Total synthesis of valeriananoids A, B, and C via autocatalytic diastereoselective domino Michael reaction

Article abstract of DOI:10.1016/j.tet.2007.04.095

Natural enantiomers of unique tricyclic sesquiterpenoids, valeriananoids A-C 1-3, have been synthesized starting from bicyclo[2.2.2]octane-2,5-dione derivative 11, which was obtained by diastereoselective catalytic domino Michael reaction of oxophorone 5

Full text of DOI:10.1016/j.tet.2007.04.095

Tetrahedron 63 (2007) 7154–7164
Total synthesis of valeriananoids A, B, and C via autocatalytic
diastereoselective domino Michael reaction
Masakazu Fukushima,a Akihiro Morii,a Takashi Hoshi,b Toshio Suzukib and Hisahiro Hagiwaraa,
*
aGraduate School of Science and Technology, Niigata University, 8050, 2-Nocho, Ikarashi, Niigata 950-2181, Japan
bFaculty of Engineering, Niigata University, 8050, 2-Nocho, Ikarashi, Niigata 950-2181, Japan
Received 9 April 2007; revised 25 April 2007; accepted 26 April 2007
Available online 3 May 2007
Abstract—Natural enantiomers of unique tricyclic sesquiterpenoids, valeriananoids A–C 1–3, have been synthesized starting from bicy-
clo[2.2.2]octane-2,5-dione derivative 11, which was obtained by diastereoselective catalytic domino Michael reaction of oxophorone 5
with 8-phenylmenthyl acrylate 10 by LDA or silica-gel-base (NMAP-Li). The tricyclic ring was closed selectively by intramolecular
6-endo-trig mode cyclization of the ketyl radical, which was generated from keto-allylether 25 by either lithium or sodium naphthalenide.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
formation of the diol 2 as a minor metabolite in the biotrans-
formation of patchouli alcohol 4 by the fungus Botrytis cin-
erea.5 The relative stereochemistry of valeriananoid A 1
was elucidated by a single crystal X-ray analysis, whereas
configurations of the hydroxy groups of B 2 and C 3 were as-
signed by NOE experiment.4 Absolute configuration of 1 was
suggested employing CD octant rule,4 though application of
empirical rule to the compound having very small extinction
coefficient of the spectrum created someambiguity on the ab-
solute stereochemistry.
A folk medicine prepared from rhizomes and roots of Valeri-
ana fauriei has been used for sedative and antispasmodic
purposes in Japan. Similarly in China, roots of Valeriana
jatamansii have been utilized as a folk medicine, which has
hypnotic, tranquilizing, and antiviral activities. In 1995,
Takeya and co-workers investigated the ethyl acetate extracts
of the roots of V. fauriei and identified two new tricyclic ses-
quiterpenoids, 8-hydroxy-and 8-acetoxypatchouli alcohols 2
and 3,1 which have a unique carbon framework as that of
seychellene2 or patchouli alcohol 4.3 Subsequently in 1997,
Yu and co-workers reported the isolation and the structure
determination of three sesquiterpenoids from V. jatamansii
(Fig. 1), and named independently these compounds valeria-
nanoids A 1, B 2, and C 3.4 Collado et al. reported the
Our ongoing interest toward the total synthesis of bi- and tri-
cyclic natural products via the domino Michael protocol6
prompted us to investigate the synthesis of these natural
products and led us to report already the first total synthesis
of racemic valeriananoid A 1 via Lewis acid catalyzed dom-
ino Michael strategy starting from oxophorone 5 followed
by intramolecular 6-endo-trig cyclization of a ketyl radical.7
Recently, Srikrishna and Satyanarayana have also reported
the total synthesis of these compounds 1–3 in natural enan-
tiomeric form via similar domino Michael strategy8 starting
from (R)-carvone,9 in which relative and absolute stereo-
chemistries of 1–3 have been established.
O
OH
HO
HO
HO
HO
1
2
8
OAc
2. Results and discussion
3
4
We disclose herein diastereoselective total synthesis of
valeriananoid A 1 and its congeners 2 and 3 in enantiomeri-
cally pure form via an autocatalytic diastereoselective
domino Michael reaction.
Figure 1. Valeriananoids A–C 1–3 and pachouli alcohol 4.
Keywords: Bicyclic aliphatic compounds; Tricyclic aliphatic compounds;
Domino Michael reactions; Sesquiterpenoid; Valeriananoid.
* Corresponding author. Tel./fax: +81 25 262 7368; e-mail: hagiwara@gs.
niigata-u.ac.jp
The synthetic strategy is outlined in Scheme 1. A tricyclic
compound 9, an immediate precursor of valeriananoid A 1,
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.095

M. Fukushima et al. / Tetrahedron 63 (2007) 7154–7164
7155
could be obtained by intramolecular 6-endo-trig mode cycli-
zation of a ketyl radical generated on a bicyclic allylether 8,
which in turn could be synthesized from the domino Michael
product 6 of oxophorone 5 followed by equilibration of the
carbonyl unit to the same side as the carbonyl group leading
to 7.
2).12 It is worthy of note that the NMAP pellets could be
re-used up to six times.
One issue of the present synthetic strategy is how to prepare
the optically pure bicyclic compound 6. Enantioselective
domino Michael reaction leading to optically active bicy-
clo[2.2.2]octane-2,5-dione framework has not been reported
in spite of extensive efforts. In diastereoselective domino
Michael reaction, there have been several precedents, in
which the reaction with acrylate having chiral auxiliary in
a,b-unsaturated carboxylate moiety exhibited successful
diastereoselectivity.13 On the other hand, the result of the re-
action with acrylate having chiral auxiliary in an alkoxy por-
tion was not fruitful. Actually, the domino Michael reaction
of isophorone with 8-phenylmenthyl acrylate 10 recorded
only about 40% diastereoselection.14
O
CO2R
O
Catalytic domino
O
Michael reaction
O
5
6
O
OR
R
O
O
O
Based on these backgrounds, it was challenging to investi-
gate a diastereoselective catalytic domino Michael reaction
of oxophorone 5 with 8-phenylmenthyl acrylate 10 (Scheme
3). Fortunately, the domino Michael reaction with oxophor-
one 5 and 8-phenylmenthyl acrylate 10 proceeded in the
presence of 0.1 equiv of LDA to furnish separable bicyclic
compound 11 and its diastereomer in highly diastereoselec-
tive manner (92% de) in high yield (96%) (Scheme 3). The
reaction was catalyzed also by NMAP-Li12 with the same ef-
ficiency as LDA. Recrystallization from n-hexane provided
single crystals. Relative as well as absolute stereochemistry
of the domino Michael product 11 was established by an
X-ray crystallography, since the absolute stereochemistry
of phenylmenthyl moiety was known (Fig. 2).
O
O
O
8
7
e
6–endo–trig cyclization
O
O
1 ~ 3
HO
9
Scheme 1. Synthetic strategy.
In our previous domino Michael reaction leading to the bicy-
clic compound 6, silyl enol ether of oxophorone 5 and methyl
acrylate were employed in the presence of diethylaluminum
chloride,10 because the domino reaction of oxophorone 5
under basic reaction condition provided capricious results
(Scheme 2). However, we recently found that a catalytic
amount of LDA is sufficient to provide the bicyclic com-
pound 6, and indicated that the reaction was catalyzed by
the enolate of the product as a base (autocatalytic pathway).11
O
O
+
O
O
5
10
€
Subsequently, it was found that a Bronsted base (NMAP-Li)
generated on N-methylaminopropylated silica-gel (NMAP)
surface also catalyzed the reaction (Equation 1, Scheme
O
O
O
LDA (0.1 equiv)
HMPA (0.4 equiv), THF
95% (92% d.e.)
O
O
11
CO2R
CO2R
O
Scheme 3. Diastereoselective catalytic domino Michael reaction.
O
O
The stereochemical outcome of the diastereoselective reac-
tion is easily understood by the approach of the enolate of
oxophorone 5 to si-face of the acrylate 10, which reacted
with s-cis conformation (Fig. 3). The phenyl group on the
menthyl moiety works very effectively as a steric shielding
in this particular reaction, which is recognized from the OR-
TEP drawing of 11 (Fig. 3) providing that the conformation
is the same in solution, Moreover, increased steric bias of the
a-axial methyl group of the dienolate of oxophorone 5 than
that of isophorone might facilitate approach of the acrylate
10 to the b-face of the dienolate of 5. Very high diastereo-
control is worthy of note.
5
6
TMSI / (TMS)2NH
LDA (1 eq)
LDA (0.1 eq)
NMAP-Li (0.1 eq)/
HMPA
30% (R = Me)10
21% (R = Me)10
92% (R = Cy)11
90% (R = Cy)12
Scheme 2. Domino Michael reaction of oxophorone.
H
H
N
H
O
N
Li
O
O
Si
O
O
Si
O
Si
O
Si
O
OMe
O
OMe
O
n-BuLi
SiO2 bed
NMAP
SiO2 bed
NMAP-Li
With optically active bicyclic compound 11 in hand, a syn-
thetic study of valeriananoids 1–3 started (Scheme 4). Con-
ventional ketalization of the bicyclic compound 11 allowed
Equation 1. Reversed phase silica-gel and its conjugated base.

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M. Fukushima et al. / Tetrahedron 63 (2007) 7154–7164
O
CO2R
O
O
O
i
O
O
O
11
12
(R = 8-phenylmenthyl)
ii
RO2C
HO
O
O
O
iii
O
O
O
HO
O
14
iv
13
(R = 8-phenylmenthyl)
O
OHC
O
+
+
O
O
O
O
15
16
v
Figure 2. An ORTEP drawing of 11.
OH
O
O
O
O
O
O
O
O
10
17
16
open
Scheme 4. Reagents, conditions, and yields: (i) ethylene glycol, PTSA,
benzene, reflux, 100%; (ii) KOH, EtOH, reflux, 76% for 13, 23% for 12;
˚
(iii) LiAlH4 (1.5 equiv), THF, reflux, 90%; (iv) PCC, AcONa, MS-4 A,
O
O
CH2Cl2, rt, 69–95% (inseparable mixture of 15 and 16); (v) MeLi
(1.5 equiv), THF, ꢀ78 to ꢀ10 ꢁC.
hindered
auxiliary at earlier stage of the synthetic sequence would im-
prove efficiency of recovery of 8-phenylmenthol. (2) Forma-
tion of the lactone 16 (Scheme 4) would be prevented by
oxidation of anti-diol 18. (3) Equilibration from 20 to 21
would be much easier (Scheme 5) than equilibration from
12 to 13 due to the absence of bulky phenylmenthyl group.
(4) Difficulty to separate 12 and 13 due to similar polarity
would be solved (Scheme 4). To this end, the ketal 12 was re-
duced with LAH in refluxing THF to give a separable dia-
stereomeric mixture of diol 18 (less polar/more polar
diastereomer¼3:1) and 8-phenylmenthol in 96 and 100%
yields, respectively (Scheme 5). The major less polar diaste-
reomer has an endo-secondary hydroxyl group judged from
W-type coupling as shown in Figure 4. Swern oxidation of
the mixture of the diol 18 provided the keto-aldehyde, which
was reacted with methylmagnesium bromide to give alcohol
19 selectively in 90% yield in two steps. Addition of methyl-
lithium was not effective even in the presence of HMPA or
CeCl3. Subsequent PCC oxidation afforded methylketone
20 in 98% yield. Treatment of the methylketone 20 with po-
tassium hydroxide in methanol resulted in an equilibrium
mixture of the desired endo-methylketone 21 and recovered
starting ketone 20 in 81 and 12% yields, respectively, which
were separated easily by recrystallization. Equilibrium ratio
was apparently improved employing the methylketone 20
rather than the ester 12. The relative stereochemistry of 21
was confirmed by the disappearance of the W-type long range
O
O
10
Figure 3. Diastereoselective domino Michael reaction.
selective protection of the less congested ketone to provide
ketal 12 quantitatively. Base catalyzed isomerization of 12
under reflux of ethanolic solution of potassium hydroxide re-
sulted in an equilibrium mixture of 12 and 13 in 23 and 76%
yields, respectively. Steric bulkiness of 8-phenylmenthyl
moiety might circumvent complete isomerization into 13,
since methyl ester equivalent of 12 resulted in complete
isomerization in the previous racemic total synthesis.7 Lith-
ium aluminum hydride (LAH) reduction of the keto-ester 13
in refluxing THF provided the diol 14 and 8-phenylmenthol
in 90 and 93% yields, respectively. Repeated PCC oxidation
of the diol 14 afforded an inseparable mixture of the desired
keto-aldehyde 15 and the lactone 16 in varying yields. Other
methods of oxidation including Swern and its modified pro-
cedure were unsuccessful. Attempted formation of methyl-
ketone from the lactone 16 by addition of methyllithium to
the mixture of 15 and 16 resulted in unsatisfactory results.
In order to solve several issues cited above, an alternative
synthetic sequence was designed, in which several advan-
tages were expected as follows. (1) Removal of the chiral

M. Fukushima et al. / Tetrahedron 63 (2007) 7154–7164
7157
O
CO2R
O
OH
O
OHC
i
O
O
O
O
O
HO
O
O
O
O
12
18
15
21
(R = 8-phenylmenthyl)
ii, iii
OH
i
i
O
OR'
R'
R
O
iv
O
O
O
ii
O
O
v
O
O
O
HO
O
O
O
20
19
22 R' = H
23 R' = MOM
24a R = OH, R' = Me
24b R = Me, R' = OH
iii
25a R = OMOM, R' = Me
25b R = Me, R' = OMOM
O
O
iv
R
OMOM
R
O
21
+
O
O
Scheme 5. Reagents, conditions, and yields: (i) LiAlH4 (4 equiv), THF,
reflux, 96% (less polar/more polar isomer¼3:1); (ii) oxalyl chloride
(3 equiv), DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC; (iii) MeMgBr (3 equiv), THF,
O
O
HO
HO
9 R = Me
26 R = H
27 R = Me
˚
90% in two steps; (iv) PCC (2 equiv), AcONa, MS-4 A, CH2Cl2, rt, 98%;
(v) KOH, MeOH, reflux, 81%.
v
O
H
OH
O
H
O
O
H
vii
O
H
O
+
1
2
O
O
OH
W-type
HO
viii
28
18
20
vi
3
Figure 4. Relative stereochemistries of the less polar diol 18 and the
methylketone 20.
Scheme 6. Reagents, conditions, and yields: (i) vinylmagnesium chloride
(5 equiv), THF, ꢀ20 ꢁC, 80%; (ii) MOMBr (4 equiv), NaH, THF, 0 ꢁC,
75%; (iii) MOMCl (5 equiv), (i-Pr)2NEt (6 equiv), DMF, 89% for 25a and
95% for 25b; (iv) see Table 1; (v) H2, Pd–C, AcOEt, rt; (vi) PTSA, H2O,
THF, rt, 90% in two steps; (vii) NaBH4 (20 equiv), MeOH, rt, 99%; (viii)
Ac2O (10 equiv), Py, DMAP, CH2Cl2, 0 ꢁC, 99%.
coupling between an endo-proton next to the ketal group and
a proton on a carbon bearing an acyl group (Fig. 4).
With the requisite methylketone 21 in hand, closure of the
third ring was investigated by 6-endo-trig mode radical cycli-
zation (Scheme 6).16 Addition of vinylmagnesium chloride
in THF at ꢀ30 ꢁC to ꢀ20 ꢁC to the methylketone 21 fur-
nished two separable less polar (22%) and more polar diaste-
reomers (58%). In diethyl ether, no diastereoselectivity was
observed. Addition of cerium chloride, magnesium bromide
or HMPA did not change diastereomeric ratio or total yield.
The relative stereochemistries of 24a and 24b were deter-
mined from the relative stereochemistry of MOM-ether 27
(vide infra) by NOE experiments (Fig. 5). This result
indicates that vinylmagnesium chloride attacked the less
hindered re face of the carbonyl group of 21 from its outer
face. Addition at low temperature was critical to realize
good yield. The more polar diastereomer 24a was protected
with excess methoxymethylchloride (MOMCl) and diisopro-
pylethylamine to provide methoxymethyl (MOM) ether 25a
at 60 ꢁC in 89% yield. The less polar diastereomer 24b was
also transformed into MOM-ether 25b at 60 ꢁC in 95% yield.
NOE 2.3%
OMOM
NOE 2.3%
OMOM
H
H
H
O
O
O
NOESY
HO
O
NOE 3.9%
Figure 5. Relative stereochemistry of 27.
ether 25a in a similar manner in the presence of HMPA pro-
vided the desired product 9 in 44% yield (Table 1, entry 2).
In order to improve both yield and 6-endo- versus 5-exo-trig
selectivity,15 more active reducing reagent which is applica-
ble at low temperature was investigated, and the cyclization
was improved remarkably employing lithium or sodium
naphthalenide in THF at ꢀ55 ꢁC to give 9 in 94 or 95% yield,
respectively. The reaction by samarium iodide in the pres-
ence or absence of HMPA (entry 1), or zinc with titanium
tetrachloride resulted in low yields (entry 3). On the other
hand, the reaction of diastereomeric MOM-ether 25b with
lithium naphthalenide in THF resulted in formation of 5-
exo-trig product 27 as a major product (entry 6). Fortunately,
In order to close the third ring, we initially employed
a method by Bertrand16 and Spreitzer17 employing sodium
in refluxing THF. The reaction of MOM-ether 23 under the
reaction condition was successful to give the tricyclic com-
pound 26 in 61% yield. However, cyclization of the MOM-

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M. Fukushima et al. / Tetrahedron 63 (2007) 7154–7164
Table 1. Ketyl radical cyclization of MOM-ethers 25a and 25b
Entry
Substrate
Solvent
Reducing agent
Reaction condition
Yield (%)
9
27
25
1
2
3
4
5
25a
THF/HMPA
THF
SmI2/Sm/t-BuOH
Na
Zn/TiCl4
Li/naphthalene
Na/naphthalene
0 ꢁC–reflux
Reflux
20
44
—
94
95
6
50
ꢀ20–rt
—
—
—
89
—
—
ꢀ55 ꢁC
ꢀ55 ꢁC
6
7
8
9
10
25b
Li/naphthalene
ꢀ55 ꢁC
33
46
14
35
25
29
THF/HMPA
Diethyl ether
THF/Et3N
Trace
15
32
84
29
12
THF/dioxane
54
OMOM
this unfavorable selectivity was improved to reverse the ratio
of 5-exo- versus 6-endo-trig product ratio employing THF
and dioxane (3:2) and to provide 9 (54%) and 27 (29%),
respectively (entry 10). Since dioxane has lower electron do-
nor number and thus has the lowest Lewis basicity than other
solvents tested, destabilization of lithium cation might be
effective in the desired selectivity.18
O
O
25
O
e–
a
b
OMOM
The relative stereochemistry of the MOM-ether 27 was es-
tablished by NOE experiments as shown in Figure 5. Since
the MOM-ether 27 was obtained from 25b, the relative ste-
reochemistries of 24a, 24b, 25a, and 25b were established as
shown in Scheme 6.
O
O
O
O
O
–O
29
30
O
OMOM
In the present cyclization, there might be two alternative
pathways. One is the initial generation of the allyl radical19
followed by intramolecular addition to carbonyl group
(Scheme 7, path b) and the other is initial generation of ketyl
radical followed by intramolecular addition to vinyl group of
the allyloxy moiety (Scheme 7, path a). In order to justify the
pathway, compound 31 was synthesized and subjected to
radical cyclization with lithium naphthalenide at ꢀ55 ꢁC,
which resulted only in reduction of the carbonyl group.
The allyloxy moiety of 31 was intact under the reaction con-
dition. Thus, it is clear that the present cyclization started
from ketyl radical formation.
O
O
O
O
O
O
20
31
Li/naphthalene
OMOM
O
O
HO
32
Scheme 7. Formation of ketyl radical.
In order to evaluate selectivity between 6-endo- and 5-exo-
trig ketyl radical cyclizations, two assumptions were
made. (1) The reaction proceeds under kinetic control. (2)
The vinyl group in the substrate 25a or 25b orients anti to
MOM-oxy group due to 1,3-allylic strain. Based on these as-
sumptions, stable conformer of the ketyl radical from 25a
was postulated to be 29a0 due to the less steric congestion
mainly with a methyl group according to molecular model
inspection (Scheme 8). Thus, subsequent intramolecular
cyclization provided 6-endo-trig product 9 specifically in
high yield. On the other hand, the conformer 29b derived
from 25b is the stable conformer to give both 6-endo- and
5-exo-trig products 9 and 27.
these compounds were identical with those kindly provided
by Professors Yu and Srikrishna. The optical rotations of
valeriananoids B and C were identical with those reported
by Itokawa et al.1 However, a large difference was observed
between our synthetic {[a]2D0 ꢀ82.3 (c 0.266, CHCl3)} and
natural valeriananoid A4 {[a]D20 ꢀ34.6 (c 0.231, CHCl3)}.
Synthetic valeriananoid A by Srikrishna9 also had different
optical rotational value {[a]2D4 ꢀ33.3 (c 0.3, CHCl3)}. To
this end, valeriananoid B 2 was synthesized from the domino
Michael product 11 of 92% de and transformed into its
(S)-MTPA-ester with DCC. The NMR spectrum of the
MTPA-ester exhibited the diastereomeric excess of 91%.
Since there was no procedure that destroys enantioselectiv-
ity during the synthetic sequence, the present absolute value
of optical rotation must be proper.
Final transformation was conventional. Catalytic hydroge-
nation of the olefin 9 proceeded selectively from the less
hindered outer si-face of 9 to give ketal 28, which was depro-
tected in 90% yield in two steps to furnish valeriananoid A
1 (Scheme 6). Reduction of 1 with sodium borohydride pro-
vided in 99% yield valeriananoid B 2, which was acetylated
to give valeriananoid C 3 in 99% yield. The spectral data of
In summary, we have completed the total synthesis of valer-
iananoid A 1 in 12 steps in 34% overall yield from oxophor-
one 5 along with valeriananoid B 2 and C 3 via autocatalytic

M. Fukushima et al. / Tetrahedron 63 (2007) 7154–7164
7159
0.69 mmol) at 0 ꢁC under nitrogen atmosphere. To the solu-
tion was added oxophorone 5 (1.263 g, 8.30 mmol) in THF
(15 mL) at ꢀ78 ꢁC. After being stirred for 15 min, a solution
of (ꢀ)-8-phenylmenthyl acrylate 10 (1.977 g, 6.90 mmol) in
THF (15 mL) and subsequently HMPA (480 mL, 2.76 mmol)
were added dropwise. The solution was stirred for 14 h to
ꢀ40 ꢁC. The reaction was quenched by 1 N hydrochloric
acid. The product was extracted with ethyl acetate twice.
The organic layer was washed with water, brine and dried
over anhyd sodium sulfate. Evaporation of the solvent and
Kugel-Rohr distillation (80–100 ꢁC, 2 mmHg) left crude
product, which was recrystallized from hexane three times
to afford enantiomerically pure domino Michael product 11
(2.685 g, 89%, colorless crystals). The mother liquor was
purified by medium pressure LC (eluent: ethyl acetate/n-
hexane¼1:3) to give 11 (117 mg, 3%) and its diastereomer
(120 mg, 4%): mp 105–106 ꢁC; [a]D20 +50.2 (c 1.01, CHCl3);
OMOM
O
O
O
O
O
H
O
25a
29a
O
O
H
O
29a'
O
O
IR (CHCl3) 3051, 2403, 1723, 1240, 1224, 1196, 908 cmꢀ1
;
OH
9
1H NMR (200 MHz, CDCl3) d 0.84 (s, 3H), 0.89 (d,
J¼6.5 Hz, 3H), 0.99 (s, 3H), 1.13 (s, 3H), 1.16 (s, 3H),
1.25 (s, 3H), 0.80–1.30 (m, 2H), 1.35–1.62 (m, 3H), 1.62–
1.80 (m, 1H), 1.94 (dd, J¼1.6, 19.6 Hz, 1H), 1.80–2.22 (m,
5H), 2.33 (t, J¼2.8 Hz, 1H), 2.81 (d, J¼19.6 Hz, 1H), 4.76
(dt, J¼10.8, 4.3 Hz, 1H), 7.00–7.13 (m, 1H), 7.18–7.35 (m,
4H); 13C NMR (50 MHz, CDCl3) d 17.2 (q), 21.8 (q), 22.2
(q), 23.0 (q), 23.3 (t), 24.9 (t), 26.0 (q), 30.3 (q), 31.2 (d),
34.4 (t), 39.3 (s), 41.0 (d), 41.1 (t), 41.5 (t), 43.8 (s), 47.8
(s), 49.9 (d), 55.7 (d), 75.4 (d), 124.7 (d), 125.0 (d), 127.7
(d), 152.3 (s), 172.0 (s), 209.8 (s), 214.8 (s); HRMS m/z calcd
for C28H38O4 438.2770, found 438.2769.
OMOM
O
O
OH
O
27
OMOM
H
O
H
O
O
O
O
29b
3.1.2. (2S,1R,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)-
cyclohexyl (6S,7S)-6,10,10-trimethyl-11-oxospiro[1,3-di-
oxolane-2,80-bicyclo[2.2.2]octane]-7-carboxylate (12). A
stirred mixture of the diketone 11 (308 mg, 0.71 mmol), eth-
ylene glycol (0.40 mL, 7.2 mmol), and p-toluenesulfonic
acid (18 mg, 0.093 mmol) in benzene was heated at reflux
for 17 h in a Dean–Stark water separator under nitrogen at-
mosphere. After addition of aq sodium hydrogen carbonate,
the product was extracted with ethyl acetate twice. The
organic layer was washed with water, brine and dried over
anhyd sodium sulfate and evaporated to dryness. The residue
was purified by medium pressure LC (eluent: ethyl acetate/
n-hexane¼2:5) to give the ketal 12 (338 mg, 100%, colorless
amorphous solid): [a]D20 +42.7 (c 1.01, CHCl3); IR (CHCl3)
3115, 2961, 1717, 1460, 1385, 1190, 1093 cmꢀ1; 1H NMR
(270 MHz, CDCl3) d 0.76 (s, 3H), 0.87 (d, J¼6.8 Hz, 3H),
1.07 (s, 3H), 1.16 (s, 3H), 1.26 (s, 6H), 1.60 (dd, J¼1.6,
15.2 Hz, 1H), 1.80–1.89 (m, 2H), 2.02–2.15 (m, 1H),
2.30–2.41 (m, 1H), 2.45 (d, J¼15.2 Hz, 1H), 0.91–1.95
(m, 8H), 3.80–3.98 (m, 4H), 4.78 (dt, J¼10.8, 4.3 Hz, 1H),
7.00–7.10 (m, 1H), 7.18–7.32 (m, 4H); 13C NMR
(50 MHz, CDCl3) d 17.8 (q), 21.8 (q), 23.0 (q), 23.5 (t),
25.4 (q), 26.3 (t), 26.6 (q), 29.6 (q), 31.3 (d), 34.5 (t), 39.4
(s), 40.4 (t), 40.6 (d), 41.7 (t), 43.8 (s), 45.6 (d), 46.5 (s),
50.0 (d), 63.3 (t), 64.0 (t), 75.0 (d), 109.2 (s), 124.7 (d),
125.0 (d), 127.7 (d), 152.2 (s), 172.5 (s), 217.7 (s); HRMS
m/z calcd for C30H42O5 482.3032, found 482.3036.
25b
Scheme 8. Selectivity between 6-endo- and 5-exo-trig cyclizations.
diastereoselective domino Michael reaction to construct the
bicyclic framework and subsequent ketyl radical cyclization
to close the tricyclic ring. Value of optical rotation of valer-
iananoid A 1 was corrected.
3. Experimental
3.1. General
THF was distilled from benzophenone ketyl prior to use.
Dichloromethane was distilled from CaH2 prior to use.
NMR spectra were measured in CDCl3 with TMS as internal
standard on Varian Unity 500 plus (500 MHz), JNM-EX-
CALIBUR (270 MHz), or Varian Gemini-200 at room tem-
perature. IR spectra were recorded on Shimadzu FTIR-4200
using sodium chloride optics. Mass spectra were recorded on
JMS-GCMATE BU-20 using EI method. Analytical TLC
was carried out on Kieselgel 60 F254 plates employing n-hex-
ane/ethyl acetate as the mobile phase. Product was purified
by medium pressure liquid chromatography (MPLC) with
n-hexane/ethyl acetate as an eluent.
3.1.1. (2S,1R,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)-
cyclohexyl (1S,2S)-1,5,5-trimethyl-6,8-dioxobicyclo[2.2.2]-
octane-2-carboxylate (11). To a stirred solution of
diisopropylamine (90 mL, 0.69 mmol) in THF (20 mL) was
added n-butyllithium (440 mL, 1.59 M solution in n-hexane,
3.1.3. (2S,1R,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)-
cyclohexyl (6S,7R)-6,10,10-trimethyl-11-oxospiro[1,3-di-
oxolane-2,80-bicyclo[2.2.2]octane]-7-carboxylate (13). A
solution of the acetal 12 (500 mg, 1.04 mmol) and potassium

7160
M. Fukushima et al. / Tetrahedron 63 (2007) 7154–7164
hydroxide (90 mg, 1.60 mmol) in ethanol (35 mL) was
heated at reflux for 23 h. The reaction was quenched by ad-
dition of 1 N hydrochloric acid. The product was extracted
with ethyl acetate twice. The organic layer was washed
with water, brine and dried over anhyd sodium sulfate. Evap-
oration of the solvent followed by medium pressure LC
(eluent: ethyl acetate/n-hexane¼1:4) of the residue provided
the endo-product 13 (378 mg, 76%) along with recovered
starting material 12 (117 mg, 23%, colorless amorphous
solid).
medium pressure LC (eluent: ethyl acetate/n-hexane¼2:1)
afforded an inseparable mixture of the aldehyde 15 and the
lactone 16 in 3:1 ratio (NMR).
Aldehyde 15: IR (CCl4) 3410, 2973, 2934, 2880, 1788, 1722,
1
1458, 1358, 1230, 1093, 1035 cmꢀ1; H NMR (200 MHz,
CDCl3) d 1.09 (s, 3H), 1.18 (s, 3H), 1.28 (s, 3H), 1.84 (dd,
J¼3.1, 2.9 Hz, 1H), 2.02 (m, 2H), 2.04 (ddd, J¼14.3, 6.9,
2.3 Hz, 1H), 2.23 (ddd, J¼14.3, 10.8, 3.6 Hz, 1H), 2.77
(ddd, J¼10.8, 6.9, 3.6 Hz, 1H), 3.87–4.05 (m, 4H), 9.52
(d, J¼3.6 Hz, 1H); 13C NMR (50 MHz, CDCl3) d 17.8 (q),
19.8 (t), 24.4 (q), 26.6 (q), 45.2 (d), 45.7 (s), 46.0 (s), 46.6
(d), 52.0 (t), 63.2 (t), 64.9 (t), 109.0 (s), 201.7 (s), 218.0 (s).
endo-Product 13: mp 119 ꢁC; [a]D20 ꢀ36.0 (c 1.02, CHCl3);
1
IR (CHCl3) 3046, 2402, 1728, 1194, 1096, 814 cmꢀ1; H
NMR (200 MHz, CDCl3) d 0.70–2.06 (m, 9H), 0.85 (d,
J¼6.4 Hz, 3H), 0.98 (s, 3H), 1.18 (s, 3H), 1.21 (s, 3H),
1.26 (s, 3H), 1.32 (s, 3H), 1.60 (ddd, J¼13.3, 6.7, 2.4 Hz,
1H), 1.80 (d, J¼14.9 Hz, 1H), 1.91 (d, J¼14.9 Hz, 1H),
2.26 (ddd, J¼13.3, 11.6, 3.4 Hz, 1H), 2.44 (dd, J¼11.6,
6.7 Hz, 1H), 3.80–4.05 (m, 4H), 4.78 (td, J¼10.6, 4.3 Hz,
1H), 7.00–7.50 (m, 5H); 13C NMR (50 MHz, CDCl3)
d 19.0, 22.4, 24.5, 25.6, 26.1, 27.6, 28.5, 31.9, 35.1, 40.7,
42.1, 45.4, 46.4, 46.8, 50.8, 63.7, 64.9, 75.9, 109.9, 125.8,
126.1, 128.6, 151.7, 174.2, 217.8; HRMS m/z calcd for
C30H42O5 482.3032, found 482.3036.
Lactone 16: mp 71–72 ꢁC; IR (CCl4) 2994, 1776, 1469,
1
1362, 1128, 1086, 1019, 978 cmꢀ1; H NMR (200 MHz,
CDCl3) d 1.05 (s, 3H), 1.11 (s, 3H), 1.14 (s, 3H), 1.81 (m,
1H), 1.89 (ddd, J¼14.8, 3.6, 1.5 Hz, 1H), 1.95 (d,
J¼8.6 Hz, 2H), 2.05–2.18 (m, 1H), 2.41 (ddd, J¼14.8,
10.8, 2.2 Hz, 1H), 3.73 (s, 1H), 3.80–4.01 (m, 4H); HRMS
m/z calcd for C14H20O4 252.1361, found 252.1361.
3.1.6. (6S,11R)-11-(Hydroxyethyl)-6,8,8-trimethyl-
spiro[1,3-dioxolane-2,80-bicyclo[2.2.2]octane]-7-one
(17). To a solution of the aldehyde 15 and the lactone 16
(29 mg, 0.12 mmol) in THF (2 mL) was added ethereal solu-
tion of methyllithium (172 mL, 0.98 M, 0.17 mmol) at
ꢀ78 ꢁC under nitrogen atmosphere. After being stirred for
7 h at ꢀ78 ꢁC to ꢀ10 ꢁC, the reaction was quenched by addi-
tion of aq ammonium chloride. The product was extracted
with ethyl acetate twice. The combined organic layer was
washed with water, brine and dried over anhyd sodium sul-
fate. Evaporation of the solvent followed by medium pres-
sure LC (eluent: ethyl acetate/n-hexane¼2:1) provided
a mixture of the alcohol 17 and lactone 16 (26 mg): IR
(CHCl3) 3605, 2978, 2930, 2882, 1714, 1481, 1460, 1350,
3.1.4. (6S,11R)-11-(Hydroxymethyl)-6,8,8-trimethyl-
spiro[1,3-dioxolane-2,80-bicyclo[2.2.2]octane]-7-ol (14).
To a stirred slurry of LAH (24 mg, 0.64 mmol) in THF
(10 mL) was added the menthyl ester 13 (125 mg,
0.26 mmol) in THF under nitrogen atmosphere. After being
heated at reflux for 3 h, the reaction was quenched by addi-
tion of aq ammonium chloride. After decantation of the
organic layer, the residue was rinsed with ethyl acetate. The
combined organic layer was dried over anhyd sodium sulfate
and evaporated to dryness. The residue was purified by col-
umn chromatography (eluent: ethyl acetate/n-hexane¼1:5 to
3:1) to give the diol 14 (60 mg, 90%, colorless crystals) and
8-phenylmenthol (56 mg, 93%): mp 114 ꢁC; [a]D20 ꢀ66.2 (c
0.99, CHCl3); IR (CHCl3) 3632, 3392, 3051, 2922, 1479,
1
1101, 1037, 1014, 468 cmꢀ1; H NMR (200 MHz, CDCl3)
d 1.02 (s, 3H), 1.11 (d, J¼6.5 Hz, 3H), 1.22 (s, 3H), 1.24
(s, 3H), 2.10–1.70 (m, 6H), 4.05–3.80 (m, 4H), 4.18–3.05
(m, 1H); 13C NMR (50 MHz, CDCl3) d 17.2 (q), 19.0 (t),
20.7 (q), 24.5 (q), 26.9 (q), 44.6 (s), 45.5 (d), 46.3 (t), 46.7
(d), 47.0 (s), 62.8 (t), 63.8 (t), 64.6 (d), 109.5 (s), 222.0 (s).
Anal. Calcd for C15H24O4: C, 67.14; H, 9.01. Found: C,
67.18; H, 9.12.
1456, 1134, 1099, 1064, 1005, 956 cmꢀ1
;
1H NMR
(200 MHz, CDCl3) d 0.98 (s, 3H), 1.06 (s, 3H), 1.17 (s,
3H), 1.40 (d like, J¼3.2 Hz, 1H), 1.54 (dd, J¼14.3,
1.0 Hz, 1H), 1.75 (d, J¼14.3 Hz, 1H), 1.83–2.00 (m, 2H),
3.12 (s, 1H), 3.47 (dd, J¼11.4, 3.2 Hz, 1H), 3.46–3.73 (br
s, 2H), 3.81 (dd, J¼11.4, 1.6 Hz, 1H), 3.80–4.00 (m, 4H);
13C NMR (50 MHz, CDCl3) d 21.8 (t), 22.3 (q), 25.1 (q),
33.3 (q), 26.5 (s), 40.0 (d), 45.4 (d), 49.8 (t), 60.9 (t), 63.5
(t), 64.3 (t), 82.0 (d), 111.6 (s). Anal. Calcd for C14H24O4:
C, 65.59; H, 9.44. Found: C, 65.46; H, 9.47.
3.1.7. (6S,11S)-11-(Hydroxymethyl)-6,8,8-trimethyl-
spiro[1,3-dioxolane-2,80-bicyclo[2.2.2]octane]-7-ol (18).
A mixture of the ketal 12 (28 mg, 0.058 mmol) and LAH
(8 mg, 0.20 mmol) in THF (4 mL) was heated at reflux for
2 h under nitrogen atmosphere. The reaction was quenched
by addition of aq ammonium chloride. After decantation
of the organic layer, the residue was rinsed with ethyl ace-
tate. The combined organic layer was evaporated in vacuo.
The residue was purified by column chromatography (elu-
ent: ethyl acetate/n-hexane¼1:3 to 3:1) to give 8-phenyl-
menthol (14 mg, 100%). Combined polar fractions were
purified again by medium pressure LC (eluent: ethyl ace-
tate/n-hexane¼3:1) to provide the diol 18 (less polar diaste-
reomer: 11 mg, 71%, more polar diastereomer: 4 mg, 25%).
3.1.5. (6S,7R)-6,10,10-Trimethyl-11-oxospiro[1,3-dioxo-
lane-2,80-bicyclo[2.2.2]octane]-7-carbaldehyde (15) and
(12S)-12,15,15-trimethyl-10-oxaspiro[1,3-dioxolane-2,90-
tricyclo[4.3.1.03,7]decane]-9-one (16).
A mixture of
PCC (268 mg, 1.24 mmol), sodium acetate (103 mg,
˚
1.26 mmol), MS-4 A (one pellet), and Celite (503 mg) was
evacuated for 1 h at rt. To the mixture was added dichloro-
methane (2 mL) and then a solution of the diol 14 (32 mg,
0.12 mmol) in dichloromethane (3 mL) under nitrogen at-
mosphere. After being stirred for 30 min, the organic layer
was passed through silica-gel short column. The residue
was rinsed with ethyl acetate. Evaporation of the solvents
followed by column chromatography and subsequent
More polar 18: mp 166–167 ꢁC; [a]D20 +38.5 (c 0.954,
CHCl3); IR (CHCl3) 3636, 3455, 2930, 1410, 1356, 1244,
1089, 1013, 953 cmꢀ1
;
1H NMR (200 MHz, CDCl3)

M. Fukushima et al. / Tetrahedron 63 (2007) 7154–7164
7161
d 0.94 (s, 3H), 1.04 (s, 3H), 1.23 (s, 3H), 1.44 (dd, J¼15.0,
1.4 Hz, 1H), 2.06 (d, J¼15.0 Hz, 1H), 1.35–2.10 (m, 4H),
3.17 (s, 1H), 3.62–3.75 (m, 2H), 3.75–4.05 (m, 4H); 13C
NMR (50 MHz, CDCl3) d 21.4 (q), 24.0 (q), 24.2 (t), 31.4
(q), 32.0 (d), 35.9 (s), 38.5 (s), 43.3 (t), 44.6 (d), 62.7 (t),
63.9 (t), 64.7 (t), 83.2 (d), 110.7 (s); HRMS m/z calcd for
C14H24O4 256.1674, found 256.1676.
1.68 (m, 1H), 1.75 (dd, J¼15.5, 1.4 Hz, 1H), 1.76–2.14
(m, 2H), 2.33 (d, J¼15.5 Hz, 1H), 3.82–4.02 (m, 4H),
4.02–4.17 (m, 1H); 13C NMR (50 MHz, CDCl3) d 18.6
(q), 21.9 (q), 23.8 (t), 25.9 (q), 26.2 (q), 40.9 (t), 41.1 (d),
43.9 (s), 45.7 (d), 47.5 (s), 63.0 (t), 64.1 (t), 70.3 (d), 109.5
(s), 219.4 (s); HRMS m/z calcd for C15H24O4 268.1674,
found 268.1674.
Less polar 18: mp 91–92 ꢁC; [a]D20 +51.6 (c 0.988, CHCl3);
IR (CHCl3) 3624, 3488, 3003, 1468, 1348, 1229, 1194,
Less polar 19: [a]D20 ꢀ17.0 (c 1.06, CHCl3); IR (CHCl3)
3500, 2934, 1717, 1462, 1389, 1098, 1010 cmꢀ1; 1H NMR
(200 MHz, CDCl3) d 1.06 (s, 3H), 1.14 (d, J¼6.5 Hz, 3H),
1.18 (s, 3H), 1.27 (s, 3H), 1.32–1.48 (m, 1H), 1.74 (dd,
J¼14.6, 1.2 Hz, 1H), 1.81–2.05 (m, 2H), 2.14 (ddd,
J¼14.5, 7.1, 2.6 Hz, 1H), 2.54 (d, J¼14.6 Hz, 1H), 3.11
(d, J¼9.2 Hz, 1H), 3.85–4.05 (m, 4H), 4.41 (ddq, J¼9.2,
6.5, 2.6 Hz, 1H); 13C NMR (50 MHz, CDCl3) d 17.2 (q),
19.5 (t), 22.8 (q), 25.6 (q), 26.2 (q), 40.2 (d), 40.5 (t), 44.2
(s), 46.5 (d), 47.4 (s), 62.9 (t), 64.3 (t), 67.4 (d), 109.6 (s),
219.0 (s); HRMS m/z calcd for C15H24O4 268.1674, found
268.1673.
1096, 1014, 953 cmꢀ1
;
1H NMR (200 MHz, CDCl3)
d 0.96 (s, 3H), 1.11 (s, 3H), 1.17 (s, 3H), 1.39 (dd, J¼3.8,
2.1 Hz, 1H), 1.58 (dd, J¼13.8, 2.1 Hz, 1H), 1.64–1.77 (m,
2H), 1.92 (ddd, J¼13.8, 10.3, 3.8 Hz, 1H), 2.99 (d,
J¼6.2 Hz, 1H), 3.60–3.81 (m, 2H), 3.81–4.05 (m, 4H); 13C
NMR (50 MHz, CDCl3) d 20.5 (q), 24.3 (t), 24.6 (q), 31.6
(q), 35.7 (t), 36.8 (s), 39.2 (s), 39.4 (d), 43.4 (d), 62.7 (t),
63.9 (t), 64.2 (t), 81.3 (d), 111.2 (s); HRMS m/z calcd for
C14H24O4 256.1674, found 256.1676.
3.1.8. (6S,11S)-11-(Hydroxyethyl)-6,8,8-trimethyl-
spiro[1,3-dioxolane-2,80-bicyclo[2.2.2]octane]-7-one
(19). To a stirred solution of oxalyl chloride (1.3 mL,
15.6 mmol) in dichloromethane (40 mL) was added dime-
thylsulfoxide (2.2 mL, 31.3 mmol) at ꢀ78 ꢁC under nitrogen
atmosphere. After being stirred for 10 min, the diol 18
(1.002 g, 3.91 mmol) in dimethylsulfoxide (2 mL) and di-
chloromethane (20 mL) was added at ꢀ78 ꢁC. The stirring
was continued for 1.5 h and triethylamine (4.4 mL,
31.3 mmol) was added. After being stirred for 1 h, the reac-
tion was quenched by addition of phosphate buffer (pH 7).
The organic layer was separated and the aq layer was ex-
tracted with ethyl acetate twice. The combined organic layer
was dried over anhyd sodium sulfate and evaporated to dry-
ness to give (6S,7S)-6,10,10-trimethyl-11-oxospiro[1,3-di-
oxolane-2,80-bicyclo[2.2.2]octane]-7-carbaldehyde: [a]2D0
ꢀ48.7 (c 1.11, CHCl3); IR (CHCl3) 3048, 1721, 1462, 1389,
3.1.9. (6S,11S)-11-(Hydroxyethyl)-6,8,8-trimethyl-
spiro[1,3-dioxolane-2,80-bicyclo[2.2.2]octane]-7-one
(20). A mixture of PCC (354 mg, 1.64 mmol), sodium ace-
˚
tate (137 mg, 1.64 mmol), MS-4 A (120 mg, powder), and
Celite (100 mg) was evacuated at rt for 1 h. To the mixture
was added dichloromethane (3 mL) and then a solution of
the alcohol 19 (219 mg, 0.82 mmol) in dichloromethane
(7 mL) was added successively under nitrogen atmosphere.
After being stirred for 30 min, the slurry was passed through
silica-gel short column. Evaporation of the solvent followed
by medium pressure LC purification of the residue (eluent:
ethyl acetate/n-hexane¼1:1) provided the ketone 20
(213 mg, 98%, colorless oil): [a]2D0 +26.1 (c 1.03, CHCl3);
1
IR (CHCl3) 3040, 2363, 1713, 1357, 1096, 1013 cmꢀ1; H
NMR (200 MHz, CDCl3) d 1.03 (s, 3H), 1.20 (s, 3H), 1.29
(s, 3H), 1.69 (dd, J¼15.3, 1.6 Hz, 1H), 1.86 (t, J¼2.9 Hz,
1H), 2.17 (s, 3H), 2.05–2.30 (m, 1H), 2.55 (dd, J¼11.6,
7.0 Hz, 1H), 2.73 (d, J¼15.3 Hz, 1H), 3.80–4.05 (m, 4H);
13C NMR (50 MHz, CDCl3) d 17.3 (q), 23.5 (t), 25.8 (q),
26.1 (q), 31.0 (q), 39.7 (t), 44.1 (s), 45.9 (d), 46.6 (d), 63.1
(t), 64.1 (t), 109.1 (s), 207.6 (s), 217.9 (s); HRMS m/z calcd
for C15H22O4 266.1518, found 266.1518.
1
1350, 1096, 1037, 1013, 951 cmꢀ1; H NMR (200 MHz,
CDCl3) d 1.12 (s, 3H), 1.19 (s, 3H), 1.30 (s, 3H), 1.92 (dd,
J¼15.0, 1.6 Hz, 1H), 2.08 (dd, J¼13.6, 2.8 Hz, 1H), 2.23
(d, J¼15.0 Hz, 1H), 1.82–2.25 (m, 2H), 2.48 (ddd, J¼13.6,
4.2, 2.9 Hz, 1H), 3.85–4.05 (m, 4H), 9.82 (d, J¼2.9 Hz,
1H); 13C NMR (50 MHz, CDCl3) d 17.5 (q), 20.2 (t), 25.5
(q), 26.0 (q), 41.3 (t), 44.6 (s), 45.8 (d), 46.1 (s), 47.7 (d),
63.2 (t), 64.4 (t), 108.9 (s), 201.9 (d), 217.2 (s); HRMS m/z
calcd for C14H20O4 252.1361, found 252.1359.
3.1.10. (6S,11R)-11-(Hydroxyethyl)-6,8,8-trimethyl-
spiro[1,3-dioxolane-2,80-bicyclo[2.2.2]octane]-7-one
(21). A solution of the endo-methylketone 20 (58 mg,
0.22 mmol) and potassium hydroxide (50 mL, 2.2 M solution
in ethanol, 0.11 mmol) in ethanol (7 mL) was heated at re-
flux for 19 h under nitrogen atmosphere. The reaction was
quenched by addition of aq ammonium chloride. The prod-
uct was extracted with ethyl acetate twice and the combined
organic layer was washed with water, brine and dried over
anhyd sodium sulfate. Evaporation of the solvent followed
by medium pressure LC (eluent: ethyl acetate/n-hexane¼
1:1) gave the exo-methylketone 21 (47 mg, 81%, colorless
crystals) along with recovered endo-methylketone 20
(7 mg, 12%).
To a solution of the crude aldehyde (1.054 g) in ether
(50 mL) was added an ethereal solution of methylmagne-
sium bromide (3.9 mL, 3.0 M, 11.7 mmol) at 0 ꢁC under ni-
trogen atmosphere. After being stirred for 1.5 h, the reaction
was quenched by addition of aq ammonium chloride. The
product was extracted with ethyl acetate twice. The com-
bined organic layer was washed with water, brine and dried
over anhyd sodium sulfate. Evaporation of the solvent fol-
lowed by column chromatography (eluent: ethyl acetate/n-
hexane¼1:2) of the residue gave an inseparable mixture of
two diastereomeric alcohols 19 (940 mg, 90%, colorless oil).
More polar 19: [a]D20 +0.99 (c 1.00, CHCl3); IR (CHCl3)
3607, 3484, 2990, 2890, 1715, 1462, 1387, 1350,
exo-Methylketone 21: mp 80–82 ꢁC; [a]D20 ꢀ60.3 (c 1.02,
CHCl3); IR (CHCl3) 2980, 2930, 2882, 1730, 1549, 1354,
1
1
1097 cmꢀ1; H NMR (200 MHz, CDCl3) d 1.11 (s, 3H),
1099, 796 cmꢀ1; H NMR (200 MHz, CDCl3) d 0.95 (s,
3H), 1.22 (s, 3H), 1.27 (s, 3H), 1.73–1.95 (m, 4H), 2.16 (s,
1.18 (s, 3H), 1.26 (s, 3H), 1.31 (d, J¼6.5 Hz, 3H), 1.52–

7162
M. Fukushima et al. / Tetrahedron 63 (2007) 7154–7164
3H), 2.33 (ddd, J¼14, 11, 4 Hz, 1H), 3.05 (dd, J¼11, 7 Hz,
1H), 3.85–4.04 (m, 4H); 13C NMR (50 MHz, CDCl3)
d 18.0 (q), 23.8 (t), 24.8 (q), 26.9 (q), 31.7 (q), 44.7 (s),
45.7 (d), 45.8 (t), 46.4 (s), 52.5 (d), 63.0 (t), 64.2 (t), 109.2
(s), 210.7 (s), 217.2 (s). Anal. Calcd for C15H22O4: C,
67.65; H, 8.33. Found: C, 67.24; H, 8.45.
ethyl acetate/n-hexane¼1:1) gave the allylether 25a
(133 mg, 89%, colorless oil): [a]2D0 ꢀ85.1 (c 1.24, CHCl3);
IR (CHCl3) 2982, 1718, 1141, 1097, 1084, 1064, 1024,
1
929, 761, 744 cmꢀ1; H NMR (200 MHz, CDCl3) d 1.10
(s, 3H), 1.14 (s, 3H), 1.20 (s, 3H), 1.27 (s, 3H), 1.35–2.30
(m, 6H), 3.08 (s, 3H), 3.83–4.00 (m, 4H), 4.48 (d,
J¼7.0 Hz, 1H), 4.65 (d, J¼7.0 Hz, 1H), 5.16 (dd, J¼17,
1.4 Hz, 1H), 5.24 (dd, J¼11, 1.4 Hz, 1H), 5.73 (dd, J¼17,
11 Hz, 1H); 13C NMR (50 MHz, CDCl3) d 20.4 (q), 21.3
(q), 23.8 (t), 24.6 (q), 27.7 (q), 45.1 (s), 45.6 (d), 48.5 (t),
48.8 (s), 49.7 (d), 56.7 (q), 63.1 (t), 64.1 (t), 82.6 (s), 91.4
(t), 109.5 (s), 117.9 (t), 139.9 (d), 221.0 (s); HRMS m/z calcd
for C19H30O5 338.2093, found 338.2089.
3.1.11. 11-((1R)-1-Hydroxy-1-methylprop-2-
enyl)(6S,11R)-6,8,8-trimethylspiro[1,3-dioxolane-2,80-bi-
cyclo[2.2.2]octane]-7-one (24a) and 11-((1S)-1-hydroxy-
1-methylprop-2-enyl)(6S,11R)-6,8,8-trimethylspiro[1,3-
dioxolane-2,80-bicyclo[2.2.2]octane]-7-one (24b). To a
stirred solution of vinylmagnesium chloride (2.3 mL,
1.32 M solution in THF, 3.1 mmol) in THF (3 mL) was
added a solution of methylketone 21 (163 mg, 0.61 mmol)
in THF (3 mL) at ꢀ30 ꢁC under nitrogen atmosphere. After
being stirred for 3 h to ꢀ20 ꢁC, the reaction was quenched
by addition of aq ammonium chloride. After extraction
with ethyl acetate, the combined organic layer was washed
with water, brine and dried over anhyd sodium sulfate. After
evaporation of the solvent, the residue was purified by me-
dium pressure LC (eluent: ethyl acetate/n-hexane¼1:1) to
give two diastereomers, less polar alcohol 24b (40 mg,
22%, colorless crystals) and more polar alcohol 24a
(105 mg, 58%, colorless crystals).
3.1.13. 11-[(1S)-1-(Methoxymethoxy)-1-methylprop-2-
enyl](6S,11R)-6,8,8-trimethylspiro[1,3-dioxolane-2,80-bi-
cyclo[2.2.2]octane]-7-one (25b). To a solution of the allyl-
alcohol 24b (52 mg, 0.18 mmol) in DMF (1 mL) were
added diisopropylethylamine (185 mL, 1.07 mmol) and
chloromethylmethyl ether (67 mL, 0.89 mmol) at 0 ꢁC under
nitrogen atmosphere. After being stirred for 6 h at 60 ꢁC, the
reaction was quenched by addition of water. The product
was extracted with ethyl acetate twice. The combined
organic layer was washed with water, brine and dried over
anhyd sodium sulfate. Evaporation of the solvent followed
by purification by medium pressure LC (eluent: ethyl ace-
tate/n-hexane¼1:1) gave the allylether 25b (57 mg, 95%,
colorless oil): [a]D20 ꢀ35.1 (c 1.13, CHCl3); IR (CHCl3)
2978, 2885, 1720, 1454, 1412, 1346, 1180, 972, 951,
Less polar 24b: mp 86–88 ꢁC; [a]D20 ꢀ63.7 (c 1.23, CHCl3);
IR (CHCl3) 3584, 2980, 2934, 2882, 1714, 1454, 1386,
1197, 1153, 1097, 1037, 918, 775 cmꢀ1
;
1H NMR
1
(200 MHz, CDCl3) d 1.06 (s, 3H), 1.18 (s, 3H), 1.21 (s,
3H), 1.22 (s, 3H), 1.68–2.21 (m, 6H), 3.86–4.02 (m, 4H),
5.00 (dd, J¼10.7, 1.0 Hz, 1H), 5.19 (dd, J¼17, 1.0 Hz,
1H), 6.01 (dd, J¼17, 10.7 Hz, 1H); 13C NMR (50 MHz,
CDCl3) d 21.0 (q), 23.6 (t), 24.5 (q), 27.1 (q), 27.2 (q),
48.2 (s), 45.5 (d), 47.9 (t), 48.6 (s), 49.6 (d), 63.1 (t), 64.1
(t), 76.1 (s), 109.4 (s), 111.0 (t), 146.7 (d), 222.0 (s). Anal.
Calcd for C17H26O4: C, 69.36; H, 8.91. Found: C, 69.43;
H, 8.94.
927 cmꢀ1; H NMR (200 MHz, CDCl3) d 1.15 (s, 3H),
1.16 (s, 3H), 1.18 (s, 3H), 1.22 (s, 3H), 1.20–2.23 (m, 6H),
3.36 (s, 3H), 3.82–4.00 (m, 4H), 4.51 (d, J¼7 Hz, 1H),
4.63 (d, J¼7 Hz, 1H), 5.07 (dd, J¼18, 1 Hz, 1H), 5.16 (dd,
J¼11, 1 Hz, 1H), 5.77 (dd, J¼18, 11 Hz, 1H); 13C NMR
(50 MHz, CDCl3) d 18.1 (q), 20.5 (q), 24.3 (t), 24.5 (q),
27.7 (q), 45.0 (s), 45.5 (d), 48.4 (t), 48.6 (s), 49.0 (d), 56.0
(q), 63.1 (t), 64.1 (t), 82.0 (s), 91.6 (t), 109.5 (s), 115.1 (t),
142.8 (d), 220.7 (s); HRMS m/z calcd for C19H30O5
338.2093, found 338.2089.
More polar 24a: mp 87–89 ꢁC; [a]D20 ꢀ51.2 (c 1.10, CHCl3);
IR (CHCl3) 3611, 2976, 1720, 1477, 1386, 1196, 1140,
3.1.14. (12S,13S)-7,7,11,13-Tetramethylspiro[1,3-dioxo-
lane-2,100-tricyclo[5.3.1.03,8]undecane]-10-en-8-ol (9). A
mixture of sodium (24 mg, 1.04 mmol) and naphthalene
(91 mg, 0.71 mmol) in THF (2.5 mL) was stirred vigorously
at ꢀ55 ꢁC to rt under nitrogen atmosphere, when the color
developed dark green. After being cooled again at ꢀ55 ꢁC
for 10 min, a solution of the allylether 25a (40 mg,
0.12 mmol) in THF (2.5 mL) was added. Stirring was con-
tinued for 2.5 h maintaining the color dark green. The reac-
tion was quenched by addition of aq ammonium chloride.
The product was extracted with ethyl acetate twice and the
combined organic layer was washed with water, brine and
dried over anhyd sodium sulfate. Evaporation of the solvent
followed by medium pressure LC purification (eluent: ethyl
acetate/n-hexane¼1:1) gave tricyclic alkene 9 (31 mg, 95%,
colorless solid): mp 123 ꢁC; [a]D20 +29.8 (c 1.31, CHCl3); IR
(CHCl3) 2964, 2930, 2363, 1726, 1450, 1091, 1064,
1097, 1035, 927 cmꢀ1
;
1H NMR (200 MHz, CDCl3)
d 1.14 (s, 3H), 1.16 (s, 3H), 1.21 (s, 3H), 1.28 (s, 3H),
1.39–2.21 (m, 6H), 3.86–4.02 (m, 4H), 5.07 (dd, J¼10.7,
1.3 Hz, 1H), 5.18 (dd, J¼17.3, 1.3 Hz, 1H), 5.85 (dd,
J¼17.3, 10.7 Hz, 1H); 13C NMR (50 MHz, CDCl3) d 20.3
(q), 24.3 (t), 24.5 (q), 26.9 (q), 27.6 (q), 45.0 (s), 45.5 (d),
48.3 (t), 48.5 (s), 49.6 (d), 49.6 (s), 63.1 (t), 64.1 (t), 109.4
(s), 113.7 (t), 142.4 (d), 220.8 (s); HRMS m/z calcd for
C17H26O4 294.1831, found 294.1832.
3.1.12. 11-[(1R)-1-(Methoxymethoxy)-1-methylprop-
2-enyl](6S,11R)-6,8,8-trimethylspiro[1,3-dioxolane-2,80-
bicyclo[2.2.2]octane]-7-one (25a). To a solution of the
allylalcohol 24a (130 mg, 0.44 mmol) in DMF (2 mL)
were added diisopropylethylamine (465 mL, 2.67 mmol) and
chloromethylmethyl ether (170 mL, 2.23 mmol) at 0 ꢁC
under nitrogen atmosphere. After being stirred for 6 h at
60 ꢁC, the reaction was quenched by addition of water.
The product was extracted with ethyl acetate twice. The
combined organic layer was washed with water, brine and
dried over anhyd sodium sulfate. Evaporation of the solvent
followed by purification by medium pressure LC (eluent:
1
758 cmꢀ1; H NMR (500 MHz, CDCl3) d 0.85 (s, 3H),
1.12 (s, 3H), 1.24 (s, 3H), 1.27 (s, 3H), 1.25–1.61 (m, 3H),
1.61–1.65 (m, 3H), 1.67–2.40 (m, 5H), 3.75–4.05 (m, 4H),
5.10–5.20 (m, 1H); 13C NMR (125 MHz, CDCl3) d 20.6
(q), 22.2 (q), 25.6 (t), 26.6 (q), 28.2 (q), 35.2 (t), 38.5 (s),
40.5 (s), 41.7 (t), 42.8 (d), 45.6 (d), 62.5 (t), 63.9 (t), 74.0

M. Fukushima et al. / Tetrahedron 63 (2007) 7154–7164
7163
(s), 110.7 (s), 118.5 (d), 138.6 (s); HRMS m/z calcd for
C17H26O3 278.1882, found 278.1877.
1H), 1.90 (t like, 1H), 2.04 (m, 1H), 2.64 (d, J¼19 Hz,
1H); 13C NMR (125 MHz, CDCl3) d 18.7 (q), 19.5 (q),
20.9 (q), 23.0 (q), 27.7 (q), 27.9 (d), 28.3 (t), 33.1 (t), 40.5
(s), 42.4 (d), 43.6 (d), 46.5 (t), 57.7 (d), 74.3 (s), 216.1 (s).
Anal. Calcd for C15H24O2: C, 76.23; H, 10.24. Found: C,
75.53; H, 10.24.
3.1.15. (12S,9R,10R,11R)-10-(Methoxymethoxy)-7,7,9,
10,12-pentamethylspiro[1,3-dioxolane-2,90-tricy-
clo[4.3.1.03,7]decane]-8-ol (27). A mixture of lithium
(19 mg, 0.8 mmol) and naphthalene (118 mg, 0.92 mmol)
in THF (4 mL) and 1,4-dioxane (1.5 mL) was stirred vigor-
ously at ꢀ55 ꢁC to 0 ꢁC under nitrogen atmosphere, when
the color developed dark green. After being cooled again
at ꢀ55 ꢁC, a solution of the allylether 25b (52 mg,
0.16 mmol) in THF (2 mL) and 1,4-dioxane (2 mL) was
added. Stirring was continued for 3 h maintaining the color
dark green. The reaction was quenched by addition of aq am-
monium chloride. The product was extracted with ethyl ace-
tate twice. The combined organic layer was washed with
water, brine and dried over anhyd sodium sulfate. Evapora-
tion of the solvent followed by medium pressure LC purifi-
cation (eluent: ethyl acetate/n-hexane¼3:5) gave 6-endo-
trig tricyclic alkene 9 (23 mg, 54%, colorless oil) along
with 5-exo-trig product 27 (15 mg, 29%, colorless oil).
3.1.17. (6S,7S,8S,10R)-2,2,6,8-Tetramethyltricyclo-
[5.3.1.03,8]undecane-3,10-diol (valeriananoid B 2). To a
solution of valeriananoid A 1 (177 mg, 0.75 mmol) was
added in methanol (10 mL) sodium borohydride (573 mg,
15.1 mmol) at 0 ꢁC under nitrogen atmosphere. After being
stirred for 12 h at rt, the reaction was quenched by addition
of aq ammonium chloride. The product was extracted with
ethyl acetate twice. The combined organic layer was washed
with water, brine and dried over anhyd sodium sulfate. Evap-
oration of the solvent followed by column chromatography
(eluent: ethyl acetate/n-hexane¼1:8 to 1:1) gave valeriana-
noid B 2 (177 mg, 99%): mp 171 ꢁC decomposition (lit.1
133–135 ꢁC; lit.4 200–202 ꢁC; lit.5 179–181 ꢁC; lit.9 185–
187 ꢁC); [a]2D4 ꢀ117.7 (c 0.69, CHCl3) {lit.1 ꢀ115.8 (c
0.41, MeOH); lit.4 ꢀ57.87 (c 0.197, CHCl3); lit.5 ꢀ75.4 (c
1.1, CHCl3); lit.9 ꢀ90.0 (c 1.0, CHCl3)}; IR (CHCl3)
5-exo-trig Product 27: IR (CHCl3) 3632, 2936, 1730, 1462,
1389, 1146, 1086, 1028 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 0.91 (s, 3H), 1.03 (d, J¼8.0 Hz, 3H), 1.04 (s, 3H), 1.15 (s,
3H), 1.19 (t, J¼2.5 Hz, 1H), 1.44 (s, 3H), 1.57 (dd, J¼15.0,
1.0 Hz, 1H), 1.74 (dd, J¼10.5, 2.5 Hz, 1H), 1.92 (ddd,
J¼14.5, 10.5, 2.5 Hz, 1H), 1.97 (d, J¼15.0 Hz, 1H), 2.20
(dt, J¼14.5, 2.5 Hz, 1H), 2.55 (q, J¼8.0 Hz, 1H), 3.40 (s,
3H), 3.87–4.99 (m, 4H), 4.59 (d, J¼7.0 Hz, 1H), 4.67 (d,
J¼7.0 Hz, 1H), 4.59 (d, J¼7.0 Hz, 1H); 13C NMR
(50 MHz, CDCl3) d 14.1 (q), 21.2 (t), 23.5 (q), 24.1 (q),
26.5 (q), 27.3 (q), 41.6 (d), 42.7 (s), 44.8 (d), 45.8 (s), 47.1
(d), 48.6 (d), 55.7 (q), 62.4 (t), 63.8 (t), 81.3 (s), 84.1 (s),
92.1 (t), 109.9 (s); HRMS m/z calcd for C19H32O5
340.2250, found 340.2253.
3665, 3455, 1728, 1601, 1463, 909 cmꢀ1
;
1H NMR
(270 MHz, CDCl3) d 0.80 (d, J¼6.8 Hz, 3H), 0.90 (s, 3H),
1.12 (s, 3H), 1.24 (s, 3H), 1.60 (dd, J¼13.8, 10.3 Hz, 1H),
1.20–1.80 (m, 10H), 1.88 (dd, J¼13.8, 7.8 Hz, 1H), 1.90–
2.00 (m, 1H), 3.92 (br t, 1H); 13C NMR (67.5 MHz,
CDCl3) d 18.9, 20.2, 24.2, 25.5, 27.7, 28.2, 28.6, 32.6,
39.4, 39.5, 40.4, 42.5, 46.8, 72.5, 75.1; HRMS m/z calcd
for C15H26O2 238.1933, found 238.1934.
3.1.18. (6S,7S,8S,10R)-3-Hydroxy-2,2,6,8-tetramethyltri-
cyclo[5.3.1.03,8]undec-10-yl acetate (valeriananoid C 3).
To a solution of valeriananoid B 2 (105 mg, 0.44 mmol)
and DMAP (26 mg, 0.21 mmol) in dichloromethane
(5 mL) were added pyridine (430 mL, 5.32 mmol) and acetic
anhydride (415 mL, 4.39 mmol) at 0 ꢁC under nitrogen at-
mosphere. After being stirred for 3 h, the reaction was
quenched by addition of water. The product was extracted
with ethyl acetate twice. The combined organic layer was
washed with water, brine and dried over anhyd sodium
sulfate. Evaporation followed by medium pressure LC puri-
fication (eluent: ethyl acetate/n-hexane¼1:3) gave valeria-
nanoid C 3 (123 mg, 100%): mp 84 ꢁC (lit.1 85–86 ꢁC; lit.4
79–80 ꢁC; lit.9 74–76 ꢁC); [a]D24 ꢀ109.8 (c 0.37, CHCl3)
{lit.1 ꢀ114.8 (c 3.3, CHCl3); lit.4 ꢀ56.88 (c 0.16, CHCl3);
lit.5 ꢀ77.3 (c 1.1, CHCl3); lit.9 ꢀ116.0 (c 1.0, CHCl3)}; IR
3.1.16. (6S,7S,8S)-3-Hydroxy-2,2,6,8-tetramethyltri-
cyclo[5.3.1.03,8]undecan-10-one (valeriananoid A 1). To
a solution of the tricyclic alkene 9 (231 mg, 0.83 mmol) in
ethyl acetate (2 mL) was added palladium on carbon
(165 mg, 5% Pd wet) and the system was purged with hydro-
gen. After being stirred for 210 h at rt, the suspension was
passed through silica-gel short column and the solvent was
evaporated to dryness.
To a solution of the residue in water (1 mL) and THF (1 mL),
p-toluenesulfonic acid (2 mg, 0.015 mmol) was added. After
being stirred for 20 min at rt, the reaction was quenched by
addition of aq sodium hydrogen carbonate. The product was
extracted with ethyl acetate. The combined organic layer
was washed with water, brine and dried over anhyd sodium
sulfate. Evaporation of the solvent followed by medium
pressure LC purification (eluent: ethyl acetate/n-
hexane¼2:3) gave valeriananoid A 1 (177 mg, 90% in two
steps): mp 123–124 ꢁC (lit.4 122–124 ꢁC; lit.9 117–
118 ꢁC); [a]2D0 ꢀ82.3 (c 0.27, CHCl3) {lit.4 ꢀ34.6 (c
0.231, CHCl3); lit.9 ꢀ33.3 (c 0.3, CHCl3)}; IR (CHCl3)
3440, 1720, 1470, 1390, 1340, 1220, 1100, 1070, 1050,
(CHCl3) 3603, 3117, 2957, 1723, 1464, 1368, 1265 cmꢀ1
;
1H NMR (270 MHz, CDCl3) d 0.80 (d, J¼6.5 Hz, 3H),
0.90 (s, 3H), 1.10 (s, 3H), 1.15 (s, 3H), 1.20–1.80 (m, 7H),
1.37 (ddd, J¼10.0, 6.5, 3.0 Hz, 1H), 1.44 (dd, J¼14.0,
1.9 Hz, 1H), 1.90–2.04 (m, 1H), 1.96 (dd, J¼14.0, 7.8 Hz,
1H), 2.02 (s, 3H), 4.80 (ddd, J¼10.0, 7.8, 1.9 Hz, 1H); 13C
NMR (67.5 MHz, CDCl3) d 18.8, 20.0, 21.7, 23.6, 25.1,
27.7, 27.9, 28.6, 32.7, 36.0, 39.1, 40.1, 42.5, 43.3, 74.5,
75.0, 170.6; HRMS m/z calcd for C17H28O3 280.2038, found
280.2032.
1
1000, 890, 590 cmꢀ1; H NMR (500 MHz, CDCl3) d 0.85
3.2. Crystallographic data of 11 (23 ꢁC)
(d, J¼6.7 Hz, 3H), 0.98 (s, 3H), 1.02 (s, 3H), 1.18 (s, 3H),
1.38–1.50 (m, 2H), 1.50–1.58 (m, 2H), 1.62 (m, 1H), 1.74
(m, 1H), 1.78 (d, J¼19 Hz, 1H), 1.85 (dd, J¼11.9, 5.5 Hz,
Colorless crystals (from n-hexane); formula C28H38O4,
fw¼438.61; monoclinic, space group P21 (no. 4),

7164
M. Fukushima et al. / Tetrahedron 63 (2007) 7154–7164
˚
˚
˚
Ohtsubo, S.; Kato, M.; Uda, H. J. Org. Chem. 2002, 67, 5969
and earlier references cited therein.
7. Hagiwara, H.; Morii, A.; Yamada, Y.; Hoshi, T.; Suzuki, T.
Tetrahedron Lett. 2003, 44, 1595.
8. Tietze, L. F.; Beifuss, U. Domino Reactions in Organic
Synthesis; John Wiley & Sons: New York, NY, 2006.
9. Srikrishna, A.; Satyanarayana, G. Org. Lett. 2004, 6, 2337;
Srikrishna, A.; Satyanarayana, G. Tetrahedron: Asymmetry
2005, 16, 3992.
a¼9.309(3) A, b¼10.200(7) A, c¼13.450(3) A; b¼
91.47(2)ꢁ; V¼1276.6(8) A , Z¼2, Dcalcd¼1.141 g/cm3,
3
˚
m(Mo Ka)¼0.90 mmꢀ1. A total of 3281 reflections, 1931
(I>3.00s(I)) were used in refinement: R¼0.051, Rw¼
0.048. The reflection intensities were collected on a Rigaku
AFC7S diffractometer with a rotating anode (50 kV, 30 mA)
˚
using graphite monochromated Mo Ka (l¼0.7107 A).
10. Hagiwara, H.; Yamada, Y.; Sakai, H.; Suzuki, T.; Ando, M.
Tetrahedron 1998, 54, 10999.
Acknowledgements
11. Hagiwara, H.; Endou, S.; Fukushima, M.; Hoshi, T.; Suzuki, T.
Org. Lett. 2004, 6, 1115.
12. Fukushima, M.; Endou, S.; Hoshi, T.; Suzuki, T.; Hagiwara, H.
Tetrahedron Lett. 2005, 46, 3287.
13. Representative papers picked up arbitrarily: Miyaoka, H.;
Yokokura, T.; Okamura, T.; Nagaoka, H.; Yamada, Y. Synlett
2002, 227; Braun, N. A.; Spitzner, D. Tetrahedron Lett. 1996,
37, 9187.
We thank Professors De Quan Yu, Peking Union Medical
College and A. Srikrishna, Indian Institute of Science, for
providing spectral data of valeriananoid A 1. Thanks are
also due to Shorai Foundation for Science and Technology
(for H.H.), and Grant-in-Aid for Scientific Research on Pri-
ority Areas (17035031 for H.H. and T.S.) from The Ministry
of Education, Culture, Sports, Science and Technology
(MEXT).
14. Unpublished results from this laboratory.
15. Curran, D. P. Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4,
p 715.
References and notes
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17. Spreitzer, H.; Kalchhauser, H. Liebigs Ann. Chem. 1990, 709;
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6. Hagiwara, H.; Kobayashi, K.; Miya, S.; Hoshi, T.; Suzuki, T.;
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