate in acetic
anhydride.14a,33 Finally, several procedures are known to
effect the resolution of Corey lactones.34
In conclusion, the synthesis of compounds 1 and 2 reported
here is the result of a project aimed at achieving a practical
route to obtain the targeted compounds and other similar
compounds. The protocol we have devised, with all the
variants just shown, has characteristic features that bode well
for its general applicability in the preparation of a variety of
alkyl-substituted and functionalized cyclopentane scaffolds
like compounds 1 and 2. The wide range of unsaturated and
monoprotected 1,4-diols easily available as starting materials,
the general applicability of the reactions involved, the nature
of the reagents used, and the mildness of the reaction
conditions are noteworthy. The generality of this approach
is encouraging for the future development of a three-
component parallel synthesis of prostanoids in which the
cyclopentanic core structure is an element of molecular
diversity.
The bicyclic core of lactone exo-2 is widely known to be
the key intermediate in the synthesis of PGA and 11-deoxy
PGs while the endo-2 isomer was used in the total synthesis
of the iridoid iridomyrmicin.29 The conversion of exo-2 into
the Corey lactone derivative 1 constitutes a practical entry
to F-prostaglandins and all primary PGs. Moreover, it was
used in stereoselective synthesis of tromboxanes TXB2 and
30
TXB3 and in that of all four didemnenones,31 cyclopen-
tenone cytotoxic metabolites isolated from the didemnide
tunicate Didemnum Voeltskowi. The seemingly simple task
of converting compound 2 into the final target 1, the Corey
lactone derivative, was achieved by treatment of the mixture
of diastereoisomers 2 with NBS in DME/water 1:1. The
reaction occurred at room temperature and, giving the
bromohydrins 9 in 70% yield with almost the same diaste-
reoisomeric ratio as previously observed for the parent
compounds, proceeded in a completely regio- and stereose-
lective fashion. At this stage, each compound 9 was easily
obtained diastereoisomerically pure by flash column chro-
matography, and spectroscopic analysis led to a structural
assignment of epimers. Bromohydrins endo-9 and exo-9
could be hydrodebrominated by using tributyltin hydride in
benzene and AIBN as initiator. However, to avoid the
problems associated with the price, toxicity, and mainly the
removal of tin residues, the hydrodehalogenation of bromo-
Acknowledgment. This work was supported by the
Ministero dell’Universita` e della Ricerca Scientifica e
Tecnologica (MURST), Italy, by the Consiglio Nazionale
delle Ricerche (CNR), Italy, and by the University of
Bologna, Italy (Progetto d’Ateneo: Biomodulatori Organici
and National Project Stereoselezione in Sintesi Organica.
Metodologie ed Applicazioni).
(26) The mechanism of the bicyclization precludes the synthesis of
enantiomerically pure bicyclo[3.2.0]hept-3-en-6-ones from the corresponding
enantiomerically pure 3-hydroxy acids: Marotta, E.; Medici, M.; Righi,
P.; Rosini, G. J. Org. Chem. 1994, 59, 7529. However, for an efficient
procedure to obtain enantiomerically pure bicyclo[3.2.0]hept-3-en-6-ones
by resolution of the corresponding endo-alcohols, see: Marotta, E.; Pagani,
I.; Righi, P.; Rosini, G.; Bertolasi, V.; Medici, A. Tetrahedron: Asymmetry
1995, 6, 2319. Moreover, microorganisms have been used for an effective
and practical resolution of these promising substrates: (a) Fantin, G.;
Fogagnolo, M.; Medici, A.; Pedrini, P.; Marotta, E.; Monti, M. Righi, P.
Tetrahedron: Asymmetry 1996, 7, 277. (b) Fantin, G.; Fogagnolo, M.;
Marotta, E.; Medici, A.; Pedrini, P.; Righi, P. Chem. Lett. 1996, 511.
(27) For an excellent review on the Baeyer-Villiger oxidation of ketones,
see: Strukul, G. Angew. Chem., Int. Ed. 1998, 37, 1198.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 1-5 and
7-13 and 1H and 13C NMR spectra for compounds 1-5 and
8-12. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL006664V
(28) Roland, A.; Durand, T.; Rondot, B.; Vidal, J.-P.; Rossi, J.-C. Bull.
Soc. Chim. Fr. 1996, 133, 1149 and literature cited therein.
(29) Grieco, P. A.; Srinivasan, C. V. J. Org. Chem. 1981, 46, 2591.
(30) Nakamura, N.; Nagai, H.; Yoneda, M.; Suga, H.; Kawamura, M.;
Iguchi, S. Chem. Pharm. Bull. 1993, 41, 1769 and literature cited therein.
(31) Sugahara, T.; Yamada, O.; Satoh, I.; Takano, S. Chem. Pharm. Bull.
1995, 43, 147 and literature cited therein.
(32) (a) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. Cs. J. Org. Chem.
1993, 58, 6838. (b) Jang, D. O Tetrahedron Lett. 1996, 37, 5367.
(33) Corey, E. J.; Snider, B. B. J. Org. Chem. 1974, 39, 256.
(34) (a) Sugahara, T.; Satoh, I.; Yamada, O.; Takano, S. Chem. Pharm.
Bull. 1991, 39, 2758 and literature cited therein; (b) Weidner, J.; Theil, F.;
Schick H. Liebigs Ann. Chem. 1991, 1301.
4148
Org. Lett., Vol. 2, No. 26, 2000