Preparation of gem-dimethylcyclopropane-fused compounds through sigmatropic rearrangements. On/off-switching of the tautomerization of 3,4-homotropilidene by steric hindrance

Article abstract of DOI:10.1016/S0040-4020(02)01193-6

Cyclopropanation of 4,8,8-trimethylcycloheptatriene having an ether function at the 3-position by unsubstituted carbenoid addition resulted in a complex mixture mainly due to quick valence tautomerization of the produced 3,4-homotropilidene analogue durin

Full text of DOI:10.1016/S0040-4020(02)01193-6

Tetrahedron 58 (2002) 9279–9287
Preparation of gem-dimethylcyclopropane-fused compounds
through sigmatropic rearrangements. On/off-switching of the
tautomerization of 3,4-homotropilidene by steric hindrance
*
Tohru Futagawa, Norio Nishiyama, Akira Tai, Tadashi Okuyama and Takashi Sugimura
Graduate School of Science, Himeji Institute of Technology, 3-2-1 Kohto, Kamigori, Ako-gun, Hyogo 678-1297, Japan
Received 23 July 2002; accepted 11 September 2002
Abstract—Cyclopropanation of 4,8,8-trimethylcycloheptatriene having an ether function at the 3-position by unsubstituted carbenoid
addition resulted in a complex mixture mainly due to quick valence tautomerization of the produced 3,4-homotropilidene analogue during the
reaction. Dihalocarbene addition to the same substrate proceeded exclusively at the 3,4-position to give an adduct, where the tautomerization
process was interrupted by steric hindrance caused by the halogen substituents. Removal of the halogen atoms by reduction promotes the
tautomerization to give a gem-dimethylcyclopropane-fused product. Stereospecificity of the tautomerization was also demonstrated by
obtaining the product in an optically pure state. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
gem-Dimethylcyclopropane-fused carbocyclic compounds
are common in natural terpenes produced by cationic
cyclization of linear isoprenoids.1 Although a variety of
synthetic methods are available for cyclopropyl units,2
application thereof to the preparation of a gem-dimethyl-
cyclopropane is not always possible. For example, trans-
formation of a cycloalkene to a gem-dimethylcyclopropane-
fused cycloalkane by cycloaddition can be only possible for
Scheme 1.
specific substrates by the two-step procedure of 1,3-dipole
addition of 2-diazopropane and subsequent photolysis of the
adduct.3 We have assumed that gem-dimethylcyclopropane-
synthetic purposes. In this report, we would like to present a
fused cycloheptadiene, a key intermediate for various
natural products, can be prepared by using valence
tautomerization of bicyclo[5.1.0]octa-2,5-diene (3,4-homo-
tropilidene), which consists of a quick thermal [3,3]
sigmatropic rearrangement to convert the two cyclopro-
pane-fused compounds each other.4 This tautomerization
should proceed much faster through cisoid conformers than
through transoid conformers (Scheme 1), because of the
maximum overlap of the frontier orbitals at the transition
state.5 Hence, the reaction is strongly suggested to be
stereospecific, and is a potent useful tool for stereoselective
synthesis of a cyclopropyl compound.
highly regio-controlled cyclopropanation of a cyclohepta-
triene at the 3,4-position under the kinetic interruption of the
tautomerization by a steric fence. After the cyclopropana-
tion, removal of the fence caused the tautomerization to give
the desired gem-dimethylcyclopropane with a sufficiently
large equilibrium constant. The stereospecificity of this
rearrangement was also proved by obtaining an optically
active product.6
2. Reaction design
Substrate 1 was designed for the synthesis of 3, a key
intermediate for dimethylcyclopropane-fused natural
products such as ingenol.7 The silyloxy substituent at the
3-position of 1 is expected to promote electrophilic
cyclopropanation at the 3,4-position. Even if the cyclo-
addition to 1 proceeds with sufficiently high regioselectivity
(including suppression of the reaction as a valence isomer
The tautomerization of 3,4-homotropilidene has been well
studied for mechanistic interests, but has not been used for
Keywords: electrocyclic reaction; stereospecificity; steric effects;
cyclopropanes.
*
Corresponding author. Tel.: þ81-791-58-0168; fax: þ81-791-58-0115;
e-mail: sugimura@sci.himeji-tech.ac.jp
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01193-6

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Table 1. Calculated heats of formation (kcal/mol) for tautomers
standardized by that of the trans-conformer of the reactant at the AM-1
level
is 3.72 kcal/mol more stable than the 4,4-dimethyl tautomer
(the parent form of 2). Thus, the basic reaction design is
reasonable in the sense of thermodynamic control of the
tautomerization. In the present case with 2, the ether
function cooperates the control. The tautomerization
process from 2 to 3 is mimicked by a MO calculation at
the AM-1 level of the conformational pairs of the two
tautomers. Heats of formation for the process starting with
transoid-2 are calculated, and the relative values are given
in Table 1 (entry 1) after standardization with that of
transoid-2. The results suggest that the tautomerization of 2
to give 3 through their cisoid-conformers occurs readily. In
contrast, when a halogen atom is placed at the exo-8-
position of 2 (5–7), the cisoid-conformers of the reactant
and rearranged compound are not even energy minimum
structures. By applying the structure of cisoid-2 skeleton
(Fig. 1), the energy of cisoid-6 of the dibromo-analogue is
estimated to be ca. 30 kcal/mol higher than that of transoid-
6. Thus, the tautomerization through the cisoid-conformer is
expected to be inhibited unless the halogen substituent at the
exo-8-position is removed (Scheme 2).
Entry
Reactant
cisoid
Tautomer
cisoid
transoid
1
2
3
4
5
2
5
6
7
8
1.94
a
212.44
–
217.68
29.23
25.56
29.78
216.23
a
–
(ca. 30)a,b
–
a
a
a
–
2.33
–
23.29
a
Energy minimum is not found for the conformer.
Estimated energy using the structure of cisoid-2.
b
Figure 1. Structure of cisoid-2 obtained by AM-1.
3. Results and discussion
4), over-reactions leading to the second and third cyclo-
propanations as well as the decomposition of the product
should also be considered. Under the cyclopropanation
conditions, the unconjugated olefins of the produced 2 may
be more reactive than the 3,4-position of 1, and unconju-
gated enol ether of 3 must be much more reactive. Thus, the
rapid tautomerization from 2 to 3 is a disadvantage in a
sense for the chemoselective cyclopropanation of 1, and
should be interrupted during the cyclopropanation reaction.
3.1. Regioselective cyclopropanation of cycloheptatriene
Precursor 1 was prepared from 9 in four steps as shown in
Scheme 3. Enol ether formation from 9 (94% yield)
followed by chloromethylcarbenoid addition gave a
diastereomeric mixture of 10 (72%) in a ratio of exo/
endo¼6/4 (the exo-isomer has the chlorine substituent at the
inner position of the bicyclo ring). The ring expansion of 10
needs a comment because standard conditions8 of the
thermal reaction, refluxing methanol in the presence of
triethylamine, afforded 11 only in 24% yield. The low yield
is attributable both to the instability of 11, which is further
transformed to 12 and to the low reactivity of endo-10, the
minor isomer. After several attempts, we have found that
treatment of exo-10 with tetrabutylammonium fluoride
(TBAF) at room temperature under anhydrous conditions
gives 11 in quantitative yield. Under the same conditions,
endo-10 can be converted to 11 in 50% yield, where simple
de-silylation is the side reaction. When the diastereomeric
mixture of 10 as obtained was treated with TBAF, 11 was
obtained in 62% yield. Fixation of the enol form of 11 with
To prevent the tautomerization during the cyclopropanation
reaction and to turn it on after the reaction, we introduced an
on/off-switch by steric hindrance. Since the tautomerization
should take place through cisoid-conformers, substitution of
2 at the exo-8-position (inner position of the bicyclo ring) to
cause steric overlap with the endo-4-methyl in the transition
state is expected to interfere with the tautomerization;
removal of the substituent after the cyclopropanation will
give 3.
By ab initio MO calculations at the HF/6-31G level, 8,8-
dimethylbicyclo[5.1.0]octa-2,5-diene (the parent form of 3)
Scheme 2.

T. Futagawa et al. / Tetrahedron 58 (2002) 9279–9287
9281
Scheme 3.
the t-butyldimethylsilyl (TBS) group gave cyclic triene 1 in
96% yield.
should proceed via an oxy-anion intermediate, which is
expected to enhance the rate of the tautomerization.9 Under
these conditions, the obtained products did not include the
dimethylcyclopropane skeleton, but were 14 and 15.
Cyclopropanation of 1 with an unsubstituted carbenoid
resulted in a complex mixture consisting of poly-cyclopro-
panated compounds. For example, when 1 was treated with
Et2Zn and CH2I2 in ether at room temperate, more than five
products were formed. The reactions with other reagents,
Zn–Cu/CH2I2, Sm/CH2I2, Sm/CH2Cl2/HgCl2, or AlMe3/
CH2I2, also resulted in a complex mixture or recovery of the
reactant.
3.2. Tautomerization by removing the steric fence
Now, the steric fence inhibiting the tautomerization of 5–7
is removed by replacing a halogen atom at the inner-exo-
position with a hydrogen. Dehalogenation of 5 and 6 was
performed by reduction with metallic sodium and methanol
in ether at 08C. During the reaction, only one product was
detected by TLC analysis, and was assigned as 3. However,
extraction and purification by silica gel chromatography
promoted decomposition of 3 to reduce its isolated yield.
The highest isolated yield of 3 was 33% from 5 and 29%
from 6 after purification. The major side product did not
contain the TBS group, and was identified as 20, which is
derived from 3. If the recovered amount of 5 (10–30% in
most cases) is considered, the combined yield of 3 and 20 is
very high. Reduction of 5 or 6 with metallic lithium in liquid
ammonia gave a similar result to that with sodium, but the
isolated yield of 3 is somewhat lower; 28% from 5 and 26%
from 6.
In contrast, the reaction of 1 with dihalocarbene proceeded
smoothly. Under the conventional procedure for a gener-
ation of dichlorocarbene (aqueous NaOH solution and
benzlytriethylammonium chloride catalyst with CHCl3),
adduct 5 was obtained in 98% isolated yield. Use of
bromoform instead of chloroform gave adduct 6 in 98%
yield. These high yields with no side products are quite
satisfactory from a synthetic point of view. The reaction of
zinc mono-bromocarbenoid by the treatment of 1 with
Et2Zn and CHBr3 under dry air gave adduct 7 in 26% yield.
Interestingly, 7 was stereochemically pure, and its dia-
stereomer 8 was not found in the reaction mixture. This
apparent stereoselectivity could be due to the over-reaction
of the endo-bromo-isomer 8 through its tautomerization,
and as a result, unreactive exo-isomer 7 remains.
Dehalogenation of 6 is also possible by metalation at the
8-position and subsequent protonation. When 6 was treated
with a 1 equiv. of butyllithium at 2958C followed by the
treatment with water at the same temperature, unreacted 6
and product 7 was obtained in a 1 to 1 ratio (ca. 60% yield
for the mixture). This procedure is not recommended for
practical synthesis of 7 due to the difficulty in the separation
of 6 and 7. When the amount of butyllithium was increased
to 2.5 equiv., yields of both 6 and 7 were decreased (6% as a
1 to 1 mixture). Under these conditions, the major products
were 16 (29.3%) and 17 (20.5%). When the reaction mixture
The thermal stability of adducts 5 and 6 were enough to
handle them at ambient temperature, and they are stable
even at 1008C. When a benzene-d6 solution of 6 in a sealed
NMR tube was heated at 1308C, 6 was converted to 13 with
a half-life of 6 h (ca. 70% yield). In the presence of
tetramethylethylenediamine, the reaction to give 13 became
faster (t1/2¼3.3 h, quantitative yield). Treatment of 5 or 6
with TBAF in anhydrous THF to result in de-silylation
Scheme 4.

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T. Futagawa et al. / Tetrahedron 58 (2002) 9279–9287
3.3. Chiral approach for the synthesis of optically active
products
The results using an achiral substrate 1 suggest that the
tautomerization only proceeds through cisoid conformers
and should be stereospecific. To directly prove the
stereospecificity of the tautomerization, optically active
compounds corresponding to 5 were prepared. Acetal 22
was prepared from (2R,4R)-2,4-pentanediol and ketone 2110
(77.8%). Dibromination of 22 with excess pyridinium
perbromide (87%) followed by debromination with potas-
sium t-butoxide in DMSO afforded 23 (22%). The low yield
of 23 is due to the formation of an exo-methylene product.
Treatment of 23 with trimethylsilyl trifluoromethane-
sulfonate in the presence of triethylamine followed by
de-silylation resulted in chiral starting material 24 (70%).
Dichlorocarbene addition to 24 was again highly regio-
selective to give a diastereomeric mixture of 25 in a ratio of
2.3/1 (100%). Each diastereomer of 25 was isolated and
reduced with sodium/methanol to give 26a or 26b in
33–36% yield. Each isomer of 26 and their derivative 27 are
Scheme 5.
with 1 equiv. of butyllithium was warmed up to 08C before
the protonation, the product was sharply switched to 18
(36.2%). Other isolated compounds from this reaction were
6 and 7 (isolated as a 1 to 1 mixture, ca. 10%). All products
in this series of reactions can be understood by the reaction
from a lithiated intermediate shown in Scheme 4 and a
carbene produced from it; thus, there is no evidence that
tautomerization occurred during the reaction. However,
when 7 was treated with sec-butyllithium (ca. 1 equiv.) in
ether at 2708C, 3 was obtained (ca. 30% yield) after
treatment with water at the same temperature. Increase of
the reagent drastically decreased the yield of 3 and gave a
complex mixture. Radical reduction, such as tributyltin
hydride with azobisisobutyronitrile, can also replace a
halogen atom with a hydrogen atom, but reaction of 7 with
these reagents only induced decomposition.
1
over 97% diastereomerically pure deduced from their H
NMR spectra. Thus, stereospecificity of the tautomerization
of 3,4-homotropilidene has been for the first time experi-
mentally established. From 27a, optically active 19, 20 and
their dihydro derivative were obtained. Since the stereo-
chemistries of 20 and its dihydro derivative are known,
structures of the present products can be assigned as shown
in Scheme 6.
The formation of 3 by the reductive dehalogenations with
metallic sodium or lithium must be a result of the formation
and the rapid tautomerization of 2. The H NMR of 3 was
not changed until 2958C. The spectrum was also unchanged
up to 1008C for several hours. By these experiments, the
tautomerization from 2 to 3 is confirmed to be quick, but
practically irreversible as expected from the MO calcu-
lations. By conventional methods, 3 was converted to two
ketones, 19 and 20, in high yields. The 1H and 13C spectra of
obtained 20 were identical with reported ones (Scheme 5).7
1
4. Conclusions
The present study demonstrates synthetic use of the
tautomerization of 3,4-homotropilidene. The results display
Scheme 6.

T. Futagawa et al. / Tetrahedron 58 (2002) 9279–9287
9283
that the kinetic control of the tautomerization is indis-
pensable for achievement of a highly selective synthesis of
the desired product by cyclopropanation. Stereoselective
cyclopropanation of 24 with zinc carbenoid11 would be
difficult to obtain a singly cyclopropanated product deduced
from the result of the reaction with 1. Actually, the second
cyclopropanation could not be interrupted even under well-
optimized conditions for an analogue of 24.12 Development
of a proper method for the stereoselective cyclopropanation
inhibiting over-reactions will enhance the versatility of the
present system.
1008C; endo-10, 6.59 min, exo-10, 5.44 min). A part of the
mixture was purified by silica gel chromatography (hexane).
endo-10 (first eluate): IR (neat) 2950, 2930, 2860, 1460,
1470, 1400, 1250, 1220, 1180, 1140, 1090 cm21. 1H NMR
(CDCl3) d 5.67–5.66 (m, 2H), 1.93 (dd, J¼14.7, 10.8 Hz,
1H), 1.54 (ddd, J¼10.8, 4.9, 1.5 Hz, 1H), 1.44 (s, 3H), 1.41
(dd, J¼14.7, 4.9 Hz, 1H), 1.10 (s, 3H), 0.92 (s, 3H), 0.20 (s,
9H). 13C NMR d 142.12, 123.50, 59.02, 52.39, 35.42, 30.63,
30.48, 30.15, 28.53, 18.82, 1.19. High-MS calcd for
C13H23OClSi 258.1207, observed 258.1205. exo-10 (second
eluate): IR (neat) 2950, 2930, 2860, 1460, 1400, 1380, 1250,
1200, 1110, 1070 cm21. 1H NMR (CDCl3) d 5.66–5.65 (m,
2H), 1.92 (dd, J¼15.1, 10.3 Hz, 1H), 1.69 (s, 3H), 1.66 (dd,
J¼15.1, 4.4 Hz, 1H), 1.19 (ddd, J¼10.3, 4.4, 1.5 Hz, 1H),
1.11 (s, 3H), 0.96 (s, 3H), 0.17 (s, 9H). 13C NMR (CDCl3) d
141.39, 123.54, 60.46, 56.16, 35.95, 30.42, 30.19, 30.03,
27.70, 23.92, 1.31. High-MS calcd for C13H23OClSi
258.1207, observed 258.1205. The reaction mixture was
employed for the next step after passing through a silica gel
pad eluted with hexane.
5. Experimental
5.1. General
All temperatures are uncorrected. 1H NMR (400 MHz) and
13C NMR (100 MHz) spectra were recorded on a JEOL
GX-400 spectrometer. IR spectra were obtained on a
JASCO FT/IR-410 spectrometer. Mass spectra were
obtained on a JEOL JMS-AX-505HA. Optical rotations
were measured on a Perkin–Elmer 243B polarimeter.
Analytical GLC was conducted with a Shimadzu gas
chromatograph GC-17A using a capillary column. The
MPLC was carried out using an FMI pump (10 mL/min) and
a Lobar column (MERCK Si-60 type B). (2R,4R)-Pentane-
diol was obtained by the hydrogenation of 2,4-pentanedione
over (R,R)-tartaric acid-modified Raney nickel followed by
three recrystallizations (.99.6% ee).13 All solvents were
purified by distillation. Reactions were carried out under a
dry nitrogen atmosphere. Energy minimization was per-
formed on a PC using MOPAC93 with Gaussian 98W.
5.1.2. Preparation of dienone 11. To a solution of 10 (a
diastereomeric mixture, 2.11 g, 9.31 mmol) in dry THF
(42 mL) was added K2CO3 (1.41 g, 10.25 mmol) and
tetrabutylammonium fluoride (0.28 M in THF, 43.7 mL,
12.2 mmol) at room temperature. After 1.5 h, the reaction
mixture was extracted with ether (400 mL£2) and washed
with water (400 mL£2). Drying over Na2SO4 and silica gel
column chromatography (elution with 3% ethyl acetate in
hexane) gave 11 as a colorless oil (868 mg, 62.0% yield)
and de-silylated product from endo-10 (280 mg). Data for
11: IR (neat) 2950, 2930, 2870, 1660, 1640, 1620, 1470,
1450, 1410, 1380, 1360, 1230, 1080 cm21 1H NMR
.
(CDCl3) d 6.36 (m, 1H), 6.24 (dm, J¼12.2 Hz, 1H), 5.92
(d, J¼12.2 Hz, 1H), 2.42–2.40 (m, 2H), 1.90 (m, 3H), 1.14
(s, 6H). Anal. calcd for C10H14O C: 79.96, H: 9.39, found C:
79.30, H: 9.50. Data for the de-silylated product from endo-
10: IR (neat) 3400, 2950, 2930, 2860, 1470, 1380, 1360,
5.1.1. Preparation of 10. A solution of LDA was prepared
from diisopropylamine (54.5 mL, 389 mmol) and butyl-
lithium (1.59 M in hexane, 225 mL, 258 mmol) in THF
(780 mL) at 2788C. To this solution, 4,4-dimethylcyclo-
hex-2-en-1-one (9) (40.04 g, 322 mmol) in THF (32 mL)
was added in 20 min. After 1 h, freshly distilled trimethyl-
silyl chloride (70 mL, 552 mmol) was added in 10 min; then
the resulting solution was allowed to warm up to room
temperature. After concentration of the reaction mixture
under vacuum, the residue was suspended in pentane and
filtered through Celite. The filter cake was washed twice
with pentane (100 mL). Evaporation of the combined filtrate
gave 68.72 g of a yellow oil. Distillation of the oil gave
59.45 g of the enol silyl ether as a colorless oil (64–
658C/6 Torr, 93.9% yield). IR (neat) 3050, 2950, 1660,
1180, 1120, 1090 cm21 1H NMR (CDCl3) d 5.80 (dd,
.
J¼9.8, 1.0 Hz, 1H), 5.65 (dd, J¼9.8, 1.5 Hz, 1H), 1.94 (ddd,
J¼14.7, 10.3, 1.0 Hz, 1H), 1.54 (ddd, J¼10.3, 5.4, 2.0 Hz,
1H), 1.51 (s, 3H), 1.40 (dd, J¼14.7, 5.4 Hz, 1H), 1.12 (s,
3H), 0.94 (s, 3H).
5.1.3. Preparation of triene 1. To a mixture of 11 (1.00 g,
6.65 mmol) and triethylamine (1.21 mL, 8.71 mmol) in dry
CH2Cl2 (17 mL) was added t-butyldimetylsilyl trifluoro-
methanesulfonate (1.64 mL, 7.16 mmol) at 08C. After 1 h,
cold saturated aqueous NaHCO3 solution was added to the
reaction mixture. Extraction with CH2Cl2 (50 mL£2),
washing with water (30 mL£2), drying over Na2SO4, and
silica gel column chromatography (elution with hexane)
gave 1 as a colorless oil (1.72 g, 96.2% yield). IR (neat)
2960, 2930, 2900, 2860, 1630, 1550, 1480, 1400, 1380,
1
1400, 1380, 1260, 1210, 900 cm21. H NMR (CDCl3) d
5.55 (m, 2H), 4.79 (t, J¼4.9 Hz, 1H), 2.12 (d, J¼4.9 Hz,
2H), 1.01 (s, 6H), 0.19 (s, 9H). Anal. calcd for C11H20OSi C:
67.29, H: 10.27, found C: 67.42, H: 10.30. A mixture of the
enol silyl ether (20.92 g, 107 mmol) and 1,1-dichloroethane
(28.7 mL, 341 mmol) in dry ether (41 mL) was cooled to
2408C. To this solution, a solution of butyllithium (1.59 M
in hexane, 134 mL, 213 mmol) was added for 2.5 h. The
reaction mixture was allowed to warm up to 08C, and then,
100 mL of water was added. Extraction with ether
(200 mL£3), washing with water (100 mL£2), drying
(Na2SO4), and concentration gave a mixture of crude 10
as a diastereomeric mixture. The isomer ratio of 10 was
determined by GLC to be exo/endo¼6/4 (PEG 20 M, 25 m,
1260, 1220, 1180 cm21 1H NMR (CDCl3) d 5.89 (d,
.
J¼10.3 Hz, 1H), 5.84 (d, J¼10.7 Hz, 1H), 5.14 (d,
J¼10.7 Hz, 1H), 5.00 (d, J¼10.3 Hz, 1H), 1.93 (s, 3H),
1.00 (s, 6H), 0.98 (s, 9H), 0.12 (s, 6H). Anal. calcd for
C16H28OSi C: 72.66, H: 10.67, found C: 72.12, H: 10.80.
5.1.4. Dichlorocarbene addition to 1 to give 5. To a
solution of 1 (305 mg, 1.14 mmol) in chloroform (9 mL)
was added benzyltriethylammonium chloride (75 mg) at

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T. Futagawa et al. / Tetrahedron 58 (2002) 9279–9287
08C. To this solution, cold 50% aqueous NaOH (8.5 g) was
added in 5 min under sufficient stirring. After 1 h at 08C and
then 2 h at room temperature, the mixture was diluted with
water (20 mL), and then extracted with CH2Cl2 (50 mL£4).
The organic layer was washed with water (50 mL£2), dried
over Na2SO4, and then concentrated. Purification of the
crude product by silica gel column chromatography (elution
with hexane) gave 397 mg of 5 as a colorless oil (99.1%
yield). IR (neat) 2960, 2930, 2850, 1480, 1470, 1260, 1200,
13C NMR (CDCl3) d 150.97, 137.83, 135.39, 132.31,
128.70, 124.19, 118.65, 110.95, 26.24, 25.86, 20.71, 19.20,
18.44, 23.76. High-MS calcd for C17H27OBrSi 354.10145,
observed 354.10160.
5.1.8. Reaction of 5 and 6 with TBAF. Dihalocarbene
adduct, 5 or 6, was treated with 5–7 equiv. of tetrabutyl-
ammonium fluoride (TBAF) in dry THF at 08C for 30 min.
The mixture was extracted with ether, washed with water,
and dried over Na2SO4. A ratio of produced 14 and 15 was
determined by GLC analysis (PEG 20 M, 50 m, 1608C,
18.8 min for 14 (X¼Cl), 23.3 min for 15 (X¼Cl), 26.8 min
for 14 (X¼Br), and 53.9 min for 15 (X¼Br)). The products
were isolated by preparative GLC (OV-101, 2008C).
Compound 14 (X¼Cl): IR 3030, 2970, 2870, 1760, 1700,
1660, 1470, 1460, 1380, 1300, 1220, 1170 cm21. 1H NMR
(CDCl3) d 6.19 (s, 1H), 6.15 (dd, J¼12.9, 2.2 Hz, 1H), 5.97
(d, J¼12.9 Hz, 1H), 5.69 (dd, J¼12.2, 2.2 Hz, 1H), 5.39 (d,
J¼12.2 Hz, 1H), 1.48 (s, 3H), 1.29 (s, 3H), 1.24 (s, 3H). 13C
NMR (CDCl3) d 195.73, 149.38, 140.09, 125.27, 125.04,
78.79, 41.58, 40.53, 31.67, 29.55, 19.47. High-MS calcd for
C11H14OCl2 232.0423, observed 232.0421. Compound 15
(X¼Cl): IR 3000, 2970, 2930, 2870, 1660, 1470, 1380,
1
1180, 1140, 1110, 1100, 900 cm21. H NMR (CDCl3) d
5.85 (dd, J¼10.7, 1.0 Hz, 1H), 5.69 (d, J¼10.7 Hz, 1H),
5.64 (dd, J¼10.3, 1.0 Hz), 5.43 (d, J¼10.3 Hz, 1H), 1.38 (s,
3H), 1.32 (s, 3H), 1.17 (s, 3H), 0.97 (s, 9H), 0.24 (s, 3H),
0.20 (s, 3H). 13C NMR (CDCl3) d 145.02, 141.39, 127.93,
125.16, 70.14, 64.87, 39.32, 35.67, 32.09, 30.93, 25.94,
18.67, 17.80, 22.69, 23.14. Anal. calcd for C17H28OCl2Si
C: 58.78, H: 8.12, found C: 58.39, H: 8.20.
5.1.5. Dibromocarbene addition to 1 to give 6. To a
solution of 1 (322 mg, 1.20 mmol) in bromoform (10 mL)
was added benzyltriethylammonium chloride (114 mg) at
08C. To this solution, cold 50% aqueous NaOH (8.5 g) was
added in 3 min under sufficient stirring. After stirring 1 h at
room temperature, the mixture was diluted with water
(10 mL), and then extracted with CH2Cl2 (50 mL£4). The
organic layer was washed with water (50 mL£2), dried over
Na2SO4, and then concentrated. Purification of the crude
product by silica gel column chromatography (elution with
hexane) gave 514 mg of 6 as a pale yellow oil (97.2% yield).
IR (neat) 2960, 2930, 2850, 1480, 1470, 1260, 1200, 1170,
1140, 1110, 1100, 890, 860 cm21. 1H NMR (CDCl3) d 5.83
(dd, J¼11.0, 1.2 Hz, 1H), 5.65 (d, J¼10.5 Hz, 1H), 5.64 (dd,
J¼11.0, 1.2 Hz), 5.37 (d, J¼10.5 Hz, 1H), 1.41 (s, 3H), 1.31
(s, 3H), 1.17 (s, 3H), 0.92 (s, 9H), 0.29 (s, 3H), 0.20 (s, 3H).
High-MS calcd for C17H28OBr2Si 434.0276, observed
434.0277.
1240, 1130, 780 cm21 1H NMR (CDCl3) d 6.38 (d,
.
J¼12.2 Hz, 1H), 6.08 (d, J¼12.2 Hz, 1H), 5.86 (dd,
J¼11.2, 0.7 Hz, 1H), 5.49 (d, J¼12.2 Hz, 1H), 2.01 (d,
J¼0.7 Hz, 1H), 1.31 (s, 6H). 13C NMR (CDCl3) d 154.82,
140.48, 137.57, 129.31, 127.75, 124.90, 38.49, 28.94, 19.89.
High-MS calcd for C11H13OCl 196.0656, observed
196.0644. Compound 14 (X¼Br): IR 3030, 2970, 2930,
2870, 1760, 1700, 1660, 1470, 1450, 1380, 1290, 1200,
1
1160 cm21. H NMR (CDCl3) d 6.13 (dd, J¼12.9, 2.2 Hz,
1H), 6.07 (s, 1H), 5.99 (d, J¼12.9 Hz, 1H), 5.70 (dd,
J¼12.0, 2.2 Hz, 1H), 5.39 (d, J¼12.0 Hz, 1H), 1.54 (s, 3H),
1.31 (s, 3H), 1.23 (s, 3H). 13C NMR (CDCl3) d 198.37,
148.62, 140.39, 126.72, 124.82, 124.60, 54.32, 41.72, 31.13,
30.94, 29.06. High-MS calcd for C11H14OBr2 319.9411,
observed 319.9405. Compound 15 (X¼Br): IR 3000, 2960,
5.1.6. Monobromocarbenoid addition to 1 to give 7. To a
solution of 1 (216 mg, 0.82 mmol) in dry hexane (2 mL)
was added diethylzinc (1.0 M in hexane, 1.7 mL,
1.7 mmol). To the mixture after cooling it to 08C, bromo-
form (0.22 mL, 2.5 mmol) was added under bubbling of dry
air. After 5 min, the mixture was allowed to warm up to
room temperature, stirred for 20 min, and then treated with
saturated aqueous ammonium chloride (10 mL). Extraction
with ether (10 mL£3), drying over Na2SO4, and purification
by MLPC (elution with hexane) afforded 7 as a colorless oil
(74.7 mg, 26.4% yield). IR (neat) 2950, 2930, 2900, 2850,
1460, 1260, 1130, 860, 840, 780 cm21. 1H NMR (CDCl3) d
5.78 (dd, J¼10.8, 1.0 Hz, 1H), 5.67 (dd, J¼10.5, 1.0 Hz,
1H), 5.52 (d, J¼10.8 Hz, 1H), 5.23 (d, J¼10.5 Hz, 1H), 2.89
(s, 1H), 1.37 (s, 3H), 1.34 (s, 3H), 1.16 (s, 3H), 0.88 (s, 9H),
0.17 (s, 3H), 0.15 (s, 3H). High-MS calcd for C17H29OBrSi
356.1171, observed 356.1177.
1
2930, 2870, 1660, 1470, 1380, 1230, 1130, 770 cm21. H
NMR (CDCl3) d 6.34 (d, J¼12.0 Hz, 1H), 6.03 (d,
J¼12.0 Hz, 1H), 5.86 (dd, J¼11.2, 0.7 Hz, 1H), 5.44 (d,
J¼12.2 Hz, 1H), 2.00 (d, J¼0.7 Hz, 1H), 1.30 (s, 6H). 13C
NMR (CDCl3) d 154.12, 140.09, 136.44, 128.43, 128.12,
114.25, 38.59, 29.07, 21.71. High-MS calcd for C11H13OBr
240.0150, observed 240.0117.
5.1.9. Reduction of 5 (6) with sodium/methanol. A
solution of 5 (69.2 mg, 0.197 mmol) in ether (4 mL) was
cooled with ice-water bath. To this solution was added a
piece of sodium metal (195 mg, 8.48 mmol) followed by
dropwise addition of a mixture of methanol and water
(2.5 mL, 100/3.3) in 30 min. After 1 h, the mixture was
diluted with water (20 mL) and extracted with ether
(20 mL£4). Drying and evaporation under vacuum resulted
in a colorless oil (54.4 mg). Purification by MPLC on silica
gel (elution with hexane) gave 3 (18.3 mg, 32.9%) and 20
(13.8 mg, 42.6%) in addition to some recovered 5 (ca. 10%).
Reduction of 6 by this method proceeded similarly. Data for
3: IR (neat) 2960, 2930, 2860, 1670, 1480, 1470, 1340,
5.1.7. Thermolysis of 6. A solution of 6 (ca. 20 mg) in
benzene-d6 (0.5 mL) was sealed in an NMR tube, and the
tube was heated in an oil bath at 1308C. Reactant 6 was
1
completely converted to 13 after 17 h monitored by the H
NMR spectrometer. IR (neat) 2950, 2930, 2850, 1590, 1480,
1
1260, 1230, 1200, 1140, 1130 cm21. H NMR (CDCl3) d
1300, 1260, 1040 cm21
.
1H NMR (CDCl3) d 6.90 (d,
5.36 (m, 1H), 4.82 (m, 1H), 3.58 (dm, J¼16.8 Hz, 1H), 2.10
(dm, J¼16.8 Hz, 1H), 1.73–1.72 (m, 3H), 1.24–1.17 (m,
2H), 1.09 (s, 3H), 0.87 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H). 13C
J¼8.3 Hz, 1H), 6.68 (d, J¼8.3 Hz, 1H), 6.16 (8s, 1H), 2.32
(s, 3H), 1.88 (s, 3H), 1.63 (s, 3H), 1.05 (8s, 9H), 0.25 (s, 6H).

T. Futagawa et al. / Tetrahedron 58 (2002) 9279–9287
9285
NMR (CDCl3) d 152.62, 134.82, 121.89, 103.98, 39.09,
28.47, 27.63, 26.13, 25.76, 25.52, 19.25, 17.98, 16.51,
24.26, 24.52, High-MS calcd for C17H30OSi 278.2066,
observed 278.2066.
IR (neat) 2950, 2930, 2860, 1720, 1460, 1380, 1270, 1250,
1
1200 cm21. H NMR (CDCl3) d 5.51 (m, 1H), 3.57 (dm,
J¼16.1 Hz, 1H), 2.57 (d, J¼16.1 Hz, 1H), 2.51 (dd, J¼15.4,
6.6 Hz, 1H), 2.28 (dd, J¼15.4, 10.5 Hz, 1H), 1.74–1.73 (m,
3H), 1.30 (ddm, J¼8.6, 2.2 Hz, 1H), 1.09 (s, 3H), 1.00 (s,
3H), 0.91 (m, 1H). 13C NMR (CDCl3) d 209.41, 134.18,
123.35, 48.46, 38.52, 27.59, 25.74, 24.76, 22.78, 17.46,
15.79. High-MS calcd for C11H16O 164.1202, observed
164.1190.
5.1.10. Reduction of 5 (6) with lithium in ammonia. A
solution of lithium was prepared by addition of lithium
(32 mg, 4.63 mmol) to a mixture of ammonia (ca. 10 mL)
and dry ether (2 mL) at 2788C. A solution of 5 (244 mg,
0.693 mmol) in dry ether (2 mL) was added to this solution
over 5 min. After 30 min, sodium benzoate (1.01 g,
70.1 mmol) and pentane (15 mL) was added, and then,
ammonia was removed by warming the mixture to room
temperature. The resulting mixture was extracted with ether
(30 mL£5), washed with aqueous sodium bicarbonate
solution, dried over Na2SO4, and purified by column
chromatography on silica gel (elution with hexane). The
first eluate was further purified by MPLC (hexane) to give 3
(54.2 mg, 27.7%), and the second eluate was purified by
MPLC (10% ethyl acetate in hexane) to give 20 (40.8 mg,
35.8%). Reduction of 6 by this method proceeded similarly.
5.1.13. Preparation of 20 from 19. A mixture of 19
(10.2 mg) and K2CO3 (5 mg) in methanol–water (10/1,
1 mL) was stirred for 1 h at room temperature. Extraction of
the mixture with ether (5 mL £3) gave essentially pure 20
(9.6 mg, 95%). The product was further purified by a short
silica gel column (elution with 10% ethyl acetate in hexane).
IR (neat) 2980, 2950, 1660, 1650, 1620, 1460, 1440, 1380,
1
1290, 1200 cm21. H NMR (CDCl3) d 5.87 (m, 1H), 2.71
(ddd, J¼13.9, 7.1, 5.4 Hz, 1H), 2.41–2.29 (m, 3H), 2.02 (m,
3H), 1.18 (s, 3H), 1.14 (ddd, J¼11.0, 9.0, 6.1 Hz, 1H), 1.08
(s, 3H), 0.74 (ddd, J¼12.0, 9.0, 5.4 Hz, 1H). MS (EI) 164
(Mþ, 30%), 149 (10%), 121 (10%), 82 (100%). Anal. calcd
for C11H16O, C: 80.44, H: 9.82, found C: 80.12, H: 9.96.
5.1.11. Reaction of 6 with butyllithium. To a solution of 6
(200–400 mg) in dry THF (5–10 mL) was added butyl-
lithium (1.5 M hexane solution, 1.06 or 2.5 equiv.) in
15 min at 2958C. After stirring for 2.5 h at the same
temperature (or after warming to 08C for 2 h), a mixture of
THF-water (10/1, 5 mL) was added to the reaction mixture.
The crude product obtained by the extraction procedure was
purified by MPLC (elution with 6% ethyl acetate). The
isolated yields of 7 and 16–18 are shown in the text. Data
for 16: IR (neat) 2960, 2930, 2870, 2850, 1460, 1390, 1230,
5.1.14. Preparation of acetal 22. A solution of 2,5,5-
trimethylcyclohexan-2-en-1-one (12.03 g, 79.0 mmol) in
ethyl acetate (170 mL) was stirred with Pd–C (5%,
700 mg) under a hydrogen atmosphere for 10 h. Filtration
and concentration of the mixture gave essentially pure 21
(12.00 g, 98.6%). A mixture of 21 (1.22 g, 7.89 mmol),
(2R,4R)-2,4-pentanediol
(.99.6%
pure,
1.07 g,
10.3 mmol), and pyridinium p-toluenesulfonate (32 mg)
was dissolved in benzene (80 mL). The solution was heated
to boiling in a flask fitted with a Dean–Stark trap for 68 h.
After cooling, triethylamine (1 mL) and then aqueous
saturated NaHCO3 (80 mL) was added to the mixture.
Extraction with ether (70 mL£4), drying over MgSO4, and
concentration resulted in a yellow oil (1.76 g), which was
purified by silica gel column chromatography (elution with
3% ethyl acetate in hexane) to give a colorless oil (1.29 g,
68.0%, a diastereomeric mixture in a ratio of 2/3). Bp 80–
888C/7 Torr. IR (neat) 2950, 2870, 1380, 1160, 1080,
1
1080, 1040 cm21. H NMR (CDCl3) d 5.72 (dd, J¼11.0,
1.2 Hz, 1H), 5.63 (d, J¼11.0 Hz, 1H), 5.50 (dd, J¼10.7,
1.2 Hz, 1H), 5.32 (d, J¼10.7 Hz, 1H), 1.81 (s, 1H), 1.48 (s,
3H), 1.29 (s, 3H), 1.16 (s, 3H), 1.06 (s, 9H), 0.27 (s, 3H),
0.26 (s, 3H). 13C NMR (CDCl3) d 142.55, 138.94, 131.93,
127.69, 124.90, 67.40, 40.64, 38.62, 35.50, 32.24, 31.80,
28.62, 18.38, 20.72, 21.25. High MS calcd for C17H29-
OSiBr 356.1171, observed 356.1150. Data for 17: IR (neat)
2960, 2870, 1640, 1600, 1380, 1320, 1250, 1190 cm21. 1H
NMR (CDCl3) d 6.21 (d, J¼12.5 Hz, 1H), 6.19 (s, 1H), 6.07
(dd, J¼12.5, 0.5 Hz, 1H), 5.86 (d, J¼12.0 Hz, H), 5.76 (d,
J¼12.0 Hz, 1H), 2.05 (s, 3H), 1.32 (s, 6H). 13C NMR
(CDCl3) d 192.46, 152.39, 145.32, 144.80, 131.54, 131.13,
128.10, 37.49, 36.68, 27.62, 26.74. High MS calcd for
C11H14O 162.10447, observed 162.10443. Data for 18: IR
(neat) 2960, 2940, 2900, 2850, 1660, 1600, 1260, 1220,
1
1060 cm21. H NMR (CDCl3) d 4.05–3.90 (m, 2H), 1.94
(m, 0.6H), 1.82 (m, 0.4H), 1.66–1.22 (m, 10H), 1.20 (d,
J¼6.4 Hz, 1.2H), 1.19 (d, J¼6.3 Hz, 1.8H), 1.16 (d,
J¼6.3 Hz, 1.8H), 1.14 (d, J¼6.4 Hz, 1.2H), 0.85 (d,
J¼6.8 Hz, 1.2H), 0.92 (d, J¼7.1 Hz, 1.8H), 0.87 (s, 1.8H),
0.86 (s, 1.8H), 1.86 (s, 1.2H), 0.84 (s, 1.2H). Anal. calcd for
C15H28O2 C: 74.85, H: 11.74, found C: 74.53, H: 11.84.
1
1130 cm21. H NMR (CDCl3) d 6.00 (d, J¼12.0 Hz, 1H),
5.99 (dd, J¼11.5, 0.7 Hz, 1H), 5.82 (d, J¼12.0 Hz, 1H),
5.19 (d, J¼11.5 Hz, 1H), 1.91 (d, J¼0.7 Hz, 3H), 1.27 (s,
6H), 0.97 (s, 9H), 0.11 (s, 6H). 13C NMR (CDCl3) d 304.98,
148.54, 145.68, 142.72, 136.09, 134.10, 130.07, 38.66,
29.00, 27.34, 22.46, 19.14, 23.71. High MS calcd for
C17H28OSi 276.19094, observed 279.19099.
5.1.15. Preparation of 23 from 22. To a solution of 22
(800 mg, 3.32 mmol) in THF (20 mL) was added pyri-
dinium perbromide (2.72 g, 8.50 mmol) at 2788C. The
reaction mixture was warmed up to room temperature over
2.5 h. Pyridine (0.9 mL), and then an aqueous solution of
NaHCO3 (10%, 75 mL) containing Na2SO3 (100 mg) were
added to the mixture. The resulting solution was extracted
with ether (25 mL£3), washed with water, dried over
Na2SO4, and then concentrated to give a yellow oil (2.11 g).
Purification of this by silica gel column chromatography
(elution with 1% ethyl acetate in hexane) gave a
diastereomeric mixture of the dibromoacetal as a colorless
oil (1.10 g, 86.9%).
5.1.12. Preparation of 19 from 3. Treatment of 3 (12.0 mg)
in a mixture of THF (1 mL) and 2N HCl (0.3 mL) for
30 min at room temperature followed by extraction with
ether gave 7.1 mg of 19 (100% yield); the 1H NMR
spectrum did not show any detectable signals except for
those of 19. The product was further purified by preparative
TLC (silica gel, elution with 10% ethyl acetate in hexane).

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T. Futagawa et al. / Tetrahedron 58 (2002) 9279–9287
Potassium t-butoxide (1.04 g, 9.27 mmol) was placed in a
flask, and was dissolved in dry DMSO (20 mL) at 508C.
After cooling, a solution of the dibromoacetal (1.68 g,
4.23 mmol) in dry DMSO (15 mL) was added to the flask,
and the mixture stirred for 45 h. After the addition of water
(50 mL), the mixture was extracted with ether (80 mL£4),
dried over Na2SO4, concentrated, and purified by MPLC on
silica gel (elution with 1% ethyl acetate in hexane) to give
23 (221.6 mg, 22.2%) and its exo-regioisomer (238.6 mg,
23.9% yield). Data for 23: [a]2D5¼5.40 (c 1.1, methanol). IR
(neat) 2970, 2940, 2900, 2870, 1380, 1360, 1160, 1110,
1060, 1010 cm21. 1H NMR (CDCl3) d 5.64 (d, J¼12.2 Hz,
1H), 5.62 (m, 1H), 5.33 (d, J¼12.2 Hz, 1H), 4.04 (ddm,
J¼7.8, 6.1 Hz, 1H), 3.88 (ddm, J¼7.6, 6.3 Hz, 1H), 2.50
(dd, J¼13.4, 7.6 Hz, 1H), 2.32 (dd, J¼13.4, 7.8 Hz, 1H),
1.84 (m, 3H), 1.63 (t, J¼7.6 Hz, 2H), 1.20 (d, J¼6.1 Hz,
3H), 1.20 (d, J¼6.3 Hz, 3H), 0.98 (s, 3H), 0.96 (s, 3H).
High-MS calcd for C15H24O2 236.1777, observed 236.1765.
(41.5 mg, 35%) and 25b (20.3 mg, 17.1%). Data for 25a:
[a]2D5¼210.3 (c 1.0, methanol). IR (neat) 3400, 2950, 1380,
1
1120, 760 cm21. H NMR (CDCl3) d 5.89 (dd, J¼11.5,
1.5 Hz, 1H), 5.70 (d, J¼11.5 Hz, 1H), 5.57 (dd, J¼11.0,
1.5 Hz, 1H), 5.35 (d, J¼11.0 Hz, 1H), 4.31 (m, 1H), 4.17
(m, 1H), 2.90 (brs, 1H, OH), 1.85 (ddd, J¼14.4, 9.3, 4.9 Hz,
1H), 1.62 (ddd, J¼14.4, 5.1, 2.5 Hz, 1H), 1.40 (s, 3H), 1.27
(s, 3H), 1.26 (d, J¼6.4 Hz, 3H), 1.20 (d, J¼6.4 Hz, 3H),
1.18 (s, 3H). 13C NMR (CDCl3) d 145.74, 140.75, 126.43,
122.58, 77.41, 72.14, 68.26, 64.37, 45.02, 40.51, 36.64,
32.23, 31.35, 23.71, 20.48, 18.94. EI-MS (m/e) 318 (Mþ,
0.5%), 283 (1.7%), 232 (40%), 217 (15%), and 197 (100%).
High MS calcd for C16H24Cl2O2 318.1153, observed
318.1180. Data for 25b: mp 71.0–72.08C. [a]2D5¼231.6 (c
0.7, methanol). IR (neat) 3400, 2950, 1460, 1380, 1120,
1040, 900, 760 cm21. 1H NMR (CDCl3) d 6.01 (dd, J¼11.0,
1.2 Hz, 1H), 5.75 (d, J¼11.0 Hz, 1H), 5.66 (dd, J¼10.7,
1.2 Hz, 1H), 5.41 (d, J¼10.7 Hz, 1H), 4.30 (m, 1H), 4.13
(m, 1H), 2.67 (brs, 1H, OH), 1.76 (ddd, J¼14.5, 9.0, 3.9 Hz,
1H), 1.63 (ddd, J¼14.5, 6.1, 2.7 Hz, 1H), 1.42 (s, 3H), 1.36
(d, J¼6.3 Hz, 3H), 1.34 (s, 3H), 1.19 (s, 3H), 1.18 (d,
J¼6.1 Hz, 3H). 13C NMR (CDCl3) d 147.57, 141.37,
127.78, 122.53, 77.30, 71.09, 66.92, 64.47, 45.06, 39.31,
35.72, 32.15, 31.13, 23.51, 20.49, 18.09. Anal. calcd for
C16H24O2Cl2 C: 60.19, H: 7.58, found C: 59.87, H: 7.60.
5.1.16. Preparation of 24 from 23. To a solution of 23
(214 mg, 0.91 mmol) and triethylamine (0.25 mL,
0.91 mmol) in dry CH2Cl2, trimethylsilyl trifluoromethane-
sulfonate (0.27 mL, 1.4 mmol) was added in 5 min at 08C.
The same amounts of triethylamine and trimethylsilyl
trifluoromethanesulfonate were added three more times at
6, 12, and 18 h; then the mixture was poured onto saturated
aqueous NaHCO3 (20 mL). Extraction with CH2Cl2
(20 mL£3) and purification by column chromatography on
alumina (10% water, elution with hexane) gave the enol
trimethylsilyl ether (272.5 mg, 97.5% yield). IR (neat)
5.1.18. Preparation of 26a and 26b by sodium/methanol
reduction. To a solution of 25a (42.3 mg, 0.13 mmol) in
ether (20 mL) was added a piece of sodium (ca. 300 mg) and
methanol (1.2 mL, 3.3% water) at 08C. After 28 h, the
remaining sodium metal was removed from the flask, and
the reaction mixture was diluted with water (30 mL).
Extraction with ether (35 mL £5), drying over Na2SO4,
and concentration gave a yellow oil (32.0 mg). Purification
by column chromatography on alumina (elution with 3%
ethyl acetate in hexane) gave 26a as a colorless oil (11.8 mg,
35.6%). Data for 26a: [a]2D5¼259.2 (c 0.6, methanol). IR
(neat) 3400, 2950, 1660, 1380, 1220, 1120 cm21. 1H NMR
(C6D6) d 5.43 (brs, 1H), 4.63 (brs, 1H), 4.25 (m, 1H), 3.91
(m, 1H), 3.83 (d, J¼15.2 Hz, 1H), 2.18 (ddd, J¼15.2, 2.0,
1.0 Hz, 1H), 1.75 (m, 3H, 5-Me), 1.59 (ddd, J¼14.2, 8.1,
3.2 Hz, 1H), 1.50–1.32 (m, 4H), 1.16 (d, J¼6.1 Hz, 3H),
1.13 (s, 3H), 1.09 (s, 3H), 1.05 (d, J¼6.4 Hz, 3H). High-MS
of the acetate calcd for C18H28O3 292.2038, observed
292.2052. By the same procedure, 25b was converted to 26b
(33%). Data for 26b: [a]D25¼225.8 (c 0.2, methanol). IR
(neat) 3400, 2950, 1660, 1380, 1220, 1180, 1120 cm21. 1H
NMR (C6D6) d 5.44 (s, 1H), 4.59 (s, 1H), 4.30 (m, 1H), 3.94
(m, 1H), 3.84 (d, J¼15.2 Hz, 1H), 2.18 (dd, J¼15.2, 0.9 Hz,
1H), 1.72 (m, 3H), 1.62–1.30 (m, 5H), 1.13 (s, 3H), 1.12 (d,
J¼5.9 Hz, 3H), 1.10 (s, 3H), 1.07 (d, J¼6.1 Hz, 3H). High-
MS of the acetate calcd for C18H28O3 292.2038, observed
292.2048.
1
2950, 1380, 1260, 1180, 1120, 1060, 840 cm21. H NMR
(C6D6) d 6.24 (d, J¼10.5 Hz, 1H), 6.00 (d, J¼10.3 Hz, 1H),
5.25 (dm, J¼10.5 Hz, 1H), 5.15 (dm, J¼10.3 Hz, 1H), 4.44
(m, 1H), 4.23 (m, 1H), 2.12 (s, 3H), 1.79 (ddd, J¼13.9, 8.8,
3.3 Hz, 1H), 1.64 (ddd, J¼13.9, 9.0, 3.4 Hz, 1H), 1.17 (s,
3H), 1.16 (d, J¼6.1 Hz, 3H), 1.14 (d, J¼6.1 Hz, 3H), 0.98
(s, 3H), 0.20 (s, 9H). A solution of this compound
(272.6 mg, 0.88 mmol) in methanol (15 mL) was stirred
with NaOH (as pellets, ca. 60 mg) for 20 h at room
temperature. Addition of water (30 mL), extraction with
ether (40 mL£4), drying over Na2SO4, concentration, and
purification by MPLC on silica gel afforded 24 as a colorless
oil (145.7 mg, 69.8%). [a]2D0¼245.1 (c 0.8, methanol). IR
(neat) 3400, 3000, 2900, 1380, 1220, 1180, 1120, 740 cm21
.
1H NMR (CDCl3) d 5.98 (d, J¼10.5 Hz, 1H), 5.90 (d,
J¼10.3 Hz, 1H), 5.27 (dm, J¼10.5 Hz, 1H), 5.02 (dm,
J¼10.3 Hz, 1H), 4.33 (m, 1H). 4.17 (m, 1H), 2.32 (brs, 1H,
–OH), 1.95 (s, 3H), 1.80–1.67 (m, 2H), 1.24 (d, J¼6.4 Hz,
3H), 1.17 (d, J¼6.1 Hz, 3H), 1.17 (s, 3H), 0.83 (s, 3H).
High-MS calcd for C15H24O2 236.1777, observed 236.1780.
5.1.17. Dichlorocarbene addition of 24 to give 25a and
25b. To a solution of 24 (87.8 mg, 0.37 mmol) in chloro-
form (190 mL) was added aqueous 50% NaOH (1.69 g,
21.12 mmol) and then benzyltriethylammonium chloride
(9.8 mg) at 08C. After 4 h, the mixture was diluted with
water (30 mL), extracted with chloroform (30 mL£3), and
concentrated. Purification of the residue by MPLC on silica
gel (elution with 10% ethyl acetate in hexane) gave a
colorless oil (120.5 mg, 100%). This material contains 25a
5.1.19. Formation of 27a and 27b. By the treatment of 26
with pyridinium p-toluenesulfonate in benzene, 27 was
obtained in quantitative yield. Further purification was
performed by column chromatography on silica gel (elution
with 3% ethyl acetate in hexane). Data for 27a: [a]2D5¼65.8
(c 0.3, methanol). IR (neat) 2950, 1380, 1160, 1100 cm21
.
1
and 25b in a ratio of 2.3/1 deduced from the H NMR
spectrum. Further purification by preparative HPLC on
ODS (elution with 20% water in methanol) gave 25a
1H NMR (CDCl3) d 5.17 (s, 1H), 4.05–3.47 (m, 2H), 2.78
(d, J¼13.4 Hz, 1H), 2.20 (d, J¼13.4 Hz, 1H), 2.14 (dd,
J¼14.4, 4.9 Hz, 1H), 1.70 (brs, 3H), 1.63–1.58 (m, 4H),

T. Futagawa et al. / Tetrahedron 58 (2002) 9279–9287
9287
2. The Chemistry of the Cyclopropyl Group, Rappoport, Z., Ed.;
Wiley: Chichester, 1987; Part 1 and 2.
1.21 (d, J¼6.1 Hz, 3H), 1.17 (d, J¼6.4 Hz, 3H), 1.04 (s,
3H), 0.95 (s, 3H), 0.74 (ddd, J¼12.7, 8.5, 4.9 Hz, 1H). 13C
NMR (CDCl3) d 137.90, 121.96, 102.73, 62.58, 62.20,
42.32, 38.20, 30.55, 28.12, 25.75, 24.64, 22.21, 21.78,
21.62, 18.53, 16.14. High-MS calcd for C11H26O2 250.1934,
observed 250.1930. Data for 27b: [a]2D5¼259.0 (c 0.2,
3. Newmann, M. F. Angew. Chem. Int. Ed. Engl. 1968, 7, 65–67.
4. (a) Doering, W. E.; Roth, W. R. Tetrahedron 1963, 19,
715–737. (b) Gu¨nther, H.; Pawliczek, J. B.; Ulmen, J.;
Grimme, W. Angew. Chem. Int. Ed. Engl. 1972, 11, 517–518.
(c) Bicker, R.; Kessler, H.; Steigel, A.; Stohrer, W. Chem. Ber.
1975, 108, 2708–2721. (d) Gu¨nther, H.; Ulmen, J. Chem. Ber.
1975, 108, 3132–3140. (e) Gu¨nther, H.; Pawliczek, J.; Ulmen,
J.; Grimme, W. Chem. Ber. 1975, 108, 3141–3150. (f) Bicke,
R.; Kessler, H.; Ott, W. Chem. Ber. 1975, 108, 3151–3158.
(g) Kessler, H.; Ott, W. J. Am. Chem. Soc. 1976, 98,
5014–5016. (h) Fu¨hlhuber, H. D.; Gousetis, C.; Troll, T.;
Sauer, J. Tetrahedron Lett. 1978, 3903–3906. (i) Dyllick-
Brenziger, R.; Oto, J. F. M.; Fu¨hlhuber, H. D.; Gousetis, C.;
Troll, T.; Sauer, J. Tetrahedron Lett. 1978, 3907–3910.
(j) Kessler, H.; Ott, W.; Lindner, H. J.; Schnering, H. G.;
Peters, E.; Peters, K. Chem. Ber. 1980, 113, 90–103. (k) Maas,
G.; Kettenring, J. K. Chem. Ber. 1982, 115, 627–644. (l) Maas,
G.; Kettenring, J. K. Chem. Ber. 1984, 117, 575–584.
(m) Kettenring, J. K.; Maas, G. Tetrahedron 1984, 40,
391–403.
methanol). IR (neat) 2950, 1380, 1150, 1100 cm21 1H
.
NMR (CDCl3) d 5.26 (s, 1H), 4.09–3.97 (m, 2H), 2.93 (d,
J¼13.0 Hz, 1H), 2.20 (d, J¼13.0 Hz, 1H), 2.15 (dd, J¼14.2,
5.1 Hz, 1H), 1.73 (brs, 3H), 1.63–1.57 (m, 4H), 1.22 (d,
J¼6.3 Hz, 3H), 1.15 (d, J¼6.3 Hz, 3H), 1.03 (s, 3H), 0.94
(s, 3H), 0.86 (m, 1H). High-MS calcd for C16H26O2
250.1934, observed 250.1945.
5.1.20. Preparation and reaction of optically active 19
and its dihydroderivative. Treatment of 26 or 27 with a
catalytic amount of pyridinium p-toluenesulfonate in wet
benzene for 4 h at room temperature gave 19 as the sole
product. Spectroscopic data of 19 obtained was identical
with that from racemic mixture. Conjugated compound 20
was also obtained as the optically active compound. (1S,7S)-
19 (obtained from 27a): [a]2D5¼426 (c 1.1, methanol).
(1R,7R)-19 (obtained from 27b): [a]2D5¼2390 (c 0.5,
methanol). (1S,7R)-20: [a]2D5¼178 (c 0.4, methanol).
Hydrogenation of (1S,7R)-20 in ethyl acetate in the presence
of Pd–C (5%) afforded (1S,5R,7R)-5,8,8-trimethylbicyclo-
[5.1.0]octan-3-one, whose data are identical with the
reported ones. [a]2D5¼195.1 (c 0.76, CHCl3), (lit.7 215 (c
2.9, CHCl3)). IR (neat) 2950, 1710, 1460, 1380, 1290, 1160,
5. (a) Simonetta, M.; Favini, G.; Mariani, C.; Gramaccioni, P.
J. Am. Chem. Soc. 1968, 90, 1280–1289. (b) Schneider, M. P.;
Rau, A. J. Am. Chem. Soc. 1979, 101, 4426–4427.
6. For a preliminary communication, see: Sugimura, T.;
Futagawa, T.; Katagiri, T.; Nishiyama, N.; Tai, A.
Tetrahedron Lett. 1996, 37, 7303–7306.
7. Satoh, T.; Kaneko, Y.; Okuda, T.; Uwaya, S.; Yamakawa, K.
Chem. Pharm. Bull. 1984, 32, 3452–3460.
1
740 cm21. H NMR (CDCl3) d 2.62–2.54 (m, 2H), 2.32
(dd, J¼11.4, 5.7 Hz, 1H), 2.19–2.09 (m, 2H), 1.81 (ddd,
J¼14.8, 5.4, 3.5 Hz, 1H), 1.26 (m, 1H), 1.10 (s, 3H), 1.05 (d,
J¼6.8 Hz, 3H), 1.01 (s, 3H), 0.81 (ddd, J¼11.4, 8.8, 5.4 Hz,
1H), 0.72 (dd, J¼9.5, 8.1 Hz, 1H). High-MS calcd for
C11H18O 166.1358, observed 166.1350.
8. Blanco, L.; Amice, P.; Conia, J. M. Synthesis 1981, 289.
9. Wilson, S. R. Organic Reactions, Wiley: New York, 1993;
Vol. 43. pp 93–250.
10. (a) Ito, Y.; Fujii, S.; Saegusa, T. J. Org. Chem. 1976, 41,
2073–2074. (b) Paquette, L. A.; Ham, W. H. J. Am. Chem.
Soc. 1987, 109, 3025–3036.
11. (a) Sugimura, T.; Futagawa, T.; Tai, A. Tetrahedron Lett.
1988, 29, 5775–5778. (b) Sugimura, T.; Yoshikawa, M.;
Futagawa, T.; Tai, A. Tetrahedron 1990, 46, 5955–5966.
(c) Sugimura, T.; Yoshikawa, M.; Mizuguchi, M.; Tai, A.
Chem. Lett. 1999, 831–832. (d) Sugimura, T.; Futagawa, T.;
Yoshikawa, M.; Katagiri, T.; Miyashige, R.; Mizuguchi, M.;
Nagano, S.; Sugimori, S.; Tai, A.; Tei, T.; Okuyama, T.
Tetrahedron 2001, 57, 7495–7499.
Acknowledgements
The authors thank Mr Katsuhiro Hashimoto of Sumitomo
Pharmaceutical Co. for help with the MO calculations. The
present work was partially supported by a Grant-in-Aid for
Scientific Research No. 03740279.
12. Tei, T.; Sugimura, T.; Katagiri, T.; Tai, A.; Okuyama, T.
Tetrahedron: Asymmetry 2001, 12, 2727–2730.
References
13. Tai, A.; Kikukawa, T.; Sugimura, T.; Inoue, Y.; Abe, S.;
Osawa, T.; Harada, T. Bull. Chem. Soc. Jpn 1994, 67,
2473–2477.
1. Cane, D. E. Comprehensive Natural Products Chemistry,
Elsevier: Amsterdam, 1999; Vol. 2.