New entry to the synthesis of clerodane diterpenes. The first enantioselective syntheses of 7-oxo-kolavenic acid and methyl solidagonate

Article abstract of DOI:10.1016/S0040-4020(01)00821-3

Using (1S,5S)-(-)-verbenone (8b), readily obtainable from (+)-nopinone (3), as the chiral source, we have established the general method for preparation of three kinds of key intermediates, conjugate enones 9 and 10 for the syntheses of neo-trans-clerodanes and 11 for those of neo-cis-clerodanes. Starting with the compound 10, the first enantioselective syntheses of (-)-(5R,8S,9S,10R)-7-oxo-cleroda-3,13E-dien-15-oic acid (7-oxo-kolavenic acid) (1) and solidagonic acid (2) as its methyl ester (48) were achieved.

Full text of DOI:10.1016/S0040-4020(01)00821-3

TETRAHEDRON
Pergamon
Tetrahedron 57 -2001) 8243±8256
New entry to the synthesis of clerodane diterpenes.
The ®rst enantioselective syntheses of 7-oxo-kolavenic acid
and methyl solidagonate
Michiharu Kato,a,p Hiroshi Kosugi,a Tsuyoshi Ichiyanagi,a Hisahiro Hagiwara,b Ariko Kodaira,a
Takashi Kusakari,a Takao Suzuki,a Minako Ando,a Jasmine Lee,a Peter Drechselc
and Bernhard Voglerc
aInstitute for Chemical Reaction Science, Tohoku University, Katahira, Aoba-ku, Sendai 980-8577, Japan
bGraduate School of Science and Technology, Niigata University, 8050, 2-nocho, Ikarashi 950-2181, Japan
cInstitut fur Chemie, Universitat Hohenheim, Garbenstr. 30, Stuttgart 70599, Germany
Received 15 March 2001; accepted 2 August 2001
AbstractÐUsing -1S,5S)--2)-verbenone -8b), readily obtainable from -1)-nopinone -3), as the chiralsource, we have estabilshed the
generalmethod for preparation of three kinds of key intermediates, conjugate enones 9 and 10 for the syntheses of neo-trans-clerodanes and
11 for those of neo-cis-clerodanes. Starting with the compound 10, the ®rst enantioselective syntheses of -2)--5R,8S,9S,10R)-7-oxo-cleroda-
3,13E-dien-15-oic acid -7-oxo-kolavenic acid) -1) and solidagonic acid -2) as its methylester - 48) were achieved. q 2001 Elsevier Science
Ltd. All rights reserved.
1. Background
combined reagent, BF3´OEt2/Zn-OAc)2/Ac2O,5 proceeded
with little loss of optical integrity to give in good to high
yields of enol acetates 5 and 6, respectively, enantio-
selective syntheses starting with these enol acetates as the
chiralbuilding bol ck have been carried out in some natural
products, i.e. cryptone and p-menthan-type sesquiterpenes
from 5,6 and elemane7 and nardosinane sesquiterpenes8
from 6. In preparation of the above substituted nopinones,
stereoselective conjugate additions of -1)-apoverbenone
-7) and -1)-verbenone -8a), both readily available from
3,9 with alkyl nucleophiles were used as the key reaction.
Furthermore, we have established a convenient conversion
of 7 into -2)-verbenone -8b),10 indicating that -1)-nopi-
none -3), consequently its precursor -2)-b-pinene as well,
serves as the common chiralsource for the asymmetric
synthesis in terms of absolute con®guration of the target
naturalproducts. In fact, starting with 8b, enantioselective
syntheses of lobane diterpenes have been accomplished.11
As part of our naturalproduct synthesis by use of 8b as
the chiral template, we now chose clerodane diterpenoids
as the target naturalproduct. We wish to report prepara-
tion of generalkey intermediates 9 and 10 for the syn-
thesis of neo-trans clerodanes as well as the ®rst
enantioselective syntheses of -2)--5R,8S,9S,10R)-7-oxo-
cleroda-3,13E-dien-15-oic acid -7-oxo-kolavenic acid)
-1)12,13 and solidagonic acid -2)13,14 as the application. In
addition, preparation of the promising synthetic inter-
mediate 11 necessary for the syntheses of ent-neo-cis-clero-
danes will be discussed.
Clerodanes constitute a large class of diterpenoid.1 The
numbers of isolations and structural elucidation of clero-
dane diterpenes reportedly amount to more than eight
hundred. Most of clerodanes display unique biological
activities in which the insect antifeedant and antitumour
activities shown by clerodin2 and terpentecin,3 respectively,
are well-known. Since the substituent of the C-4) position of
major clerodanes presents as an ole®n-methyl or exo-
methylene group from the biosynthetic reasons,1,4 the
most important characteristic in stereochemistry of clero-
danes is the contiguously arranged four chiral centers;
C-5)±C-10)±C-9)±C-8) [for example, see 7-oxo-kolavenic
acid -1) as a representative of neo-trans-clerodanes], so that
synthetic efforts have been practically focused on reali-
zation of this unique carbon±carbon arrangement in a
stereocontrolled fashion.1b
We have been studying the utility of -1)-nopinone -3),
readily obtainable in large quantities by ozonolysis of
-2)-b-pinene, as the chiralsource in enantioseelctive syn-
thesis of naturalproducts. Since we found that cyclobutane-
ring opening of 3 and alkyl substituted nopinones 4 with the
Keywords: naturalproducts; asymmetric synthesis; cleavage reactions; ene
reactions.
Corresponding author; e-mail: hidemi.kato@mb3.seikyou.ne.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020-01)00821-3

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M. Kato et al. / Tetrahedron 57 22001) 8243±8256
Scheme 1.
while conjugate enones 9 and 10 are employed as the
trans-octalone i, the carbon nucleophile synthetically
equivalent to the C-9)-substituent in the target clerodane
may be chosen as the nucleophile -R2) in the conjugate
addition reaction. First, to make sure that our methodology
is consistent with clerodane synthesis, conjugate addition of
a vinylgroup to 9 followed by methylation and epimeri-
zation was studied.
2.1. Preparation of trans-octalone 9and a model study
directed toward neo-trans-clerodane synthesis
-2)-Verbenone -8b) was prepared from -1)-nopinone -3)
via 7 according to our synthetic method established
earlier.10 Conjugate addition reaction of 8b with the vinyl
Grignard reagent in the presence of copper-I) iodide in THF
proceeded smoothly in a stereoselective fashion to give 12
in a quantitative yield -Scheme 2).7a Stereochemistry of the
vinylgroup was assigned as shown by the wel-known reac-
tivity characteristic of pinane-type compounds, that is, the
nucleophile approaches from the less hindered side away
from the gem-dimethylbridge.
7a
In the above conjugate
addition reaction, trapping the resulting enolate with MeI
provided 50% yield of trans-3-methylnopinone 1316 along
with unreacted 12 -23%). Methylation of 12 was examined
next. After a few experimentation, treatment of the lithium
salt of 12 with MeI in the presence of 10 equiv. of 1-methyl-
2-pyrrolidinone -NMP)17 at room temperature was
employed as optimum, thus giving 13 in 63% yield -74%
yield from the consumed 12) along with unreacted 12
-15%). Epimerization of 13 with 5% KOH in methanol
gave thermodymamically stable cis-3-methylnopinone
1416 in high yield. NOE correlations of 13 and 14 supported
their stereostructures as shown in iv and v, respectively.18
Cyclobutane opening of 13 with our combined reagent,
BF3´OEt2/Zn-OAc)2/Ac2O,5 proceeded in a regioselective
fashion to give enolacetate 15 in 60% yield as the sole
product. However, attempted ring opening of 14 with the
above combined reagent proved to be fruitless, mostly
recovering unreacted 14 even on heating at 608C.19
2. Results and discussion
Most of clerodanes could be regarded as 4,5,8,9-tetra-
methyldecalins or octalins possessing a functionalized six-
carbon substituent at the C-9) position.15 Upon installation
of the substituent at this position, reductive alkylation of
D9,10-8-octalones -usually, substrates derived from the
Wieland±Miescher ketone and its analogue) with Li in
liquid NH3 followed by addition of some carbon electro-
philes has so far been employed as the general synthetic
methodology.1b In the present synthesis, we designed one-
step stereo- and regioselective installation of not only the
C-9)-alkyl group, but also the C-8)-methyl one by use of
stereocontrolled conjugate addition of carbon nucleophiles
-R2) to trans-octalone i followed by trapping of the
resulting enolate anion with MeI in a kinetically controlled
fashion to give ii -Scheme 1). Subsequent epimerization of
the newly introduced methyl group in ii with a base may
lead to the thermodynamically stable isomer iii which
possesses all alkyl substituents with the same stereo-
chemistry as those of neo-trans-clerodanes. In practice,
Our synthesis was then followed, prior to the cyclobutane
opening, by chemicaltransformation of the vinylgroup in
13.20 Hydroboration of 13 with H3B/THF followed by
oxidation with H2O2 under the alkaline conditions gave a
mixture of diastereomeric diols, 16 and 17, in ca 2:1 ratio.
Con®guration of the sec-hydroxy groups was tentatively

M. Kato et al. / Tetrahedron 57 22001) 8243±8256
8245
Scheme 2.
assigned as S for the major and R for the minor on the basis
of characteristic reactivity of pinanes.7a Regioselective
acetylation of the mixture of diols, 16 and 17, provided a
mixture of diacetates 18 and hydroxy acetates, 19 and 20, in
23 and 58% overall yield from 13, respectively. Lithium
aluminum hydride reduction of 18 made possible clean
reconversion to the starting diols, 16 and 17. Swern
oxidation of the mixture of hydroxy acetates, 19 and 20,
gave trans-3-methylnopinone 21 in nearly quantitative
yield. Although BF3-promoted cyclobutane opening of 21
was sluggish at room temperature, this reaction underwent
essentially to completion, after stirring for two days, to
produce enolacetate 22.21 Hydrolysis of 22 with K2CO3 in
methanolgave a mixture -a 1:4 ratio) of ketone 24 and
thermodynamically stable ketone 23 which was produced
by concomitant epimerization of the initialproduct 24.
Treatment of 24 with KOH in methanolprovided an equi-
followed by Swern oxidation of the resulting alcohol 28
provided, in 93% overall yield from 25, aldehyde 29, the
precursor directed toward trans-decalin synthesis. Exposure
of 29 upon Et2AlCl in CH2Cl2 at 08C underwent the ene
reaction smoothly to give bicyclic alcohol 30 as the sole
product. It can be assumed that this ene reaction proceeds
predominantly via six-membered transition state x with
chair conformation to give the trans-decalin with an axial
25
1
hydroxylgroup.
The H NMR spectrum of 30 shows
absorption due to the proton on the carbon bearing the
newly formed hydroxy group at d 4.17 as a broad singlet
with the half band width -12 Hz), indicating the hydrogen
atom to be equatorial. Swern oxidation of 30 led to decon-
jugate enone 31 and conjugate enone 9 in 78 and 5% yields,
respectively.26 Upon treatment with DBU, the former 31
readily isomerized to the latter 9. After all, the requisite
trans-conjugate enone 9 was obtainable in 13 steps and ca
21% overall yield from -2)-verbenone 8b.
1
librium mixture of 23 and 24 in a ratio of 4:1 -from H
NMR), indicating that the sec-methylgroup in 23 possesses
thermodynamically stable equatorial con®guration.22
Acetylation of the mixture, 23 and 24, gave a separable
mixture -a 4:1 ratio) of acetates, 25 and 26. The former 25
was submitted to a further series of reactions.
With the trans-enones 9 available, attention was focused on
stereoselective installation of two alkyl substituents at the
C-8) and -9) positions by use of the conjugate addition
reaction with a carbon nucleophile followed by methylation.
First, we examined stereoselectivity in the conjugate
addition of 9 with the vinylGrignard reagent. Drieding
model experiments indicate that the nucleophile may
approach 9 from less hindered face away from the angular
methylgroup. This conjugate addition reaction was
performed in the presence of CuI in THF to give the adduct
Construction of trans-octalone skeleton by the intramolecu-
lar ene-reaction was performed next. Acetalization of 25
was successfully carried out upon treating with 2,20--ethyl-
enedioxy)bis-trimethylsilane) in the presence of TMSOTf23
to give acetal 27 in high yield24 -Scheme 3). Hydrolysis

8246
M. Kato et al. / Tetrahedron 57 22001) 8243±8256
Scheme 3.
32 in a stereoselective fashion -Scheme 4). Stereostructure
of 32 was assigned on the basis of detailed NMR analyses in
which not only does NOE correlations xi indicate that
con®guration of the vinyland methylfunctions at the C-9)
position are equatorial and axial, respectively, but also the
W-letter long range coupling -2.0 Hz) between the C-6)±H
-equatorial) and C-8)±H -equatorial) suggests conformation
of the B ring to be a chair form. Then, methylation of the
enolate anion generated in the above conjugate addition
reaction with MeI was examined in the presence or absence
of HMPA. However, no methylated compound was
obtained except procurement of the initialadduct 32
-40,50%). No effect was observed in addition of
thermodynamically stable compound 34 which possesses
the same four contiguously arranged asymmetric centers
with those of natural neo-trans-clerodanes.
27
BF3´OEt2 in these reactions. One step installation of two
alkyl substituents was effected by treating 9 with lithium
divinyl cuprate in the presence of HMPA followed by
trapping of the resulting enolate anion with excess MeI,
thus giving 33 in a stereocontrolled fashion along with 32
-30%). However, the isolated yield of 33 was disappoint-
ingly low -21%). Little effect was exerted by the addition of
BF3´OEt2 in the above reaction.27 Fortunately, methylation
of the lithium salt of the adduct 32, prepared with
-TMS)2NLi in THF, resulted in formation of 33 in a
regio- and stereoselective fashion in 61% isolated yield
along with unreacted 32 -13%).
2.2. Preparation of the synthetic intermediate 10 and
syntheses of some neo-trans-clerodanes
In view of the fact that most clerodanes possess an ole®n
methylgroup at the C-4) position, preparation of the second
key intermediate, trans-enone 10, was examined next. In
Scheme 5 is shown the regio- and stereoselective reduction
of the ketone 25 with lithium tri-tert-butoxyaluminum
hydride in which the hydride may approach exclusively
from less hindered b face of the molecule 25 to give alcohol
35. Stereochemistry of the hydroxy group in 35 was
assigned to be axialfrom the 1H NMR study in which
a broad siglet -d 3.84) due to the proton on the carbon
¯anking the hydroxy group shows the small half band
width -12 Hz), indicating the hydrogen atom to be equa-
torial. Treatment of 35 with phosphorus oxychloride in
Stereostructure of 33 was determined by the 1H NMR analy-
sis, especially by NOE correlations. It is worth mentioning
that the compound 33 is in equilibrium between the con-
former xiia possessing a boat form in the B ring and the
conformer xiib possessing a chair form. The molecular
mechanics calculation -CAChe system/MM2 force ®eld)
of 33 gave the information that xiia is more stable by
0.56 kcalmol 21 than xiib. Finally, epimerization of 33
with 5% KOH in methanolprovided in high yiedl the
Scheme 4.

M. Kato et al. / Tetrahedron 57 22001) 8243±8256
8247
Scheme 5.
pyridine followed by deprotection of the resulting diene 36
provided alcohol 37 in a high overall yield. Chemical trans-
formation of 37 into the target 10 was carried out straight-
forwardly according to the method described for preparation
of 9 from 28; Et2AlCl-induced ene reaction of aldehyde 38,
prepared from 37 by Swern oxidation, proceeded smoothly
to give bicyclic alcohol 39 possessing the axially oriented
hydroxy group. Swern oxidation of 39 gave deconjugate
enone 40 and conjugate enone 10 in 15 and 64% yields,
respectively. The former 40 was readily converted into the
latter 10 by treatment with DBU. After all, the key inter-
mediate 10 was procured from 25 in 7 steps and more than
50% overall yield.
-8%) along with unreacted 10 -63%). After a few experi-
mentation, CH2vCHCH2CH2Cu´BF3, generated from this
Grignard reagent, CuI and BF3´OEt2 in THF, underwent
smoothly the conjugate addition reaction to lead to 41 in
86% yield. Stereostructure of 41 was characterized by the
1H NMR analysis, especially by the NOE correlations.
Methylation of 41 with MeI under the kinetically controlled
conditions using LHMDS gave 4228 which was then epimer-
ized by 5% KOH in methanol to the thermodynamically
stable octalone 43 in ca 50% overall yield from 41. NOE
correlations of 43 supported its stereostructure as shown in
xiii.
Palladium-catalyzed oxidation of the terminal ole®n in 43
provided diketone 44 in 79% yield. Construction of the
3-methyl-2-pentenoate side chain was accomplished by
treating 44 with the sodium salt of trimethyl phosphono-
acetate in THF to give a mixture -a 5:1 ratio) of the
-E)-unsaturated ester 45 and the -Z)-isomer 46. Since the
ring carbonylgroup in 44 is sterically highly hindered, as
can be presumed from the Dreiding models, the above
The key intermediate 10 may be advantageous to the syn-
thesis of oxygenated neo-trans-clerodanes, especially those
possessing a ketone function at the C-7) position. Then, we
®rst envisioned the enantioselective synthesis of -5R,8S,
9S,10R)-7-oxo-clerodan-3,13E-dien-15-oic acid -7-oxo-
kolavenic acid) -1), isolated as a minor component from
an extract of the aerialpart of Platychaete aucheri by
Zdero et al.12 Our synthesis began with installation of a
homoallyl group at the C-9) position of 10 -Scheme 6).
Attempted conjugate addition of 10 with the homoallyl
Grignard reagent in the presence of CuI in THF resulted
in formation of the adduct 41 in a disappointing low yield
Horner±Wadsworth±Emmons
condensation
reaction
occurred regioselectively at the ketone in the side chain to
produce both 45 and 46, not only in a large excess of the
phosphonate reagent, but also on heating at 608C. Stereo-
chemicalassignment of the esters was easiyl performed by
Scheme 6.

8248
M. Kato et al. / Tetrahedron 57 22001) 8243±8256
decalin-ring junction,1a the compound 11 could serve as
the key intermediate for the synthesis of cis-clerodanes by
use of our conjugate addition of a carbon nucleophile±
methylation sequence.
3. Conclusion
Scheme 7.
Synthetic study of clerodane diterpenoids in optically active
forms is of recent origin. Accordingly, asymmetric total
syntheses have been small in number. In the present
study, we prepared versatile bicyclic conjugate enones 9
and 10, starting with -1)-nopinone -3) as the chiralsource.
By use of stereocontrolled conjugate addition reactions of
the vinyl and homoallyl Grignard reagents to 9 and 10,
respectively, followed by methylation and epimerization,
two kinds of intermediates 34 and 43, both utilizable for
the synthesis of neo-trans-clerodanes, were prepared.
While the acetal function at the C-3) position of 34 could
serve as a clue for construction of oxygenated A ring, the
octalone 43 could act as the promising intermediate for the
synthesis of clerodanes possessing an ole®n methyl group at
the C-4)-position. In common with both intermediates, 34
and 43, the ketone function in the B-ring could be utilizable
for the construction of highly oxygenated B ring. Clero-
danes are generally regarded as variations of the six-carbon
side chain at the C-9) position, so that a variety of carbon
nucleophiles synthetically equivalent to the side chain could
be employed in the conjugate addition reactions using
9 and 10. In the present study, the synthesis of
-2)--5R,8S,9S,10R)-7-oxo-clerodan-3,13E-dien-15-oic acid
-7-oxo-kolavenic acid) -1) was accomplished via 43 in 24
steps and ca 7% overall yield from -2)-verbenone -8b). In
addition, solidagonic acid -2) was obtained as its methyl
ester 48 from methy 7-oxo-kolavenate -45). Finally, we
found that the trans-enone 10 is thermodynamically
unstable, being easily convertible upon exposure to acids
into the stable cis-enone 11, which could be served as the
promising key intermediate for the synthesis of neo-cis-
clerodanes.
1
comparison of their H NMR spectra; the chemicalshift
[d 2.29 -s, 3H)] of the ole®n methyl in the side chain in
45 shows deshielding -0.39 ppm) by the proximate ester
group, compared with that [d 1.90 -s, 3H)] of 46. Finally,
alkaline hydrolysis of 45 provided the target naturalproduct
1 as an oil, [a]D ˆ295.2 -CHCl3). The 1H NMR
19
-400 MHz) spectraldata of our synthetic 1 and 45 were
identicalwith those of natural 1 and its methylester,
12
respectively. As there are no records with respect to the
speci®c rotation of the natural 1 and its methylester in the
literature,12 we could present here the synthesis of -2)-
-5R,8S,9S,10R)-7-oxo-clerodan-3,13E-dien-15-oic acid as
the naturalproduct 1.
Solidagonic acid -2) was isolated as a bitter principle from
the root of Solidago altissima by Kotake et al.14 We
accomplished the synthesis of 2 as its methylester 48.
Reduction of 45 with NaBH4 proceeded in a stereoselective
fashion, as anticipated from the Dreiding models, to give
alcohol 47 as the sole product. Con®guration of the hydroxy
group was assigned to be axialfrom the 1H NMR study in
which a broad siglet [d 4.04, C-7)±H] possesses the half
band width -9.0 Hz). The hydroxy group in 47 considerably
resisted acetylation, probably because of steric hindrance.
After all, the requisite methyl solidagonate 48, [a]Dˆ283.4
-EtOH); lit., [a]Dˆ298.8 -EtOH),14 was obtained in 54%
yield -82% yield from the consumed 47) upon treatment
with Ac2O in the presence of 4-dimethylaminopyridine.
1
The H NMR -400 MHz) spectraldata of our synthetic 48
were identicalwith those of the methylester of natural 2.
As we have established chemical transformation of -1)-
nopinone -3) into -1)-verbenone -8a),9 the present syn-
theses of -2)-1 and -2)-48 are formalsyntheses of their
enantiomers, -1)-1 and -1)-48.
2.3. Preparation of cis-enone 11 as the key intermediate
for the synthesis of neo-cis-clerodanes
We have detected that trans-enone 10 is thermodynamically
unstable, and isomerized to the stable cis-enone 11. In
practice, 10 was mostly recovered unchanged on treatment
with bases -DBU in toluene, heating; KOBut in THF, rt).
However, isomerization occurred easily and quantitatively
upon treatment with HClin methanolat 0 8C to give cis-
enone 11 -Scheme 7).
4. Experimental
4.1. General
In this study, -1)-nopinone -3), 98% ee, was used as the
starting material. -2)-Verbenone -8b) was prepared accord-
ing to our synthetic procedure reported earlier.10 Melting
The molecular mechanics calculations -CAChe system/
MM2 force ®eld) indicated the cis-enone 11 is more stable
by 2.21 kcalmol 21 than the trans-enone 10. In the ®gure xiv
are shown the principalNOE correaltions in which the
presence of cis-fused ring system is revealed. In addition,
on the basis of a doublet of doublets -d 1.62, Ja,aˆ11.7 and
Ja,eˆ2.9 Hz) due to the proton at the C-10) position in the 1H
NMR -C6D6), conformation of 11 was assigned as xiv in
which the orientation of the C-10)-hydrogen atom in the A
ring is axial. As one-fourths in number of clerodanes
isolated so far are known as cis congener regarding the
1
points are uncorrected. H NMR spectra were recorded at
400 MHz. [a] Values are given in units of 1021
deg cm2 g21. All reactions were carried out under dry N2
or Ar atmosphere with use of standard procedures for the
exclusion of moisture. Extracts obtained on aqueous workup
of the reaction mixtures were washed successively with
water and brine, and dried over Na2SO4, unless otherwise
stated. Medium-pressure chromatography -MPLC) utilized
a 22B£300 mm silica gel -10 mm) column. Column and

M. Kato et al. / Tetrahedron 57 22001) 8243±8256
8249
¯ash column chromatography were performed on 70±230
and 230±400 mesh silica gel -Merck), respectively.
Solvents for elution are shown in parentheses. Ether refers
to diethylether.
was stirred at rt for 5 h, quenched with aqueous NH4Cland
extracted with ether. Concentration of the extract left an oil
which was chromatographed on silica gel -hexane±AcOEt,
6:1) to give 14 -40 mg, 94%) as an oil; IR -CHCl3) 3060,
1
1708, 1635, 910 cm21; H NMR -CDCl3) d 0.93 -s, 3H),
4.1.1. /1S,4R,5R)-4,6,6-Trimethyl-4-vinylbicyclo[3.1.1]-
heptan-2-one /12). To a stirred mixture of copper-I) iodide
-950 mg, 5.0 mmol) in THF -15 ml) was added at 2788C a
solution of 1.01 M vinylmagnesium bromide in THF -24 ml,
24 mmol), followed by a solution of 8b -1.50 g, 10 mmol) in
THF -10 ml). After being stirred for 3 h, the reaction
mixture was quenched with aqueous NH4Cl, and extracted
with ether. Concentration of the extract followed by puri®-
cation of the oily residue by chromatography on silica gel
-hexane±AcOEt, 7:1) gave 12 -1.78 g, quant) whose IR and
1H NMR spectra were identicalof those of an authentic
sample.7a
1.10 -s, 3H), 1.18 -d, Jˆ6.8 Hz, 3H), 1.37 -s, 3H), 1.72 -d,
Jˆ10.8 Hz, 1H), 2.10 -dd, Jˆ5.7, 5.5 Hz, 1H), 2.40 -ddd,
Jˆ10.8, 5.7, 5.5 Hz, 1H), 2.57 -t, Jˆ5.5 Hz, 1H), 2.62 -q,
Jˆ7.2 Hz, 1H), 4.94 -d, Jˆ17.4 Hz, 1H), 4.98 -d, Jˆ
11.2 Hz, 1H), 5.87 -dd, Jˆ17.4, 11.2 Hz, 1H). Anal. Calcd
for C13H20O: C, 81.17; H, 10.22. Found: C, 81.40; H, 10.01.
4.1.4. /4R,5R,6R)-5,6-Dimethyl-4-/1-methylvinyl)-5-vinyl-
cyclohex-1-enyl acetate /15). To a stirred mixture of 13
-95 mg, 0.5 mmol) and zinc acetate -93 mg, 0.5 mmol) in
acetic anhydride -1 ml) was added boron trifuluoride diethyl
etherate -61 ml, 0.5 mmol). After being stirred for 15 h at
608C, the reaction mixture was cooled to rt, and water was
added, followed by aqueous NaHCO3. After being stirred
brie¯y, the product was extracted with ether. Concentration
of the extract left an oil which was chromatographed on
silica gel -hexane±AcOEt, 12:1) to give 15 -70 mg, 60%)
along with unreacted 13 -5 mg, 5%). 15: an oil; IR -CHCl3)
3070, 1751, 1636, 1114, 918, 794 cm21; 1H NMR -CDCl3)
d 0.99 -d, Jˆ7.0 Hz, 3H), 1.16 -s, 3H), 1.74 -s, 3H), 2.12 -s,
3H), 2.08,2.15 -m, 1H), 2.21 -m, 2H), 2.33 -br t, Jˆ7.1 Hz,
1H), 4.82 -br s, 1H), 4.83 -d, Jˆ10.8 Hz, 1H), 5.02 -d,
Jˆ17.8 Hz, 1H), 5.03 -br s, 1H), 5.34 -br t, Jˆ3.9 Hz,
1H), 5.95 -dd, Jˆ17.8, 10.8 Hz, 1H). Anal. Calcd for
C15H22O2: C, 76.88; H, 9.46. Found: C, 76.52; H, 9.47.
4.1.2. /1S,3R,4R,5S)-3,4,6,6-Tetramethyl-4-vinylbicyclo-
[3.1.1]heptan-2-one /13). -1) To a stirred solution of diiso-
propylamine -0.32 ml, 2.4 mmol) in THF -2.0 ml) was
added dropwise at 08C a solution of 1.66 M BuLi in hexane
-1.4 ml, 2.2 mmol). After being stirred for 20 min, a
solution of 12 -178 mg, 1.0 mmol) in THF -2.0 ml) was
added dropwise, and stirring was continued for an additional
1 h. A solution of 1-methyl-2-pyrrolidinone -0.96 ml,
10 mmol) was added to the reaction mixture, and after
being stirred for 10 min, MeI -0.62 ml, 10 mmol) was
added. Stirring was continued for 40 min at 08C, and then
at rt for an additional40 min. The reaction mixture was
quenched with aqueous NH4Cl, and extracted with ether.
Concentration of the extract followed by puri®cation of
the residue by chromatography on silica gel -hexane±
AcOEt, 6:1) gave unreacted 12 -27 mg, 15%) and 13
-121 mg, 63%; 74% based on consumed 12) as an oil:
4.1.5. 2-[/1S,2R,3R,4R,5S)-4-Hydroxy-2,3,6,6-tetramethyl-
bicyclo[3.1.1]hept-2-yl]ethyl acetate /19) and 2-[/1S,2R,
3R,4S,5S)-4-hydroxy-2,3,6,6-tetramethylbicyclo[3.1.1]-
hept-2-yl]ethyl acetate /20). To a stirred solution of 13
-15.54 g, 80.9 mmol) in THF -80 ml) was added dropwise
at 08C a 1.0 M solution of BH3´THF in THF -162 ml,
162 mmol). The reaction mixture was stirred for 1 h and
allowed to warm to rt over 10 h, and then quenched by
addition of 25% aqueous THF -10 ml). To the reaction
mixture, 3 M aqueous NaOH -20 ml) followed by 30%
aqueous H2O2 -20 ml) was added slowly, and stirring was
17
[a]D ˆ213.2 -c 0.51, CHCl3); IR -CHCl3) 3060, 1710,
1
1636, 911 cm21; H NMR -CDCl3) d 1.15 -s, 3H), 1.18
-d, Jˆ7.6 Hz, 3H), 1.28 -s, 3H), 1.38 -s, 3H), 1.60 -d with
®ne splittings, Jˆ8.4 Hz, 1H), 2.07 -t, Jˆ5.7 Hz, 1H), 2.44
-q, Jˆ7.6 Hz, 1H), 2.55±2.61 -m, 2H), 4.92 -dd, Jˆ17.5,
1.2 Hz, 1H), 5.04 -dd, Jˆ11.2, 1.2 Hz, 1H), 5.99 -dd, Jˆ
17.5, 11.2 Hz, 1H). Anal. Calcd for C13H20O: C, 81.17; H,
10.22. Found: C, 81.20; H, 10.48.
continued for an additional12 h. Extraction with CHCl
3
followed by concentration of the extract left a crystalline
mixture of 16 and 17 [ca 17.1 g, 16/17ˆca 2:1 from the 1H
NMR analysis]. Pure 16 and 17 were obtained by chromato-
graphy on silica gel -hexane±AcOEt, 2:5).
-2) To a stirred mixture of copper-I) iodide -95 mg,
0.5 mmol) in THF -3 ml) was added at 2788C a solution
of 1.01 M vinylmagnesium bromide in THF -2.4 ml,
2.4 mmol). After being stirred brie¯y, a solution of 8b
-150 mg, 1.0 mmol) in THF -2 ml) was added. Stirring
was continued for an additional2 h, after which the reaction
mixture was treated with a solution of MeI -623 ml,
10.0 mmol) and HMPA -696 ml, 4.0 mmol) in THF -1 ml).
The reaction mixture was allowed to stir for 10 h, during
which the reaction temperature rose slowly to rt, quenched
with aqueous NH4Cl, and extracted with ether. Concen-
tration of the extract followed by chromatography of the
residue on silica gel -hexane±AcOEt, 6:1) gave unreacted
8b -42 mg, 23%) and 13 -96 mg, 50%).
4.1.6. /1S,2R,3R,4R,5S)-4-/2-Hydroxyethyl)-3,4,6,6-tetra-
methylbicyclo[3.1.1]heptan-2-ol /16). Crystals; mp 159±
1608C; IR -KBr) 3247 -br), 3227 -br) cm21 1H NMR
;
-CDCl3) d 0.99 -d, Jˆ10.6 Hz, 1H), 1.07 -d, Jˆ7.2 Hz,
3H), 1.08 -s, 3H), 1.23 -s, 3H), 1.28 -s, 3H), 1.3±1.39 -m,
1H), 1.5 -s, 2H, OH£2), 1.70 -t, Jˆ5.5 Hz, 1H), 1.84 -m,
1H), 1.98±2.07 -m, 3H), 3.45 -m, 1H), 3.52±3.65 -m, 2H).
Anal. Calcd for C13H24O2: C, 73.39; H, 11.68. Found: C,
73.54; H, 11.39.
4.1.7. /1S,2S,3R,4R,5S)-4-/2-Hydroxyethyl)-3,4,6,6-tetra-
methylbicyclo[3.1.1]heptan-2-ol /17). Semi-solid; IR
4.1.3. /1S,3S,4R,5S)-3,4,6,6-Tetramethyl-4-vinylbicyclo-
[3.1.1]heptan-2-one /14). The compound 13 -46 mg,
0.24 mmol) was dissolved in a solution of 5% aqueous
KOH -1.0 ml) and methanol -1.0 ml). The reaction mixture
-KBr) 3300 -br), 3250 -br) cm21 1H NMR -CDCl3) d
;
0.99 -d, Jˆ7.5 Hz, 3H), 1.31 -s, 3H), 1.13 -s, 3H), 1.31 -s,
3H), 1.35 -m, 2H), 1.59 -d, Jˆ10.2 Hz, 1H), 1.70 -t, Jˆ

8250
M. Kato et al. / Tetrahedron 57 22001) 8243±8256
5.9 Hz, 1H), 1.95±2.05 -m, 3H), 2.16 -q, Jˆ5.3 Hz, 1H),
2.26 -qd, Jˆ7.5, 5.8 Hz, 1H), 3.45±3.56 -m, 1H), 3.67 -m,
1H), 4.14 -dd, Jˆ5.9, 5.5 Hz, 1H).
1H), 1.54 -m, 1H), 1.89 -m, 1H), 2.04 -s, 3H), 2.05 -m, 1H),
2.52 -q, Jˆ7.3 Hz, 1H), 2.53±2.62 -m, 2H), 3.97±4.10 -m,
2H). Anal. Calcd for C15H24O3: C, 71.32; H, 9.47. Found: C,
71.39; H, 9.59.
The mixture, 16 and 17, obtained above was dissolved in
pyridine -50 ml) and acetic anhydride -13 ml) at 08C. The
reaction mixture was stirred for 1.5 h, and quenched by
addition of methanol-13 m)l. After being stirred brie¯y,
aqueous NaHCO3 was added and the product was extracted
with ether. The combined extracts were washed succes-
sively with water, aqueous CuSO4, water and brine, and
dried. Concentration left an oil which was chromatographed
on silica gel -hexane±AcOEt, 3:1) to give a mixture
-11.96 g, 58%) of 19 and 20 in a 2:1 ratio, and 18 -3.23 g,
13%). Pure 19 and 20 were obtained by MPLC -hexane±
AcOEt, 3:1).
4.1.10.
2-[/1R,2R,6R)-3-Acetyloxy-1,2-dimethyl-6-/1-
methylvinyl)cyclohex-3-enyl]ethyl acetate /22). To a
stirred mixture of 21 -1.38 g, 5.48 mmol) and zinc acetate
-1.01 g, 5.48 mmol) in acetic anhydride -15 ml) was added
at 08C a solution of boron tri¯uoride diethyl etherate
-0.33 ml, 2.74 mmol). The reaction mixture was stirred at
rt for 2 d, and quenched by addition of water. After being
stirred for 2 h, the aqueous mixture was extracted with ether.
The combined extracts were washed successively with
aqueous NaHCO3, water and brine, and dried. Evaporation
of the solvent left an oil which was chromatographed on
silica gel -hexane±AcOEt, 5:1) to give 22 -1.61 g, quant)
17
Compound 19: oil; [a]D ˆ216.7-c 0.67, CHCl3); IR -®lm)
17
as an oil: [a]D ˆ161.1 -c 2.77, CHCl3); IR -®lm) 3074,
1
1
3613, 3480, 1732 cm21; H NMR -CDCl3) d 0.95 -d, Jˆ
1736 cm21; H NMR -CDCl3) d 1.04 -d, Jˆ7.0 Hz, 3H),
10.4 Hz, 1H), 1.02 -d, Jˆ7.2 Hz, 3H), 1.09 -s, 3H), 1.24 -s,
3H), 1.29 -s, 3H), 1.39 -m, 1H), 1.71 -s, 1H, OH), 1.75 -t,
Jˆ5.7 Hz, 1H), 1.87 -m, 1H), 2.03 -s, 3H), 2.04 -m, 2H),
2.22 -dt, Jˆ10.4, 6.2 Hz, 1H), 3.63 -d, Jˆ6.4 Hz, 1H), 3.92
and 4.01 -m, 1H each). Anal. Calcd for C15H26O3: C, 70.78;
H, 10.17. Found: C, 70.83; H, 10.30.
1.07 -s, 3H), 1.59 -m, 2H), 1.72 -s, 3H), 2.04 -s, 3H), 2.12
-s, 3H), 2.0±2.19 -m, 2 H), 2.2±2.30 -m, 2H), 4.07±4.15 -m,
2H), 4.82 and 4.91 -s, 1H each), 5.29 -dd, Jˆ4.6, 1.8 Hz,
1H). Anal. Calcd for C17H26O4: C, 69.20; H, 9.21. Found: C,
69.36; H, 8.90.
4.1.11. 2-[/1R,2S,6R)-1,2-Dimethyl-6-/1-methylvinyl)-3-
oxocyclohexyl]ethyl acetate /25) and 2-[/1R,2R,6R)-1,2-
dimethyl-6-/1-methylvinyl)-3-oxocyclohexyl]ethyl ace-
tate /26). A mixture of 22 -1.22 g, 4.14 mmol) and K2CO3
-970 mg, 7.03 mmol) in methanol -20 ml) was stirred at rt
for 1 h, and quenched by addition of aqueous NH4Cl.
Extraction with ether followed by concentration of the
extract left the residue, which was ®ltered through a short
silica gel column -ether) to give a mixture of 23 and 24 in a
Compound 20: oil; IR -®lm) 3620, 3471 -br), 1731 cm21; 1H
NMR -CDCl3) d 0.99 -d, Jˆ7.5 Hz, 3H), 1.01 -s, 3H), 1.13
-s, 3H), 1.31 -s, 3H), 1.35 -m, 1H), 1.59 -d, Jˆ10.2 Hz, 1H),
1.70 -t, Jˆ5.9 Hz, 1H), 2.01 -s, 3H), 1.95±2.05 -m, 3H),
2.16 -q, Jˆ5.3 Hz, 1H), 2.26 -qd, Jˆ7.5, 5.8 Hz, 1H), 3.45±
3.56 -m, 1H), 3.67 -m, 1H), 4.14 -dd, Jˆ5.9, 5.5 Hz, 1H).
Anal. Calcd for C15H26O3: C, 70.78; H, 10.17. Found: C,
70.91; H, 10.45.
1
4:1 ratio -from H NMR). Pure samples were obtained by
puri®cation with MPLC -hexane±AcOEt, 1:1).
4.1.8. 2-[/1S,2R,3R,5S)-4-Acetyloxy-2,3,6,6-tetramethyl-
bicyclo[3.1.1]hept-2-yl]ethyl acetate /18). Oil; IR -®lm)
1
1740, 1243, 1027 cm21; H NMR -CDCl3) d 0.97 -d, Jˆ
4.1.12. /2S,3R,4R)-3-/2-Hydroxyethyl)-2,3-dimethyl-4-
17
7.1 Hz, 3H), 1.06 -d, Jˆ10.7 Hz, 1H), 1.11 -s, 3H), 1.20 -s,
3H), 1.26 -s, 3H), 1.40 -ddd, Jˆ13.4, 10.7, 5.1 Hz, 1H), 1.77
-t, Jˆ5.6 Hz, 1H), 1.89 -m, 1H), 2.07 -s, 6H), 2.09 -m, 1H),
2.21,2.28 -m, 2H), 3.90 -td, Jˆ10.7, 6.1 Hz, 1H), 4.02 -td,
Jˆ10.7 Hz, 5.1, 1H), 4.80 -dd, Jˆ7.8, 2.0 Hz, 1H). Anal.
Calcd for C17H28O4: C, 68.89; H, 9.52. Found: C, 68.72; H,
9.49.
/1-methylvinyl)cyclohexan-1-one /23). Oil; [a]D ˆ12.0
-c 0.82, CHCl3); IR -®lm) 3620, 3491-br), 3075, 1707 cm21
;
1H NMR -CDCl3) d 0.77 -s, 3H), 0.99 -d, Jˆ6.8 Hz, 3H),
1.19 -br s, 1H, OH), 1.5±1.71 -m, 2H), 1.79 -s, 3H), 1.71±
1.85 -m, 1 H), 2.0 -m, 1H), 2.33±2.45 -m, 3H), 2.66 -dd,
Jˆ12.8, 3.8 Hz, 1H), 3.74 and 3.89 -m, 1H each), 4.82 and
4.95 -s, 1H each). Anal. Calcd for C13H22O2: C, 74.24; H,
10.54. Found: C, 73.86; H, 10.82.
4.1.9. 2-[/1S,2R,3R,5S)-2,3,6,6-Tetramethyl-4-oxobicyclo-
[3.1.1]hept-2-yl]ethyl acetate /21). To a stirred solution of
oxalyl chloride -4.68 ml, 53.7 mmol) in CH2Cl2 -30 ml) was
added a solution of DMSO -7.62 ml, 107.3 mmol) in
CH2Cl2 -30 ml) at 2788C. After being stirred for 10 min,
a solution of a mixture, 19 and 20, -6.83 g, 26.85 mmol) in
CH2Cl2 -60 ml) was added dropwise. Stirring was continued
for an additional45 min, after which triethylamine -18.7 ml,
134.0 mmol) was added. The reaction mixture was stirred
for an additional2 h at 2788C, and then for 2 h at 08C, and
quenched by addition of aqueous NH4Cl. Extraction with
ether followed by concentration of the combined extracts
left an oil which was chromatographed on silica gel
-hexane±AcOEt, 4:1) to give 21 -6.52 g, 96%) as crystals:
4.1.13. /2R,3R,4R)-3-/2-Hydroxyethyl)-2,3-dimethyl-4-
/1-methylvinyl)cyclohexan-1-one /24). Oil; IR -®lm)
3620, 3465-br), 3074, 1702 cm21 1H NMR -CDCl3) d
;
0.96 -s, 3H) 1.18 -d, Jˆ7.3 Hz, 3H), 1.24 -br s, 1H, OH),
1.55±1.62 -m, 1H), 1.68±1.75 -m, 1H), 1.80 -s, 3H), 1.80±
1.85 -m, 1 H), 1.99 -m, 1H), 2.21±2.29 -m, 2H), 2.51±2.61
-m, 2H), 3.65 -m, 2H), 4.78 and 4.96 -s, 1H each).
A
mixture of keto-alcohols, 23 and 24, -878 mg,
4.17 mmol), acetic anhydride -5 ml) and pyridine -5 ml)
was stirred at 08C for 1.5 h. The reaction mixture was
quenched by addition of methanol-5 m)l, and stirring was
continued for an additional1 h. Water was added and the
product was extracted with ether. The combined extracts
were washed successively with water, aqueous CuSO4,
water and brine, and dried. Removal of the solvent followed
17
mp 73±748C; [a]D ˆ23.7 -c 1.63, CHCl3); IR -®lm) 1733,
1
1700 cm21; H NMR -CDCl3) d 1.12 -s, 3H), 1.19 -d, Jˆ
7.3 Hz, 3H), 1.24 -s, 3H), 1.38 -s, 3H), 1.46 -d, Jˆ10.7 Hz,

M. Kato et al. / Tetrahedron 57 22001) 8243±8256
8251
by chromatography of the residue with MPLC -hexane±
AcOEt, 3:1) gave 25 -723 mg, 69%) and 26 -187 mg, 18%).
20.65 mmol) was added, and the reaction mixture was
stirred for additional1 h, quenched by addition of aqueous
NH4Cl, and extracted with ether. Removal of the solvent left
an oily residue whose puri®cation with chromatography on
silica gel -hexane±AcOEt, 3:1) gave 29 -963 mg, 93%) as
17
Compound 25: oil; [a]D ˆ14.39 -c 7.13, CHCl3); IR -®lm)
1
3076, 1732, 1709 cm21; H NMR -CDCl3) d 0.78 -s, 3H),
17
0.99 -d, Jˆ6.8 Hz, 3H), 1.65±1.72 -m, 2H), 1.80 -s, 3H),
1.89 -m, 1H), 2.0 -m, 1H), 2.05 -s, 3H), 2.32±2.48 -m, 3 H),
2.65 -dd, Jˆ12.6, 3.8 Hz, 1H), 4.11±4.29 -m, 2H), 4.82 and
4.97 -s, 1H each). Anal. Calcd for C15H24O3: C, 71.39; H,
9.59. Found: C, 71.29; H, 9.80.
an oil: [a]D ˆ21.8 -c 1.31, CHCl3); IR -®lm) 3076, 1731,
1
1656 cm21; H NMR -CDCl3) d 1.06 -d, Jˆ7.1 Hz, 3H),
1.36 -s, 3H), 1.48±1.63 -m, 2H), 1.73 -s, 3H), 1.69±1.75
-m, 1H), 1.76±1.93 -m, 2H), 2.19 -dd, Jˆ12.1, 3.4 Hz, 1H),
2.33±2.43 -m, 2H), 3.84±3.97 -m, 4H), 4.71 and 4.91 -s, 1H
each), 9.85 -dd, Jˆ3.3, 2.4 Hz, 1H). Anal. Calcd for
C15H24O3: C, 71.39; H, 9.59. Found: C, 71.03 H, 9.33.
1
Compound 26: oil; IR -®lm) 3077, 1732, 1706 cm21; H
NMR -CDCl3) d 0.98 -s, 3H), 1.19 -d, Jˆ6.8 Hz, 3H),
1.60 -m, 1H), 1.71±1.86 -m, 2H), 1.79 -s, 3H), 1.94±2.04
-m, 1H), 2.04 -s, 3H), 2.24±2.30 -m, 2 H), 2.52±2.62 -m,
2H), 4.00±4.12 -m, 2H), 4.78 and 4. 96 -s, 1H each). Anal.
Calcd for C15H24O3: C, 71.39; H, 9.59. Found: C, 71.52; H,
9.50.
4.1.17. /1R,3S,6R,10S)-1,10-Dimethyl-5-methylenespiro-
[10,30-dioxolane-20,9-bicyclo[4.4.0]decan]-3-ol /30). To a
stirred solution of 29 -1.17 g, 4.64 mmol) in CH2Cl2 -50 ml)
was added dropwise at 08C a solution of 0.95 M diethyl-
aluminum chloride in hexane -4.90 ml, 4.64 mmol). The
reaction mixture was stirred for 40 min, quenched by
addition of aqueous NH4Cl, and extracted with ether±
CH2Cl2 -1:1). The combined extracts were washed succes-
sively with aqueous NaHCO3, water and brine, and dried.
Removal of the solvent left an oily residue which was
chromatographed on silica gel -hexane±AcOEt, 3:1) to
4.1.14. 2-[/6S,7R,8R)-6,7-Dimethyl-8-/1-methylvinyl)-1,4-
dioxaspiro[4.5]dec-7-yl]ethyl acetate /27). To a stirred
mixture of 25 -255 mg, 1.01 mmol) and 2,20--ethylene-
dioxy)-bis-trimethylsilane) -825 ml, 4.0 mmol) in CH2Cl2
-5 ml) was added at 2308C a solution of trimethylsilyl
tri¯ate -97 ml, 0.5 mmol). The reaction mixture was stirred
for 2 h, quenched by addition of aqueous NaHCO3, and
extracted with ether. The combined extracts were washed
successively with aqueous NaHCO3, water, and brine, and
dried. Concentration followed by puri®cation of the residue
with MPLC -hexane±AcOEt, 3:1) gave 27 -272 mg, 92%)
17
give 30 -950 mg, 81%) as an oil: [a]D ˆ226.8 -c 1.70,
1
CHCl3); IR -®lm) 3610, 3461 -br), 3084, 1649 cm21; H
NMR -CDCl3) d 0.87 -d, Jˆ7.0 Hz, 3H), 1.01 -s, 3H),
1.34 -dd, Jˆ14.2, 3.7 Hz, 1H), 1.40±1.48 -m, 2H), 1.56±
1.68 -m, 3H), 1.86 -d, Jˆ11.0 Hz, 1H), 1.92 -dt, Jˆ13.2,
3.0 Hz, 1H), 2.04 -d, Jˆ14.0 Hz, 1H), 2.39 -s, 2H), 3.77±
4.03 -m, 4H), 4.17 -s with ®ne splittings, 1/2Hˆ12 Hz,
1H),29 4.71 and 4.92 -s, 1H each). Anal. Calcd for
C15H24O3: C, 71.39; H, 9.59. Found: C, 71.27; H, 9.82.
17
as an oil: [a]D ˆ13.20 -c 1.63, CHCl3); IR -®lm) 3074,
1
1728 cm21; H NMR -CDCl3) d 0.88 -d, Jˆ6.5 Hz, 3H),
0.89 -s, 3H), 1.36±1.48 -m, 2H), 1.59±1.66 -m, 3H), 1.75
-s, 3H), 1.7±1.75 -m, 1H), 1.79±1.86 -m, 1H), 2.00 -s, 3H),
2.15 -dd, Jˆ11.9, 2.2 Hz, 1H), 3.77±4.16 -m, 6H), 4.71 and
4.91 -s, 1H each). Anal. Calcd for C17H28O4: C, 68.89; H,
9.52. Found: C, 68.72; H, 9.75.
4.1.18.
/1R,6R,10S)-1,10-Dimethyl-5-methylenespiro-
[10,30-dioxolane-20,9-bicyclo[4.4.0]decan]-3-one /31) and
/4aR,8S,8aR)-4,8,8a-trimethylspiro[10,30-dioxolane-20,7-
1,4a,5,6,7,8,8a-heptahydronaphthalen]-2-one /9). To a
stirred solution of oxalyl chloride -0.51 ml, 5.86 mmol) in
CH2Cl2 -12 ml) was added at 2788C a solution of DMSO
-0.83 ml, 11.72 mmol) in CH2Cl2 -15 ml). After being
stirred for 10 min, a solution of 27 -740 mg, 2.93 mmol)
in CH2Cl2 -10 ml) was added dropwise, and stirring was
continued for additional45 min, after which triethyalmine
-2.0 ml, 14.65 mmol) was added. The reaction mixture was
stirred for additional10 min at 2788C, and for 5 min at rt,
quenched by addition of aqueous NH4Cl, and extracted with
ether. Removal of the solvent left an oily residue which was
puri®ed by MPLC -hexane±AcOEt, 1:1) to give 31
-574 mg, 78%) and 9 -36 mg, 5%).
4.1.15. 2-[/6S,7R,8R)-6,7-Dimethyl-8-/1-methylvinyl)-1,4-
dioxaspiro[4.5]dec-7-yl]ethan-1-ol /28). A mixture of 27
-1.49 g, 5.02 mmol) and K2CO3 -1.39 g, 10.04 mmol) in
methanol-30 m)l was stirred at 0 8C for 2 h and warmed at
rt brie¯y. Filtration followed by concentration of the ®ltrate
left an oily residue which was dissolved in ether. The ether
solution was washed successively with water and brine, and
dried. Concentration left an oil which was chromatographed
on silica gel -hexane±AcOEt, 3:2) to give 28 -1.29 g, quant)
17
as an oil: [a]D ˆ22.90 -c 1.49, CHCl3); IR -®lm) 3619,
1
3463 -br), 3074, 1637 cm21; H NMR -CDCl3) d 0.87 -d,
Jˆ6.5 Hz, 3H), 0.89 -s, 3H), 1.15 -br s, 1H, OH), 1.34±1.45
-m, 2H), 1.75 -s, 3H), 1.6±1.88 -m, 4H), 1.79±1.86 -m, 1H),
2.13 -dd, Jˆ11.9, 2.2 Hz, 1H), 3.59±4.02 -m, 6H), 4.72 and
4.91 -s, 1H each). Anal. Calcd for C15H26O3: C, 70.83; H,
10.30. Found: C, 70.62; H, 10.25.
17
Compound 31: oil; [a]D ˆ247.5 -c 1.69, CHCl3); IR -®lm)
1
3092, 1713, 1648 cm21; H NMR -CDCl3) d 0.71 -s, 3H),
0.87 -d, Jˆ7.0 Hz, 3H), 1.53 -td, Jˆ13.3, 4.2 Hz, 1H), 1.64
-td, Jˆ12.8, 2.7 Hz, 1H), 1.73±1.83 -m, 1H), 1.80 -q,
Jˆ7.0 Hz, 1H), 1.95 -dt, Jˆ12.5, 2.9 Hz, 1H), 2.15 -d, Jˆ
13.9 Hz, 1H), 2.25 -d, Jˆ12.8 Hz, 1H), 2.52 -dd, Jˆ13.9,
2.0 Hz, 1H), 3.08 -dd, Jˆ15.1, 2.0 Hz, 1H), 3.14 -d, Jˆ
15.1 Hz, 1H), 3.79±4.03 -m, 4H), 4.71 and 4.85 -s, 1H
each). Anal. Calcd for C15H22O3: C, 71.97; H, 8.86.
Found: C, 71.71; H, 8.71.
4.1.16. 2-[/6S,7R,8R)-6,7-Dimethyl-8-/1-methylvinyl)-1,4-
dioxaspiro[4.5]dec-7-yl]ethanal /29). To a stirred solution
of oxalyl chloride -0.72 ml, 8.26 mmol) in CH2Cl2 -5 ml)
was added a solution of DMSO -1.17 ml, 16.52 mmol) in
CH2Cl2 -5 ml) at 2788C. After being stirred for 10 min, a
solution of 28 -1.05 g, 4.13 mmol) in CH2Cl2 -10 ml) was
added dropwise, and stirring was continued for additional
45 min. To the reaction mixture, triethylamine -2.88 ml,
17
Compound 9: crystals; mp 88±898C; [a]D ˆ282.4 -c 1.19,

8252
M. Kato et al. / Tetrahedron 57 22001) 8243±8256
1
CHCl3); IR -®lm) 3016, 1666 cm21; H NMR -CDCl3) d
0.88 -d, Jˆ7.0 Hz, 3H), 0.92 -s, 3H), 1.48±1.61 -m, 2H),
1.79 -q, Jˆ7.0 Hz, 1H), 1.92 -s, 3H), 1.9±2.05 -m, 2H), 2.09
-d, Jˆ16.1 Hz, 1H), 2.39 -d, Jˆ10.9 Hz, 1H), 2.45 -d, Jˆ
16.1 Hz, 1H), 3.81±4.04 -m, 4H), 5.87 -s, 1H). Anal. Calcd
for C15H22O3: C, 71.97; H, 8.86. Found: C, 71.70; H, 8.70.
5.58 -dd, Jˆ17.4, 10.9 Hz, 1H). Anal. Calcd for C18H28O3:
C, 73.93; H, 9.65. Found: C, 73.70; H, 9.54.
-2) From 9. To a stirred mixture of copper-I) iodide -85 mg,
0.45 mmol) and isopropenyl sul®de -0.19 ml, 1.35 mmol) in
THF -3 ml) was added a 1.0 M solution of vinyllithium in
THF -0.74 ml, 0.87 mmol) dropwise at 2788C, and the
reaction mixture was allowed to warm to 2408C over 2 h,
then cooled to 2788C. To the reaction mixture was added a
solution of 9 -75 mg, 0.30 mmol) in THF -1 ml). After being
stirred at 2788C for 10 min, the reaction was allowed to
warm to 2408C, and a solution of methyl iodide -255 mg,
1.80 mmol) in HMPA -0.3 ml) and THF -1 ml) was added.
The reaction mixture was allowed to stir for 7 h, during
which the reaction temperature rose to rt. Extractive workup
followed by puri®cation of the residue by MPLC -hexane±
AcOEt, 3:1) gave 33 -18 mg, 21%).
Isomerization of 31 to 9. A mixture of 31 -399 mg,
1.60 mmol) and DBU -0.36 ml, 2.40 mmol) in CH2Cl2
-20 ml) was stirred for 1 h, quenched with aqueous
NH4Cl, and extracted with ether. Concentration of the
combined extracts followed by puri®cation of the residue
by chromatography on silica gel -hexane±AcOEt, 1:1) gave
9 -399 mg, quant).
4.1.19. /1R,5R,6R,10S)-1,5,10-Trimethyl-5-vinylspiro-
[10,30-dioxolane-20,9-bicyclo[4.4.0]decan]-3-one /32). To
a stirred mixture of copper-I) iodide -230 mg, 1.14 mmol)
in THF -5 ml) was added at 2788C a solution of 0.97 M
vinylmagnesium bromide in THF -3.5 ml, 3.41 mmol), and
stirring was continued for 30 min. To the reaction mixture, a
solution of 9 -568 mg, 2.27 mmol) in THF -5 ml) was added
dropwise. The reaction mixture was stirred for an additional
1.5 h, quenched by addition of aqueous NH4Cl, and
extracted with ether. Concentration of the extract followed
by puri®cation of the residue with MPLC -hexane±AcOEt,
4:1) gave 32 -422 mg, 67%) as crystals: mp 84±858C;
4.1.21. /1R,4S,5R,6R,10S)-1,4,5,10-Tetramethyl-5-vinyl-
spiro[10,30-dioxolane-20,9-bicyclo[4.4.0]decane]-3-one
/34). The compound 33 -132 mg, 0.45 mmol) was dissolved
in 5% KOH±methanol solution -15 ml), and the reaction
mixture was stirred for 12 h at rt. The solvent was mostly
removed under reduced pressure, and water was added to the
oily residue. Extraction with AcOEt followed by concen-
tration of the extract left an oil which was puri®ed by MPLC
-hexane±AcOEt, 4:1) to give 34 -119 mg, 90%) as crystals:
17
17
[a]D ˆ24.6 -c 1.36, CHCl3); IR -®lm) 3088, 1706,
mp 104±1058C; [a]D ˆ17.8 -c 1.48, CHCl3); IR -®lm)
1637 cm21; H NMR -600 MHz, CDCl3) d 0.81 -d, Jˆ
3087, 1705, 1636 cm21; H NMR -CDCl3) d 0.80 -s, 3H),
1
1
7.0 Hz, 3H), 0.94 -s, 3H), 1.04 -s, 3H), 1.42 -td, Jˆ13.5,
4.0 Hz, 1H), 1.47 -td, Jˆ13.7, 3.3 Hz, 1H), 1.59±1.62 -m,
2H), 1.77 -q, Jˆ7.0 Hz, 1H), 1.88 -dt, Jˆ12.5, 2.7 Hz, 1H),
2.09 -dd, Jˆ13.5, 2.5 Hz, 1H), 2.13 -d, Jˆ13.5 Hz, 1H),
2.39 -dd, Jˆ13.1, 2.5 Hz, 1H), 2.42 -d, Jˆ13.1 Hz, 1H),
3.74±3.81 -m, 1H, OCHHCH2O), 3.89±3.94 -m, 2H,
OCHHCHHO), 3.97±4.01 -m, 1H, OCHHCHHO), 4.97
-d, Jˆ17.4 Hz, 1H), 5.03 -d, Jˆ10.7 Hz, 1H), 5.76 -dd,
Jˆ17.4, 10.7 Hz, 1H). Anal. Calcd for C17H26O3: C,
73.35; H, 9.41. Found: C, 73.44; H, 9.34.
0.80 -d, Jˆ6.8 Hz, 3H), 0.85 -d, Jˆ6.8 Hz, 3H), 0.90 -s,
3H), 1.41±1.52 -m, 2H), 1.57±1.65 -m, 2H), 1.79 -q, Jˆ
6.8 Hz, 1H), 1.87 -dd, Jˆ10.0, 2.4 Hz, 1H), 2.18 and 2.42
-d, Jˆ11.7 Hz, 1H each), 2.41 -q, Jˆ6.8 Hz, 1H), 3.78±4.00
-m, 4H), 4.94 -d, Jˆ17.3 Hz, 1H), 5.14 -d, Jˆ10.8 Hz, 1H),
5.62 -dd, Jˆ17.3, 10.8 Hz, 1H). Anal. Calcd for C18H28O3:
C, 73.93; H, 9.65. Found: C, 73.83; H, 9.82.
4.1.22. 2-[/1R,2S,3R,6R)-3-Hydroxy-1,2-dimethyl-6-/1-
methylvinyl)cyclohexyl]ethyl acetate /35). To a stirred
solution of 25 -54 mg, 0.22 mmol) in THF -1.5 ml) was
added dropwise at 08C a 0.4 M solution of lithium tri-tert-
butoxyaluminum hydride in THF -0.91 ml, 0.32 mmol). The
reaction mixture was stirred for 20 min, quenched by
addition of aqueous NH4Cl, and extracted with ether.
Removal of the solvent left an oil which was puri®ed by
MPLC -hexane±AcOEt, 2:1) to give 35 -58 mg, quant) as
4.1.20. /1R,4R,5R,6R,10S)-1,4,5,10-Tetramethyl-5-vinyl-
spiro[10,30-dioxolane-20,9-bicyclo[4.4.0]decan]-3-one /33).
-1) From 32. To a stirred solution of 1.66 M BuLi in hexane
-2.41 ml, 4.0 mmol) was added dropwise at 08C a solution
of 1,1,1,3,3,3-hexamethyldisilazane -0.84 ml, 4.0 mmol),
and stirring was continued for 30 min. The solvent was
removed off under reduced pressure, and crystals thereby
formed were dissolved in THF -8 ml). To a stirred solution
of 32 -306 mg, 1.1 mmol) in THF -8 ml) was added at 08C
the solution of LHMDS in THF prepared above. After being
stirred for 1 h at rt, methyliodide -0.68 ml, 11.0 mmol) was
added. The reaction mixture was stirred for an additional
2 h, quenched by addition of aqueous NH4Cl, and extracted
with AcOEt. Removal of the solvent left an oily residue
which was puri®ed by MPLC -hexane±AcOEt, 3:1) to
give 33 -196 mg, 61%) as crystals: mp 67±698C;
17
crystals: mp 38±408C, [a]D ˆ211.1 -c 2.77, CHCl3); IR
1
-®lm) 3520, 3027, 1728, 1635 cm21; H NMR -CDCl3) d
0.98 -s, 3H) -d, Jˆ7.1 Hz, 3H), 1.31±1.36 -m, 1H), 1.41±
1.57 -m, 3H), 1.61 -t, Jˆ7.5 Hz, 2H), 1.77 -s, 3H), 1.86 -dq,
Jˆ13.9, 2.3 Hz, 1H), 1.97±2.06 -m, 1H), 2.04 -s, 3H), 2.13
-dd, Jˆ12.7, 2.5 Hz, 1H), 3.84 -br s, 1H), 4.12 -m, 2H), 4.72
and 4.90 -s, 1H each). Anal. Calcd for C15H26O3: C, 70.66;
H, 10.22. Found: C, 70.83; H, 10.30.
4.1.23. 2-[/1R,6R)-1,2-Dimethyl-6-/1-methylvinyl)cyclo-
hex-2-enyl]ethyl acetate /36). To a stirred solution of 35
-838 mg, 3.29 mmol) in pyridine -10 ml) was added drop-
wise at rt a solution of phosphorus oxychloride -1.54 ml,
16.5 mmol), and stirring was continued for 2 h. The reaction
mixture was poured into ice water, and the product was
extracted with ether. The combined extracts were washed
successively with 1 M HCl solution, water, aqueous
17
[a]D ˆ247.5 -c 2.15, CHCl3); IR -®lm) 3087, 1701,
1637 cm21; H NMR -CDCl3) d 0.83 -d, Jˆ6.8 Hz, 3H),
1
1.02 -d, Jˆ7.0 Hz, 3H), 1.10 -s, 3H), 1.13 -s, 3H), 1.37±
1.41 -m, 1H), 1.46±1.51 -m, 2H), 1.61 -m, 1H), 1.69 -q, Jˆ
6.8 Hz, 1H), 1.86 -dd, Jˆ10.1, 1.6 Hz, 1H), 2.24 and 2.32
-d, Jˆ15.0 Hz, 1H each), 2.42 -q, Jˆ7.0 Hz, 1H), 3.77±4.02
-m, 4H), 4.93 -d, Jˆ17.4 Hz, 1H), 5.06 -d, Jˆ10.9 Hz, 1H),

M. Kato et al. / Tetrahedron 57 22001) 8243±8256
8253
NaHCO3, water and brine, and dried. Concentration of the
extract followed by chromatography of the residue on silica
gel-hexane±AcOEt, 10:1) gave 36 -723 mg, 93%) as an oil:
8a-hexahydronaphthalen-2-one /40) and /4aR,8aR)-
4,8,8a-trimethyl-1,4a,5,6,8a-pentahydronaphthalen-2-
one /10). According to the procedure described for the
preparation of the mixture of 9 and 31 from 30, a solution
of oxalyl chloride -0.11 ml, 1.22 mmol) and DMSO
-0.17 ml, 2.43 mmol) in CH2Cl2 -5 ml) was stirred at
2788C for 10 min. To the reaction mixture was added a
solution of 39 -117 mg, 0.61 mmol) in CH2Cl2 -3 ml),
followed by triethylamine -0.60 ml, 4.29 mmol), and
stirring was continued for an additional2 h. Aqueous
workup followed by puri®cation of the residue by MPLC
-hexane±AcOEt, 3:1) gave 40 -18 mg, 15%) and 10 -74 mg,
64%).
17
[a]D ˆ278.5 -c 2.47, CHCl3); IR -®lm) 3074, 1732,
1
1635 cm21; H NMR -CDCl3) d 0.96 -s, 3H), 1.50±1.56
-m, 1H), 1.63±1.72 -m, 2H), 1.66 -s, 3H), 1.80 -s, 3H),
1.87±1.93 -m, 1H), 1.95±2.01 -m, 2H), 2.04 -s, 3H), 2.28
-dd, Jˆ12.2, 2.7 Hz, 1H), 3.89 -dt, Jˆ10.8, 4.9 Hz, 1H),
4.17 -dt, Jˆ10.8, 5.9 Hz, 1H), 4.76 and 4.90 -s, 1H each),
5.46 -s, 1H). Anal. Calcd for C15H24O2: C, 76.27; H, 10.22.
Found: C, 76.23; H, 10.23.
4.1.24. 2-[/1R,6R)-1,2-Dimethyl-6-/1-methylvinyl)cyclo-
hex-2-enyl]ethan-1-ol /37). A mixture of 36 -29 mg,
0.12 mmol) and K2CO3 -34 mg, 0.25 mmol) in methanol
-2 ml) was stirred at rt for 3 h, and diluted with water.
Extraction with ether followed by concentration of the
extract left an oily residue which was puri®ed by MPLC
-hexane±AcOEt, 2:1) to give 37 -24 mg, 99%) as crystals:
17
Compound 40: oil; [a]D ˆ2250.1 -c 0.77, CHCl3); IR
1
-®lm) 3080, 1712, 1651 cm21; H NMR -CDCl3) d 0.79
-s, 3H), 1.57±1.67 -m, 1H), 1.64 -s, 3H), 1.82 -m, 1H),
2.12±2.18 -m, 2H), 2.29 -d, Jˆ14.0 Hz, 1H), 2.47 -d, Jˆ
12.0 Hz, 1H), 2.59 -dd, Jˆ14.0, 1.2 Hz, 1H), 3.14 -br s, 2H),
4.57 and 4.88 -s, 1H each), 5.38 -br s, 1H). Anal. Calcd for
C13H18O: C, 82.06; H, 9.54. Found: C, 82.00; H, 9.52.
17
mp 39±408C, [a]D ˆ2127.4 -c 1.84, CHCl3); IR -®lm)
1
3621, 3451 -br), 3074, 1635 cm21; H NMR -CDCl3) d
0.96 -s, 3H), 1.50±1.55 -m, 2H), 1.63±1.74 -m, 2H), 1.68
-s, 3H), 1.78 -s, 3H), 1.81±1.90 -m, 1H), 1.95±2.00 -m, 2H),
2.27 -dd, Jˆ12.4, 2.7 Hz, 1H), 3.50 -dt, Jˆ10.3, 5.1 Hz,
1H), 3.77 -dt, Jˆ10.3, 5.9 Hz, 1H), 4.73 and 4.93 -s, 1H
each), 5.44 -s, 1H). Anal. Calcd for C13H22O: C, 80.35; H,
11.41. Found: C, 80.51; H, 11.03.
17
Compound 10: crystals; mp 41±428C; [a]D ˆ2214.2 -c
1
0.64, CHCl3); IR -®lm) 3033, 1655, 1619 cm21; H NMR
-CDCl3) d 0.99 -s, 3H), 1.48±1.62 -m, 1H) 1.64 -s, 3H),
1.97 -s, 3H), 2.02±2.06 -m, 1H), 2.13±2.22 -m, 3H), 2.60 -d,
Jˆ16.0 Hz, 2H), 5.32 -s, 1H), 5.94 -s, 1H). Anal. Calcd for
C13H18O: C, 82.06; H, 9.54. Found: C, 81.95; H, 9.50.
4.1.25. 2-[/1R,6R)-1,2-Dimethyl-6-/1-methylvimyl)cyclo-
hex-2-enyl]ethanal /38). According to the procedure
described for the preparation of 29 from 28, oxalyl chloride
-0.15 ml, 1,72 mmol) was treated with DMSO -0.24 ml,
3.43 mmol) in CH2Cl2 -7 ml) at 2788C. After being stirred
for 10 min, a solution of 37 -167 mg, 0.86 mmol) in CH2Cl2
-4 ml) was added, followed by triethylamine -0.60 ml,
4.29 mmol), and the reaction mixture was stirred for
additional 1 h. Aqueous workup followed by puri®cation
of the residue by chromatography on silica gel -pentane±
ether, 29:1) gave 38 -153 mg, 93%) as an oil; IR -®lm) 3076,
1716, 1635 cm21; 1H NMR -CDCl3) d 1.03 -s, 3H), 1.61 -m,
1H), 1.72 -s, 3H), 1.76 -s, 3H), 1.72±1.80 -m, 1H), 2.04±
2.09 -m, 2H), 2.38 -dd, Jˆ12.2, 2.7 Hz, 1H), 2.42 -dd, Jˆ
16.3, 1.7 Hz, 1H), 2.58 -dd, Jˆ16.3, 2.7 Hz, 1H), 4.71 and
4.96 -s, 1H each), 5.54 -s, 1H), 9.67 -dd, Jˆ2.7, 1.7 Hz, 1H).
The compound 38 was unstable, and used for the next
reaction without further puri®cation.
According to the procedure described for the preparation
of 9 from 31, treatment of 40 with DBU provided 10 quanti-
tatively.
4.1.28.
/4S,4aR,8aR)-4-/But-3-enyl)-4,8,8a-trimethyl-
1,3,4,4a,5,6,8a-heptahydronaphthalen-2-one /41). To a
stirred mixture of copper-I) iodide -931 mg, 4.60 mmol) in
THF -5 ml) was added dropwise at 2208C a solution of
1.02 M homoallylmagmesium bromide in THF -5.0 ml,
5.10 mmol). After being stirred brie¯y, the reaction mixture
was cooled at 2788C, and boron tri¯uoride diethyletherate
-0.57 ml, 4.6 mmol) was added. After being stirred for
30 min, a solution of 10 -442 mg, 2.30 mmol) in THF
-5 ml) was added dropwise, and stirring was continued for
6 h, during which the reaction temperature rose slowly to
2208C. The reaction mixture was quenched by addition of
aqueous NH4Cl, and extracted with ether. Concentration of
the extract followed by chromatography of the residue on
silica gel -hexane±AcOEt, 3:1) gave 41 -491 mg, 86%) as
4.1.26. /2S,4aR,8aR)-8,8a-Dimethyl-4-methylene-1,2,3,
4a,5,6,8a-heptahydronaphthalen-2-ol /39). According to
the procedure described for the preparation of 30 from 29,
a solution of 38 -153 mg, 0.80 mmol) in CH2Cl2 -8 ml) was
treated with a solution of 0.97 M diethylaluminum chloride
in hexane -0.82 ml, 0.80 mmol). Aqueous workup followed
by puri®cation with MPLC -hexane±AcOEt, 2:1) gave 39
17
an oil: [a]D ˆ2130.1 -c 0.94, CHCl3); IR -®lm) 3075,
1
1714, 1641, 990, 910 cm21; H NMR -CDCl3) d 0.93 -s,
3H), 1.06 -s, 3H), 1.37 -m, 1H), 1.46±1.57 -m, 2H), 1.58 -s,
3H), 1.72 -dd, Jˆ13.4, 6.4 Hz, 1H), 1.82 -dd, Jˆ12.5,
2.0 Hz, 1H), 2.03 -m, 2H), 2.07±2.12 -m, 2H), 2.12 -dd,
Jˆ13.4, 1.9 Hz, 1H), 2.25 -d, Jˆ12.7 Hz, 1H), 2.41 -d,
Jˆ13.4 Hz, 1H), 2.44 -dd, Jˆ12.7, 1.9 Hz, 1H), 4.95 -d,
Jˆ11.9 Hz, 1H), 5.03 -d, Jˆ17.0 Hz, 1H), 5.28 -s, 1H),
5.80 -ddt, Jˆ17.0, 11.9, 6.4 Hz, 1H). Anal. Calcd for
C17H26O: C, 82.87; H, 10.64. Found: C, 82.60 H, 10.61.
17
-100 mg, 65%) as crystals: mp 57±588C, [a]D ˆ2233.9 -c
1.29, CHCl3); IR -®lm) 3611, 3454 -br), 3082, 1651 cm21
;
1H NMR -CDCl3) d 1.10 -s, 3H), 1.40 -m, 1H), 1.53 -dd,
Jˆ14.4, 3.7 Hz, 1H), 1.62±1.68 -m, 2H), 1.66 -s, 3H), 2.03±
2.11 -m, 4H), 2.41 -m, 2H), 4.23 -s, 1/2Hˆ10.9 Hz, 1H),29
4.72 and 4.95 -s, 1H each), 5.20 -s, 1H). Anal. Calcd for
C13H20O: C, 81.20; H, 10.48. Found: C, 81.50; H, 10.75.
4.1.29. /3R,4R,4aR,8aR)-4-/But-3-enyl)-3,4,8,8a-tetra-
methyl-1,3,4,4a,5,6,8a-heptahydronaphthalen-2-one /42).
To a stirred solution of 41 -141 mg, 0.57 mmol) in THF
-4 ml) was added dropwise at 08C a 0.5 M solution of
4.1.27. /4aR,8aR)-8,8a-Dimethyl-4-methylene-1,3,4a,5,6,

8254
M. Kato et al. / Tetrahedron 57 22001) 8243±8256
LHMDS in THF -1.75 ml, 0.88 mmol), and stirring was
continued at rt for an additional1 h. After cooinl g at
2208C, methyliodide -0.36 m,l 5.7 mmo)l was added.
The reaction mixture was stirred overnight, quenched by
addition of aqueous NH4Cl, and extracted with ether.
Concentration of the extract followed by puri®cation of
the residue with MPLC -hexane±AcOEt, 9:1) gave 42
-44 mg, 30%; 50% from the consumed 41) and unreacted
-2.5 ml) was added at 08C a solution of trimethyl
phosphonoacetate -60.7 mg, 0.33 mmol) in THF -0.5 ml).
The reaction mixture was stirred for 1 h, after which a
solution of 44 -18 mg, 0.065 mmol) in THF -1 ml) was
added. The resulting mixture was heated at 608C with
stirring for 12 h, after cooling to rt, quenched with aqueous
NH4Cl, and extracted with ether. Removal of the solvent
followed by puri®cation of the residue with MPLC
-hexane±AcOEt, 4:1) gave 45 -15 mg, 69%) and 46
-3.5 mg, 16%) along with unreacted 44 -2 mg, 11%).
17
41 -63 mg). 42: oil; [a]D ˆ2144.1 -c 0.38, CHCl3); IR
-®lm) 3080, 1709, 1641, 995, 910 cm21
;
1H NMR
-CDCl3) d 0.98 -s, 3H), 1.10 -d, Jˆ6.8 Hz, 3H), 1.18 -s,
3H), 1.31±1.59 -m, 3H), 1.60 -s, 3H), 1.71 -dd, Jˆ13.2,
6.6 Hz, 1H), 1.78 -dd, Jˆ12.8, 2.0 Hz, 1H), 1.90 -m, 2H),
2.02±2.16 -m, 2H), 2.32 -d, Jˆ15.4 Hz, 1H), 2.39 -d,
Jˆ15.4 Hz, 1H), 2.46 -d, Jˆ6.8 Hz, 1H), 4.93 -d, Jˆ
10.3 Hz, 1H), 5.00 -d, Jˆ17.1 Hz, 1H), 5.26 -s, 1H), 5.75
-ddt, Jˆ17.1, 10.3, 6.6 Hz, 1H). Anal. Calcd for C18H28O:
C, 83.02; H, 10.84. Found: C, 82.58 H, 10.99.
24
Compound 45: crystals; mp 65±65.58C; [a]D ˆ294.2 -c
0.47, CHCl3); IR -®lm) 1721, 1715, 1646, 1228, 1140 cm21
;
1H NMR -CDCl3) d 0.72 -s, 3H), 0.94 -d, Jˆ6.8 Hz, 3H),
0.97 -s, 3H), 1.41 -m, 1H), 1.57 -s, 3H), 1.65±1.73 -m, 3H),
1.98 -dd, Jˆ12.2, 1.7 Hz, 1H), 2.00±2.17 -m, 4H), 2.29 -d,
Jˆ1.2 Hz, 3H), 2.30 -d, Jˆ11.7 Hz, 1H), 2.46 -d, Jˆ
11.7 Hz, 1H), 2.55 -q, Jˆ6.8 Hz, 1H), 3.69 -s, 3H), 5.29
-s, 1H), 5.69 -s, 1H). Anal. Calcd for C21H32O3: C, 75.86;
H, 9.70. Found: C, 75.53; H, 9.60.
4.1.30.
/3S,4R,4aR,8aR)-4-/But-3-enyl)-3,4,8,8a-tetra-
methyl-1,3,4,4a,5,6,8a-heptahydronaphthalen-2-one /43).
According to the procedure described for the preparation of
34 from 33, a solution of 42 -29 mg, 0.11 mmol) in 5%
KOH±methanol-2 m)l was stirred at rt for 1 d. Workup
followed by puri®cation with MPLC -hexane±AcOEt, 9:1)
24
Compound 46: oil; [a]D ˆ2104.4 -c 0.39, CHCl3); IR
1
-®lm) 1718, 1652, 1210, 1156 cm21; H NMR -CDCl3) d
0.37-s, 3H), 0.98 -s, 3H), 0.99 -d, Jˆ6.8 Hz, 3H), 1.36 -m,
1H), 1.55±1.58 -m, 1H), 1.58 -s, 3H), 1.71 -m, 1H), 1.83
-dd, Jˆ13.1, 6.1 Hz, 1H), 1.90 -s, 3H), 2.04 -dd, Jˆ12.2,
1.5 Hz, 1H), 2.17±2.21 -m, 2H), 2.33 -d, Jˆ11.7 Hz, 1H),
2.46 -d, Jˆ11.7 Hz, 1H), 2.60 -m, 2H), 2.69 -q, Jˆ6.8 Hz,
1H), 3.67 -s, 3H), 5.29 -s, 1H), 5.67 -s, 1H).
17
gave 43 -29 mg, quant) as an oil: [a]D ˆ299.9 -c 0.93,
1
CHCl3); IR -®lm) 3075, 1713, 1641, 996, 910 cm21; H
NMR -CDCl3) d 0.72 -s, 3H), 0.94 -d, Jˆ6.6 Hz, 3H),
0.98 -s, 3H), 1.35 -m, 1H), 1.51±1.68 -m, 4H), 1.57 -s,
3H), 2.00 -dd, Jˆ10.5, 1.9 Hz, 1H), 2.02 -m, 1H), 2.12
-m, 2H), 2.29 -d, Jˆ11.7 Hz, 1H), 2.46 -d, Jˆ11.7 Hz,
1H), 2.59 -q, Jˆ6.6 Hz, 1H), 4.98 -d, Jˆ11.0 Hz, 1H),
5.03 -d, Jˆ17.0 Hz, 1H), 5.27 -s, 1H), 5.81 -ddt, Jˆ17.0,
11.0, 6.4 Hz, 1H). Anal. Calcd for C18H28O: C, 83.02; H,
10.84. Found: C, 82.70; H, 10.51.
4.1.33. /2E)-5-[/1R,2S,4aR,8aR)-1,2,4a,5-Tetramethyl-3-
oxo-1,2,4,4a,7,8,8a-heptahydronaphthyl]-3-methylpent-
2-enoic acid /7-oxo-kolavenic acid) /1). To a stirred
solution of 45 -25 mg, 0.08 mmol) in methanol -1.5 ml)
was added a 0.5 M KOH aqueous solution -1.5 ml,
0.75 mmol). The reaction mixture was heated at 408C for
6 h, cooled to rt, made acidic with 0.5 M HCl solution, and
extracted with ether. Concentration followed by puri®cation
of the residue with HPLC -hexane±AcOEt, 4:1) gave 1
4.1.31. /3S,4R,4aR,8aR)-3,4,8,8a-Tetramethyl-4-/3-oxo-
butyl)-1,3,4,4a,5,6,8a-heptahydronaphthalen-2-one /44).
A mixture of palladium chloride -3 mg, 0.02 mmol) and
copper-I) chloride -8.8 mg, 0.08 mmol) in 10% aqueous
DMF -2.2 ml) was stirred for 30 min in a stream of oxygen,
after which a solution of 43 -22 mg, 0.09 mmol) in 10%
aqueous DMF -1.1 ml) was added. The reaction mixture
was stirred for an additional3 h, and ®tlered through a
short silica gel column -ether). The ®ltrate was washed
with water and brine, and dried. Concentration followed
by chromatography of the residue on silica gel -hexane±
AcOEt, 4:1) gave 44 -19 mg, 79%) as crystals: mp 87±
19
-17 mg, 69%) as an oil: [a]D ˆ295.2 -c 0.82, CHCl3)
whose spectraldata -IR and 1H NMR) were identicalwith
those of natural 1.12
4.2. Methyl solidagonate /48)
To a stirred solution of 45 -14 mg, 0.04 mmol) in methanol
-1.5 ml) was added at 2508C sodium borohydride -1.5 mg,
0.04 mmol), and stirring was continued for 3.5 h. The
solvent was mostly removed off under reduced pressure,
and the oily residue was ®ltered through a short silica gel
column -ether). Concentration of the ®ltrate followed by
puri®cation of the residue with MPLC -hexane±AcOEt,
4:1) gave 47 -14 mg, 99%).
17
888C, [a]D ˆ283.3 -c 0.39, CHCl3); IR -®lm)
1
1713 cm21; H NMR -CDCl3) d 0.76 -s, 3H), 0.94 -d, Jˆ
6.6 Hz, 3H), 0.98 -s, 3H), 1.50±1.68 -m, 4H), 1.58 -s, 3H),
1.80±1.89 -m, 1H), 1.87 -dd, Jˆ12.2, 1.7 Hz, 1H), 2.01±
2.09 -m, 1H), 2.18 -s, 3H), 2.29 -d, Jˆ11.7 Hz, 1H), 2.37±
2.47 -m, 3H), 2.47 -d, Jˆ11.7 Hz, 1H), 5.28 -s, 1H). Anal.
Calcd for C18H28O2: C, 78.21; H, 10.21. Found: C, 78.26; H,
10.12.
4.2.1. Methyl /2E)-5-[/1R,2R,3S,4R,6R)-4-hydroxy-2,3,
6,7-tetramethylbicyclo[4.4.0]dec-7-en-2-yl]-3-methyl-
13
pent-2-enoate /47). Oil; [a]D ˆ276.8 -c 0.73, CHCl3); IR
-®lm) 3536, 1717, 1645, 1210, 1153 cm21 1H NMR
;
4.1.32. Methyl /2E)-5-[/1R,2S,4aR,8aR)-1,2,4a,5-tetra-
methyl-3-oxo-1,2,4,4a,7,8,8a-heptahydronaphthyl]-3-
methylpent-2-enoate /45) and methyl /2Z)-5-[/1R,2S,
4aR,8aR)-1,2,4a,5-tetramethyl-3-oxo-1,2,4,4a,7,8,8a-
heptahydronaphthyl]-3-methylpent-2-enoate /46). To a
stirred mixture of NaH -13.2 mg, 0.33 mmol) in THF
-CDCl3) d 1.01 -s, 3H), 1.03 -d, Jˆ7.0 Hz, 3H), 1.29 -s,
3H), 1.35±1.43 -m, 3H), 1.46±1.62 -m, 5H), 1.63 -s, 3H),
1.88±2.12 -m, 4H), 2.11 -dd, Jˆ14.3, 2.8 Hz, 1H), 2.17 -d,
Jˆ1.2 Hz, 3H), 3.69 -s, 3H), 4.04 -s, 1/2Hˆ9.0 Hz, 1H),29
5.16 -s, 1H), 5.66 -s, 1H).

M. Kato et al. / Tetrahedron 57 22001) 8243±8256
8255
The Total Synthesis of Natural Products; ApSimon, J., Ed.;
Wiley-Interscience: New York, 1988; Vol. 7, p. 275.
5. Kato, M.; Kamat, V. P.; Tooyama, Y.; Yoshikoshi, A. J. Org.
Chem. 1989, 54, 1536.
A mixture of 47 -11.4 mg, 0.034 mmol), 4-dimethylamino-
pyridine -a catalytic amount), acetic anhydride -0.01 ml,
0.11 mmol), and pyridine -0.5 ml) was stirred for 1 h,
quenched with methanol -0.01 ml) followed by aqueous
NH4Cl, and extracted with ether. Concentration of the
extract left an oily residue, which was ®ltered through a
short silica gel column -ether). Removal of the solvent
followed by puri®cation of the residue with MPLC -hex-
ane±AcOEt, 6:1) gave unreacted 47 -2 mg, 18%) and 48
6. -a) Kato, M.; Watanabe, M.; Vogler, B. Y.; Tooyama, Y.;
Yoshikoshi, A. J. Chem. Soc., Chem. Commun. 1990, 1704.
-b) Kato, M.; Watanabe, M.; Tooyama, Y.; Vogler, B.;
Yoshikoshi, A. Synthesis 1992, 1055.
7. -a) Kato, M.; Watanabe, M.; Vogler, B.; Awen, B. Z.; Masuda,
Y.; Tooyama, Y.; Yoshikoshi J. Org. Chem. 1991, 56, 7071.
-b) Kato, M.; Kido, F.; Watanabe, M.; Masuda, Y.; Awen,
B. Z. J. Chem. Soc., Perkin Trans. 1 1993, 2813.
8. Kato, M.; Watanabe, M.; Awen, B. Z. J. Org. Chem. 1993, 58,
5145.
13
-6 mg, 44%): crystals; 104±1058C; [a]D ˆ283.4 -c 0.24,
EtOH), [a]D ˆ275.9 -c 0.29, CHCl3); lit.14 [a]D ˆ298.8
13
12
-c 1.80, EtOH); IR -KBr) 1732, 1720, 1645, 1252,
1
1145 cm21; H NMR -CDCl3) d 0.91 -d, Jˆ7.0 Hz, 3H),
0.99 -s, 3H), 1.18 -s, 3H), 1.45 -m, 3H), 1.49±1.70 -m,
4H), 1.59 -s, 3H), 1.88±2.14 -m, 4H), 2.06 -s, 3H), 2.13
-dd, Jˆ14.8, 2.8 Hz, 1H), 2.15 -d, Jˆ1.2 Hz, 3H), 3.63 -s,
3H), 5.12 -m, 1H), 5.16 -s, 1H), 5.66 -s, 1H). Spectraldata
-IR and 1H NMR) of synthetic 48 were identicalwith those
of methylester of natural 2.14
9. Kosugi, H.; Ku, J.; Kato, M. J. Org. Chem. 1998, 63, 6939.
10. -a) Watanabe, M.; Awen, B. Z.; Kato, M. J. Org. Chem. 1993,
58, 3923. From -a-pinene) -b) Lajunene, M.; Koskinene,
A. M. P. Tetrahedron Lett. 1994, 35, 4461.
11. -a) Kosugi, H.; Yamabe, O.; Kato, M. J. Chem. Soc., Perkin
Trans. 1 1998, 217. -b) Kato, M.; Kosugi, H.; Ichiyanagi, T.;
Yamabe, O. J. Chem. Soc., Perkin Trans. 1 1999, 783.
12. Rustaiyan, A.; Habibi, Z.; Zedero, C. Phytochemistry 1990,
29, 985.
4.2.2.
/4aS,8aR)-4,8,8a-Trimethyl-1,4a,5,6,8a-penta-
hydronaphthalen-2-one /11). A solution of 10 -52 mg,
0.27 mmol) and acetyl chloride -0.04 ml, 0.54 mmol) in
methanol-1 m)l was stirred at 0 8C for 1 h, and ®ltered
through a short silica gel column -ether). Evaporation of
the solvent followed by puri®cation of the oily residue by
MPLC -hexane±AcOEt, 4:1) gave 11 -48 mg, 92%): oil;
13. Reported in part in preliminary communications: -a) Kato, M.;
Kosugi, H.; Kodaira, A.; Hagiwara, H.; Vogler, B.
Tetrahedron Lett. 1997, 38, 6845. -b) Kato, M.; Kosugi, H.;
Ichiyanagi, T.; Suzuki, T.; Kodaira, A.; Drechsel, P.; Hagi-
wara, H. Tetrahedron Lett. 1999, 40, 5377.
26
[a]D ˆ2125.3 -c 0.27, CHCl3); IR -®lm) 3026, 1668,
1
1619, 882, 836, 803 cm21; H NMR -CDCl3) d 1.12 -s,
14. Kusumoto, S.; Okazaki, T.; Ohsuka, A.; Kotake, M. Bull.
Chem. Soc. Jpn 1969, 42, 812.
3H), 1.53±1.61 -m, 1H), 1.65 -s with ®ne splittings, 3H),
1.87±1.93 -m, 1H), 2.01 -d, Jˆ1.2 Hz, 3H), 2.04±2.13 -m,
2H), 2.40 -m, 3H), 5.42 -d, Jˆ1.2 Hz, 1H), 5.86 -s, 1H); 1H
NMR -C6D6) d 0.91 -s, 3H), 1.16±1.26 -m, 1H), 1.39±1.42
-m 1H), 1.42 -d, Jˆ1.2 Hz, 3H), 1.44 -s with ®ne splittings,
3H), 1.62 -dd, Jˆ11.7, 2.9 Hz, 1H), 1.70±1.79 -m, 2H), 2.27
-d, Jˆ16.4 Hz, 1H), 2.39 -d, Jˆ16.4 Hz, 1H), 5.19 -s with
®ne splittings, 1H), 5.87 -d, Jˆ1.2 Hz, 1H); HRMS m/z
calcd for C13H18O [M]1: 190.1358; found 190.1350. Anal.
Calcd for C13H18O: C, 82.06; H, 9.54. Found: C, 82.10; H,
9.60.
15. The numbering system used here except that in Section 4
follows the natural product numbering for clerodanes.
16. The term trans and cis refer to whether the C-3)-methylgroup
points away from -trans) or toward -cis) the gem-dimethyl
bridge.
17. Koga, M.; Kageyama, K.; Tahara, T.; Fujii, T. Synth.
Commun. 1994, 24, 1447.
18. For discussion on isomerization of a substituent at the C-3)
position, see Ref. 9.
19. Such a trend was observed in cyclobutane-ring opening of
3,4,4-trisubstituted nopinones possessing the C-3)-alkyl
group with cis con®guration toward the gem-dimethylbridge.
This may be caused by competing facile enolization of the
ketone function in these nopinones. Details will be reported
elsewhere together with results on other related substrates.
20. This is because there is no regioselectivity in the hydro-
boration reaction using 9-BBN between the two double
bonds of the diene vi which was prepared from 15 with
hydrolysis followed by acetallization.
Acknowledgements
This work was supported by a Grant-in Aid for Special
Project Research -08680625). We thank Soda Aromatic
Co. for providing us with a sample of natural -2)-verbe-
none.
References
1. -a) Merritt, A. T.; Ley, S. V. Nat. Prod. Rep. 1992, 9, 243.
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21. In analogy with 14, cyclobutane opening of cis-3-methylnopi-
none vii, prepared from 14 according to the method described
for preparation of 21 from 13, was unsuccessfulat room
temperature. On heating at 608C, the reaction provided enol
acetate viii -44%) and ring-opened enolacetate ix -11%) along
with unreacted vii -30%). See Ref. 19.
3. Tamura, T.; Sawa, T.; Isshiki, K.; Masuda, T.; Honnma, Y.;
Iinuma, H.; Naganawa, H.; Hamada, M.; Takeuchi, T.;
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8256
M. Kato et al. / Tetrahedron 57 22001) 8243±8256
p-TsOH in re¯uxing benzene was proved to be unsuccessful,
mostly recovering the starting material 25.
25. Snider, B. B. The Prins and Carbonyl Ene Reactions in
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 2, p. 527.
26. Facile isomerization of 31 into 9 was observed on puri®cation
of the reaction mixture by silica-gel column chromatography.
27. Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1986, 25, 947.
28. NOE correlations indicated that the compound 42 is in equi-
librium between the boat and chair conformation with regard
to the B-ring, in analogy with 33 mentioned above.
22. Stereochemistry of the C-3) chiralcenter in this compound
was evidenced by the NOE correlations of 32 -vide infra).
23. Tunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980,
21, 1357.
29. The term 1/2H refers to the half band width.
24. Attempted azeotropic acetalization using ethylene glycol and