Skeletal rearrangements of bicyclo[2.2.2]lactones: A short and efficient route towards Corey's lactone

Article abstract of DOI:10.1016/j.tetlet.2005.03.204

The application of a unique tandem radical-initiated, Br?nsted acid-catalysed, skeletal rearrangement of bicyclo[2.2.2]lactones provides a novel route towards Corey's lactone 2. The strategy also features a high-pressure promoted inverse electron-demand Diels-Alder (IEDDA) reaction of 3-carbomethoxy-2-pyrone (3-CMP), which proceeds with complete regio- and diastereocontrol.

Full text of DOI:10.1016/j.tetlet.2005.03.204

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3895–3899
Skeletal rearrangements of bicyclo[2.2.2]lactones: a short
and efficient route towards CoreyÕs lactone
*
ˆ ´ ´
Benoıt Augustyns, Nuno Maulide and Istvan E. Marko
´ ´ ˆ
Universite catholique de Louvain, Departement de Chimie, Batiment Lavoisier Place Louis Pasteur 1, 1348 Louvain-la-Neuve, Belgium
Received 21 February 2005; revised 17 March 2005; accepted 23 March 2005
Available online 12 April 2005
Abstract—The application of a unique tandem radical-initiated, Bro¨nsted acid-catalysed, skeletal rearrangement of bicyclo[2.2.2]-
lactones provides a novel route towards CoreyÕs lactone 2. The strategy also features a high-pressure promoted inverse electron-
demand Diels–Alder (IEDDA) reaction of 3-carbomethoxy-2-pyrone (3-CMP), which proceeds with complete regio- and
diastereocontrol.
Ó 2005 Elsevier Ltd. All rights reserved.
The prostaglandins (represented by PGF2a 1) belong to
a class of natural products that has been extensively
studied.1 Indeed, few other families of compounds have
generated such a wealth of elegant research and creativ-
ity, culminating in a plethora of total syntheses and for-
mal approaches.2 Among these, the strategy developed
by Corey in the late 1960Õs remains a milestone in syn-
thetic organic chemistry, both for its conciseness and
its versatility.3 Particularly appealing is the possibility
of generating the entire prostaglandin family from a sin-
gle, common precursor, which conceals all the required
functionalities within a bicyclo[3.3.0]lactone moiety.
Such a versatile compound is suitably referred to as
ÔCoreyÕs LactoneÕ 2 (Fig. 1).4
Recently, we have described a novel tandem radical-ini-
tiated, Bro¨nsted acid-catalysed, skeletal translocation of
bicyclo[2.2.2]lactones (Scheme 1).5 This rearrangement
proceeds with complete transfer of relative and absolute
stereochemistry and, depending upon the conditions
employed, yields either the isomeric bicyclo[3.2.1]- or
the bicyclo[3.3.0]lactones, respectively. Thus, treatment
of the IEDDA adduct 3 with Ph3SnH, under standard
radical conditions, affords the rearranged bicyclo[3.3.0]-
lactone 4 whereas reaction of 3 in the presence of
tris(trimethylsilyl)silane generates the unprecedented,
O
H
O
CO2Me
O
Ph3SnH
AIBN
O
O
H
HO
SePh
CO2Me
O
4
3
COOH
HO
OMe
HO
Silica gel
O
AcO
PGF2α
1
Corey's lactone 2
(Me3Si)3SiH
Figure 1. CoreyÕs retrosynthetic analysis.
O
AIBN
CO2Me
Keywords: Lactones; Bicyclic; Radical; Rearrangement; CoreyÕs
lactone; 3-CMP; Diels–Alder.
5
*
Corresponding author. Tel.: +32 010 47 87 73; fax: +32 010 47 27
88; e-mail: marko@chim.ucl.ac.be
Scheme 1. Skeletal rearrangements of bicyclo[2.2.2]lactones.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.204

3896
B. Augustyns et al. / Tetrahedron Letters 46 (2005) 3895–3899
bridged lactone 5, which could be smoothly converted to
the aforementioned isomer 4 by simple stirring with
silica gel in dichloromethane.5
MeO
MeO
(i)
SePh
(98%)
11
12
We were intrigued by the possibility of preparing
CoreyÕs lactone 2 via the rearrangement of a suitable
bicyclo[2.2.2]lactone precursor. In this communication,
we wish to report our results on the successful imple-
mentation of this methodology and its application to a
short and efficient assembly of racemic 2. Our proposed
antithetic analysis is presented in Scheme 2. The fused
lactone 6 was selected as an advanced precursor, easily
convertible into CoreyÕs intermediate 2.6 Applying our
rearrangement protocol in a retrosynthetic sense leads,
via the bicyclic lactone 7, to the Diels–Alder adduct
8a. Compound 8a would, in turn, derive from 3-carbo-
methoxy-2-pyrone 9 (3-CMP) and vinylselenide 10a by
an inverse electron-demand [4+2] cycloaddition reaction
(vide infra). In this novel approach, the requisite stereo-
chemical relationships will be implemented at an early
stage (cycloaddition step) and will be preserved through-
out the subsequent stereospecific operations.
MeO
SePh
(ii)
(71%)
10a
MeO
SePh
13
Scheme 3. Preparation of vinyl selenide 10a. Reagents and conditions:
(i) n-BuLi, THF, À78 °C then PhSeBr or PhSeCl, À78 °C to rt;
(ii) Cp2Zr(H)Cl, THF, rt then NH4Cl (aq).
Partial reduction of the C„C of 12 proved to be a chal-
lenge in its own right. Initial attempts at hydrogenation
under conventional Lindlar conditions (Pd/C, BaSO4,
quinoline)7 or using palladium on charcoal resulted in
recovery of the starting material, most likely due to irre-
versible poisoning of the catalyst by the selenium atom.
Although effective for similar substrates, DiBAL-H re-
sulted mainly in cleavage of the carbon–selenium bond,
affording mostly alkyne 11.8 The use of diimide
(HN@NH) as the reducing agent delivered for the first
time alkene 10a.9 Unfortunately, this procedure was
plagued by the formation of considerable amounts of
over-reduced material.
This convergent approach requires the preparation of
vinylselenide 10a, 3-CMP 9 being nowadays commer-
cially available. It was anticipated that 10a could be
readily accessed by a host of different routes. In practice,
however, the path presented in Scheme 3 proved to be
the most successful one.
Commercially available methylpropargyl ether 11 was
treated with n-butyllithium, in THF, at À78 °C. The
resulting anion was then slowly added to 1.1 equiv of
freshly prepared PhSeBr or PhSeCl, affording seleno-
alkyne 12 in 98% isolated yield. The success of this
reaction appears to be highly dependent upon both the
rate of addition and the source of electrophilic selenium.
Indeed, the use of diphenyldiselenide and/or prolonged
addition times led to the formation of several unidenti-
fied by-products.
Inspired by a recent report describing the successful
hydrozirconation of related chalcogenides,10 alkyne 12
was treated with SchwartzÕs reagent, Cp2Zr(H)Cl, fol-
lowed by an aqueous quench. Gratifyingly, the cis-
alkene 10a was obtained in pure form (71% yield). It is
noteworthy that olefin 10a is prone to light-induced
isomerisation, eventually providing a 1:1 mixture of
O
O
O
O
O
O
CO2Me
MeO
OMe
AcO
OMe
7
6
2
O
OMe
CO2Me
O
CO2Me
O
+
SePh
OMe
O
SePh
9
10a
8a
Scheme 2. Antithetic analysis of CoreyÕs lactone 2.

B. Augustyns et al. / Tetrahedron Letters 46 (2005) 3895–3899
3897
the E/Z isomers 13 and 10a after extended periods of
time.11 Therefore, the hydrozirconation protocol was
best performed in the dark and alkene 10a directly
engaged in the subsequent step.
desired IEDDA-adduct 8a, in quantitative yield. Only
the endo-isomer, possessing the correct regiochemistry,
was produced under these conditions (Table 1, entry
1). Other selenium-containing dienophiles could also
be added to 3-CMP 9 in good to excellent yields (Table
1), testifying to the substrate generality and efficiency of
these high-pressure conditions.
With a ready access to the desired dienophile 10a finally
secured, we next turned our attention to the assembly of
the key intermediate: bicyclo[2.2.2]lactone 8a, by
employing an inverse electron-demand Diels–Alder
(IEDDA) cycloaddition with 3-CMP.12 It was antici-
pated that the presence of a selenium atom on the dieno-
phile would considerably hamper the reaction, mainly
due to the weaker electron-donating ability of selenium,
as compared to sulfur- and oxygen-containing ana-
logues.13 To our delight, reaction of 3-CMP 9 with
10a, at 15 kbar and 45 °C, for 3 days, provided the
With large quantities of the suitably functionalised
cycloadduct 8a in hand, the stage was now set for the
application of our tandem radical rearrangement/acid-
catalysed translocation methodology. In the event
(Scheme 4), sequential treatment of bicyclo[2.2.2]lactone
8a with tris(trimethylsilyl)silane (TTMSS) and AIBN, in
boiling benzene, generated quantitatively the bridged
lactone 7, which upon stirring overnight with silica gel
Table 1. High-pressure cycloadditions of 3-CMP 9
O
R2
R3
SePh
R1
CO2Me
R2
CO2Me
O
O
15 Kbar, 45°C
R3
+
O
SePh
R1
9
10a-d
8a-d
Entry
Dienophile
Adduct
Yielda (%)
O
CO2Me
O
MeO
SePh
1
94
10a
SePh
MeO
O
8a
O
CO2Me
SePh
2
60
10b
SePh
Me
8b
O
CO2Me
O
3
60
Me
SePh
10c
SePh
8c
O
CO2Me
O
Me
4
80
SePh
10d
SePh
8d
a All yields are for pure, isolated products.

3898
B. Augustyns et al. / Tetrahedron Letters 46 (2005) 3895–3899
O
O
O
O
CO2Me
O
(i)
O
(ii)
CO2Me
CO2Me
MeO
(78% overall)
SePh
MeO
OMe
14
7
8a
O
O
O
O
O
O
(iii)
(83%)
(v)
(70%)
(iv)
(91%)
Br
OMe
OMe
OMe
AcO
AcO
6
15
2
Scheme 4. Tandem rearrangement/translocation of 8 and completion of the synthesis. Reagents and conditions: (i) (Me3Si)3SiH, AIBN, benzene,
reflux; (ii) silica gel, CH2Cl2, rt; (iii) LiCl, DMSO/H2O, 110 °C; (iv) (a) NBA, acetone/H2O, rt; (b) AcCl, py, CH2Cl2, 0 °C to rt; (v) Bu3SnH, AIBN,
benzene, reflux.
in dichloromethane, smoothly afforded the fused adduct
14. This cascade of rearrangements took place in an
impressive 78% overall yield, providing the advanced
intermediate 14 in diastereomerically pure form. The
striking simplicity of this protocol, as opposed to the
remarkable structural changes it imposes on the starting
cycloadduct, bodes well for future applications to more
heavily functionalised substrates.
Acknowledgements
Financial support of this work by the Universite catho-
´
lique de Louvain, the Actions de Recherche Concertees
´
(convention 96/01-197), the Fonds de la Recherche
Fondamentale Collective (dossier no. 2.4571.98), the
European Union (Socrates/Erasmus studentship to
N.M.) and Merck, Sharp and Do¨hme (Merck Academic
Development Award) is gratefully acknowledged.
At this juncture, removal of the excedentary methyl ester
appendage of 14 could be achieved in a straightforward
manner by using the decarboxylation protocol devel-
oped by Krapcho and subsequently modified by Ander-
son and Villhauer.14 Accordingly (Scheme 4), heating
lactone 14 with LiCl in wet DMSO provided, in 83%
yield, the decarbomethoxylated intermediate 6. This
intermediate could be readily converted to CoreyÕs
lactone 2 by a simple three-step procedure involving
bromohydrin formation, acetylation and reductive
cleavage of the bromine atom to afford, in 56% overall
yield (three steps), the desired prostaglandin precursor 2.
References and notes
1. (a) Bindra, J. S.; Bindra, R. Prostaglandin Synthesis;
Academic: New York, 1977; (b) Mitra, A. The Synthesis of
Prostaglandins; Wiley Interscience: New York, 1977.
2. Selected syntheses: (a) Stork, G.; Raucher, S. J. Am.
Chem. Soc. 1976, 98, 1583; (b) Goldstein, S.; Vannes, P.;
Houge, C.; Frisque-Hesbain, A.-M.; Wiaux-Zamar, C.;
Ghosez, L. J. Am. Chem. Soc. 1981, 103, 4616; (c) Tanaka,
T.; Hazato, A.; Bannai, K.; Okamura, N.; Sugiura, S.;
Manabe, K.; Toru, T.; Kurozumi, S.; Suzuki, M.; Kawa-
gishi, T.; Noyori, R. Tetrahedron 1987, 43, 813; (d)
Morita, Y.; Suzuki, M.; Noyori, R. J. Org. Chem. 1989,
54, 1785; (e) Danishefsky, S. J.; Cabal, M. P.; Chow, K.
J. Am. Chem. Soc. 1989, 111, 3456; (f) Johnson, C. R.;
Penning, T. D. J. Am. Chem. Soc. 1988, 110, 4726.
3. (a) Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.;
Huber, W. J. Am. Chem. Soc. 1969, 91, 5675; (b) Corey, E.
J.; Albonico, S. M.; Koelliker, U.; Schaaf, T. K.; Varma,
R. K. J. Am. Chem. Soc. 1971, 93, 1491; (c) Corey, E. J.;
Becker, K. B.; Varma, R. K. J. Am. Chem. Soc. 1972, 94,
8616; (d) Corey, E. J.; Cheng, X.-M. The Logic of Chemical
Synthesis; John Wiley and Sons: New York, 1989.
In summary, we have shown that the tandem radical-
initiated, acid-catalysed skeletal rearrangement of
bicyclo[2.2.2]lactones provides an efficient access to
CoreyÕs lactone 2 and its derivatives. Using this method-
ology, the highly functionalised intermediate 6 was
assembled in only five steps and in 25% overall yield,
from commercially available products. Moreover, the
entire sequence proceeds with complete diastereocontrol
and further exemplifies the usefulness of high-pressure
conditions in promoting resilient IEDDA cycloaddi-
tions. Current efforts are now directed towards the
establishment of an enantioselective version of this syn-
thetic route and towards broadening the scope and
applications of this novel tandem rearrangement/trans-
location methodology. The results of these investiga-
tions will be reported in due course.
4. See, for example: Nicolaou, K. C.; Sorensen, E. J. Classics
in Total Synthesis; VCH: Weinhein, 1996.
5. Marko, I. E.; Warriner, S. L.; Augustyns, B. Org. Lett.
2000, 2, 3123.
6. Ranganathan, S.; Ranganathan, D.; Mehrotra, A. K.
Tetrahedron Lett. 1975, 14, 1215.
´

B. Augustyns et al. / Tetrahedron Letters 46 (2005) 3895–3899
3899
7. Gutmann, H.; Lindlar, H. Chem. Acet. 1969, 355.
8. Dabdoub, M. J.; Cassol, T. M.; Barbosa, S. L. Tetrahe-
dron Lett. 1996, 37, 831.
9. Generated, for example, according to the following
protocol: Magnus, P.; Gallagher, T.; Brown, P.; Huffman,
J. C. J. Am. Chem. Soc. 1984, 106, 2105.
G. R.; Declercq, J.-P. Tetrahedron 1994, 50, 4557; For
other leading references in this field, see, for example: (e)
Posner, G. H.; Johnson, N. J. Org. Chem. 1994, 59, 7855;
For a review on Diels–Alder cycloadditions of 2-pyrones,
see: (f) Afarinkia, K.; Vinader, V.; Nelson, T. D.; Posner,
G. H. Tetrahedron 1992, 48, 9111.
10. Dabdoub, M. J.; Begnin, M. L.; Guerrero, G. P., Jr.
Tetrahedron 1998, 54, 2371.
11. For a similar case, see: Fryzuk, M. D.; Bates, G. S.; Stone,
C. J. Org. Chem. 1991, 56, 7201.
13. Although Lewis-acid catalysed reaction of phenylvinyl
selenide with 3-CMP afforded the desired adduct 3 in up to
65% ee, no [4+2] cycloaddition was observed when substi-
tuted vinylselenides such as 10a were employed. Recourse
to high-pressure conditions thus became mandatory.
14. (a) Krapcho, A. P. Synthesis 1982, 805; (b) Krapcho, A.
P.; Gadamasetti, G. J. Org. Chem. 1987, 52, 1880; (c)
Anderson, R. C.; Villhauer, E. B. J. Org. Chem. 1987, 52,
1186.
´
12. (a) See, for example: Marko, I. E.; Evans, G. R.
Tetrahedron Lett. 1993, 34, 7309; (b) Marko, I. E.; Evans,
´
´
G. R. Synlett 1994, 6, 431; (c) Marko, I. E.; Evans, G. R.;
Seres, P.; Chelle-Regnault, I.; Leroy, B.; Warriner, S. L.
´
´
Tetrahedron Lett. 1997, 38, 4269; (d) Marko, I. E.; Evans,