Concise and connective synthesis of exo-methylene-γ-butyrolactones

Article abstract of DOI:10.1016/S0040-4039(02)00240-X

A novel sequence, combining an ene-reaction of the substituted allylsilane 2 with a variety of aldehydes, followed by an oxidative double desilylation, provides an efficient access to a wide range of exo-methylene-γ-butyrolactones.

Full text of DOI:10.1016/S0040-4039(02)00240-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2307–2311
Concise and connective synthesis of
exo-methylene-g-butyrolactones
Raphae¨l Dumeunier, Ce´dric Leclercq and Istva´n E. Marko´*
Universite´ catholique de Louvain, De´partement de Chimie, Unite´ de Chimie Organique et Me´dicinale, Baˆtiment Lavoisier,
Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium
Received 12 November 2001; revised 24 January 2002; accepted 31 January 2002
Abstract—A novel sequence, combining an ene-reaction of the substituted allylsilane 2 with a variety of aldehydes, followed by
an oxidative double desilylation, provides an efficient access to a wide range of exo-methylene-g-butyrolactones. © 2002 Elsevier
Science Ltd. All rights reserved.
Exo-methylene-g-butyrolactones are ubiquitous frag-
ments in a wide range of biologically active natural
products.1 Their remarkable physiological properties,
and their versatile synthetic utility, has prompted con-
siderable interest in their preparation and subsequent
transformation.2
ether formation, bromination and fragmentation pro-
vided the desired exo-methylene-g-butyrolactones 5.
Although the final three steps could be performed
sequentially, in the same reaction vessel, this initial
route proved to be rather lengthy and to require an
extremely precise control of the experimental protocol.
In a previous communication, we have disclosed some
of our results on a new synthesis of a-(trimethylsilyl-
methyl)-g-butyrolactones 4, and on their subsequent
conversion into functionalised exo-methylene-g-butyro-
lactones 5 (Fig. 1).3
We reasoned that a shorter and more efficient access to
exo-methylene-g-butyrolactones 5 might involve the
conversion of readily available ene-adducts 3 into the
cyclic silylated acetals 6. Oxidative desilylation would
then provide, in a two-step operation, the desired lac-
tones 5. In this article, we wish to report the successful
implementation of this strategy.
This approach embodied an initial ene-reaction between
aldehyde 1 and allylsilane 2, followed by a chemoselec-
tive desilylation/oxidative cyclisation of 3, affording 4
as a mixture of diastereoisomers. Subsequent silyl enol
A variety of ene adducts 3 were prepared according to
our previously reported procedure4 and submitted to
R1
O
OTBS
SiMe3
O
OTBS
SiMe3
OH
Et2AlCl
1. TBAF
O
+
2. TPAP/NMO
R1
R1
H
SiMe3
3
4
1
2
1. LDA / TMSCl
2. NBS
3. TBAF
R1
R1
O
O
O
OTBS
6
5
Figure 1.
Keywords: ene reactions; silicon; exo-methylene lactones; lactones; halocyclisation.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00240-X

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R. Dumeunier et al. / Tetrahedron Letters 43 (2002) 2307–2311
various cyclisation/desilylation conditions. Though ini-
tial attempts proved frustrating, we were gratified to
find that the reaction of NBS with ene-adducts 3 pro-
ceeded smoothly and afforded, in essentially quantita-
tive yields, the corresponding brominated acetals 7
(Table 1).5
intramolecular cyclisation (entries 4 and 5). Moreover,
this transformation proceeds in a highly stereoselective
manner, resulting in the exclusive formation of a single
diastereoisomer, possessing the relative stereochemistry
depicted in Table 1.7 The sole generation of this isomer
can be rationalised by considering the intermediate of
the bromocyclisation, as shown in Fig. 2.
This intramolecular bromoetherification displays sev-
eral noteworthy features. Not only are the correspond-
ing bromoacetals produced in quantitative yields but
the reaction is complete within 5 min. The cyclisation
also tolerates a range of functionalities and, in all cases,
only the silyl enol ether function undergoes electrophilic
addition.6 Carbonꢀcarbon double and triple bonds are
unaffected, even when suitably positioned to undergo
In this intermediate, both the silyl ether and trimethyl-
silylmethyl substituents are locked in a syn relationship,
due to the initial enol ether double bond geometry. The
substituent located a to the hydroxyl function controls
the folding of the five-membered ring envelope confor-
mation and preferentially positions itself in a pseudo-
equatorial orientation. In the other possible conformer,
Table 1. Bromocyclisation of ene-adducts 3
O
R1
OTBS
TMS
NBS, 1 eq.
OTBS
TMS
OH
THF, 25°C
R1
Br
3
7
Yields(a)
> 95 %
Entry
1
Substrate
Product
O
OTBS
TMS
OTBS
TMS
OH
Br
O
OTBS
TMS
OH
OTBS
TMS
> 95 %
> 95 %
> 95 %
> 95 %
2
3
4
Br
O
OTBS
TMS
OTBS
TMS
OH
3
4
Br
O
OTBS
TMS
OTBS
TMS
C5H11
OH
OH
C5H11
Br
O
OTBS
TMS
OTBS
TMS
5
Br
a All yields are for crude compounds. These can be purified but substantial decomposition occurs resulting in significant losses in yields. The crude
products are sufficiently pure (>95%) to be engaged as such in the next step. The stereochemistry of adducts 7 has been established by careful
NMR studies including selective irradiations.
Figure 2.

R. Dumeunier et al. / Tetrahedron Letters 43 (2002) 2307–2311
Table 2. Double desilylation of acetals 7
2309
OH
O
R1
O
R1
OTBS
TMS
TBAF, 2 eq.
OH
H
+
R1
THF, 25°C
O
7
8
Br
9
Yields(a) [8:9]
Entry
Substrate
Product (major)
O
OTBS
TMS
OH
1
2
3
4
5
73 % [89:11]
H
H
Br
O
O
OH
OTBS
TMS
88 % [64:36]
65 % [80:20]
72 % [78:22]
90 % [78:22]
Br
O
O
OTBS
TMS
OH
3
H
Br
O
4
O
OTBS
TMS
C5H11
OH
H
H
C5H11
Br
O
O
OTBS
TMS
OH
Br
O
a
Isolated yields after purification by column chromatography. The ratios of 8:9 were determined by 1H NMR spectroscopy.
several purifications, implying that a dynamic equi-
librium is established between the open and closed
forms of enal 8.9 The preference in favour of the open
form 8 probably reflects an increased Pitzer strain in
the closed form 9 coupled with the loss of conjugation
present in enal 8.
this substituent would be disposed in a pseudoaxial
orientation, encountering severe 1,3-diaxial interactions
with the trimethylsilylmethyl group. It is also probable
that the silyloxy function assists the halocyclisation by
electron-donation towards the bromonium ion; hence
this type of cyclisation is likely a 5-exo- rather than a
5-endo-process.8
The existence of this equilibrium is, however, of no
consequence for the subsequent step. Indeed, oxidative
cyclisation to form the desired exo-methylene-g-butyro-
lactones 5 proceeded smoothly upon treatment of a
mixture of aldehyde 8 and lactol 9 with freshly pre-
pared MnO2, in the presence of catalytic amounts of
cyanide ion.10 The final lactones were obtained in good
to excellent yields, as shown in Table 3.
Whilst bromoacetals 7 can be readily and quantitatively
obtained, they proved to be rather unstable, undergoing
significant decomposition under purification conditions
or simple storage. It was therefore found more conve-
nient and higher yielding to use the crude reaction
product (>95% pure) immediately for the subsequent
transformation (Table 2).
In summary, we have developed a simple and efficient
route to exo-methylene-g-butyrolactones from readily
available ene adducts 3. This novel procedure, which
involves a three-step sequence starting from easily
accessible aldehydes, displays excellent tolerance
towards a variety of functional groups and is amenable
to the synthesis of large quantities of the desired lac-
Addition of 2 equiv. of TBAF to a THF solution of
crude bromoacetals 7 resulted in a smooth double
desilylation/elimination reaction affording, rather unex-
pectedly, the corresponding b%-hydroxy enals 8. Careful
analysis of the NMR spectra of 8 revealed the presence
of variable amounts of the cyclic lactols 9. The ratio of
8 to 9 remained constant for a given pair, even after

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R. Dumeunier et al. / Tetrahedron Letters 43 (2002) 2307–2311
Table 3. Oxidative cyclisation of enals 8
a
All the reactions were performed on the equilibrating mixture of enals and cyclic lactols.
Isolated yields after purification by column chromatography.
b
tones.11 Furthermore, a wide variety of substituents can
be readily incorporated on the heterocyclic ring system.
References
Current efforts are now being directed towards delineat-
ing the full scope of this connective methodology,
uncovering an enantioselective version of this new exo-
methylene-g-butyrolactones synthesis and applying this
novel approach to the total synthesis of complex natural
products. The results of these investigations will be
reported in due course.
1. (a) Matsuda, H.; Shimoda, H.; Uemura, T.; Yoshikawa,
M. Bioorg. Med. Chem. Lett. 1999, 9, 2647; (b) Fardella,
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2000, 41, 10215.
Acknowledgements
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Financial support of this work by the Universite´
catholique de Louvain, the Actions de Recherche Con-
certe´es (convention 96/01-197), the Fonds pour la For-
mation a` la Recherche dans l’Industrie et dans
l’Agriculture (FRIA), the Fonds de la Recherche Fon-
damentale Collective (dossier n° 2.4571.98) and the
Fond National de la Recherche Scientifique (FNRS) for
R. Dumeunier (Aspirant FNRS) is gratefully acknowl-
eged. I.E.M. is thankful to Merck & Co. for its contin-
uing support and for receiving the Merck Young
Investigator Award.
5. Takano, S.; Sekiguchi, Y.; Shimazaki, Y.; Ogasawara, K.
Tetrahedron Lett. 1989, 30, 4001. For a review on the
synthesis of substituted tetrahydrofurans by 5-exo and
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6. It is interesting to note that this ambident silyl enol
ether/allylsilane function typically reacts with elec-
trophiles as an allylsilane and not as an enol ether. The
bromocyclisation reported above is a rare example of the

R. Dumeunier et al. / Tetrahedron Letters 43 (2002) 2307–2311
2311
chemoselective involvement of the enol silane system in
electrophilically-induced cyclisations.
in 15 mL of THF was added Bu4NF in THF (2.44 mL of
1 M, 2.44 mmol). A yellow colour appeared immediately.
The mixture was stirred for 5 min at 25°C, diluted with 20
mL of diethyl ether and washed with 20 mL of brine. The
aqueous layer was extracted twice with 20 mL of diethyl
ether. The combined extracts were dried (MgSO4) and
concentrated in vacuo. Chromatography of the residue
over silica gel (eluted with EtOAc–hexane, 1:3) gave 125
mg of the corresponding aldehyde 8 (73%) as a thick oil.
This sensitive material was directly used in the oxidation
step. Thus, to a cold solution (0°C) of aldehyde 8 (0.33 g,
2.30 mmol) in 20 mL of acetonitrile were added succes-
sively, MnO2 (4 g, 46 mmol) and KCN (15 mg, 0.23
mmol). The mixture was stirred for 25 min at 0°C and
filtered over silica-gel. The filtrate was concentrated under
reduced pressure and the resulting oil purified by silica-gel
column chromatography (with EtOAc–hexane, 1:13), giv-
ing 275 mg (84%) of pure a-methylene-g-butyrolactone 5.
1H NMR (300 MHz, CDCl3) lH (ppm): 6.20 (1H, t,
J=2.8 Hz), 5.61 (1H, t, J=2.7 Hz), 4.56–4.47 (1H, m),
3.00 (1H, ddt, J=17, 7.6, 2.5 Hz), 2.56 (1H, ddt, J=17,
5.9, 2.8 Hz), 1.48–1.33 (4H, m), 0.95 (3H, t, J=7.2
Hz).13C NMR (50 MHz, CDCl3) lC (ppm): 170.20,
134.86, 121.67, 77.23, 38.36, 33.60, 18.18, 13.72. MS (EI)
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11. Typical experimental procedure: To a solution of 0.40 g of
ene adduct 3 [Table 1, entry 1, 1.22 mmol] in 10 mL of
THF was added 0.22 g of N-bromosuccinimide (1.22
mmol). The mixture was stirred at 25°C for 5 min.
Volatiles were then removed under reduced pressure. The
residue, a white solid, was stirred with pentane (10 mL)
for 1 min and filtered. The resulting solution was concen-
trated in vacuo, giving 0.51 g of pure bromoacetal 7
(>99%). To a solution of 7 [Table 2, entry 1, 1.22 mmol]
+
+
+
’
’
m/z: 141 (M +H , 80), 140 (M , 36). IR (film): 2961–
2874, 1765, 1666, 1466, 1399, 1273, 1187, 1001, 940, 813
cm−1. RN: [58557-51-3].