New strategies for the efficient synthesis of medium-sized bicyclic γ-Alkylidenebutenolides based on regioselective cyclizations of 1,3-Bis(trimethylsilyloxy)-1,3-butadienes with oxalyl chloride

Article abstract of DOI:10.1002/1099-0690(200110)2001:19<3657::AID-EJOC3657>3.0.CO;2-5

Medium-sized bicyclic γ-alkylidenebutenolides were efficiently prepared by Me₃SiOTf-catalyzed cyclization of cyclic bis(silyl enol ethers) with oxalyl chloride. In addition, a new strategy for the synthesis of medium-sized bicyclic hybrids of b

Full text of DOI:10.1002/1099-0690(200110)2001:19<3657::AID-EJOC3657>3.0.CO;2-5

FULL PAPER
New Strategies for the Efficient Synthesis of Medium-Sized Bicyclic γ-
Alkylidenebutenolides Based on Regioselective Cyclizations of 1,3-
Bis(trimethylsilyloxy)-1,3-butadienes with Oxalyl Chloride
[a]
[a]
[a]
[a]
´
Peter Langer,* Tobias Eckardt, Nehad N. R. Saleh, Inass Karime, and
Peter Müller[b]
Keywords: Cyclizations / Homogeneous catalysis / Medium-sized rings / Ring-closing metathesis / Silyl enol ethers
Medium-sized bicyclic γ-alkylidenebutenolides were effi-
ciently prepared by Me3SiOTf-catalyzed cyclization of cyclic
bis(silyl enol ethers) with oxalyl chloride. In addition, a new
of butenolides and medium-sized cyclic ethers − based on
sequential [3+2] cyclization of 1,3-bis(trimethylsilyloxy)-1,3-
butadienes, Mitsunobu reaction, and ring-closing metathesis
strategy for the synthesis of medium-sized bicyclic hybrids − is reported.
Introduction
new natural products and analogues often constitute prom-
ising lead structures, but their isolation is generally very dif-
ficult and time-consuming.[11] The hybrid concept is also
found in nature in the biosynthesis of vitamin E, which is
formed from a terpene and shikimic acid.[12] The hybrid
vincristine is made up of an aspidosperma and an iboga
alkaloid component.[13]
Bicyclic γ-alkylidenebutenolides are present in a variety
of biologically relevant natural products. These include
structures containing medium-sized rings, which are often
difficult to prepare. A number of antibiotics belong to the
highly oxygenated sesquiterpene classes of the hirsutinol-
ides and glaucolides.[1] Other natural products, such as cal-
axin, tagitinin A, zexbrevin and ciliarin, are included in the
group of the tagitinins.[2] The germacranolides, lactone ana-
logues of the sesquiterpene germacrone, exhibit cytotoxic
activity.[3] In the context of our interest in the development
of cyclization reactions of dianions and dianion equivalents
with 1,2-dielectrophiles,[4,5] we have recently reported a new
synthesis of γ-alkylidenebutenolides by means of the first
reported cyclizations of 1,3-dicarbonyl dianions with oxalic
acid dielectrophiles.[4a,4b] Here we wish to report full details
of our studies related to the synthesis of C-1Ј/C-4-annulated
5,n-bicyclic γ-alkylidenebutenolides (n ϭ 5Ϫ12), which rep-
resent analogues of pharmacologically relevant sesquiter-
pene natural products.[6] In addition, we report on a new
and efficient approach to C-3/C-4-annulated 5,n-bicyclic
butenolides (n ϭ 7, 8), which can be regarded as hybrids of
γ-alkylidenebutenolides[7,8] and medium-sized cyclic
ethers,[9] both of which are biologically relevant substruc-
tures. These compounds were efficiently prepared by se-
quential Me3SiOTf-catalyzed cyclization of functionalized
1,3-bis(trimethylsilyloxy)-1,3-butadienes with oxalyl chlor-
ide, Mitsunobu reaction, and ring-closing metathesis
(RCM).[10] The hybrid concept for the construction of bio-
logically active compounds has been devised recently, since
Results and Discussion
Synthesis of C-1Ј/C-4-Bicyclic γ-Alkylidenebutenolides
Application of our recently reported dianion methodo-
logy[4a] for the synthesis of γ-alkylidenebutenolides to cyclic
1,3-dicarbonyl compounds was unsuccessful; treatment of
the dianion of ethyl 2-oxocyclohexanecarboxylate with
N,NЈ-dimethoxy-N,NЈ-dimethylethanediamide, the Weinreb
amide of oxalic acid, resulted in formation of a complex
mixture. We therefore considered the use of electroneutral
dianion equivalents (masked dianions).[14]
[a]
Institut für Organische Chemie der Georg-August-Universität
Göttingen,
Tammannstr. 2, 37077 Göttingen, Germany
Fax: (internat.) ϩ 49-551/399475
E-mail: planger@gwdg.de
[b]
Institut für Anorganische Chemie der Georg-August-
The 12-membered cyclic 1,3-bis(trimethylsilyloxy)-1,3-
butadiene 3a, a masked dianion of 1a, was prepared in two
Universität Göttingen,
Tammannstr. 4, 37077 Göttingen, Germany
Eur. J. Org. Chem. 2001, 3657Ϫ3667
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/1019Ϫ3657 $ 17.50ϩ.50/0
3657

´
P. Langer, T. Eckardt, N. N. R. Saleh, I. Karime, P. Müller
FULL PAPER
steps as described for the synthesis of related open-chain
dienes.[14b,14c] Silylation of methyl 2-oxocyclododecanecar-
boxylate (1a) afforded the silyl enol ether 2 (96% yield),
which was transformed into 3a in high yield by treatment
with LDA at Ϫ78 °C and subsequent addition of Me3SiCl
(Scheme 1).[15] Surprisingly, this methodology was not suc-
cessful for substrates of smaller ring size. However, the
10-, 8-, 7-, 6-, and 5-membered cyclic 1,3-bis(trimethylsilyl-
oxy)-1,3-butadienes 3bϪn could be prepared in high yields
by treatment of the dianions of the corresponding 1,3-dicar-
Table 1. Synthesis of bicyclic γ-alkylidenebutenolides 4a؊n
bonyl compounds 1bϪn with
2 equiv. of Me3SiCl
(Scheme 2).[15] Interestingly, treatment of Me3SiCl with the
dianions of open-chain β-oxo esters has been reported to
result in silylation of the terminal carbon atom of the dian-
ion rather than in formation of 1,3-bis(trimethylsilyloxy)-
1,3-butadienes.[14b]
Scheme 1. Synthesis of the 12-membered cyclic 1,3-bis(trimethylsi-
lyloxy)-1,3-butadiene 3a according to Molander et al.[15]
[a] Isolated yield. Only one isomer was formed for 4b؊n. Butenolide
4a was obtained as a mixture of isomers [(E)/(Z) ϭ 4:1].
Scheme 2. Synthesis of the 5,10-bicyclic γ-alkylidenebutenolide 4b
Cyclization of oxalyl chloride with bis(silyl enol ether) 3c
regioselectively afforded the 5,8-bicyclic butenolide 4c.
From dienes 3d and 3e, the 5,7-bicyclic butenolides 4d and
The Me3SiOTf-catalyzed cyclization of oxalyl chloride 4e were obtained in good yields and with very good regiose-
with bis(silyl enol ether) 3b, prepared from methyl 2-oxocy- lectivities, while cyclization of the 6-membered cyclic dienes
clodecanecarboxylate in 94% yield, afforded the (Z)-config- 3fϪm afforded the corresponding 5,6-bicyclic products
ured 5,10-bicyclic γ-alkylidenebutenolide 4b in 73% yield 4fϪm in good yields. The presence of an additional sub-
and with very good regioselectivity (Scheme 2). The reac- stituent in the cases of dienes 3j and 3k did not result in
tion proceeded by attack of the terminal carbon atom of any significant decrease in the yield. From 1,3-bis(trimethyl-
the diene onto the dielectrophile and subsequent cyclization silyloxy)-1,3-butadiene 3n, the 5,5-bicyclic γ-alkylidenebut-
through the oxygen atom of the diene. In order to study enolide 4n was obtained.
the preparative scope of this reaction, the ring size and the
The applicability of our methodology to the synthesis of
substituents on the 1,3-bis(trimethylsilyloxy)-1,3-butadienes medium-sized bicyclic butenolides with different substitu-
were varied systematically (Table 1). Cyclization of oxalyl tion patterns was studied next. 1,3-Bis(trimethylsilyloxy)-
chloride with bis(silyl enol ether) 3a gave the 5,12-bicyclic 1,3-butadiene 5 was prepared from cyclooctane-1,3-dione in
butenolide 4a as a mixture of geometric isomers [(E)/ one step. The Me3SiOTf-catalyzed cyclization of 5 with ox-
(Z) ϭ 4:1].
alyl chloride afforded the 5,8-bicyclic butenolide 6 in ac-
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Eur. J. Org. Chem. 2001, 3657Ϫ3667

New Strategies for the Efficient Synthesis of Medium-Sized Bicyclic γ-Alkylidenebutenolides
FULL PAPER
ceptable yield and with very good regioselectivity
(Scheme 3).
Chemoselective alkylation of the α-hydroxy group of but-
enolide 10 initially proved difficult; treatment of 10 with
allyl bromide in the presence of K2CO3 afforded the desired
butenolide 11a, but only in 22% yield. The low yield can be
explained by base-induced ring-opening. Moreover, treat-
ment of 10 with 2-bromo-3-butene resulted in formation of
an inseparable mixture of products, presumably due to de-
composition and competing SN/SNЈ reactions. The problem
was eventually solved by use of the Mitsunobu reaction.
Treatment of 10 with allylic alcohol, 2-hydroxy-3-butene,
and 3-hydroxy-1-pentene in the presence of PPh3/DEAD af-
forded the corresponding butenolides 11aϪc in good yields.
These transformations represent the first examples (to the
best of our knowledge) of chemoselective O-alkylation reac-
tions of γ-alkylidene-α-hydroxybutenolides.[16] To our satis-
faction, ring-closing metathesis (RCM)[17] of 11aϪc using
Grubbs’ catalyst 12 proceeded uneventfully and afforded
the 5,7-bicyclic γ-alkylidenebutenolides 13aϪc (Scheme 4).
The application of the RCM reaction to the formation of
medium-sized rings is currently the object of some atten-
tion, although only relatively few examples have been re-
ported so far.[18] In this context, the synthesis of butenolide
ring ether hybrids containing eight-membered rings was of
special interest. Mitsunobu reaction of 10 with 1-hydroxy-
3-butene, 2-hydroxy-4-pentene, and 1-hydroxy-2-methyl-3-
butene gave butenolides 14a؊c in good yields. RCM treat-
ment of 14a؊c afforded the 5,8-bicyclic butenolides 15a؊c
in acceptable yields (Scheme 5).
Scheme 3. Synthesis of 5,8-bicyclic γ-alkylidenebutenolide 6
Synthesis of C-3/C-4-Bicyclic Hybrids of γ-Alkylidene-
butenolides and Medium-Sized Cyclic Ethers
Ethyl 3-oxohept-6-enoate (7) was prepared in 82% yield
by treatment of the dianion of ethyl acetoacetate with allyl
bromide. Direct cyclization of the dianion of 7 with N,NЈ-
dimethoxy-N,NЈ-dimethylethanediamide was unsuccessful.
To overcome this problem, the corresponding masked dian-
ion 9[14c] was prepared in high yield by silylation of the
carbanion of silyl enol ether 8, which was readily available
from 7 in 96% yield (Scheme 4). To our satisfaction, the
Me3SiOTf-catalyzed cyclization of diene 9 with oxalyl
chloride afforded the desired γ-alkylidenebutenolide 10 in
73% yield with very good regio- and (Z)-diastereoselectivi-
ties.
Scheme 5. Synthesis of 5,8-bicyclic γ-alkylidenebutenolides 15aϪc
To control the position of the endocyclic double bond
and to construct isomers of 5,8-bicyclic butenolides 15, the
masked dianion 18 was prepared as follows. Treatment of
dilithiated ethyl acetoacetate with 1-bromo-3-butene af-
forded ethyl 3-oxooct-7-enoate (16). Silylation of 16 gave
silyl enol ether 17 (95%), which was transformed into the
1,3-bis(trimethylsilyloxy)-1,3-butadiene 18 in 86% yield
(Scheme 6). The Me3SiOTf-catalyzed cyclization of 18 with
oxalyl chloride afforded the γ-alkylidenebutenolide 19 in
72% yield and with very good regio- and (Z)-selectivities.
Mitsunobu reaction of 19 with allylic alcohol, 2-hydroxy-3-
butene, and 3-hydroxy-1-pentene gave the cyclization pre-
cursors 20aϪc, respectively. To our satisfaction, RCM of
Scheme 4. Synthesis of 5,7-bicyclic γ-alkylidenebutenolides 13aϪc
Eur. J. Org. Chem. 2001, 3657Ϫ3667
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P. Langer, T. Eckardt, N. N. R. Saleh, I. Karime, P. Müller
FULL PAPER
20aϪc proceeded uneventfully and afforded the medium-
sized 5,8-bicyclic butenolides 21aϪc. Butenolides 21a and
21b are isomers of butenolides 15a and 15b, respectively.
Figure 1. ORTEP plot of 21a; the thermal ellipsoids of 50% prob-
ability are shown for the non-hydrogen atoms; selected bond
˚
lengths [A] and angles [°]: O(3)ϪC(4) 1.3365(14), O(3)ϪC(12)
1.4656(14), C(12)ϪC(11) 1.4997(17), O(2)ϪC(5) 1.1993(15),
C(11)ϪC(10) 1.3327(18), O(1)ϪC(5) 1.3773(14), O(1)ϪC(2)
1.3890(13), C(10)ϪC(9) 1.5004(18), O(4)ϪC(7) 1.2071(14),
C(9)ϪC(8) 1.5327(17), O(5)ϪC(7) 1.3516(14), C(8)ϪC(3)
1.5053(16), C(3)ϪC(4) 1.3533(16), C(3)ϪC(2) 1.4631(15),
C(4)ϪC(5) 1.4791(16), C(2)ϪC(6) 1.3421(16), C(6)ϪC(7)
1.4777(16); C(4)ϪO(3)ϪC(12) 116.10(9); O(3)ϪC(12)ϪC(11)
112.11(10), C(10)ϪC(11)ϪC(12) 128.58(11), C(5)ϪO(1)ϪC(2)
107.53(9), C(10)ϪC(9)ϪC(8) 118.16(10), C(3)ϪC(8)ϪC(9)
113.03(10), C(4)ϪC(3)ϪC(2) 105.56(10), O(3)ϪC(4)ϪC(3)
135.24(11), O(2)ϪC(5)ϪO(1) 122.03(11), O(4)ϪC(7)ϪC(6)
126.85(11)
Experimental Section
Scheme 6. Synthesis of 5,8-bicyclic γ-alkylidenebutenolides 21aϪc
General: All solvents were dried by standard methods and all reac-
tions were carried out under an inert gas. Ϫ For the 1H and 13C
NMR spectra (1H NMR: 250 and 300 MHz; 13C NMR: 62.5 and
75 MHz) the deuterated solvents indicated were used. Ϫ Mass-
spectrometric data (MS) were obtained using the electron ioniza-
tion (70 eV) or the chemical ionization techniques (CI, H2O). Ϫ
Single-crystal X-ray structure determination showed that
21a had crystallized in the monoclinic space group P21/c,
with one molecule in the asymmetric unit. The γ-alkylidene-
butenolide part of the molecule [including the ethoxy group
and the C(8)ϪC(3)ϪC(4)ϪO(3)ϪC(12) part of the cyclo- For preparative-scale chromatography, silica gel (60Ϫ200 mesh)
was used. Ϫ Melting points are uncorrected. Ϫ Elemental analyses
were performed at the microanalytical laboratory of the University
of Göttingen.
octane-1,5-diene ring] forms one plane with a mean devi-
ation of 0.07 A. Another plane, with a dihedral angle of
˚
110.4(4)° to the first one, is formed by the atoms C(8) to
˚
C(12) (mean deviation 0.02 A). The exocyclic double bond
Methyl 2-Trimethylsilyloxycyclododec-1-ene-1-carboxylate (2):
NEt3 (2.22 g, 22 mmol) and TMSCl (2.40 g, 22 mmol) were added
at 20 °C to a THF solution (20 mL) of methyl 2-oxocyclododecane-
carboxylate (3.15 g, 13.11 mmol). After the suspension had been
stirred for 24 h, the solvent was removed in vacuo. Petroleum ether
was added to the residue, the suspension was filtered under nitro-
gen and the filtrate solvent was removed in vacuo. The residue was
distilled using a Kugelrohr apparatus (oven temp. 110 °C; 0.1 Torr)
possesses the (Z) configuration. Figure 1 gives a picture of
the structure, with selected bond lengths and angles.
In summary, we have developed an efficient synthesis of
bicyclic γ-alkylidenebutenolides containing 5- to 12-mem-
bered ring moieties. The products were prepared in good
yields from readily available starting materials. In addition,
an efficient synthesis of γ-alkylidenebutenolide/medium-
sized cyclic ether hybrids has been developed, relying on the
chemo-, regio-, and (Z)-diastereoselective Me3SiOTf-cata-
lyzed cyclization of allyl- and homoallyl-substituted 1,3-bis-
(trimethylsilyloxy)-1,3-butadienes with oxalyl chloride. Ap-
1
to give 2 as a colourless oil (3.68 g, 90%).[15] Ϫ H NMR (CDCl3,
250 MHz): δ ϭ 0.18, (s, 9 H, Me3Si), 1.05Ϫ1.50 (m, 14 H, CH2),
1.55Ϫ1.65 (m, 2 H, CH2), 1.80, 2.22, 2.46, 3.52 (4 ϫ m, 4 ϫ 1 H,
CH2), 3.72 (s, 3 H, OCH3). Ϫ 13C NMR (CDCl3, 62.5 MHz): δ ϭ
0.68, 24.10, 24.75, 24.83, 24.85, 25.13, 25.40, 25.52, 25.72, 25.80,
plication of Mitsunobu reaction conditions allowed chemo- 33.50, 50.62, 115.12, 165.52, 169.98. Ϫ MS (EI, 70 eV): m/z (%) ϭ
312 (62) [Mϩ], 297 (100), 73 (80); the exact molecular mass m/z ϭ
selective O-alkylation of γ-alkylidenebutenolides to be ac-
complished for the first time. Cyclization was achieved by
RCM, clearly demonstrating the applicability of this meth-
312.2121 Ϯ 2 mD [Mϩ] for C17H32O3Si was confirmed by HRMS
(EI, 70 eV).
odology to the construction of medium-sized cyclic ethers.
The bicyclic butenolides reported here represent analogues
of biologically relevant sesquiterpene natural products.
3-[Methoxy(trimethylsilyloxy)methylidene]-2-trimethylsilyloxy-
cyclododec-1-ene (3a): A THF solution (1.5 mL) of silyl enol ether
2 (1.18 g, 3.8 mmol) was added at Ϫ78 °C to a THF solution of
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New Strategies for the Efficient Synthesis of Medium-Sized Bicyclic γ-Alkylidenebutenolides
FULL PAPER
LDA [prepared by addition of nBuLi (4.4 mmol, 2.35  solution
in n-hexane) to a THF solution (7 mL) of diisopropylamine
(2 ϫ s, 2 ϫ 9 H, Me3Si), 1.22 (t, J ϭ 7.0 Hz, 3 H, CH3), 1.45Ϫ1.65
(2 ϫ m, 2 ϫ 2 H, CH2), 1.95, 2.18 (2 ϫ m, 2 ϫ 2 H, CH2), 3.82
(4.4 mmol) at 0 °C]. After this had stirred for 1.5 h at Ϫ78 °C, (q, J ϭ 7.0 Hz, 2 H, OCH2CH3), 4.94 (t, J ϭ 6.5 Hz, 1 H, CH). Ϫ
TMSCl (0.52 g, 4.8 mmol) was added. The temperature of the solu-
13C NMR (CDCl3, 62.5 MHz): δ ϭ 0.30, 0.34, 15.04, 25.64, 26.84,
27.57, 30.38, 63.52, 98.75, 109.35, 150.66, 152.22. Ϫ MS (EI,
tion was allowed to rise to 0 °C over 1 h and the solution was
stirred for 4 h. The solvent was removed in vacuo and pentane was 70 eV): m/z (%) ϭ 328 (62) [Mϩ], 199 (25), 73 (100); the exact
added to the residue. The precipitated lithium chloride was re-
moved by filtration under nitrogen and the filtrate solvent was re-
moved in vacuo to give 3a as a light yellow oil [1.38 g, 95%, (E)/
molecular mass m/z ϭ 328.1890 Ϯ 2 mD [Mϩ] for C16H32O3Si2
was confirmed by HRMS (EI, 70 eV).
3-[tert-Butyl(trimethylsilyloxy)methylidene]-2-trimethylsilyl-
oxycyclohept-1-ene (3e): Starting from 2-pivaloylcycloheptanone
(1.76 g, 9.00 mmol), 3e was isolated as a slightly yellow oil (2.94 g,
1
(Z) ϭ 4:1].[15] Ϫ H NMR (CDCl3, 250 MHz, major isomer): δ ϭ
0.14, 0.18 (2 ϫ s, 2 ϫ 9 H, Me3Si), 1.20Ϫ1.40 (m, 14 H, CH2),
2.00Ϫ2.10 (m, 4 H, CH2), 3.48 (s, 3 H, OCH3), 4.54 (t, J ϭ 7.0 Hz,
1 H, CH). Ϫ 13C NMR (CDCl3, 62.5 MHz): δ ϭ 0.26, 0.35, 24.33,
24.75, 25.79, 26.15, 26.25, 26.15, 26.25, 26.60, 26.84, 56.40, 101.26,
113.78, 146.07, 151.15. Ϫ MS (EI, 70 eV): m/z (%) ϭ 384 (56) [Mϩ],
369 (40), 353 (92), 73 (100); the exact molecular mass m/z ϭ
384.2616 Ϯ 2 mD [Mϩ] for C20H40O3Si2 was confirmed by HRMS
(EI, 70 eV).
1
96%). Ϫ H NMR (CDCl3, 250 MHz): δ ϭ 0.10, 0.19 (2 ϫ s, 2 ϫ
9 H, Me3Si), 1.18 (s, 9 H, CH3), 1.35Ϫ1.75 (m, 6 H, CH2), 1.98
(m, 2 H, CH2), 4.90 (t, J ϭ 6.5 Hz, 1 H, CH). Ϫ 13C NMR (CDCl3,
62.5 MHz): δ ϭ 0.56, 1.26, 25.78, 26.90, 29.17, 30.32, 31.70, 37.26,
109.25, 117.10, 154.81, 155.69. Ϫ MS (EI, 70 eV): m/z (%) ϭ 340
(56) [Mϩ], 283 (36), 215 (57), 73 (100); the exact molecular mass
m/z ϭ 340.2254 Ϯ 2 mD [Mϩ] for C18H36O2Si2 was confirmed by
HRMS (EI, 70 eV).
General Procedure for the Preparation of Bis(silyl enol ethers) 3b؊n:
Ethyl 2-oxocycloheptanecarboxylate (1d) (2.69 g, 14.6 mmol) was
added dropwise at 0 °C to a THF solution (30 mL) of LDA [pre-
pared by addition of nBuLi (23.8 mL, 36.5 mmol, solution in n-
3-[Ethoxy(trimethylsilyloxy)methylidene]-2-trimethylsilyloxy-
cyclohex-1-ene (3f): Starting from ethyl 2-oxocyclohexanecarboxyl-
ate (1.02 g, 6.00 mmol), 3f was isolated as a slightly yellow oil
(1.73 g, 92%). Ϫ 1H NMR (CDCl3, 250 MHz): δ ϭ 0.14, 0.21 (2
ϫ s, 2 ϫ 9 H, Me3Si), 1.22 (t, J ϭ 8.0 Hz, 3 H, CH3), 1.58 (m,
2 H, CH2), 2.06, 2.31 (2 ϫ m, 2 ϫ 2 H, CH2), 3.79 (q, J ϭ 8.0 Hz,
2 H, OCH2), 4.78 (t, J ϭ 6.0 Hz, 1 H, CH). Ϫ 13C NMR (CDCl3,
62.5 MHz): δ ϭ 0.61, 0.66, 14.80, 23.38, 24.88, 25.62, 63.84, 97.19,
107.25, 147.46, 147.92. Ϫ MS (EI, 70 eV): m/z (%) ϭ 314 (60) [Mϩ],
73 (100); the exact molecular mass m/z ϭ 314.1734 Ϯ 2 mD [Mϩ]
for C15H30O3Si2 was confirmed by HRMS (EI, 70 eV).
hexane) to
a THF solution of diisopropylamine (4.2 mL,
32.0 mmol)]. After stirring of the yellow solution for 1.5 h at 0 °C
(for 3b: stirring for 2 h at Ϫ78 °C), chlorotrimethylsilane (5.5 mL,
43.8 mmol, 3 equiv.) was added in one portion (for 3b: 5 equiv.).
After this had stirred for 3 h at 0 °C, the solvent was removed in
vacuo (for 3b: warming to 0 °C within 1 h and stirring for 3 h).
Petroleum ether was added to the residue and the suspension ob-
tained was filtered under nitrogen. The filtrate solvent was removed
in vacuo to give essentially pure 1,3-bis(trimethylsilyloxy)-1,3-buta-
diene 3d in 95% crude yield. The bis(silyl enol ether)s 3 were used
without further purification and were stored at Ϫ30 °C under nitro-
gen.
3-[Isopropoxy(trimethylsilyloxy)methylidene]-2-trimethylsilyloxy-
cyclohex-1-ene (3g): Starting from isopropyl 2-oxocyclohexanecar-
boxylate (1.012 g, 5.50 mmol), 3g was isolated as a slightly yellow
1
oil (1.73 g, 96%). Ϫ H NMR (CDCl3, 250 MHz): δ ϭ 0.18, 0.21
3-[Methoxy(trimethylsilyloxy)methylidene]-2-trimethylsilyloxy-
cyclodec-1-ene (3b): Starting from methyl 2-oxocyclodecanecarbox-
ylate (1.00 g, 4.71 mmol), 3b was isolated as a slightly yellow oil
(2 ϫ s, 2 ϫ 9 H, Me3Si), 1.20 (d, J ϭ 8.0 Hz, 6 H, CH3), 1.60 (m,
2 H, CH2), 2.11, 2.32 (2 ϫ m, 2 ϫ 2 H, CH2), 4.30 (sept, J ϭ
8.0 Hz, 1 H, OCH), 4.80 (t, J ϭ 6.0 Hz, 1 H, CH). Ϫ 13C NMR
(CDCl3, 62.5 MHz): δ ϭ 0.22, 0.23, 21.87, 23.44, 24.98, 25.98,
69.30, 98.48, 107.55, 146.61, 147.62. Ϫ MS (EI, 70 eV): m/z (%) ϭ
328 (52) [Mϩ], 73 (100); the exact molecular mass m/z ϭ 328.1890
Ϯ 2 mD [Mϩ] for C16H32O3Si2 was confirmed by HRMS (EI,
70 eV).
(1.58 g, 94%).[15]
Ϫ
1H NMR (CDCl3, 250 MHz): δ ϭ 0.10, 0.18
(2 ϫ s, 2 ϫ 9 H, Me3Si), 1.20Ϫ1.45 (m, 10 H, CH2), 2.00, 2.10 (2
ϫ m, 2 ϫ 2 H, CH2), 3.48 (s, 3 H, OCH3), 4.74 (t, J ϭ 8.0 Hz, 1
H, CH). Ϫ 13C NMR (CDCl3, 62.5 MHz): δ ϭ 0.32, 0.50, 24.48,
24.55, 24.60, 25.34, 25.64, 26.94, 28.20, 56.24, 101.64, 115.02,
145.48, 149.96. Ϫ MS (EI, 70 eV): m/z (%) ϭ 356 (92) [Mϩ], 341
(62), 73 (100); the exact molecular mass m/z ϭ 356.2203Ϯ2 mD
[Mϩ] for C18H36O3Si2 was confirmed by HRMS (EI, 70 eV).
3-[(2-Methoxyethoxy)(trimethylsilyloxy)methylidene]-2-trimethyl-
silyloxycyclohex-1-ene (3h): Starting from 2-methoxyethyl 2-oxocy-
clohexanecarboxylate (1.20 g, 6.00 mmol), 3h was isolated as a
1
3-[Ethoxy(trimethylsilyloxy)methylidene]-2-trimethylsilyloxy-
cyclooct-1-ene (3c): Starting from ethyl 2-oxocyclooctanecarboxyl-
ate (1.98 g, 10.00 mmol), 3c was isolated as a slightly yellow oil
slightly yellow oil (1.96 g, 95%). Ϫ H NMR (CDCl3, 250 MHz):
δ ϭ 0.11, 0.20 (2 ϫ s, 2 ϫ 9 H, Me3Si), 1.58 (m, 2 H, CH2), 2.08,
2.32 (2 ϫ m, 2 ϫ 2 H, CH2), 3.36 (s, 3 H, OCH3), 3.55, 3.89 (2 ϫ
m, 2 ϫ 2 H, OCH2), 4.80 (t, J ϭ 6.0 Hz, 1 H, CH). Ϫ 13C NMR
(CDCl3, 62.5 MHz): δ ϭ 0.11, 0.17, 23.27, 24.82, 25.37, 58.81,
67.08, 71.06, 97.45, 107.54, 147.25, 147.60. Ϫ MS (EI, 70 eV): m/z
(%) ϭ 344 (62) [Mϩ], 73 (100); the exact molecular mass m/z ϭ
344.1839 Ϯ 2 mD [Mϩ] for C16H32O4Si2 was confirmed by HRMS
(EI, 70 eV).
(3.25 g, 95%).[15]
Ϫ
1H NMR (CDCl3, 250 MHz): δ ϭ 0.17, 0.20
(2 ϫ s, 2 ϫ 9 H, Me3Si), 1.25 (t, J ϭ 7.0 Hz, 3 H, CH3), 1.45Ϫ1.55
(m, 6 H, CH2), 1.95, 2.18 (2 ϫ m, 2 ϫ 2 H, CH2), 3.82 (q, J ϭ
7.0 Hz, 2 H, OCH2CH3), 4.75 (t, J ϭ 7.0 Hz, 1 H, CH). Ϫ 13C
NMR (CDCl3, 62.5 MHz): δ ϭ 0.92, 1.32, 15.74, 26.42, 27.34,
28.30, 30.02, 30.22, 64.82, 99.36, 107.68, 149.88, 150.66. Ϫ MS (EI,
70 eV): m/z (%) ϭ 342 (80) [Mϩ], 317 (32), 73 (100); the exact mo-
lecular mass m/z ϭ 342.2047 Ϯ 2 mD [Mϩ] for C17H34O3Si2 was
confirmed by HRMS (EI, 70 eV).
3-[Phenyl(trimethylsilyloxy)methylidene]-2-trimethylsilyloxy-
cyclohex-1-ene (3i): Starting from 2-benzoylcyclohexanone (1.21 g,
6.00 mmol), 3i was isolated as a slightly yellow oil (1.97 g, 95%). Ϫ
1H NMR (CDCl3, 250 MHz): δ ϭ 0.12, 0.20 (2 ϫ s, 2 ϫ 9 H,
Me3Si), 1.40Ϫ1.70 (2 ϫ m, 2 H, CH2), 1.90Ϫ2.20 (m, 4 H, CH2),
3-[Ethoxy(trimethylsilyloxy)methylidene]-2-trimethylsilyloxy-
cyclohept-1-ene (3d): Starting from ethyl 2-oxocycloheptanecarbox-
ylate (2.69 g, 14.60 mmol), 3d was isolated as a slightly yellow oil 4.90 (t, J ϭ 6.0 Hz, 1 H, CH), 7.10Ϫ7.50 (m, 5 H, Ph). Ϫ MS (EI,
(4.55 g, 95%).[15] 1H NMR (CDCl3, 250 MHz): δ ϭ 0.10, 0.21 70 eV): m/z (%) ϭ 346 (22) [Mϩ], 73 (100); the exact molecular
Ϫ
Eur. J. Org. Chem. 2001, 3657Ϫ3667
3661

´
P. Langer, T. Eckardt, N. N. R. Saleh, I. Karime, P. Müller
FULL PAPER
mass m/z ϭ 346.1784 Ϯ 2 mD [Mϩ] for C19H30O2Si2 was confirmed 4 H, CH2), 3.78 (s, 3 H, OCH3), 8.00 (br, 1 H, OH). Ϫ 13C NMR
by HRMS (EI, 70 eV).
(CDCl3, 62.5 MHz): (Z) isomer: δ ϭ 20.30, 20.42, 23.22, 23.27,
24.61, 24.89, 25.39, 25.54, 25.65 (CH2), 52.33 (OCH3), 117.69,
126.33, 142.75, 146.60, 164.64, 167.61 (C); (E) isomer: δ ϭ 20.40,
22.63, 23.01, 23.22, 23.97, 24.45, 25.07, 25.23, 26.67, 29.28 (CH2),
52.00 (OCH3), 118.06, 126.83, 145.48, 154.16, 164.16, 168.30 (C).
Ϫ IR (KBr): ν˜ ϭ 3384 (br), 2926 (s), 2854 (s), 1747 (s), 1714 (s),
3-[Ethoxy(trimethylsilyloxy)methylidene]-6-methyl-2-trimethylsilyl-
oxycyclohex-1-ene (3j): Starting from ethyl 5-methyl-2-oxocyclohex-
anecarboxylate (938 mg, 5.09 mmol), 3j was isolated as a slightly
yellow oil (1.652 g, 99%). Ϫ 1H NMR (CDCl3, 250 MHz): δ ϭ
0.17, 0.21 (2 ϫ s, 2 ϫ 9 H, Me3Si), 0.96 (d, J ϭ 8.0 Hz, 3 H,
CHCH3), 1.23 (t, J ϭ 8.0 Hz, 3 H, CH2CH3), 1.15, 2.70, 2.12, 2.32,
2.50 (5 ϫ m, 5 ϫ 1 H, CH, CH2), 4.81 (q, J ϭ 8.0 Hz, 2 H, OCH2),
4.68 (d, J ϭ 5.0 Hz, 1 H, ϭCH). Ϫ 13C NMR [CDCl3, 62.5 MHz,
(E)/(Z) mixture]: δ ϭ 0.11, 0.20, 1.83, 2.86, 14.40, 14.78, 19.19,
21.11, 22.24, 24.29, 24.71, 30.36, 31.94, 40.45, 47.35, 59.43, 63.83,
97.05, 108.95, 114.11, 146.87, 148.03, 158.54, 167.50.
1668 (m), 1468 (m), 1445 (m), 1402 (m), 1274 (m), 1157 (m) cmϪ1
.
Ϫ MS (EI, 70 eV): m/z (%) ϭ 294 (40) [Mϩ], 263 (58), 249 (39),
234 (79). Ϫ C16H22O5 (294.3): C 65.29, H 7.53; found C 64.87,
H 7.32.
γ-Alkylidenebutenolide 4b: Starting from 1,3-bis(trimethylsilyloxy)-
1,3-butadiene 3b (1.032 g, 2.90 mmol), 4b was isolated as a colour-
less solid (564 mg, 73%). Ϫ 1H NMR (CDCl3, 250 MHz): δ ϭ 1.50
(m, 6 H, CH2), 1.68 (m, 4 H, CH2), 2.72 (m, 4 H, CH2), 3.79 (s, 3
H, OCH3), 7.90 (br, 1 H, OH). Ϫ 13C NMR (CDCl3, 62.5 MHz):
δ ϭ 20.75, 21.59, 22.95, 24.62, 25.45, 26.41, 27.05 (CH2), 52.39
(OCH3), 117.70, 127.38, 143.39, 148.75, 164.81, 167.49 (C). Ϫ IR
(neat): ν˜ ϭ 3319 (br), 2933 (s), 2870 (m), 1776 (s), 1713 (s), 1650
6-Ethyl-3-[methoxy(trimethylsilyloxy)methylidene]-2-trimethylsilyl-
oxycyclohex-1-ene (3k): Starting from methyl 6-ethyl-2-oxocy-
clohexanecarboxylate (693 mg, 3.76 mmol), 3k was isolated as a
1
slightly yellow oil (751 mg, 61%). Ϫ H NMR (CDCl3, 250 MHz):
δ ϭ 0.12, 0.22 (2 ϫ s, 2 ϫ 9 H, Me3Si), 0.88 (t, J ϭ 7.0 Hz, 3 H,
CH3), 1.10Ϫ1.40 (m, 4 H, CH2), 1.75, 2.10, 2.45 (3 ϫ m, 3 ϫ 1 H,
CH, CH2), 3.50 (s, 3 H, OCH3), 4.75 (d, J ϭ 5.0 Hz, 1 H, ϭCH).
(s), 1619 (s), 1438 (s), 1306 (m), 1245 (s), 1220 (s), 1071 (m) cmϪ1
.
Ϫ MS (EI, 70 eV): m/z (%) ϭ 266 (60) [Mϩ]; the exact molecular
mass m/z ϭ 266.1154 Ϯ 2 mD [Mϩ] for C14H18O5 was confirmed
by HRMS (EI, 70 eV).
3-[Ethoxy(trimethylsilyloxy)methylidene]-5-phenyl-2-trimethylsilyl-
oxycyclohex-1-ene (3l): Starting from ethyl 2-oxo-4-phenylcyclohex-
anecarboxylate (2.804 g, 11.38 mmol), 3l was isolated as a slightly
yellow oil (3.905 g, 88%). Ϫ 1H NMR (CDCl3, 250 MHz): δ ϭ
0.25, 0.35 (2 ϫ s, 2 ϫ 9 H, Me3Si), 1.28 (t, J ϭ 7.0 Hz, 3 H, CH3),
2.45, 2.95 (m, 5 H, CH, CH2), 3.90 (q, J ϭ 7.0 Hz, 2 H, OCH2),
4.98 (t, J ϭ 5.0 Hz, 1 H, ϭCH).
γ-Alkylidenebutenolide 4c: Starting from 1,3-bis(trimethylsilyloxy)-
1,3-butadiene 3c (1.094 g, 3.20 mmol), 4c was isolated as a colour-
less solid (596 mg, 74%), m.p. 92 °C. Ϫ 1H NMR (CDCl3,
250 MHz): δ ϭ 1.27 (t, J ϭ 7.0 Hz, 3 H, CH2CH3), 1.48 (m, 2 H,
CH2), 1.72 (m, 4 H, CH2), 2.75, 2.80 (2 ϫ t, J ϭ 6.0 Hz, 2 ϫ 2 H,
CH2), 4.24 (q, J ϭ 7.0 Hz, 2 H, OCH2), 8.00 (br, 1 H, OH). Ϫ 13C
NMR (CDCl3, 62.5 MHz): δ ϭ 14.02 (CH3), 21.35, 22.38, 25.33,
25.34, 26.41 (CH2), 61.36 (OCH2), 111.73, 125.80, 142.75, 153.06,
5-tert-Butyl-3-[ethoxy(trimethylsilyloxy)methylidene]-2-trimeth-
ylsilyloxycyclohex-1-ene (3m): Starting from ethyl 4-tert-butyl-2-ox-
ocyclohexanecarboxylate (2.299 g, 10.16 mmol), 3m was isolated as
˜
165.26, 166.83 (C). Ϫ IR (KBr): ν ϭ 3320 (s), 3060 (m), 2991 (s),
a
slightly yellow oil (2.820 g, 75%). Ϫ
1H NMR (CDCl3,
2939 (s), 2922 (s), 2913 (s), 2856 (s), 1748 (s), 1710 (s), 1664 (s),
1613 (s), 1488 (m), 1450 (s), 1402 (s), 1359 (s), 1279 (s), 1258 (s),
1207 (s), 1177 (s), 1159 (s), 1138 (s) 1080 (s) cmϪ1. Ϫ MS (EI,
70 eV): m/z (%) ϭ 252 (32) [Mϩ], Ϫ C13H16O5 (252.3): C 61.89, H
6.39; found C 62.15, H 6.34.
250 MHz): δ ϭ 0.10Ϫ0.30 (4 ϫ s, 18 H, Me3Si), 0.80Ϫ0.95 (s ϫ s,
9 H, tBu), 1.25 (m, 3 H, CH3), 1.60Ϫ2.75 (m, 5 H, CH, CH2), 3.80
(q, J ϭ 7.0 Hz, 2 H, OCH2), 4.80 (m, 1 H, CH).
3-[Ethoxy(trimethylsilyloxy)methylidene]-2-trimethylsilyl-
oxycyclopent-1-ene (3n): Starting from ethyl 2-oxocyclopentanecar-
boxylate (1.02 g, 6.53 mmol), 3n was isolated as an inseparable 2:1
γ-Alkylidenebutenolide 4d: Starting from 1,3-bis(trimethylsilyloxy)-
1,3-butadiene 3d (1.08 g, 3.29 mmol), 4d was isolated as a colour-
less solid (656 mg, 84%), m.p. 78 °C. Ϫ 1H NMR (CDCl3,
250 MHz): δ ϭ 1.28 (t, J ϭ 6.0 Hz, 3 H, CH3), 1.65Ϫ1.90 (m, 4 H,
CH2), 2.64 (m, 4 H, CH2), 4.25 (q, J ϭ 6.0 Hz, 2 H, OCH2CH3),
8.00 (br, 1 H, OH). Ϫ 13C NMR (CDCl3, 62.5 MHz): δ ϭ 13.91
(CH3), 23.88, 24.01, 26.59, 28.53 (CH2), 61.55 (OCH2CH3), 117.21,
1
mixture with the corresponding monosilyl enol ether. Ϫ H NMR
(CDCl3, 250 MHz): δ ϭ 0.21, 0.23 (2 ϫ s, 2 ϫ 9 H, Me3Si), 1.21
(t, J ϭ 8.0 Hz, 3 H, CH3), 1.20Ϫ1.30 (m, 2 H, CH2), 2.24 (m, 2 H,
CH2), 3.80 (q, J ϭ 8.0 Hz, 2 H, OCH2CH3), 4.71 (t, J ϭ 5.0 Hz, 1
H, CH). Ϫ MS (EI, 70 eV): m/z (%) ϭ 300 (12) [Mϩ], 73 (100).
˜
126.85, 141.60, 148.68, 164.82, 167.18 (C). Ϫ IR (KBr): ν ϭ 3300
General Procedure for the Synthesis of γ-Alkylidenebutenolides
4a؊n: A CH2Cl2 solution (7 mL) of Me3SiOTf (0.18 mL, 0.3
equiv.) was added at Ϫ78 °C to a CH2Cl2 solution (60 mL) of ox-
alyl chloride (3.94 mmol, 0.34 mL) and 1,3-bis(trimethylsilyloxy)-
1,3-butadiene 3d (3.28 mmol, 1.08 g). The temperature of the reac-
tion mixture was allowed to rise to 20 °C over 12 h. After the mix-
ture had stirred for 2 h at 20 °C, a saturated solution of NaCl was
added, the organic layer was separated and the aqueous layer was
repeatedly extracted with ether. The combined organic extracts
were dried (MgSO4) and filtered, and the filtrate solvent was re-
moved in vacuo. The residue was purified by column chromato-
graphy (silica gel; ether/petroleum ether, 1:10 Ǟ 1:1) to give 4d
(781 mg, 84%) as a colourless solid, m.p. 78 °C.
(s), 3058 (w), 2992 (m), 2961 (m), 2939 (m), 2904 (m), 1741 (s),
1713 (s), 1656 (s), 1611 (s), 1456 (m), 1410 (s), 1350 (s), 1242 (s),
1198 (s), 1153 (s), 1139 (s), 1047 (s) cmϪ1. Ϫ MS (EI, 70 eV): m/z
(%) ϭ 238 (100) [Mϩ]. Ϫ C12H14O5 (238.2): C 60.50, H 5.92; found
C 60.34, H 5.58.
γ-Alkylidenebutenolide 4e: Starting from 1,3-bis(trimethylsilyloxy)-
1,3-butadiene 3e (1.088 g, 3.20 mmol), 4e was isolated as a colour-
less solid (600 mg, 75%), m.p. 84 °C. Ϫ 1H NMR (CDCl3,
250 MHz): δ ϭ 1.15 (s, 9 H, CH3), 1.65Ϫ1.90 (m, 4 H, CH2), 2.42,
2.59 (2 ϫ t, J ϭ 5.0 Hz, 2 ϫ 2 H, CH2), 7.90 (br, 1 H, OH). Ϫ 13C
NMR (CDCl3, 62.5 MHz): δ ϭ 24.64, 24.75 (CH2), 27.07 (CH3),
27.15, 30.91 (CH2), 44.18 [C(CH3)3], 126.38, 127.24, 140.14, 141.54,
164.85, 213.56 (C). Ϫ IR (KBr): ν˜ ϭ 3299 (s), 2976 (m), 2944 (m),
2932 (m), 1755 (s), 1690 (s), 1652 (m), 1477 (m), 1433 (m), 1412
(s), 1240 (m), 1159 (s), 1040 (m) cmϪ1. Ϫ MS (EI, 70 eV): m/z
γ-Alkylidenebutenolide 4a: Starting from 1,3-bis(trimethylsilyloxy)-
1,3-butadiene 3a (1.152 g, 3.00 mmol), 4a was isolated as a colour-
less solid [615 mg, 70%, (E)/(Z) ϭ 4:1], m.p. 82 °C. Ϫ 1H NMR (%) ϭ 250 (58) [Mϩ]. Ϫ C14H18O4 (250.3): C 67.18, H 7.25; found
(CDCl3, 250 MHz): δ ϭ 1.20Ϫ1.60 (m, 14 H, CH2), 2.32Ϫ2.55 (m, C 67.07, H 6.80.
3662
Eur. J. Org. Chem. 2001, 3657Ϫ3667

New Strategies for the Efficient Synthesis of Medium-Sized Bicyclic γ-Alkylidenebutenolides
γ-Alkylidenebutenolide 4f:[4b] Starting from 1,3-bis(trimethylsily-
less solid (368 mg, 68%). Ϫ 1H NMR ([D6]acetone, 250 MHz): δ ϭ
FULL PAPER
loxy)-1,3-butadiene 3f (566 mg, 1.80 mmol), 4f was isolated as a 0.96 (t, J ϭ 6.0 Hz, 3 H, CH3), 1.45Ϫ1.90 (m, 4 H, CH2), 2.46 (m,
slightly yellow oil (305 mg, 76%). Ϫ 1H NMR ([D6]acetone, 2 H, CH2), 2.75 (quint, J ϭ 5.0 Hz, 1 H, CH), 3.75 (s, 3 H, OCH3),
250 MHz): δ ϭ 1.28 (t, J ϭ 6.0 Hz, 3 H, CH3), 1.80 (quint, J ϭ
5.0 Hz, 2 H, CH2), 2.52 (t, J ϭ 5.0 Hz, 2 H, CH2), 2.58 (t, J ϭ
9.65 (br, 1 H, OH). Ϫ 13C NMR ([D6]acetone, 75 MHz): δ ϭ 11.67
(CH3), 22.61, 25.16, 26.85 (CH2), 34.13 (CH), 51.88 (OCH3),
5.0 Hz, 2 H, CH2), 4.18 (q, J ϭ 6.0 Hz, 2 H, OCH2). Ϫ 13C NMR 107.34, 126.03, 140.22, 152.52, 165.32, 165.40. Ϫ IR (KBr): ν ϭ
˜
([D6]acetone, 75 MHz): δ ϭ 14.57 (CH3), 21.16, 22.53, 25.14 (CH2),
3216 (br), 3012 (m), 2963 (m), 2879 (w), 1782 (s), 1667 (s), 1647
60.99 (OCH2), 107.91, 123.13, 139.97, 152.72 (C), 165.08, 165.37 (s), 1395 (m), 1290 (m), 1265 (m), 1136 (m), 1072 (m) cmϪ1. Ϫ MS
(CO). Ϫ IR (KBr): ν ϭ 3282 (br), 2989 (m), 2952 (m), 2900 (w),
(EI, 70 eV): m/z (%) ϭ 238 (73) [Mϩ], 206 (100), 178 (65). Ϫ
˜
1785 (s), 1672 (s), 1644 (s), 1473 (m), 1398 (s), 1382 (s), 1357 (m), C12H14O5 (238.2): C 60.50, H 5.92; found C 60.77, H 5.82.
1323 (s), 1286 (s), 1193 (s), 1161 (s), 1136 (s), 1045 (s) cmϪ1. Ϫ MS
γ-Alkylidenebutenolide 4l: Starting from 1,3-bis(trimethylsilyloxy)-
(EI, 70 eV): m/z (%) ϭ 224 (35) [Mϩ], 178 (100), 150 (61). Ϫ
1,3-butadiene 3l (2.804 g, 11.38 mmol), 4l was isolated as a colour-
C11H12O5 (224.2): C 58.93, H 5.39; found C 59.08, H 5.30.
less solid (2.254 g, 66%). Ϫ 1H NMR ([D6]acetone, 250 MHz): δ ϭ
γ-Alkylidenebutenolide 4g: Starting from 1,3-bis(trimethylsilyloxy)-
1,3-butadiene 3g (590 mg, 1.80 mmol), 4g was isolated as a slightly
yellow oil (318 mg, 74%). Ϫ 1H NMR ([D6]acetone, 250 MHz): δ ϭ
1.24 (d, J ϭ 6.0 Hz, 6 H, CH3), 1.76 (quint, J ϭ 6.0 Hz, 2 H, CH2),
2.46 (t, J ϭ 6.0 Hz, 2 H, CH2), 2.54 (t, J ϭ 6.0 Hz, 2 H, CH2), 4.99
(sept, J ϭ 6.0 Hz, 1 H, OCH). Ϫ 13C NMR ([D6]acetone, 75 MHz):
1.25 (t, J ϭ 7.0 Hz, 2 H, CH2), 2.50Ϫ2.75 (m, 2 H, CH2),
2.80Ϫ3.20 (m, 3 H, CH, CH2), 4.19 (q, J ϭ 7.0 Hz, 2 H, OCH2),
7.15Ϫ7.45 (m, 5 H, Ph). Ϫ 13C NMR ([D6]acetone, 75 MHz): δ ϭ
14.52 (CH3), 28.06, 32.91 (CH2), 40.69 (CH), 61.10 (OCH2),
107.27, 123.12 (C), 127.57, 127.73, 129.38 (CH, Ph), 140.16, 144.75,
152.58, 164.78, 165.50 (C). Ϫ IR (KBr): ν˜ ϭ 3310 (br), 3063 (w),
3028 (w), 2992 (w), 2929 (w), 1790 (s), 1675 (s), 1643 (m), 1400 (s),
1374 (m), 1288 (m), 1265 (s), 1245 (m), 1161 (m), 1136 (m), 1032
(m) cmϪ1. Ϫ MS (EI, 70 eV): m/z (%) ϭ 300 (41) [Mϩ], 272 (14),
254 (38), 226 (100); the exact molecular mass m/z ϭ 300.0997 Ϯ 2
mD [Mϩ] for C12H14O5 was confirmed by HRMS (EI, 70 eV).
δ
ϭ 20.99 (CH2), 21.98 (CH3), 22.34, 24.98 (CH2), 68.46
[OCH(CH3)2], 108.23, 123.09, 139.64, 152.43, 164.47, 165.20 (C).
Ϫ IR (KBr): ν˜ ϭ 3238 (br), 2981 (w), 2954 (w), 1789 (s), 1670 (s),
1645 (m), 1378 (m), 1333 (m), 1288 (s), 1137 (m), 1051 (m) cmϪ1
.
Ϫ MS (EI, 70 eV): m/z (%) ϭ 238 (42) [Mϩ]. Ϫ C12H14O5 (238.2):
C 60.50, H 5.92; found C 61.06, H 6.10.
γ-Alkylidenebutenolide 4m: Starting from 1,3-bis(trimethylsilyloxy)-
1,3-butadiene 3m (1.012 g, 2.70 mmol), 4m was isolated as a slightly
yellow oil (393 mg, 52%). Ϫ 1H NMR (CDCl3, 250 MHz): δ ϭ 0.90
(m, 2 H, CH2), 0.97 (s, 9 H, tBu), 1.35 (t, J ϭ 7.0 Hz, 3 H,
CH2CH3), 2.00Ϫ2.25 (m, 2 H, CH2), 2.75Ϫ2.95 (dt, 2 H, CH2),
4.30 (q, J ϭ 7.0 Hz, 2 H, OCH2). Ϫ 13C NMR (CDCl3, 75 MHz):
δ ϭ 14.26, 21.89, 27.35, 32.43, 44.40, 61.22, 109.46, 124.27, 138.10,
γ-Alkylidenebutenolide 4h: Starting from 1,3-bis(trimethylsilyloxy)-
1,3-butadiene 3h (1.032 g, 3.00 mmol), 4h was isolated as a slightly
yellow oil (572 mg, 75%). Ϫ 1H NMR ([D4]MeOH, 250 MHz): δ ϭ
1.78 (quint, J ϭ 7.0 Hz, 2 H, CH2), 2.50 (2 ϫ t, J ϭ 7.0 Hz, 4 H,
CH2), 3.38 (s, 3 H, CH3), 3.62, 4.27 (2 ϫ t, J ϭ 5.0 Hz, 2 ϫ 2 H,
OCH2). Ϫ 13C NMR ([D4]MeOH, 62.5 MHz): δ ϭ 21.39, 22.88,
25.35 (CH2), 59.22 (OCH3), 64.90, 71.46 (OCH2), 107.57, 122.98,
˜
151.19, 165.05, 166.20, 168.10. Ϫ IR (neat): ν ϭ 3214 (br), 3063
˜
140.90, 154.25, 166.14, 166.27 (C). Ϫ IR (KBr): ν ϭ 3379 (br),
(m), 2962 (s), 2870 (m), 1793 (s), 1735 (m), 1673 (s), 1653 (m), 1398
(m), 1366 (m), 1282 (m), 1260 (m), 1044 (m) cmϪ1. Ϫ MS (EI,
70 eV): m/z (%) ϭ 280 (22) [Mϩ], 252 (12), 224 (22), 177 (51). Ϫ A
small amount of an unknown impurity could not be separated from
the product.
2988 (m), 2955 (m), 2885 (m), 1787 (s), 1698 (s), 1662 (s), 1644 (s),
1440 (m), 1375 (s), 1358 (s), 1265 (s), 1244 (s), 1086 (s) cmϪ1. Ϫ
MS (EI, 70 eV): m/z (%) ϭ 254 (40) [Mϩ]. Ϫ C12H14O6 (254.2): C
56.69, H 5.55; found C 56.94, H 5.36.
γ-Alkylidenebutenolide 4i:[4b] Starting from 1,3-bis(trimethylsily-
loxy)-1,3-butadiene 3i (622 mg, 1.80 mmol), 4i was isolated as a
slightly yellow oil (312 mg, 68%). Ϫ 1H NMR ([D6]acetone,
250 MHz): δ ϭ 1.90 (quint, J ϭ 5.0 Hz, 2 H, CH2), 2.66 (2 ϫ t,
J ϭ 5.0 Hz, 4 H, CH2), 5.80 (br, 1 H, OH), 7.40Ϫ7.85 (m, 5 H,
Ph). Ϫ 13C NMR ([D6]acetone, 75 MHz): δ ϭ 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). Ϫ MS (EI, 70 eV):
m/z (%) ϭ 256 (100) [Mϩ], 227 (46), 105 (58), 77 (56).
γ-Alkylidenebutenolide 4n: Starting from 1,3-bis(trimethylsilyloxy)-
1,3-butadiene 3n (540 mg, 1.80 mmol), 4n was isolated as a colour-
less solid (208 mg, 55%). Ϫ 1H NMR (CDCl3, 250 MHz): δ ϭ 1.35
(t, J ϭ 6.0 Hz, 3 H, CH3), 2.78, 3.02 (2 ϫ m, 2 ϫ 2 H, CH2), 4.28
(q, J ϭ 6.0 Hz, 2 H, OCH2), 5.30 (br, 1 H, OH). Ϫ 13C NMR
([D6]acetone, 62.5 MHz): δ ϭ 13.75 (CH3), 20.35, 31.79 (CH2),
60.00 (OCH2CH3), 108.19, 132.80, 135.91, 156.49, 162.39, 168.34
˜
(C). Ϫ IR (KBr): ν ϭ 3296 (s), 2989 (m), 2966 (m), 2940 (m), 1799
(s), 1759 (m), 1676 (s), 1647 (s), 1463 (m), 1422 (s), 1402 (s), 1386
(s), 1367 (s), 1357 (s), 1305 (s), 1286 (s), 1255 (s), 1238 (s), 1127 (s)
1029 (s) cmϪ1. Ϫ MS (EI, 70 eV): m/z (%) ϭ 210 (68) [Mϩ], 180
(31), 165 (100); the exact molecular mass m/z ϭ 210.0528 Ϯ 2 mD
[Mϩ] was confirmed by HRMS (EI, 70 eV). Ϫ C10H10O5 (210.2):
C 57.14, H 4.80; found C 57.97, H 5.15.
γ-Alkylidenebutenolide 4j: Starting from 1,3-bis(trimethylsilyloxy)-
1,3-butadiene 3j (1.652 mg, 5.03 mmol), 4j was isolated as a slightly
yellow oil (778 mg, 65%). Ϫ 1H NMR ([D6]acetone, 250 MHz): δ ϭ
1.25 (d, J ϭ 6.0 Hz, 3 H, CHCH3), 1.26 (t, J ϭ 6.0 Hz, 3 H,
CH2CH3), 1.55, 1.85 (2 ϫ m, 2 ϫ 1 H, CH2), 2.35Ϫ2.70 (m, 2 H,
CH2), 2.88 (quint, J ϭ 5.0 Hz, 1 H, CH), 4.19 (q, J ϭ 6.0 Hz, 2 H,
OCH2), 9.55 (br, 1 H, OH). Ϫ 13C NMR ([D6]acetone, 75 MHz):
δ ϭ 13.72, 16.82 (CH3), 22.48 (CH2), 27.27 (CH), 29.76 (CH2),
60.20 (OCH2), 107.09, 126.03, 139.21, 151.57, 164.12, 164.69 (C).
Synthesis of 1,3-Bis(trimethylsilyloxy)-1,3-cyclooctadiene (5): Diene
5 was prepared according to the procedure for the synthesis of di-
enes 3bϪn, in the presence of HMPTA (2 equiv.). Starting from
cyclooctane-1,3-dione (840 mg, 6.00 mmol), 5 was isolated as a yel-
lowish oil (1.30 g, 76%). The crude product was used for the cyc-
˜
Ϫ IR (KBr): ν ϭ 3270 (br), 2989 (m), 2967 (m), 2941 (m), 1786
(s), 1669 (s), 1643 (s), 1399 (s), 1380 (s), 13610 (s), 1272 (s), 1142
(m), 1115 (m), 1072 (s) cmϪ1. Ϫ MS (EI, 70 eV): m/z (%) ϭ 238
(42) [Mϩ], 192 (100), 164 (50). Ϫ C12H14O5 (238.2): C 60.50, H
5.92; found C 60.70, H 5.66.
1
lization with oxalyl chloride. Ϫ H NMR (CDCl3, 250 MHz): δ ϭ
0.12, 0.22 (2 ϫ s, 2 ϫ 9 H, Me3Si), 1.40Ϫ1.70 (m, 4 H, CH2), 1.98,
2.24 (2 ϫ m, 2 ϫ 2 H, CH2), 4.90 (t, J ϭ 11.0 Hz, 1 H, CH), 4.98
(s, 1 H, CH). Ϫ MS (EI, 70 eV): m/z (%) ϭ 284 (12) [Mϩ], 73
(100); the exact molecular mass m/z ϭ 284.1628 Ϯ 2 mD [Mϩ] for
γ-Alkylidenebutenolide 4k: Starting from 1,3-bis(trimethylsilyloxy)-
1,3-butadiene 3k (751 mg, 2.28 mmol), 4k was isolated as a colour- C14H28O2Si2 was confirmed by HRMS (EI, 70 eV).
Eur. J. Org. Chem. 2001, 3657Ϫ3667
3663

´
P. Langer, T. Eckardt, N. N. R. Saleh, I. Karime, P. Müller
FULL PAPER
Synthesis of γ-Alkylidenebutenolide 6: Butenolide 6 was prepared
according to the procedure for the synthesis of butenolides 4aϪn.
Starting from 1,3-bis(trimethylsilyloxy)-1,3-butadiene 5 (425 mg,
([D6]acetone, 62.5 MHz): δ ϭ 14.52 (CH3), 26.61 (CH2CHCH2),
60.64 (OCH2CH3), 96.42 (CCHCO), 117.16 (CH2CHϭCH2),
122.60 (C), 133.99 (CH, CHϭCH2), 144.97, 157.61 (C), 163.57,
1.49 mmol), 6 was isolated as a slightly yellow oil (148 mg, 51%). 164.62 (CϭO). Ϫ MS (EI, 70 eV): m/z (%) ϭ 224 (11) [Mϩ], 178
1
Ϫ H NMR (CDCl3, 250 MHz): δ ϭ 1.72, 1.95 (2 ϫ m, 2 ϫ 2 H, (34), 168 (26), 150 (84), 122 (27), 109 (100); the exact molecular
CH2), 2.57 (m, 4 H, CH2), 5.79 (s, 1 H, CH), 7.40 (br, 1 H, OH). mass m/z ϭ 224.0684 Ϯ 2 mD [Mϩ] for C11H12O5 was confirmed
Ϫ
13C NMR (CDCl3, 62.5 MHz): δ ϭ 19.68, 21.81, 25.67, 41.75 by HRMS (EI, 70 eV). Ϫ C11H12O5 (224.2): C 58.93, H 5.39; found
(CH2), 108.02 (CH), 122.78, 144.44, 157.08, 164.48 (C), 204.71
(CO). Ϫ MS (EI, 70 eV): m/z (%) ϭ 194 (28) [Mϩ]. Ϫ A small
amount of an unknown impurity could not be separated.
C 58.78, H 5.66.
Synthesis of γ-Alkylidenebutenolide 19: Butenolide 19 was prepared
according to the procedure for the synthesis of butenolides 4aϪn.
Starting from 1,3-bis(trimethylsilyloxy)-1,3-butadiene 18 (590 mg,
1.80 mmol), 19 was isolated as a colourless oil (308 mg, 72%). Ϫ
1H NMR ([D6]acetone, 250 MHz): δ ϭ 1.23 (t, J ϭ 7.0 Hz, 3 H,
CH3), 2.33 (m, 2 H, CH2CHϭCH2), 2.54 (m, 2 H, CCH2), 4.14 (q,
J ϭ 7.0 Hz, 2 H, OCH2CH3), 4.92Ϫ5.10 (m, 2 H, CH2CHϭCH2),
5.45 (s, 1 H, ϭCHCO2Et), 5.80Ϫ6.00 (m, 1 H, CH2CHϭCH2),
10.10 (br, 1 H, OH). Ϫ 13C NMR ([D6]acetone, 62.5 MHz): δ ϭ
14.48 (CH3), 22.17, 32.59 (CH2CH2), 60.61 (OCH2CH3), 96.03
(CCHCO), 115.96 (CH2CHϭCH2), 124.58 (C), 137.84 (CH, CHϭ
CH2), 144.60, 157.80 (C), 163.59, 164.63 (CϭO). Ϫ MS (EI, 70 eV):
m/z (%) ϭ 238 (22) [Mϩ]; the exact molecular mass m/z ϭ 238.0841
Ϯ 2 mD [Mϩ] for C12H14O5 was confirmed by HRMS (EI, 70 eV).
Ϫ C12H14O5 (238.2): C 60.50, H 5.92; found C 60.24, H 6.10.
Ethyl 3-Trimethylsilyloxyhepta-2,6-dienoate (8): Triethylamine
(8.88 mL, 64 mmol) and Me3SiCl (8.1 mL, 64 mmol) were added
to a benzene solution (100 mL) of ethyl 3-oxohept-6-enoate (8.28 g,
49 mmol). After stirring for 24 h at 20 °C, the mixture was filtered
and the filtrate was concentrated in vacuo. The residue was distilled
(75Ϫ80 °C, 0.005 mbar) to give 8 as a colourless oil (11.50 g, 96%).
1
Ϫ H NMR (CDCl3, 250 MHz): δ ϭ 0.27 (s, 9 H, Me3Si), 1.26 (t,
J ϭ 6.0 Hz, 3 H, CH3), 2.25 (dt, 2 H, CH2), 2.81 (t, J ϭ 6.0 Hz, 2
H, CH2), 4.11 (q, J ϭ 6.0 Hz, 2 H, OCH2CH3), 4.85Ϫ5.10 (m, 2 H,
CH2CHϭCH2), 5.06 (s, 1 H, CCHCO), 5.83 (tt, 1 H, CH2CHϭ
CH2).
1-Ethoxy-1,3-bis(trimethylsilyloxy)-hepta-1,3,6-triene (9): Com-
pound 8 (5.34 g, 22 mmol) was added at Ϫ78 °C to a THF solution
(50 mL) of LDA [prepared by addition of nBuLi (15.7 mL,
General Procedure for Mitsunobu Treatment of γ-Alkylidenebutenol-
ides: A THF solution (2 mL) of DEAD (0.205 mL, 1.32 mmol) was
added to a degassed THF solution (6 mL) of 10 (240 mg,
1.1 mmol), 3-hydroxy-1-pentene (114 mg, 1.32 mmol) and PPh3
(347 mg, 1.32 mmol). The solution was stirred at 20 °C for 14 h.
The solvent was removed in vacuo and the residue was purified by
chromatography (silica gel; ether/petroleum ether, 1:3) to give 11c
as a slightly yellow oil (180 mg, 56%).
39 mmol) to
a THF solution of diisopropylamine (5.2 mL,
39 mmol)]. After this had stirred for 60 min, Me3SiCl (6.2 mL,
48 mmol) was added. The solution was stirred for a further 60 min,
allowed to warm to 20 °C over 2 h and stirred for 60 min at 20 °C.
The solvent was removed in vacuo and petroleum ether was added.
The mixture was filtered and the filtrate was concentrated in vacuo.
The residue was distilled (60Ϫ63 °C, 0.05 mbar) to give 9 as a col-
ourless oil (6.21 g, 90%). Ϫ 1H NMR (CDCl3, 250 MHz): δ ϭ 0.17,
0.25 (2 ϫ s, 2 ϫ 9 H, Me3Si), 1.28 (t, J ϭ 6.0 Hz, 3 H, CH3), 2.81
(dd, 2 H, 5-H), 3.81 (q, J ϭ 6.0 Hz, 2 H, OCH2CH3), 3.87 (s, 1 H,
2-H), 4.85Ϫ5.15 (m, 3 H, 4-H, CH2CHϭCH2), 5.81 (tt, 1 H,
CH2CHϭCH2).
γ-Alkylidenebutenolide 11a: Starting from 10 (450 mg, 2.0 mmol),
11a was isolated as a slightly yellow oil (370 mg, 70%). Ϫ 1H NMR
(CDCl3, 250 MHz): δ ϭ 1.28 (t, J ϭ 7.0 Hz, 3 H OCH2CH3), 3.16
(m, 2 H, CH2CHϭCH2), 4.21 (q, J ϭ 7.0 Hz, 2 H, OCH2CH3),
4.94Ϫ5.41 (m,
7 H, CHCϭO, OCH2CHϭCH2, CHϭCH2),
5.73Ϫ6.01 (m, 2 H, CH2CHϭCH2). Ϫ MS (70 eV, EI): m/z (%) ϭ
264 (24) [Mϩ]; the exact molecular mass m/z ϭ 264.0998 Ϯ 2 mD
[Mϩ] for C14H16O5 was confirmed by HRMS (EI, 70 eV).
Ethyl 3-Trimethylsilyloxyocta-2,7-dienoate (17): Silyl enol ether 17
was prepared according to the procedure for the synthesis of 8,
without distillation. Starting from ethyl 3-oxooct-7-enoate (3.06 g,
16.6 mmol), 17 was isolated as a slightly yellow oil (4.06 g, 95%).
γ-Alkylidenebutenolide 11b: Starting from 10 (448 mg, 2.0 mmol),
11b was isolated as a slightly yellow oil (345 mg, 62%). Ϫ 1H NMR
(CDCl3, 250 MHz): δ ϭ 1.25 (t, J ϭ 7.0 Hz, 3 H, CH2CH3), 1.35
(d, J ϭ 6.0 Hz, 3 H, CH3), 3.08 (m, 2 H, CH2CHϭCH2), 4.18 (q,
J ϭ 7.0 Hz, 2 H, OCH2CH3), 5.05Ϫ5.25 (m, 5 H, CHCH3, 2 ϫ
CHϭCH2), 5.30 (s, 1 H, CHCϭO), 5.65Ϫ5.90 (m, 2 H, CHϭCH2).
Ϫ MS (70 eV, EI): m/z (%) ϭ 278 (18) [Mϩ]; the exact molecular
mass m/z ϭ 278.1154 Ϯ 2 mD [Mϩ] for C15H18O5 was confirmed
by HRMS (EI, 70 eV).
1
Ϫ H NMR (CDCl3, 250 MHz): δ ϭ 0.27 (s, 9 H, Me3Si), 1.26 (t,
J ϭ 7.0 Hz, 3 H, CH3), 1.60 (pent, 2 H, 5-H), 2.07 (m, 2 H, 4-H),
2.71 (t, J ϭ 6.0 Hz, 6-H), 4.10 (q, J ϭ 7.0 Hz, 2 H, OCH2CH3),
4.90Ϫ5.02 (m, 2 H, CH2CHϭCH2), 5.06 (s, 1 H, CCHCO), 5.80
(m, 1 H, CH2CHϭCH2).
1-Ethoxy-1,3-bis(trimethylsilyloxy)octa-1,3,7-triene (18): Bis(silyl
enol ether) 18 was prepared according to the procedure for the
synthesis of 9, without distillation. Starting from 17 (9.00 g,
35.1 mmol), 18 was isolated as a slightly yellow oil (9.90 g, 86%). Ϫ
1H NMR (CDCl3, 250 MHz): δ ϭ 0.10Ϫ0.30 (4 ϫ s, 18 H, Me3Si),
1.10Ϫ2.20 (m, 4 H, CH2), 3.70Ϫ3.90 (m, 3 H, OCH2CH3, 2-H),
4.80Ϫ5.10 (m, 3 H, 4-H, CH2CHϭCH2), 5.80 (m, 1 H, CH2CHϭ
CH2).
γ-Alkylidenebutenolide 11c: Starting from 10 (240 mg, 1.1 mmol),
11c was isolated as a slightly yellow oil (180 mg, 56%). Ϫ 1H NMR
(CDCl3, 250 MHz): δ ϭ 0.95, 1.28 (2 ϫ t, J ϭ 7.0 Hz, 2 ϫ 3 H, 2
ϫ CH3), 1.75 (m, 2 H, CHCH2), 3.10 (m, 2 H, CH2CHϭCH), 4.22
(q, J ϭ 7.0 Hz, 2 H, OCH2CH3), 5.00Ϫ5.40 (m, 6 H, CHCH2CH3,
CHCϭO, 2 ϫ CHϭCH2), 5.60Ϫ5.90 (m, 2 H, CHϭCH2). Ϫ 13C
NMR (CDCl3, 62.5 MHz): δ ϭ 9.15, 14.16, 26.50, 28.03, 60.69,
82.99, 96.86, 117.56, 119.05, 129.61, 132.18, 136.27, 144.60, 155.46,
162.49, 163.37. Ϫ MS (70 eV, EI): m/z (%) ϭ 292 (20) [Mϩ]; the
exact molecular mass m/z ϭ 292.1311 Ϯ 2 mD [Mϩ] for C16H20O5
was confirmed by HRMS (EI, 70 eV).
Synthesis of γ-Alkylidenebutenolide 10: Butenolide 10 was prepared
according to the procedure for the synthesis of butenolides 4aϪn.
Starting from 1,3-bis(trimethylsilyloxy)-1,3-butadiene 9 (566 mg,
1.80 mmol), 10 was isolated as a colourless solid (295 mg, 73%),
1
m.p. 88 °C. Ϫ H NMR ([D6]acetone, 250 MHz): δ ϭ 1.31 (t, J ϭ
5.0 Hz, 3 H, CH3), 3.31 (d, J ϭ 5.0 Hz, 2 H, CCH2CH), 4.21 (q,
J ϭ 5.0 Hz, 2 H, OCH2CH3), 5.21 (m, 2 H, CH2CHϭCH2), 5.48
γ-Alkylidenebutenolide 14a: Starting from 10 (300 mg, 1.26 mmol),
(s, 1 H, CCHCO), 5.94 (m, 1 H, CH2CHϭCH2). Ϫ 13C NMR 14a was isolated as a slightly yellow oil (238 mg, 68%). Ϫ 1H NMR
3664
Eur. J. Org. Chem. 2001, 3657Ϫ3667

New Strategies for the Efficient Synthesis of Medium-Sized Bicyclic γ-Alkylidenebutenolides
FULL PAPER
(CDCl3, 250 MHz): δ ϭ 1.24 (t, J ϭ 6.0 Hz, 3 H, CH3), 2.23, 2.41 117.90 (CHϭCH2), 131.74 (C), 136.29, 137.71 (CH), 144.16,
(2 ϫ m, 2 ϫ 2 H, CH2), 4.18 (q, J ϭ 6.0 Hz, 2 H, OCH2CH3), 4.92 155.84, 162.58, 163.45 (C). Ϫ MS (70 eV, EI): m/z (%) ϭ 292 (2)
(d, J ϭ 6.0 Hz, 2 H, OCH2CHϭCH2), 4.90Ϫ5.05, 5.20Ϫ5.40 (2 ϫ [Mϩ]. Ϫ A small amount of an unknown impurity could not be
m, 2 ϫ 2 H, CH2CHϭCH2), 5.35 (s, 1 H, ϭCHCO2Et), 5.65Ϫ6.00 separated.
(2 ϫ m, 2 ϫ 1 H, CH2CHϭCH2). Ϫ 13C NMR (CDCl3,
γ-Alkylidenebutenolide 20c: Starting from 19c (200 mg, 0.84 mmol),
62.5 MHz): δ ϭ 13.93 (CH3), 21.91, 31.94, 60.69, 71.35 (CH2),
20c was isolated as a slightly yellow oil (162 mg, 63%). Ϫ 1H NMR
96.46 (ϭCHCO2Et), 116.17, 119.44 (CH2CHϭCH2), 130.62 (C),
(CDCl3, 250 MHz): δ ϭ 0.95 (t, J ϭ 7.0 Hz, 3 H, CH3), 1.31 (t,
132.22, 136.12 (CHϭCH2), 144.23, 155.63, 162.31, 163.30 (C). Ϫ
J ϭ 7.0 Hz, 3 H, OCH2CH3), 1.55Ϫ1.90 (m, 2 H, CHCH2CH3),
MS (70 eV, EI): m/z (%) ϭ 278 (38) [Mϩ]; the exact molecular mass
2.32, 2.44 (2 ϫ m, 2 ϫ 2 H, CH2CH2), 4.23 (q, J ϭ 7.0 Hz, 2 H,
m/z ϭ 278.1154 Ϯ 2 mD [Mϩ] for C15H18O5 was confirmed by
OCH2CH3), 5.00Ϫ5.30 (m, 4 H, CHϭCH2), 5.31 (s, 1 H, ϭ
HRMS (EI, 70 eV).
CHCO2Et), 5.43 (q, J ϭ 7.0 Hz, 1 H, OCHCH2), 5.70Ϫ5.90 (m, 2
H, CHϭCH2). Ϫ 13C NMR (CDCl3, 62.5 MHz): δ ϭ 9.24, 14.22,
γ-Alkylidenebutenolide 14b: Starting from 10 (300 mg, 1.26 mmol),
14b was isolated as a slightly yellow oil (240 mg, 65%). Ϫ 1H NMR
22.02, 28.10, 32.05, 60.78, 82.77, 96.28, 116.19, 119.19, 131.52,
136.32, 136.35, 144.42, 155.90, 162.58, 163.50. Ϫ IR (neat): ν˜ ϭ
3444 (br), 3061 (w), 2981 (m), 2933 (m), 1735 (s), 1656 (s), 1599
(s), 1589 (s), 1572 (s), 1447 (m), 1384 (s), 1254 (m), 1164 (s), 1022
(m) cmϪ1. Ϫ MS (70 eV, EI): m/z (%) ϭ 306 (2) [Mϩ], 239 (40), 69
(100); the exact molecular mass m/z ϭ 306.1467 Ϯ 2 mD [Mϩ] for
C17H22O5 was confirmed by HRMS (EI, 70 eV). Ϫ C17H22O5
(306.4): C 66.65, H 7.24; found C 66.38, H 7.50.
(CDCl3, 250 MHz): δ ϭ 1.07 (d, t, 2 ϫ 3 H, CH2CH3, CHCH3),
2.25Ϫ2.50 (m, 2 H, CHCH2CHϭCH2), 3.11 (d, J ϭ 6.0 Hz, 2 H,
CH2CHϭCH2), 4.23 (q, J ϭ 6.0 Hz, 2 H, OCH2CH3), 5.05Ϫ5.20
(m, 4 H, CH2CHϭCH2), 5.22 (sext, J ϭ 7.0 Hz, 1 H, OCHCH3),
5.34 (s, 1 H, ϭCHCO2Et), 5.68Ϫ5.90 (m, 2 H, CH2CHϭCH2). Ϫ
13C NMR (CDCl3, 62.5 MHz): δ ϭ 14.21, 20.38 (CH3), 26.55,
41.15 (CH2), 60.73 (OCH2), 76.88 (CH), 96.85 (ϭCHCO2Et),
117.58, 118.29 (CH2CHϭCH2), 128.77 (C), 132.18, 132.99 (CHϭ
CH2), 144.45, 155.51, 162.44, 163.41 (C). Ϫ MS (70 eV, EI): m/z
(%) ϭ 292 (8) [Mϩ]; the exact molecular mass m/z ϭ 292.1310Ϯ2
mD [Mϩ] for C16H20O5 was confirmed by HRMS (EI, 70 eV).
General Procedure for the Synthesis of Bicyclic γ-Alkylidenebutenol-
ides by Ring-Closing Metathesis: Grubbs’ catalyst 12 (19 mg, 10
mol %) was added to a degassed benzene solution (8 mL) of buten-
olide 11c (66 mg, 0.23 mmol). The solution was stirred for 12 h
under argon and for 4 h in air. The solvent was removed in vacuo
and the residue was purified by chromatography (silica gel; ether/
petroleum ether, 1:1) to give 13c as a slightly yellow oil (36 mg,
60%).
γ-Alkylidenebutenolide 14c: Starting from 10 (300 mg, 1.26 mmol),
14c was isolated as a slightly yellow oil (236 mg, 64%). Ϫ 1H NMR
(CDCl3, 250 MHz): δ ϭ 1.07 (d, J ϭ 7.0 Hz, 3 H, CHCH3), 1.31
(t, J ϭ 6.0 Hz, 3 H, CH2CH3), 2.56 (quint, J ϭ 7.0 Hz, 1 H,
CHCH3), 3.11 (d, J ϭ 6.0 Hz, 2 H, CH2CHϭCH2), 4.23 (q, J ϭ
6.0 Hz, 2 H, OCH2CH3), 4.34 (dd, J ϭ 7, J ϭ 3.0 Hz, 2 H,
OCH2CH), 5.00Ϫ5.20 (m, 4 H, CH2CHϭCH2), 5.34 (s, 1 H, ϭ
CHCO2Et), 5.66Ϫ5.90 (m, 2 H, CH2CHϭCH2). Ϫ 13C NMR
(CDCl3, 62.5 MHz): δ ϭ 14.22, 15.92 (CH3), 26.62 (CH2), 38.14
(CH), 60.75, 75.08 (OCH2), 96.90 (ϭCHCO2Et), 115.57, 117.64
(CH2CHϭCH2), 127.54 (C), 132.18, 139.27 (CHϭCH2), 144.89,
155.47, 162.32, 163.39 (C). Ϫ MS (70 eV, EI): m/z (%) ϭ 292 (9)
[Mϩ], 247 (8), 225 (18), 196 (18), 69 (100); the exact molecular mass
m/z ϭ 292.1310 Ϯ 2 mD [Mϩ] for C16H20O5 was confirmed by
HRMS (EI, 70 eV).
γ-Alkylidenebutenolide 13a: Starting from 11a (41 mg, 0.16 mmol),
1
13a was isolated as a slightly yellow oil (26 mg, 70%). Ϫ H NMR
(CDCl3, 250 MHz): δ ϭ 1.24 (t, J ϭ 7.0 Hz, 3 H, OCH2CH3), 3.25
(d, J ϭ 5.0 Hz, 2 H, OCH2CHϭCHCH2), 4.21 (q, J ϭ 7.0 Hz, 2
H, OCH2CH3), 4.75 (d, J ϭ 7.0 Hz, 2 H, CHϭCHCH2O), 5.29 (s,
1 H, CHCϭO), 5.99Ϫ6.21 (m, 2 H, CH2CHϭCHCH2O). Ϫ 13C
NMR (CDCl3, 62.5 MHz):
δ ϭ 13.97 (OCH2CH3), 23.12
CH2CHϭCHCH2O), 60.85 (OCH2CH3), 67.79 (CH2CHϭ
CHCH2O), 95.97 (CHCϭO), 121.22 (C), 126.87, 132.88 (CH2CHϭ
CHCH2O), 147.37, 156.03 (C), 162.69, 163.33 (CO). Ϫ MS (70 eV,
EI): m/z (%) ϭ 236 (100) [Mϩ]; the exact molecular mass m/z ϭ
236.0685 Ϯ 2 mD [Mϩ] for C12H12O5 was confirmed by HRMS
(EI, 70 eV). Ϫ C12H12O5 (236.2): C 61.01, H 5.12; found C 60.72,
H 5.27.
γ-Alkylidenebutenolide 20a: Starting from 19a (200 mg, 0.84 mmol),
20a was isolated as a slightly yellow oil (159 mg, 68%). Ϫ 1H NMR
(CDCl3, 250 MHz): δ ϭ 1.28 (t, J ϭ 7.0 Hz, 3 H, OCH2CH3), 2.26,
2.42 (2 ϫ m, 2 ϫ 2 H, CH2CH2), 4.21 (q, J ϭ 7.0 Hz, 2 H,
OCH2CH3), 4.92 (d, J ϭ 8.0 Hz, 2 H, OCH2CHϭCH), 5.32 (s, 1
H, CHCϭO), 4.95Ϫ5.40 (m, 4 H, CHϭCH2), 5.65Ϫ6.00 (2 ϫ m,
2 ϫ 1 H, CHϭCH2). Ϫ 13C NMR (C6D6, 62.5 MHz): δ ϭ 14.12
(OCH2CH3), 21.91, 31.94 (CH2CH2), 60.69, 71.35 (OCH2), 96.46
(CHCϭO), 116.17, 119.44 (CHϭCH2), 130.62 (C), 132.22, 136.12
(CHϭCH), 144.24, 155.63, 162.31, 163.30 (C). Ϫ MS (70 eV, EI):
m/z (%) ϭ 278 (4) [Mϩ], 233 (22), 209 (100); the exact molecular
mass m/z ϭ 278.1154 Ϯ 2 mD [Mϩ] for C15H18O5 was confirmed
by HRMS (EI, 70 eV).
γ-Alkylidenebutenolide 13b: Starting from 11b (216 mg, 0.78 mmol),
13b was isolated as a slightly yellow oil (120 mg, 62%). Ϫ 1H NMR
(CDCl3, 250 MHz): δ ϭ 1.31 (t, J ϭ 7.0 Hz, 3 H, OCH2CH3), 1.52
2
3
(d, J ϭ 7.0 Hz, 3 H, CHCH3), 2.92 (dd, J ϭ 20.0, J ϭ 8.0 Hz, 1
H, CCH2CHϭCH), 3.47 (dd, J ϭ 20.0, J ϭ 3.0, 1 H, CCH2CHϭ
CH), 4.23 (q, J ϭ 7.0 Hz, 2 H, OCH2CH3), 5.13 (m, 1 H, CHCH3),
5.26 (s, 1 H, CHCϭO), 5.80Ϫ5.87, 6.00Ϫ6.06 (2 ϫ m, 2 ϫ 1 H,
CHϭCH). Ϫ 13C NMR (CDCl3, 62.5 MHz): δ ϭ 14.21, 20.69
(CH3), 22.45 (CH2), 60.70 (OCH2), 75.33 (CHCH3), 95.63 (ϭ
CHCO), 120.49 (C), 130.99, 133.05 (CH), 146.58, 156.21, 163.33,
163.34 (C). Ϫ MS (70 eV, EI): m/z (%) ϭ 250 (100) [Mϩ]; the exact
molecular mass m/z ϭ 250.0841 Ϯ 2 mD [Mϩ] for C13H14O5 was
confirmed by HRMS (EI, 70 eV). Ϫ C13H14O5 (250.3): C 62.39, H
5.64; found C 62.10, H 5.42.
γ-Alkylidenebutenolide 20b: Starting from 19b (200 mg, 0.84 mmol),
20b was isolated as a slightly yellow oil (152 mg, 62%). Ϫ 1H NMR
(CDCl3, 250 MHz): δ ϭ 1.30 (t, J ϭ 7.0 Hz, 3 H, 3 H, CH2CH3),
1.39 (d, J ϭ 6.0 Hz, 3 H, 3 H, CHCH3), 2.28, 2.42 (2 ϫ m, 2 ϫ 2
H, CH2CH2), 4.23 (q, J ϭ 7.0 Hz, 2 H, OCH2CH3), 4.98Ϫ5.30 (m,
γ-Alkylidenebutenolide 13c: Starting from 11c (66 mg, 0.23 mmol),
1
4 H, CHϭCH2), 5.32 (s, 1 H, ϭCHCO2Et), 5.60Ϫ5.75 (quint, J ϭ 13c was isolated as a slightly yellow oil (36 mg, 60%). Ϫ H NMR
6.0 Hz, 1 H, OCHCH3), 5.80Ϫ5.90 (m, 2 H, CHϭCH2). Ϫ 13C (CDCl3, 250 MHz): δ ϭ 1.05, 1.31 (2 ϫ t, J ϭ 7.0 Hz, 2 ϫ 3 H,
NMR (CDCl3, 62.5 MHz): δ ϭ 14.22, 21.11 (CH3), 21.99, 32.02
CH2CH3), 1.85 (m, 2 H, CH2), 2.93 (dd, J ϭ 17.0, J ϭ 7.0, 1 H,
(CH2), 60.77 (OCH2), 77.70 (CH), 96.43 (ϭCHCO2Et), 116.19, CCH2CHϭCH), 3.45 (dt, J ϭ 17.0, J ϭ 3.0, 1 H, CCH2CHϭCH),
Eur. J. Org. Chem. 2001, 3657Ϫ3667
3665

´
P. Langer, T. Eckardt, N. N. R. Saleh, I. Karime, P. Müller
FULL PAPER
4.22 (q, J ϭ 7.0 Hz, 2 H, OCH2CH3), 4.87 (m, 1 H, CHCH2CH3), 122.50 (CHϭCH), 124.28 (C), 136.67 (CHϭCH), 144.56, 157.11,
˜
5.25 (s, 1 H, CHCϭO), 5.85, 6.10 (2 ϫ m, 2 ϫ 1 H, CHϭCH). Ϫ 163.30, 163.35 (C). Ϫ IR (KBr): ν ϭ 3088 (w), 3001 (w), 2991 (w),
13C NMR (CDCl3, 62.5 MHz): δ ϭ 9.31, 14.21, 22.60, 27.62, 60.78, 2969 (w), 2917 (w), 1794 (s), 1718 (m), 1654 (m), 1629 (s), 1432
80.14, 95.59, 120.57, 131.23, 131.86, 146.74, 156.30, 162.81, 163.44. (m), 1392 (m), 1331 (m), 1293 (m), 1159 (s), 1129 (m), 1086 (m),
Ϫ MS (70 eV, EI): m/z (%) ϭ 264 (100) [Mϩ]; the exact molecular 1041 (m) cmϪ1. Ϫ MS (70 eV, EI): m/z (%) ϭ 250 (44) [Mϩ], 204
mass m/z ϭ 264.0998 Ϯ 2 mD [Mϩ] for C14H16O5 was confirmed
by HRMS (EI, 70 eV). Ϫ C14H16O5 (264.3): C 63.63, H 6.10; found
C 63.35, H 6.32.
(100), 176 (99), 148 (43); the exact molecular mass m/z ϭ 250.0841
Ϯ 2 mD [Mϩ] for C13H14O5 was confirmed by HRMS (EI, 70 eV).
Ϫ C13H14O5 (250.3): C 62.39, H 5.64; found C 62.05, H 5.88.
Crystal Structure Analysis of 21a: C13H14O5, Mr ϭ 250.24, crystal
size: 0.4 ϫ 0.2 ϫ 0.1 mm, monoclinic, P21/c, unit cell dimensions:
γ-Alkylidenebutenolide 15a: Starting from 14a (112 mg, 0.40 mmol),
15a was isolated as a slightly yellow oil (52 mg, 52%). Ϫ H NMR
1
˚
˚
˚
a ϭ 7.537(2) A, b ϭ 11.207(2) A, c ϭ 14.357(3) A, β ϭ 103.97(3)°,
(CDCl3, 250 MHz): δ ϭ 1.23 (t, J ϭ 7.0 Hz, 3 H, OCH2CH3), 2.72,
3.25 (2 ϫ m, J ϭ 5.0 Hz, 2 ϫ 2 H, CH2CHϭCHCH2), 4.21 (q,
J ϭ 7.0 Hz, 2 H, OCH2CH3), 5.38 (t, J ϭ 6.0 Hz, 2 H, OCH2),
5.41 (s, 1 H, CHCϭO), 5.65Ϫ5.90 (m, 2 H, CH2CHϭCHCH2O). Ϫ
13C NMR (CDCl3, 50 MHz): δ ϭ 14.17 (OCH2CH3), 20.86, 32.87
(CH2CHϭCHCH2), 60.73, 68.72 (OCH2), 95.94 (CHCϭO), 124.20
(C), 123.64, 129.42 (CHϭCH), 145.78, 156.05, 163.31, 163.32 (C).
Ϫ MS (70 eV, EI): m/z (%) ϭ 250 (12) [Mϩ]; the exact molecular
mass m/z ϭ 250.0841 Ϯ 2 mD [Mϩ] for C13H14O5 was confirmed
by HRMS (EI, 70 eV).
3
V ϭ 1176.7(4) A , Z ϭ 4, ρcalcd. ϭ 1.412 Mg/m3, µ ϭ 0.109 mmϪ1
,
˚
F(000) ϭ 528; total number of reflections measured 27908, unique
2683 (Rint ϭ 0.0440). Data/restraints/parameters 2683/0/164, data
collection range 2.3° Յ θ Յ 27.4°. Final R indices: R1 ϭ Σ|Fo Ϫ
2
2 2
4 1/2
Fc|/Σ|Fo| ϭ 0.0380, wR2 ϭ [Σw(Fo Ϫ Fc ) /ΣwFo ] ϭ 0.0993 on
data with I Ͼ 2σ(I) and R1 ϭ 0.0408, wR2 ϭ 0.1014 on all data,
goodness of fit S ϭ [Σw(Fo Ϫ Fc2)2/Σ(n Ϫ p)]1/2) ϭ 1.076; largest
2
difference peak/hole 0.306/Ϫ0.243 e·AϪ3. The crystal was mounted
˚
on a glass fibre in a rapidly cooled perfluoropolyether.[19] Diffrac-
tion data were collected with a StoeϪSiemensϪHuber four-circle
diffractometer coupled to a Siemens CCD area detector at 133(2)
K, with graphite-monochromated Mo-Kα radiation (λ ϭ 0.71073
γ-Alkylidenebutenolide 15b: Starting from 14b (125 mg, 0.53 mmol),
1
15b was isolated as a slightly yellow oil (88 mg, 63%). Ϫ H NMR
˚
(CDCl3, 250 MHz): δ ϭ 1.07 (t, J ϭ 7.0 Hz, 3 H, CH2CH3), 1.41
(d, J ϭ 6.0 Hz, 3 H, CHCH3), 2.91 (dd, J ϭ 17.0, J ϭ 7.0, 2 H,
CHCH2CHϭCH), 3.35 (dd, J ϭ 17.0, J ϭ 7.0, 2 H, CH2CHϭCH),
4.23 (q, J ϭ 7.0 Hz, 2 H, OCH2CH3), 4.88 (m, 1 H, OCHCH3),
5.40 (s, 1 H, ϭCHCO2Et), 5.65Ϫ5.90 (m, 2 H, CHϭCH). Ϫ 13C
NMR (CDCl3, 62.5 MHz): δ ϭ 14.17 (CH3), 21.78 (CH2), 21.86
(CH3), 38.00 (CH2), 60.79 (OCH2), 77.05 (CH), 96.23 (ϭ
CHCO2Et), 123.99 (CH), 127.75 (C), 129.23 (CH), 144.82, 156.14,
A), performing - and ω-scans. The structure was solved by direct
methods using SHELXS-97[20] and refined against F2 on all data
by full-matrix least squares with SHELXL-97.[21] All non-hydrogen
atoms were refined anisotropically. All hydrogen atoms were in-
cluded in the model at geometrically calculated positions and re-
fined using a riding model. The final fractional atomic coordinates
and other crystallographic data for the structure have been depos-
ited with the Cambridge Crystallographic Data Centre as supple-
mentary publication no. CCDC-158694. Copies of the data can be
obtained free of charge on application to the CCDC, 12 Union
Road, Cambridge CB21EZ, UK [Fax: (internat.) ϩ 44-1223/336-
033; E-mail: deposit@ccdc.cam.ac.uk].
˜
163.42, 163.52 (C). Ϫ IR (neat): ν ϭ 3360 (br), 3062 (m), 2960 (s),
2924 (s), 2852 (s), 1780 (s), 1732 (s), 1668 (s), 1651 (s), 1462 (s),
1448 (s), 1372 (s), 1262 (s), 1158 (s), 1095 (s), 1030 (s) cmϪ1. Ϫ MS
(70 eV, EI): m/z (%) ϭ 264 (59) [Mϩ]; the exact molecular mass m/
z ϭ 264.0998 Ϯ 2 mD [Mϩ] for C14H16O5 was confirmed by HRMS
(EI, 70 eV). Ϫ C14H16O5 (264.3): C 63.63, H 6.10; found C 63.38,
H 6.28.
γ-Alkylidenebutenolide 21b: Starting from 20b (125 mg, 0.55 mmol),
1
21b was isolated as a slightly yellow oil (80 mg, 55%). Ϫ H NMR
(CDCl3, 250 MHz): δ ϭ 1.28 (t, J ϭ 7.0 Hz, 3 H, CH2CH3), 1.51
(d, J ϭ 6.0 Hz, 3 H, CHCH3), 2.40Ϫ3.10 (3 ϫ m, 4 H, CH2CH2),
4.22 (q, J ϭ 7.0 Hz, 2 H, OCH2CH3), 5.38 (s, 1 H, ϭCHCO2Et),
5.40Ϫ5.60, 5.90 (m, 3 H, OCHCH3, CHϭCH). Ϫ 13C NMR
(CDCl3, 62.5 MHz): δ ϭ 14.24, 21.43 (CH3), 22.33, 29.42 (CH2),
60.76 (OCH2), 72.97 (OCH), 95.13 (CHCO2Et), 123.87 (C), 129.41,
133.94 (CH), 144.63, 156.84, 163.38, 163.60 (C). Ϫ MS (70 eV, EI):
m/z (%) ϭ 264 (68) [Mϩ], 218 (80), 190 (100); the exact molecular
mass m/z ϭ 264.0998 Ϯ 2 mD [Mϩ] for C14H16O5 was confirmed
by HRMS (EI, 70 eV). Ϫ A small amount of a minor isomer could
not be separated.
γ-Alkylidenebutenolide 15c: Starting from 14c (155 mg, 0.66 mmol),
15c was isolated as a slightly yellow oil (106 mg, 61%). Ϫ 1H NMR
(CDCl3, 250 MHz): δ ϭ 1.12 (d, J ϭ 7.0 Hz, 3 H, CHCH3), 1.31
(t, J ϭ 7.0 Hz, 3 H, CH2CH3), 2.87 (m, 1 H, CHCH3), 3.14 (t, J ϭ
5.5 Hz, 2 H, CH2CHϭCH2), 4.24 (q, J ϭ 7.0 Hz, 2 H, OCH2CH3),
4.25Ϫ4.52 (m, 2 H, OCH2CH), 5.42 (s, 1 H, ϭCHCO2Et),
5.55Ϫ5.80 (m, 2 H, CHϭCH). Ϫ 13C NMR (CDCl3, 62.5 MHz):
δ ϭ 14.17, 17.38 (CH3), 21.07 (CH2), 37.20 (CH), 60.81, 74.02
(OCH2), 96.17 (ϭCHCO2Et), 122.01 (CH), 125.41 (C), 135.83
˜
(CH), 146.01, 156.00, 163.02, 163.40 (C). Ϫ IR (neat): ν ϭ 3407
(br), 2978 (m), 2935 (m), 1793 (s), 1721 (m), 1635 (s), 1448 (m),
1372 (m), 1311 (m), 1277 (m), 1123 (s), 1035 (s) cmϪ1. Ϫ MS
(70 eV, EI): m/z (%) ϭ 264 (59) [Mϩ]; the exact molecular mass m/
z ϭ 264.0998 Ϯ 2 mD [Mϩ] for C14H16O5 was confirmed by HRMS
(EI, 70 eV). Ϫ C14H16O5 (264.3): C 63.63, H 6.10; found C 63.45,
H 6.22.
γ-Alkylidenebutenolide 21c: Starting from 20c (140 mg, 0.56 mmol),
21c was isolated as a slightly yellow oil (100 mg, 64%). Ϫ 1H NMR
(CDCl3, 250 MHz): δ ϭ 1.02 (t, J ϭ 7.0 Hz, 3 H, CH3), 1.30 (t,
J ϭ 7.0 Hz, 3 H, OCH2CH3), 1.63Ϫ2.00 (m, 2 H, CHCH2CH3),
2.40Ϫ2.60 (m, 2 H, CH2CHϭCH), 2.75, 3.05 (2 ϫ m, 2 ϫ 1 H,
CH2CHϭCH), 4.22 (q, J ϭ 7.0 Hz, 2 H, OCH2CH3), 5.21 (m, 1
H, OCHCH2), 5.36 (s, 1 H, ϭCHCO2Et), 5.45, 5.95 (2 ϫ m, 2 ϫ
γ-Alkylidenebutenolide 21a: Starting from 20a (125 mg, 0.50 mmol),
21a was isolated as a slightly yellow oil (83 mg, 66%). Ϫ H NMR 1 H, CHϭCH). Ϫ 13C NMR (CDCl3, 62.5 MHz): δ ϭ 9.65, 14.21
(CDCl3, 250 MHz): δ ϭ 1.29 (t, J ϭ 7.0 Hz, 3 H, OCH2CH3), 2.63, (CH3), 22.38, 28.49, 29.24 (CH2), 60.70 (OCH2), 28.17 (OCH),
2.77 (2 ϫ m, 2 ϫ 2 H, CH2CH2CHϭCH), 4.22 (q, J ϭ 7.0 Hz, 2 95.05 (ϭCHCO2Et), 124.07 (C), 128.30, 134.38 (CH), 144.77,
1
˜
H, OCH2CH3), 4.86 (d, J ϭ 8.0 Hz, 2 H, OCH2CHϭCH), 5.38 (s, 156.86, 163.34, 163.57 (C). Ϫ IR (neat): ν ϭ 3415 (w), 3022 (m),
1 H, CHCϭO), 5.77Ϫ5.85, 6.00Ϫ6.10 (2 ϫ m, 2 ϫ 1 H, CHϭCH). 2969 (s), 2933 (s), 2903 (m), 2887 (m), 1796 (s), 1718 (s), 1660 (s),
Ϫ
13C NMR (C6D6, 62.5 MHz): δ ϭ 14.34 (OCH2CH3), 21.83, 1632 (s), 1474 (m), 1461 (m), 1431 (m), 1395 (s), 1336 (s), 1296 (s),
29.06 (CHϭCHCH2CH2), 60.45, 65.15 (OCH2), 95.19 (CHCϭO), 1283 (s), 1160 (s), 1044 (s) cmϪ1. Ϫ MS (70 eV, EI): m/z (%) ϭ 278
3666 Eur. J. Org. Chem. 2001, 3657Ϫ3667

New Strategies for the Efficient Synthesis of Medium-Sized Bicyclic γ-Alkylidenebutenolides
(71) [Mϩ], 232 (63), 204 (100); the exact molecular mass m/z ϭ
FULL PAPER
[7c]
Pattenden, Prog. Chem. Nat. Prod. 1978, 35, 133. Ϫ
D. W.
Knight, Contemp. Org. Synth. 1994, 1, 287. Ϫ [7d] E.-i. Negishi,
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278.1154 Ϯ 2 mD [Mϩ] for C15H18O5 was confirmed by HRMS
(EI, 70 eV).
[8]
For other approaches to γ-alkylidenebutenolides, see for ex-
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[8b]
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P. L. thanks Professor A. de Meijere for his support. Financial
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ship and funds for P. L.) and from the Deutsche Forschungsgeme-
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[9]
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[1e]
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´
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[3]
[4]
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3667