Chemoenzymatic preparation of functionalized bicyclo[3.2.1]octenone and practical utilization

Article abstract of DOI:10.1016/j.tetasy.2007.12.009

A practical route for the synthesis of both enantiomers of a functionalized bicyclo[3.2.1]octenone, which is potentially useful as a versatile chiral building block, has been developed from 1,4-cyclohexanedione monoethylene acetal by employing proline-cat

Full text of DOI:10.1016/j.tetasy.2007.12.009

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 176–185
Chemoenzymatic preparation of functionalized bicyclo[3.2.1]octenone
and practical utilization
Shinichiro Ito, Ayako Tosaka, Keisuke Hanada, Masatoshi Shibuya,
Kunio Ogasawara and Yoshiharu Iwabuchi*
Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 1 October 2007; accepted 7 December 2007
Available online 24 January 2008
Abstract—A practical route for the synthesis of both enantiomers of a functionalized bicyclo[3.2.1]octenone, which is potentially useful
as a versatile chiral building block, has been developed from 1,4-cyclohexanedione monoethylene acetal by employing proline-catalyzed
diastereoselective intramolecular aldolization and lipase-mediated kinetic resolution as the key steps. The synthetic utility of the bicy-
clo[3.2.1]octenone has been demonstrated by the conversion into a chiral bicyclo[5.3.0]decane, which should serve as the key intermediate
for the synthesis of the pseudoguaianolide class of antitumor sesquiterpenes.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
in 2 prompted us to study the stereocontrolled construction
of 3 via organocatalytic intramolecular aldolization6 of the
r-symmetrical ketoaldehyde 4. We report here a new
chemoenzymatic preparation of 2 in both enantiomeric
forms and the diastereocontrolled conversion of 2 to a chi-
ral bicyclo[5.3.0]decane, which should serve as a key inter-
mediate for the synthesis of the pseudoguaianolide class of
antitumor sesquiterpenes,7,8 to extend its versatility as a
chiral building block (Scheme 1).
Molecules that possess steric and stereoelectronic biases
render their derivatives useful in organic synthesis.1,2 We
have recently developed enone 1,3 and its structural isomer
2,4 having a bicyclo[3.2.1]octane framework in both enan-
tiomeric forms starting from racemic norbornadiene-2,5-
dione5 by a route involving either an enzymatic or chemical
resolution step. Owing to their chemical nature with a ste-
rically biased structure containing two oxygen functional-
ities, they exhibit inherent convex-face selectivity enabling
the diastereocontrolled modification of their enone func-
tionality and various tactical skeletal rearrangements that
make them versatile building blocks. They have already
been used in the stereocontrolled syntheses of the antibiotic
diterpene (+)-ferruginol,3a the morphinan alkaloid (ꢀ)-
morphine3b and (ꢀ)-O-methylpallidinine,3c the hormonal
substances calcitriol4a,b and estrone,4c and the indole alka-
loid (ꢀ)-dihydrocorynantheol.4e Since we are further inter-
ested in developing the synthetic utility of enone 2, and
since the acquisition of 2 requires an additional three-step
sequence4a from enone 1 involving alkaline epoxidation,
Wharton rearrangement, and manganese(IV) oxidation of
the resulting alcohol, we planned to develop a more effi-
cient route to 2. The masked aldol functionality embedded
2. Result and discussion
2.1. Organocatalytic construction of endo-7-hydroxy-
bicyclo[3.2.1]octan-2-one
The r-symmetrical ketoaldehyde 4 was readily prepared
from commercially available 1,4-cyclohexanedione mono-
ethylene acetal 5 in five steps. Thus, the Horner–Wads-
worth–Emmons olefination of 5 with triethyl phos-
phonoacetate and the following catalytic hydrogenation
afforded ester 6. The lithium aluminum hydride reduction
of 6, the hydrolytic deprotection of an acetal group, and
Swern oxidation of the resulting alcohol 79 furnished keto-
aldehyde 4 (Scheme 2).
At first, the chemical and diastereofacial preferences of the
r-symmetrical ketoaldehyde 4 for the intramolecular aldol-
ization were evaluated using K2CO3 or pyrrolidine as the
*
Corresponding author. Tel.: +81 22 795 6846; fax: +81 22 795 6845;
e-mail: iwabuchi@mail.pharm.tohoku.ac.jp
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.12.009

S. Ito et al. / Tetrahedron: Asymmetry 19 (2008) 176–185
177
O
3 steps
O
O
This work
OMOM
(-)-2
This work
OMOM
lit. 3
O
(+)-1
O
OH
O
organocatalysis
3 steps
O
CHO
3
4
O
OMOM
(+)-2
OMOM
(-)-1
Scheme 1. Synthetic outlines of chiral bicyclo[3.2.1]octenones.
uct in 77% ee under identical conditions,10 the discovery
of catalysts and cofactors that bring about a practical level
of asymmetric induction poses a serious challenge, which is
now a subject of our intensive studies.
1) (EtO)2P(O)CH2CO2Et
O
O
1) LAH, THF
O
O
NaH, THF
2) H2, Pd/C, AcOEt
(2 steps, 91%)
2) 10% HCl aq.
acetone
(2 steps, 89%)
O
5
CO2Et
6
2.2. Enzymatic kinetic resolution
O
O
(COCl)2, DMSO
Et3N
With our several successes in the lipase-mediated kinetic
resolution of closely related bicyclo[3.2.1]octane deriva-
tives,11 aldol 3 was transformed into allylic alcohol 8 in
three steps. Thus, the hydroxyl group of 3 was protected
with a methoxymethyl group to give a MOM ether, which
was oxidized by IBX12 in warm DMSO to enone 2 in 68%
yield. The treatment of 2 with DIBAL furnished the endo-
alcohol 8 (Scheme 4).
CH2Cl2, -78 °C
(75%)
OH
CHO
4
7
Scheme 2. Synthesis of r-symmetric ketoaldehyde 4.
1) MOMCl
i-Pr2NEt
catalyst. In both cases, the bicyclo[3.2.1]octane product 3
was produced as a 1:1 and 1.6:1 mixture of endo/exo-diaste-
reomers, and no bicyclo[2.2.1]octane products were de-
tected. We were, therefore, pleased to find that L-proline
catalyzed10 the diastereoselective aldolization of 4 to fur-
nish endo-3 in 50% yield with 90% de, although the enanti-
oselectivity was 9% ee (Scheme 3).
DIBAL
O
OH
O
OH
OMOM
CH2Cl2
(83%)
2) IBX, DMSO
(2 steps, 68%)
OMOM
8
2
3
Scheme 4. Conversion of 3 to endo-alcohol 8.
Unfortunately, all attempts at the enzymatic transesterifi-
cation of the alcohol were unsatisfactory; that is, no reac-
tion was observed using lipase MY, AK, PS, and vinyl
acetate. Only a moderate level of resolution was promoted
by lipase LIP, giving acetate 9A in 43% yield with 70% ee
after 15 days. We then examined the lipase-mediated enan-
tioselective hydrolysis of ester derivatives 9A and 9B
(Scheme 5).
O
L-proline
(13 mol%)
O
MeCN, 0 °C, 36 h
OH
CHO
(50%, 90% de, 9% ee)
4
3
O
Table 1 summarizes the results of the attempted hydrolysis
in 0.1 M phosphate buffer (pH 7.0) and acetone (9:1) in the
presence of lipase PS. It is interesting to note that both the
acyl portion and temperature exert critical effects on the
resolution of this particular bicyclo[3.2.1]octane.
L-proline
(25 mol%)
MeCN, 0 °C, 36 h
O
OH
(70%, 97% de, 77% ee)
CHO
Under optimized conditions, the butyryl ester ( )-9B was
hydrolyzed by lipase PS in phosphate buffer-acetone at
45 °C to afford (+)-8 and (+)-9B with an E-value13 of 451.
Thus, 9B was resolved in a clear-cut manner in the presence
of twice (w/w) the amount of lipase PS at 45 °C for 5 days to
give an ester in 43% yield with 99% ee. The remaining buty-
rate (+)-9B with a purity of 90% ee was resolved again un-
der hydrolysis conditions to give the enantiopure butyrate
(+)-9B. Finally, the enantiopure enone (+)-2 was obtained
Scheme 3. L-Proline-catalyzed aldolization of 4.
Then, suitable conditions for increasing enantioselectivity
were investigated. However, we were unable to find condi-
tions that would allow us to obtain an ee exceeding 33%.10
In light of the fact that the homologous r-symmetrical
ketoaldehyde affords the corresponding aldolization prod-

178
S. Ito et al. / Tetrahedron: Asymmetry 19 (2008) 176–185
A) Acetyl chloride
1
10
Py, DMAP
8
O
OR
OMOM
OH
OMOM
O
5
B) Butyryl chloride
OMOM
(—)-2
O
Py. DMAP(cat.)
(confertin numbering)
A) R = Ac
9
8
B) R = butyryl
10
H
H
1
lipase PS
8
OH
O
O
5
+
OR
OMOM
see Table 1
OMOM
O
O
RO
(+)-9
(+)-confertin 27
(+)-8
Scheme 5. Synthesis and lipase-mediated enantioselective hydrolysis of 9.
Scheme 7. Synthesis plan for the key intermediate of (+)-confertin.
Thus, the treatment of (ꢀ)-2 with a cuprate, which was
generated in situ from methylmagnesium iodide in the pres-
ence of copper(I) cyanide and LiCl, furnished ketone (ꢀ)-
10 in 92% yield as a single stereoisomer. To prepare for
the installation of a quaternary center corresponding to
C-5 (confertin numbering), a formal ‘aldol transposition’
was conducted in a four-step sequence involving NaBH4
reduction, protection of the resulting secondary alcohols
by a benzyl group, the deprotection of the MOM group,
and PCC oxidation to furnish (+)-13. Again ketone 13
exhibited an inherent convex-face selectivity to allow the
diastereoselective construction of a quaternary stereogenic
center next to the carbonyl functionality. Thus, sequential
methylation and allylation proceeded in turn from the con-
vex face to furnish ketone (+)-15.
Table 1. Lipase-mediated enantioselective hydrolysis of 9
Substrate Lipase PS Time Temp Conversion ee
E-value
(w/w)
(day)
(%)
(%)
9A
9B
9B
9B
1
1
4
2
12
60
5
30
30
30
45
44
39
41
43
74
99
90
99
12
383
377
451
5
from the former by oxidation, and the enantiomer (ꢀ)-2
was obtained from the latter by the sequential alkaline
methanolysis and the oxidation of the resulting alcohol
(ꢀ)-8, both in satisfactory yields (Scheme 6).
O
MnO2
OH
Having constructed the requisite C-10 tertiary and C-5
quaternary centers (confertin numbering), we then focussed
our attention to the construction of a seven-membered
ring. To this end, the O-benzyl group was removed and
the resulting alcohol (ꢀ)-16 was oxidized to give diketone
(ꢀ)-17. When sodium methoxide was added to a stirred
solution of (ꢀ)-17 in MeOH, a facile and regioselective
retro-Dieckmann reaction occurred instantly to afford
ketoester (ꢀ)-18 in 85% yield exclusively. The observed
regioselectivity might be a consequence of the preferential
attack of a methoxide anion onto the sterically more acces-
sible C-2 carbonyl group. Ketone (ꢀ)-18 was reduced with
NaBH4, and the resulting alcohol was protected by a
benzyl group. Upon Weinreb amide formation and the
reaction of 20 with methyllithium and with TBSOTf in
the presence of triethylamine, 20 furnished the silyl enol
ether 23. The ring-closing metathesis16 of 23 using the sec-
ond generation Grubbs’ catalyst17 enabled us to obtain
bicyclo[5.3.0]decane 24, which furnishes a comparable
functionality to the key synthetic intermediate of confer-
tin14 (Scheme 8).
CH2Cl2
(96%)
OMOM
OMOM
(+)-8
(+)-2
(43% : >99% ee)
[α]D26 = +212.7 (c 0.24, CHCl3)
lit. [α]D = +204.1 (c 0.70, CHCl3)
27
lipase PS
O
O
OMOM
(+)-8
(+)-9B
+
(75%: 99% ee)
buffer (pH=7.0)-
acetone(9:1)
n-Pr
(+)-9B
45 °C, 1.5 d
(50% : 90%ee)
1) NaOMe / MeOH
(+)-9B
(75%: 99%ee)
O
OMOM
(—)-2
2) MnO2 / CH2Cl2
(2 steps, 90%)
[α]D30 = −200.3 (c 1.00, CHCl3)
Scheme 6. Synthesis of both enantiomers of the bicyclo[3.2.1]octenone 2.
2.3. Synthetic transformation to the bicyclo[5.3.0]decane
system
3. Conclusion
In summary, we developed an alternative method for the
efficient chemoenzymatic synthesis of a 7-oxybicyclo-
[3.2.1]octenone-type chiral building block from commer-
cially available 1,4-cyclohexanedione monoethylene acetal.
The results of the current work are as follows: (1) A nearly
racemic 7-hydroxybicyclo[3.2.1]octan-2-one 2 was easily
prepared in a diastereocontrolled manner via an L-proline-
To demonstrate the synthetic potential of 2, its conversion
to a chiral bicyclo[5.3.0]decane, which has served as a key
intermediate14 for the synthesis of confertin,15 a pseudo-
guaianolide-class antitumor sesquiterpene lactone, was
examined on the basis of its functionality and stereochem-
ical background (Scheme 7).

S. Ito et al. / Tetrahedron: Asymmetry 19 (2008) 176–185
179
1) NaBH4
MeMgI, CuCN
LiCl
HCl
PCC
MeOH
O
O
MeOH
(91%)
CH2Cl2
(97%)
2) NaH, BnBr
TBAI, THF
OBn
OMOM
(—)-11
OBn
OH
(+)-12
THF
OMOM
(92%)
OMOM
(—)-10
(88% 2 steps)
(—)-2
Br
DDQ
NaH, MeI
PCC
t-BuOK
OBn
aq. CH2Cl2
THF
OH
(—)-16
CH2Cl2
(99%)
OBn
(+)-14
THF
OBn
(82%)
(96%)
(86%)
O
O
O
O
(+)-13
(+)-15
O
O
1) NaBH4
MeOH
AlMe3
H
H
NaOMe
MeONHMe•HCl
2
OMe
OMe
O
MeOH
(85%)
2) NaH, BnBr
TBAI, THF
CH2Cl2
(67%)
7
RO
O
O
(2 steps 95%)
(3:5 mixture)
R=H, 19
R=Bn, 20
(—)-17
(—)-18
O
O
H
H
H
OMe
TBSOTf
25
N
OTBS
Et3N
MeLi
THF
benzene
reflux
MeCN
BnO
(quant.)
(85%)
BnO
BnO
(61%)
21
22
23
H
H
MesN
NMes
H
TBAF
O
O
Cl
Cl
O
Ru
PPh3
OTBS
THF
Ph
O
(+)-confertin 27
(32%)
BnO
BnO
24
26
2nd generation
Grubbs cat. 25
Scheme 8. Synthesis of the key intermediate of (+)-confertin.
catalyzed intramolecular aldolization of the r-symmetric
ketoaldehyde 4. (2) The highly enantiomerically enriched
bicyclo[3.2.1]octenones (+)-2 and (ꢀ)-2 were synthesized
by a lipase-mediated enantioselective hydrolysis of racemic
9B. (3) The newly developed synthesis route for (+)-2 en-
tails operationally facile 12 steps, enabling more straight-
forward access to (+)-2 compared with the previously
reported 14-step route. The synthetic use of 2 was demon-
strated by converting it into a key intermediate of antitu-
mor sesquiterpene (+)-confertin 27. We are presently
continuing this study for the expansion of the use of (+)-
2 and (ꢀ)-2 in the enantio- and diastereo-controlled synthe-
ses of various natural products.
drous THF and CH2Cl2 were purchased from Kanto
Chemical Co., Inc. Organic extracts were dried by stirring
them over anhydrous MgSO4, filtered through a Celite pad,
and concentrated under reduced pressure using a rotary
evaporator. Column chromatography was carried out
using Merck 60N (63–210 mesh) silica gel. Reactions were
analyzed on precoated silica gel 60 F254 plates (Merck) and
compounds were visualized with a UV lamp (254 nm) and
by staining with p-anisaldehyde in EtOH or phospho-
molybdic acid (in EtOH). Melting point (mp) was
uncorrected. IR spectra were recorded on a JASCO IR-
700 spectrometer. 1H and 13C NMR spectra were recorded
on a Gemini 2000 (300 MHz) or JEOL AL-400 (400 MHz)
spectrometer. Mass spectra were recorded on a JEOLJMS-
DX303 instrument. Optical rotation was measured with a
JASCO DIP-370 digital polarimeter.
4. Experimental
4.1. General methods
4.2. Ethyl 2-{4,4-(ethylenedioxy)cyclohexylidene}acetate
Unless otherwise mentioned, all reactions were performed
in oven-dried glassware under argon atmosphere. Anhy-
To a stirred suspension of sodium hydride (60%, 1.0 g,
25.2 mmol) in dry THF (75 mL) was added dropwise

180
S. Ito et al. / Tetrahedron: Asymmetry 19 (2008) 176–185
triethyl phosphonoacetate (5 mL, 25.2 mmol) at 0 °C and
the resulting mixture was stirred for 30 min. Then, 1,4-
cyclohexanedione monoethylene acetal (3.28 g, 21 mmol)
in THF (30 mL) was added to the mixture at 0 °C and stir-
red for 30 min. The mixture was diluted with Et2O and
H2O. The mixture was extracted with EtOAc, and the ex-
tract was washed with brine, dried over anhydrous MgSO4,
and concentrated to give a crude product, which was chro-
matographed on silica gel (eluent: EtOAc/hexane, 1/6) to
give an ester (colorless oil; yield: 4.62 g, 20 mmol, 97%).
4.5. (4-Oxocyclohexyl)acetaldehyde 4
A solution of oxalyl chloride (7.27 mL, 83.3 mmol) in
CH2Cl2 (300 mL) at ꢀ78 °C was treated with DMSO
(11.8 mL, 167 mmol) dropwise and the mixture was stirred
for 10 min. Alcohol 7 (3.00 g, 20.8 mmol) in CH2Cl2
(50 mmol) was then added to the mixture at ꢀ78 °C. After
15 min, Et3N (34.9 mL, 250 mmol) was added dropwise at
the same temperature. The mixture was then warmed to
room temperature and H2O was added. The mixture was
extracted with AcOEt, washed with brine, dried (MgSO4),
concentrated, and chromatographed on silica gel (EtOAc/
hexane, 1/2) to give 4 (colorless oil; yield: 2.19 g,
15.6 mmol, 75%). IR mmax (neat) cmꢀ1: 1712. 1H NMR
(400 MHz, CDCl3) d: 9.81 (1H, s), 2.50 (2H, dd, J = 6.3,
1.8 Hz), 2.45–2.39 (4H, m), 2.12 (2H, dt, J = 14.7,
3.3 Hz), 1.65 (1H, s), 1.52–1.47 (2H, m). 13C NMR
(100 MHz, CDCl3) d: 210.6, 200.9, 49.3, 40.5, 32.4, 30.5.
MS m/z: 140 (M+), 96 (100%). HRMS Calcd for
C8H12O2 (M+): 140.0837. Found: 140.0807.
1
IR mmax (neat) cmꢀ1: 1712. H NMR (400 MHz, CDCl3)
d: 5.67 (1H, s), 4.15 (2H, q, J = 7.1 Hz), 3.98 (4H, s),
3.00 (2H, t, J = 7.4 Hz), 2.37 (2H, t, J = 6.4 Hz), 1.76
(4H, td, J = 7.4, 6.4 Hz), 1.24 (3H, t, J = 7.1 Hz). 13C
NMR (100 MHz, CDCl3) d: 166.4, 160.0, 114.2, 107.9,
64.4, 59.6, 35.8, 35.0, 34.6, 26.1, 14.4. MS m/z: 226 (M+,
100%). HRMS Calcd for C12H18O4(M+): 226.1204. Found:
226.1190.
4.3. Ethyl 2-{4,4-(ethylenedioxy)cyclohexyl}acetate 6
4.6. (1R*,5S*,7S*)-7-Hydroxybicyclo[3.2.1]octan-2-one 3
A solution of ester (4.62 g, 20 mmol) in AcOEt (100 mL)
was hydrogenated on 10% Pd–C (460 mg) using a H2 bal-
loon for 2 h. The mixture was filtered and the filtrate was
concentrated under reduced pressure to give a crude prod-
uct, which was chromatographed on silica gel (eluent:
EtOAc/hexane, 1/6) to give 6 (colorless oil; yield: 4.27 g,
18.7 mmol, 94%). IR mmax (neat) cmꢀ1: 1731. 1H NMR
(400 MHz, CDCl3) d: 4.12 (2H, q, J = 7.1 Hz), 3.93 (4H,
s), 2.22 (2H, d, J = 7.1 Hz), 1.86–1.82 (1H, m), 1.78–1.69
(4H, m), 1.57 (2H, td, J = 12.7, 3.6 Hz), 1.30 (2H, dd,
J = 12.7, 9.52 Hz), 1.25 (3H, t, J = 7.1 Hz). 13C NMR
(100 MHz, CDCl3) d: 172.7, 108.5, 64.2, 60.2, 41.0, 34.3,
33.4, 30.0, 14.3. MS m/z: 228 (M+), 99 (100%). HRMS
Calcd for C12H20O4 (M+): 228.1360. Found: 228.1355.
To a stirred solution of aldehyde 4 (623 mg, 4.45 mmol) in
MeCN (4.45 mL) was added L-proline (64.0 mg,
0.56 mmol) at 0 °C. After 36 h, H2O was added and the
mixture was extracted with AcOEt. The extract was washed
with brine, dried (MgSO4), evaporated under reduced pres-
sure, and chromatographed on silica gel (EtOAc/hexane,
1/2) to give 3 (colorless oil; yield: 313 mg, 2.24 mmol,
50%, 90% de, 9% ee). IR mmax (neat) cmꢀ1: 3417, 1697.
1H NMR (400 MHz, CDCl3) d: 4.60 (0.95H, m), 4.32
(0.05H, d, J = 5.8 Hz), 2.88 (0.1H, s), 2.80 (1.9H, s) 2.68–
2.59 (1H, m) 2.50–2.26 (2.85H, m), 2.19 (0.15H, dd,
J = 14.7, 6.8 Hz), 2.10–1.83 (3H, m), 1.82–1.63 (2H, m),
1.57 (1H, dt J = 13.5, 3.3 Hz). 13C NMR (100 MHz,
CDCl3) d: 212.8, 73.9, 57.7, 40.4, 36.2, 33.4, 31.5, 30.6.
MS m/z: 140 (M+), 80 (100%). HRMS Calcd for
C8H12O2 (M+): 140.0837. Found: 140.0816.
4.4. 4-(2-Hydroxyethyl)cyclohexanone 7
To a stirred suspension of LiAlH4 (532 mg, 14 mmol) in
THF (37 mL) was added 6 (4.27 g, 18.7 mmol) in THF
(10 mL) at 0 °C, and the mixture was continuously stirred
at the same temperature. After 10 min, the mixture was
diluted with Et2O and H2O. The resulting mixture was
filtered through a Celite pad. The filtrate was evaporated
under reduced pressure.
4.7. (1R*,5S*,7S*)-7-Methoxymethoxybicyclo[3.2.1]-octan-
2-one
To a stirred solution of alcohol 3 (118 mg, 0.844 mmol) in
CH2Cl2 (12 mL) was added i-Pr2NEt (0.6 mL, 3.36 mmol)
at 0 °C, and the mixture was stirred for 10 min at the same
temperature. To the mixture was then added dropwise
methoxymethylchloride (0.13 mL, 1.68 mmol). After 12 h,
H2O was added to the mixture and the mixture was
extracted with EtOAc. The extract was washed with brine,
dried (MgSO4), and concentrated to give a crude product,
which was chromatographed on silica gel (EtOAc/hexane,
1/6) to give a MOM ether (colorless oil; yield 145 mg,
0.79 mmol, 94%). IR mmax (neat) cmꢀ1: 1712. 1H NMR
(400 MHz, CDCl3) d: 4.61–4.56 (2H, m), 4.41 (1H dt,
J = 12.2, 4.3 Hz), 3.33 (3H, s), 2.94 (1H, t, J = 5.1 Hz),
2.68–2.58 (1H, m) 2.44–2.33 (3H, m), 2.45–2.33 (2H, m),
1.99–1.87 (2H, m), 1.73 (1H, dt, J = 8.9, 3.6 Hz). 13C
NMR (100 MHz, CDCl3) d: 211.0, 95.5, 78.4, 55.5, 36.3,
35.9, 34.7, 33.0, 31.7, 30.6. MS m/z: 184 (M+), 45
(100%). HRMS Calcd for C10H16O3 (M+): 184.1094.
Found: 184.1080.
The residue was dissolved in acetone (28 mL) and 10% aq
HCl (1.8 mL) was added to the solution. Then, the mixture
was refluxed for 20 min. A saturated aqueous NaHCO3
solution was added to the cooled reaction mixture and
extracted with EtOAc. The extract was washed with brine,
dried (MgSO4), concentrated, and chromatographed on sil-
ica gel (EtOAc/hexane, 1/1) to give 7 (colorless oil; yield:
2.37 g, 16.7 mmol, 89%, 2 steps). IR mmax (neat) cmꢀ1
:
1
3408, 1704. H NMR (400 MHz, CDCl3) d: 3.75 (2H, t,
J = 6.6 Hz), 2.36 (2H, dd, J = 11.0, 3.9 Hz), 2.37–2.31
(2H, m), 2.08 (2H, dd, J = 13.1, 2.9 Hz), 1.98–1.92 (1H,
m), 1.62–1.55 (3H, m), 1.43 (2H, dd, J = 11.9, 5.9 Hz).
13C NMR (100 MHz, CDCl3) d: 212.3, 60.7, 40.8, 38.3,
32.7, 32.6. MS m/z: 142 (M+), 98 (100%). HRMS Calcd
for C8H14O2(M+): 142.0977. Found: 142.1004.

S. Ito et al. / Tetrahedron: Asymmetry 19 (2008) 176–185
181
4.8. (1R*,5S*,7S*)-7-Methoxymethoxybicyclo[3.2.1]oct-3-
en-2-one 2
J = 6.8 Hz), 4.60 (1H, d, J = 6.8 Hz), 4.59–4.56 (1H, m),
3.36 (3H, s), 2.81 (1H, d, J = 5.1 Hz), 2.35–2.20 (2H, m),
2.28 (2H, dt, J = 14.9, 7.7 Hz), 2.02 (1H, dd, J = 11.7,
3.2 Hz), 1.77 (2H, td, J = 12.1, 3.2 Hz), 1.66 (2H, q,
J = 7.3 Hz), 0.95 (3H, t, J = 7.3 Hz). 13C NMR
(100 MHz, CDCl3) d: 173.3, 137.5, 124.8, 95.3, 78.3, 76.3,
55.1, 41.8, 41.0, 36.9, 36.4, 34.1, 18.4, 13.8. MS m/z: 254
(M+), 134 (100%). HRMS Calcd for C14H22O4 (M+):
254.1517. Found: 254.1508.
To a stirred solution of an MOM ether (1.6 g, 8.73 mmol)
in DMSO (12 mL) was added IBX (28 g, 35.4 mmol) at
0 °C. The mixture was then heated at 60 °C for 36 h. After
cooling to rt, saturated aqueous NaHCO3 was added to the
mixture, which was then extracted with AcOEt. The organ-
ic extract was washed with brine, dried (MgSO4), concen-
trated, and chromatographed on silica gel (EtOAc/
hexane, 1/2) to give 2 (colorless oil; yield: 1.12 g,
6.25 mmol, 72%). IR mmax (neat) cmꢀ1: 1680. 1H NMR
(400 MHz, CDCl3) d: 7.38 (1H, ddd, J = 9.6, 6.9, 1.6 Hz),
5.96 (1H, dd, J = 9.6, 1.6 Hz), 4.65 (1H, ddd, J = 8.7,
6.4, 2.7 Hz), 4.64 (1H, d, J = 6.9 Hz), 4.51 (1H, d,
J = 6.9 Hz), 3.33 (3H, s), 3.26 (1H, t, J = 6.4 Hz), 2.77
(1H, dd, J = 6.6, 4.2 Hz), 2.32 (1H, ddd, J = 13.7, 9.3,
6.6 Hz), 2.10 (1H, dd, J = 11.8, 3.0 Hz), 1.70–1.78 (2H,
m). 13C NMR (100 MHz, CDCl3) d: 200.1, 157.0, 128.7,
95.6, 75.6, 55.5, 55.2, 39.2, 37.2, 36.0. MS m/z: 182 (M+),
45 (100%). HRMS Calcd for C10H14O3 (M+): 182.0942.
Found: 182.0960.
4.11. (1S,2R,5S,7S)-7-Methoxymethoxybicyclo[3.2.1]oct-3-
en-2-ol (+)-8
4.11.1. (1S,2S,5R,7R)-Butyric acid-7-methoxymethoxybicy-
clo-[3.2.1]-oct-3-en-2-yl ester (+)-9B. To a stirred solution
of ester ( )-9B (1.0 g, 3.9 mmol) in 0.1 M phosphate buffer
(pH 7.0, 35 mL) and acetone (4 mL) was added lipase PS
(2 g) at 45 °C. After 5 days, the mixture was diluted with
AcOEt and filtered through a Celite pad. The filtrate was
extracted with AcOEt, and the organic extract was washed
with brine, dried (MgSO4), evaporated, and chromato-
graphed on silica gel (eluent: EtOAc/hexane, 1/4 or 1/2,
respectively) to give ester (+)-9B (colorless oil; yield:
495 mg, 1.95 mmol, 50%) and allyl alcohol (+)-8 (colorless
oil; yield: 309 mg, 1.68 mmol, 43%).
4.9. (1R*,2R*,5S*,7S*)-7-Methoxymethoxybicyclo-
[3.2.1]oct-3-en-2-ol 8
To a stirred solution of enone 2 (394 mg, 2.16 mmol) in
CH2Cl2 (43 mL) was added DIBAL in hexane (1.0 M,
2.89 mL, 4.33 mmol) at ꢀ78 °C and the mixture was con-
tinuously stirred at the same temperature. After 30 min,
the mixture was diluted with Et2O and H2O was added
to the mixture. The mixture was filtered through a Celite
pad, and the filtrate was concentrated, and chromato-
graphed on silica gel (EtOAc/hexane, 1/2) to give 8 (color-
less oil; yield: 286 mg, 1.56 mmol, 83%). IR mmax (neat)
cmꢀ1: 3508. 1H NMR (400 MHz, CDCl3) d: 6.01 (1H,
ddt, J = 9.5, 7.8, 1.7 Hz), 5.62 (1H, td, J = 9.5, 1.7 Hz),
4.68 (1H, d, J = 6.8 Hz), 4.66 (1H, d, J = 6.8 Hz), 4.59–
4.48 (1H, m), 4.24 (1H, d, J = 11.0 Hz), 3.39 (3H, s), 2.76
(1H, dd, J = 10.7, 5.1 Hz), 2.31(1H, dd, J = 9.8, 5.6 Hz),
2.12 (1H, ddd, J = 13.2, 9.5, 5.9 Hz), 1.79 (1H, dd,
J = 13.2, 2.7 Hz), 1.72–1.63 (2H, m). 13C NMR
(100 MHz, CDCl3) d: 134.9, 130.2, 95.7, 82.0, 72.3, 55.8,
43.7, 41.9, 36.9, 34.5. MS m/z: 152 (M+ꢀOMeꢀH), 78
(100%). HRMS Calcd for C9H12O2 (M+ꢀOMeꢀH):
152.0837. Found: 152.0844.
The spectroscopic data of (+)-9B and (+)-8 thus obtained
were identical with those of the racemates.
The enantiomeric excess was determined to be esters (+)-
9B (90% ee) and (+)-8 (99% ee) by HPLC using a column
with a chiral stationary phase (CHIRALCEL OD-H, elu-
ent: i-PrOH/hexane, 4:96 v/v), as described above, after
transformation into enone 2.
29
Allyl alcohol (+)-8: ½aꢁD ¼ þ78:1 (c 0.15, CHCl3).
To a stirred mixture of ester 9B (495 mg, 1.95 mmol, 90%
ee) in 0.1 M phosphate buffer (pH 7.0, 18 mL) and acetone
(2 mL) was added lipase PS (990 mg) at 45 °C. After 1.5
days, the mixture was diluted with AcOEt and filtered
through a Celite pad. The filtrate was extracted with
AcOEt, and the organic extract was washed with brine,
dried (MgSO4), evaporated, and chromatographed on
silica gel (EtOAc/hexane, 1/2) to give (+)-9B (colorless
oil; 371 mg, 1.46 mmol, 75%).
4.10. (1R*,2R*,5S*,7S*)-Butyric acid 7-methoxy-methoxy
bicyclo[3.2.1]oct-3-en-2-yl ester 9B
27
Ester (+)-9B: ½aꢁD ¼ þ57:8 (c 1.00, CHCl3).
Enantiomeric excess was determined to be ester (+)-9B
(99% ee) by HPLC as above after transformation into 2.
To a stirred solution of allyl alcohol 8 (3.00 g, 16.3 mmol)
in CH2Cl2 (82 mL) was added pyridine (3.55 mL,
48.9 mmol), butyryl chloride (3.39 mL, 32.6 mmol), and
DMAP (199 mg, 1.63 mmol) at 0 °C. After 6 h, saturated
aqueous NaHCO3 was added to the mixture, which was
then extracted with AcOEt. The organic extract was
washed with 10% aqueous NaOH, brine, dried (MgSO4),
concentrated, and chromatographed on silica gel (EtOAc/
hexane, 4/1) to give 9B (colorless oil; yield: 3.52 g,
13.9 mmol, 85%). IR mmax (neat) cmꢀ1: 1725. 1H NMR
(400 MHz, CDCl3) d: 6.14 (1H, dd, J = 9.5, 7.8 Hz), 5.80
(1H, s), 5.51 (1H, d, J = 9.5 Hz), 4.67 (1H, d,
4.12. (1R,5S,7S)-7-Methoxymethoxybicyclo[3.2.1]oct-3-
en-2-one (+)-2
To a stirred solution of (+)-8 (532 mg, 14 mmol) in CH2Cl2
(22 mL) was added MnO2 (815 mg) at rt. After 10 min, the
mixture was diluted with Et2O, and filtered through a Cel-
ite pad. The filtrate was evaporated and chromatographed
on silica gel (EtOAc/hexane, 1/2) to give (+)-2 (colorless
oil; yield: 76.9 mg, 0.42 mmol, 96%).

182
S. Ito et al. / Tetrahedron: Asymmetry 19 (2008) 176–185
26
(+)-2 ½aꢁD ¼ þ212:7 (c 0.24, CHCl3).
2.45 (1H, br s), 2.24–2.16 (1H, m), 2.00–1.82 (3H, m),
1.74 (1H, dd, J = 12.9, 5.61 Hz), 1.59 (1H, d, J = 12.56,
5.61 Hz), 1.41 (1H, d, J = 13.7 Hz), 1.33–1.28 (2H, m),
1.00 (3H, d, J = 6.59 Hz). 13C NMR (100 MHz, CDCl3)
d: 96.1, 80.4, 71.0, 55.7, 44.7, 39.7, 37.1, 36.0, 34.8, 29.2,
19.8; MS m/z: 182 (M+ꢀH2O), 94 (100%); HRMS Calcd
C11H18O2: 182.1306. Found: 182.1292.
4.13. (1S,5R,7R)-7-Methoxymethoxybicyclo[3.2.1]oct-3-en-
2-one (ꢀ)-2
To a stirred solution of (+)-9B (87.5 mg, 0.34 mmol) in
MeOH (17 mL) was added NaOMe (13.8 mg, 0.034 mmol)
at 0 °C for 5 min. After evaporating the solvent, the residue
was treated with saturated aqueous NH4Cl and the mixture
was extracted with AcOEt. The organic extract was washed
with brine, dried (MgSO4), and evaporated to leave crude
alcohol.
To a stirred solution of the alcohol (100 mg, 0.5 mmol) in
dry THF (2.5 mL) was added sodium hydride (40 mg,
1.00 mmol) at 0 °C. After 30 min, benzyl bromide
(0.01 mL, 1.13 mmol) and tetrabutyl ammonium iodide
(18.5 mg, 0.05 mmol) were added to the mixture at 0 °C.
The mixture was heated at reflux overnight. After cooling
to rt, the mixture was diluted with Et2O, and H2O was
added to the mixture. The mixture was extracted with
EtOAc, and the organic extract was washed with brine,
dried (MgSO4), and evaporated to leave a crude product,
which was chromatographed on silica gel (eluent: EtOAc/
The crude alcohol was dissolved in CH2Cl2 (17 mL), and
MnO2 (632 mg) was added to the mixture. The mixture
was stirred for 10 min, diluted with Et2O and filtered
through a Celite pad. The filtrate was evaporated and chro-
matographed on silica gel (EtOAc/hexane, 1/2) to give (ꢀ)-
2 (colorless oil; yield: 55.7 mg, 0.31 mmol, 90%).
hexane, 1/10) to give (ꢀ)-11 (colorless oil; yield: 138 mg,
30
23
(ꢀ)-2 ½aꢁD ¼ ꢀ200:3 (c 1.00, CHCl3).
48 mmol, 96%). ½aꢁD ¼ ꢀ20:6 (c 1.3 CHCl3). 1H NMR
(400 MHz, CDCl3) d: 7.35–7.21 (5H, m), 4.75 (1H, d,
J = 6.83 Hz), 4.56 (1H, d, J = 6.59 Hz), 4.52 (2H, s), 4.34
(1H, ddd, J = 10.72, 5.36, 5.36 Hz), 3.60 (1H, ddd,
J = 11.71, 5.37, 2.20 Hz), 3.35 (3H, s), 2.54 (1H, br s),
2.27 (1H, ddd, J = 13.78, 11.10, 7.07 Hz), 2.18 (1H, dt,
J = 12.14, 6.59 Hz), 1.91–1.83 (2H, m), 1.65 (1H, dd, J =
12.56, 5.61 Hz), 1.56 (1H, dd, J = 12.44, 3.17 Hz), 1.43
(2H, m), 0.98 (3H, d, J = 7.07 Hz). 13C NMR (100 MHz,
CDCl3) d: 139.3, 128.1, 127.2, 127.0, 95.6, 77.8, 76.7,
70.2, 55.1, 40.4, 39.3, 37.5, 34.7, 31.9, 30.0, 19.9. MS m/z:
290 (M+), 91 (100%). HRMS Calcd for C18H26O3:
290.1882. Found: 290.1854.
4.14. (1R,4S,5S,7S)-7-Methoxymethoxy-4-methyl-bicyclo-
[3.2.1]octan-2-one (ꢀ)-10
To a stirred solution of CuCN (1.48 g, 16.5 mmol) and
LiCl (1.40 g, 33.0 mmol) in dry THF (38 mL) was added
methylmagnesium iodide (8.8 mL, 2.5 M in Et2O) at
ꢀ78 °C. After 30 min, enone 2 (1.00 g) in THF (10 mL)
was added dropwise to the mixture at ꢀ78 °C. After
30 min, the mixture was diluted with Et2O, water was
added to the mixture and the mixture was extracted with
EtOAc. The extract was washed with brine, dried (MgSO4),
and evaporated under reduced pressure to leave a crude
product, which was chromatographed on silica gel (eluent:
4.16. (1R,2S,4S,5S,6R)-4-Benzyloxy-2-methylbicyclo-
[3.2.1]octan-6-ol (+)-12
EtOAc/hexane, 1/6) to give ketone 10 (colorless oil; yield:
29
1.00 g, 5.0 mmol, 92%). ½aꢁD ¼ ꢀ92:7 (c 1.5, CHCl3); IR
1
(neat): 1713 cmꢀ1; H NMR (400 MHz, CDCl3) d: 4.58
To a solution of ether (ꢀ)-11 (139 mg, 0.48 mmol) in
MeOH (2.0 mL) was added saturated HCl in MeOH
(0.5 mL) at 0 °C. After 5 h, the solvent was evaporated to
leave a crude product, which was chromatographed on
(2H, dd, J = 12.6, 6.8 Hz), 4.39 (1H, m), 3.31 (3H, s),
2.91 (1H, dd, J = 5.1, 5.1 Hz), 2.82 (1H, dd, J = 16.4,
8.2 Hz), 2.50–2.42 (1H, m), 2.23 (1H, m), 2.09–1.96 (2H,
m), 1.02 (3H, d, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3)
d: 216.5, 95.9, 77.9, 55.7, 55.6, 43.8, 39.2, 36.6, 35.8, 30.1,
20.6; MS m/z: 198 (M+), 45 (100%); HRMS Calcd
C11H18O3: 198.1256. Found: 195.1282.
silica gel (eluent: EtOAc/hexane, 1/10) to give 12 (colorless
27
oil; yield: 107 mg, 43 mmol, 91%). ½aꢁD ¼ þ24:7 (c 1.2
1
CHCl3). IR mmax (neat) cmꢀ1: 3508. H NMR (400 MHz,
CDCl3) d: 7.35–7.26 (5H, m), 4.57 (2H, dd, J = 14.64,
11.95 Hz), 4.43 (1H, m), 4.22 (1H, d, J = 4.88 Hz), 3.87–
3.83 (1H, ddd, J = 10.55, 6.52, 3.35 Hz), 2.55 (1H, dd,
J = 5.38, 3.38 Hz), 2.27 (1H, ddd, J = 13.86, 10.59,
7.08 Hz), 2.09 (1H, m), 1.96–1.92 (2H, m), 1.80 (1H, dd,
J = 13.17, 6.10 Hz), 1.58 (1H, s), 1.54 (1H, dd, J = 12.32,
2.81 Hz), 1.44–1.36 (2H, m), 0.99 (3H, d, J = 7.08 Hz).
13C NMR (100 MHz, CDCl3) d: 138.1, 128.3, 127.5,
127.4, 77.4, 74.7, 70.1, 41.8, 40.3, 40.1, 34.4, 32.3, 29.1,
19.8. MS m/z: 246 (M+), 91 (100%). HRMS Calcd for
C16H22O2: 246.1620. Found: 246.1627.
4.15. (1R,2S,4S,5R,6R)-4-Benzyloxy-6-methoxymethoxy-2-
methylbicyclo[3.2.1]octane (ꢀ)-11
To a solution of 10 (407 mg, 2.06 mmol) in MeOH
(10.3 mL) was added NaBH4 (58.5 mg, 1.55 mmol) at
ꢀ78 °C, and the mixture was stirred for 2 h at the same
temperature. Then, the mixture was diluted with Et2O
and acetone was added to the mixture. The mixture was ex-
tracted with Et2O, and the organic extract was washed with
brine, dried (MgSO4), and evaporated to leave a crude
product, which was chromatographed on silica gel (eluent:
4.17. (1R,2S,4S,5R)-4-Benzyloxy-2-methylbicyclo-
[3.2.1]octan-6-one (+)-13
EtOAc/hexane, 1/4) to give an alcohol (colorless oil; yield:
27
378 mg, 1.89 mmol, 92%). ½aꢁD ¼ ꢀ87:6 (c 0.50, CHCl3);
IR (neat): 3547 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d:
A mixture of alcohol (+)-12 (459 mg, 1.86 mmol), PCC
(802 mg, 3.72 mmol), and silica gel (459 mg) in CH2Cl2
(9.3 mL) was stirred at rt for 2 h. The mixture was then
4.65 (2H, d, J = 4.39 Hz), 4.37 (1H, dd, J = 6.59 Hz),
3.74 (1H, br s), 3.39 (3H, s), 3.23 (1H, d, J = 11.0 Hz)

S. Ito et al. / Tetrahedron: Asymmetry 19 (2008) 176–185
183
diluted with Et2O and filtered through a Celite pad. The
filtrate was evaporated to leave a crude product, which
was chromatographed on silica gel (eluent: EtOAc/hexane,
dd, J = 15.98, 14.5 Hz), 1.67 (1H, d, J = 12.93 Hz), 1.58–
1.46 (2H, m), 1.10 (3H, d, J = 7.08 Hz), 1.06 (3H, s). 13C
NMR (100 MHz, CDCl3) d: 220.5, 138.4, 132.9, 128.2,
127.4, 127.4, 127.3, 118.6, 76.1, 69.8, 52.1, 50.1, 48.8,
45.0, 33.6, 33.3, 26.1, 20.0, 16.1. MS m/z: 298 (M+), 91
(100%). HRMS Calcd for C20H26O2: 298.1933. Found:
298.1944.
1/10) to give (+)-13 (colorless oil; yield: 439 mg,
23
1.80 mmol, 97%). ½aꢁD ¼ þ140:1 (c 2.0 CHCl3). IR mmax
1
(neat) cmꢀ1: 1739. H NMR (400 MHz, CDCl3) d: 7.38–
7.26 (5H, m), 4.71 (1H, d, J = 11.95 Hz), 4.47 (1H, d,
J = 12.20 Hz), 3.70 (1H, ddd, J = 11.71, 5.87, 3.42 Hz),
2.66 (1H, s), 2.33 (1H, s), 2.29 (1H, d, J = 6.83), 2.09–
1.70 (2H, m), 1.91–1.76 (3H, m), 1.66 (1H, ddd,
J = 12.93, 12.93, 6.83 Hz), 1.10 (2H, m), 1.65 (1H, dd,
J = 12.56, 5.61 Hz), 1.56 (1H, dd, J = 12.44, 3.17 Hz),
1.43 (3H, d, J = 7.08). 13C NMR (100 MHz, CDCl3) d:
217.8, 128.3, 127.5, 127.4, 75.9, 69.8, 49.5, 45.1, 37.6,
33.1, 32.8, 28.8, 19.8. MS m/z: 244 (M+), 91 (100%).
HRMS Calcd for C16H20O2: 244.1463. Found: 244.1448.
4.20. (1R,2S,4S,5R,7S)-7-Allyl-4-hydroxy-2,7-dimethyl-
bicyclo[3.2.1]octan-6-one (ꢀ)-16
A mixture of benzyl ether (+)-15 (85 mg, 0.29 mmol), H2O
(0.15 mL), and DDQ (194 mg, 0.85 mmol) in CH2Cl2
(1.3 mL) was stirred at rt overnight. The mixture was
diluted with Et2O, and saturated aqueous NaHCO3 was
added to the mixture. The mixture was extracted with
Et2O, and the organic extract was washed with brine, dried
(MgSO4), and evaporated to leave a crude product, which
was chromatographed on silica gel (eluent: EtOAc/hexane,
4.18. (1S,2S,4S,5R,7S)-4-Benzyloxy-2,7-dimethylbicyclo-
[3.2.1]octan-6-one (+)-14
1/4) to give 16 (colorless oil; yield: 49 mg, 23.7 mmol, 82%).
31
To a stirred solution of ketone (+)-13 (74 mg, 0.3 mmol) in
dry THF (1.5 mL) was added sodium hydride (18 mg,
0.45 mmol) at 0 °C. After 30 min, to the mixture was added
methyl iodide (0.19 mL, 3.0 mmol) at rt for 3 h. The mix-
ture was diluted with Et2O, and H2O was added to the mix-
ture. The mixture was extracted with EtOAc, and the
organic extract was washed with brine, dried (MgSO4),
and evaporated to leave a crude product, which was chro-
matographed on silica gel (eluent: EtOAc/hexane, 1/10) to
½aꢁD ¼ ꢀ32:2 (c 0.4 CHCl3). IR mmax (neat) cmꢀ1: 3424,
1
1733. H NMR (400 MHz, CDCl3) d: 5.89–5.77 (1H, m),
5.13 (1H, dd, J = 10.12, 0.85 Hz), 5.07 (1H, dd,
J = 17.08, 0.85 Hz), 3.98–3.88 (1H, m), 2.52 (1H, br s),
2.22 (1H, dd, J = 14.15, 8.05 Hz), 2.16–2.01 (3H, m), 1.94
(1H, br s), 1.89 (1H, d, J = 9.03 Hz), 1.84 (1H, dd,
J = 14.27, 6.22 Hz), 1.74 (1H, d, J = 13.17 Hz), 1.28 (1H,
ddd, J = 14.03, 11.59, 7.08 Hz), 1.12 (3H, d, J =
7.08 Hz), 1.05 (3H, s). 13C NMR (100 MHz, CDCl3) d:
220.7, 138.4, 133.3, 128.3, 127.6, 127.4, 118.3, 69.7, 51.7,
48.8, 45.1, 41.0, 33.8, 28.9, 25.7, 20.6, 14.6. MS m/z: 208
(M+), 114 (100%). HRMS Calcd for C13H20O2: 208.1463.
Found: 208.1484.
give 14 (colorless oil; yield: 74 mg, 28.8 mmol, 96%).
23
½aꢁD ¼ þ121:9 (c 0.7 CHCl3). IR mmax (neat) cmꢀ1: 1736.
1H NMR (400 MHz, CDCl3) d: 7.36–7.21 (5H, m), 4.69
(1H, d, J = 12.20), 4.44 (1H, d, J = 11.95 Hz), 3.69 (1H,
ddd, J = 11.71, 5.85, 3.42 Hz), 2.66 (1H, br s), 2.05–1.96
(2H, m), 1.94–1.97 (2H, m), 1.82–1.71 (2H, m), 1.61 (1H,
ddd, J = 14.15, 11.71, 6.83 Hz), 1.11 (3H, d, J =
7.56 Hz), 1.07 (3H, d, J = 7.32 Hz). 13C NMR (100 MHz,
CDCl3) d: 220.5, 138.4, 128.2, 127.4, 127.4, 127.3, 76.1,
69.8, 50.1, 48.8, 45.0, 33.6, 33.3, 26.1, 20.0, 16.1. MS m/z:
258 (M+), 91 (100%). HRMS Calcd for C17H22O2:
258.1620. Found: 258.1614.
4.21. (1R,4S,5S,6S)-6-Allyl-4,6-dimethyl-bicyclo[3.2.1]-
octane-2,7-dione (ꢀ)-17
A mixture of alcohol 16 (49 mg, 0.24 mmol), PCC (101 mg,
0.47 mmol), and silica gel (49 mg) in CH2Cl2 (1.12 mL) was
stirred for 2 h. The mixture was diluted with Et2O and fil-
tered through a Celite pad. The filtrate was evaporated to
leave a crude product, which was chromatographed on sil-
4.19. (1S,2S,4S,5R,7S)-7-Allyl-4-benzyloxy-2,7-dimethyl
bicyclo[3.2.1]octan-6-one (+)-15
ica gel (eluent: EtOAc/hexane, 1/10) to give 17 (colorless
31
oil; yield: 48 mg, 23.8 mmol, 99%). ½aꢁD ¼ ꢀ201:5 (c 0.8
CHCl3). IR mmax (neat) cmꢀ1: 1743, 1711. 1H NMR
(400 MHz, CDCl3) d: 5.82–5.71 (1H, m), 5.17 (1H, dt,
J = 10.25, 0.98 Hz), 5.11 (1H, ddd, J = 16.83, 3.05,
1.46 Hz), 3.25 (1H, dt, J = 5.12, 1.46 Hz), 2.45–2.34 (3H,
m), 2.26 (1H, dd, J = 14.15, 8.29 Hz), 2.22–2.12 (2H, m),
1.55 (2H, s), 1.22 (3H, s), 1.16 (3H, d, J = 7.07 Hz). MS
m/z: 206 (M+). HRMS Calcd for C13H18O2: 206.1307.
Found: 206.1279.
To a stirred solution of ketone (+)-14 (272 mg, 1.05 mmol)
in dry THF (5.3 mL) was added t-BuOK (177 mg,
1.58 mmol) at rt. After 30 min, to the mixture was added
3-bromopropene (0.2 mL, 2.1 mmol), and the mixture
was stirred for 5 min. The mixture was diluted with Et2O
and saturated aqueous NH4Cl was added to the mixture.
The mixture was extracted with Et2O, and the organic
extract was washed with brine, dried (MgSO4), and evapo-
rated to leave a crude product, which was chromato-
graphed on silica gel (eluent: EtOAc/hexane, 1/10) to
4.22. (S)-Methyl 3-{(1S,2S)-2-allyl-2-methyl-3-oxo-cyclo-
pentyl}butanoate (ꢀ)-18
give 15 (colorless oil; yield: 258 mg, 0.90 mmol, 86%).
26
½aꢁD ¼ þ74:5 (c 0.7 CHCl3). IR mmax (neat) cmꢀ1: 1734.
To a solution of diketone (ꢀ)-17 (48 mg, 0.23 mmol) in
MeOH (1.17 mL) was added NaOMe (15 mg, 0.28 mmol)
at ꢀ20 °C. After stirring for 10 min, the mixture was di-
luted with Et2O, and saturated aqueous NH4Cl was added
to the mixture. The mixture was extracted with Et2O, and
the organic extract was washed with brine, dried (MgSO4),
1H NMR (400 MHz, CDCl3) d: 7.38–7.22 (5H, m), 5.75
(1H, m), 5.11 (1H, d, J = 8.54 Hz), 5.05 (1H, dd,
J = 16.83, 1.46 Hz), 3.71 (1H, ddd, J = 11.71, 6.10,
3.42 Hz), 2.80–2.75 (1H, m), 2.19 (2H, dd, J = 14.15,
8.05 Hz), 2.14–2.20 (2H, m), 1.93 (2H, br s), 1.77 (1H,

184
S. Ito et al. / Tetrahedron: Asymmetry 19 (2008) 176–185
and evaporated to leave a crude product, which was chro-
matographed on silica gel (eluent: EtOAc/hexane, 1/6) to
4.25. (S)-3-{(1S,2S,3RS)-2-Allyl-3-benzyloxy-2-methyl-
cyclopentyl}-N-methoxy-N-methylbutanamide 21
give 18 (colorless oil; yield: 47 mg, 0.20 mmol, 85%).
31
½aꢁD ¼ ꢀ101:5 (c 1.3 CHCl3). IR mmax (neat) cmꢀ1: 3424,
To a stirred solution of MeNHOMeHCl (0.64 mg,
1
1735. H NMR (400 MHz, CDCl3) d: 5.62–5.46 (1H, m),
0.66 mmol) in dry CH2Cl2 (0.55 mL) was added AlMe3
(1.0 M in n-hexane, 0.66 mL, 0.66 mmol) at ꢀ15 °C. After
30 min, ester 20 (33 mg, 0.11 mmol) in dry CH2Cl2 (1 mL)
was added to the mixture at 0 °C and stirred for 3 h. The
mixture was diluted with Et2O, and H2O was added to
the mixture. The mixture was extracted with EtOAc, and
the organic extract was washed with brine, dried (MgSO4),
and evaporated to leave a crude product, which was chro-
matographed on silica gel (eluent: EtOAc/hexane, 1/4) to
give 21 (colorless oil; yield: 22 mg, 0.074 mmol, 67%). IR
5.05 (1H, d, J = 10.98 Hz), 5.01 (1H, d, J = 18.79 Hz),
3.69 (3H, s), 2.57 (1H, dd, J = 14.03, 5.98 Hz), 2.51 (1H,
dd, J = 19.27, 8.29 Hz), 2.43–2.32 (1H, m), 2.19 (1H, dd,
J = 14.03, 9.15 Hz), 2.15–1.94 (5H, m), 1.54–1.42 (1H,
m), 1.07 (3H, d, J = 6.10 Hz), 0.96 (3H, s). MS m/z: 238
(M+). HRMS Calcd for C14H22O3: 238.1569. Found:
238.1568.
4.23. (S)-Methyl 3-{(1S,2S,3RS)-2-allyl-3-hydroxy-2-meth-
ylcyclopentyl}butanoate 19
1
mmax (neat) cmꢀ1: 1660. H NMR (400 MHz, CDCl3) d:
7.37–7.22 (5H, m), 5.90–5.75 (1H, m), 5.06–4.99 (2H, m),
4.68 (1H, s), 4.53 (1H, t, J = 12.08 Hz), 4.39 (0.39H, d,
J = 11.95 Hz), 4.29 (0.61H, d, J = 11.71 Hz), 3.64 (3H, s),
3.54 (0.39H, t, J = 7.82 Hz), 3.43 (0.61H, d, J = 2.68 Hz),
3.17 (3H, s), 2.60–2.52 (1H, m), 2.50–2.06 (5H, m), 2.01–
1.64 (5H, m), 1.54–1.38 (2H, m), 1.01 (1.21H, d,
J = 7.07 Hz), 0.99 (1.79H, d, J = 6.83 Hz), 0.91 (1.21H,
s), 0.81(1.79H, s). MS m/z: 359 (M+), 91 (100%). HRMS
Calcd for C22H33NO3: 359.2460. Found: 359.2447.
To a solution of 18 (306 mg, 1.29 mmol) in MeOH
(6.45 mL) was added NaBH4 (37 mg, 0.97 mmol) at
ꢀ78 °C, and the mixture was stirred for 3 h at the same
temperature. Then, the mixture was diluted with Et2O
and acetone was added to the mixture. The mixture was ex-
tracted with Et2O, and the organic extract was washed with
brine, dried (MgSO4), and evaporated to leave a crude
product, which was chromatographed on silica gel (eluent:
EtOAc/hexane, 1/4) to give 19 (colorless oil; yield: 297 mg,
1.25 mmol, 97%).
4.26. (S)-4-{(1S,2S,3RS)-2-Allyl-3-benzyloxy-2-methyl-
cyclopentyl}pentan-2-one 22
IR mmax (neat) cmꢀ1: 3514, 1722. 1H NMR (400 MHz,
CDCl3) d: 6.04–5.88 (1H, m), 5.12 (1H, t, J = 6.95 Hz),
5.06 (1H, d, J = 10.00 Hz), 3.84 (0.36H, t, J = 8.54 Hz),
3.77 (0.6H, d, J = 5.12 Hz), 3.67 (3H, s), 2.50–2.28 (1.5H,
m), 2.12–1.86 (5H, m), 1.80–1.65 (1.5H, m), 1.55–1.23
(3H, m), 1.02 (3H, t, J = 6.83 Hz), 0.85 (3H, d, J =
7.81 Hz). MS m/z: 222 (M+–H2O), 107 (100%). HRMS
Calcd for C14H24O3: 222.1620. Found: 222.1606.
To a solution of amide 21 (22 mg, 0.06 mmol) in THF
(1 mL) was added MeLi (0.99 M in Et2O, 0.14 mL,
0.15 mmol) at ꢀ78 °C. After stirring for 1 h, the mixture
was diluted with Et2O and saturated aqueous NaHCO3
was added to the mixture. The mixture was extracted with
Et2O, and the organic extract was washed with brine, dried
(MgSO4), and evaporated to leave a crude product, which
was chromatographed on silica gel (eluent: EtOAc/hexane,
1/10) to give 22 (colorless oil; yield: 16 mg, 0.051 mmol,
85%). IR mmax (neat) cmꢀ1: 1712. 1H NMR (400 MHz,
CDCl3) d: 7.35–7.22 (5H, m), 5.88–5.72 (1H, m), 5.06–
4.88 (2H, m), 4.53 (1H, t, J = 12.20 Hz), 4.39 (0.40H, d,
J = 11.95 Hz), 4.30 (0.60H, d, J = 11.71 Hz), 3.53 (0.4H,
t, J = 8.17), 3.43 (0.60H, dd, J = 4.39, 1.95 Hz), 2.58–
2.49 (1H, m), 2.47 (0.6H, d, J = 2.45 Hz), 2.32 (0.4H, dd,
J = 7.81 14.15 Hz), 2.24–2.04 (3H, m), 2.12 (1.2H, s),
2.11 (1.8H, s), 1.99–1.20 (6H, m), 0.96 (1.20H, d,
J = 4.64 Hz), 0.95 (1.80H, d, J = 6.34 Hz), 0.90 (1.20H,
s), 0.80(1.80H, s). MS m/z: 314 (M+), 91 (100%). HRMS
Calcd for C21H30O2: 314.2246. Found: 314.2240.
4.24. (S)-Methyl 3-{(1S,2S,3RS)-2-allyl-3-benzyloxy-2-
methylcyclopentyl}butanoate 20
To a stirred solution of 19 (13 mg, 0.054 mmol) in dry THF
(0.27 mL) was added sodium hydride (4.32 mg, 0.1 mmol)
at 0 °C. After 30 min, benzyl bromide (0.01 mL, 0.12
mmol) and tetrabutyl ammonium iodide (2 mg,
0.005 mmol) were added to the mixture at 0 °C. The mix-
ture was heated at reflux overnight. After cooling to rt,
the mixture was diluted with Et2O, and H2O was added
to the mixture. The mixture was extracted with EtOAc,
and the organic extract was washed with brine, dried
(MgSO4), and evaporated to leave a crude product, which
was chromatographed on silica gel (eluent: EtOAc/hexane,
1/10) to give 20 (colorless oil; yield: 11 mg, 0.033 mmol, 61
%). IR mmax (neat) cmꢀ1: 1734. 1H NMR (400 MHz,
CDCl3) d: 7.37–7.23 (5H, m), 5.87–5.74 (1H, m), 4.54
(1H, t, J = 12.69 Hz), 4.39 (0.41H, d, J = 11.95 Hz), 4.39
(0.59H, d, J = 11.71 Hz), 3.66 (3H, s), 3.54 (0.41H, t,
J = 8.12 Hz), 3.43 (0.59H, q, J = 2.20 Hz), 2.55 (0.59H,
dd, J = 13.66, 6.34 Hz), 2.45 (1H, dd, J = 19.64,
8.29 Hz), 2.34 (0.41H, dd, J = 14.15, 7.81 Hz), 2.23–1.24
(10H, m), 1.01 (3H, dd, J = 7.81, 6.34 Hz), 0.94 (1.23H,
s), 0.84 (1.77H, s). MS m/z: 330 (M+), 91 (100%). HRMS
Calcd for C21H30O3: 330.2195. Found: 330.2186.
4.27. (1S,5S)-1-Allyl-2-methoxy-1-methyl-5-{(S)-4-(2,3,3-
trimethylbutan-2-yloxy)pent-4-en-2-yl}cyclopentane 23
To a stirred solution of 22 (15 mg, 0.048 mmol) in dry
MeCN (0.24 mL) were added Et3N (40 lL, 0.28 mmol)
and TBSOTf (40 lL, 0.19 mmol) at rt. After 10 min, the
mixture was diluted with Et2O, and saturated aqueous
NH4Cl was added to the mixture at 0 °C. The mixture
was extracted with Et2O, and the organic extract was
washed with brine, dried (MgSO4), and evaporated to leave
a crude product, which was chromatographed on silica gel
(eluent: hexane) to give 23 (colorless oil; yield: 20 mg,
0.048 mmol, quant.). 1H NMR (400 MHz, CDCl3) d:

S. Ito et al. / Tetrahedron: Asymmetry 19 (2008) 176–185
185
Chem. Commun. 2001, 1094; (c) Hanada, K.; Miyazawa, N.;
Ogasawara, K. Org. Lett. 2002, 4, 4515.
7.19–7.12 (5H, m), 5.72–5.57 (1H, m), 4.88–4.70 (2H, m),
4.38 (1H, d, J = 11.46 Hz), 4.23 (0.60H, d, J = 11.95 Hz),
4.13 (0.40H, d, J = 11.71 Hz), 3.86 (1.2H, s), 3.81 (0.80H,
s), 3.37 (0.4H, t, J = 8.29 Hz), 3.26 (0.6H, d,
J = 5.00 Hz), 2.37 (0.4H, dd, J = 12.69, 5.61 Hz), 2.19
(0.6H, dd, J = 13.91, 8.05 Hz), 1.98 (0.6H, dd, J = 14.15,
6.83 Hz), 2.15–1.03 (7H, m), 0.85–0.60 (15H, m), 0.17
(6H, d, J = 2.44 Hz). MS m/z: 428 (M+), 199 (100%).
HRMS Calcd for C27H44OSi: 428.3111. Found: 428.3097.
4. (a) Hanada, K.; Miyazawa, N.; Nagata, H.; Ogasawara, K.
Synlett 2002, 125; (b) Miyazawa, N.; Tosaka, A.; Hanada,
K.; Ogasawara, K. Heterocycles 2003, 59, 491; (c) Hanada,
K.; Miyazawa, N.; Ogasawara, K. Chem. Pharm. Bull. 2003,
51, 104; (d) Miyazawa, N.; Ogasawara, K. Tetrahedron Lett.
2002, 43, 4773; (e) Tosaka, A.; Ito, S.; Miyazawa, N.;
Shibuya, M.; Ogasawara, K.; Iwabuchi, Y. Heterocycles
2006, 70, 153.
5. Hawkins, R. T.; Hsu, R. S.; Wood, S. G. J. Org. Chem. 1978,
43, 4648.
6. Reviews: (a) List, B. Acc. Chem. Res. 2004, 37, 548; (b) Saito,
S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570; (c) Notz,
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7. Hansch, C. Comprehensive Medicinal Chemistry: The
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8. (a) Scotti, M. T.; Fernandes, M. B.; Ferreira, M. J. P.;
Emerenciano, V. P. Bioorg. Med. Chem. 2007, 15, 2927; (b)
Siedel, B.; Garcia-Pineres, A. J.; Murillo, R.; Schulte-Mo¨n-
4.28. (1RS,3aS,8aS,4S)-1-Benzyloxy-4,8a-dimethyl-6-tert-
butyl-dimethylsilyloxy-1,2,3,3a,4,5,8,8a-octahydroazulen 24
To a stirred solution of 23 (23 mg, 0.054 mmol) in benzene
(5.37 mL) was added second generation Grubbs’s catalyst
(4.5 mg, 0.005 mmol) at rt. After 20 h, the solvent was
evaporated to leave a crude product, which was chromato-
graphed on silica gel (eluent: hexane) to give 24 (colorless
oil; yield: 13 mg, 0.033 mmol, 61%). MS m/z: 400 (M+),
185 (100%). HRMS Calcd for C25H40O2Si: 400.2797.
Found: 400.2811.
ting, J.; Castro, V.; Rungeler, P.; Klaas, C. A.; Da Costa, F.
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B.; Kisiel, W.; Merfort, I. J. Med. Chem. 2004, 47, 6042.
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8016.
10. Itagaki, N.; Kimura, M.; Sugahara, T.; Iwabuchi, Y. Org.
Lett. 2005, 7, 4185.
4.29. (1RS,3S,4S,8aS)-1-Benzyloxy-4,8a-dimethyl-
octahydroazulen-6-one 26
11. (a) Nagata, H.; Miyazawa, N.; Ogasawara, K. Synthesis
2000, 2013; (b) Nagata, H.; Kawamura, M.; Ogasawara, K.
Synthesis 2000, 1825; (c) Taniguchi, T.; Takeuchi, M.;
Kadota, K.; ElAzab, A. S.; Ogasawara, K. Synthesis 1999,
1325.
12. (a) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem.
Soc. 2000, 122, 7595; (b) Nicolaou, K. C.; Montagnon, T.;
Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc. 2002, 124, 2245.
13. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am.
Chem. Soc. 1982, 104, 7294.
14. (a) Heathcock, C. H.; DelMar, E. G.; Graham, S. L. J. Am.
Chem. Soc. 1982, 104, 1907; (b) Welch, M. C.; Bryson, T. A.
Tetrahedron Lett. 1988, 29, 521; (c) Quinkert, G.; Schmalz, H.
G.; Walzer, E.; Kowalczyk-Przewloka, T.; Durner, G. J.;
Bats, W. Angew. Chem., Int. Ed. Engl. 1987, 26, 61; (d)
Money, T.; Wong, M. K. C. Tetrahedron 1996, 52, 6307; (e)
Ohtsuka, M.; Takekawa, Y.; Shishido, K. Tetrahedron Lett.
1998, 39, 5803.
To a stirred solution of 24 (13 mg, 0.03 mmol) in dry THF
(0.163 mL) was added TBAF (1.0 M in THF, 0.05 mL,
0.05 mmol) at rt. After 3 h, the solvent was evaporated un-
der reduced pressure to leave a crude product, which was
chromatographed on silica gel (eluent: hexane) to give 26
as a colorless oil; yield: 3 mg, 9.6 lmol (32%). IR mmax
1
(neat) cmꢀ1: 1695. H NMR (300 MHz, CDCl3) d: 7.52–
7.25 (5H, m), 4.61 (0.6H, d, J = 9.61 Hz), 4.53 (0.4H, d,
J = 12.91 Hz), 4.42 (0.6H, d, J = 11.26 Hz), 4.32 (0.40H,
d, J = 12.36 Hz), 3.36 (0.40H, d, J = 7.97 Hz), 3.30
(0.60H, d, J = 5.31 Hz), 2.82 (0.6H, t, J = 11.26 Hz),
2.62–1.86 (5.4H, m), 1.82–1.44 (6H, m), 0.95 (3H, d,
J = 7.42 Hz), 0.80 (1.8H, s), 0.73 (1.2H, s). MS m/z: 286
(M+), 91 (100%). HRMS Calcd for C19H26O2: 286.1933.
Found: 286.1903.
15. (a) Romo, J.; Romo de Vivar, A.; Velez, A.; Urbina, E. Can.
J. Chem. 1968, 46, 1535; (b) Kupchan, S. M.; Eakin, M. A.;
Thomas, A. M. J. Med. Chem. 1971, 14, 1147.
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¨