Stereoselective total synthesis of (±)-α-vetispirene, (±)-hinesol, and (±)-β-vetivone based on a Claisen rearrangement

Article abstract of DOI:10.1016/j.tet.2006.04.049

The stereoselective total syntheses of (±)-α-vetispirene, (±)-hinesol, and (±)-β-vetivone were accomplished based on a Claisen rearrangement in an alkenyl bicyclic dihydropyran system. The most striking feature of this approach is that the Claisen rearrangement of bicyclic dihydropyran proceeds stereoselectively to provide a multi-functionalized spiro[4.5]decane, which is an efficient precursor for the synthesis of the vetivane sesquiterpenes.

Full text of DOI:10.1016/j.tet.2006.04.049

Tetrahedron 62 (2006) 6264–6271
Stereoselective total synthesis of ( )-a-vetispirene, ( )-hinesol,
and ( )-b-vetivone based on a Claisen rearrangement
*
Atsuo Nakazaki, Tomohiro Era, Yuko Numada and Susumu Kobayashi
Faculty of Pharmaceutical Sciences, Tokyo University of Science (RIKADAI), 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan
Received 7 March 2006; revised 17 April 2006; accepted 19 April 2006
Available online 19 May 2006
Abstract—The stereoselective total syntheses of (ꢀ)-a-vetispirene, (ꢀ)-hinesol, and (ꢀ)-b-vetivone were accomplished based on a Claisen
rearrangement in an alkenyl bicyclic dihydropyran system. The most striking feature of this approach is that the Claisen rearrangement of
bicyclic dihydropyran proceeds stereoselectively to provide a multi-functionalized spiro[4.5]decane, which is an efficient precursor for the
synthesis of the vetivane sesquiterpenes.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
activities. Especially, (ꢁ)-2 is a relatively specific inhibitor
of H+, K+-ATPase and an active ingredient of cerebral circu-
lation and metabolism improvers.2c Because of their unique
structures and biological activities, a number of synthetic
approaches to these terpenes have been reported, including
intramolecular alkylations, palladium-based cyclizations,
and intermolecular cycloadditions.5,6
a-Vetispirene (1),1 hinesol (2),2 and b-vetivone (3)3 are rep-
resentative members of the vetivane sesquiterpene family,
which possess a spiro[4.5]decane core and a branched three-
carbon unit on a cyclopentane framework (Fig. 1). Related
spirocyclic terpenes such as lubimin and gleenol, substituted
with an oxy-functional group at a position adjacent to the
spirocyclic carbon center, have been also isolated.4 Some
of these spirocyclic terpenes exhibit interesting biological
We have recently developed a new approach to multi-sub-
stituted spiro[4.5]decanes based on a Claisen rearrangement,
in order to produce a more efficient general synthetic method
for spirocyclic terpenes (Eq. 1).7 Claisen rearrangement is
one of the most reliable and efficient methods of introducing
asymmetry and as such may be quite useful for the synthesis
of the functionalized spiro[4.5]decane B.8 The strategy
involves a rearrangement of bicyclic dihydropyran A, sub-
stituted in the 4-position with a high-oxidation state group
(Eq. 1, Y), thereby introducing a functional group at a posi-
tion adjacent to the spirocyclic carbon center in B. By means
of varying the groups R, X, and Y, this strategy could be
applicable to the synthesis of multi-functionalized spiro-
cyclic frameworks.
HO
O
α-Vetispirene (1)
β-Vetivone (3)
Hinesol (2)
CHO
OH
O
R
Claisen
O
Y
Rearrangement
ð1Þ
R
Y
OH
Lubimin
4
A
X
X
Gleenol
B
Figure 1. Terpenes with spiro[4.5]decane framework.
It is worth noting that the choice of the functional group Y is
an important key to success in this rearrangement. Indeed,
the expected rearrangement of alkenyl dihydroxypyrone
(Y]O) did not proceed; instead the ring-opening product
was mainly obtained (Eq. 2). On the other hand, the rear-
rangement of dihydropyrans, substituted in the 4-position
Keywords: Vetivane sesquiterpene; Spiro[4.5]decane; Claisen rearrange-
ment.
* Corresponding author. Tel./fax: +81 4 7121 3671; e-mail: kobayash@rs.
noda.tus.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.049

A. Nakazaki et al. / Tetrahedron 62 (2006) 6264–6271
6265
with a non-enolizable group such as a double bond or a siloxy
group, proceeds in excellent yields and with high stereo-
selectivities (Eqs. 3 and 4).7 This is the first report of success-
ful Claisen rearrangement in bicyclic dihydropyran systems
with a high-oxidation state functionality in the 4-position.9
obtainable from the corresponding dihydropyrone 4, which
would be readily available from a racemic hydroxy-1,3-di-
ketone 8a by acid-catalyzed cyclization. In turn, synthesis
of diketone 8a was envisaged from aldehyde 7 by means
of several simple manipulations. As non-racemic 7 is easily
prepared in high enantiomeric excess by several ways,10 the
present strategy would be applicable to the total synthesis of
the optically active vetivane sesquiterpenes.
PdCl2(PhCN)2
O
∆, Lewis acid,
O
O
HO
+
or microwave
irradiation
O
O
2.1. Stereoselectivesynthesisofalkenyldihydropyranes5
4
trace
major product
Our first step was the preparation of substrate 5 according to
a modified version of our procedure (Scheme 2);7 treatment
of the known aldehyde 7 (racemate)11 with the enolate
derived from cyclopentanone afforded the aldol adduct as
a mixture of diastereomers. This aldol adduct was converted
to 1,3-diketone 8b by DMSO/TFAA oxidation in good
yield.12 Notably, other oxidants, such as Dess–Martin
periodinane, DMSO/(COCl)2, and PCC were less effective.
Next, removal of the TBS group of 8b and acid-catalyzed
cyclization proceeded in a single operation by an excess of
TFA to afford alkenyl dihydropyrone 4 in 85% yield.
Dihydropyrone 4 thus obtained was reduced by LiAlH4 to
afford 9, followed by protection of the hydroxy group to
give the requisite alkenyl dihydropyran 5a (R¼PMB) or
5b (R¼TBS) as single diastereomer. The relative stereo-
chemistry shown for 5b was determined by the NOESY
correlation.
ð2Þ
ð3Þ
68% dr
OMe
O
68% dr 250 °C
O
toluene
98%
OMe
>95% dr
O
250 °C
OTBS
O
toluene
ð4Þ
OTBS
6b >95% dr
5b
69%
(unoptimized yield)
We focused our attention on the siloxy spiro[4.5]decane 6b
because this spirocycle 6b would be a suitable precursor for
the synthesis of vetivane sesquiterpenes. The present paper
details optimization of the Claisen rearrangement of alkenyl
bicyclic dihydropyran and the stereoselective total synthesis
of (ꢀ)-a-vetispirene, (ꢀ)-hinesol, and (ꢀ)-b-vetivone.
TBSO
O
a, b
TBSO
CHO
O
7 (racemate)
8b
2. Results and discussion
c
d
O
Our retrosynthetic analysis for the stereoselective synthesis
of vetivane sesquiterpenes is outlined in Scheme 1. As
shown, access to these spirocyclic terpenes was envisioned
from a key intermediate 16, which would be converted from
spiro[4.5]decane 6. The Claisen rearrangement of 4-oxy-
functionalized alkenyl dihydropyran 5 would provide 6 in
a stereoselective manner. Dihydropyran 5 should be
O
O
OH
O
9 >95% dr
4
e or f
OR
5a: R = PMB
5b: R = TBS
>95% dr
MeO2C
Scheme 2. Preparation of substrates 5a and 5b for the Claisen rearrange-
ment. Reagents and conditions: (a) LDA, cyclopentanone, 91%; (b)
DMSO, TFAA, then Et3N, ꢁ78 ꢂC, 87%; (c) TFA, CH2Cl2, 0 ꢂC/rt,
85%; (d) LiAlH4, Et2O, 0 ꢂC; (e) PMBCl, NaH, 57% (two steps); (f)
TBSCl, imidazole, rt, 73% (two steps).
O
Spirocyclic
O
OR
Terpenes
16
6
2.2. Optimization of the Claisen rearrangement
Key Intermediate
Next, we examined the construction of the spiro[4.5]decane
framework by thermolytically induced Claisen rearrange-
ment. After careful optimization, it was found that the choice
of solvent, hydroxy protecting group, and temperature
appears to be important for the success of this rearrangement
(Table 1). The rearrangement of dihydropyran 5a (R¼PMB),
in 1,2,4-trichlorobenzene (1,2,4-TCB) at 250 ꢂC, provided
a trace amount of the desired rearrangement product 6a,
along with an elimination product as the major component
(entry 1). In contrast, the rearrangement of 5b, which was
protected by a bulkier group on the 4-hydroxy group, in the
O
O
4
OR
O
5
4
O
O
HO
TBSO
CHO
8a
7
Scheme 1. Retrosynthetic analysis.

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A. Nakazaki et al. / Tetrahedron 62 (2006) 6264–6271
Table 1. Claisen rearrangement of the alkenyl dihydropyrans
hydroxy ester 12 by a two-step sequence. Chemoselective
oxidation of the primary alcohol by the Merck method
(TEMPO/NaClO2/NaClO) to afford the corresponding car-
boxylic acid,16 followed by methyl esterification (MeI,
KHCO3), led to 12 in 84% yield for the two steps. The
hydroxy ester 12 was then mesylated and eliminated to pro-
vide the desired a,b-unsaturated ester 14. Removal of the
TBS group of 14 with an aqueous solution of hydrogen fluo-
ride in CH3CN, followed by Dess–Martin oxidation,17 led
to the key intermediate ketone 16. This compound would
be a versatile intermediate for the syntheses of a variety of
spirocyclic terpenes.
O
O
OR
temperature
OR
solvent
5 or 9 >95% dr
>95% dr
6
Entry Substrate (R) Solvent
Temperature (ꢂC) Product Yield (%)
1
2
3
4
5
5a (PMB)
5b (TBS)
5b
5b
9 (H)
1,2,4-TCB 250
1,2,4-TCB 250
6a
6b
6b
6b
6c
Trace
28
87
Trace
0
Toluene
1,2,4-TCB 165
250
1,2,4-TCB 70–100
MeO2C
2
same solvent, afforded rearrangement product 6b. While this
was a better result than the previous one it was still poor
(28% yield, entry 2). In addition to changing the protective
group, use of a less polar solvent provided much better re-
sults. Thus, alkenyl dihydropyran 5b was heated at 250 ꢂC
in toluene to provide the desired spiro[4.5]decane 6b in
87% yield as a single diastereomer (entry 3).13 The rear-
rangement of 5b or 9 (R¼H) at lower temperature in
1,2,4-TCB afforded only elimination products; none of the
desired products were obtained (entries 4 and 5).
O
O
O
a
b
OP
OP
OP
P = TBS
6b
10
11
MeO2C
HO
HO
HO
c
OP
OP
+
12
13
d, e
The stereochemical assignment of 6b was verified by NOE
experiments on the tricycle, derived from 6b in two steps
[(1) LiAlH4, Et2O, 0 ꢂC; (2) 2,2-dimethoxypropane, PPTS,
CH2Cl2] (Fig. 2).7 This stereochemical outcome suggests
that the bicyclic dihydropyran 5b undergoes the rearrange-
ment through a boat-like transition state (Fig. 3).14
MeO2C
MeO2C
f, g
i
OP
O
12
16
NOE
14: P = TBS
15: P = H
H
Me
h
Key Intermediate
H
1. LiAlH4, Et2O, 0 °C
Me
O
6b
Me
O
H
2. (MeO)2CMe2
PPTS, CH2Cl2
Scheme 3. Preparation of the key intermediate 16. Reagents and conditions:
(a) Pd/C, H2 (1 atm), EtOH; (b) KH, (MeO)2CO, THF, 95 ꢂC, 86% (two
steps); (c) NaBH4, MeOH, 12 67% (based on the recovered S.M.: 74%), 13
20%;(d)TEMPO,NaClO2, NaClO;(e)MeI,KHCO3, DMF, 84%(twosteps);
(f) MsCl, pyridine, 0 ꢂC; (g) DBU, CH2Cl2, rt, 92% (two steps); (h) 48% HF
aq, CH3CN, rt; (i) Dess–Martin periodinane, CH2Cl2, rt, 88% (two steps).
49% (>95% dr)
Figure 2. Stereochemical determination of 6b.
O
O
2.4. Total synthesis of ( )-a-vetispirene
Me
Me
5b
We next explored the final steps to (ꢀ)-a-vetispirene (1).
Treatment of ketone 16 with excess MeLi, followed by
acid-catalyzed dehydration with TsOH$H2O, led to (ꢀ)-1,
along with inseparable byproducts. Thus, we chose an alter-
native stepwise route, whereby ketone 16 was first trans-
formed into exo-methylene 17 under Nozaki’s conditions
(TiCl4, CH2I2, and Zn) (Scheme 4).2c,18 Acid-catalyzed
isomerization of 17 provided the endo-isomer, which after
treatment with an excess of MeLi, followed by dehydration
led to (ꢀ)-a-vetispirene (1) in good overall yield.19
H
H
6b
TBSO
TBSO
Figure 3. A possible transition state of Claisen rearrangement.
2.3. Synthesis of a key intermediate 16
With the multi-functionalized spiro[4.5]decane framework
in hand, we next synthesized 16, a common key intermediate
for the synthesis of vetivane sesquiterpenes, as shown in
Scheme 3. The double bond in ketone 6b could be saturated
under 1 atm of hydrogen gas in the presence of 5% Pd on
charcoal.15 Although introduction of one-carbon unit at the
C2-position of the spiro[4.5]decane framework has been
achieved with difficulty,6 exposure of ketone 10 to an excess
of KH and dimethyl carbonate smoothly produced the de-
sired keto ester 11 in good yield as a mixture of diastereo-
mers. Next, the reduction with NaBH4 was performed to
give hydroxy ester 12 in moderate yield, along with the un-
expected diol 13 in 20% yield. Diol 13 could be converted to
MeO2C
MeO2C
b-d
a
O
16
17
( )-α-Vetispirene (1)
Scheme 4. Total synthesis of (ꢀ)-a-vetispirene (1). Reagents and condi-
tions: (a) CH2I2, TiCl4, Zn, THF–CH2Cl2, 72%; (b) cat. TsOH$H2O, PhH,
reflux; (c) MeLi, THF; (d) cat. CSA, PhH, 60 ꢂC, 87% (three steps).

A. Nakazaki et al. / Tetrahedron 62 (2006) 6264–6271
6267
2.5. Total synthesis of ( )-hinesol and ( )-b-vetivone
at either 400 MHz (1H) or 100 MHz (13C) or on a JEOL
AL-300 spectrometer operating at either 300 MHz (1H) or
75 MHz (13C). Chemical shifts are reported in d units and
are referenced to the solvent, i.e., 7.26/77.1 for CDCl3.
Multiplicities are indicated as br (broadened), s (singlet),
d (doublet), t (triplet), q (quartet), quint (quintet), sept (sep-
tet), or m (multiplet). Coupling constants (J) are reported
in Hertz (Hz). Infrared spectra were recorded on a Jasco
FT-IR410 spectrometer. Electron impact mass spectra were
performed on a HITACHI M-80B mass spectrometer. Elec-
trospray ionization mass spectra were recorded on an
Applied Biosystems API QSTAR pulsar i as high resolution,
using poly(ethylene glycol) as internal standard. Thin-layer
chromatography (TLC) was performed on silica gel 60 F254
(Merck 1.05715.0009) plates. Flash column chromatography
was performed on a PSQ100B silica gel (Fuji Silysia Co.,
Ltd, Japan). THF and Et2O were purchased from Wako Pure
Chemical Industries Ltd, in anhydrous grade. CH2Cl2 was
distilled from CaH2 immediately before use. Diisopropyl-
amine was distilled from CaH2 and stored over KOH pellets.
(ꢀ)-Hinesol (2) was also synthesized from the key interme-
diate 16 in a stereoselective manner (Scheme 5). Ketone 16
was subjected to hydrogenolysis to afford the desired ester
18 in 97% as an 87:13 mixture of separable diastereomers.20
The keto carbonyl of 18 was converted to an exo-methylene
group using Nozaki’s conditions. Finally acid-catalyzed
isomerization, to give endo-isomer followed by treatment
with an excess of MeMgI, provided (ꢀ)-hinesol (2) in
90% yield for the two steps. (ꢀ)-b-Vetivone (3) was synthe-
sized from (ꢀ)-hinesol by a reported procedure.21 The regio-
selective allylic oxidation of (ꢀ)-hinesol (2) by means of
CrO3/3,5-dimethylpyrazole (3,5-DMP) afforded hinesolone
20 in moderate yield.22 Then, treatment of 20 with acetic
anhydride followed by BF3$OEt2 yielded (ꢀ)-b-vetivone
(3) contaminated with the exo-methylene isomer as an insep-
arable mixture (86:14 mixture of 3 and the exo-isomer) in
64% yield.23
MeO2C
MeO2C
MeO2C
4.1.1. 1,3-Diketone 8b. To the solution of diisopropylamine
(0.982 mL, 7.05 mmol) in THF (14 mL) was added a solu-
tion of n-BuLi (4.6 mL of 1.52 M solution in hexane,
7.05 mmol) at 0 ꢂC, then the resulting mixture was stirred at
that temperature for 30 min and cooled to ꢁ78 ꢂC. To this
mixture was added cyclopentanone (0.567 mL, 6.41 mmol)
at ꢁ78 ꢂC, then this mixture was stirred at that temperature
for 1 h. To this mixture was added a solution of aldehyde 7
(732 mg, 3.21 mmol) in THF (6 mL) at ꢁ78 ꢂC, then this
mixture was stirred at that temperature for 1 h 20 min. The
reaction mixture was quenched with a saturated aqueous
solution of NH4Cl. The aqueous layer was extracted two
times with EtOAc. The combined organic layer was washed
with brine, dried over Na2SO4, filtrated, and concentrated
under reduced pressure. Purification by silica-gel column
chromatography (hexane/EtOAc¼95:5/90:10/80:20)
gave 908 mg (91% yield, a mixture of diastereomers by 1H
NMR analysis) of the aldol adduct: Rf 0.64, 0.52 (hexane/
a
b
O
O
CH2
16
18
19
HO
HO
f, g
c, d
e
O
20
( )-Hinesol (2)
O
( )-β-Vetivone (3)
Scheme 5. Total synthesis of (ꢀ)-hinesol (2) and (ꢀ)-b-vetivone (3).
Reagents and conditions: (a) Pd/C, H2 (1 atm), EtOH, 97% (87% dr), then
separation; (b) CH2I2, TiCl4, Zn, THF–CH2Cl2, 80%; (c) cat. TsOH$H2O,
PhH, reflux; (d) MeMgI, Et2O, 0 ꢂC to rt, 90% (two steps); (e) CrO3, 3,5-
DMP, CH2Cl2, 0 ꢂC, 60%; (f) Ac2O, NaOAc, 140 ꢂC, 93%; (g) BF3$OEt2,
rt, 64% (based on the recovered S.M.: 84%, 86:14 mixture of 3 and the
exo-isomer).
1
EtOAc¼75:25); H NMR (400 MHz, CDCl3) d 5.64–5.32
(m, 2H), 4.47–4.18 (m, 2H), 3.36 (br s, 0.8H), 3.21 (br s,
0.2H), 2.25 (br dd, J¼16.3, 7.3 Hz, 1H), 2.13–1.95 (m,
4H), 1.76–1.59 (m, 7H), 0.851 (s, 6.3H), 0.840 (s, 2.7H),
0.0378 (s, 3H), 0.01 (s, 3H); IR (neat, cmꢁ1) 3504, 1726;
HR-ESIMS calcd for C17H32O3NaSi: 335.2018, found:
335.2018. To the solution of DMSO (1.24 mL, 17.4 mmol)
in CH2Cl2 (10 mL) was added (CF3CO)2O (1.21 mL,
8.72 mmol) at ꢁ78 ꢂC, then the resulting mixture was stirred
at that temperature for 40 min. To this mixture was added
a solution of the aldol adduct (908 mg, 2.91 mmol) in
CH2Cl2 (10 mL) at ꢁ78 ꢂC, then this mixture was stirred
at that temperature for 40 min. To this mixture was added
Et3N (3.65 mL, 26.2 mmol) at ꢁ78 ꢂC, then this mixture
was stirred at that temperature for 40 min. The reaction mix-
ture was quenched with a saturated aqueous solution of
NH4Cl. The aqueous layer was extracted two times with
EtOAc. The combined organic layer was washed with brine,
dried over Na2SO4, filtrated, and concentrated under reduced
pressure. Purification by silica-gel column chromatography
(hexane/EtOAc¼90:10) gave 820 mg of 1,3-diketone 8b
3. Conclusion
We were able to achieve the stereoselective total syntheses of
(ꢀ)-a-vetispirene, (ꢀ)-hinesol, and (ꢀ)-b-vetivone based on
a Claisen rearrangement of a functionalized alkenyl bicyclic
dihydropyran system. Our strategy is unique and efficient,
and could be applicable to other terpenes with a multi-func-
tionalized spiro[4.5]decane framework. Further investiga-
tions into its application to the synthesis of optically active
spirocyclic terpenes are in progress.
4. Experimental
4.1. General
All reactions sensitive to oxygen and moisture were per-
formed in flame-dried glassware under a static argon atmo-
1
(91% yield, a mixture of diastereomers by H NMR analy-
1
1
sphere unless otherwise noted. H and 13C NMR spectra
wererecordedonaJEOLJNM-LD400spectrometeroperating
sis): Rf 0.81 (hexane/EtOAc¼75:25); H NMR (400 MHz,
CDCl3) d 13.6 (br s, 0.5H), 5.68–5.56 (m, 1H), 5.49–5.35

6268
A. Nakazaki et al. / Tetrahedron 62 (2006) 6264–6271
(m, 1H), 4.62–4.48 (m, 1H), 2.65–2.20 (m, 7H), 1.90–1.85
(m, 1.5H), 1.68–1.64 (m, 3H), 0.842 (s, 6.3H), 0.836 (s,
2.7H), 0.0311 (s, 0.6H), 0.0220 (s, 0.6H), 0.0085 (s, 0.6H),
0.001 (s, 2.7H), ꢁ0.014 (s, 1.5H); IR (neat, cmꢁ1) 1712,
1662, 1617; HR-ESIMS calcd for C17H30O3NaSi:
333.1856, found: 333.1869.
were cooled to rt, and concentrated. Purification by silica-
gel column chromatography (hexane/EtOAc¼100/1) gave
1
40 mg (87% yield, >95% dr by H NMR analysis) of 6b
as a colorless clear oil. Multigram-scale synthesis (4.839 g,
250 ꢂC, 12 h) was also performed to afford 3.623 g of 6b
(75% yield, >95% dr by H NMR analysis). The stereo-
1
chemical assignment to 6b was verified by the NOE experi-
ments on the tricycle.7 Rf 0.51 (hexane/EtOAc¼90:10);
1H NMR (400 MHz, CDCl3) d 5.52–5.40 (m, 2H), 4.13
(dd, J¼9.5, 6.1 Hz, 1H), 2.27–2.20 (m, 4H), 2.06–1.87 (m,
3H), 1.81–1.62 (m, 2H), 0.892 (d, J¼7.4 Hz, 3H), 0.777
(s, 9H), 0.00 (s, 3H), ꢁ0.0281 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 220.5, 131.1, 123.1, 66.0, 56.4, 40.0,
37.2, 33.2, 29.1, 25.8, 18.7, 17.9, 17.6, ꢁ4.1, ꢁ5.3; IR
(neat, cmꢁ1) 1734; HR-ESIMS calcd for C17H30O2NaSi:
317.1907, found: 317.1903.
4.1.2. Dihydropyrone 4. To a solution of 1,3-diketone
8b (7.80 g, 25.1 mmol) in CH2Cl2 (200 mL) was added
CF3COOH (7.8 mL, 101.0 mmol) via a dropping funnel at
0 ꢂC, then the resulting mixture was stirred at that tempera-
ture for 15 min. This mixture was warmed to rt and stirred at
that temperature for 3 h. The reaction mixture was quenched
with a saturated aqueous solution of NaHCO3. The aqueous
layer was extracted two times with CH2Cl2. The combined
organic layer was dried over MgSO4, filtrated, and concen-
trated under reduced pressure. Purification by silica-gel col-
umn chromatography (hexane/EtOAc¼95:5/83:17) gave
3.779 g (85% yield) of dihydropyrone 4: Rf 0.38 (hexane/
4.1.5. Keto ester 11. To a solution of spiro[4.5]decane 6b
(3.456 g, 11.7 mmol) in EtOH (234 mL) was added 10%
Pd/charcoal (2.49 g) under argon atmosphere. The argon
atmosphere was replaced by H2 from a double balloon, the
reaction mixture was stirred at rt for 5 h. After the H2 atmo-
sphere was replaced by argon, the resulting mixture was
filtrated through a pad of Celite, and the solvent was concen-
trated to give 3.529 g of crude 10 (quantitative yield, >95%
dr by 1H NMR analysis) as a colorless clear oil: Rf 0.51 (hex-
ane/EtOAc¼90:10); 1H NMR (400 MHz, CDCl3) d 3.97 (dd,
J¼9.8, 4.2 Hz, 1H), 2.34–2.20 (m, 2H), 2.12–2.02 (m, 1H),
1.93–1.73 (m, 5H), 1.61–1.25 (m, 5H), 0.910 (d, J¼7.3 Hz,
3H), 0.831 (s, 9H), 0.0310 (s, 3H), ꢁ0.0044 (s, 3H);
13C NMR (100 MHz, CDCl3) d 221.3, 68.9, 57.7, 39.7,
33.5, 31.7, 30.0, 28.8, 25.8, 19.1, 19.0, 18.0, 15.4, ꢁ4.1,
ꢁ5.1; IR (neat, cmꢁ1) 1733; HR-ESIMS calcd for
C17H32O2NaSi: 319.2069, found: 319.2083. To a suspension
of KH (4.83 g, 60 wt % in mineral oil, 72.3 mmol) in THF
(68 mL) was added a solution of crude ketone 10 in THF
(50 mL) and dimethyl carbonate (9.92 mL, 118 mmol) at
rt. The resulting mixture was heated at 95 ꢂC, and stirred at
that temperature for 9 h 15 min. The resulting mixture was
cooled to rt, and the reaction mixture was quenched with a
saturated aqueous solution of NH4Cl. The aqueous layer
was extracted two times with Et2O. The combined organic
layer was dried over Na2SO4, filtrated, and concentrated
under reduced pressure. Purification by silica-gel column
chromatography (hexane/EtOAc¼20:1) gave 3.591 g of
keto ester 11 (86% yield for the two steps, a mixture of dia-
1
EtOAc¼75:25); H NMR (300 MHz, CDCl3) d 5.88 (ddq,
J¼15.4, 0.72, 6.4 Hz, 1H), 5.66 (ddq, J¼15.4, 7.2, 1.5 Hz,
1H), 4.88 (ddd, J¼12.5, 7.2, 4.3 Hz, 1H), 2.60–2.50
(m, 5H), 2.41 (dd, J¼16.9, 4.1 Hz, 1H), 1.92 (quint, J¼
7.5 Hz, 2H), 1.77 (ddd, J¼6.4, 1.5, 0.7 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 189.7, 178.4, 131.4, 127.8, 114.0, 81.6,
40.9, 32.7, 25.4, 19.1, 17.7; IR (neat, cmꢁ1) 1779, 1666,
1613, 1426, 1154, 965; HR-EIMS calcd for C11H14O2:
178.0994, found: 178.0987.
4.1.3. Dihydropyran 5b. To a solution of dihydropyrone 4
(153 mg, 0.859 mmol) in dry Et2O was added LiAlH4
(41 mg, 1.08 mmol) at 0 ꢂC, then the resulting mixture was
stirred for 25 min at that temperature. The reaction mixture
was quenched with Na2SO4$10H2O, and allowed to warm to
rt. To this mixture was added hexane and dry Na2SO4, then
stirred for 10 min. The resulting mixture was filtrated, and
concentrated under reduced pressure to afford crude alcohol
9. To a solution of crude alcohol 9 and imidazole (94 mg,
1.37 mmol) in CH2Cl2 (6 mL) was added TBSCl (194 mg,
1.29 mmol) at 0 ꢂC, then the resulting mixture was allowed
to warm to rt and stirred for 1.5 h at that temperature. The
reaction was poured into a cold saturated aqueous solution
of NaHCO3. The aqueous layer was extracted two times
with CH2Cl2. The combined organic layer was dried over
Na2SO4, filtrated, and concentrated under reduced pressure.
Purification by silica-gel column chromatography (hexane/
EtOAc¼98:2/96:4) gave 184 mg (73% yield for the two
1
stereomers by H NMR analysis) as a pink oil: Rf 0.47,
1
1
steps, >95% dr by H NMR analysis) of dihydropyran 5b
0.41 (hexane/EtOAc¼10:1); H NMR (400 MHz, CDCl3)
as a colorless clear oil. The relative stereochemistry was
established by the NOESY correlation between a-oxy-
methyne protons: Rf 0.56 (hexane/EtOAc¼90:10); 1H NMR
(300 MHz, CDCl3) d 5.70 (dq, J¼15.3, 6.2 Hz, 1H), 5.55
(dd, J¼15.3, 7.3 Hz, 1H), 4.38–4.27 (m, 2H), 2.42–2.08
(m, 5H), 1.94 (ddd, J¼13.4, 6.5, 2.2 Hz, 1H), 1.81–1.72
(m, 2H), 1.63 (d, J¼6.2 Hz, 3H), 0.815 (s, 9H), 0.00 (s,
3H), ꢁ0.0104 (s, 3H); 13C NMR (75 MHz, CDCl3) d 153.0,
130.4, 129.0, 110.6, 77.4, 64.7, 38.8, 31.4, 28.9, 25.8, 19.9,
18.2, 17.7, ꢁ4.6, ꢁ4.9; IR (neat, cmꢁ1) 1686; HR-ESIMS
calcd for C17H30O2NaSi: 317.1907, found: 317.1897.
d 4.03–4.00 (m, 1H), 3.733 (s, 1.35H), 3.730 (s, 1.65H),
3.27 (t, J¼2.5 Hz, 0.45H), 3.07 (t, J¼2.4 Hz, 0.55H), 2.34–
1.24 (m, 11H), 0.907 (d, J¼7.3 Hz, 1.65H), 0.886 (d,
J¼7.3 Hz, 1.35H), 0.859 (s, 4.05H), 0.823 (s, 4.95H),
0.0464 (s, 1.65H), 0.0409 (s, 1.35H), 0.0342 (s, 1.65H),
0.0134 (s, 1.35H); IR (neat, cmꢁ1) 1753, 1727; HR-ESIMS
calcd for C19H34O4NaSi: 377.2124, found: 377.2141.
4.1.6. Hydroxy ketone 12. To a solution of keto ester 11
(50 mg, 0.141 mmol) in dry MeOH (1.4 mL) was added
NaBH4 (53 mg, 1.41 mmol) at 0 ꢂC, then the resulting mix-
ture was stirred at that temperature for 35 min. The reaction
mixture was quenched with an aqueous solution of NH4Cl.
The aqueous layer was extracted two times with Et2O. The
combined organic layer was dried over Na2SO4, filtrated,
4.1.4. Spiro[4.5]decane 6b. Degassed solutions of 5b
(47 mg, >95% dr) in dry toluene (1.7 mL) were heated at
250 ꢂC for 14 h in sealed tubes. The resulting mixtures

A. Nakazaki et al. / Tetrahedron 62 (2006) 6264–6271
6269
and concentrated under reduced pressure. Purification by
silica-gel column chromatography (hexane/EtOAc¼10:1)
35.9, 31.1 (br s), 31.0, 30.6, 19.8, 16.2; IR (neat, cmꢁ1
)
3454, 1717, 1634. To a solution of crude alcohol 15
in CH2Cl2 (6 mL) was added Dess–Martin periodinane
(275 mg, 0.648 mmol) at rt, then the resulting mixture was
stirred at that temperature for 30 min. The reaction mixture
was quenched with a saturated aqueous solution of NaHCO3.
The aqueous layer was extracted two times with CH2Cl2.
The combined organic layer was dried over MgSO4, fil-
trated, and concentrated under reduced pressure. Purification
by silica-gel column chromatography (hexane/EtOAc¼
85:15) gave 25 mg of ketone 16 (88% yield for the two steps,
gave 35 mg of hydroxy ketone 12 (67% yield, a mixture
1
of diastereomers by H NMR analysis) and 9 mg of diol
13 (20% yield, a mixture of diastereomers by 1H NMR anal-
ysis). Hydroxy ketone 12: Rf 0.25, 0.20; 1H NMR (400 MHz,
CDCl3) d 4.11–4.07 (m, 1H), 3.91 (t, J¼9.5 Hz, 1H), 3.712
(s, 0.9H), 3.706 (s, 2.1H), 2.88–2.78 (m, 1H), 2.41 (br d,
J¼9.5 Hz, 1H), 2.14–2.02 (m, 1H), 1.95–1.26 (m, 10H),
1.13 (d, J¼7.3 Hz, 2.1H), 1.05 (d, J¼7.1 Hz, 0.9H), 0.902
(s, 6.3H), 0.886 (s, 2.7H), 0.113 (s, 2.1H), 0.110 (s, 2.1H),
0.0537 (s, 0.9H), 0.0495 (s, 0.9H); HR-ESIMS calcd for
C19H36O4NaSi: 379.2275, found: 379.2272. Diol 13: Rf
0.13, 0.063 (hexane/EtOAc¼10:1); 1H NMR (400 MHz,
CDCl3) d 4.08 (dd, J¼11.5, 4.2 Hz, 1H), 3.87–3.42 (m,
4H), 2.59 (br d, J¼11.2 Hz, 1H), 2.28–1.26 (m, 12H), 1.15
(d, J¼7.3 Hz, 1.8H), 1.05 (d, J¼7.6 Hz, 1.2H), 0.904 (s,
3.6H), 0.894 (s, 5.4H), 0.120 (s, 1.2H), 0.117 (s, 1.2H),
0.055 (s, 1.8H), 0.051 (s, 1.8H); HR-ESIMS calcd for
C18H36O3NaSi: 351.2325, found: 351.2317.
1
>95% dr by H NMR analysis) as a colorless clear oil: Rf
1
0.41 (hexane/EtOAc¼75:25); H NMR (400 MHz, CDCl3)
d 6.77 (t, J¼2.0 Hz, 1H), 3.74 (s, 3H), 2.66–2.40 (m, 5H),
2.08–2.03 (m, 1H), 1.88–1.62 (m, 5H), 0.940 (d, J¼
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 210.2, 165.0,
141.2, 138.7, 69.8, 51.6, 42.8, 39.5, 30.9, 30.7, 28.6, 25.2,
16.8; IR (neat, cmꢁ1) 1713, 1630, 1299, 1260, 1213, 1154;
HR-ESIMS calcd for C13H18O3Na: 245.1148, found:
245.1144.
4.1.7. a,b-Unsaturated ester 14. To a solution of 12
(1.39 g, 3.90 mmol) in pyridine (40 mL) was added MsCl
(2.7 mL, 35.1 mmol) at 0 ꢂC, then the resulting mixture
was stirred at that temperature for 15 h 40 min. The reaction
mixture was quenched with H2O. The aqueous layer was ex-
tracted two times with CH2Cl2. The combined organic layer
was dried over Na2SO4, filtrated, and concentrated under re-
duced pressure to give the crude mesylate. To a solution of
the crude mesylate in CH2Cl2 (66.5 mL) was added DBU
(5.0 mL, 33.00 mmol) at rt. After stirring for 2 h, the result-
ing mixture was concentrated under reduced pressure.
Purification by silica-gel column chromatography (hexane/
EtOAc¼20:1) gave 1.227 g of a,b-unsaturated ester 14
(93% yield for the two steps, >95% dr by 1H NMR analysis)
as a colorless clear oil: Rf 0.63 (hexane/EtOAc¼90:10); 1H
NMR (400 MHz, C6D6) d 6.77 (t, J¼2.0 Hz, 1H), 3.52–
3.51 (m, 1H), 3.47 (s, 3H), 2.69 (dddd, J¼16.8, 9.5, 5.1,
2.0 Hz, 1H), 2.61 (dddd, J¼16.8, 8.6, 6.4, 2.0 Hz, 1H),
2.00 (ddd, J¼13.5, 9.5, 6.1 Hz, 1H), 1.94–1.85 (m, 1H),
1.70 (ddd, J¼13.5, 9.0, 5.0 Hz, 2H), 1.48–1.30 (m, 4H),
1.06–0.898 (m, 1H), 0.966 (s, 9H), 0.752 (d, J¼6.8 Hz,
3H), 0.0079 (s, 3H), 0.00 (s, 3H); 13C NMR (100 MHz,
C6D6) d 165.2, 145.8, 137.9, 73.8, 60.2, 51.0, 35.5, 32.6,
31.4, 31.4, 31.4, 26.1, 20.3, 18.3, 16.7, ꢁ4.1, ꢁ5.0; IR (neat,
cmꢁ1) 1712, 1635; HR-ESIMS calcd for C19H34O3NaSi:
361.2169, found: 361.2172.
4.1.9. exo-Methylene 17. To a suspension of Zn (1.75 g,
26.8 mmol) in THF (20 mL) was added freshly distilled
CH2I2 (1.19 mL, 14.74 mmol) at rt, then the resulting mix-
ture was stirred at that temperature for 30 min. After the
resulting mixture was cooled to 0 ꢂC, to this mixture was
added a solution of TiCl4 in CH2Cl2 (1.0 M, 2.76 mL) at
0 ꢂC, and stirred for 30 min. To this suspension was added
a solution of 16 (318 mg, 1.42 mmol) in CH2Cl2 (17 mL)
at rt, then the resulting mixture was stirred at that tempera-
ture for 30 min. The reaction mixture was quenched with
a saturated aqueous solution of NH4Cl, and Et2O was added.
The organic layer was washed with brine, dried over
Na2SO4, filtrated, and concentrated under reduced pressure.
Purification by silica-gel column chromatography (hexane/
EtOAc¼50:1) gave 225 mg (72% yield) of 17 as a colorless
clear oil: Rf 0.55 (hexane/EtOAc¼90:10); 1H NMR
(300 MHz, CDCl3) d 6.85 (t, J¼1.8 Hz, 1H), 4.72 (br s,
1H), 4.57 (br s, 1H), 3.75 (s, 3H), 2.56 (td, J¼7.6, 1.6 Hz,
2H), 2.27–2.17 (m, 2H), 2.05 (t, J¼7.0 Hz, 2H), 1.82–1.43
(m, 5H), 0.916 (d, J¼7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 165.8, 151.0, 148.0, 135.1, 107.8, 59.8, 51.3, 39.3,
34.7, 33.6, 30.3, 30.2, 22.8, 16.0; IR (neat, cmꢁ1) 3077,
2933, 1719, 1636; HR-ESIMS calcd for C14H20O2Na:
243.1360, found: 243.1369.
4.1.10. ( )-a-Vetispirene (1). To a solution of exo-isomer 17
(10 mg) in benzene (2.5 mL) was added TsOH$H2O
(1.6 mg, 0.0084 mmol) at rt, then the resulting mixture
was heated at 95 ꢂC for 14 h. The resulting mixture was
cooled to rt, and the reaction mixture was quenched with a
saturated aqueous solution of NaHCO3. The aqueous layer
was extracted two times with CH2Cl2. The combined
organic layer was dried over MgSO4, filtrated, and concen-
trated under reduced pressure to afford 12 mg of crude
endo-isomer. To a solution of crude endo-isomer in THF
(2 mL) was added a solution of MeLi (0.98 M, 1 mL,
0.98 mmol) at 0 ꢂC, then the resulting mixture was warmed
to rt over 30 min. The reaction mixture was quenched with
H2O. The aqueous layer was extracted two times with
Et2O. The combined organic layer was dried over MgSO4,
filtrated, and concentrated under reduced pressure to afford
crude tert-alcohol. To a solution of this tert-alcohol in
4.1.8. Ketone 16. To a solution of silyl ether 14 (43 mg,
0.128 mmol) in CH3CN (3 mL) was added aqueous solution
of HF (46–48%, 30 drops via a pipette) at rt, then the result-
ing mixture was stirred at that temperature for 1 h. The reac-
tion mixture was quenched with a saturated aqueous solution
of NaHCO3. The aqueous layer was extracted two times with
EtOAc. The combined organic layer was dried over MgSO4,
filtrated, and concentrated under reduced pressure to afford
crude alcohol 15: Rf 0.27 (hexane/EtOAc¼75:25); 1H
NMR (400 MHz, CDCl3) d 6.68 (t, J¼1.9 Hz, 1H), 3.74 (s,
3H), 3.73–3.70 (m, 1H), 2.61 (dddd, J¼16.9, 9.5, 5.4,
1.9 Hz, 1H), 2.56 (dddd, J¼16.9, 8.8, 6.8, 1.9 Hz, 1H),
2.10 (ddd, J¼13.5, 9.3, 6.9 Hz, 1H), 1.91–1.51 (m, 8H),
1.30–1.21 (m, 1H), 0.874 (d, J¼7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 165.7, 146.0, 137.5, 72.3, 59.4, 51.5,

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A. Nakazaki et al. / Tetrahedron 62 (2006) 6264–6271
benzene (2 mL) was added camphorsulfonic acid (2.3 mg,
0.0099 mmol) at rt. The resulting mixture was warmed to
60 ꢂC and stirred at that temperature for 1 h 20 min. The
resulting mixture was cooled to rt, and the reaction mixture
was quenched with a saturated aqueous solution of NaHCO3.
The aqueous layer was extracted two times with hexane. The
combined organic layer was washed with brine, dried over
MgSO4, filtrated, and concentrated under reduced pressure.
Purification by silica-gel column chromatography (hexane)
gave 8.6 mg of (ꢀ)-a-vetispirene (1) (87% yield for the three
steps, >95% dr by 1H NMR analysis) as a colorless clear oil:
Rf 0.71 (hexane); 1H NMR (400 MHz, CDCl3) d 5.51 (br s,
1H), 5.40–5.38 (m, 1H), 4.91 (br s, 1H), 4.88 (br s, 1H),
2.60–2.46 (m, 2H), 2.09–1.93 (m, 3H), 1.94 (s, 3H), 1.83
(ddd, J¼13.7, 9.0, 5.8 Hz, 1H), 1.70–1.61 (m, 2H), 1.56
(d, J¼1.5 Hz, 3H), 1.46–1.38 (m, 1H), 0.859 (d, J¼6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 143.8, 140.3, 138.7,
132.7, 121.7, 112.3, 57.3, 37.8, 34.4, 32.3, 28.2, 23.8,
20.7, 19.9, 16.5; IR (neat, cmꢁ1) 3087, 2960, 1773, 1630,
1597, 1375, 1200, 1076, 881, 842, 796; HR-EIMS calcd
for C15H22: 202.1721, found: 202.1717.
NMR (400 MHz, CDCl3) d 5.31 (br s, 1H), 2.00–1.90 (m,
3H), 1.79–1.25 (m, 13H), 1.20 (s, 6H), 0.922 (d, J¼
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 140.0, 121.7,
72.0, 51.4, 48.7, 36.7, 35.7, 33.3, 28.4, 28.0, 27.9, 27.7,
24.2, 19.9, 16.2; IR (neat, cmꢁ1) 3400, 1659; HR-ESIMS
calcd for C15H26ONa: 245.1881, found: 245.1876.
4.1.13. ( )-Hinesolone (20). To a suspension of CrO3
(360 mg, 3.60 mmol; need to dry by heating under reduced
pressure just before use) in CH2Cl2 (5 mL) was added 3,5-
dimethylpyrrazole (346 mg, 3.60 mmol) at ꢁ20 ꢂC, then
the resulting mixture was stirred at that temperature for
30 min. After allowing to warm to 0 ꢂC, to this mixture
was added a solution of 2 (40 mg, 0.180 mmol) in CH2Cl2
(4 mL), then the resulting mixture was stirred for 2.5 h.
The resulting mixture was filtrated with a pad of Florisil.
The filtrate was washed with 1 N HCl and brine. The
combined organic layer was dried over Na2SO4, filtrated,
and concentrated under reduced pressure. Purification by
silica-gel column chromatography (hexane/EtOAc¼2:1)
gave 26 mg (60%) of 20 as a colorless needle: mp: 112.5–
115.0 ꢂC; Rf 0.13 (hexane/EtOAc¼2:1); 1H NMR
(400 MHz, CDCl3) d 5.76 (s, 1H), 2.44 (dd, J¼16.6,
4.2 Hz, 1H), 2.22 (dd, J¼16.6, 9.8 Hz, 1H), 2.14–2.02 (m,
2H), 1.97 (s, 3H), 1.90–1.81 (m, 4H), 1.68–1.61 (m, 1H),
1.50 (dd, J¼13.3, 12.3 Hz, 1H), 1.25 (s, 3H), 1.24 (s, 3H),
1.02 (d, J¼6.8 Hz, 3H), 0.867 (br s, 1H); 13C NMR
(100 MHz, CDCl3) d 199.3, 168.2, 125.9, 71.4, 50.8,
50.3, 42.8, 37.1, 34.8, 31.7, 28.7, 28.5, 27.6, 20.8, 16.4;
4.1.11. Ester 18. To a solution of a,b-unsaturated ester 16
(58 mg, 0.261 mmol) in EtOH (5.23 mL) was added 10%
Pd/charcoal (56 mg) under argon atmosphere. The argon
atmosphere was replaced by H2 from a double balloon, the
reaction mixture was stirred at rt for 2 h 20 min. After re-
placed by argon, the resulting mixture was filtrated through a
pad of Celite, and the solvent was concentrated. Purification
by silica-gel column chromatography (hexane/EtOAc¼5:1)
gave 57 mg (97% yield, 87% dr by 1H NMR analysis) of 18:
Rf 0.32 (hexane/EtOAc¼5:1); 1H NMR (400 MHz, CDCl3)
d 3.67 (s, 3H), 2.74 (tt, J¼8.7, 8.6 Hz, 1H), 2.42 (t, J¼
6.8 Hz, 2H), 2.34 (ddd, J¼12.9, 7.6, 3.1 Hz, 1H), 2.12 (dd,
J¼13.7, 8.2 Hz, 1H), 1.98–1.67 (m, 7H), 1.60–1.46
(m, 2H), 0.940 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 213.5, 175.5, 60.6, 51.7, 44.0, 41.2, 38.3, 33.6,
33.1, 30.4, 29.1, 24.1, 16.0; IR (neat, cmꢁ1) 1735, 1704;
HR-EIMS calcd for C13H20O3Na: 247.1304, found:
247.1310.
IR (KBr, cmꢁ1
) 3410, 1653; HR-EIMS calcd for
C15H24O2Na: 259.1673, found: 259.1682.
4.1.14. ( )-b-Vetivone (3). A mixture of 20 (28 mg, 0.118
mmol) and NaOAc (19 mg, 0.236 mmol) in Ac2O
(1.18 mL) was heated to 140 ꢂC for 2 h in a sealed tube,
cooled to rt. The reaction mixture was quenched with a satu-
rated aqueous solution of NaHCO3. The aqueous layer was
extracted two times with CH2Cl2. The combined organic
layer was washed with brine, dried over Na2SO4, filtrated,
and concentrated under reduced pressure to afford a crude
product. Purification by silica-gel column chromatography
(hexane/EtOAc¼83:17) gave 31 mg (93% yield) of the
acetate as a colorless clear oil. To a solution of this acetate
in Et2O (2.19 mL) was added BF3$OEt2 (0.104 mL,
0.822 mmol) at rt, then the mixture was stirred at that tem-
perature for 6 h. The reaction mixture was quenched with
a 5% aqueous solution of NaOH. The aqueous layer was
extracted two times with Et2O. The combined organic layer
was washed with brine, dried over MgSO4, filtrated, and
concentrated under reduced pressure. Purification by silica-
gel column chromatography (hexane/EtOAc¼83:17) gave
15 mg of (ꢀ)-b-Vetivone (3) and the inseparable exo-isomer
[64% yield (84%: based on the recovered S.M.), 3/exo-iso-
4.1.12. ( )-Hinesol (2). To a solution of exo-isomer 19
(200 mg, 0.90 mmol) in benzene (45 mL) was added
TsOH$H2O (29.1 mg, 0.153 mmol) at rt, then the resulting
mixture was heated at 95 ꢂC for 12 h. The resulting mixture
was cooled to rt, and the reaction mixture was quenched with
a saturated aqueous solution of NaHCO3. The aqueous layer
was extracted two times with CH2Cl2. The combined
organic layer was dried over Na2SO4, filtrated, and con-
centrated under reduced pressure to afford the crude endo-
isomer. To a solution of MeMgI (1 M, 15.7 mL) in dry
Et2O (120 mL) was added a solution of the crude endo-
isomer in dry Et2O (42 mL) at 0 ꢂC, then the resulting mix-
ture was stirred at that temperature for 30 min. The resulting
mixture was allowed to warm to rt, then stirred at that tem-
perature for 3 h. The reaction mixture was quenched with
H2O. The aqueous layer was extracted two times with
Et2O. The combined organic layer was washed with brine,
dried over Na2SO4, filtrated, and concentrated under reduced
pressure. Purification by silica-gel column chromatography
(hexane/EtOAc¼15:1) gave 181 mg of (ꢀ)-hinesol (2)
(89% yield for the two steps, >95% dr by 1H NMR analysis)
1
mer¼86:14 by H NMR analysis] and recovered acetate
1
(24%): Rf 0.66 (hexane/EtOAc¼2:1); H NMR (400 MHz,
CDCl3) d 5.79 (br s, 1H), 5.76 (br s, 0.17H), 4.74 (br s,
0.34H), 2.94–1.94 (m, 9.5H), 2.66 (dd, J¼16.9, 4.8 Hz,
1H), 2.54 (dd, J¼12.0, 5.4 Hz, 0.17H), 1.92 (d, J¼1.2 Hz,
0.5H), 1.90 (d, J¼1.2 Hz, 3H), 1.76 (s, 0.5H), 1.67 (s, 3H),
1.63 (s, 3H), 1.04 (d, J¼6.6 Hz, 0.5H), 0.971 (d,
J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 199.1,
167.15, 147.4, 133.8, 126.0, 122.6, 109.0, 51.1, 50.2, 47.0,
42.9, 42.9, 39.0, 38.1, 37.7, 35.4, 35.0, 32.1, 29.7, 29.4,
1
as a colorless clear oil: Rf 0.34 (hexane/EtOAc¼5:1); H

A. Nakazaki et al. / Tetrahedron 62 (2006) 6264–6271
6271
21.7, 21.3, 21.1, 21.0, 20.7, 16.6, 16.6; IR (KBr, cmꢁ1) 1668,
1613; HR-ESIMS calcd for C15H22O3Na: 245.1562, found:
245.1564.
Chem. Rev. 1988, 88, 1423–1452; (c) Wipf, P. Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H.,
Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 827–873; (d) Enders,
D.; Knopp, M.; Sciffers, R. Tetrahedron: Asymmetry 1996, 7,
1847–1882; (e) Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28,
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Acknowledgements
´
´
We thank Professor Istvan E. Marko (Universite Catholique
de Louvain) for providing the spectra of a-vetispirene.
We also thank Shin-Etsu Chemical Co., Ltd, for the gift of
silicone oil.
9. For examples of synthesis of spirocycles by Claisen rearrange-
ment of bicyclic dihydropyrans without a high-oxidation state
functionality in the 4-position, see: (a) Ireland, R. E.; Aristoff,
P. A. J. Org. Chem. 1979, 44, 4323–4331; (b) Shishido, K.;
Hiroya, K.; Fukumoto, K.; Kametani, T. Tetrahedron Lett.
1986, 27, 971–974; (c) Brugnolotti, M.; Corsico Coda, A.;
Desimoni, G.; Faita, G.; Gamba Invernizzi, A.; Righetti, P. P.;
Tacconi, G. Tetrahedron 1988, 44, 5229–5242; (d) Desimoni,
G.; Faita, G.; Gamba, A.; Righetti, P. P.; Tacconi, G.; Toma,
L. Tetrahedron 1990, 46, 2165–2178; Very recently, an example
of Claisen rearrangement in 4-hydroxy-2-(alkenyl)dihydro-
pyran system to afford the spirocycle by the side reaction was
reported, see: (e) Morency, L.; Barriault, L. J. Org. Chem.
2005, 70, 8841–8853.
10. Paterson, I.; Wren, S. P. J. Chem. Soc., Chem. Commun. 1993,
1790–1792.
11. Collins, I.; Nadin, A.; Holmes, A. B.; Long, M. E.; Man, J.;
Baker, R. J. Chem. Soc., Perkin Trans. 1 1994, 2205–2215.
12. Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1976, 41,
3329–3331.
References and notes
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Syrdal, D. D. Tetrahedron Lett. 1970, 11, 1759–1762; For total
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Hayakawa, Y.; Hirata, Y. Tetrahedron Lett. 1973, 14, 4967–
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Ibuka, T.; Hayashi, K.; Minakata, H.; Ito, Y.; Inubushi, Y.
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2. For the structure and first total synthesis of (ꢀ)-2, see: (a)
Marshall, J. A.; Brady, S. F. J. Org. Chem. 1970, 35, 4068–
4077; For total synthesis of this substance, see: (b) Nystrom,
¨
J.-E.; Helquist, P. J. Org. Chem. 1989, 54, 4695–4698; For first
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13. The diluted condition was essential for obtaining 6b in good
yield (0.1 mol/L: 87% yield; 0.3 mol/L: 46% yield). Multi-
gram-scale synthesis was also performed to afford 6b in 75%
yield as a single diastereomer.
3. For the structure and first total synthesis of 3, see: (a) Marshall,
J. A.; Johnson, P. C. J. Chem. Soc., Chem. Commun. 1968, 391–
392; For total synthesis of this substance, see: (b) Yamada, K.;
Nagase, H.; Hayakawa, Y.; Aoki, K.; Hirata, Y. Tetrahedron
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4. Some biologically active spirocyclic terpenes have been iso-
lated. For lubimin, see: (a) Murai, A.; Sato, S.; Masamune, T.
J. Chem. Soc., Chem. Commun. 1982, 513–514; For gleenol,
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Dubovenko, Zh. V.; Pentegova, V. A. Khim. Prir. Soedin.
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Fattorusso, E.; Magno, S.; Mayol, L.; Pedone, C.; Santacroce,
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14. Buchi, G.; Powell, J. E., Jr. J. Am. Chem. Soc. 1970, 92, 3126–
¨
3133.
15. Longer reaction time (2 h/3 h) caused isomerization of the
methyl group in 10. In contrast, the Crabtree catalyst,
[Ir(cod)(PCy3)(py)]PF6, gave no isomerized 10 in 80% yield
with >95% dr. For this catalyst, see: Crabtree, R. H.; Davis,
M. W. J. Org. Chem. 1986, 51, 2655–2661.
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Tetrahedron 1999, 55, 9007–9071; (c) Pradhan, R.; Patra, M.;
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19. Similar transformation has been reported, see Refs. 1b and 6.
20. Similar stereoselectivity was observed, see Ref. 2c.
21. Yoshioka, I.; Kimura, T. Chem. Pharm. Bull. 1965, 13, 1430–
1434.
22. For similar allylic oxidation, see: (a) Dauben, W. G.; Lorber,
M.; Fullerton, D. S. J. Org. Chem. 1969, 34, 3587–3592; (b)
Hwu, J. R.; Wetzel, J. M. J. Org. Chem. 1992, 57, 922–928;
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vetivane sesquiterpenes, see: Maulide, N.; Vanherck, J.-C.;
´
Marko, I. E. Eur. J. Org. Chem. 2004, 3962–3967 and refer-
ences cited therein.
´
(c) Blay, G.; Cardona, L.; Collado, A. M.; Garcıa, B.;
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in the ratio of 89:11, see: Marshall, J. A.; Johnson, P. C.
J. Org. Chem. 1970, 35, 192–196.
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