Synthesis of bicyclo[4.n.1]alkanones

Article abstract of DOI:10.1021/jo048923q

Cyclic β-keto ester monoanions react with 1,4-dihalobutenes to give C-alkylated products which subsequently undergo a stereoselective S _N2′ O-alkylation reaction to yield functionalized enol ethers. When the starting material was ethyl cyclopen

Full text of DOI:10.1021/jo048923q

Syn th esis of Bicyclo[4.n .1]a lk a n on es
J oaquin Montalt, Fre´de´ric Linker, Fre´de´ric Ratel, and Michel Miesch*
Laboratoire de Chimie Organique Synthe´tique associe´ au CNRS (UMR 7123), Faculte´ de Chimie,
Universite´ Louis Pasteur, 1, rue Blaise Pascal BP, 296/ R8, F-67008 Strasbourg Cedex, France
miesch@chimie.u-strasbg.fr
Received J une 25, 2004
Cyclic â-keto ester monoanions react with 1,4-dihalobutenes to give C-alkylated products which
subsequently undergo a stereoselective SN2′ O-alkylation reaction to yield functionalized enol ethers.
When the starting material was ethyl cyclopentanone carboxylate, the C-alkylated product, treated
with a base, directly afforded the functionalized bicyclo[4.2.1]nonanone. The enol ethers were
submitted to a flash vacuum thermolysis (FVT) reaction to readily afford functionalized bicyclo-
[4.n.1]alkanones (n ) 3, 4). This reaction sequence was applied to the synthesis of a functionalized
tricyclo[7.4.1.01,5]tetradecanone, which represents an analogue to the tricyclic core of ingenol.
SCHEME 1
In tr od u ction
Functionalized bicyclo[4.n.1]alkanes are important
substructures present in numerous natural bioactive
compounds. For example, the bicyclo[4.2.1]nonane, bicyclo-
[4.3.1]decane, and bicyclo[4.4.1]undecane skeletons are
respectively present in mediterraneol 1,1 phomoidride B
2,2 and ingenol 33 (Scheme 1). We have previously
reported that the Michae¨l adducts, resulting from the
addition of cyclic â-keto ester monoanions to ethyl pro-
pynoate led, after acidic treatment, to bicyclic bridgehead
ketones and not to the corresponding Robinson annula-
tion products.4 In this context, the reactivity of (di)anions
derived from (a)cyclic mono(or di)-activated ketones was
extensively studied by Zhao et al.,5 Rodriguez et al.,6 and
Langer et al.7 However, to the best of our knowledge, the
reactivity of â-keto ester monoanions toward 1,4-diha-
lobutene has not yet been reported in the literature.
Hereafter, we report our results concerning the synthesis
of bicyclo[4.n.1]alkanone skeletons, starting from cyclic
â-keto ester and from 1,4-dihalobutenes. This study
allowed us to develop a new approach to an analogue of
the tricyclic core present in ingenol.
* To whom correspondence should be addressed. Tel-Fax: +33(0)3
90 24 17 52.
(1) (a) Francisco, C.; Banaigs, B.; Valls, R.; Codomier, L. Tetrahedron
Lett. 1985, 26, 2629. (b) Francisco, C.; Banaigs, B.; Teste, J . J . Org.
Chem. 1986, 51, 1115.
Resu lts a n d Discu ssion
(2) (a) Dabrah, T. T.; Kaneko, T.; Massefski, W., J r.; Whipple, E. B.
J . Am. Chem. Soc. 1997, 119, 1594. (b) Dabrah, T. T.; Harwood: H. J .;
Huang, L. H.; J ankovich, N. D.; Kaneko, T.; Li, J . C.; Lindsey, S.;
Moshier, P. M.; Subashi, T. A.; Therrien, M.; Watts, P. C. J . Antibiot.
1997, 50, 1.
(3) (a) Hecker, E. Cancer Res. 1968, 28, 2338. (b) Zechmeister, K.;
Brandl, F.; Hoppe, W.; Hecker, E.; Opferkuch, H. J .; Adolf, W.
Tetrahedron Lett. 1970, 47, 4075.
We ran our first reaction starting from ethyl cyclopen-
tanone carboxylate 4. The treatment of the later in
refluxing acetone with potassium carbonate, followed by
addition of Z-1,4-dichlorobutene, afforded the C-alkylated
product 5 in 80% yield.8 Subsequently, compound 5 was
treated with a suspension of potassium hydride in THF
at -78 °C in the presence of a catalytic amount of
t-BuOH, to afford the desired bicyclo[4.2.1]nonanone 6
in 90% yield (Scheme 2).9a
(4) Miesch, M.; Mislin, G.; Franck-Neumann, M. Tetrahedron Lett.
1998, 38, 6873.
(5) Wang, P.; Chen, J .; Zhao, K. J . Org. Chem. 1995, 60, 2668. Wang,
T.; Chen, J .; Landrey, D. W.; Zhao, K. Synlett 1995, 543. Wang, T.;
Hong, F.; Zhao, K. Tetrahedron Lett. 1995, 36, 6407.
(6) Lavoisier, T.; Rodriguez, J . Synlett 1995, 1241. Lavoisier, T.;
Rodriguez, J . Synlett 1996, 339. Lavoisier-Gallo, T.; Charonnet, E.;
Pons, J . M.; Rajzman, M.; Faure, R.; Rodriguez, J . Chem. Eur. J . 2001,
7, 1056 and references therein.
(7) Langer, P.; Holtz, E. Angew. Chem. 2000, 112, 3208; Angew.
Chem., Int. Ed. 2000, 39, 3086. Langer, P.; Holtz, E.; Karime´, I.; Saleh,
N. N. R. J . Org. Chem. 2001, 66, 6057. Langer, P.; Holtz, E.; Saleh, N.
N. R. Chem. Eur. J . 2002, 8, 917.
(8) Barco, S.; Benetti, S.; Pollini, G. P. Synthesis 1973, 216.
(9) (a) The 1H NMR and 13C NMR analysis of the crude reaction
mixture did not show any significant difference with the analysis of
product 6 obtained after being purified on a silica gel column; however,
we noticed an important loss of material when the crude reaction
mixture was subjected to a silica gel column (see Experimental
Section); (b) Same remarks as for compound 6.
10.1021/jo048923q CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/08/2004
J . Org. Chem. 2004, 69, 6715-6721
6715

Montalt et al.
SCHEME 2. Syn th esis of Bicyclo[4.2.1]n on a n on e
6a
SCHEME 4. Syn th esis of En ol Eth er s 11, 12, a n d
16a
a
Reagents and conditions: (a) K2CO3, Z-1,4-dichlorobutene,
acteone, 56 °C; (b) KH, t-BuOH cat., THF, -78 °C to rt.
SCHEME 3. Syn th esis of En ol Eth er s 11 a n d 12a
a
Reagents and conditions: (a) K2CO3, E-1,4-dichlorobutene,
acetone, reflux; (b) t-BuOK, THF or Et2O, 25 °C; (*) NaH/DMF,
25 °C; (**) crude yields.
SCHEME 5. "On e-P ot" Rea ction a
a
Reagents and conditions: (a) K2CO3, Z-1,4-dichlorobutene,
acetone, reflux; (b) for 11: t-BuOK, Et2O, 25 °C; for 12: KH,
t-BuOH cat., THF, -78 to 25 °C; (*) NaH/DMF, 25 °C; (**) crude
yields.
The same reaction conditions were utilized starting
from the â-keto esters 7 and 8 respectively derived from
cyclohexanone and cycloheptanone, to give the C-alkyl-
ated products 9 and 10 in good yields. When the latter
were treated as above (KH/t-BuOH cat./THF), no func-
tionalized bridged bicycloalkanones were formed. Indeed,
this reaction led stereospecifically to the enol ethers 11
and 12 by an SN2′ O-alkylation reaction (Scheme 3).9b The
relative configurations indicated for compounds 11 and
12 deduced from NMR studies were in agreement with
those reported for analogous compounds.5-7
a
Reagents and conditions: (a) t-BuOK (3 equiv), E-1,4-dibro-
mobutene, THF, 25 °C; (*) not detected.
SCHEME 6. Rea ctivity of th e En ol Eth er s 11 a n d
12a
Our preliminary results were quite different from those
described by Rodriguez et al.6 Indeed, these authors
always observed the formation of functionalized bridged
bicycloalkanones when dianions, derived from R,R′ acti-
vated cycloalkanones, reacted with Z-1,4-dichlorobutene.
However, Zhao et al. reported that the enol ether of type
11 could be prepared stereospecifically by alkylation of
2-phenylcyclohexanone with Z-1,4-dichlorobutene, and
subsequent intramolecular O-alkylation.5
Next, we turned our attention toward the C-alkylation
reaction between â-keto esters 4, 7, and 8 and E-1,4-
dibromobutene. The corresponding adducts 13, 14, and
15 were easily obtained. The C-alkylation products 13,
14, and 15 were not formed when DBU was used as a
base. In this case, only the starting material was recov-
ered. Compounds 13-15 underwent a SN2′ O-alkylation
reaction as above when treated with KH/t-BuOH cat. in
THF to give the enol ethers 11 and 12 in good yields.
However, the C-alkylated product 13, treated under the
same reaction conditions, led to a “sluggish” reaction
mixture from which the enol ether 16 was identified. This
compound could not be isolated pure, probably because
of the inherent strain of the compound. We also observed
that the same yields were obtained when the base system
KH/t-BuOH was advantageously replaced by t-BuOK,
which is much more convenient (Scheme 4). Our results
were in accord with those reported by Zhao et al. and
Rodriguez et al.5,6
a
Reagents and conditions: (a) HCl 10%, THF, 20 °C, 10 h; (b)
HCl 10%, Et2O, 20 °C, 2 h; (c) HCl 10%, THF, 20 °C, 4 h or HCl
10%, Et2O, 20 °C, 40 h.
7 and 8. The dimers 18 and 19 were also generated as
the result of a double addition of the â-keto ester anions
to E-1,4-dibromobutene. However, we were unable to
obtain the corresponding compounds 16 and 17 when
ethyl cyclopentanone carboxylate was used as starting
material. So, in our hands, the “one-pot” method was not
advantageous compared to the two-step reaction. More-
over, the scale-up of the “one-pot” reaction was not very
efficient when amounts greater than 1 mmol were used,
and the yields dropped dramatically (approximatively
20%). This is not the case for the two-step reaction.
We also noticed that the enol ether 12, treated with
dilute hydrochloric acid in THF at room temperature for
10 h, led quantitatively to the spirolactone 20. When the
reaction was carried out in ether for 2 h at room
temperature, the hydroxy derivative 21 was quantita-
tively recovered. Compound 21 can be readily trans-
formed into the spiro lactone 20 under acidic conditions
(Scheme 6). However, when the enol ether 11 was
submitted to the same conditions, only the hydroxy
derivative 22 (supported by X-ray crystallographic struc-
ture) was quantitatively obtained. When more drastic
conditions (THF, reflux) were used, decomposition oc-
It was also possible to run these two-step reactions as
a “one-pot ” reaction (Scheme 5). The desired products
11 and 12 were obtained starting from the â-keto esters
6716 J . Org. Chem., Vol. 69, No. 20, 2004

Synthesis of Bicyclo[4.n.1]alkanones
SCHEME 7. F la sh Va cu u m Th er m olysis
SCHEME 9. Alk yla tion of Com p ou n d 26a
SCHEME 8
a
Reagents and conditions: (i) K2CO3, E-1,4-dibromobutene,
acetone, reflux 2 h.
SCHEME 10. Syn th esis of En ol Eth er s 29 a n d 30
curred and the corresponding spirolactone derivative was
not isolated.10
To obtain the desired bicyclo[4.n.1]alkanones, the enol
ethers 11 and 12 were heated at 190 °C in 1,2,4-
trichlorobenzene for 14 h to promote a Claisen rear-
rangement. Under these conditions, the bicyclo[4.3.1]-
decanone 23 and the bicyclo[4.4.1]undecanone 24 were
formed. Unfortunately, we were unable to separate these
compounds from side products; the yield was estimated
to be approximatively 50%. To avoid these problems,
compounds 11 and 12 were treated under flash-vacuum
thermolysis (FVT) conditions (600 °C, 10-2 Torr). Thus,
the desired bridgehead ketones 23 and 24 were isolated
in 72% and 60% yields, respectively (Scheme 7). It should
be noted that bicyclo[4.2.1]decanone 6 and bicyclo[4.3.1]-
undecanone 23 were also obtained by Snider et al. using
a Mn(III)-based oxidative free radical cyclization of
unsaturated ketones.11 However, our reaction sequence
led to these functionalized bridged bicycloalkanones in
higher yields and as pure compounds. Finally, to the best
of our knowledge, compound 24 has not yet been de-
scribed in the literature.
pound with use of our photochemical ring enlargement
reaction of condensed electrophilic cyclobutenes.13
The C-alkylation reaction was carried out with E-1,4-
dibromobutene in the presence of potassium carbonate
as a base (Scheme 9). Two separable compounds, 27 and
28, were formed in a 4/1 ratio in 69% overall yield. It is
reasonable to postulate that the major compound 27
results from a favorable approach of the alkylating
reagent on the less hindered face (â-face) of the hydroa-
zulene derivative 26.
Following our model studies, the major compound 27
was treated with t-BuOK to afford the two enol ethers
29 and 30 (ratio 90/10; overall yield 75%). The observed
1,3-diasteroselectivity is explained by the destabilization
of the transition state 27b (Scheme 10) as suggested in
previous work by Zhao et al.5
In summary, we were able to develop a general method
for the preparation of bicyclo[4.n.1]alkanones (n ) 2, 3,
4) in good overall yields, starting from the corresponding
â-keto esters, thanks to the use of the FVT technique.
These results prompted us to use this reaction sequence
to develop an original approach to an analogue of the
tricyclic substructure found in ingenol, i.e. the tricyclic
derivative 25 (Scheme 8).12 The starting material, i.e. the
hydroazulene derivative 26, is a readily available com-
We were unable to separate the two enol ethers 29 and
30, and a one-pot reaction led to a complex mixture of
products. Therefore, the later mixture was subjected to
a FVT reaction at various temperatures. The results were
disappointing compared to those obtained during our
model studies. Indeed, in all cases, the yields were low
and a complex mixture was obtained. We were unable to
obtain the desired tricyclic derivative 25 as a pure
compound. Compound 25, which would have resulted
from a Claisen rearrangement, was always contaminated
with unseparable side products. A second product was
isolated as a pure compound, i.e., compound 31 resulting
from a tandem Claisen-Cope rearrangement. When the
(10) Bode, J . W.; Uesuka, H.; Suzuki, K. Org. Lett. 2003, 5, 395.
(11) (a) Kates, S. A.; Dombroski, M. A.; Snider, B. B. J . Org. Chem.
1990, 55, 2427. (b) Snider, B. B.; Cole, B. M. J . Org. Chem. 1995, 60,
5376. (c) Cole, B. M.; Han, L.; Snider, B. B. J . Org. Chem. 1996, 61,
7832. (d). It also has to be noted that compound 6 was described earlier
but without any spectral data. See: Sands, R. D. J . Org. Chem. 1964,
29, 2488.
(12) For
a review toward ingenol and analogues see: Kim, S.;
Winkler, J . D. Chem. Soc. Rev. 1997, 26, 387. For selected more recent
references see: (a) Rigby, J . H.; Bazin, B.; Meyer, J . H.; Mohammadi,
F. Org. Lett. 2002, 4, 799. (b) Tang, H.; Yusuff, N.; Wood, J . L. Org.
Lett. 2001, 3, 1563. (c) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D.
Tetrahedron Lett. 2000, 41, 3927. (d) Winkler, J . D.; Kim, S.; Harrison,
S.; Lewin, N. E.; Blumberg, P. M. J . Am. Chem. Soc. 1999, 121, 296.
Total synthesis of ingenol: (a) Winkler, J . D.; Rouse, M. B.; Greaney,
M. F.; Harrison, S. J .; J eon, Y. T. J . Am. Chem. Soc. 2002, 124, 9726.
(b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.;
Takahashi, Y.; Kuwajima, I. J . Am. Chem. Soc. 2003, 125, 1498.
(13) Mislin, G. L.; Miesch, M. J . Org. Chem. 2003, 68, 433.
J . Org. Chem, Vol. 69, No. 20, 2004 6717

Montalt et al.
SCHEME 11. F la sh Va cu u m Th er m olysisa
bridged bicycloalkanone skeleton as their main substruc-
ture. In this context, new approaches to ingenol ana-
logues are currently under investigation in our group.
Exp er im en ta l Section
Gen er a l Con sid er a tion s. Reactions were carried out
under argon with magnetic stirring and degassed solvents.
Et2O and THF were distilled from Na/benzophenone. Dioxane,
benzene, and toluene were dried and distilled over CaH2, and
CH2Cl2 over P2O5. Thin-layer chromatography (TLC) was
carried out on silica gel plates and the spots were visualized
under UV lamp (254 or 365 nm) and/or sprayed with a solution
of vanillin (25 g) in EtOH/H2SO4 (98/2; 1 L) followed by heating
on a hot plate. For column chromatography, silica gel (40-60
µm) was used. Melting points (mp) were measured on a hot
stage. IR spectra were recorded as CCl4 solutions. 1H NMR
spectra were recorded at 200 or 300 MHz and 13C NMR spectra
at 50 or 75 MHz, using the signal of the residual nondeuter-
ated solvent as internal reference. Significant 1H NMR data
are tabulated in the following order: chemical shift (δ) ex-
pressed in ppm, multiplicity (s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet), coupling constants in hertz, number
of protons. The ratio of compounds indicated below was
calculated according to the NMR integrations.
a
Conditions: (a) ∆∆, 520 °C, 10-2 mmHg; (b) ∆∆, 600 °C, 10-2
mmHg.
SCHEME 12. Syn th esis of
Tr icyclo[7.4.1.01,5]tetr a d eca n on e 36a
Gen er a l P r oced u r e for th e SN′2 O-Alk yla tion Rea ction .
(a ) Meth od A: KH/t-Bu OH ca t./THF . To a suspension of
KH (1.2 equiv; washed 3× with hexane) in THF (2 mL/1 mmol
of KH) was added t-BuOH (2 drops) and the suspension was
cooled to -78 °C. A solution of the C-alkylated product (1
equiv) in THF (1 mL/1 mmol of starting material) was added
dropwise to the suspension and the resulting mixture was
stirred 10 min at -78 °C. The cooling bath was removed, and
the mixture became orange and was stirred 1 h 30 min at room
temperature and cooled at -78 °C. Water was added (2 mL/1
mmol of KH) and the mixture was extrated with ether (3 × 5
mL for 1 mmol of starting material). The organic layers were
washed with a saturated aqueous NaCl solution, dried over
MgSO4, and filtered and the solvents were removed under
reduced pressure (10 mmHg/25 °C). In general, it is unneces-
sary to purify the crude reaction mixture. There are no
a
Reagents and conditions: (a) H2, Pd/C, EtOAc, 25 °C; (b)
K2CO3, acetone, reflux, E-1,4-dibromobutene; (c) t-BuOK, THF,
25 °C; (d) ∆∆, 520 °C.
temperature was increased to 600 °C, only the Claisen-
Cope rearrangement product 31 was isolated in low yield
from a complex mixture. Below 500 °C, the starting
material was recovered.
1
significant differences when the crude H NMR spectra were
To avoid the formation of compound 31, and to favor
the formation of the desired tricyclic derivative, the same
reaction sequence was run starting from the hyroazulene
derivative 32 (Scheme 12). Compound 32 results from
the catalytic hydrogenation of compound 26. Hydroazu-
lene 32 was first submitted to the C-alkylation reaction,
leading to product 33 along with unreacted starting
material. The former was added to a suspension of
t-BuOK in THF at room temperature to afford the enol
ethers 34 and 35 that we were unable to separate (ratio
9/1; overall yield 95%). The mixture of these compounds
was submitted to a FVT reaction to readily afford the
tricyclic derivative 36 in 74% yield. Compund 36 repre-
sents an analogue of the tricyclic substructure found in
ingenol (Scheme 12).
compared to those of the chromatographed material. Moreover,
we noticed that the yield dropped significantly (10-15%) after
running a chromatography. An analytical sample was obtained
by chromatography on a silica gel column, using a mixture of
EtOAc/hexane as eluent. Compounds 11 and 12 were prepared
according to this experimental procedure.
(b) Meth od B: t-Bu OK/THF or Et2O. A solution of the
C-alkylated product (1 equiv) in THF or Et2O (1 mL for 1
mmol) was added dropwise at room temperature to a suspen-
sion of t-BuOK (1.7-1.8 equiv) in THF (3 mL for 1 mmol). After
5 min of stirring, the mixture became orange and was
hydrolyzed with 50% aqueous NH4Cl solution (1 mL for 1 mmol
of starting material) and then with water (2 mL for 1 mmol of
starting material). After 15 to 30 min of gentle stirring, the
mixture was extracted with Et2O (3 × 5 mL for 1 mmol of
starting material), the organic layers were dried over MgSO4
and filtered, and the solvent was removed under reduced
pressure (10 mmHg/25 °C). In general, it is unnecessary to
purify the crude reaction mixture (there are no significant
differences when the crude 1H NMR spectra were compared
to those of the chromatographed material). Moreover, we
noticed that the yield dropped down significantly (10-15%)
after running a chromatography. An analytical sample was
obtained by chromatography on a silica gel column, using a
mixture of EtOAc/hexane as eluent. Compounds 11, 12, 16,
29, 30, 34, and 35 were prepared according to this experimen-
tal procedure.
Con clu sion
In conclusion, we have shown that â-keto ester monoan-
ions reacted with 1,4-dihalobutenes to give, in good
yields, functionalized enol ethers that undergo a Claisen
rearrangement under FVT reaction conditions. By using
this reaction sequence, we were able to isolate tricyclic
ring systems which are analogous to those found in
natural products belonging to the ingenane family. These
strategies might be a promising tool for developing new
routes to natural compounds bearing a functionalized
En ol Eth er (11). Meth od B: starting material 9 (1.00 g,
3.86 mmol), KH (780 mg, 6.95 mmol), t BuOH (2 drops), enol
ether 11 (740 mg, 3.32 mmol, yield 86%). Meth od B: starting
6718 J . Org. Chem., Vol. 69, No. 20, 2004

Synthesis of Bicyclo[4.n.1]alkanones
material 14 (452 mg, 1.49 mmol), t-BuOK (287 mg, 2.56 mmol);
enol ether 11 (285 mg, 1.28 mmol, yield 86%); colorless oil; IR
10.4, 6.6 Hz, 1H). Anal. Calcd for C17H24O3 (mixture of
isomers): C, 73.88; H, 8.75. Found: C, 74.091; H, 8.74.
1
(CCl4) 1730, 1446 cm-1; H NMR (CDCl3, 200 MHz) δ 1.20 (t,
“On e-P ot” Rea ction : Dim er 18. A solution of the â-keto
ester 7 (162 mg, 0.95 mmol) in THF (10 mL) was added
dropwise at room temperature to a suspension of t-BuOK (275
mg, 2.45 mmol) in THF (85 mL) with stirring for 30 min. E-1,4-
Dibromobutene (306 mg, 1.43 mmol) in THF (5 mL) was then
added rapidly and the mixture was stirred 1 h 40 min at room
temperature and hydrolyzed with a saturated aqueous NH4-
Cl solution (5 mL). The mixture was extracted with Et2O (3 ×
15 mL), the organic layers were dried over MgSO4 and filtered,
and the solvent was removed under reduced pressure (10
mmHg/30 °C). The crude product (166 mg) was purified on a
silica gel column (15 g SiO2, EtOAc/hexane 1/99) leading to
enol ether 11 (95 mg, 0.43 mmol, 45% yield) and to the dimer
18 (29 mg, 0.08 mmol, 15% yield): colorless oil; IR (CCl4) 1716
J ) 7.2 Hz, 3H), 1.25-1.75 (m, 4H), 1.90-2.10 (m, 2H), 2.30-
2.50 (m, 2H), 4.13 (qd, J ) 7.2, 2.2 Hz, 2H), 4.45-4.60 (m,
1H), 4.81 (t, J ) 3.6 Hz, 2H), 5.08 (dt, J ) 10.2, 1.0 Hz, 1H),
5.23 (dt, J ) 17.0, 1.0 Hz, 1H), 5.75 (ddd, J ) 17.0, 10.2, 7.0
Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ 14.0, 19.4, 22.4, 32.1,
43.0, 51.9, 61.0, 79.3, 94.5, 117.1, 136.9, 154.3, 173.9. Anal.
Calcd for C13H18O3: C, 70.24; H, 8.16. Found: C, 69.97; H,
8.30.
En ol Eth er (12). Meth od A: starting material 10 (1.335
g, 4.89 mmol), KH (236 mg, 5.87 mmol), t-BuOH (2 drops),
enol ether 12 (1.070 g, 4.53 mmol, yield 92%); Met h od B:
starting material 15 (825 mg, 2.60 mmol), t-BuOK (501 mg,
4.46 mmol); enol ether 12 (538 mg, 2.27 mmol, yield 87%);
colorless oil; IR (CCl4) 1712, 1689, 1445 cm-1; 1H NMR (CDCl3,
200 MHz) δ 1.30 (t, J ) 7.1 Hz, 3H), 1.53-1.61 (m, 3H), 1.70-
1.94 (m, 3H), 1.95-2.11 (m, 2H), 2.11-2.42 (m, 1H), 2.51 (dd,
J ) 5.2, 13.0 Hz, 1H), 4.25 (q, J ) 7.1 Hz, 2H), 4.40-4.60 (m,
1H), 5.18 (d, J ) 10.1 Hz, 1H), 5.20 (t, J ) 6.5 Hz, 1H), 5.30
(dt, J ) 17.2, 1.0 Hz, 1H), 5.82 (ddd, J ) 17.2, 10.1, 6.9 Hz,
1H); 13C NMR (CDCl3, 50 MHz) δ 14.2, 24.5, 27.1, 27.4, 35.9,
46.4, 56.5, 61.0, 79.2, 98.7, 117.2, 136.6, 159.0, 173.4. Anal.
Calcd for C14H20O3: C, 71.16; H, 8.53. Found: C, 71.08; H,
8.46.
1
cm-1; H NMR (CDCl3, 200 MHz) δ 1.15 (t, J ) 7.1 Hz, 6H),
1.20-1.70 (m, 8H), 1.75-2.00 (m, 2H), 2.10-2.50 (m, 10H),
4.08 (q, J ) 7.1 Hz, 4H), 5.28 (t, J ) 4.1 Hz, 2H); 13C NMR
(CDCl3, 50 MHz) 14.1, 22.4, 27.4, 35.5, 35.6, 37.9, 41.1, 60.9,
61.1, 128.6, 171.4, 207.5. Anal. Calcd for C22H32O6: C, 67.32;
H, 8.22. Found: C, 67.15; H, 8.31.
Dim er 19. To a suspension of t-BuOK (290 mg, 2.58 mmol)
in THF (85 mL) was added at room temperature the â-keto
ester 8 (189 mg, 1.02 mmol) in THF (10 mL). The mixture
became yellow and was stirred 1 h 30 min at room tempera-
ture. Two drops of t-BuOH was added followed by a fast
addition of E-1,4-dibromobutene (330 mg, 1.54 mmol) in THF
(5 mL). The mixture was stirred for 2 h 30 min and hydrolyzed
with a saturated aqueous NH4Cl solution (15 mL). The mixture
was extracted with Et2O (3 × 15 mL), the organic layers were
dried over MgSO4 and filtered, and the solvent was removed
under reduced pressure (10 mmHg/30 °C). The crude product
(187 mg) was purified on a silica gel column (15 g SiO2, EtOAc/
hexane 1/99) leading to enol ether 12 (72 mg, 0.30 mmol, 30%
yield) and to the dimer 19 (103 mg, 0.24 mmol, 48% yield):
colorless oil; IR (CCl4) 1712, 1455 cm-1; 1H NMR (CDCl3, 200
MHz) δ 1.21 (t, J ) 7.1 Hz, 6H), 1.43-1.90 (m, 7H), 1.91-
2.74 (m, 5H), 4.13 (q, J ) 7.1 Hz, 4H); 5.35 (t, J ) 4.1 Hz,
2H); 13C NMR (CDCl3, 50 MHz) δ 14.1, 24.5, 24.6, 25.5, 29.8,
32.0, 38.3, 41.0, 61.0, 62.8, 129.2, 171.9, 209.1. Anal. Calcd
for C24H36O6: C, 68.54; H, 8.63. Found: C, 68.27; H, 8.55.
En ol Eth er (16). Meth od B: starting material 13 (288 mg,
0.99 mmol), t-BuOK (192 mg, 1.75 mmol), enol ether 16 not
pure (10 mg, yield 5%); colorless oil; 1H NMR (CDCl3, 200 MHz)
δ 1.29 (t, J ) 7.1 Hz, 3H), 1.50-1.70 (m, 2H), 1.85 (ddd, J )
8.3, 9.7, 11.0 Hz, 1H), 2.25-2.50 (m, 2H), 2.63 (dd, J ) 5.3,
12.0 Hz, 1H), 2.88 (dddd, J ) 1.4, 5.9, 9.7, 14.3 Hz, 1H), 4.20
(q, J ) 7.1 Hz, 2H), 4.60 (dd, J ) 1.1, 3.4 Hz, 1H), 5.19 (dt, J
) 1.1, 10.4 Hz, 1H), 5.31 (dt, J ) 1.1, 16.9 Hz, 1H), 5.90 (ddd,
J ) 7.3, 10.1, 17.2 Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ 14.2,
33.9, 36.3, 41.6, 61.2, 61.9, 90.6, 93.2, 117.4, 137.8, 162.4, 174.2.
P r od u ct 29. Meth od B: starting material 27 (108 mg, 0.30
mmol), t-BuOK (59 mg, 0.52 mmol), enol ether 29 (62 mg; 0.22
mmol; yield 75% crude, mixture of isomers 29/30 90/10);
colorless oil; IR (mixture of isomers, CCl4) 1728, 1685, 1446,
1
1426 cm-1; H NMR (C6D6, 300 MHz) δ 0.99 (t, J ) 7.1 Hz,
3H), 1.30-1.50 (m, 2H), 1.60-1.80 (m, 2H), 1.85 (dd, J ) 11.8,
10.9 Hz, 1H), 2.00-2.20 (m, 1H), 2.30-2.45 (m, 1H), 2.50-
2.80 (m, 3H), 2.91 (ddt, J ) 16.9, 8.6, 2.2 Hz, 1H), 4.02 (ABX3,
J AB ) 10.8 Hz, J AX ) 7.1 Hz, 2H), 4.74 (dddt, J ) 10.9, 6.5,
5.1, 09 Hz, 1H), 5.01 (ddd, J ) 10.3, 1.65, 1.1 Hz, 1H), 5.24
(ddd, J ) 17.01, 1.65, 1.1 Hz, 1H), 5.78 (ddd, J ) 8.5, 2.4, 1.1
Hz, 1H), 5.81 (ddd, J ) 17.0, 10.4, 5.5 Hz, 1H), 5.95 (ddd, J )
10.2, 8.5, 5.5 Hz, 1H); 13C NMR (C6D6, 75 MHz) δ 13.7, 23.4,
28.8, 29.9, 35.6, 42.2, 44.5, 55.8, 60.9, 78.2, 116.0, 116.7, 129.7,
133.1, 138.0, 144.3, 172.5. Minor isomer (30): 4.59 (ddq, J )
9.4, 4.8, 1.5 Hz, 1H), 5.39 (dt, J ) 17.1, 1.8 Hz, 1H). Anal.
(mixture of isomers) Calcd for C17H22O3: C, 74.42; H, 8.08.
Found: C, 74.19; H, 7.92.
Aceta l 21. To a solution of enol ether 11 (160 mg, 0.72
mmol) in ether (40 mL) was added at room temperature HCl
10% (9 mL). After 2.5 h of stirring at room temperature, a
saturated aqueous NaHCO3 solution (10 mL) was added and
the mixture was extracted with Et2O (3 × 5 mL). The organic
layers were collected, dried over MgSO4, and filtered and the
solvents were removed under reduced pressure (25 °C, 10
mmHg) affording pure acetal 21 (183 mg, 0.72 mmol, quan-
titative yield): colorless oil; IR (CCl4) 3602, 3480, 1733, 1454
1
cm-1; H NMR (CDCl3, 200 MHz) δ 1.27 (t, J ) 7.1 Hz, 3H),
1.45-1.82 (m, 7H), 1.82-2.30 (m, 4H), 2.87 (dd, J ) 13.0, 7.6
Hz, 1H), 4.18 (q, J ) 7.1 Hz, 2H), 4.68 (ddt, J ) 15.0, 7.1, 1.0
Hz, 1H), 5.14 (dt, J ) 17.0, 1.4 Hz, 1H), 5.91 (ddd, J ) 17.0,
10.1, 6.4 Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ 14.0, 22.3, 23.5,
30.0, 36.3, 38.7, 42.0, 60.8, 60.9, 76.3, 107.6, 115.9, 137.9, 175.1.
Anal. Calcd for C14H22O4: C, 66.12; H, 8.72. Found: C, 66.08;
H, 8.57.
P r od u ct 34. Meth od B: starting material 33, 32 (ratio 32/
33 1/1, 168 mg, 0.29 mmol of 33 and 0.29 mmol of 32), t-BuOK
(90 mg, 0.80 mmol), enol ether 34/35 (ratio 90/10) (76 mg, 0.27
mmol, yield 95%); colorless oil; IR (mixture of isomers, CCl4)
1728, 1556, 1448 cm-1. Major isomer 34: 1H NMR (C6D6, 300
MHz) δ 1.02 (t, J ) 7.1 Hz, 3H), 1.10-1.40 (m, 1H), 1.70-
1.90 (m, 6H), 1.90-2.10 (m, 1H), 2.20-2.40 (m, 3H), 2.60-
2.90 (m, 2H), 4.06 (ABX3, J AB ) 10.8 Hz, J AX ) 7.1 Hz, 2H),
4.79 (dddt, J ) 11.3, 6.3, 4.9, 1.1 Hz, 1H), 5.04 (ddd, J ) 10.2,
1.6, 1.1 Hz, 1H), 5.27 (ddd, J ) 17.0, 1.6, 1.1 Hz, 1H), 5.84
(ddd, J ) 17.0, 10.2, 6.4 Hz, 1H); 13C NMR (C6D6, 75 MHz) δ
13.9, 23.7, 24.4, 29.2, 30.6, 33.0, 36.4, 41.4, 46.3, 54.4, 60.4,
78.4, 115.7, 115.8, 138.0, 148.5, 174.2. Minor isomer 35: 1H
NMR (C6D6, 300 MHz) δ 1.00 (t, J ) 7.1 Hz, 3H), 1.15-2.0
(m, 4H), 2.30-3.10 (m, 5H), 4.05 (q, J ) 7.1 Hz, 2H), 4.74 (dddt,
J ) 11.3, 6.3, 5.2, 1.1 Hz, 1H), 5.04 (ddd, J ) 10.2, 1.6, 1.1 Hz,
1H), 5.25 (ddd, J ) 17.0, 1.5, 1.2 1H), 5.85 (ddd, J ) 17.0,
Aceta l 22: same procedure as above; starting material:
enol ether 12 (198 mg, 0.84 mmol), HCl 10% (12 mL), Et2O
(50 mL), acetal 22 (201 mg, quant. yield): colorless oil; IR
1
(CCl4): 3602, 3300, 1732 cm-1; H NMR (CDCl3, 200 MHz) δ
1.30 (t, J ) 7.0 Hz, 3H), 1.40-2.20 (m, 9H), 2.81 (dd, J ) 10.0,
12.5 Hz, 1H), 3.51 (s, 1H), 4.22 (q, J ) 7.0 Hz, 2H), 4.70-4.85
(m, 1H), 5.13 (dt, J ) 10.3, 1.0 Hz, 1H), 5.31 (dt, J ) 17.0, 1.0
Hz, 1H), 5.989 (ddd, J ) 6.6, 10.3, 17.0 Hz, 1H); 13C NMR
(CDCl3, 50 MHz) δ 14.1, 22.4, 22.9, 33.8, 34.7, 40.2, 55.0, 60.9,
76.4, 104.0, 115.12, 139.4, 174.7. Anal. Calcd for C13H20O4: C,
64.98; H, 8.39. Found: C, 65.12; H, 8.51
La cton e 20. From acetal 21: same procedure as above,
but THF was used instead of ether: acetal 21 (270 mg, 1.06
J . Org. Chem, Vol. 69, No. 20, 2004 6719

Montalt et al.
mmol), HCl 10% (5 mL), THF (5 mL), lactone 20 (182 mg, 087
mmol, 82% yield). From enol ether 12: same procedure as
above: enol ether 12 (120 mg, 0.51 mmol), HCl 10% (1 mL),
THF (2 mL), lactone 20 (105 mg, 0.51 mmol, quantitative
yield): colorless oil; IR (CCl4) 1771, 1712, 1454 cm-1; 1H NMR
(CDCl3, 200 MHz) δ 1.07-1.68 (m, 3H), 1.68-2.30 (m, 6H),
2.41-2.62 (m, 1H), 2.83 (ddd, J ) 13.3, 8.6, 1.0 Hz, 1H), 3.10
(dt, J ) 2.7, 11.8 Hz, 1H), 4.87 (ddt, J ) 7.0, 15.8, 1.0 Hz,
1H), 5.28 (dt, J ) 10.1, 1.0 Hz, 1H), 5.37 (dt, J ) 17.2, 1.0 Hz,
1H), 5.94 (ddd, J ) 17.2, 10.1, 7.0 Hz, 1H); 13C NMR (CDCl3,
50 MHz) δ 24.7, 24.8, 29.5, 33.1, 36.1, 40.9, 60.3, 77.7, 117.9,
134.7, 174.7, 207.2. Anal. Calcd for C12H16O3: C, 69.21; H, 7.74.
Found: C, 68.98; H, 7.82.
0.17 mmol, yield 13%) and to the C-alkylated product 27 (259
mg, 0.73 mmol, yield 56%).
Data for 27: colorless oil; IR (CCl4) 1746, 1709, 1685 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.24 (t, J ) 7.1 Hz, 3H), 1.40-
1.60 (m, 3H), 1.65-1.80 (m, 1H), 1.80-2.00 (m, 1H), 2.05-
2.15 (m, 2H), 2.23 (dddt, J ) 14.2, 9.4, 6.2, 2.2 Hz, 1H), 2.40-
2.70 (m, 3H), 3.24 (ddd, J ) 10.1, 8.1, 5.3 Hz, 1H), 3.86 (d, J
) 6.8 Hz, 2H), 4.16 (ABX3, J AB ) 10.8 Hz, J AX ) 7.1 Hz, 2H),
5.52 (dd, J ) 10.6, 2.2 Hz, 1H), 5.72 (m, 2H), 6.07 (ddd, J )
10.6, 8.3, 6.2 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.9, 25.4,
25.7, 29.4, 32.2, 32.6, 38.8, 47.1, 50.9, 61.3, 66.2, 128.3, 130.3,
132.6, 170.6, 210.4. Anal. Calcd for C17H23Br O3: C, 57.47; H,
6.53. Found: C, 57.72; H, 6.46.
Data for 28: colorless oil; IR (CCl4) 1746, 1709, 1685 cm-1
;
Bicyclo[4.2.1]n on a n on e (6). To a suspension of KH (54
mg, 1.34 mmol) in THF (5 mL) was added t-BuOH (1 drop).
The mixture was cooled to -78 °C and a solution of compound
5 (298 mg, 1.20 mmol) in THF (5 mL) was added dropwise.
The cooling bath was removed and the mixture was stirred
for 30 min at room temperature. The mixture was hydrolyzed
with water (5 mL) and extracted with Et2O (3 × 5 mL). The
organic layer was washed with a saturated aqueous NaCl
solution, dried over MgSO4, and filtered and the solvents were
removed under reduced pressure (20 °C, 10 mmHg) leading
to a crude reaction mixture (225 mg, yield 90%) that was
subjected to a silica gel column (15 g SiO2, hexane) leading to
compound 6 (113 mg, 45% yield):9a colorless oil; IR (CCl4) 1730
1H NMR (CDCl3, 300 MHz) δ 1.22 (t, J ) 7.1 Hz, 3H), 1.35-
1.55 (m, 1H), 1.60-1.95 (m, 5H), 2.00-2.30 (m, 2H), 2.30-
2.50 (m, 1H), 3.30 (ddd, J ) 10.0, 8.2, 5.5 Hz, 1H), 3.87 (dd, J
) 4.0, 2.4 Hz, 2H), 4.16 (ABX3, J AB ) 10.6 Hz, J AX ) 7.1 HZ,
2H), 5.73 (m, 2H), 5.83 (dd, J ) 10.8, 2.4 Hz, 1H), 5.95 (ddd,
J ) 10.8, 8.6, 5.3 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.0,
25.9, 26.2, 29.3, 32.6, 32.7, 37.4, 45.7, 51.87, 61.7, 66.0, 128.3,
129.8, 130.2, 130.7, 170.6, 208.0. Anal. Calcd for C17H23Br O3:
C, 57.47; H, 6.53. Found: C, 57.29; H, 6.61.
P r od u cts 25 a n d 31: starting material 29, 30 (130 mg,
0.47 mmol), temperature: 520 °C, vacuum 10-2 Torr. The
crude reaction mixture (72 mg) was purified on a silica gel
column (5 g SiO2, hexane) affording compound 25 (not pure,
18 mg, 0.065 mmol, 14% yield) and pure compound 31 (25 mg,
0.09 mmol, 19% yield).
1
cm-1; H NMR (CDCl3, 200 MHz) δ 1.22 (t, J ) 7.2 Hz, 3H),
1.60-1.75 (m, 1H), 1.85-2.05 (m, 1H), 2.10-2.60 (m, 6H),
2.65-2.75 (m, 1H), 4.17 (q, J ) 7.2 Hz, 2H), 5.50-5.75 (m,
2H); 13C NMR (CDCl3, 50 MHz) δ 14.1, 25.4, 30.8, 31.4, 32.6,
34.6, 45.9, 59.1, 61.3, 125.7, 126.5, 172.2, 217.5. Anal. Calcd
for C12H16O3: C, 69.21; H, 7.74. Found: C, 69.42; H, 8.01
Data for 25: colorless oil; IR 1737, 1446 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 1.25 (t, J ) 7.1 Hz, 3H), 1.30-1.60 (m,
3H), 1.65-2.15 (m, 5H), 2.20-2.30 (m, 2H), 2.50 (dt, J ) 15.6,
6.3 Hz, 2H), 2.68 (dd, J ) 14.9, 6.4 Hz, 1H), 2.85 (dd, J ) 15.6,
6.3 Hz, 1H), 4.20 (ABX3, J AB ) 10.8, J AX ) 7.1 Hz, 2H), 5.48
(dd, J ) 10.6, 2.5 Hz, 1H), 5.70-5.90 (m, 2H), 5.90-6.00 (m,
1H); 13C NMR (CDCl3, 75 MHz) δ 13.9, 23.5, 31.1, 34.4, 35.4,
35.5, 37.0, 18.3, 61.4, 64.7, 66.5, 129.1, 129.6, 130.3, 131.0,
171.9, 210.9.
Data for 31: colorless oil; IR 1732, 1680, 1447 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 1.10-1.20 (m, 3H), 1.31 (t, J ) 7.1 Hz,
3H), 1.70-1.90 (m, 4H), 1.90-2.10 (m, 2H), 2.26 (dt, J ) 13.5,
8.4 Hz, 1H), 2.42 (ddd, J ) 12.3, 9.3, 2.8 Hz, 1H), 2.78 (q, J )
8.2 Hz, 1H), 2.92 (dt, J ) 9.3, 2.6 Hz, 1H), 4.25 (q, J ) 7.1 Hz,
2H), 4.96 (dt, J ) 10.2, 1.1 Hz, 1H), 5.04 (dt, J ) 17.0, 1.3 Hz,
1H), 5.64 (ddd, J ) 17.0, 10.2, 7.7 Hz, 1H), 7.70 (d, J ) 9.0
Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 14.1, 23.3, 29.7, 34.6,
34.8, 35.6, 39.5, 41.1, 41.4, 61.1, 61.3, 114.6, 137.4, 141.1, 156.6,
166.1, 202.0. Anal. Calcd for C17H22O3: C, 74.42; H, 8.08.
Found: C, 74.35; H, 8.12.
Gen er a l P r oced u r e for th e F VT Rea ction . The starting
material was placed into a round-bottom flask fixed to the FVT
apparatus and warmed so that the product flushed through
the quartz tube heated at the indicated temperature. The
reaction products were collected on a finger cooled with liquid
nitrogen. The finger was rinced with ether and the organic
layer was dried over MgSO4, filtered, and evaporated under
reduced pressure (25 °C, 10 mmHg). The crude reaction
mixture was purified by chromatography on a silica gel column
eluting with a EtOAc/hexane mixture.
Bicyclo[4.3.1]d eca n on e (23): starting material 11 (208
mg, 0.93 mmol), temperature 600 °C, vacuum 10-2 Torr,
compound 23 (150 mg, 0.67 mmol, 72% yield); colorless oil; IR
1
(CCl4) 1712, 1559 cm-1; H NMR (CDCl3, 200 MHz) δ 1.27 (t,
J ) 7.2 Hz, 3H), 1.50-1.65 (m, 2H), 1.85-2.50 (m, 6H), 2.55-
2.65 (m, 2H), 2.75-2.90 (m, 1H), 4.17 (q, J ) 7.2 Hz, 2H), 5.75-
5.95 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ 14.0, 18.7, 30.7,
32.4, 33.0, 35.9, 47.3, 61.1, 61.2, 128.9, 129.4, 173.2, 212.0.
Anal. Calcd for C13H18O3: C, 70.24; H, 8.16. Found: C, 70.05;
H, 8.13.
P r od u ct 32. To a solution of â-keto ester 26 (420 mg, 1.89
mmol) in EtOAc (40 mL) was added 10% Pd/C (5 mg) and the
reaction mixture was stirred under a hydrogen atmosphere
for 5 h at room temperature. The crude reaction mixture was
filtered on a Celite pad, and the solvent was removed under
reduced pressure (10 mmHg, 25 °C) to give compound 32 as a
mixture of isomers (422 mg, 1.89 mmol, quantitative yield);
Bicyclo[4.4.1]u n d eca n on e (24): starting material 12 (200
mg, 0.84 mmol), temperature 600 °C, vacuum: 10-2 Torr,
compound 24 (118 mg, 0.50 mmol, 59% yield); colorless oil; IR
1
(CCl4) 1710 cm-1; H NMR (CDCl3, 200 MHz) δ 1.24 (t, J )
colorless oil; IR (mixture of isomers, CCl4) 1746, 1709 cm-1
.
Major isomer: 1H NMR (CDCl3, 300 MHz) δ 1.22 (t, J ) 7.1
Hz, 3H), 0.95-1.15 (m, 1H), 1.15-1.30 (m, 1H), 1.30-1.50 (m,
2H), 1.55-1.80 (m, 5H), 1.85-2.00 (m, 2H), 2.05-2.15 (m, 1H),
2.20-2.40 (m, 1H), 3.15 (q, J ) 9.2 Hz, 1H), 3.60 (dd, J ) 11.6,
3.4 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.1, 24.2, 25.2, 26.4,
27.8, 32.5, 34.3, 39.3, 55.8, 57.8, 59.9, 169.1, 207.2. Minor
isomer: 1H NMR (CDCl3, 300 MHz) δ 1.23 (t, J ) 7.1 Hz, 3H),
3.28 (dd, J ) 11.5, 3.5 Hz, 1H), 3.40 (dt, J ) 11.1, 8.1 Hz, 1H),
the other signals overlapped with those of the major isomer;
13C NMR (CDCl3, 75 MHz) δ 13.1, 23.5, 24.6, 25.4, 25.7, 29.3,
33.8, 39.7-8, 50.9, 57.1, 60.2, 169.5, 207.2. Anal. (mixture of
isomers) Calcd for C13H20O3: C, 69.61; H, 8.99. Found: C,
70.00; H, 8.78.
7.2 Hz, 3H), 1.30-2.15 (m, 9H), 2.30-2.45 (m, 2H), 2.70-3.00
(m, 2H), 4.15 (qd, J ) 7.2, 1.0 Hz, 2H), 5.05-5.30 (m, 2H); 13
C
NMR (CDCl3, 50 MHz) δ 14.0, 25.2, 25.5, 29.5, 30.5, 30.6, 33.5,
54.0, 60.9, 65.2, 126.8, 127.3, 173.4, 212.0. Anal. Calcd for
C
14H20O3: C, 71.16; H, 8.53. Found: C, 71.32; H, 8.43.
P r od u ct 27. To a suspension of K2CO3 (718 mg, 5.20 mmol)
in acetone (20 mL) was added E-1,4-dibromobutene (2.78 g,
12.99 mmol) and the â-keto ester 26 (289 mg, 1.30 mmol). The
mixture was heated under reflux for 2 h. After being cooled to
room temperature, the reaction mixture was filtered and the
solvents were evaporated. The crude product was filtered on
a silica gel column to eliminate the excess E-1,4-dibromobutene
leading to a mixture of C-alkylated products. The latter (373
mg) was purified on a silica gel column (15 g SiO2, EtOAc/
hexane: 1/99) leading to the C-alkylated product 28 (62 mg,
P r od u ct 33. To a solution of â-keto ester 32 (189 mg, 0.84
mmol) in acetone (15 mL) was added K2CO3 (465 mg, 3.37
6720 J . Org. Chem., Vol. 69, No. 20, 2004

Synthesis of Bicyclo[4.n.1]alkanones
mmol) and E-1,4-dibromobutene (1.80 g, 8.41 mmol). The
mixture was heated under reflux during 3 h. The mixture was
filtered through a pad of Celite and the sovent was evaporated
under reduced pressure (25 °C, 10 mmHg). The crude reaction
mixture was chromatographed on a silica gel column (15 g
SiO2, hexane) affording the excess 1,4-trans-dibromobutene
and an unseparable 1/1 mixture of starting material 32 and
of compound 33 [168 mg, yield for 33 52% based on consumed
starting material]; colorless oil; 1H NMR (CDCl3, 300 MHz) δ
1.25 (t, J ) 7.1 Hz, 3H), 1.00-2.40 (m, 9H), 2.63 (d, J ) 6.9
Hz, 2H), 3.90 (d, J ) 7.2 Hz, 2H), 4.18 (q, J ) 7.1 Hz, 2H),
5.55-5.80 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 22.8,
24.7, 26.0, 30.3, 30.4, 31.4, 34.2, 36.3, 39.7, 49.7, 60.0, 61.8,
129.0, 129.4, 171.1, 209.0.
3H), 1.30-2.20 (m, 12H), 2.20-2.40 (m, 2H), 2.50 (dd, J ) 15.7,
6.0 Hz, 1H), 2.77 (ddt, J ) 15.7, 5.5, 1.3 Hz, 1H), 4.17 (ABX3,
J AB ) 10.8 Hz, J AX ) 7.1 Hz, 2H), 5.80 (ddt, J ) 11.0, 6.0, 1.6
Hz, 1H), 5.93 (ddd, J ) 11.0, 6.8, 5.8 Hz, 1H); 13C NMR (CDCl3,
75 MHz) δ 14.0, 22.3, 22.7, 31.3, 33.2, 34.1, 34.7, 36.3, 40.3,
46.5, 60.8, 62.7, 64.8, 128.9, 129.4, 173.8, 211.8. Anal. Calcd
for C17H24O3: C, 73.88; H, 8.75. Found: C, 73.67; H, 8.81.
Ack n ow led gm en t. We thank Dr. J ennifer Wytko
for her help in preparing the manuscript and the CNRS
and ULP for financial support.
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
data in CIF format for compound 22. This material is available
free of charge via the Internet at http://pubs.acs.org.
P r od u ct 36: starting material 34 + 35 (85 mg, 0.30 mmol),
temperature 520 °C, vacuum 10-2 Torr, product 36 (63 mg,
0.023 mmol, 74% yield), colorless oil; IR (CCl4) 1737, 1694,
1
1454 cm-1; H NMR (CDCl3, 300 MHz) δ 1.25 (t, J ) 7.1 Hz,
J O048923Q
J . Org. Chem, Vol. 69, No. 20, 2004 6721