Domino reaction of 1,3-bis(trimethylsilyloxy)-1,3-dienes with oxalyl chloride: General and stereoselective synthesis of γ-alkylidenebutenolides

Article abstract of DOI:10.1002/1521-3765(20000901)6:17<3204::AID-CHEM3204>3.0.CO;2-G

The Lewis acid catalyzed cyclization of oxalyl chloride with 1,3-bis-(trimethylsilyloxy)-1,3-dienes 3, derived from 1,3-dicarbonyl compounds 1, provides a new and general approach for the synthesis of γ-alkylidenebutenolides 4, a pharmacologically and syn

Full text of DOI:10.1002/1521-3765(20000901)6:17<3204::AID-CHEM3204>3.0.CO;2-G

FULL PAPER
Domino Reaction of 1,3-Bis(trimethylsilyloxy)-1,3-dienes with Oxalyl
Chloride: General and Stereoselective Synthesis of g-Alkylidenebutenolides
Peter Langer,*[a] Toni Schneider,[a] and Martin Stoll[a]
Dedicated to Professor H. Martin R. Hoffmann on the occasion of his 65th birthday
Abstract: The Lewis acid catalyzed cyc-
lization of oxalyl chloride with 1,3-bis-
(trimethylsilyloxy)-1,3-dienes 3, derived
from 1,3-dicarbonyl compounds 1, pro-
vides a new and general approach for
the synthesis of g-alkylidenebutenolides
4, a pharmacologically and synthetically
important class of substances. A variety
of butenolides were efficiently prepared
in good yields and with very good regio-
and stereoselectivities. An up-scaling of
the reaction was possible. The use of the
Lewis acid trimethylsilyl-trifluorome-
thanesulfonate (TMSOTf) proved to be
superior to other activation conditions.
Sterically undemanding g-alkylidenebu-
tenolides could be prepared alternative-
ly by reaction of the corresponding 1,3-
dicarbonyl dianions with N,N'-dimeth-
oxy-N,N'-dimethylethanediamide (2d).
In contrast to the dianion method, the
Lewis acid catalyzed reaction also facili-
tated the cyclization of sterically hin-
dered, base-labile, cyclic and functional-
ized substrates. From a methodology
viewpoint, the dianion reaction repre-
sents the first cyclization of a bis-Wein-
reb amide and the first cyclization of an
oxalic acid-synthon with an ambident
dianion. The TMSOTf-catalyzed reac-
tions are both the first cyclizations of 1,3-
bis(trimethylsilyloxy)-1,3-dienes with a
C2 dielectrophile and the first cycliza-
tions of 1,3-bis(trimethylsilyloxy)-1,3-di-
enes with a carboxylic acid dichloride or
a related dielectrophile.
Keywords: butenolides ´ catalysts ´
cycloadditions ´ 1,3-dienes ´ stereo-
selective synthesis
employed for the direct preparation of substituted buteno-
lides. However, many naturally occurring g-alkylidenebute-
nolides contain substituents at both the a- and the b-position
or at the exocyclic double bond. Unfunctionalized, z-config-
ured g-alkylidenebutenolides have been stereoselectively
prepared by AgI-catalyzed isomerization of (Z)-2-en-4-ynoic
acids.[4] Other known methods for the preparation of
g-alkylidenebutenolides proceed with low[5] or no[6] stereo-
selectivity or with undesired regiochemistry.[7] To the best of
our knowledge, no method was available which provided a direct
and stereoselective approach to functionalized g-alkylidene-
butenolides with a wide range of substitution patterns.
To fill this gap, we have investigated the concept of direct
cyclization of 1,3-dicarbonyl compounds with oxalic acid
dielectrophiles. Despite the simplicity of this idea, the
cyclization of 1,3-dicarbonyl compounds that contain a
terminal hydrogen atom (e.g. acetylacetone) with oxalyl
chloride in the presence of Lewis acids was not achieved until
1990.[8] The cyclization proceeds through the central carbon
atom and an oxygen atom of the 1,3-diketone. Recently, we
developed the first cyclization reactions of 1,3-dicarbonyl
compounds 1 with oxalic acid dielectrophiles which proceed
by attackof a terminal carbon atom of the nucleophile.[9] To
achieve the desired regioselectivity, the 1,3-dicarbonyl com-
Introduction
Many natural products, such as the prominent compounds
freelingyne, tetrenolin, dihydroxerulin and patulin, belong to
the pharmacologically important group of g-alkylidenebute-
nolides.[1] In particular, a-hydroxy-g-alkylidenebutenolides[2]
and the related isotetronic acids[3] are currently of great
interest since they are key intermediates in several natural
product syntheses. In this context, transition metal catalyzed
coupling or reduction reactions via enol triflates have been
used to transform g-alkylidenebutenolides into natural prod-
ucts.[2] It was only recently that an efficient stereoselective
route was introduced to obtain a specific member of the class
of g-alkylidenebutenolides, namely 5-(2-hydroxyethylidene)-
2(5H)-furanone, by stereospecific elimination of l- and d-
gulono-1,4-lactone.[2] Since a carbohydrate derivative is used
as the substrate for this reaction, this method cannot be
[a] Dr. P. Langer, T. Schneider, M. Stoll
Institut für Organische Chemie der
Georg-August-Universität Göttingen
Tammannstrasse 2, 37077 Göttingen (Germany)
Fax : (‡49)551-399475
E-mail: planger@uni-goettingen.de
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Chem. Eur. J. 2000, 6, No. 17

3204±3214
pounds were used in the corresponding ambident dianionic
form.[10], [11] The use of N,N'-dimethoxy-N,N'-dimethylethane-
diamide (2d)[12] as the dielectrophile was mandatory to induce
a cyclization reaction rather than polymerization.[13] Although
this reaction provided convenient access to a variety of g-
alkylidenebutenolides, there is still the need for the develop-
ment of a more general method which also allows the use of
base-labile, sterically hindered, cyclic and functionalized
substrates. Herein, we report full details of our dianion
methodology and the development of a completely new and
general method for the preparation of g-alkylidenebuteno-
lides. Based on the Mukaiyama aldol reaction,[14] we have
developed the first Lewis acid catalyzed cyclization of 1,3-
bis(trimethylsilyloxy)-1,3-dienes 3 with oxalyl chloride (2b),
1,3-Bis(trimethylsilyloxy)-1,3-dienes (3) represent synthons
of 1,3-dianions that have been treated with monofunctional
electrophiles in the presence of Lewis acids.[15] Cyclization
reactions of 1,3-bis(trimethylsilyloxy)-1,3-dienes with C3, C4,
and C5 dielectrophiles (ketones, aldehydes or acetals) have
been reported and proceed generally with participation of the
terminal and the central carbon atom of the 1,3-bis(trime-
thylsilyloxy)-1,3-diene.[16] Despite the synthetic potential of
these building blocks, to the best of our knowledge, no
cyclization reactions of 1,3-bis(trimethylsilyloxy)-1,3-dienes
with C2 dielectrophiles, such as oxalyl chloride, have been
reported so far.[17] Presumably, this can be attributed to the
relative lability of the oxalic acid substructure which can give
rise to several drawbacks in the reaction with nucleophiles.[18]
In addition, to the best of our knowledge, no cyclization
reactions of 1,3-bis(trimethylsilyloxy)-1,3-dienes with carbox-
ylic acid dichlorides or related dielectrophiles have yet been
reported.[19]
Results and Discussion
Cyclization of 1,3-dianions with N,N'-dimethoxy-N,N'-dime-
thylethanediamide (2d): Initial experiments showed that
reactions of the dianion of ethyl acetoacetate (1a) with
diethyl oxalate (2a) or oxalyl chloride (2b) led to the
formation of complex, inseparable mixtures (owing to over-
addition, polymerization, or decomposition). The reaction of
the dianion of 1a with 1,4-dimethylpiperazine-2,3-dione
(2c)[20] was also unsuccessful, although 2c had previously
been reported to undergo condensation reactions with two
equivalents of monofunctional organolithium compounds.
Fortunately, the problem could be finally solved with the use
of N,N'-dimethoxy-N,N'-dimethylethanediamide (2d). This
compound was first reported in 1995 and was used only in
condensation reactions with simple monolithium compounds
such as phenyllithium.[12] Exposure of this Weinreb oxalic
amide to the dianion of ethyl acetoacetate (1a) induced a
cyclization reaction, and the g-alkylidenebutenolide 4a was
obtained in 75% yield (Scheme 1). The product was formed
which provides direct access to a great variety of g-alkyli-
denebutenolides.
Abstract in German: Die Lewis Säure katalysierte Cyclisie-
rung von Oxalylchlorid mit 1,3-Bis(trimethylsilyloxy)-1,3-
dienen 3 bietet einen neuartigen und generellen Zugang zu
der pharmakologisch und für die Naturstoffsynthese wichtigen
Substanzklasse der g-Alkylidenbutenolide 4. Die benötigten
Diene 3 wurden ausgehend von 1,3-Dicarbonylverbindungen 1
dargestellt. Eine groûe Bandbreite von Butenoliden 4 konnte in
guten Ausbeuten und mit sehr guten Regio- und Stereoselekti-
vitäten hergestellt werden, wobei an zwei Beispielen gezeigt
wurde, daû ein Up-Scaling der Reaktion möglich ist. Als
optimale Lewis Säure hat sich Trimethylsilyl-trifluormethan-
sulfonat (TMSOTf) erwiesen. Sterisch weniger anspruchsvolle
g-Alkylidenebutenolide konnten durch direkte Umsetzung
dilithiierter 1,3-Dicarbonyl-Dianionen mit N,N'-Dimethoxy-
N,N'-dimethylethandiamid (2d) hergestellt werden. Im Unter-
schied zu der Dianion-Methode erlaubt die Lewis Säure
katalysierte Variante darüber hinaus eine erfolgreiche Cyclisie-
rung von sterisch gehinderten, basenlabilen, cyclischen und
funktionalisierten Substraten. Aus methodischem Blickwinkel
stellt die Dianion-Methode die bisher erste Cyclisierungsre-
aktion eines Bis-Weinrebamids und die erste Cyclisierung eines
Oxalsäure-Dielektrophils mit einem ambidenten Dianion dar.
Bei der TMSOTf-katalysierten Reaktion handelt es sich sowohl
um die erste Cyclisierung eines 1,3-Bis(trimethylsilyloxy)-1,3-
diens mit einem C2-Dielektrophil als auch um die erste
Cyclisierung eines 1,3-Bis(trimethylsilyloxy)-1,3-diens mit ei-
nem Dicarbonsäuredichlorid.
Scheme 1. Possible mechanism for the reaction of 1,3-dianions with N,N'-
dimethoxy-N,N'-dimethylethanediamide (2d).
Chem. Eur. J. 2000, 6, No. 17
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P. Langer et al.
FULL PAPER
Table 1. Optimization of the reaction of 1,3-bis(trimethylsiloxy)-1,3-diene
3a with oxalyl chloride.
both regioselectively (by cyclization of the terminal carbon
and the neighboring oxygen atom of the dianion) and with
complete stereoselectivity. Optimized yields were obtained by
the use of 1.2 equivalents of the dianion, addition of 2d at
À788C, and warming of the reaction mixture to room
temperature within a period of six hours, followed by treat-
ment with hydrochloric acid.
Entry
Lewis acid
Equiv
t[h][a]
E:Z[b]
[%][c]
1
2
3
4
5
6
7
8
9
none
TiCl4
TiCl4
SnCl4
6 ‡ 14
6 ‡ 14
6 ‡ 14
6 ‡ 14
6 ‡ 14
6 ‡ 14
6 ‡ 14
6 ‡ 14
6 ‡ 1
> 98:2
> 98:2
> 98:2
> 98:2
> 98:2
11:1
15:1
14:1
> 98:2
> 98:2
> 98:2
> 98:2
22
18
20
24
33
58
56
27
74
88
70
87
2
0.3
2
0.3
2
0.3
2
2
2
0.3
0.3
ZnBr2
According to Harris et al., the reaction of the bis(N-
methoxy-N-methylamide) of a glutaric acid derivative with
the dianion of tert-butylacetoacetate 1b led to formation of an
open-chain product.[21a] No conversion was observed, how-
ever, in the reaction of the simple N-methoxy-N-methyl-
acetamide with the monoanion of acetophenone.[21b] For the
cyclization reaction reported herein, the intramolecular for-
mation of the five-membered ring must be preferred over the
formation of any open-chain 1:2 product. The product is
probably formed by a regioselective attackof the terminal
carbon atom of the dianion on the substrate and a subsequent
cyclization step that also proceeds regioselectively at the
neighboring oxygen atom. Our working hypothesis to explain
the regioselectivity of the ring closure is based on the
complexation of the lithium atom by both the amide and
the enolate functionalities (intermediate A; Scheme 1). This
chelation step brings the amide and the enolate functionalities
close to each other, thus favoring a regioselective ring closure
and formation of intermediate B.[22] Both five-membered
chelate complexes are subsequently cleaved with hydrochlor-
ic acid to form the carbonyl groups. The preparative scope and
the limitations of the dianion methodology are discussed in
the next section in order to directly compare it with the new
Lewis acid mediated cyclization reaction reported herein.
CF3COOH
CF3COOH
C5H6NCl
TMSOTf
TMSOTf
TMSOTf
TMSOTf
10
11
12
6 ‡ 14
6 ‡ 1
6 ‡ 14
[a] Reaction time (À78 !208C) ‡ reaction time at 208C. [b] Integration of
the 1H NMR spectra of the crude products. [c] Yields of isolated products.
Importantly, in contrast to the dianion method, an up-scaling
of the reaction to 40 mmol was possible to give the butenolide
4a in excellent yield and with a very high stereoselectivity
(vide infra).
The formation of the butenolide 4a can be explained by the
following working hypothesis (Scheme 2): attack of the
terminal carbon atom of the 1,3-bis(trimethylsilyloxy)-1,3-
Cyclization of 1,3-bis(trimethylsilyloxy)-1,3-dienes (3) with
oxalyl chloride (2b): Our first attempts to induce a cyclization
reaction between the 1,3-bis(trimethylsilyloxy)-1,3-diene 3a
and oxalic acid dielectrophiles were unsuccessful: reaction of
3a with diethyl oxalate (2a) in dichloromethane in the
presence of stoichiometric amounts of titanium(iv) chloride
resulted in a complex mixture. In contrast, reaction of the
diene 3a with oxalyl chloride (2b) in the absence of a Lewis
acid gave the E-configured butenolide 4a, however, in only
22% yield. Our first attempts to improve the yield by the use
of tin(iv) chloride or zinc(ii) bromide as the Lewis acid were
unsuccessful (Table 1). Interestingly, significantly improved
yields were obtained by using stoichiometric or catalytic
amounts of trifluoroacetic acid (TFA). However, the stereo-
selectivities decreased to 11:1 and 15:1, respectively. Low
yields of 4a were also obtained when pyridinium hydro-
chloride was employed. Fortunately, use of the Lewis acid
trimethylsilyl-trifluoromethanesulfonate (TMSOTf)[16e] led to
a dramatic improvement: butenolide 4a was isolated in 88%
yield with excellent regio- and stereoselectivity when stoi-
chiometric amounts of TMSOTf were employed. Much to our
satisfaction, the use of substoichiometric amounts (0.3 equiv)
of TMSOTf resulted in the stereoselective formation of 4a in
87% yield. Optimized yields were obtained when a solution of
the catalyst in CH2Cl2 was added to a solution of 2b and 1,3-
bis(trimethylsilyloxy)-1,3-diene 3a in CH2Cl2 at À788C. The
reaction mixture was allowed to warm to 208C over 6 h.
Scheme 2. Possible mechanism for the TMSOTf-mediated reaction of 1,3-
bis(trimethylsilyloxy)-1,3-dienes 3 with oxalyl chloride (2b).
diene on oxalyl chloride (which is activated by TMSOTf)
followed by expulsion of trimethylchlorosilane (TMSCl) gives
intermediate C. Intramolecular silyl migration results in
formation of intermediate D and in the generation of an
ester function (intermediate E). The product is finally formed
by attackof the oxygen atom on the activated carboxylic acid
chloride, expulsion of TMSCl, and regeneration of the
catalyst. The lactonization under formation of the five-
membered ring must be preferred over the formation of any
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g-Alkylidenebutenolides
3204±3214
open-chain 1:2-products. The regioselective cyclization that
involves the oxygen atom suggests that the latter was
deprotected during the cyclization and that the silyl groups
were transferred from their original positions to the oxygen
atoms of the oxalic acid subunit to result in an activation of
the second carboxylic acid chloride function.
An attempt to prepare E-configured g-alkylidenebuteno-
lides by stereospecific elimination at insufficiently low
temperatures led to a mixture of geometric isomers.[2c] This
also occurred upon treatment of E-configured g-alkylidene-
butenolides with chlorosulfonic acid.[7c] These observations
strongly support the assumption that the stereoselectivity
observed in this study to preferentially give g-alkylidenebu-
tenolides with an E-configuration is not thermodynamically
but kinetically controlled. In fact, the formation of the E-
configured products obtained by the use of both this and the
dianion method can be explained by the formation of a
stabilizing intramolecular hydrogen bond C À H ´´´ O or by
the W-shaped configurations of intermediates A and E which
allow a minimization of the dipole ± dipole repulsion of the
oxygen atoms.
From a methodology viewpoint, the TMSOTf-mediated
reaction reported herein represents, to the best of our
knowledge, both the first cyclization of a 1,3-bis(trimethyl-
silyloxy)-1,3-diene with a C2 dielectrophile and the first
cyclization of a 1,3-bis(trimethylsilyloxy)-1,3-diene with a
carboxylic acid dichloride or a related dielectrophile. In
addition, a cyclization reaction that involves the terminal
carbon and the neighboring oxygen atom of a 1,3-bis(trimeth-
ylsilyloxy)-1,3-diene has not been reported to date.
Scheme 4. Synthesis of 1,3-bis(trimethylsilyloxy)-1,3-dienes 3.
iently prepared in only one step by treatment of the 1,3-
diketones with two equivalents of TMSOTf (method B).[24] It
is noteworthy, that 1,3-bis(trimethylsilyloxy)-1,3-dienes 3 are
not accessible by reaction of 1,3-dicarbonyl dianions with
TMSCl (owing to attackof the chlorosilane at the carbon
atom of the dianions to give the C-silylated silyl enol ethers 6).
We observed that, upon heating, the ester-derived 1,3-
bis(trimethylsilyloxy)-1,3-dienes that contain a substituent at
C2 readily underwent a 1 !5 silyl migration reaction to give
the silyl enol ethers 6.[25] To avoid this rearrangement, the
respective bis-silyl enol ethers had to be used within two days
of their preparation. In some cases, it was advantageous to
remove the solvent at 08C rather than at room temperature.
In spite of the precautions, amide-derived 1,3-bis(trimethyl-
silyloxy)-1,3-dienes could not be obtained (owing to rear-
rangement of the silyl group from the oxygen to the terminal
carbon atom). However, most of the 1,3-bis(trimethylsilyl-
oxy)-1,3-dienes prepared were stable for months when stored
under an inert atmosphere at À208C.
To investigate the preparative scope and the limitations of
the two methods for the preparation of g-alkylidenebuteno-
lides, the substituents of the substrates were systematically
varied (Scheme 3, Table 2). The starting materials were
Reaction of 2d with the dianions of ethyl acetoacetate, tert-
butyl acetoacetate, benzoylacetone, 5,5-dimethyl-2,4-hexane-
dione, and acetylacetone afforded the g-alkylidenebuteno-
lides 4a ± e in good yields and with excellent stereoselectiv-
ities (Table 2). The TMSOTf-catalyzed reaction of oxalyl
chloride with the 1,3-bis(trimethylsilyloxy)-1,3-dienes 3a and
3c ± e afforded the butenolides 4a and 4c ± e in significantly
improved yields. Reaction of the dianion of S-tert-butyl
thioacetoacetate[26a] and of N,N-diethyl acetoacetamide[26b]
with the bis-Weinreb amide 2d afforded the butenolides 4 f
and 4g in good yields and with very good stereoselectivities.
Butenolide 4g could not be prepared by the Lewis acid
mediated cyclization reaction, since the required amide-
derived bis-silyl enol ether could not be prepared (see above).
Starting with 1,3-bis(trimethylsilyloxy)-1,3-dienes 3h ± k, con-
taining a methyl, ethyl, butyl, and benzyl group, respectively,
at the terminal carbon atom, the corresponding Z-configured
butenolides 4h ± k could be isolated in good yields and with
very good stereoselectivities. The change of the stereoselec-
tivity from E- to Z-configuration can be explained by the
steric influence of the substituents R2 and by the absence of
the stereodirecting hydrogen bonds. Importantly, the use of
the dianion method gave the butenolides 4h ± k in signifi-
cantly lower yields or did not generate them at all.
Scheme 3. Synthesis of g-alkylidenebutenolides 4a ± aj.
prepared as follows: bis-silyl enol ethers (3) derived from 1,3-
keto esters were obtained in two steps. The 1,3-dicarbonyl
compounds were converted into the corresponding silyl enol
ethers 5, generally high yields, by reaction with TMSCl in the
presence of triethylamine (Scheme 4).[23] The desired 1,3-
bis(trimethylsilyloxy)-1,3-dienes 3 were obtained by treat-
ment of the silyl enol ethers 5 with lithium diisopropylamide
(LDA) at À788C and subsequent treatment with TMSCl
(method A).[16e] Avariety of bis-silyl enol ethers were conven-
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P. Langer et al.
FULL PAPER
Table 2. Synthesis of the g-alkylidenebutenolides 4a ± aj.
3
Condi-
tions[a]
R1
R2
4
Dianion method
yield[%][b]
TMSOTf method
yield[%][b]
a
b
c
d
e
f
A
±
B
B
B
±
OEt
O(tBu)
Ph
tBu
Me
±
±
±
±
±
±
±
75
73
57
80
56
67
63
87
±
80
84
74
±
S(tBu)
NEt2
g
±
±
h
i
j
A
A
A
OMe
OEt
OEt
Me
Et
Bu
70
54
0
80
76
70
k
A
OEt
Bn
0
68
l
A
±
±
0
85
m
C
±
±
0
43
n
o
p
B
A
A
Me
OEt
OEt
Me
Me
Et
72
71
43
77
71
66
q
r
s
t
A
A
A
A
OEt
Ph
OEt
Ph
Bu
Allyl
Ph
0
0
0
0
62
45
56
62
Bn
u
C
±
±
0
48
v
w
x
B
B
B
H
Me
H
H
H
Me
0
0
0
70
64
66
±
±
y
z
A
A
H
73
60
±
Me
41
aa
ab
A
D
±
±
n ˆ 1
n ˆ 2
75
23[c]
±
22[c]
ac
±
±
±
61
±
[c]
[c]
ad
ae
af
D
A
B
Me
OEt
Ph
n ˆ 2
n ˆ 2
n ˆ 2
n ˆ 1
0
0
0
71
50
26
ag
A
OEt
ah
ai
B
B
±
±
±
74
52
81
60
±
aj
B
±
±
22
28
[a] Reaction conditions for the preparation of the dienes 3: A ˆ 1) NEt3, TMSCl, 2) LDA, TMSCl; B ˆ NEt3, TMSOTf; C ˆ TMSCl (2 equiv), ZnCl2, NEt3;
D ˆ 1) NEt3, TMSCl, 2) NEt3, TMSOTf. [b] Yields of isolated products. In all cases, the stereoselectivity was >98:2 in favor of the drawn isomers. For the
butenolides 4e, 4 f, 4n, 4r, 4s and 4t the E:Z-ratios were 5:1, 10:1, 3.5:1, 1:3, 7:1 and 1:3, respectively. [c] A 3:1 mixture of the regioisomers 4ab and 4ad was
obtained in 72% yield from which a sample of 4ab was separated in 23% yield.
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g-Alkylidenebutenolides
3204±3214
On account of their polyketide structure, many natural
products contain a methoxy- or a related group in the b-
position of the butenolide.[27] The synthesis of butenolide 4l,
which contains a methoxy group in the b-position and an
unprotected hydroxy group in the a-position,[28] was therefore
of special interest. This compound was prepared in good yield
and with very good stereoselectivity by reaction of diene 3l[29]
with oxalyl chloride. Importantly, starting with the corre-
sponding dianion, butenolide 4l could not be prepared.
Silylation of methyl triacetate afforded the diene 3m.[30]
Reaction of 3m with oxalyl chloride gave the Z-configured
ester-functionalized butenolide 4m. This compound could not
be prepared by the dianion method. Starting with the 1,3-
bis(trimethylsilyloxy)-1,3-dienes 3n ± t, substituted at the
central carbon atoms, the butenolides 4n ± t were isolated in
good yields. Despite the fact that these butenolides bear
substituents at their exocyclic double bonds, good to excellent
stereoselectivities were observed. Starting with the corre-
sponding dianions, the methyl- and the ethyl-substituted
butenolides 4n ± p were obtained, in moderate to good yields.
The butyl, allyl-, phenyl-, and the benzyl-substituted buteno-
lides, 4q ± t respectively, could not be prepared at all.
Silylation of methyl 2-acetylacetoacetate afforded the 1,3-
bis(trimethylsilyloxy)-1,3-diene 3u.[31] Reaction of 3u with
oxalyl chloride afforded the butenolide 4u, which proved to
be very sensitive towards hydrolysis. Butenolide 4u could not
be obtained from the reaction of the corresponding dianion
with 2d. Reaction of oxalyl chloride with the cyclic 1,3-
bis(trimethylsilyloxy)-1,3-dienes 3v ± x[24] afforded the inter-
esting g-alkylidenebutenolides 4v ± x in good yields. It is again
noteworthy that these butenolides could not be prepared by
the reaction of the corresponding dianions[32] with 2d. The
bicyclic core structure of the butenolides 4v± x is present in a
variety of natural products, such as xylerythrine, peniophor-
ine, or peniosanguine.[33] Treatment of oxalyl chloride with the
1,3-bis(trimethylsilyloxy)-1,3-diene of 2-acetyl-g-butyrolac-
tone 3z gave the butenolide 4z in moderate yield with very
good stereoselectivity. Butenolides 4y ± z could be prepared in
better yields by the dianion methodology. Butenolide 4aa
could not be prepared by the TMSOTf method on account of
problems associated with the preparation of the required
diene 3aa. In contrast, butenolide 4aa could be prepared in
good yield from the dianion[34] of 2-acetylcyclopentanone. The
1,3-bis(trimethylsilyloxy)-1,3-diene 3ab could be prepared in
pure form for the first time by a new regioselective two-step
procedure:[35] reaction of 2-acetylcyclohexanone with TMSCl/
NEt3 in benzene regioselectively afforded 2-acetyl-1-tri-
methylsiloxycyclohexene which was cleanly converted into
3ab by treatment with one equivalent of TMSOTf/NEt3 in
ether. However, reaction of oxalyl chloride with 3ab afforded
a 3:1 mixture of the regioisomeric butenolides 4ab and 4ad.
Similar results were obtained when the dianion of 2-acetylcy-
clohexanone[36] was employed. Reaction of the dianion of
2-acetyldecalone with 2d regio- and stereoselectively afford-
ed the butenolide 4ac in good yield.
The related phenyl-substituted diene 3af was prepared from
the corresponding 1,3-dione in one step (method B). Reaction
of 3af with oxalyl chloride afforded the butenolide 4af.
Reaction of oxalyl chloride with the diene 3ag, which was
prepared from ethyl cyclopentanone-2-carboxylate in two
steps, afforded the butenolide 4ag which contains a 5,5-ring
system. Importantly, the bicyclic butenolides 4ae ± ag could
not be prepared by the use of the dianion method although the
required dianions have been previously reported.[37] Reaction
of oxalyl chloride with the 1,3-bis(trimethylsilyloxy)-1,3-diene
3ah, prepared in one step from 2-acetyltetralone, afforded the
butenolide 4ah in good yield and with very good stereo-
selectivity. This product could be equally successfully pre-
pared from the corresponding dianion. The 1,3-bis(trimethyl-
silyloxy)-1,3-diene 3ai was prepared in one step from 3-acetyl-
2,3-dihydrobenzofuran-2-one in good yield. Reaction of
oxalyl chloride with the diene 3ai gave the g-alkylidenebu-
tenolide 4ai, a derivative of the natural product calycine,[38] in
good yield and with very good stereoselectivity. The yield of
this product was much lower when the corresponding dianion
was employed. Reaction of oxalyl chloride with the 1,3-
bis(trimethylsilyloxy)-1,3-diene 3aj, which was obtained from
2-acetylbenzopentan-1-one in one step, stereoselectively
afforded the g-alkylidenebutenolide 4aj. This product was
also obtained with the dianion methodology. The 1,3-bis(tri-
methylsilyloxy)-1,3-dienes which lead to butenolides 4ae ± 4aj
have not been previously reported.
All reactions presented herein were carried out on a 1.5 to
3.5 mmol scale. Importantly, an up-scaling is possible for the
TMSOTf-catalyzed cyclization reaction. For example, the g-
alkylidenebutenolides 4a and 4l were conveniently prepared
with excellent stereoselectivities on a 40 mmol scale in 83%
and 84% yields, respectively. Depending on the substrate, an
extension of the reaction times from 2 to 14 h was necessary in
order to obtain good yields. The yields decreased when the
reaction mixtures were stirred at 208C for longer than 20 h
because of decomposition.
Conclusions
The TMSOTf-catalyzed cyclization of oxalyl chloride with
1,3-bis(trimethylsilyloxy)-1,3-dienes provides a new and gen-
eral approach to a variety of g-alkylidenebutenolides which
are of pharmacological relevance and of importance for
natural product syntheses. Although several side-reactions
are, in principle, possible (owing to the labile nature of the
oxalic acid substructure)[18] the butenolides 4a ± aj could be
prepared in good yields and with very good regio- and
stereoselectivities. In most cases, the yields were higher than
in the corresponding cyclization reactions of 1,3-dianions with
N,N'-dimethoxy-N,N'-dimethylethanediamide (2d). Both
methods are comparable in terms of the regio- and stereo-
selectivities achieved. In those cases where the dianion
method performs well it has the advantage that the 1,3-
dicarbonyl compounds can be directly used. In contrast to the
dianion methodology, the Lewis acid catalyzed cyclization
allows the use of sterically hindered, base-labile, cyclic and
functionalized substrates. For unsubstituted butenolides and
The new 1,3-bis(trimethylsilyloxy)-1,3-diene 3ae was pre-
pared from ethyl cyclohexanone-2-carboxylate in two steps
(method A). Reaction of 3ae with oxalyl chloride afforded
the bicyclic butenolide 4ae which contains a 5,6-ring system.
Chem. Eur. J. 2000, 6, No. 17
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3209

P. Langer et al.
FULL PAPER
(1H NMR: 200 or 300 MHz, 13C NMR: 50 or 75 MHz) the deuterated
solvents indicated were used. The multiplicity of the 13C NMR signals were
determined with the DEPT135 technique and quoted as: CH3, CH2, CH,
and C for primary, secondary, tertiary and quaternary carbon atoms. Yields
refer to analytically pure samples. Isomer ratios were derived from suitable
1H NMR integrals. Mass spectral data (MS) were obtained by means of
electron ionization (70 eV) or chemical ionization (CI, H2O). For
preparative-scale chromatography, silica gel (Merck, 60 ± 200 mesh) was
used. Melting points were measured on a Dr. Tottoli apparatus (Büchi) and
are uncorrected. Elemental analyses were performed at the microanalytical
laboratory of the Universität Göttingen. IR spectra were recorded on a
Perkin ± Elmer 1600Series FT-IR spectrometer. The configurations of the
exocyclic double bonds of several butenolides were proven by NOE
measurements. For E-configured butenolides, the signals (1H NMR) of
both the ring and the exocyclic CH groups are shifted downfield relative to
the respective signals of the Z isomers. This observation, which has already
been previously made,[2a] was also useful for determining the configuration
of the products.
for butenolides containing a substituent at the exocyclic
double bond, very good E-selectivities were generally ob-
tained. The best stereoselectivities were observed in the case
of ester-derived butenolides. In contrast, only moderate
selectivities were obtained in the case of acetylacetone-
derived butenolides 4e and 4n (R1 ˆ Me). On the other hand,
very good stereoselectivities were observed for the ketone-
derived butenolides 4c and 4d that contain a phenyl and a
tert-butyl group, respectively. For most of the butenolides
prepared, the tautomeric form F is adopted exclusively which
General procedure for the two-step preparation of 1,3-bis(trimethylsilyl-
oxy)-1,3-dienes (3) (method A): First step: To a solution of the 1,3-keto
ester (49 mmol) in benzene (100 mL) was added NEt3 (64 mmol) and
TMSCl (64 mmol) at 208C. The suspension was stirred for 14 h; the
precipitated salts were removed by filtration, and the solvent was removed
in vacuo. The residue was distilled in vacuo to give the silylenolethers 5 in
80 ± 90% yields. Second step: To a solution of LDA in THF, prepared by
accounts for the excellent stereoselectivities obtained. In con-
trast, tautomer G is present in the case of the butenolide that
contains an aldehyde group (R1 ˆ H).[39] For the butenolides
4e and 4n, relatively broad signals (1H NMR) were observed
for the CH-hydrogen atoms of the two geometric isomers. The
tautomeric ester form G could not be detected in solution. A
rapid equilibrium between the structures F, G, and H presum-
ably accounts for the moderate stereoselectivities obtained for
butenolides 4e and 4n. Surprisingly good E-selectivities were
observed for ester-derived butenolides that contain a sub-
stituent at the exocyclic double bond. In the case of butenolides
that contain a substituent at the ring system, very good Z-
selectivities were generally obtained owing to steric reasons.
From a methodology viewpoint, the dianion reaction
represents both the first cyclization of an oxalic acid
dielectrophile with an ambident dianion as well as the first
cyclization of a bis-Weinreb amide. To the best of our
knowledge, the Lewis acid-catalyzed reactions reported here-
in represent both the first cyclizations of 1,3-bis(trimethyl-
silyloxy)-1,3-dienes with a C2 dielectrophile and the first
cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-dienes with a
carboxylic acid dichloride or a related dielectrophile. These
reactions also represent the first examples of cyclizations
which involve the terminal carbon and the neighboring
oxygen atom of a 1,3-bis(trimethylsilyloxy)-1,3-diene. In
conclusion, the Lewis acid mediated cyclization reaction of
oxalyl chloride with 1,3-bis(trimethylsilyloxy)-1,3-dienes rep-
resents a new and general method for the synthesis of g-
alkylidenebutenolides and constitutes a significant expansion
of the methods known today for the preparation of this
important type of compound. We are currently working
towards the application of this methodology to the synthesis
of natural products.
addition of nBuLi (39 mmol, 2.35m in n-hexane) to
a solution of
diisopropylamine (39 mmol) in THF (50 mL) at 08C, was added a solution
of the silylenolether 5 (22 mmol) in THF at À788C. After the mixture had
been stirred for 1 h at À788C, TMSCl (48 mmol) was added. The solution
was allowed to warm to ambient temperature over a period of 2 h and the
solution was stirred for 1 h at 208C. The solvent was removed in vacuo and
petrol ether was added to the residue. The precipitated lithium chloride was
removed by filtration under inert conditions and the solvent of the filtrate
was removed in vacuo to give a yellow oil which was distilled in vacuo in a
bulb-to-bulb distillation apparatus.
General procedure for the one-step preparation of 1,3-bis(trimethylsilyl-
oxy)-1,3-dienes (3) (method B): To
a solution of the 1,3-diketone
(10 mmol) and of triethylamine (2.84 mL, 20.40 mmol) in diethyl ether
(20 mL), was slowly added TMSOTf (3.54 mL, 19.6 mmol ) at 08C. The
suspension was stirred for 2 h and the organic layer was separated from the
salt with
a syringe. After addition of a small amount of sodium
triphenylmethoxide, the solvent was removed and the residue was distilled
in vacuo.
General procedure for the preparation of g-alkylidenebutenolides (4) by
cyclization of 1,3-dianions with N,N'-dimethoxy-N,N'-dimethylethanedi-
amide (2d): A solution of LDA in THF was prepared by addition of nBuLi
(1.44 mL, 3.4 mmol, 2.35m in n-hexane) to a solution of diisopropylamine
(0.44 mL, 3.4 mmol) in THF (20 mL) at 08C. After the mixture had been
stirred for 15 min at 08C, the 1,3-dicarbonyl compound 1 (1.47 mmol) was
added and the solution was stirred for 45 min at 08C. The mixture was
cooled to À788C and a solution of 2d (220 mg, 1.25 mmol) in THF (4 mL)
was added. The solution was allowed to warm to 08C over a period of 5.5 h.
The cooling bath was removed and the solution was stirred for 30 min at
208C. An aqueous solution of HCl (10%, 4 mL) was added and the mixture
was stirred for 10 min. Additional HCl solution (20 mL) was added and the
aqueous layer was repeatedly extracted with diethyl ether/THF (1:1). The
combined organic layers were dried (MgSO4), filtered and the solvent of
the filtrate was removed in vacuo. The residue was purified by column
chromatography (silica gel, ether/petrol ether).
4a: Prepared from ethyl acetoacetate (0.19 mL, 1.47 mmol). Colorless
solid; yield: 170 mg (75%); m. p. 588C; 1H NMR ([D6]acetone, 200 MHz):
d ˆ 1.32 (t, J ˆ 8 Hz, 3H; CH3), 4.22 (q, J ˆ 8 Hz, 2H; CH2), 5.71 (s, 1H;
CHCO2Et), 7.20 (s, 1H; ring-CH); 13C NMR ([D6]acetone, 50 MHz): d ˆ
14.43 (CH3), 60.94 (CH2), 98.68 (CHCO2Et), 108.76 (ring-CH), 150.34,
Experimental Section
‡
160.74, 164.22, 166.10 (C); MS (EI, 70 eV): 184 ([M ], 17), 156 (20), 139
(69), 69 (100); IR (KBr): nÄ ˆ 3229, 3149, 3082, 2986, 1776, 1694, 1626, 1384,
1268, 1146, 1088, 1038 cmÀ1; elemental analysis calcd for C8H8O5: C 52.18,
H 4.38; found: C 52.41, H 4.65.
General comments: All solvents were dried by standard methods and all
reactions were carried out under an inert atmosphere in oven-dried
(1508C) glassware. THF was freshly distilled from Na, and CH2Cl2 from
CaH2. N,N'-Dimethoxy-N,N'-dimethylethanediamide (2d) was prepared
according to a literature procedure.[12] For the 1H and 13C NMR spectra
4b: Prepared from tert-butyl acetoacetate (0.25 mL, 1.51 mmol). Colorless
solid; yield: 193 mg (73%); m.p. 608C; 1H NMR ([D6]acetone, 200 MHz):
3210
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Chem. Eur. J. 2000, 6, No. 17

g-Alkylidenebutenolides
3204±3214
d ˆ 1.50 (s, 9H; C(CH3)3), 5.56 (s, 1H; CHCO2tBu), 7.13 (s, 1H; ring-CH);
13C NMR ([D6]acetone, 50 MHz): d ˆ 28.29 (C(CH3)3), 81.39 (C(CH3)3),
100.65 (CHCO2tBu), 108.94 (ring-CH), 150.05, 160.03, 164.28, 165.48 (C);
MS (EI, 70 eV): 212 ([M ], 24), 157 (89), 139 (85), 57 (100); elemental
analysis calcd for C10H12O5: C 56.60, H 5.70; found: C 56.59, H 5.77.
elemental analysis calcd for C10H12O5: C 56.60, H 5.70; found: C 56.65, H
5.64.
4n: Prepared from 3-methyl-2,4-pentanedione (0.20 mL, 1.48 mmol).
Yellow solid; yield: 180 mg (72%, E:Z ˆ 3.5:1); m.p. 718C; E isomer:
1H NMR ([D6]acetone, 200 MHz): d ˆ 2.18 (s, 3H; CH3), 2.38 (s, 3H;
COCH3), 7.16 (s, 1H; ring-CH); 13C NMR ([D6]acetone, 50 MHz): d ˆ
13.37 (CH3), 29.68 (COCH3), 111.01 (CH), 115,63, 149.42, 153.53 (C),
‡
4c: Prepared from benzoylacetone (239 mg, 1.48 mmol). Colorless solid;
yield: 182 mg (57%); m.p. 568C; 1H NMR ([D6]acetone, 200 MHz): d ˆ
7.02 (s, 1H; CH), 7.37 (s, 1H; ring-CH), 7.65 (m, 3H; Ph), 8.08 (m, 2H; Ph);
13C NMR ([D6]acetone, 75 MHz): d ˆ 102.20 (COCH), 109.68 (ring-CH),
128.81 (CH, Ph), 129.56 (CH, Ph), 133.85 (CH, Ph), 139.44 (C, Ph), 151.87,
164.47 (OCOC), 199.80 (CO);
Z
isomer: 1H NMR ([D6]acetone,
200 MHz): d ˆ 1.91 (s, 3H; CH3), 2.53 (s, 3H; COCH3), 6.96 (s, 1H; ring-
CH); 13C NMR ([D6]acetone, 50 MHz): d ˆ 12.50 (CH3), 31.95 (COCH3),
110.24 (CH), 115.57, 147.87, 152.77 (C), 164.46 (OCOC), 196.74 (CO); MS
‡
161.27, 164.39 (C), 189.94 (CO); MS (EI, 70 eV): 216 ([M ], 58), 188 (16),
‡
160 (27), 139 (35), 105 (100); IR (KBr): nÄ ˆ 3419, 3160, 2684, 2434, 1765,
1662, 1606, 1451, 1397, 1255, 1174, 1089, 1043 cmÀ1; elemental analysis calcd
for C12H8O4: C 66.67, H 3.73; found: C 66.60, H 3.84.
(EI, 70 eV): 168 ([M ], 100), 153 (89), 139 (11), 112 (25), 83 (63), 69 (31); IR
(KBr): nÄ ˆ 3560, 3433, 3099, 2970, 2831, 2645, 2487, 1784, 1687, 1619, 1437,
1421, 1369, 1330, 1268, 1109, 1075 cmÀ1; elemental analysis calcd for
C8H8O4: C 57.14, H 4.80; found: C 56.92, H 4.66.
4d: Prepared from 5,5-dimethyl-2,4-hexanedione (210 mg, 1.48 mmol).
Colorless solid; yield: 232 mg (80%); m.p. 658C; 1H NMR ([D6]acetone,
200 MHz): d ˆ 1.20 (s, 9H; C(CH3)3), 6.46 (s, 1H; CCHCO), 7.21 (s, 1H;
ring-CH); 13C NMR ([D6]acetone, 50 MHz): d ˆ 26.37 (C(CH3)3), 44.67
(C(CH3)3), 101.77 (CHCO), 109.59 (ring-CH), 151.14, 160.04, 164.46 (C),
4o: Prepared from ethyl 3-methyl-acetoacetate (192 mg, 1.48 mmol).
Colorless solid; yield: 206 mg (71%); m.p. 748C; 1H NMR ([D6]acetone,
200 MHz): d ˆ 1.35 (t, J ˆ 6 Hz, 3H; CH2CH3), 2.03 (s, 3H; CH3), 4.24 (q,
J ˆ 6 Hz, 2H; CH2), 7.23 (s, 1H; ring-CH); 13C NMR ([D6]acetone,
50 MHz): d ˆ 11.86 (CH2CH3), 13.72 (CH3), 60.70 (CH2), 108.16 (CCH3),
110.29 (ring-CH), 147.91, 154.61, 163.56, 166.30 (C); MS (EI, 70 eV): 198
‡
204.98 (CO); MS (EI, 70 eV): 196 ([M ], 11), 168 (20), 140 (100), 112 (17),
69 (41), 57 (55); IR (KBr): nÄ ˆ 3243, 3148, 2965, 2688, 2362, 1776, 1677,
1610, 1464, 1366, 1243, 1218, 1180, 1067, 1017 cmÀ1; elemental analysis calcd
for C10H12O4: C 61.22, H 6.16; found: C 61.20, H 6.35.
‡
([M ], 58), 153 (100), 124 (40), 83 (76), 69 (54), 55 (32); elemental analysis
calcd for C9H10O5: C 54.55, H 5.09; found: C 55.12, H 5.40.
4e: Prepared from acetylacetone (220 mg, 2.21 mmol). Colorless solid;
yield: 190 mg (56%, E:Z ˆ 5:1); m. p. 608C; 1H NMR ([D4]MeOH,
200 MHz): d ˆ 2.20 (s, 3H; CH3), 6.34 (s, 1H; CHCOCH3), 6.96 (s, 1H;
ring-CH); 13C NMR ([D6]acetone, 50 MHz): d ˆ 19.74 (CH3), 115.95
(CHCOCH3), 118.26 (ring-CH), 156.15, 162.39, 169.85 (C), 182.62 (CO);
4p: Prepared from ethyl 3-ethyl-acetoacetate (0.24 mL, 1.48 mmol).
Colorless solid; yield: 135 mg (43%); m.p. 788C; 1H NMR ([D6]acetone,
200 MHz): d ˆ 1.11 (t, J ˆ 6 Hz, 3H; CCH2CH3), 1.37 (t, J ˆ 6 Hz, 3H;
OCH2CH3), 2.55 (q, J ˆ 5 Hz, 2H; CCH2CH3), 4.29 (q, J ˆ 5 Hz, 2H;
OCH2CH3), 7.24 (s, 1H; ring-CH); 13C NMR ([D6]acetone, 75 MHz): d ˆ
14.19 (CCH2CH3), 14.46 (CCH2CH3), 20.82 (OCH2CH3), 61.43
(OCH2CH3), 111.06 (CH), 115.08, 148.70, 155.17, 165.34, 166.81 (C); MS
‡
MS (EI, 70 eV): 154 ([M ], 69), 126 (31), 81 (32), 69 (100); IR (KBr): nÄ ˆ
3433, 3121, 2979, 2880, 2805, 2729, 2622, 2534, 2466, 1790, 1669, 1646, 1588,
1385, 1240, 1196, 1163, 1062 cmÀ1; elemental analysis calcd for C7H6O4: C
54.55, H 3.92; found: C 54.47, H 3.91.
‡
(EI, 70 eV): 212 ([M ], 63), 201 (22), 166 (100), 139 (89), 110 (31), 97 (37),
69 (94); IR (KBr): nÄ ˆ 3518, 3332, 3121, 2975, 2488, 2343, 1760, 1707, 1635,
1458, 1404, 1367, 1331, 1234, 1133, 1081, 1028 cmÀ1; elemental analysis calcd
for C10H12O5: C 56.60, H 5.70; found: C 56.46, H 5.82.
4 f: Prepared from S-tert-butyl-3-oxo-thiobutanoate (258 mg, 1.48 mmol).
Colorless solid; yield: 226 mg (67%, E:Z ˆ 10:1); m. p. 648C; E isomer:
1H NMR ([D6]acetone, 200 MHz): d ˆ 1.56 (s, 9H; C(CH3)3), 5.99 (s, 1H;
COCH), 7.13 (s, 1H; ring-CH); 13C NMR ([D6]acetone, 75 MHz): d ˆ 29.54
(C(CH3)3), 48.97 (C), 105.48 (ring-CH), 109.21 (COCH), 151.27, 157.12 (C),
4y: Prepared from a-acetyl-g-butyrolactone (190 mg, 1.48 mmol). Color-
less oil; yield: 196 mg (73%); 1H NMR ([D4]MeOH, 200 MHz): d ˆ 3.13 (t,
J ˆ 6 Hz, 2H; CCH2CH2O), 4.45 (t, J ˆ 6 Hz, 2H; CCH2CH2O), 7.05 (s, 1H;
ring-CH); 13C NMR ([D4]MeOH, 50 MHz): d ˆ 26.47 (CCH2), 67.55
(OCH2), 104.72 (CH), 107.46 (OCC), 149.59, 155.39, 165.31, 172.73 (C);
164.41 (OCOC), 189.56 (COS).
Z
isomer: 1H NMR ([D6]acetone,
200 MHz): d ˆ 1.55 (s, 9H; C(CH3)3), 5.66 (s, 1H; COCH), 6.57 (s, 1H;
ring-CH); 13C NMR ([D6]acetone, 75 MHz): d ˆ 29.54 (C(CH3)3), 48.58
(SC), 105.34 (ring-CH), 111.31 (COCH), 149.57, 153.51 (C), 165.22
‡
MS (EI, 70 eV): 182 ([M ], 100), 124 (48), 79 (45), 69 (17); IR (KBr): nÄ ˆ
3410, 3140, 2675, 2285, 1881, 1801, 1724, 1685, 1611, 1478, 1441, 1384, 1322,
1226, 1043, 1009 cmÀ1; elemental analysis calcd for C8H6O5: C 52.76, H
3.32; found: C 52.54, H 3.30.
‡
(OCOC), 186.33.56 (COS); MS (EI, 70 eV): 228 ([M ], 10), 139 (100), 69
(37), 57 (42); IR (KBr): nÄ ˆ 3425, 3202, 2961, 2361, 1777, 1657, 1611, 1453,
1365, 1216, 1180, 1129, 1039 cmÀ1; elemental analysis calcd for C10H12O4S:
C 52.62, H 5.30; found: C 52.47, H 5.60.
4z: Prepared from 3-acetyl-5-methyl-dihydro-furan-2-one (210 mg, 1.48
mmol). Colorless solid; yield: 174 mg (60%); m.p. 828C; 1H NMR
([D6]acetone, 200 MHz): d ˆ 1.46 (d, J ˆ 6 Hz, 3H; CH3), 2.76 (m, 1H;
CH2), 3.35 (m, 1H; CH2), 4.83 (m, J ˆ 5 Hz, 1H; OCH), 7.18 (s, 1H; ring-
CH); 13C NMR ([D6]acetone, 75 MHz): d ˆ 18.26 (CH3), 29.77 (CH2), 71.42
(CH2CH), 102.32 (C), 104.19 (ring-CH), 144.73, 149.99, 160.59, 166.30 (C);
4g: Prepared from N,N-diethyl-acetoacetamide (0.23 mL, 1.48 mmol).
Colorless oil; yield: 196 mg (63%); 1H NMR ([D6]acetone, 200 MHz):
d ˆ 1.18 (m, J ˆ 6 Hz, 6H; CH3), 3.44 (m, J ˆ 6 Hz, 4H; CH2), 6.15 (s, 1H;
COCH), 7.07 (s, 1H; ring-CH); 13C NMR ([D6]acetone, 50 MHz): d ˆ
13.41, 14.97 (CH3), 42.00, 44.04 (CH2), 99.41 (CH), 109.42 (ring-CH),
‡
MS (EI, 70 eV): 196 ([M ], 30), 152 (67), 124 (100), 79 (58), 69 (27);
‡
150.40, 159.69 (C) , 165.68, 166.62 (CO); MS (EI, 70 eV): 211 ([M ], 17),
elemental analysis calcd for C9H8O5: C 55.11, H 4.11; found: C 55.35, H
4.23.
166 (15), 139 (26), 100 (16), 72 (73), 58 (100), 44 (24); elemental analysis
calcd for C10H13O4N: C 56.87, H 6.20; found: C 56.62, H 6.32.
4aa: Prepared from 2-acetyl-cyclopentanone (0.18 mL, 1.48 mmol). Color-
less solid; yield: 200 mg (75%); m.p. 808C; 1H NMR ([D6]acetone,
200 MHz): d ˆ 1.87 (m, 2H; CH2CH2CH2CO), 2.42 (t, J ˆ 7 Hz, 2H;
CH2(CH2)2CO), 2.88 (t, J ˆ 7 Hz, 2H; CH2CO), 7.23 (s, 1H; ring-CH);
13C NMR ([D6]acetone, 50 MHz): d ˆ 21.63 (CH2CH2CH2CO), 28.73
(CH2(CH2)2CO), 41.78 (CH2CO), 109.14 (CH), 117.24, 151.01, 154.10 (C),
4h: Prepared from methyl 3-oxopentanoate (430 mg, 3.29 mmol). Colorless
solid; yield: 423 mg (70%); m.p. 678C; 1H NMR ([D6]acetone, 200 MHz):
d ˆ 2.04 (s, 3H; CH3), 3.75 (s, 3H; OCH3), 5.47 (s, 1H; CH); 13C NMR
([D6]DMSO, 50 MHz): d ˆ 6.97 (CCH3), 51.20 (OCH3), 93.98 (CH), 119.91,
‡
144.03, 157.87, 163.35, 164.04 (C); MS (EI, 70 eV): 184 ([M ], 92), 153 (100),
‡
101 (31), 83 (98), 69 (64); IR (KBr): nÄ ˆ 3423, 3157, 2588, 2362, 1781, 1693,
1666, 1443, 1412, 1365, 1300, 1146, 1039, 1012 cmÀ1; elemental analysis
calcd for C8H8O5: C 52.18, H 4.38; found: C 52.36, H 4.50.
166.64 (OCOC), 210.53 (CO); MS (EI, 70 eV): 180 ([M ], 100), 138 (48),
124 (66), 82 (20), 79 (46); IR (KBr): nÄ ˆ 3369, 3170, 2970, 2675, 2338, 1801,
1687, 1620, 1460, 1435, 1404, 1313, 1284, 1206, 1042 cmÀ1; elemental analysis
calcd for C9H8O4: C 60.03, H 4.48; found: C 59.89, H 4.74.
4i: Prepared from ethyl 3-oxo-hexanoate (0.23 mL, 1.48 mmol). Colorless
1
solid; yield: 170 mg (54%); m.p. 748C; H NMR ([D4]MeOH, 200 MHz):
4ab: This reaction gave a mixture of two regioisomeric products 4ab and
4ad in 71% yield (205 mg). Starting from 2-acetyl-cyclohexanone
(0.20 mL, 1.48 mmol), pure 4ab was isolated as a colorless oil from the
d ˆ 1.16 (t, J ˆ 6 Hz, 3H; CCH2CH3), 1.30 (t, J ˆ 6 Hz, 3H; OCH2CH3),
2.41 (q, J ˆ 6 Hz, 2H; CCH2CH3), 4.20 (q, J ˆ 6 Hz, 2H; OCH2CH3), 5.44
(s, 1H; CH); 13C NMR ([D6]acetone, 50 MHz): d ˆ 12.89 (CCH2CH3),
14.52 (OCH2CH3), 16.05 (CCH2CH3), 60.62 (OCH2CH3), 95.89 (CH),
mixture of regioisomers by repeated column chromatography. Yield: 66 mg
1
ˆ
(23%); H NMR ([D6]acetone, 200 MHz): d ˆ 1.87 (m, 4H; C CCH2), 2.47
‡
126.78, 144.04, 157.71, 163.64, 164.84 (C); MS (EI, 70 eV): 212 ([M ], 41),
(t, J ˆ 7 Hz, 2H; CH2(CH2)2CH2CO), 2.77 (t, 2H; CH2CO), 7.12 (s, 1H;
ring-CH); 13C NMR ([D6]acetone, 75 MHz): d ˆ 23.51, 23.86 (CH2(CH2)2-
CH2CO), 26.66 (CH2(CH2)3CO), 41.87 (CH2CO), 111.23 (CH), 116.92,
167 (79), 138 (58), 110 (37), 97 (66), 69 (100); IR (KBr): nÄ ˆ 3548, 3161,
2978, 2362, 1784, 1665, 1464, 1399, 1368, 1280, 1171, 1140, 1092, 1031 cmÀ1
;
Chem. Eur. J. 2000, 6, No. 17
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3211 $ 17.50+.50/0
3211

P. Langer et al.
FULL PAPER
13C NMR ([D6]acetone, 50 MHz): d ˆ13.94, 14.46 (CH3), 22.31, 22.95, 30.82
(CH2), 60.63 (OCH2), 95.73 (CCHCO), 125.32, 144.45, 158.06 (C), 163.72,
164.69 (CO); MS (EI, 70 eV): 240 ([M ], 100), 212 (16), 194 (39), 166 (58);
elemental analysis calcd for C12H16O5: C 59.99, H 6.71; found: C 59.24, H
6.67.
149.64, 152.64 (C), 164.50 (OCOC), 200.45 (CO); MS (EI, 70 eV): 194
‡
([M ], 86), 166 (52), 138 (36), 125 (100), 110 (23), 82 (30); IR (KBr): nÄ ˆ
‡
3423, 3129, 2950, 2879, 2685, 2361, 1798, 1651, 1620, 1579, 1343, 1316, 1268,
1239, 1154, 1058 cmÀ1; elemental analysis calcd for C10H10O4: C 61.85, H
5.19; found: C 61.57, H 5.23.
4k: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3k (656 mg, 1.80
mmol). Colorless solid; yield: 334 mg (68%); m.p. 928C; 1H NMR
([D6]acetone, 200 MHz): d ˆ 1.22 (t, J ˆ 5 Hz, 3H; CH3), 3.83 (s,
2H;CH2Ph), 4.08 (q, J ˆ 5 Hz, 2H; OCH2CH3), 5.38 (s, 1H; CCHCO),
7.25 (m, 5H; Ph); 13C NMR ([D6]acetone, 50 MHz): d ˆ 14.46 (CH3), 28.14
(CH2), 60.64 (OCH2CH3), 96.63 (CCHCO), 123.68 (C), 127.40, 129.01,
129.44 (CH, Ph), 138.38, 145.41, 157.71 (C), 163.53, 164.63 (CO); MS (EI,
4ac: Prepared from 2-acetyl-decalone (287 mg, 1.48 mmol). Colorless oil;
yield: 224 mg (61%, mixture of cis and trans isomers); 1H NMR
([D6]acetone, 200 MHz): d ˆ 1.87 (m, 8H), 1.32 (m, 4H), 2.23 (m, 1H),
3.09 (m,1H), 6.98 (s, 1H; ring-CH); 13C NMR ([D6]acetone, 50 MHz): d ˆ
ˆ
26.15, 26.30, 26.41, 28.82, (CH(CH2)4CH), 34.71 (C CCH2CH2), 40.92
ˆ
(C CCH2CH2), 55.87 (CHCHCO), 62.17 (CHCHCO), 111.03 (ring-CH),
ˆ
117.34 (COH), 148.91, 151.73(C C), 164.64 (C) 201.69 (CO); MS (EI,
‡
‡
70 eV): 274 ([M ], 100).
70 eV): 248 ([M ], 43), 220 (34), 126 (28), 95 (100), 79(20).
4l: Prepared from 1,4-dimethoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene
3l (436 mg, 1.50 mmol). Colorless solid; yield: 255 mg (85%); m.p. 878C;
1H NMR ([D4]MeOH, 200 MHz): d ˆ 3.75 (s, 3H; OCH3), 4.18 (t, 3H;
COOCH3), 5.44 (s, 1H; CH); 13C NMR ([D4]MeOH, 50 MHz): d ˆ 52.14
(OCH3), 59.86 (COOCH3), 94.29 (CH), 126.31, 142.53, 154.34 (C), 165.57,
165.70 (OCO); IR (KBr): nÄ ˆ 3208, 3082, 2877, 2362, 1795, 1682, 1466, 1442,
4ah: Prepared from 2-acetyl-tetralone (278 mg, 1.48 mmol). Yellow solid;
yield: 265 mg (74%); m.p. 908C; 1H NMR ([D6]acetone, 200 MHz): d ˆ
3.10 (s, 4H; CH2CH2), 7.43 (m, J ˆ 6 Hz, 2H; Ar ), 7.46 (s, 1H; ring-CH ),
7.60 (t, J ˆ 6 Hz, 1H; Ar), 8.04 (m, J ˆ 6 Hz, 1H; Ar); 13C NMR
([D6]acetone, 75 MHz): d ˆ 25.72, 28.83 (CH2), 111.15 (ring-CH), 127.71,
128.00, 129.37, 134.12 (CH, Ar), 135.00, 144.37, 150.01, 150.11, 154.09, 164.40
‡
‡
1372, 1348, 1302, 1195, 1119, 1089, 1024 cmÀ1; MS (EI, 70 eV): 200 ([M ],
(C), 187,67 (CCOC); MS (EI, 70 eV): 242 ([M ], 100), 186 (30), 141 (29),
61), 169 (50), 140 (30), 113 (64), 85 (42), 69 (100); elemental analysis calcd
for C8H8O6: C 48.01, H 4.03; found: C 47.71, H 4.28.
115 (33), 90 (16), 69 (10); IR (KBr): nÄ ˆ 3430, 3098, 2962, 2686, 2362, 1804,
1647, 1620, 1562, 1456, 1342, 1251, 1158, 1057 cmÀ1; elemental analysis calcd
for C14H10O4: C 69.42, H 4.16; found: C 69.77, H 4.34.
4m: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3m (544 mg,
1.80 mmol). Colorless solid; yield: 163 mg (43%); m.p. 1028C; 1H NMR
([D6]acetone, 200 MHz): d ˆ 2.40 (s, 3H; CH3), 3.79 (s, 3H; OCH3), 6.36 (s,
1H; CCHCO); 13C NMR ([D6]acetone, 50 MHz): d ˆ 19.62 (CH3), 52.79
(OCH3), 115.68 (CCHCO), 127.14 (C), 160.62, 164.07, 167.72 (C), 175.97
4ai: Prepared from 3-acetyl-3H-benzofuran-2-one (260 mg, 1.47 mmol).
Isolated as a yellow solid by repeated chromatography; yield: 176 mg
(52%); m.p. 948C; 1H NMR ([D6]acetone, 200 MHz): d ˆ 6.43 (s, 1H; ring-
CH), 7.07 (m, 3H; Ar), 7.60 (m, 1H; Ar); 13C NMR ([D6]acetone, 50 MHz):
d ˆ 92.39, 99.21 (C), 110.23 (CH), 122.75, 124.15, 125.33, 126.72 (CH, Ar),
151.63 (C), 163.20, 166.33 (C), 166.42, 168.70 (CO); MS (EI, 70 eV): 230
‡
(COCH3); MS (EI, 70 eV): 212 ([M ], 80), 181 (100), 154 (92); elemental
analysis calcd for C9H8O6: C 50.95, H 3.80; found: C 50.70, H 3.62.
‡
4n: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3n (388 mg, 1.50
mmol). Colorless solid; yield: 194 mg (77%, E:Z ˆ 3.5:1).
([M ], 21), 195 (8), 161 (21), 64 (25), 46 (100); IR (KBr): nÄ ˆ 3412, 3060,
2927, 2362, 1720, 1635, 1458, 1351, 1288, 1241, 1199, 1151, 1097, 1018 cmÀ1
;
elemental analysis calcd for C12H6O5: C 62.62, H 2.63; found: C 62.80, H
2.55.
4o: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3o (518 mg, 1.80
mmol). Colorless solid; yield: 253 mg (71%).
4aj: Prepared from 2-acetyl-indan-1-one (257 mg, 1.48 mmol). Yellow
solid; yield: 74 mg (22%); 1H NMR ([D8]THF, 300 MHz): d ˆ 3.88 (s, 2H;
CH2), 7.36 (s, 1H; ring-CH), 7.40, 7.59, 7.73 (m, 4H; CH, Ar); 13C NMR
([D8]THF, 75 MHz): d ˆ 25.54 (CH2), 108.33 (ring-CH), 114.71 (C), 123.96,
127.16, 128.22, 135.02 (CH, Ar), 140.70, 149.09, 150.27, 153.88 (C), 164.69,
4p: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3p (544 mg, 1.80
mmol). Colorless solid; yield: 252 mg (66%).
4q: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3q (594 mg, 1.80
mmol). Colorless solid; yield: 268 mg (62%); m.p. 788C; 1H NMR
([D6]acetone, 200 MHz): d ˆ 0.89 (t, J ˆ 6 Hz, 3H; CCH2CH3), 1.30 (t,
J ˆ 6 Hz, 3H; OCH2CH3), 1.38 (m, 4H; CH2), 2.48 (t, J ˆ 6 Hz, 2H; CH2),
4.22 (q, J ˆ 6 Hz, 2H; OCH2), 7.17 (s, 1H; CH); 13C NMR ([D6]acetone,
50 MHz): d ˆ 14.06, 14.40 (CH3), 23.04, 27.00, 32.17 (CH2), 61.29 (OCH2),
110.89 (CH), 113.66, 148.67, 155.39, 164.36 (C), 166.86 (CO); MS (EI,
‡
193.28 (CO); MS (EI, 70 eV): 228 ([M ], 100), 172 (12), 155 (23), 144 (29),
131 (34), 102 (18), 77 (11).
General procedure for the preparation of g-alkylidenebutenolides by
reaction of 1,3-bis(trimethylsilyloxy)-1,3-dienes with oxalyl chloride: To a
solution of a mixture of oxalyl chloride (1.5 mmol, 0.13 mL) and the 1,3-
bis(trimethylsilyloxy)-1,3-diene 3 (1.5 mmol) in CH2Cl2 (30 mL) was added
a solution of TMSOTf (0.45 mmol) in CH2Cl2 (7 mL) at À788C. The
reaction mixture was allowed to warm to 208C over a period of 6 h. After
the mixture had been stirred for 2 h at 208C, a saturated solution of NaCl
was added, the organic layer was separated, and the aqueous layer was
repeatedly extracted with diethyl ether. The combined organic extracts
were dried (MgSO4), filtered, and the solvent of the filtrate was removed in
vacuo. The residue was purified by column chromatography (silica gel,
diethyl ether/petrol ether).
‡
70 eV): 240 ([M ], 17), 213 (100), 171 (72), 69 (64); elemental analysis calcd
for C12H16O5: C 59.99, H 6.71; found: C 60.29, H 6.83.
4r: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3r (624 mg,
1.80 mmol). Yellow solid; yield: 208 mg (45%, E:Z ˆ 1:3); m.p. 708C; Z
isomer: 1H NMR ([D6]acetone, 200 MHz): d ˆ 3.38 (m, 2H; CCH2CH3),
ˆ
ˆ
4.90 ± 5.20 (m, 2H; CH2), 5.83 (m, 1H; CH CH2), 6.02 (s, 1H; CH), 7.45 ±
7.90 (m, 5H; Ph); 13C NMR ([D6]acetone, 50 MHz): d ˆ 37.34 (CH2), 114.51
ˆ
(CH), 121.63 ( CH2), 123.90 (C), 133.75, 134.41, 138.13 (CH), 139.52,
144.17, 151.87, 157.08, 168.81 (C), 200.25 (CO); E isomer: 1H NMR
([D6]acetone, 200 MHz): 3.35 (m, 2H; CCH2CH3), 4.90 ± 5.20 (m, 2H;
4a: Prepared from 1-ethoxy-1,3-bis(trimethylsilyloxy)-buta-1,3-diene 3a
(410 mg, 1.50 mmol). Colorless solid; yield: 277 mg (87%).
ˆ
ˆ
CH2), 5.83 (m, 1H; CH CH2), 6.98 (s, 1H; CH), 7.45 ± 7.90 (m, 5H; Ph);
13
ˆ
C NMR ([D6]acetone, 50 MHz): 37.87 (CH2), 113.20 (CH), 121.42 ( CH2),
121.95 (C), 133.61, 134.32, 138.32 (CH), 139.98, 143.41, 152.87, 157.08, 168.80
(C), 199.44 (CO); MS (EI, 70 eV): 256 ([M ], 2), 202 (8), 105 (100);
4c: Prepared from 1-phenyl-1,3-bis(trimethylsilyloxy)-1,3-butadiene 3c
(552 mg, 1.80 mmol). Colorless solid; yield: 310 mg (80%).
‡
elemental analysis calcd for C15H12O4: C 70.31, H 4.72; found: C 70.97, H
5.14.
4d: Prepared from 5,5-dimethyl-2,4-bis(trimethylsilyloxy)-1,3-hexadiene
3d (430 mg, 1.50 mmol). Colorless solid; yield: 247 mg (84%).
4s: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3s (631 mg,
1.80 mmol). Yellow solid; yield: 263 mg (56%, E:Z ˆ 7:1); m.p. 688C;
1H NMR ([D6]acetone, 200 MHz): 1.25 (t, J ˆ 6 Hz, 3H; CH3), 3.05 (br,
OH), 4.25 (q, J ˆ 6 Hz, 2H; OCH2), 6.40 (s, 1H; CH, Z isomer), 7.25 (s, 1H;
CH, E isomer), 7.38 (m, 5H; Ph); 13C NMR ([D6]acetone, 50 MHz): E
isomer: d ˆ 14.32 (CH3), 61.68 (CH2), 110.97 (CH), 113.78 (C), 128.35,
128.47, 131.26 (CH), 133.90, 148.93, 155.13, 164.47 (C), 166.60 (CO); MS
4e: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3e (368 mg, 1.50
mmol). Colorless solid; yield: 170 mg (74%, E:Z ˆ 5:1).
4h: Prepared from 1,3-bis(trimethylsilyloxy)-1-methoxy-1,3-pentadiene 3h
(494 mg, 1.80 mmol). Colorless solid; yield: 264 mg (80%).
4i: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3i (454 mg, 1.50
mmol). Colorless solid; yield: 242 mg (76%).
‡
(EI, 70 eV): 260 ([M ], 100), 215 (21), 187 (19); elemental analysis calcd for
C14H12O5: C 64.61, H 4.65; found: C 64.48, H 4.73.
4j: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3j (496 mg, 1.50
1
mmol). Colorless solid; yield: 252 mg (70%); m.p. 868C; H NMR ([D6]-
acetone, 200 MHz): d ˆ 0.92 (t, J ˆ 6 Hz, 3H; CH3), 1.25 (t, J ˆ 6 Hz, 3H;
CH3), 1.40 (m, 2H; CH2), 1.54 (m, 2H; CH2), 2.46 3.31 (t, J ˆ 6 Hz, 2H;
CH2), 2.88 (br, OH), 4.16 (q, J ˆ 6 Hz, 2H; OCH2), 5.45 (s, 1H; CCHCO);
4t: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3t (715 mg,
1.80 mmol). Yellow solid; yield: 342 mg (62%, E:Z ˆ 1:3); m.p. 828C;
1H NMR ([D6]acetone, 200 MHz): 2.85 (br, OH), 3.93 (s, 2H; CH2, E
3212
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0617-3212 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 17

g-Alkylidenebutenolides
3204±3214
isomer), 4.02 (s, 2H; CH2, Z isomer), 5.97 (s, 1H; CH, Z isomer), 7.21 (s,
1H; CH, E isomer), 7.10 ± 7.70 (m, 10H; Ph); 13C NMR ([D6]acetone,
50 MHz): Z Isomer: d ˆ 34.44 (CH2), 109.97 (CH), 120.50 (C), 127.08,
129.22, 129.37, 129.85, 133.64 (CH), 139.46, 139.92, 147.75, 152.82, 164.51
(C), 195.87 (CO); MS (EI, 70 eV): 306 ([M ], 100); elemental analysis calcd
for C19H14O4: C 74.50, H 4.61; found: C 74.33, H 4.84.
4ah: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3ah (600 mg, 1.80
mmol). Colorless solid; yield: 352 mg (81%).
4ai: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3ai (575 mg, 1.80
mmol). Isolated as a yellow solid by repeated chromatography; yield:
250 mg (60%).
‡
4aj: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3aj (477 mg, 1.50
4u: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3u (544 mg,
1.80 mmol). Yellow oil; yield: 183 mg (48%); 1H NMR ([D4]MeOH,
200 MHz): 2.40 (s, 3H; CH3), 3.80 (s, 3H; OCH3), 6.93 (s, 1H; CH);
13C NMR ([D4]MeOH, 50 MHz): d ˆ 18.89 (CH3), 53.34 (OCH3), 119.34
(CH), 123.61 (C), 154.23, 161.03, 165.73 (C), 169.46, 177.65 (CO); MS (EI,
mmol). Yellow solid; yield: 96 mg (28%).
Acknowledgements
‡
70 eV): 212 ([M ], 6), 172 (100); elemental analysis calcd for C9H8O6: C
50.95, H 3.80; found: C 50.82, H 3.57.
P.L. thanks Professor Dr. A. de Meijere for his support. Financial support
from the Fonds der Chemischen Industrie (Liebig scholarship and funds for
P.L.) is gratefully acknowledged.
4v: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-cyclohexadiene 3v
(386 mg, 1.50 mmol). Colorless solid; yield: 174 mg (70%); m.p. 1048C;
1H NMR ([D4]MeOH, 200 MHz): d ˆ 2.60 (t, J ˆ 6 Hz, 2H; CCH2CH2CO),
2.93 (t, J ˆ 6 Hz, 2H; CCH2CH2CO), 5.76 (s, 1H; CH); 13C NMR
([D4]MeOH, 50 MHz): d ˆ 18.57 (CCH2CH2CO), 36.26 (CCH2CH2CO),
105.50 (CH), 119.00 (CCH2CH2CO), 143.00 (OCCHCO), 164.84 (OCO-
[1] Reviews: a) Y. S. Rao, Chem. Rev. 1976, 76, 625 ± 694; b) G. Patten-
den, Prog. Chem. Nat. Prod. 1978, 35, 133 ± 198; c) D. W. Knight,
Contemp. Org. Synth. 1994, 1, 287 ± 315; E.-i. Negishi, M. Kotora,
Tetrahedron 1997, 53, 6707 ± 6738.
[2] a) K. Siegel, R. Brückner, Chem. Eur. J. 1998, 4, 1116 ± 1122; b) F.
Goerth, A. Umland, R. Brückner, Eur. J. Org. Chem. 1998, 1055 ±
1062; c) K. Siegel, Diplomarbeit, Universität Göttingen, 1996.
[3] a) D. Enders, H. Dyker, F. R. Leusink, Chem. Eur. J. 1998, 4, 311 ± 320;
b) for the use of isotetronic acids in the synthesis of nonactinic acids,
see: A. G. M. Barrett, H. G. Sheth, J. Org. Chem. 1983, 48, 5017 ±
5022; c) For the synthesis of erythronolide A, see: G. Stork, S. D.
Rychnovsky, J. Am. Chem. Soc. 1987, 109, 1564 ± 1565.
‡
COH), 166.13 (OCOCOH), 199.98 (CO); MS (EI, 70 eV): 166 ([M ], 100),
138 (18), 110 (58), 82 (28), 69 (62); IR (KBr): nÄ ˆ 3431, 3063, 2973, 2902,
2694, 1804, 1616, 1434, 1383, 1312, 1218, 1194, 1130, 1053 cmÀ1; elemental
analysis calcd for C8H6O4: C 57.84, H 3.64; found: C 57.72, H 3.82.
4w: Prepared from 2-methyl-1,3-bis(trimethylsilyloxy)-1,3-cyclohexadien
3w (406 mg, 1.50 mmol). Colorless solid; yield: 173 mg (64%); m.p. 1208C;
1H NMR ([D6]acetone, 200 MHz): d ˆ 1.82 (s, 3H; CH3), 2.57 (t, J ˆ 5 Hz,
2H; CCH2CH2CO), 2.93 (t, J ˆ 5 Hz, 2H; CCH2CH2CO); 13C NMR
([D6]acetone, 75 MHz): d ˆ 8.35 (CH3), 18.26 (CCH2CH2CO), 35.66
(CCH2CH2CO), 114.81 (CCH2CH2CO), 120.81, 140.47 (C), 159.12
‡
(OCC), 164.32 (OCO), 196.96 (CO); MS (EI, 70 eV): 180 ([M ], 100),
[4] M. Kotora, E.-i. Negishi, Synthesis 1997, 121 ± 128.
152 (4), 124 (16), 96 (14), 69 (10), 44 (47); IR (KBr): nÄ ˆ 3552, 3198, 2646,
[5] a) F. Bohlmann, C. Zdero, Chem. Ber. 1966, 99, 1226 ± 1228; b) J. B.
Jones, J. M. Young, J. Med. Chem. 1968, 11, 1176; c) K. Yamada, Y.
Togawa, T. Kato, Y. Hirata, Tetrahedron 1971, 27, 5445 ± 5451; d) S.
Tsuboi, H. Wada, S. Mimura, A. Takeda, Chem. Lett. 1987, 937 ± 938;
e) M. A. Khan, H. Adams, Synthesis 1995, 687 ± 692.
2365, 1783, 1682, 1622, 1432, 1400, 1376, 1341, 1206, 1096, 1053 cmÀ1
;
elemental analysis calcd for C9H8O4: C 60.00, H 4.48; found: C 59.78, H
4.62.
4x: Prepared from 1,1-dimethyl-2,4-bis(trimethylsilyloxy)-cyclohexa-2,4-
diene 3x (426 mg, 1.50 mmol). Colorless solid; yield: 192 mg (66%); m.p.
[6] a) M. Ito, Y. Hirata, Y. Shibata, K. Tsukida, J. Chem. Soc. Perkin
1
1058C; H NMR ([D6]acetone, 200 MHz): d ˆ 1.39 (s, 6H; C(CH3)2), 2.44
Trans.
1 1990, 197 ± 199; b) C. Di Nardo, L. O. Jeronic, R. M.
(s, 2H; CH2), 5.78 (s, 1H; CH); 13C NMR ([D6]acetone, 50 MHz): d ˆ 27.44
(C(CH3)2), 33.80 (C(CH3)2), 52.68 (CH2), 105.42 (CH), 127.28 (C, C(CH3)2),
Lederkremer, O. Varela, J. Org. Chem. 1996, 61, 4007 ± 4013.
[7] a) D. W. Knight, G. Pattenden, J. Chem. Soc. Perkin Trans 1 1979, 62 ±
69; b) C. F. Ingham, R. A. Massy-Westropp, G. D. Reynolds, W. D.
Thorpe, Aust. J. Chem. 1975, 28, 2499 ± 2510; c) R. A. Massy-West-
ropp, M. F. Price, Aust. J. Chem. 1980, 33, 333 ± 341; d) I. Bell, E. R. H.
Jones, M. C. Whiting, J. Chem. Soc. 1958, 1313 ± 1322; e) G. Struve, S.
Seltzer, J. Org. Chem. 1982, 47, 2109 ± 2113.
ˆ
141.58 (C), 163.22 [ C(OH)], 164.68, 196.56 (CO); MS (EI, 70 eV): 194
([M ], 100), 179 (42), 151 (62), 109 (27), 69 (33); IR (KBr): nÄ ˆ 3421, 2957,
‡
2869, 26803, 2528, 1906, 1812, 1747, 1575, 1467, 1412, 1351, 1303, 1221,
1147 cmÀ1; elemental analysis calcd for C10H10O4: C 61.85, H 5.19; found: C
61.62, H 5.43.
[8] R. W. Saalfrank, T. Lutz, Angew. Chem. 1990, 102, 1064 ± 1066;
Angew. Chem. Int. Ed. Engl. 1990, 29, 1041 ± 1043.
4z: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3z (537 mg,
1.50 mmol). Colorless solid; yield: 165 mg (41%).
[9] P. Langer, M. Stoll, Angew. Chem. 1999, 111, 1919 ± 1922; Angew.
Chem. Int. Ed. 1999, 38, 1803 ± 1805.
[10] a) L. Weiler, J. Am. Chem. Soc. 1970, 92, 6702 ± 6704; b) D. Seebach,
V. Ehrig, Angew. Chem. 1974, 86, 446 ± 448; Angew. Chem. Int. Ed.
Engl. 1974, 13, 401 ± 403.
4ab: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3ab (511 mg, 1.80
mmol) to give a 3:1 mixture of the two regioisomeric products 4ab and 4ad
which was isolated as a light yellow oil. Yield: 250 mg (72%). The pure
butenolide 4ab was isolated in 22% yield (77 mg).
4ae: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3ae (566 mg, 1.80
mmol). Light yellow oil; yield: 286 mg (71%); 1H NMR ([D6]acetone,
200 MHz): d ˆ 1.28 (t, J ˆ 6 Hz, 3H; CH3), 1.80 (quintet, J ˆ 5 Hz, 2H;
CH2), 2.52 (t, J ˆ 5 Hz, 2H; CH2), 2.58 (t, J ˆ 5 Hz, 2H; CH2), 4.18 (q, J ˆ
6 Hz, 2H; OCH2); 13C NMR ([D6]acetone, 75 MHz): d ˆ 14.57 (CH3),
21.16, 22.53, 25.14 (CH2), 60.99 (OCH2), 107.91, 123.13, 139.97, 152.72 (C),
[11] 1,3-Dicarbonyl dianions have been previously used in natural product
syntheses: a) R. W. Hoffmann, W. Ladner, K. Steinbach, W. Massa, R.
Schmidt, G. Snatzke, Chem. Ber. 1981, 114, 2786 ± 2801; b) P. G.
Willard, L. A. Grab, S. E. de Laszlo, J. Org. Chem. 1983, 48, 1123 ±
1125; c) T. Clarke, S. V. Ley, J. Chem. Soc. Perkin Trans. 1 1987, 131 ±
135; d) B. Lygo, Tetrahedron 1988, 44, 6889 ± 6896; e) S. G. Gilbreath,
C. M. Harris, T. M. Harris, J. Am. Chem. Soc. 1988, 110, 6172 ± 6179.
[12] M. P. Sibi, M. Marvin, R. Sharma, J. Org. Chem. 1995, 60, 5016 ± 5023.
[13] Cyclization reactions of dianions with dielectrophiles are much less
common than condensations with simple monofunctional electro-
philes: a) K. G. Bilyard, P. J. Garratt, R. Hunter, E. Lete, J. Org.
Chem. 1982, 47, 4731 ± 4736; b) R. B. Bates, B. Gordon, T. K. High-
smith, J. J. White, J. Org. Chem. 1984, 49, 2981 ± 2987; c) K. Tanaka, H.
Horiuchi, H. Yoda, J. Org. Chem. 1989, 54, 63 ± 70; d) A. Maercker, A.
Groos, Angew. Chem. 1996, 108, 216 ± 218; Angew. Chem. Int. Ed.
Engl. 1996, 35, 210 ± 212.
‡
165.08, 165.37 (CO); MS (EI, 70 eV): 224 ([M ], 35), 178 (100), 150 (61);
elemental analysis calcd for C11H12O5: C 58.93, H 5.39; found: C 58.76, H
5.50.
4af: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3af (622 mg, 1.80
mmol). Light yellow oil; yield: 230 mg (50%); 1H NMR ([D6]acetone,
200 MHz): d ˆ 1.90 (quintet, J ˆ 5 Hz, 2H; CH2), 2.66 (m, J ˆ 5 Hz, 4H;
CH2), 5.80 (br, OH), 7.40 ± 7.85 (m, 5H; Ph); 13C NMR ([D6]acetone,
75 MHz): d ˆ 19.23 (CH3), 20.74, 21.33, 22.77 (CH2), 115.34, 122.51 (C),
128.93, 129.93, 133.43 (CH, Ph), 139.54, 149.96 (C), 164.79, 194.14 (CO);
‡
MS (EI, 70 eV): 256 ([M ], 100), 227 (46), 105 (58), 77 (56).
4ag: Prepared from 1,3-bis(trimethylsilyloxy)-1,3-diene 3ag (540 mg, 1.80
mmol). Colorless solid; yield: 98 mg (26%); 1H NMR ([D6]acetone,
200 MHz): d ˆ 1.25 (t, J ˆ 5 Hz, 3H; CH3), 2.75 (m, 2H; CH2), 2.75 (m, 2H;
[14] T. Mukaiyama, Angew. Chem. 1977, 89, 858 ± 866; Angew. Chem. Int.
Ed. Engl. 1977, 16, 817 ± 825.
[15] a) T.-H. Chan, P. Brownbridge, J. Chem. Soc. Chem. Commun. 1979,
578 ± 579; b) T.-H. Chan, P. Brownbridge, J. Am. Chem. Soc. 1980, 102,
‡
CH2), 4.19 (q, 2H; OCH2); MS (EI, 70 eV): 210 ([M ], 100).
Chem. Eur. J. 2000, 6, No. 17
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3213

P. Langer et al.
FULL PAPER
3534 ± 3538; c) R. P. Attrill, A. G. M. Barrett, P. Quayle, J. Van der
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for the synthesis of chlorothricolide (by cycloaddition reactions at the
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1986, 51, 635 ± 648; d) K. Okumura, K. Okazaki, K. Takeda, E. Yoshii,
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Chem. 1983, 48, 3761 ± 3764.
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[28] The chemoselective differentiation between the two hydroxy groups
of ascorbic acid derivatives is problematic: a) M. G. Kulkarni, S. R.
Thopate, Tetrahedron 1996, 1293 ± 1302; b) for
a regioselective
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dienes, see: a) K. Krohn, H.-H. Ostermeyer, K. Tolkiehn, Chem. Ber.
1979, 112, 2640 ± 2649; b) C. Brisson, P. Brassard, J. Org. Chem. 1981,
46, 1810 ± 1814, and references therein.
[18] For the decarbonylation during the cyclization of glycols with oxalyl
chloride, see: T. Iida, T. Itaya, Tetrahedron 1993, 49, 10511 ± 10530.
[19] For reactions with monofunctional carboxylic acid chlorides, see:
a) T. H. Chan, D. Stössel, J. Org. Chem. 1986, 51, 2423 ± 2428; b) T. H.
Chan, D. Stössel, J. Org. Chem. 1988, 53, 4901 ± 4908.
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1851 ± 1854.
[22] For a review on the structure and reactivity of lithium enolates, see: D.
Seebach, Angew. Chem. 1988, 100, 1685 ± 1715; Angew. Chem. Int. Ed.
Engl. 1988, 27, 1624 ± 1654.
approach, see U. Beifuss, O. Kunz, G. P. Aguado, Synlett 1999, 147 ±
149.
[29] B. Simoneau, P. Brassard, Tetrahedron 1986, 14, 3767 ± 3774.
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3454; d) J. Gripenberg, Acta Chem. Scand. 1971, 25, 2999 ± 3005.
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component in a 1:4 mixture of the regioisomers 3ab and 3ad: L.
Hansson, R. Carlson, Acta Chem. Scand. 1989, 43, 304 ± 306.
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[38] B. Škermark, Acta Chem. Scand. 1961, 15, 1695 ± 1701.
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b) J. S. Hubbard, T. M. Harris, Tetrahedron Lett. 1978, 4601 ± 4602.
Received: September 20, 1999 [F2043]
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