An efficient route for the synthesis of methyl (-)-1,4a-dimethyl-5-oxodecahydronaphthalene-1-carboxylate by using baker's yeast-catalyzed asymmetric reduction

Article abstract of DOI:10.1016/j.tetasy.2006.06.015

Methyl (-)-1,4a-dimethyl-5-oxodecahydronaphthalene-1-carboxylate 1, a key synthetic intermediate for the synthesis of terpenoids, was efficiently synthesized by using a baker's yeast-catalyzed asymmetric reduction of a σ-symmetrical 1,3-cyclohexanedione d

Full text of DOI:10.1016/j.tetasy.2006.06.015

Tetrahedron: Asymmetry 17 (2006) 1655–1662
An efficient route for the synthesis of methyl (ꢀ)-1,4a-
dimethyl-5-oxodecahydronaphthalene-1-carboxylate by using
baker’s yeast-catalyzed asymmetric reduction
Takahiro Katoh, Shinsuke Mizumoto, Masato Fudesaka, Masatoshi Takeo,
Tetsuya Kajimoto and Manabu Node*
Department of Pharmaceutical Manufacturing Chemistry, 21st Century COE program, Kyoto Pharmaceutical University,
1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan
Received 18 April 2006; accepted 8 June 2006
Abstract—Methyl (ꢀ)-1,4a-dimethyl-5-oxodecahydronaphthalene-1-carboxylate 1, a key synthetic intermediate for the synthesis of terp-
enoids, was efficiently synthesized by using a baker’s yeast-catalyzed asymmetric reduction of a r-symmetrical 1,3-cyclohexanedione
derivative.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
R1
O
R2
O
Methyl (ꢀ)-1,4a-dimethyl-5-oxo-trans-decaline-1-carboxyl-
ate 1 is a key intermediate in the synthesis of many biologi-
cally active terpenoids. For example, acanthoic acid and its
derivatives were recently synthesized via (ꢀ)-1 as anti-
inflammatory agents.1 Moreover, the isolation and structure
elucidation of many bioactive diterpenes bearing (ꢀ)-1 as a
partial structure, such as globostearic acids2 and 15-meth-
oxyfasciculatins,3 have been reported to date. Methyl ester
(ꢀ)-1 has often been synthesized from Wieland–Miescher
ketone 2 that was prepared by a L-proline-catalyzed Robin-
son annelation;4 however, the enantiomeric excess of 2 pre-
pared in this method was not higher than 70% ee. Many
methods to synthesize enantiomerically pure 4a-methyl-5-
oxooctahydronaphthalene-1-carboxylate 3 were reported
to date as a part of an alternative synthetic route (Fig. 1).
For example, Theodorakis developed a novel Robinson
annelation, which was initiated by the Michael addition of
3-oxopenten-5-amide having a chiral auxiliary on the amide
group to afford two separable diastereomers, and the chiral
auxiliary of each diastereomer was successively cleaved to
afford enantiomerically pure 3.5 Tanaka et al. adopted an
intramolecular Horner–Wadsworth–Emmons reaction,
O
H
CO2Me
CO2Me
2a: R1 = R2 = O
(+)-3
(-)-1
2b: R1 = OH,
R2 = H
Figure 1. Structure of Wieland–Miescher ketone and related compounds.
where (S)-BINAP formed a phosphonate ester as a sponta-
neously removable chiral auxiliary, in the formation of the
double bond between C-1 and C-8a to afford (+)-3.6
Meanwhile, Sugai et al. established a new method to syn-
thesize derivative 2b of Wieland–Miescher ketone 2a in
good overall yield with excellent ee by using the microor-
ganism-catalyzed asymmetric reduction of r-symmetrical
1,3-cyclohexanedione.7 Although 2a and 2b have been em-
ployed as good intermediates in the synthesis of steroids,
methyl esters 3 and 1 were more direct intermediates in
the synthesis of terpenoids as mentioned above. Moreover,
asymmetric reductions of r-symmetrical cyclic 1,3-dike-
tones with baker’s yeast have been developed to construct
chiral building blocks for the synthesis of bioactive natural
compounds.8,9
*
Corresponding author. Tel.: +81 755954639; fax: +81 755954775;
e-mail: node@mb.kyoto-phu.ac.jp
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.06.015

1656
T. Katoh et al. / Tetrahedron: Asymmetry 17 (2006) 1655–1662
On the basis of our recently reported asymmetric reduction
of r-symmetrical cyclic-1,3-diketone using baker’s yeast-
catalyzed reaction as a practical method in organic synthe-
sis,10 we initiated a study on synthesis of enantiomerically
pure (ꢀ)-1 and (+)-3 by using the biocatalyst. Herein, we
would like to report our recent results obtained in this
study.
the reaction medium to increase the chemical yield (Table
1, entries 4, 5, 8, and 9). After trying several reactions by
changing the total amount of the yeast, we chose condi-
tions where 3.0 g of the yeast per 1 mmol of the substrate
was added twice with an interval of 24 h (Table 1, entry
5) in preference to that shown in entry 8 (Table 1) as the
best conditions for further synthetic study because of the
facility of the work-up procedure. In addition, the reaction
with a lower substrate concentration (Table 1, entry 6) pro-
vided 6a and 6b in higher yield while adding sucrose into
the reaction medium was more effective (Table 1, entry
7). As a conclusion up to this point, we succeed in estab-
lishing a practical method for the reduction of r-symmet-
rical 1,3-cyclohexanedione 5 into hydroxyketone 6a in
good chemical yield (74–85%) with high diastereoselectivity
(82–90% de) and high enantioselectivity (>99% ee) (Table
1, entries 7 and 8).
2. Results and discussion
Our strategy for the synthesis of a,b-unsaturated methyl
ester 3 was based on the asymmetric reduction of r-symmet-
rical methyl 5-(2-methyl-1,3-dioxocyclohexyl)-2-pentenoate
5 with baker’s yeast and successive annelation that should be
attained between the a,b-unsaturated ester and ketone. In
the beginning, the substrate 5 was synthesized by the
Michael addition of the carbanion generated from
2-methyl-1,3-cyclohexanedione 4 to acrolein, followed by
Wittig reaction (Scheme 1).
We derivatized the reduced product 6a to spiroketal 7, of
which the two isomers among four possible ones were
prepared by Brooks,9 in order to determine the stereochem-
istry of two contiguous stereogenic centers. The transfor-
mation of 6a started with the acetylation of the
secondary hydroxyl group, followed by the acetalization
of the carbonyl group with ethylene glycol in the presence
of 2-ethyl-2-methyl-1,3-dioxolane and p-toleuenesulfonic
Next, three types of baker’s yeast were tested and it was
found that only the reaction with the yeast purchased as
type II from Sigma gave the reduced products 6a and 6b
albeit in low yield (27%) (Table 1, entry 3). Thus, an
additional amount of yeast (Sigma type II) was added to
O
HO
baker's
CO2Me
yeast
CO2Me
3
O
O
5
O
O
O
CHO
a
b
5
O
4
Scheme 1. Synthetic strategy for the synthesis of 3 and preparation of 5. Reagents: (a) acrolein; (b) Ph3P@CHCO2Me.
Table 1. Baker’s yeast-catalyzed asymmetric reduction of 5
O
O
Baker's yeast
H2O- DMSO
CO2Me
CO2Me
5
+
(40 mM)
OH
OH
6b
6a
Entry
Baker’s yeast
Time (h)
Yield (%)
de (%)
ee of 6a (%)
1
2
3
4
Oriental Co. Ltd (3.0 g/mmol)
Sigma type I (3.0 g/mmol)
24
72
48
72
24 · 2
24 · 2
24 · 2
24 · 2
24 · 2
3
0
—
—
80
80
88
86
82
90
88
—
—
Sigma type II (3.0 g/mmol)
Sigma type II (5.0 g/mmol)
Sigma type II (3.0 g/mmol · 2)
Sigma type II (3.0 g/mmol · 2)
Sigma type II (3.0 g/mmol · 2)
Sigma type II (6.0 g/mmol · 2)
Sigma type II (9.0 g/mmol · 2)
27
36
67
72
85
74
60
>99
>99
>99
>99
>99
>99
>99
5
6a
7b
8
9
a Substrate concentration was 8 mM.
b In the presence of sucrose.

T. Katoh et al. / Tetrahedron: Asymmetry 17 (2006) 1655–1662
1657
acid to afford 8. Acetal 8 was ozonolyzed and worked up
with sodium borohydride to give primary alcohol 9. The
primary hydroxyl group of 9 was again acetylated by a con-
ventional method to yield 7 (Scheme 2).
Since the major product 6a of the baker’s yeast-catalyzed
asymmetric reduction had the desired configuration on
the C-2 positions, the annelation reaction between the
ketone and a,b-unsaturated ester groups was attempted
after the protection of the hydroxyl group with a methoxy-
methyl group to derive 11. The optimal reaction involved
the Michael addition of the hydride to the a,b-unsaturated
ester, followed by the addition of the resulting ester enolate
to the ketone group on the cyclohexane ring. Although many
cuprous hydrides prepared in diverse methods were re-
ported for this type of reaction, only the reagents prepared
from cuprous iodide, methyl lithium and DIBAL gave the
annelated product as a mixture of trans- and cis-isomers
12a and 12b. While the dehydration of 12a with thionyl
chloride afforded 13a, the same treatment of 12b afforded
13b. Unfortunately, migration of the double bond to trans-
form 13b into 13a proceeded in only low yield by treatment
with DBU in refluxing toluene. Deprotection of the meth-
oxymethyl group of 13a and oxidation of the alcohol 14
obtained gave (+)-3 in good overall yield (overall 64% in
two steps).
However, it was very difficult to determine the stereochem-
istry of 7 synthesized in this way on the basis of the 1H and
13C NMR spectroscopic data for (2R,3S)-7 and (2S,3S)-7
in the literature,9 because both of our two diastereomers
gave quite similar spectra, and unexpectedly, the coupling
constants of the proton signals at d 4.91 and 4.89 ppm in
the reported spectra did not coincide with our data (Table
2). Therefore, the stereochemistry of product 6a was inde-
pendently determined to have (2R,3S)-configuration by
means of X-ray crystallography after derivatizing to a p-
bromobenzoate 10 (Fig. 2).
AcO
AcO
CO2Me
a, b
c
OR
O
6a
O
78%
60%
O
O
Meanwhile, in order to introduce a methyl group at the C-1
position of 13a, the a,b-unsaturated ester on the A-ring
was reduced under the conditions of a Birch reduction to
generate the ester enolate, which was reacted further with
methyl iodide to afford 15. Finally, the methoxymethyl
group of 15 was deprotected with 6 M hydrochloric acid
to generate 16 and its hydroxyl group oxidized by Jones
8
9: R = H
7: R = Ac
a
Scheme 2. Transformation to 6a to the known derivative 7. Reagents: (a)
Ac2O, py; (b) HO(CH2)2OH, 2-methyl-2-ethyl-1,3-dioxolane, p-TsOH; (c)
O3, then NaBH4.
Table 2. Comparison of spectral data of (2R,3S)-7, (2S,3S)-7, and our synthetic 7
AcO AcO
AcO
OR
OR
OR
O
O
O
O
O
O
synthesized-7
(2R,3S)-7
(2S,3S)-7
[a]D
+23.7 (CHCl3)
1.06 (s, 3H)
+27.9 (CHCl3)
1.05 (s, 3H)
+18.5 (CHCl3)
0.92 (s, 3H)
1H NMR
1.40–1.81 (m, 10H)
2.03 (s, 3H),
1.4–1.8 (m, 10H)
2.03 (s, 6H)
1.5–1.7 (m, 10H)
2.04 (s, 6H)
2.04 (s, 3H)
3.91–3.98 (m, 4H)
3.96 (t, J = 6.7 Hz, 2H)
4.91 (dd, J = 10.5, 4.9 Hz, 1H)
3.92 (m, 6H)
3.90 (m, 4H)
4.02 (t, J = 7.0 Hz, 2H)
4.91 (dd, J = 4.0, 4.0 Hz, 1H)
4.89 (dd, J = 5.0, 3.0 Hz, 1H)
13C NMR
15.2
19.0
21.0
21.3
24.4
26.2
29.8
30.0
45.0
64.3
64.6
65.6
76.5
113.1
170.4
171.2
15.3
19.0
21.0
21.3
24.4
26.3
29.9
30.0
45.0
64.3
65.0
66.7
76.2
113.1
170.5
171.2
16.2
19.1
21.1
21.3
23.8
25.9
27.2
29.7
45.5
64.6
65.2
65.7
77.5
112.6
170.5
171.2

1658
T. Katoh et al. / Tetrahedron: Asymmetry 17 (2006) 1655–1662
O
p-BrBzCl
OH
O
Et N
DMAP,
3
MeO2C
MeO2C
(S)
Br
(R)
CH2Cl2
90 %
O
O
6a
10
Figure 2. Determination of stereochemistry of 6a by conversion to 10.11
OR
OMOM
OMOM
6a
g
e
c
(-)-1
94 %
75 %
97 %
H
a
OH
(2 steps)
95 %
CO2Me
13a
CO2Me
CO2Me
(51%)
12a
15: R = MOM
16: R = H
OMOM
f
b
f
d
37%
+
87 %
O
MeO2C
OH
OMOM
OMOM
g
11
c
(+)-3
74 %
93 %
OH
CO2Me
CO2Me
CO2Me
14
13b
12b (20%)
Scheme 3. Synthetic route of (ꢀ)-1 and (+)-3 from 6a. Reagents: (a) MOMCl, i-Pr2NEt, THF; (b) CuI, MeLi, DIBAL, THF–HMPA; (c) SOCl2, py; (d)
DBU; (e) Li, liq. NH3, then MeI; (f) 6 M HCl; (g) Jones reagent.
oxidation to afford (ꢀ)-1. All the spectral and physical data
of (ꢀ)-1 obtained completely coincided with those in the
literature9 (Scheme 3).
NMR spectra were obtained on a JEOL JNM-AL300, or a
Varian Unity INOVA-400 spectrometer with tetramethyl-
silane as an internal standard. 13C NMR spectra were
obtained on a Varian Unity INOVA-400 or a Varian
GEMINI 2000/200 spectrometer with CDCl3 as an internal
standard. Mass spectra (MS) were determined on a JEOL
JMS-SX 102A QQ or a JEOL JMS-GC-mate mass spec-
trometer. Specific rotations were recorded on a Horiba
SEPA-200 automatic digital polarimeter. Chiral HPLC
analyses were performed with a Shimadzu LC-10A Liquid
Chromatograph series using a Daicel chiral column (CHI-
RALCEL OJ or CHIRALPAK AS). Their data were
recorded on Shimadzu C-R6A Chromatopac. Wakogel
C-200 (silica gel) (100–200 mesh, Wako) was used for open
column chromatography. Flash column chromatography
was performed by using Silica Gel 60N (Kanto Chemical
Co., Inc.) as a solid support of an immobile phase. Kiesel-
gel 60 F-254 plates (0.25 mm, Merck) were used for thin
layer chromatography (TLC). Unless purification with sil-
ica gel gave compounds pure enough, the compounds were
treated further with a recycle HPLC (JAI LC-908) on GPC
column (JAIGEL 1H and 2H). Diastereomeric mixtures
were also separated by a recycle HPLC (JAI LC-908) on
silica gel column (Kusano Si-10) after the purification
mentioned above.
3. Conclusion
In conclusion, we have established an effective synthetic
route to (ꢀ)-1 and (+)-3, which are key intermediates in
the synthesis of bioactive terpenoids, by using a baker’s
yeast-catalyzed asymmetric reduction of a r-symmetrical
1,3-cyclohexanedione. Our method required only eight
and/or nine steps in order to synthesize (ꢀ)-1 and (+)-3
from commercially available 2-methylcyclohexa-1,3-dione
4, with the overall yields proving satisfactory (30% and
27%, respectively). Moreover, since the key reaction, the
baker’s yeast-catalyzed reduction of 5, was attained in an
aqueous medium and at room temperature, it can be easily
scaled up to afford large amounts of the enantiomerically
pure intermediates for the synthesis of many bioactive nat-
ural products. The synthesis of bicyclic diterpenes, which
showed potent anti-tumor activities, from (ꢀ)-1 is currently
in progress, and will be published elsewhere.10
4. Experimental
4.1. General
4.2. 3-(2-Methyl-1,3-dioxocyclohexyl)propionaldehyde 4
Acrolein (2.4 ml, 31.9 mmol) and distilled water (20 ml)
were added to a suspension of 2-methyl-1,3-cyclohexane-
dione (2.01 g, 15.9 mmol) in tetrahydrofuran (20 ml), and
Infrared (IR) spectra were recorded on a Shimadzu FTIR-
8300 diffraction grating infrared spectrophotometer and 1H

T. Katoh et al. / Tetrahedron: Asymmetry 17 (2006) 1655–1662
1659
the mixture stirred for 21 h at room temperature. After the
reaction, the reaction mixture was extracted with ethyl ace-
tate. The organic layer was washed with saturated aqueous
solution of sodium chloride, dried over magnesium sulfate,
and evaporated. The residue was purified by silica gel col-
umn chromatography (hexane–ethyl acetate = 2:1) to
through Hyflo-Super-Celꢂ, which was washed with ethyl
acetate (200 ml). The organic layer was washed with satu-
rated aqueous solution of sodium chloride, dried over mag-
nesium sulfate, and condensed in vacuo. The residue was
purified by silica gel column chromatography (hexane–
ethyl acetate = 1:1) to afford a mixture of diastereomers
6a and 6b (86 mg, 85%, 6a:6b = 91:9) as a colorless oil.
1
afford 4 (2.69 g, 93%) as a colorless oil. Compound 4; H
NMR (300 MHz, CDCl3): d 1.30 (s, 3H), 1.92–2.02 (m,
2H), 2.09–2.14 (m, 2H), 2.33–2.38 (m, 2H), 2.63–2.74 (m,
4H), 9.69 (t, J = 1.1 Hz, 1H); IR (CHCl3): 3028, 2966,
2939, 2361, 1724, 1697, 1458 cmꢀ1; MS (70 eV) m/z: 182
(M+, 28), 164 (4), 154 (17), 126 (78), 111 (37), 98 (59), 83
(21), 69 (59), 55 (100); HRMS calcd for C10H14O3 (M+):
182.0943, found: 182.0932.
20
1
Compound 6a; ½aꢁD ¼ ꢀ19:2 (c 1.06, CHCl3); H NMR
(300 MHz, CDCl3): d 1.14 (s, 3H), 1.64–2.44 (m, 11H),
3.72 (s, 3H), 3.84–3.88 (m, 1H), 5.83 (dt, J = 15.4 and
1.6 Hz, 1H), 6.95 (dt, J = 15.4 and 6.8 Hz, 1H); 13C
NMR (50 MHz, CDCl3): d 17.5, 20.5, 27.0, 28.7, 33.7,
37.7, 51.5, 54.2, 75.3, 121.0, 148.7, 166.9, 213.3; IR
(CHCl3): 2950, 1709, 1659, 1439, 1327, 1281, 1177, 1045,
961 cmꢀ1; MS (70 eV) m/z: 240 (M+, 1), 222 (2), 208 (5),
191 (10), 141 (27), 128 (91), 100 (100), 87 (71), 68 (52), 55
(52); HRMS calcd for C13H20O4 (M+): 240.1361, found:
240.1355.
4.3. Methyl (E)-5-(2-methyl-1,3-dioxocyclohexyl)-2-pente-
noate 5
A solution of 4 in toluene (5 ml) was added to a suspension
of methyl (triphenylphosphoranylidene)acetate (7.71 g,
23.0 mmol) in toluene (30 ml) at 0 ꢁC, and the mixture stir-
red for 1 h while keeping the temperature same. After the
reaction, the organic solvent was removed in vacuo and
the residue purified by silica gel column chromatography
(hexane–ethyl acetate = 1:1) to afford 5 (3.65 g, 80%) as a
25
1
Compound 6b; ½aꢁD ¼ þ58:2 (c 1.08, CHCl3); H NMR
(400 MHz, CDCl3): d 1.18 (s, 3H), 1.60–1.69 (m, 2H),
1.74–2.06 (m, 6H), 2.13–2.23 (m, 1H), 2.32–2.42 (m, 2H),
3.72 (s, 3H), 3.72–3.76 (br m, 1H), 5.84 (dt, J = 15.7 and
1.6 Hz, 1H), 6.96 (dt, J = 15.7 and 6.7 Hz, 1H); 13C
NMR (100 MHz, CDCl3): d 19.0, 20.6, 26.3, 28.8, 30.0,
37.5, 51.5, 54.1, 77.2, 121.1, 148.9, 167.0, 213.4; IR
(CHCl3): 3614, 3483, 2951, 1707, 1657, 1437, 1281, 1238,
1180, 1061, 1043 cmꢀ1; MS (20 eV) m/z: 240 (M+, 1), 222
(1), 208 (5), 191 (8), 141 (45), 128 (100), 113 (37), 100
(63), 95 (38), 81 (18), 68 (9); HRMS calcd for C13H20O4
(M+): 240.1361, found: 240.1365.
1
colorless oil. Compound 5; H NMR (300 MHz, CDCl3):
d 1.28 (s, 3H), 1.90–2.07 (m, 6H), 2.58–2.75 (m, 4H), 3.72
(s, 3H), 5.80 (dt, J = 15.5 and 1.5 Hz, 1H), 6.86 (dt,
J = 15.5 and 6.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 17.5, 21.3, 27.5, 34.0, 37.9 (2), 51.5, 64.8, 121.5, 147.7,
166.8, 215.3 (2); IR (CHCl3): 3020, 2955, 1693, 1659,
1458, 1439 cmꢀ1; MS (70 eV) m/z: 238 (M+, 2), 207 (6),
139 (26), 126 (20), 113 (100), 98 (32), 81 (43), 69 (49), 55
(38); HRMS calcd for C13H18O4 (M+): 238.1205, found:
238.1200.
4.5. (ꢀ)-(2S,3S)-3-Acetoxy-1,1-ethylenedioxy-2-methyl-2-
(3-acetoxypropyl)cyclohexane 7
4.4. (ꢀ)-Methyl (E)-5-[(2R,3S)-3-hydroxy-2-methyl-1-oxo-
cyclohexyl]-2-pentenoate 6a and methyl (E)-5-[(2S,3S)-3-
hydroxy-2-methyl-1-oxocyclohexyl]-2-pentenoate 6b
Acetic anhydride (3 ml) was added to a solution of 6a
(407 mg, 1.69 mmol) in pyridine (3 ml) and the mixture
stirred for 2 h at room temperature. After the reaction,
the mixture was quenched by adding methanol and then
condensed in vacuo. The residue was purified by silica gel
column chromatography (hexane–ethyl acetate = 3:1) to
afford the acetate (474 mg, 99%). Next, 2-ethyl-2-methyl-
1,3-dioxolane (4 ml) and p-toluenesulfonic acid (catalytic
amount) were added to a solution of the acetate (450 mg,
1.59 mmol) in ethylene glycol (2 ml), and the reaction mix-
ture then stirred for 12 h at room temperature. After the
reaction, the reaction mixture was poured into a saturated
aqueous solution of sodium bicarbonate and extracted with
ethyl acetate. The organic layer was washed with saturated
aqueous solution of sodium chloride, dried over magne-
sium sulfate, and condensed in vacuo. The residue was
purified by silica gel column chromatography (hexane–
ethyl acetate = 2:1) to afford 8 (411 mg, 79%) as a colorless
oil. Ozone gas was then bubbled into a solution of 8
(66 mg, 0.203 mmol) in methanol (5 ml) at ꢀ78 ꢁC for
30 min. After the excess ozone was excluded by bubbling
nitrogen gas, sodium borohydride (27 mg, 0.609 mmol)
was added and the reaction mixture stirred for 1 h at
0 ꢁC. The organic solvent was removed in vacuo and the
residue was extracted with ethyl acetate. The organic layer
was washed with a saturated aqueous solution of sodium
4.4.1. Condition A. A solution of 5 (1.10 g, 4.62 mmol) in
dimethyl sulfoxide (10 ml) was added to a suspension of
baker’s yeast (Sigma type II, 13.8 g) in distilled water
(100 ml) and the mixture stirred for 24 h at 30 ꢁC. Another
baker’s yeast (Sigma type II, 13.8 g) was then added to the
reaction mixture, which was stirred for a further 24 h. The
reaction mixture was filtered through Hyflo-Super-Celꢂ,
which was washed with ethyl acetate (200 ml). The organic
layer was washed with saturated aqueous solution of
sodium chloride, dried over magnesium sulfate, and con-
densed in vacuo. The residue was purified by silica gel
column chromatography (hexane–ethyl acetate = 1:1) to
afford a mixture of diastereomers 6a and 6b (651 mg,
67%, 6a:6b = 94:6) as a colorless oil.
4.4.2. Condition B. A solution of 5 (100 mg, 0.42 mmol)
in dimethyl sulfoxide (1 ml) was added to a suspension of
baker’s yeast (Sigma type II, 1.26 g) and sucrose (2.52 g)
in distilled water (10 ml) and the mixture stirred for 24 h
at 30 ꢁC. Another baker’s yeast (Sigma type II, 1.26 g)
was then added to the reaction mixture, which was stirred
for a further 24 h. The reaction mixture was filtered

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T. Katoh et al. / Tetrahedron: Asymmetry 17 (2006) 1655–1662
chloride, dried over magnesium sulfate, and condensed
in vacuo. The residue was purified by column chromatogra-
phy (hexane–ethyl acetate = 3:2) to afford the primary
alcohol 9 (34 mg, 62%). Next, acetic anhydride (1 ml) was
added to a solution of 9 (30 mg, 0.11 mmol) in pyridine
(1 ml) and the mixture stirred for 14 h at room tempera-
ture. The reaction was quenched by adding methanol,
and the organic solvent removed in vacuo. The residue
was purified by silica gel column chromatography (hex-
1.63–1.81 (m, 3H), 1.85–1.92 (m, 1H), 1.95–2.11 (m, 3H),
2.15–2.26 (m, 1H), 2.30–2.44 (m, 2H), 3.37 (s, 3H), 3.72
(dd, J = 6.0 and 3.5 Hz, 1H), 3.73 (s, 3H), 4.56 (ABd,
JAB = 7.0 Hz, 1H), 4.71 (ABd, JAB = 7.0 Hz, 1H), 5.83
(dt, J = 15.7 and 1.6 Hz, 1H), 6.95 (dt, J = 15.7 and
6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 18.2, 20.4,
25.3, 26.8, 33.9, 37.8, 51.5, 53.8, 55.9, 80.7, 95.5, 121.1,
148.8, 167.0, 213.3; IR (CHCl3): 3034, 3020, 2951, 1706,
1655, 1437, 1036 cmꢀ1; MS (20 eV) m/z: 284 (M+, 3), 252
(4), 220 (8), 190 (21), 172 (21), 153 (33), 123 (28), 110
(100), 95 (16), 81 (23), 68 (12); HRMS calcd for
C15H24O5 (M+): 284.1616, found: 286.1624.
ane–ethyl acetate = 3:2) to afford 7 (33 mg, 96%) as a col-
25
orless oil. Compound 7; ½aꢁD ¼ þ23:7 (c 1.48, CHCl3); IR
(CHCl3): 2959, 2885, 1728, 1369, 1253, 1196, 1038 cmꢀ1
;
MS (FAB) m/z: 337 (M++Na, 65); HRMS calcd for
C16H26O6Na (M++Na): 337.1627, found: 337.1631. 1H
and 13C NMR are shown in Table 2.
4.8. (+)-Methyl (2R,4aR,5S,8aS)-8a-hydroxy-5-methoxy-
methoxy-4a-methyldecahydronaphthalene-1-carboxylate 12a
and (ꢀ)-methyl (2R,4aR,5S,8aR)-8a-hydroxy-5-methoxy-
methoxy-4a-methyldecahydronaphthalene-1-carboxylate 12b
4.6. (+)-Methyl (E)-5-[(2R,3S)-3-(4-bromobenzoyloxy)-2-
methyl-1-oxocyclohexyl]-2-pentenoate 10
Methyllithium (1.07 M solution in Et2O, 1.64 ml,
1.76 mmol) was added to a suspension of cuprous iodide
(335 mg, 1.76 mmol) in tetrahydrofuran (2 ml) at ꢀ50 ꢁC
and the mixture was stirred for 30 min. HMPA (0.6 ml)
and DIBAL-H (1.0 M solution in n-hexane, 1.76 mmol,
1.76 ml) were added to the mixture and the mixture was
stirred for another 30 min. A solution of (+)-11 (50 mg,
0.17 mmol) in THF (1 ml) was added dropwise to the reac-
tion mixture, which was stirred for 2 h while keeping the
temperature at ꢀ50 ꢁC and for 48 h at room temperature.
The reaction mixture was poured into 1 M hydrochloric
acid and extracted with diethyl ether. The organic layer
was successively washed with a saturated aqueous solution
of sodium thiosulfate and that of sodium chloride, dried
over magnesium sulfate, and condensed in vacuo. The res-
idue was purified by silica gel column chromatography
(hexane–ethyl acetate = 5:1!3:1) to afford (+)-12a
(26 mg, 51%) and (ꢀ)-12b (10 mg, 20%).
p-Bromobenzoyl chloride (1.1 g, 4.84 mmol), triethylamine
(0.84 ml, 6.05 mmol), and 4-dimethylaminopyridine
(60 mg, 0.48 mmol) were added to a solution of 6a
(291 mg, 1.21 mmol) in dichloromethane (5 ml) and the
mixture refluxed for 4 days. The reaction mixture was
poured into ice-water and extracted with ethyl acetate.
The organic layer was washed with a saturated aqueous
solution of sodium chloride, dried over magnesium sulfate,
and condensed in vacuo. The residue was purified by silica
gel column chromatography (hexane–ethyl acetate = 5:1)
to afford 10 (460 mg, 90%) as colorless plates. Compound
20
10; mp 94–95 ꢁC (ethyl acetate); ½aꢁD ¼ þ44:4 (c 1.15,
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.16 (s, 3H),
1.73–1.93 (m, 3H), 1.98–2.10 (m, 3H), 2.19–2.30 (m, 2H),
2.43–2.55 (m, 2H), 3.72 (s, 3H), 5.32 (dd, J = 5.7 and
2.5 Hz, 1H), 5.83 (dt, J = 15.7 and 1.5 Hz, 1H), 6.91 (dt,
J = 15.7 and 6.8 Hz, 1H), 7.57–7.60 (m, 2H), 7.83–7.86
(m, 2H); 13C NMR (100 MHz, CDCl3): d 17.9, 20.9, 25.5,
26.6, 34.2, 37.7, 51.5, 52.8, 78.4, 121.5, 128.5, 128.7, 131.1
(2), 131.9 (2), 147.9, 164.7, 166.8, 212.1; IR (CHCl3):
1715, 1659, 1541, 1437, 1070 cmꢀ1; MS (70 eV) m/z: 424
(M++2, 1), 422 (M+, 1), 392 (8), 390 (8), 185 (53), 183
(58), 155 (13), 110 (100), 95 (11), 82 (19), 68 (15), 55 (20);
HRMS calcd for C20H23BrO5 (M+): 422.0728, found:
422.0729. Anal. Calcd for C20H23BrO5: C, 56.75; H, 5.48.
Found: C, 56.68; H, 5.53.
25
Compound 12a: coloress oil; ½aꢁD ¼ þ75:6 (c 0.97, CHCl3);
1H NMR (400 MHz, CDCl3): d 1.00 (s, 3H), 1.19–1.38 (m,
2H), 1.46–2.02 (m, 10H), 2.90 (dd, J = 14.2 and 7.0 Hz,
1H), 3.37 (s, 3H), 3.69 (s, 3H), 3.76 (s, 1H, –OH), 3.81
(dd, J = 11.5 and 4.8 Hz, 1H), 4.55 (ABd, JAB = 7.0 Hz,
1H), 4.72 (ABd, JAB = 7.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d 15.9, 19.9, 20.2, 26.0, 26.7, 29.4,
33.4, 42.9, 44.9, 52.0, 55.8, 73.3, 74.1, 95.5, 177.6; IR
(CHCl3): 3034, 2951, 2359, 2341, 1711, 1454, 1437 cmꢀ1
;
4.7. (+)-Methyl (E)-5-[(2R,3S)-(3-methoxymethoxy-2-
methyl-1-oxocyclohexyl)]-2-pentenoate 11
MS (20 eV) m/z: 286 (M+, 2), 254 (12), 241 (30), 236
(37), 224 (48), 206 (66), 192 (100), 170 (54), 138 (94), 121
(47), 85 (59); HRMS calcd for C15H26O5 (M+): 286.1780,
found: 286.1784.
Di-i-propylethylamine (2.73 ml, 35.5 mmol) and meth-
oxymethyl chloride (2.25 ml, 29.6 mmol) were added to a
suspension of 6a (1.42 g, 5.91 mmol) in tetrahydrofuran
(20 ml) and the mixture refluxed for 12 h. After the reac-
tion, the reaction mixture was diluted with a saturated
aqueous solution of ammonium chloride (50 ml) and ex-
tracted with ethyl acetate. The organic layer was washed
with saturated aqueous solution of sodium chloride, dried
over magnesium sulfate, and condensed in vacuo. The res-
idue was purified by silica gel column chromatography
Compound 12b: colorless needles; mp 68 ꢁC (hexane/ethyl
23
acetate); ½aꢁD ¼ ꢀ31:9 (c 0.35, CHCl3); 1H NMR
(400 MHz, CDCl3): d 1.10–1.16 (m, 1H), 1.20 (s, 3H),
1.48–1.80 (m, 9H), 1.80–1.93 (m, 1H), 1.98 (dt, J = 13.6
and 4.2 Hz, 1H), 2.81–2.87 (m, 1H), 3.40 (s, 3H), 3.40
(m, 1H), 3.70 (s, 3H), 4.25 (s, 1H, –OH), 4.59 (ABd,
JAB = 7.1 Hz, 1H), 4.70 (ABd, JAB = 7.1 Hz, 1H); 13C
NMR (100 MHz, CDCl3): d 15.5, 17.7, 19.8, 24.4, 25.9,
28.3, 32.2, 41.6, 48.5, 51.6, 56.1, 74.8, 83.9, 95.7, 174.7;
IR (CHCl3): 3506, 3034, 2951, 1726, 1467, 1437, 1151,
(hexane–ethyl acetate = 3:1) to afford 11 (1.50 g, 90%) as
25
a colorless oil. Compound 11; ½aꢁD ¼ þ1:86 (c 1.00,
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.14 (s, 3H),
1028 cmꢀ1
.

T. Katoh et al. / Tetrahedron: Asymmetry 17 (2006) 1655–1662
1661
4.9. (+)-Methyl (4aR,5S)-5-methoxymethoxy-4a-methyl-
2,3,4,4a,5,6,7,8-octahydronaphthalene-1-carboxylate 13a
condensed in vacuo. The residue was purified by silica gel
column chromatography (hexane–ethyl acetate = 5:1) to
afford a mixture of 13a and 13b (98 mg, 13a:13b = 62:38).
The ratio was determined on the basis of the integral values
of the olefinic protons.
Thionyl chloride (2.5 ml) was added to a solution of 12a
(1.02 g, 3.57 mmol) in pyridine (10 ml) and stirred for 1 h
at room temperature. The reaction mixture was poured
into ice-water and extracted with ethyl acetate. The organic
layer was washed with saturated solution of sodium
chloride, dried over magnesium sulfate, and condensed in
vacuo. The residue was purified by silica gel column
chromatography (hexane–ethyl acetate = 5:1) to afford
4.12. (+)-Methyl (4aR,5S)-5-hydroxy-4a-methyl-
2,3,4,4a,5,6,7,8-octahydronaphthalene-1-carboxylate 14
Hydrochloric acid (6 M, 4 ml) was added to a solution of
13a (33 mg, 0.123 mmol) in acetone (4 ml) and the mixture
stirred for 10 h at room temperature. After the reaction,
the reaction mixture was poured into a saturated aqueous
solution of sodium bicarbonate and extracted with ethyl
acetate. The organic layer was washed with saturated
aqueous solution of sodium chloride, dried over magne-
sium sulfate, and evaporated. The residue was purified
by silica gel column chromatography (hexane–ethyl ace-
13a (926 mg, 97%) as a colorless oil. Compound (+)-13a;
25
½aꢁD ¼ þ149 (c 0.98, CHCl3); 1H NMR (400 MHz,
CDCl3): d 1.11 (s, 3H), 1.18–1.32 (m, 2H), 1.42–1.72 (m,
4H), 1.74–1.86 (m, 2H), 1.86–2.04 (m, 2H), 2.14–2.30 (m,
2H), 2.68–2.76 (m, 1H), 3.26 (dd, J = 11.5 and 4.6 Hz,
1H), 3.38 (s, 3H), 3.71 (s, 3H), 4.56 (ABd, JAB = 6.8 Hz,
1H), 4.69 (ABd, JAB = 6.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d 18.1, 19.0, 23.9, 27.0, 27.6, 27.8, 35.6, 41.0,
51.4, 55.6, 84.0, 95.8, 125.9, 147.7, 171.0; IR (CHCl3):
3032, 2947, 2866, 1709, 1448, 1435, 1238, 1138, 1099,
1036 cmꢀ1; MS (20 eV) m/z: 268 (M+, 2), 236 (27), 206
(88), 192 (64), 174 (26), 164 (21), 147 (100), 131 (24), 105
(22), 91 (11); HRMS calcd for C15H22O4 (M+): 268.1674,
found: 268.1666.
tate = 2:1) to afford 14 (24 mg, 87%) as colorless needles.
25
Compound 14; mp 82–84 ꢁC, ½aꢁD ¼ þ162 (c 0.44, CHCl3);
1H NMR (400 MHz, CDCl3): d 1.09 (s, 3H), 1.22–1.38 (m,
1H), 1.22–1.74 (m, 5H), 1.74–1.84 (m, 3H), 1.93–2.05 (m,
1H), 2.17–2.31 (m, 2H), 2.70–2.78 (m, 1H), 3.39 (dd,
J = 11.6 and 4.3 Hz, 1H), 3.72 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 18.0, 18.1, 24.0, 26.8, 27.8, 30.4,
35.4, 41.3, 51.5, 78.5, 126.1, 147.5, 170.9; IR (CHCl3):
2943, 2866, 1709, 1603, 1435, 1274, 1238, 1097 cmꢀ1; MS
(70 eV) m/z: 224 (M+, 5), 206 (25), 192 (80), 180 (12);
HRMS calcd for C13H20O3 (M+): 224.1412, found:
224.1408.
4.10. (ꢀ)-Methyl (2R,4aR,5S)-5-methoxymethoxy-4a-
methyl-1,2,3,4,4a,5,6,7-octahydronaphthalene-1-carboxylate
13b
Thionyl chloride (0.5 ml) was added to a solution of 12b
(226 mg, 0.79 mmol) in pyridine (2 ml) and stirred for 1 h
at room temperature. The reaction mixture was poured
into ice-water and extracted with ethyl acetate. The organic
layer was washed with saturated solution of sodium
chloride, dried over magnesium sulfate, and condensed in
vacuo. The residue was purified by silica gel column
chromatography (hexane–ethyl acetate = 5:1) to afford
4.13. (+)-Methyl (4aR)-4a-methyl-5-oxo-2,3,4,4a,5,6,7,8-
octahydronaphthalene-1-carboxylate (+)-36
Jones’ reagent (0.5 ml) was added to a solution of 14
(24 mg, 0.107 mmol) in acetone (5 ml) at 0 ꢁC and the
mixture stirred for 30 min while keeping the temperature
constant. The reaction was then quenched by adding 2-
propanol (1 ml) to the reaction mixture, which was stirred
for another 10 min. The reaction mixture was filtered
through Hyflo-Super-Celꢂ, which was washed with ace-
tone. The filtrate was condensed in vacuo and extracted
with ethyl acetate. The organic layer was washed with a
saturated aqueous solution of sodium chloride, dried over
magnesium sulfate, and condensed in vacuo. The residue
was purified by silica gel column chromatography (hex-
13b (197 mg, 93%) as a colorless oil. Compound 13b;
22
½aꢁD ¼ ꢀ88:7 (c 0.87, CHCl3); 1H NMR (400 MHz,
CDCl3): d 1.12 (s, 3H), 1.20–1.28 (m, 1H), 1.52–1.70 (m,
4H), 1.79–1.85 (m, 1H), 1.86–1.90 (m, 1H), 1.99–2.03 (m,
1H), 2.07–2.12 (m, 2H), 3.20–3.26 (m, 1H), 3.39 (s, 3H),
3.41 (dd, J = 12.1 and 3.5 Hz, 1H), 3.71 (s, 3H), 4.62
(ABd, JAB = 6.8 Hz, 1H), 4.75 (ABd, JAB = 6.8 Hz, 1H),
5.06 (dd, J =5.4 and 3.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d 18.5, 20.8, 23.6, 24.8, 30.6, 38.4, 40.0, 46.9,
51.7, 55.7, 83.9, 95.9, 119.2, 140.1, 175.3; IR (CHCl3):
2947, 2889, 1730, 1460, 1437, 1375, 1319, 1147,
1045 cmꢀ1; MS (20 eV) m/z: 268 (M+, 2), 236 (59), 218
(11), 208 (19), 191 (21), 180 (44); HRMS calcd for
C15H22O4 (M+): 268.1674, found: 268.1679.
ane–ethyl acetate = 5:1) to afford (+)-3 (18 mg, 74%) as
25
a colorless oil. Compound (+)-3; ½aꢁD ¼ þ189 (c 0.28,
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.35 (s, 3H),
1.56–1.70 (m, 4H), 1.89–1.96 (m, 1H), 1.99–2.07 (m,
1H), 2.17–2.31 (m, 2H), 2.35–2.45 (m, 2H), 2.59–2.69
(m, 1H), 3.06–3.14 (m, 1H), 3.74 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 18.3, 23.5, 25.8, 26.6, 27.4, 30.9,
37.7, 51.3, 51.6, 127.0, 146.4, 170.1, 213.5; IR (CHCl3):
2951, 1707, 1630, 1456, 1435, 1275, 1238, 1086,
1011 cmꢀ1; MS (70 eV) m/z: 222 (M+, 19), 204 (5), 191
(7), 163 (100), 135 (25), 121 (17); HRMS calcd for
C13H18O3 (M+): 222.1256, found: 222.1252; HPLC analy-
sis >99% ee [Daicel CHIRALPAK AS (25 · 0.46), eluent;
hexane–isopropanol = 99:1, flow rate; 0.5 ml/min, temper-
ature 25 ꢁC, detector; 254 nm, (+)-3: 31 min, (ꢀ)-3:
51 min.
4.11. Isomerization from 13b to 13a
DBU (553 ll, 3.70 mmol) was added to a solution of 13b
(100 mg, 0.37 mmol) in toluene (5 ml) and the mixture re-
fluxed for 24 h. After the reaction, the reaction mixture
was poured into a saturated aqueous solution of ammo-
nium chloride and extracted with ethyl acetate. The organic
layer was washed with a saturated aqueous solution of
sodium chloride, dried over magnesium sulfate, and

1662
T. Katoh et al. / Tetrahedron: Asymmetry 17 (2006) 1655–1662
4.14. (+)-Methyl (2S,4aR,5S,8aR)-5-methoxymethoxy-1,4a-
dimethyldecahydronaphthalene-1-carboxylate 15
constant. The reaction was quenched by adding 2-propanol
(3 ml) and stirred for 10 min, after which the reaction mix-
ture was filtered through Hyflo-Super-Celꢂ which was
washed with ethyl acetate. The organic layer of the filtrate
was washed with a saturated aqueous solution of sodium
chloride, dried over magnesium sulfate, and condensed in
vacuo. The residue was purified by silica gel column chro-
matography (hexane–ethyl acetate = 8:1) to afford (ꢀ)-1
Lithium metal (130 mg, 18.7 mmol) was added to liquid
ammonia (70 ml) and the mixture stirred for 30 min at
ꢀ78 ꢁC, to which a solution of 13a (715 mg, 2.67 mmol)
in dimethoxyethane (5 ml) was added. The reaction mix-
ture was stirred for 30 min at ꢀ33 ꢁC and liquid ammonia
was removed as gas. Methyl iodide (11.6 ml, 0.187 mol)
was added and the mixture neutralized with 1 M hydro-
chloric acid followed by extraction with ethyl acetate.
The organic layer was washed with a saturated aqueous
solution of sodium chloride, dried over magnesium sulfate,
and condensed in vacuo. The residue was purified by silica
gel column chromatography (hexane–ethyl acetate = 10:1)
(237 mg, 97%) as colorless plates. Compound (ꢀ)-1; mp
25
82–84 ꢁC (diethyl ether); ½aꢁD ¼ ꢀ35:0 (c 0.82, CHCl3);
1H NMR (400 MHz, CDCl3): d 0.98 (s, 3H), 0.98–1.06
(m, 1H), 1.22 (s, 3H), 1.37–1.62 (m, 4H), 1.67–1.87 (m,
2H), 1.98–2.28 (m, 5H), 2.59 (dt, J = 14.1 and 6.4 Hz,
1H), 3.70 (s, 3H); 13C NMR (100 MHz, CDCl3): d 17.2,
19.0, 23.0, 26.7, 28.8, 33.4, 37.9, 38.2, 44.5, 49.6, 51.7,
54.8, 177.6, 215.7; IR (CHCl3): 2951, 2868, 1719, 1701,
1460, 1450, 1250, 1153 cmꢀ1; MS (70 eV) m/z: 238 (M+,
6), 210 (19), 179 (8), 163 (6), 151 (21), 135 (15), 123 (16),
109 (100), 95 (30), 81 (29), 67 (27), 55 (35); HRMS calcd
for C14H22O3 (M+): 238.1569, found: 238.1567. Anal.
Calcd for C14H22O3: C, 70.56; H, 9.30. Found: C, 70.70;
H, 9.42.
to afford 15 (568 mg, 75%) as a colorless oil. Compound
25
15; ½aꢁD ¼ þ27:6 (c 2.02, CHCl3); 1H NMR (400 MHz,
CDCl3): d 0.74 (s, 3H), 0.99–1.09 (m, 3H), 1.12–1.23 (m,
4H), 1.36–1.51 (m, 2H), 1.56–1.97 (m, 6H), 2.14–2.20 (m,
1H), 3.02 (dd, J = 11.7 and 4.7 Hz, 1H), 3.36 (s, 3H),
3.65 (s, 3H), 4.56 (ABd, JAB = 6.8 Hz, 1H), 4.69 (ABd,
JAB = 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 11.2,
19.1, 22.8, 24.8, 27.5, 28.7, 38.19, 38.23, 39.8, 43.6, 51.2,
53.9, 55.5, 86.0, 95.7, 177.8; IR (CHCl3): 2939, 1717,
1603, 1466, 1448, 1144, 1043, 1030 cmꢀ1; MS (20 eV)
m/z: 284 (M+, 2), 252 (24), 234 (10), 222 (25), 207 (13),
179 (38), 161 (100), 147 (20), 134 (22), 122 (33), 107 (43),
94 (28), 81 (25), 71 (24); HRMS calcd for C16H28O4
(M+): 284.1989, found: 284.1987.
References
1. Lam, T.; Ling, T.; Chowdhury, C.; Chao, T.-H.; Bahjat, F.
R.; Lloyd, G. K.; Moldawer, L. L.; Palladino, M. A.;
Teodorakis, E. A. Bioorg. Med. Chem. Lett. 2003, 13, 3217–
3221.
4.15. (+)-Methyl (2S,4aR,5S,8aR)-5-hydroxy-1,4a-dimeth-
yldecahydronaphthalene-1-carboxylate 16
2. Fouad, M.; Edrada, R. A.; Ebel, R.; Wray, V.; Muller, W. E.
¨
G.; Lin, W. H.; Proksch, P. J. Nat. Prod. 2006, 69, 211–218.
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5. (a) Ling, T.; Kramer, B. A.; Palladino, M. A.; Theodorakis,
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6. Bedekar, A. V.; Watanabe, T.; Tanaka, K.; Fuji, K. Tetra-
hedron: Asymmetry 2002, 13, 721–727.
Hydrochloric acid (6 M, 4 ml) was added to a solution of
15 (20 mg, 0.076 mmol) in acetone (4 ml) and the mixture
stirred for 3 h at room temperature. The reaction mixture
was poured into a saturated aqueous solution of sodium
bicarbonate and extracted with ethyl acetate. The organic
layer was washed with a saturated aqueous solution of
sodium chloride, dried over magnesium sulfate, and con-
densed in vacuo. The residue was purified by (hexane–
7. Fuhshuku, K.; Funa, N.; Akeboshi, T.; Ohta, H.; Hosomi,
H.; Ohba, S.; Sugai, T. J. Org. Chem. 2000, 65, 129–135.
8. For example (a) Iwamoto, M.; Kawada, H.; Tanaka, T.;
Nakada, M. Tetrahedron Lett. 2003, 44, 7239–7243; (b)
Watanabe, H.; Iwamoto, M.; Nakada, M. J. Org. Chem.
2005, 70, 4652–4658; (c) Wei, Z.-L.; Li, Z. Y.; Lin, G.-Q.
Tetrahedron: Asymmetry 2001, 12, 229–233; (d) Wei, Z.-L.;
Li, Z.-Y.; Lin, G.-Q. Synthesis 2000, 1673–1676; (e) Inoue, T.;
Hosomi, K.; Araki, M.; Nishide, K.; Node, M. Tetrahedron:
Asymmetry 1995, 6, 31–34; (f) Kitahara, T.; Miyake, M.;
Kido, M.; Mori, K. Tetrahedron: Asymmetry 1990, 1, 775; (g)
Mori, K.; Fujiwhara, M. Tetrahedron 1988, 44, 343–354; (h)
Mori, K.; Mori, H. Org. Synth. 1990, 68, 56–63; (i) Brooks,
D. W.; Grothaus, P. G.; Irwin, W. L. J. Org. Chem. 1982, 47,
2820–2821.
ethyl acetate = 2:1) to afford 16 (17 mg, 99%) as a colorless
25
oil. Compound 16; ½aꢁ ¼ þ20:2 (c 2.27, CHCl3); 1H NMR
(400 MHz, CDCl3): dD0.72 (s, 3H), 1.00–1.14 (m, 3H), 1.18
(s, 3H), 1.19–1.28 (m, 1H), 1.34 (br s, 1H), 1.38–1.53 (m,
2H), 1.58–1.71 (m, 2H), 1.76–1.91 (m, 4H), 2.16–2.21 (m,
1H), 3.13–3.16 (m, 1H), 3.65 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 10.2, 19.1, 22.8, 24.8, 28.7, 30.3,
37.9, 38.2, 39.9, 43.6, 51.2, 53.4, 80.6, 177.7; IR (CHCl3):
3612, 2937, 2860, 1717, 1448, 1157, 1051 cmꢀ1; MS
(70 eV) m/z: 240 (M+, 1), 222 (4), 208 (2), 190 (2), 181
(24), 163 (15), 121 (9), 107 (13), 83 (100), 69 (18), 55 (31);
HRMS calcd for C14H24O3 (M+): 240.1732, found:
240.1725.
9. Brooks, D. W.; Mazdiyashi, H.; Grothaus, P. G. J. Org.
Chem. 1987, 52, 3223–3225.
10. Katoh, T.; Mizumoto, S.; Fudesaka, M.; Kajimoto, T.; Node,
M. Chem. Pharm. Bull. 2006, 54, in press.
4.16. (ꢀ)-Methyl (2S,4aR,8aR)-1,4a-dimethyl-5-oxodeca-
hydronaphthalene-1-carboxylate (ꢀ)-19
Jones’ reagent (1 ml) was added to a solution of 16
(258 mg, 1.07 mmol) in acetone (20 ml) at 0 ꢁC, and the
mixture stirred for 30 min while keeping the temperature
11. Crystal data for Figure
2 have been deposited with
the Cambridge Crystallographic Data Centre (Deposition
number 610 518).