Synthesis of variously substituted spirobenzocyclobutenes

Article abstract of DOI:10.1055/s-1998-2048

The cobalt(I)-mediated cocyclization between bis(trimethylsilyl)ethyne and monocyclic diyne 8 led to new spirobenzocyclobutene 9. This quite stable compound was easily transformed into variously substituted spirobenzocyclobutenes which are versatile synthetic intermediates. The full details of the preparation of such compounds are presented.

Full text of DOI:10.1055/s-1998-2048

FEATURE ARTICLE
436
Synthesis of Variously Substituted Spirobenzocyclobutenes
Phannarath Phansavath, Robert Stammler, Corinne Aubert, Max Malacria*
Université P. et M. Curie, Laboratoire de Chimie Organique de Synthèse, associé au CNRS, Tour 44–54, B. 229, 4,
place Jussieu 75252 Paris Cedex, France
Fax: +33(144)277360; E-mail: malacria@ccr.jussieu.fr
Received 17 October 1997; revised 18 January 1998
Abstract: The cobalt(I)-mediated cocyclization between bis(tri-
methylsilyl)ethyne and monocyclic diyne 8 led to new spiroben-
zocyclobutene 9. This quite stable compound was easily
transformed into variously substituted spirobenzocyclobutenes
which are versatile synthetic intermediates. The full details of the
preparation of such compounds are presented.
sively the tetracyclic compound, we thought that the
dienophile has to be set in the axial position and bear an
electron-withdrawing group. Thus, to prepare those vari-
ously substituted benzocyclobutenes, we attached a sub-
stituent such as an ester group to the cyclohexane which
was conceived to facilitate selective introduction of dif-
ferently susbtituted dienophiles and to render the equato-
rial/axial ratio more favorable.
Key words: cobalt(I), [2+2+2] cycloaddition, spirobenzocy-
clobutenes, orthoquinodimethanes, [4+2] cyclisation
Substituted benzocyclobutenes have been employed via Herein we present the full details of the preparation of
the intermediacy of o-xylylene isomers as versatile build- these substituted spirobenzocyclobutenes which are easy
ing blocks in the construction of complex molecules.1, 2 In to handle, quite stable compounds and versatile synthetic
connection with our ongoing program aimed at the rapid intermediates.
construction of the basic skeleton of tetracyclic diter-
As a target material, we chose the benzocyclobutene 10,
penes,3 we were interested in the stereoselective approach
prepared as depicted in Scheme 2.
of aphidicolin4 and stemodin 1,5 using a common synthet-
Commercially available ethyl 4-oxocyclohexane-
carboxylate8 was quantitatively protected as 1,3-diox-
olane 2. The quaternary center was created by alkylation
of the corresponding lithium ester enolate with propargyl
bromide leading quantitatively to compound 3. Reduction
of the ester function either with LAH or 2.2 equivalents of
DIBAH9 gave the corresponding alcohol and the follow-
ic pathway, based on cobalt-mediated alkyne cyclotrimer-
izations to give benzocyclobutenes in tandem with in-
tramolecular Diels–Alder cycloadditions involving the
resulting o-quinodimethane intermediates.6
Recently, we have shown7 that such a tandem strategy al-
lowed the formation of the stemodan skeleton (Scheme 1).
This synthetic sequence deserves various comments: (i) ing Swern oxidation afforded the aldehyde 5 in 97% yield.
the cobalt-mediated cocyclization between 1,2-bis(tri- It was transformed by chain extension to the alkyne using
methylsilyl)ethyne (BTMSE) and the monocyclic diyne Corey’s procedure.10 Reaction of 5 with carbon tetrabro-
led to substituted spirobenzocyclobutenes which have not mide–triphenylphosphine reagent furnished the interme-
been reported until now, (ii) when R = allyl, the intramo- diate dibromoalkene 6 in 97% yield. Reaction of this latter
lecular Diels–Alder reaction delivered an equal amount of with 3 equivalents of butyllithium and consecutive hy-
styrene derivatives resulting from a 1,5-hydrogen shift drolysis led to the diyne 7 in 95% yield. Subsequent treat-
and the stemodan framework; the ratio 1:1 meaning that ment with formic acid11 yielded quantitatively the ketone
the two processes have similar activation energy. To en- 8. Exposure of the latter to a catalytic amount of Cp-
sure the success of the [4+2] cyclization and to get exclu- Co(CO)2 in boiling 1,2-bis(trimethylsilyl)ethyne under ir-
Scheme 1

April 1998
SYNTHESIS
437
radiation led to the benzocyclobutene 9 in 75% yield. This hindered substrate, only traces of O-acylated compound
reaction can be run on gram scale, without affecting the were observed.
yield of the reaction. Acylation of the preformed lithium Having in hand this key benzocyclobutene, the next steps
enolate of 9 by methyl cyanoformate in diethyl ether12 in were devoted to the introduction of various substituents
the presence of HMPA at –100°C furnished the b-oxo es- bearing the dienophile moiety (Scheme 3). Alkylation of
ters 10 in 79% yield. Not surprisingly with this sterically the potassium enolate of 10 with propargyl bromide pro-
Biographical Sketches
Phannarath Phansavath was born in 1969 in Vientiane, Laos. She studied chemistry at
the Pierre & Marie Curie University (Paris VI). She received her Ph. D. in 1997 under
the direction of Professor Max Malacria, working on new approaches to taxanes, aphi-
dicolanes and stemodanes skeletons using cobalt-mediated [2+2+2] and [4+2] cycload-
ditions. She is currently working as a postdoctoral fellow in the group of Professor
Carsten Bolm at the Institut für Organische Chemie der RWTH Aachen, Germany.
Robert Stammler was born in 1965 and graduated from the Ecole Supérieure de Chimie
Industrielle de Lyon (ESCIL) in 1989. He received his Ph. D. degree in 1992 under the
supervision of Professor Max Malacria at the University Pierre & Marie Curie (Paris VI),
working on new approaches to the basic skeletons of aphidicolanes and stemodanes and
on cobalt-mediated Conia-ene type reactions. He is currently working in the Process De-
partment at Rhône-Poulenc Rorer, Vitry sur Seine (France), which he joined in 1992. His
interests include new synthetic routes, scale-up and development of new pharmaceutical
compounds.
Corinne Aubert was born in 1956 and graduated from the Ecole Nationale Supérieure
de Chimie de Strasbourg. She received her Ph. D. degree in 1985 at the University of
Paris-Sud, Orsay, under the direction of Dr. J.-F. Biellmann and Dr. J.-P. Bégué. She was
appointed by the CNRS in 1985 as Chargée de Recherches in the laboratory of Dr. J.-P.
Bégué and worked on fluorine chemistry. After doing postdoctoral research with Profes-
sor K. P. C. Vollhardt at the University of California, Berkeley from September 1987 to
1989, she joined the group of Professor Max Malacria at the University Pierre & Marie
Curie (Paris VI). Her research interests concern the new developments of transition met-
al-mediated reactions, the efficient approaches of basic skeletons of polycyclic natural
compounds and asymmetric synthesis.
Max Malacria was born in Marseille in 1949. He received his Ph. D. degree in 1974 at
the University of Aix-Marseille III under the supervision of Professor Marcel Bertrand.
From September 1974 to August 1981, he served as an Assistant and Maître Assistant at
the University of Lyon I and worked under the supervision of Professor Jacques Goré.
From September 1981 to December 1982, he worked as a postdoctoral fellow with Pro-
fessor K. Peter C. Vollhardt at the University of California, Berkeley. In 1983, he re-
turned to the University of Lyon I as a Maître de Conférences. In 1988, he was appointed
as a Professor at the University Pierre & Marie Curie (Paris VI). In 1991, he was elected
as a member of the “Institut Universitaire” de France. His current research interests in-
clude the development of new selective and efficient approaches to complex polycyclic
molecules, transition metal catalyzed reactions and asymmetric synthesis of natural com-
pounds of biological interests. In 1997, he received the award of the Organic Division of
the French Chemical Society.

438
Feature Article
SYNTHESIS
(a) HO(CH2)2OH, CSA, toluene, D, 20h, quant. (b) 1. LDA, THF,
–78°C; 2. C3H3Br quant. (c) LAH, Et2O, quant. (d) (COCl)2, DMSO,
NEt3, CH2Cl2, 97%. (e) CBr4, PPh3, CH2Cl2, 97%. (f) BuLi, THF,
95%. (g) HCO2H, CuSO4, pet. ether, quant. (h) CpCo(CO)2,
Me3SiCºCSiMe3, hv, D, 75%. (i) 1. LDA, Et2O, –78°C to 0°C; 2.
NCCO2Me, –100°C, HMPA, 79%.
Scheme 2
(a) 1. KH THF, 0°C; 2. C3H3Br, HMPA, D. (b) THF, 5 mol%
Pd(OAc)2, 20 mol% PPh3, diallyl carbonate. (c)1. NaH, THF, r.t.,
45 min; 2. ketone or ester, 5 mol% Pd(PPh3)4, THF
vided compound 11 as a 1:1 mixture of diastereomers in
75% yield.13
As we have already shown,7 introduction of the allyl sub-
stituent was a little troublesome and eventually Tsuji’s
procedure14 was found to be the most reproducible meth-
od. Allylation of the b-oxo ester 10 was carried out under
neutral conditions by using diallyl carbonate in the pres-
ence of a catalytic amount of Pd(0) [generated in situ from
5 mol% of Pd(OAc)2 and 20 mol% of triphenylphosphine]
Scheme 3
and furnished compound 12 as a 1.5:1 mixture of two dia-
stereomers 12a and 12b in 97% yield which were separat-
ed by flash column chromatography on silica gel. Their
structures were deduced from the assigned stereochemis-
try of their acetonide derivatives (see Scheme 4).
(a) LiAlH4, Et2O, 0°C. (b) 2,2-dimethoxypropane (100 equiv), acetone, cat. PPTS, r.t.
Scheme 4

April 1998
SYNTHESIS
439
On the other hand, allylation of 10 with 4-oxopent-2-enyl
benzoate15 was conducted under basic conditions and pro-
vided a 6:1 mixture of diastereomers (E)-13 and (Z)-13 in
73% yield. Adducts (E)-13 and (Z)-13 which were sepa-
rated, consisted of an inseparable 1:2 mixture of dia-
stereomers. Similarly, allylation of 10, under the same
conditions with 4-ethylbenzoyloxycrotonate15 led in 90%
yield to a 10:1 mixture of (E)-14 and (Z)-14 each of which
is a 1:2 mixture of diastereomers.
In order to force the dienophile to occupy an axial posi-
tion, we decided to reduce the b-oxo ester moiety and to
transform it into the corresponding acetonides. The con-
version of compounds 12a and 12b into their acetonides
is outlined in Scheme 4. Reduction of the b-oxo esters
with LAH in diethyl ether provided a 4.3:1 mixture of di-
E=CO2Me
Scheme 6
¢
astereomers 15a:15 a in 90% yield and a 2.5:1 mixture of
In summary, the cobalt(I)-mediated [2+2+2] cycloaddi-
tion reaction between bis(trimethylsilyl)ethyne and a
monocyclic diyne 8 allowed us to prepare a new spiroben-
zocyclobutene 9. We showed that this compound was
easy to handle, quite stable and that it was possible to car-
ry out a wide variety of reactions for further transforma-
tions. By reduction of the b-oxo ester moiety and its
transformation to the corresponding acetonides, we have
placed the dienophile in an axial position which in con-
nection with the synthesis of tetracyclic diterpenes in the
family of stemodane augurs well for the success of the in-
tramolecular [4+2] cyclization.
¢
diols 15b:15 b in 95% yield. Acid-catalyzed protection of
the diols with 2,2-dimethoxypropane in acetone led to the
¢
¢
corresponding acetonides 16a:16 a (4.3:1) and 16b:16 b
(2.5:1) in 90% and 88% yields, respectively. Elucidation
of these structures was fully established by decoupling ex-
periments and allowed us to determine the stereochemis-
try of the previous compounds 15 and 12 (vide infra).
In addition, ozonolysis of compound 16a furnished the al-
dehyde 17 in 57% yield. This latter was submitted to the
mild alkenation procedure of Masamune et al.16 by using
lithium chloride, DBU and either (2-oxopropyl)phospho-
nate or triethyl phosphonoacetate in acetonitrile to pro-
vide the (E)-a,b-unsaturated ketone 18 or ester 19 in 85%
yield (Scheme 5).
1H NMR and 13C NMR spectra were measured on 200 MHz Bruker
AC 200, 400 MHz JEOL 65X 400 and Bruker ARX 400 spectrome-
ters. Chemical shifts are reported in ppm referenced to the residual
proton resonances of the solvents. IR spectra were recorded by using
a Perkin Elmer 1420 spectrometer. Mass spectra (MS) were obtained
on GCMS Hewlett-Packard HP 5971 apparatus. TLC was performed
on Merck silica gel 60 F 254. Silica gel Merck Geduran SI
(40–63 mm) was used for column chromatography using Still meth-
od.17 PE and EE are petroleum ether and Et2O. The melting points re-
ported are uncorrected and the compounds are not recrystallized.
First studies confirm the validity of our synthetic strategy;
for example, substrate (E)-13(a+b) gave the Diels–Alder
product 20 in 19% yield accompanied by the 1,5-hydro-
gen shift product 21 (19%) (Scheme 6). This preliminary
result which was not optimized is very encouraging. We
are already engaged in the study aimed at improving the
ratio [4+2] / 1,5-hydrogen migration processes.
8-Ethoxycarbonyl-1,4-dioxaspiro[4.5]decane (2):
A solution of ethyl 4-oxocyclohexanecarboxylate (8.0 g, 47.0 mmol),
ethylene glycol (13.0 mL, 235 mmol) and (±)-10-camphorsulfonic
acid (102 mg, 0.5 mmol) in toluene (150 mL) was refluxed with a
Dean–Stark apparatus for 20 h. The solution was cooled and toluene
was evaporated. The residue was diluted with Et2O (200 mL) and
neutralized with sat. NaHCO3 (50 mL). The organic layer was washed
with brine (3 ´ 50 mL), dried (Na2SO4), filtered and concentrated.
The residue was purified by flash chromatography (PE/EE = 80/20)
to give 2 (10.1 g, 47.0 mmol, 100%).
1H NMR (400 MHz, CDCl3) d = 4.12 (q, J = 7.0 Hz, 2H), 3.93 (s, 4H),
2.33 (tt, J = 10.3, 4,0 Hz, 1H), 1.92 (m, 2H), 1.78 (m, 4H), 1.54 (td, J
= 11.8, 4.5 Hz, 2H), 1.24 (t, J = 7.0 Hz, 3H).
13C NMR (100 MHz, CDCl3) d = 175.0, 108.0, 64.3 (2C), 60.2, 41.6,
33.8 (2C), 26.3 (2C), 14.2.
IR (neat) n = 2960, 1730, 1190, 1110 cm–1.
8-Ethoxycarbonyl-8-(prop-2-ynyl)-1,4-dioxaspiro[4.5]decane (3):
At –78°C, a solution of 2 (5.8 g, 27.0 mmol) in THF (30 mL) was add-
ed dropwise to a solution of LDA (4.4 mL, 31.4 mmol) in THF
(30 mL). The mixture was slowly warmed to 0°C, then cooled to
–78 °C and a solution of propargyl bromide (2.3 mL, 30.5 mmol) in
THF (15 mL) was added dropwise over 15 min. The mixture was
stirred at –78°C for 1h, warmed to 0°C and diluted with Et2O (60 mL),
(a) O3, CH2Cl2, –78°C; Me2S, r.t., 30 h.
(b)LiCl,MeCN,CH3C(O)CH2P(O)(OEt)2 orEtOC(O)CH2P(O)(OEt)2,
then DBU, THF: MeCN (1:1), r.t., 48 h.
Scheme 5

440
Feature Article
SYNTHESIS
(2.25 g, 11.0 mmol, 95%) as a white solid, mp 39°C (PE/EE = 60/40).
1H NMR (400 MHz, CDCl3) d = 3.92 (m, 4H), 2.38 (d, J = 2.6 Hz,
2H), 2.21 (s, 1H), 2.09 (t, J = 2.6 Hz, 1H), 1.94 (m, 2H), 1.83 (m, 2H),
1.65 (m, 4H).
The organic layer was washed with sat. NH4Cl (2 ´ 30 mL) and brine
(2 ´ 30 mL), dried (Na2SO4), filtered and concentrated. The residue
was purified by flash chromatography (PE/EE = 70/30) affording 3
(6.8 g, 27.0 mmol, 100%) as a colorless oil.
13C NMR (100 MHz, CDCl3) d = 108.2, 87.1, 80.4, 70.9 (2C), 64.2
(2C), 35.4, 34.0 (2C), 31.8, 31.6 (2C).
1H NMR (400 MHz, CDCl3) d = 4.19 (q, J = 7.0 Hz, 2H), 3.93 (s, 4H),
2.42 (d, J = 2.6 Hz, 2H), 2.05 (t, J = 2.6 Hz, 1H), 2.18 (m, 2H), 1.66
(m, 6H), 1.27 (t, J = 7.0 Hz, 3H).
IR (CHCl3) n = 3300, 3280, 2960, 2120, 1100 cm–1.
13C NMR (100 MHz, CDCl3) d = 174.7, 108.2, 79.8, 71.2, 64.3 (2C),
60.7, 45.7, 31.8 (2C), 30.6 (2C), 28.9, 14.3.
4-Ethynyl-4-(prop-2-ynyl)cyclohexanone (8):
IR (neat) n = 3300, 2960, 2120, 1730, 1190 cm–1.
A solution of 7 (1.7 g, 8.3 mmol) and formic acid (12.0 mL, 40 equiv)
dried over anhyd CuSO4 in PE (6 mL) was stirred at r.t. for 20 min.
The mixture was diluted with hexane (100 mL), neutralized with
K2CO3 (5 g) and with sat. NaHCO3 (2 ´ 50 mL). The organic layer was
washed with brine (2 ´ 20 mL), dried (Na2SO4), filtered and concen-
trated.Thecruderesiduewaspurifiedbyflashchromatography(PE/EE
= 70/30) to yield 8 (1.2 g, 7.5 mmol, 90%) as a white solid, mp 57°C.
1H NMR (400 MHz, CDCl3) d = 2.78 (td, J = 14.7, 5.9 Hz, 2H), 2.52
(d, J = 2.6 Hz, 2H), 2.36 (s, 1H), 2.35 (m, 2H), 2.15 (m, 2H), 2.13 (t,
J = 2.6 Hz, 1H), 1.87 (td, J = 13.6, 4.2 Hz, 2H).
8-Hydroxymethyl-8-(prop-2-ynyl)-1,4-dioxaspiro[4.5]decane (4):
At 0°C, a solution of 3 (5.4 g, 21 mmol) in Et2O (70 mL) was added
dropwise to a suspension of LiAlH4 (0.42 g, 11.0 mmol) in Et2O
(70 mL). After being stirred at 0°C for 5 min, the mixture was diluted
with CH2Cl2 (140 mL) and hydrolyzed with sat. Na2SO4 until a white
suspension is formed. The mixture was filtered on Celite and concen-
trated. Recrystallization (Et2O) of the crude residue furnished 4
(4.5 g, 21.0 mmol, 100%) as a white solid, mp 67°C.
13C NMR (100 MHz, CDCl3) d = 210.5, 86.0, 79.8, 72.3, 71.7, 38.3
(2C), 36.2 (2C), 35.5, 31.6.
1H NMR (400 MHz, CDCl3) d = 3.94 (s, 4H), 3.58 (s, 2H), 2.29 (d, J
= 2.6 Hz, 2H), 2.02 (t, J = 2.6 Hz, 1H), 1.61 (m, 8H).
IR (CHCl3) n = 3280, 3260, 2940, 2120, 1730 cm–1.
13C NMR (100 MHz, CDCl3) d = 108.7, 81.6, 70.7, 67.4, 64.2 (2C),
36.9, 30.4 (2C), 29.2 (2C), 24.2.
IR (CHCl3) n = 3400, 3300, 2960, 2120, 1110 cm–1.
3,4-Trimethylsilylspiro[benzocyclobutene-1,1¢-cyclohexan-4¢-
one] (9):
Anal. Calcd for C12H18O3 : C, 68.54 ; H, 8.63. Found : C, 68.43 ; H, 8.67.
The reaction was carried out under Ar in a flame-dried flask, washed
with hexamethyldisilazane and all the solutions were degassed by
three freeze-pump-thaw cycles. A solution of diyne 8 (1.1 g,
6.8 mmol) and CpCo(CO)2 (85 mL, 0.7 mmol) in degassed BTMSE
(22 mL) and xylenes (22 mL) was added dropwise over 15 min to a
boiling degassed solution of BTMSE (30 mL) and CpCo(CO)2
(85 mL, 0.7 mmol). Light from a projector lamp (ELW, 300W, 60%
of its power) was directed at the mixture during the addition. After the
mixture was refluxed and irradiated for 3h, the solvent was removed
by vacuum transfer. The crude residue was purified by flash chroma-
tography (PE/EE = 90/10) to give the benzocyclobutene 9 (1.7 g,
5.1 mmol, 75%) as a white solid, mp 147 °C.
8-Formyl-8-(prop-2-ynyl)-1,4-dioxaspiro[4.5]decane (5):
A solution of DMSO (2.7 mL, 38.0 mmol) in CH2Cl2 (8 mL) was add-
ed dropwise at –78 °C to a solution of oxalyl chloride (1.6 mL,
18.6 mmol) in CH2Cl2 (40 mL). After 5 min, a solution of 4 (3.4 g,
16.0 mmol) in CH2Cl2 (16 mL) was added dropwise. After stirring at
–78 °C for 15 min, Et3N (11.0 mL, 80.0 mmol) was added quickly.
The mixture was warmed to r.t. (45 min), diluted with Et2O (250 mL),
washed with sat. NH4Cl (2 ´ 100 mL), brine (2 ´ 100 mL), dried
(Na2SO4), filtered and concentrated. Purification by flash chromatog-
raphy (PE/EE = 50/50) furnished 5 (3.2 g, 15.5 mmol, 97%) as a col-
orless oil.
1H NMR (400 MHz, CDCl3) d = 7.52 (s, 1H), 7.50 (s, 1H), 3.13 (s,
2H), 2.63–2.46 (m, 4H), 2.24–2.14 (m, 4H), 0.38 (s, 9H), 0.37 (s, 9H).
13C NMR (100 MHz, CDCl3) d = 211.4, 151.2, 145.9, 144.7, 141.4,
130.2, 127.1, 49.6, 41.8, 39.9 (2C), 35.8 (2C), 2.3 (6C).
IR (CHCl3) n = 2970, 1710, 1240, 840 cm–1.
1H NMR (400 MHz, CDCl3) d = 9.51 (s, 1H), 3.87 (s, 4H), 2.29 (d,
J = 2.6 Hz, 2H), 1.98 (t, J = 2.6 Hz, 1H), 2.01 (m, 2H), 1.64 (m, 6H).
13C NMR (100 MHz, CDCl3) d = 204.6, 107.9, 79.0, 71.5, 64.3 (2C),
47.7, 31.0 (2C), 27.8 (2C), 25.0.
IR (neat) n = 3300, 2960, 2720, 2120, 1730, 1100 cm–1.
Anal. Calcd for C19H30OSi2: C, 69.02; H, 9.15. Found: C, 69.38; H,
9.31.
MS (m/z) = 330, 315, 299, 131, 73, 59.
8-(2,2-Dibromoethenyl)-8-(prop-2-ynyl)-1,4-dioxaspiro[4.5]de-
cane (6):
Compound (10):
At 0°C, a solution of CBr4 (14.6 g, 44.2 mmol) in CH2Cl2 (40 mL)
was added dropwise to a solution of PPh3 (23.2 g, 88.4 mmol) in
CH2Cl2 (40 mL). After being stirred at 0°C for 30 min, a solution of
5 (4.6 g, 22.1 mmol) in CH2Cl2 (20 mL) was added dropwise. After
the mixture was stirred for 2.5 h at 0°C, it was diluted with pentane
(400 mL), filtered on Celite and concentrated. The residue was puri-
fied by flash chromatography (PE/EE = 80/20) to yield 6 (7.8 g,
21.4 mmol, 97%): white solid, mp 70 °C.
At –78°C, a solution of 9 (2.3 g, 6.9 mmol) in Et2O (9 mL) was added
dropwise to a solution of LDA (3.7 mL, 6.9 mmol) in Et2O (18 mL).
The mixture was warmed to 0°C and stirred at 0°C for 1h. After being
cooled to –100°C, HMPA (0.74 mL, 6.9 mmol) and methyl cyanofor-
mate (0.65 mL, 8.2 mmol) were added. After being stirred for 5 min
at –100°C, the mixture was hydrolyzed at –l00°C with sat. NH4Cl
and extracted with Et2O. The organic layer was washed with brine,
dried (Na2SO4), filtered and concentrated. The residue was purified
by flash chromatography (PE/EE = 90/10) affording a mixture of the
b-oxo ester 10 and its enol form 10¢ (2.0 g, 5.2 mmol, 79%) as a white
solid, mp 136 °C.
1H NMR (400 MHz, CDCl3) d = 6.56 (s, 1H), 3.94 (s, 4H), 2.50 (d,
J = 2.6 Hz, 2H), 2.01 (t, J = 2.6 Hz, 1H), 2.16 (m, 2H), 1.64 (m, 6H).
13C NMR (100 MHz, CDCl3) d = 141.8, 107.9, 87.6, 80.5, 70.7, 64.2
(2C), 41.8, 32.4 (2C), 31.3 (2C), 27.7.
IR (CHCl3) n = 3300, 3040, 2960, 2120, 1640, 1600, 1100 cm–1.
10: 1H NMR (400 MHz, CDCl3) d = 7.46 (s, 1H), 7.33 (s, 1H), 3.79
(d, J = 7.7 Hz, 1H), 3.72 (s, 3H), 3.03 (d, J = 13.7 Hz, 1H), 2.98 (d, J
= 13.7 Hz, 1H), 2.60–1.96 (m, 6H), 0.35 (s, 9H), 0.34 (s, 9H).
10¢: 1H NMR (400 MHz, CDCl3) d = 12.21 (s, 1H), 7.45 (s, 1H), 7.33
(s, 1H), 3.77 (s, 3H), 3.00 (s, 2H), 2.59–1.97 (m, 6H), 0.34 (s, 9H),
0.33 (s, 9H).
8-Ethynyl-8-(prop-2-ynyl)-1,4-dioxaspiro[4.5]decane (7):
To a cooled (–78°C) THF (70 mL) solution of dibromoalkene 6
(4.23 g, 11.6 mmol) was added dropwise a solution of BuLi (1.5 M in
hexane, 31 mL, 46.5 mmol). After stirring at –78°C for 15 min, the
mixture was allowed to warm to 0°C and partitioned between H2O
(150 mL) and hexane (150 mL). The organic layer was washed with
sat. NH4Cl (2 ´ 50 mL), brine (3 ´ 40 mL), dried (Na2SO4), filtered
and concentrated. Flash chromatography (PE/EE = 60/40) gave 7
(10+10¢) 13C NMR (100 MHz, CDCl3) d = 205.5, 172.8, 171.7, 152.0,
145.4, 144.5, 141.6, 129.9, 126.9, 96.7, 55.6, 51.3, 48.0, 42.7, 32.8,
30.8, 27.9, 2.3.
IR (CHCl3) n = 2980, 1730, 1660, 1620, 1250, 840, 760 cm–1.

April 1998
SYNTHESIS
resulting mixture was added dropwise to a solution of freshly pre-
441
Compound (11):
At 0°C, a THF (2.0 mL) solution of benzocyclobutene 10 (0.77 g, pared tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol)
2.0 mmol) was added dropwise to a suspension of KH (0.22 g, and either 4-oxopent-2-enyl benzoate (204 mg, 1.0 mmol) or 4-ethyl-
2.2 mmol) in THF (2.0 mL). After being stirred at r.t. for 30 min, the benzoyloxycrotonate (234 mg, 1.0 mmol) in THF (4 mL). The mix-
reaction was cooled at 0°C, then HMPA(1.4 mL, 8.0 mmol) and prop- ture was stirred for an additional 15 min and partitioned between sat.
argyl bromide (0.29 mL, 2.6 mmol) were successively added. The mix- NH4Cl (15 mL) and Et2O (10 mL). The organic layer was washed
ture was refluxed for 30 min, cooled to r.t., washed with sat. NH4Cl and with brine (2 ´ 15 mL), dried (MgSO4), filtered and concentrated.
extracted with Et2O. The organic layer was washed with brine, dried
Compound 13: Purification by flash chromatography (PE/EE = 60/
(Na2SO4), filtered and concentrated. The crude residue was purified by
40) furnished the a,b-unsaturated ketones 13 (73%) as a mixture of 4
flash chromatography (pentane/Et2O= 90/10) to furnish 11 (0.64 g, 1.5
diastereomers: (Z)-13 (0.05 g, 0.1 mmol, 10%), which is a mixture of
mmol, 75%) as a 1:1 mixture of two diastereomers 11a and 11b.
11a: 1H NMR (400 MHz, CDCl3) d = 7.46 (s, 1H), 7.34 (s, 1H), 3.78
1:2 diastereomers (Z)-13a and (Z)-13b and (E)-13 (0.30 g, 0.63 mmol,
63%), which is a mixture of 1:2 diastereomers (E)-13a and (E)-13b.
(s, 3H), 3.19 (d, J = 13.7 Hz, 1H), 3.08 (d, J = 13.7 Hz, 1H), 2.88–2.55
(Z)-13a: 1H NMR (200 MHz, CDCl3) d = 7.40 (s, 1H), 7.33 (s, 1H),
(m, 6H), 2.34 (d, J = 13.7 Hz, 2H), 2.04 (t, J = 2.7 Hz, 1H), 0.37 (s,
6.18–5.92 (m, 2H), 3.60 (s, 3H), 3.29–2.46 (m, 10H), 2.11 (s, 3H),
9H), 0.36 (s, 9H).
13C NMR (100 MHz, CDCl3) d = 205.9, 171.9, 150.4, 146.2, 144.9,
141.4, 130.0, 125.7, 79.6, 71.2, 58.4, 52.7, 48.6, 43.5, 41.4, 38.8,
0.31 (s, 9H), 0.30 (s, 9H).
13C NMR (50 MHz, CDCl3) d = 207.7, 199.1, 172.8, 150.5, 145.9,
144.4, 142.6, 140.9, 130.1, 128.5, 127.9, 59.4, 52.4, 49.1, 44.8, 42.9,
36.8, 25.4, 2.3 (6C).
11b: 1H NMR (400 MHz, CDCl3) d = 7.47 (s, 1H), 7.40 (s, 1H), 3.71
(s, 3H), 3.14 (d, J = 13.7 Hz, 1H), 3.04 (d, J = 13.7 Hz, 1H), 2.93–2.58
(m, 6H), 2.38 (d, J = 13.7 Hz, 2H), 2.04 (t, J = 2.7 Hz, 1H), 0.37 (s,
39.3, 37.2, 34.9, 31.0, 2.4 (6C).
(Z)-13b: 1H NMR (200 MHz, CDCl3) d = 7.40 (s, 1H), 7.27 (s, 1H),
6.18–5.92 (m, 2H), 3.69 (s, 3H), 3.29–2.46 (m, 10H), 2.14 (s, 3H),
0.30 (s, 9H), 0.28 (s, 9H).
9H), 0.36 (s, 9H).
13C NMR (50 MHz, CDCl3) d = 207.7, 199.0, 172.8, 150.5, 146.0,
144.7, 142.3, 141.6, 130.1, 128.6, 126.3, 58.9, 52.5, 48.9, 44.5, 41.3,
39.2, 37.2, 31.5, 29.8, 2.4 (6C).
13C NMR (100 MHz, CDCl3) d = 206.0, 171.8, 150.4, 145.9, 144.5,
140.8, 130.1, 128.1, 79.7, 71.5, 58.8, 52.7, 49.0, 43.4, 42.9, 39.0,
36.9, 25.4, 2.5 (6C).
(Z)-13(a+b): IR (CH2Cl2) n = 3020, 2980, 1710, 1610, 1420, 1250,
(11a+11b) IR (CHCl3) n = 2940, 2170, 1730, 1450, 1260, 840,
840 cm–1.
690 cm–1.
(E)-13a: 1H NMR (200 MHz, CDCl3) d = 7.47 (s, 1H), 7.37 (s, 1H),
6.83–6.74 (m, 1H), 5.99 (d, J = 16.2 Hz, 1H), 3.65 (s, 3H), 3.28–2.07
(m, 10H), 2.21 (s, 3H), 0.36 (s, 9H), 0.35 (s, 9H).
13C NMR (50 MHz, CDCl3) d = 207.2, 198.5, 172.2, 150.2, 145.9,
144.4, 142.9, 140.6, 134.5, 130.1, 128.0, 59.5, 52.4, 49.2, 45.2, 42.8,
39.5, 38.8, 37.3, 26.5, 2.4 (6C).
Compound (12):
At r.t. under Ar, Pd(OAc)2 (27 mg, 0.12 mmol) was added in one por-
tion to a solution of triphenylphosphine (133 mg, 0.5 mmol) in THF
(5 mL). After stirring for 5 min, a solution of 10 (0.94 g, 2.4 mmol)
in THF (25 mL) and diallyl carbonate (0.7 mL, 4.8 mmol) were add-
ed. The mixture was stirred for 20 min and then concentrated. The
crude residue was purified by flash chromatography (PE/EE = 95/5)
to afford 12 as a 1.5:1 mixture of diastereomers 12a (0.61 g,
1.4 mmol, 59%) and 12b (0.4 g, 0.9 mmol, 38%).
(E)-13b: 1H NMR (200 MHz, CDCl3) d = 7.46 (s, 1H), 7.33 (s, 1H),
6.83–6.74 (m, 1H), 6.01 (d, J = 15.7 Hz, 1H), 3.73 (s, 3H), 3.28–2.07
(m, 10H), 2.21 (s, 3H), 0.35 (s, 9H), 0.34 (s, 9H).
13C NMR (50 MHz, CDCl3) d = 207.2, 198.5, 172.2, 150.2, 146.3,
145.0, 142.7, 141.4, 134.5, 130.1, 126.2, 59.2, 52.6, 48.8, 44.6, 41.2,
39.0, 38.6, 37.3, 26.6, 2.4 (6C).
12a: white solid mp 93°C.
1H NMR (400 MHz, CDCl3) d = 7.47 (s, 1H), 7.39 (s, 1H), 5.82 (ddt,
J = 15.9, 11.0, 7.1 Hz, 1H), 5.04 (d, J = 11.0 Hz, 1H), 5.03 (d, J = 15.9
Hz, 1H), 3.66 (s, 3H), 3.08 (d, J = 13.7 Hz, 1H), 3.00 (d, J = 13.7 Hz,
1H), 2.95 (td, J = 13.7, 5.5 Hz, 1H), 2.80 (dd, J = 14.3, 2.7 Hz, 1H),
2.58 (dd, J = 13.7, 8.0 Hz, 1H), 2.54 (dt, J = 13.7, 3.7 Hz, 1H), 2.40
(dd, J = 13.7, 7.0 Hz, 1H), 2.13 (d, J = 14.1 Hz, 1H), 2.11 (m, 2H),
0.37 (s, 9H), 0.36 (s, 9H).
(E)-13(a+b): IR (CH2Cl2) n = 3040, 2950, 1720, 1710, 1670, 1620,
1430, 1250, 850 cm 1.
Anal. Calcd. for C26H38O4Si2: C, 66.34; H, 8.13. Found: C, 66.41 ; H,
8.26.
Compound 14: Purification by flash chromatography (PE/EE = 80/
20) furnished the a,b-unsaturated esters 14 (90%) as a mixture of 4
diastereomers: (Z)-14 (0.04 g, 0.08 mmol, 8%), which is a mixture of
l:2 diastereomers (Z)-14a and (Z)-14b and (E)-14 (0.41 g, 0.82 mmol,
82%), which is a mixture of 1:2 diastereomers (E)-14a and (E)-14b.
(Z)-14a: 1H NMR (400 MHz, CDCl3) d = 7.45 (s, 1H), 7.38 (s, 1H),
6.23–6.16 (m, 1H), 5.82 (d, J = 11.7 Hz, 1H), 4.17–4.12 (m, 2H), 3.65
(s, 3H), 3.27–2.07 (m, 10H), 1.38–1.24 (m, 3H), 0.36 (s, 9H), 0.35 (s,
9H).
13C NMR (100 MHz, CDCl3) d = 207.4, 172.5, 150.5, 145.5, 144.2,
140.6, 133.6, 129.9, 128.0, 118.4, 59.5, 52.0, 49.2, 44.4, 42.7, 40.1,
39.4, 37.2, 2.6 (3C), 2.4 (3C).
12b: colorless oil.
1H NMR (400 MHz, CDCl3) d = 7.46 (s, 1H), 7.33 (s, 1H), 5.81 (ddt,
J = 15.9, 11.0, 7.1 Hz, 1H), 5.04 (d, J = 11.0 Hz, 1H), 5.03 (d, J =
15.9 Hz, 1H), 3.73 (s, 3H), 3.30 (d, J = 13.7 Hz, 1H), 3.04 (d, J = 13.7
Hz, 1H), 2.85 (td, J = 13.7, 6.1 Hz, 1H), 2.72 (dd, J = 14.3, 2.7 Hz,
1H), 2.52 (dt, J = 13.7, 3.8 Hz, 1H), 2.60 (dd, J = 13.7, 8.2 Hz, 1H),
2.35 (dd, J = 13.7, 6.5 Hz, 1H), 2.19–2.11 (m, 3H), 0.36 (s, 9H), 0.35
(s, 9H).
13C NMR (50 MHz, CDCl3) d = 207.5, 172.6, 166.1, 150.4, 145.8,
144.4, 140.8, 130.0, 128.4, 126.2, 121.8, 59.9, 59.2, 52.3, 49.1, 44.6,
42.9, 39.2, 37.1, 34.3, 14.2, 2.4 (6C).
(Z)-14b: 1H NMR (400 MHz, CDCl3) d = 7.44 (s, 1H), 7.32 (s, 1H),
6.23–6.16 (m, 1H), 5.82 (d, J = 11.7 Hz, 1H), 4.17–4.12 (m, 2H), 3.73
(s, 3H), 3.27–2.07 (m, 10H), 1.38–1.24 (m, 3H), 0.35 (s, 9H), 0.33 (s,
9H).
13C NMR (100 MHz, CDCl3) d = 207.5, 172.5, 150.6, 145.5, 144.2,
140.6, 133.6, 129.9, 128.0, 118.4, 59.5, 52.0, 49.2, 44.4, 42.7, 40.1,
39.4, 37.2, 2.6 (3C), 2.4 (3C).
13C NMR (50 MHz, CDCl3) d = 207.3, 172.6, 166.1, 150.4, 145.8,
144.4, 141.4, 130.0, 128.4, 126.2, 121.8, 59.9, 58.7, 52.5, 48.8, 44.2,
41.3, 38.9, 37.1, 34.4, 14.4, 2.5 (6C).
(12a+12b): IR (CHCl3) n = 3080, 2960, 1740, 1720, 1640, 1460,
1250, 850 cm–1.
Anal. Calcd. for C24H36O3Si2: C, 67.24; H, 8.46. Found: C, 67.38; H,
8.65.
(Z)-14(a+b): IR (CH2Cl2) n =2950, 1720, 1640, 1430, 1180,
840 cm–1.
Compounds 13 and 14; General procedure:
(E)-14a: 1H NMR (400 MHz, CDCl3) d = 7.49 (s, 1H), 7.40 (s, 1H),
A solution of benzocyclobutene 10 (0.4 g, 1.0 mmol) in THF (2 mL) 6.96–6.88 (m, 1H), 5.85 (d, J = 16.9 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H),
was added dropwise to a suspension of NaH (60% in oil, 40 mg, 3.71 (s, 3H), 3.33–2.09 (m, 10H), 1.30 (t, J = 7.1 Hz, 3H), 0.39 (s, 9H),
1.0 mmol) in THF (2 mL). After being stirred for 45 min at r.t., the 0.38 (s, 9H).

442
Feature Article
SYNTHESIS
13C NMR (100 MHz, CDCl3) d = 206.7, 172.2, 165.9, 150.5, 145.9, 1H NMR (400 MHz, CDCl3) d = 7.42 (s, 1H), 7.39 (s, 1H), 5.78–5.69
144.4, 143.5, 140.8, 130.2, 128.2, 125.0, 60.4, 59.3, 52.5, 49.3, 44.8, (m, 1H), 5.10 (d, J = 17.3 Hz, 1H), 5.08 (d, J = 9.9 Hz, 1H), 3.84 (br
42.9, 39.5, 38.4, 37.4, 14.4, 2.5 (6C).
s, 1H), 3.74 (d, J = 12.1 Hz, 1H), 3.28 (d, J = 12.1 Hz, 1H), 3.16 (d, J
(E)-14b: 1H NMR (400 MHz, CDCl3) d = 7.48 (s, 1H), 7.36 (s, 1H), = 13.2 Hz, 1H), 3.01 (d, J = 13.2 Hz, 1H), 2.58 (d, J = 14.0 Hz, 1H),
6.96–6.88 (m, 1H), 5.85 (d, J = 16.9 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.32 (dd, J = 14.3, 7.7 Hz, 1H), 2.18 (m, 1H), 1.98 (dd, J = 14.3, 6.8
3.78 (s, 3H), 3.33–2.09 (m, 10H), 1.30 (t, J = 7.1 Hz, 3H), 0.38 (s, Hz, 1H), 1.83 (m, 1H), 1.68 (m, 1H), 1.57 (m, 1H), 1.51 (s, 3H), 1.47
9H), 0.37 (s, 9H).
(s, 3H), 1.44 (m, 1H), 0.35 (s, 18H).
13C NMR (100 MHz, CDCl3) d = 206.7, 172.2, 165.9, 150.6, 146.2, 13C NMR (100 MHz, CDCl3) d = 154.1, 144.9, 144.4, 142.1, 132.5,
145.0, 143.4, 141.6, 129.8, 128.6, 126.3, 60.4, 59.1, 52.7, 48.9, 44.4, 129.8, 126.3, 118.5, 97.9, 70.3, 68.5, 49.2, 43.9, 38.3, 34.9, 34.0,
41.4, 39.0, 37.4 (2C), 14.4, 2.5 (6C).
29.9, 29.8, 25.4, 19.0, 2.4 (6C).
(E)-14(a+b): IR (CH2Cl2) n = 2950, 1720, 1650, 1430, 1200, 850 cm–1. (16+16¢)a: IR (CHCl3) n = 3080, 2980, 1640, 1250, 11 10, 850 cm–1.
Anal. Calcd. for C27H40O5Si2: C, 64.76; H, 8.05. Found: C, 64.54 ; H, Acetonides 16b were obtained from diols 15b (0.44 g, 1.09 mmol) as
8.37.
a 2.5:1 mixture of diastereomers 16b and 16¢b (88%). 16b (0.36 g,
0.81 mmol, 63%): white solid, mp 143 °C.
1H NMR (400 MHz, CDCl3) d = 7.62 (s, 1H), 7.43 (s, 1H), 5.64–5.57
(m, 1H), 5.07 (d, J = 17.0 Hz, 1H), 5.02 (d, J = 10.1 Hz, 1H), 3.84 (m,
1H), 3.63 (d, J = 11.0 Hz, 1H), 3.42 (d, J = 11.0 Hz, 1H), 2.95 (d, J =
13.8 Hz, 1H), 2.89 (d, J = 13.8 Hz, 1H), 2.87 (dd, J = 13.7, 9.2 Hz,
1H), 2.71 (dd, J = 13.7, 5.7 Hz, 1H), 2.05–1.58 (m, 6H), 1.52 (s, 3H),
1.51 (s, 3H), 0.38 (s, 9H), 0.37 (s, 9H)
Diols (15); General Procedure:
The benzocyclobutenes 12a and 12b were reduced following the pro-
cedure described above for the preparation of compound 4. The diol
15a was obtained as a 4.3:1 mixture of 2 diastereomers 15a and 15¢a
(90%).
15a: 1H NMR (400 MHz, CDCl3) d = 7.41 (s, 1H), 7.30 (s, 1H),
5.97–5.90 (m, 1H), 5.26–5.12 (m, 2H), 3.89–3.85 (m, 1H), 3.64 (m,
1H), 3.46 (m, 1H), 3.25 (m, 1H), 3.04 (m, 1H), 2.65 (m, 1H), 2.30 (m,
lH), 1.84–1.33 (m, 8H), 0.35 (s, 9H), 0.34 (s, 9H).
13C NMR (100 MHz, CDCl3) d = 152.9, 145.4, 144.4, 142.0, 134.8,
129.9, 125.9, 118.2, 78.3, 71.6, 48.4, 43.7, 42.4, 36.7, 35.0, 29.7,
28.3, 2.4 (6C).
13C NMR (100 MHz, CDCl3) d = 152.1, 144.8, 144.1, 141.8, 134.4,
129.9, 129.4, 118.7, 99.6, 76.7, 68.7, 48.9, 44.7, 37.6, 37.4, 35.8,
30.0, 28.9, 25.4, 19.4, 2.4 (6C).
16¢b (0.14 g, 0.32 mmol, 25%): white solid, mp 114°C.
1H NMR (400 MHz, CDCl3) d = 7.55 (s, 1H), 7.45 (s, 1H), 5.70–5.60
(m, 1H), 5.02 (d, J = 17.0 Hz, 1H), 5.00 (d, J = 6.6 Hz, 1H), 3.93 (br
s, 1H), 3.79 (dd, J = 13.7, 9.2 Hz, 1H), 3.26 (d, J = 11.8 Hz, 1H), 2.97
(s, 2H), 2.53–1.52 (m, 8H), 1.49 (s, 3H), 1.47 (s, 3H), 0.38 (s, 9H),
0.36 (s, 9H).
1
15¢a: H NMR (400 MHz, CDCl3) d = 7.46 (s, 1H), 7.42 (s, 1H),
5.97–5.90 (m, 1H), 5.26–5.12 (m, 2H), 3.89–3.85 (m, 1H), 3.64 (m,
1H), 3.46 (m, 1H), 3.25 (m, 1H), 3.04 (m, 1H), 2.65 (m, 1H), 2.30 (m,
1H), 1.84–1.33 (m, 8H), 0.36 (s, 9H), 0.35 (s, 9H).
13C NMR (100 MHz, CDCl3) d = 153.2, 144.9, 144.1, 141.9, 134.1,
129.9, 125.5, 118.1, 78.3, 67.4, 48.9, 44.0, 42.1, 36.7, 35.0, 30.3,
29.3, 2.4 (6C).
13C NMR (100 MHz, CDCl3) d = 153.1, 144.6, 143.7, 142.3, 132.7,
130.1, 129.0, 118.3, 97.8, 70.1, 68.5, 49.7, 45.0, 38.1, 35.6, 34.9,
29.7, 29.6, 26.2, 19.1, 2.4 (6C).
Anal. Calcd. for C26H42O2Si2: C, 70.53 ; H, 9.56. Found: C, 70.58; H,
9.61.
(15+15¢)a: IR (CH2Cl2) n = 3620, 3520, 3080, 2960, 1650, 1250, 850
cm–1.
The diol 15b was obtained as a 2.5:1 mixture of 2 diastereomers 15b Compound (17):
and 15¢b (95%).
At –78°C, a stream of ozone was bubbled through a solution of 16a
15b: 1H NMR (400 MHz, CDCl3) d = 7.56 (s, 1H), 7.44 (s, 1H), (0.49 g, 1.10 mmol) in CH2Cl2 (17 mL) until a persistent blue color
5.81–5.71 (m, 1H), 5.19–5.03 (m, 2H), 3.91–3.88 (m, 1H), 3.64 (m, was perceived, indicating an excess of ozone. The excess ozone was
1H), 3.46 (m, 1H), 3.04–1.31 (m, 10H), 0.38 (s, 9H), 0.37 (s, 9H).
15¢b: H NMR (400 MHz, CDCl3) d = 7.44 (s, 1H), 7.34 (s, 1H), give a colorless mixture. Dimethyl sulfide (2.4 mL, 33 mmol) was
5.98–5.92 (m, 1H), 5.19–5.03 (m, 2H), 4.26 (m, 1H), 3.64 (m, 1H), added dropwise and the mixture was allowed to warm to r.t. After stir-
then chased away by bubbling N2 through the solution for 20 min, to
1
3.48 (m, 1H), 3.04–1.31 (m, 10H), 0.38 (s, 9H), 0.37 (s, 9H).
ring for 30 h, the reaction was concentrated. The crude residue was
(15+15¢)b: IR (CH2Cl2) n = 3620, 3520, 3080, 2960, 1650, 1250, purified by flash chromatography (PE/EE = 80/20) to afford aldehyde
850 cm–1.
17 (0.28 g, 0.63 mmol, 57%).
1H NMR (400 MHz, CDCl3) d = 10.07 (d, J = 1.7 Hz, 1H), 7.47 (s,
1H), 7.39 (s, 1H), 3.98 (d, J = 1.6 Hz, 1H), 3.85 (t, J = 7.8 Hz, 1H),
3.72 (d, J = 1.6 Hz, 1H), 3.29 (d, J = 16.5 Hz, 1H), 3.19 (d, J = 13.6
Hz, 1H), 3.11 (d, J = 13.6 Hz, 1H), 2.58 (dd, J = 16.5, 1.7 Hz, 1H),
1.99 (m, 2H), 2.05 (d, J = 14.2 Hz, 1H), 1.72 (m, 2H), 1.64 (d, J =
14.2 Hz, 1H), 1.58 (s, 3H), 1.52 (s, 3H), 0.41 (s, 18H).
13C NMR (100 MHz, CDCl3) d = 203.0, 152.5, 145.8, 144.7, 141.9,
130.2, 126.0, 100.0, 76.3, 69.2, 48.2, 45.0, 41.4, 39.9, 38.4, 37.6,
35.6, 25.3, 19.3, 2.6 (6C).
Acetonides (16); General Procedure:
To a solution of 15a (0.51 g, 1.3 mmol) in acetone (7.8 mL, 63.4 mmol)
and 2,2-dimethoxypropane (9.3 mL, 127 mmol) was added pyridinium
p-toluenesulfonate (16 mg, 0.06 mmol) at r.t. After stirring for 10 min,
acetone was evaporated and the crude residue was partitioned between
sat. NaHCO3 and Et2O. The organic layer was washed with brine, dried
(Na2SO4), filtered and concentrated. Purification by flash chromatogra-
phy (PE/EE = 95/5) led to the acetonides 16a. They were obtained as a
4.3:1 mixture of 2 diastereomers 16a and 16¢a (90%). 16a (0.42 g, 0.95
mmol, 73%): white solid, mp 140°C.
IR (CHCl3) n = 2940, 2720, 1720, 1450, 1250, 850 cm–1.
1H NMR (400 MHz, CDCl3) d = 7.43 (s, 1H), 7.33 (s, 1H), 5.88–5.80 Compounds 18 and 19; General Procedure:
(m, 1H), 5.25 (d, J = 16.9 Hz, 1H), 5.16 (d, J = 10.1 Hz, 1H), 3.85 (dd, To a solution of lithium chloride (31 mg, 0.74 mmol) [dried 2h at
J = 11.5, 3.8 Hz, 1H), 3.66 (d, J = 11.0 Hz, 1H), 3.44 (d, J = 11.0 Hz, 100°C under vacuum 1 mmHg] in MeCN (6 mL) was added dropwise
1H), 3.28 (d, J = 13.7 Hz, 1H), 3.07 (d, J = 13.7 Hz, 1H), 2.82 (dd, J a solution of either diethyl (2-oxopropyl)phosphonate (122 mg,
= 14.0, 7.5 Hz, 1H), 2.25 (dd, J = 14.0, 6.2 Hz, 1H), 1.97–1,57 (m, 0.74 mmol) or triethyl phosphonoacetate (166 mg, 0.74 mmol) in
4H), 1.79 (d, J = 14.1 Hz, 1H), 1.54 (s, 3H), 1.49 (s, 3H), 1.39 (d, J = MeCN (3 mL). To this resulting mixture, were added dropwise DBU
14.1 Hz, 1H), 0.37 (s, 9H), 0.36 (s, 9H).
(92 mL, 0.61 mmol) and a solution of aldehyde 17 (0.273 g,
13C NMR (100 MHz, CDCl3) d = 153.2, 145.7, 144.7, 142.3, 134.7, 0.61 mmol) in a 1:1 THF:MeCN mixture (6 mL). After being stirred
130.3, 126.1, 118.7, 99.7, 76.6, 68.8, 48.6, 45.0, 37.8, 36.6, 36.2, for 48 h at r.t., the mixture was hydrolyzed with sat. NH4Cl and ex-
30.2, 29.5, 25.2, 19.5, 2.7 (6C).
16¢a (0.098 g, 0.22 mmol, 17%): white foam.
tracted with Et2O. The organic layer was washed with brine, dried
(MgSO4), filtered and concentrated. Purification of the crude residue

April 1998
SYNTHESIS
443
by flash chromatography (PE/EE = 70/30) furnished either 18 (0.25
g, 0.52 mmol, 85%) or 19 (0.27 g, 0.52 mmol, 85%).
18: white foam.
(2) For the synthesis of polycyclic molecules, see:
Oppolzer, N.; Petrzilka, M.; Bättig, K. Helv. Chim. Acta 1977,
60, 2964.
Kametani, T.; Nemoto, H.; Ishikawa, H.; Shiroyama, K.;
Matsumoto, H.; Fukumoto, K. J. Am. Chem. Soc. 1977, 99,
3461.
Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1980, 102,
5245 and 5253.
Kametani, T.; Nemoto, H. Tetrahedron 1981, 37, 3.
Ito, Y.; Nakatsuka, M.; Saegusa, T. J. Am. Chem. Soc. 1982,
104, 7609.
1H NMR (400 MHz, CDCl3) d = 7.45 (s, 1H), 7.34 (s, 1H), 6.90 (m,
1H), 6.31 (d, J = 16.3 Hz, 1H), 3.89 (dd, J = 10.7, 4.6 Hz, 1H), 3.61
(d, J = 11. 1 Hz, 1H), 3.54 (d, J = 11.1 Hz, 1H), 3.21 (d, J = 13.7 Hz,
1H), 3. 11 (d, J = 13.7 Hz, 1H), 3.01 (m, 1H), 2.43 (m, 1H), 2.25 (s,
3H), 1.95–l.59 (m, 6H), 1.55 (s, 3H), 1.49 (s, 3H), 0.38 (s, 9H), 0.37
(s, 9H).
3C NMR (100 MHz, CDCl3) d = 195.6, 153.0, 145.6, 144.3, 143.1,
141.9, 134. 1, 130.3, 125.8, 99.4, 76.0, 68.4, 48.2, 44.8, 38.0, 36.4,
35.7, 29.9, 28.6, 27.0, 25.0, 19. 1, 2.4 (3C), 2.3 (3C).
IR (CHCl3) n = 2940, 1690, 1670, 1620, 1240, 840 cm–1.
Anal. Calcd. for C28H44O3Si2: C, 69.37; H, 9.49. Found: C, 69.49; H,
9.21.
Kametani, T.; Honda, T.; Shiratori, Y.; Matsumoto, H.; Fuku-
moto, K. J. Chem. Soc.. Perkin Trans. I 1981, 1386.
Kametani, T.; Kondoh, H.; Tsubuki, K.; Honda, T. J. Chem.
Soc., Perkin Trans. I 1990, 5.
Nemoto, H.; Satoh, A.; Ando, M.; Fukumoto, K. J. Chem. Soc.,
Perkin Trans. I 1991, 1309.
Kobayashi, K.; Itoh, M.; Suginome, H. J. Chem. Soc., Perkin
Trans 1. 1991, 2135.
Basha, F. Z.; McClellan, W. J.; DeBernardini, J. F. Tetrahedron
Lett. 1991, 32, 5469 and references cited in all of these publica-
tions.
19: white foam.
1H NMR (400 MHz, CDCl3) d = 7.47 (s, 1H), 7.36 (s, 1H), 7.01 (m,
1H), 6.06 (d, J = 15.7 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.89 (dd, J =
l0.6, 4.5 Hz, 1H), 3.64 (d, J = 11.7 Hz, 1H), 3.53 (d, J = 11.7 Hz, 1H),
3.26 (d, J = 13.7 Hz, 1H), 3. 12 (d, J = 13.7 Hz, 1H), 3.01 (m, 1H),
2.41 (m, 1H), 2.00–1.66 (m, 6H), 1.55 (s, 3H), 1.49 (s, 3H), 1.30 (s,
3H), 0.40 (s, 9H), 0.39 (s, 9H).
13C NMR (100 MHz, CDCl3) d = 166.3, 152.7, 145.9, 145.6, 144.7,
141.9, 130.2, 126.0, 124.9, 99.8, 76.3, 68.7, 60.3, 48.3, 44.9, 38.8,
36.6, 35.8, 29.9, 28.4, 25. 1, 19.3, 14.4, 2.5 (6C).
(3) Aubert, C.; Gotteland, J. P.; Malacria, M. J. Org. Chem. 1993,
58, 4298.
Cruciani, P.; Stammler, R.; Aubert, C.; Malacria, M. J. Org.
Chem. 1996, 61, 2699.
Cruciani, P.; Aubert, C.; Malacria, M. Synlett 1996, 105.
(4) Dalziel, W.; Hesp, B.; Stevenson, K. M.; Jarvis, J. J. Chem.
Soc., Perkin Trans. I 1973, 2841.
(5) Manchand, P. S.; White, J. D.; Wright, H.; Clardy, J. J. Am.
Chem. Soc. 1973, 95, 2705.
(6) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539.
(7) Stammier, R.; Halvorsen, K.; Gotteland, J.-P.; Malacria, M.
Tetrahedron Lett. 1994, 35, 417.
IR (CHCl3) n – 2940, 1710, 1640, 1240, 840 cm–1.
Compound (20):
A degassed solution of benzocyclobutenes (E)-13(a+b) (0.220 g,
0.47 mmol) in decane (10 mL) was heated at reflux for 12 h. The sol-
vent was removed by vacuum transfer and the crude mixture was pu-
rified by flash chromatography (PE/EE = 80/20) to afford 20 (43 mg,
0.09 mmol, 19%) and 21 (41 mg, 0.09 mmol, 19%).
20:
1H NMR (400 MHz, CDCl3) d = 7.53 (s, 1H), 7.41 (s, 1H), 3.73 (s,
3H), 2.93–1.72 (m, 12H), 2.29 (s, 3H), 0.36 (s, 9H), 0.35 (s, 9H).
13C NMR (100 MHz, CDCl3) d = 210.0, 207.3, 171.5, 144.7, 144.0,
139.6, 135.7, 135.6, 133.9, 64.2, 54.4, 52.2, 45.9, 45.4, 43.0, 41.0,
38.7, 35.4, 34.0, 29.8, 1.9, 1.8.
(8) It can be prepared in two steps:
Sanchez, I. H.; Ortéga, A.; Garcia, G.; Larraza, M. I.; Flores, H.
J. Synth. Comm. 1985, 15, 141.
Krapcho, M. P. Synthesis 1982, 805 and 893.
(9) When the reaction was run with 1 equiv of DIBAH in conditions
described by Baeckström, P.; Li, L.; Wickramaratne, M.; Norin,
T. Synth. Comm. 1990, 20, 423, we always obtained a mixture
of the starting material 3 and the alcohol 4.
IR (CHCl3) n = 2970, 1740, 1710, 1550, 1420, 1250, 850, 750 cm–1.
(10) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(11) Gorgues, A. Bull. Soc. Chim. Fr. 1974, 529.
(12) Crabtree, S. R.; Chu, W. L. A.; Mander, L. N. Synlett 1990, 169.
(13) In our hands, even in presence of HMPA, neither the lithio nor
the sodio enolate of 10 reacted with propargyl bromide.
(14) Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura, T.; Taka-
hashi, K. J. Org. Chem. 1985, 50, 1523.
Financial suport was provided by the CNRS and MRES. The authors
are indebted to Prof. J. C. Beloeil and Dr. O. Convert, Université
Pierre et Marie Curie for running H NMR decoupling experiments
1
of the acetonides 16.
(1) For reviews see :
(15) Kato, T.; Kimura, H. Chem. Pharm. Bull. 1977, 25, 2692.
(16) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Ma-
samune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183.
Oppolzer, W. Synthesis 1978, 793.
Funk, R. L.; Vollhardt, K. P. C. Chem. Soc. Rev. 1980, 9, 41.
Charlton, J. L.; Alauddin, M. M. Tetrahedron 1987, 43, 2873.
Martin, N.; Seoane, C.; Hanack, M. Org. Prep. Proced. Int.
1991, 23, 237.
(17) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.