Synthesis of a potential key intermediate of akaterpin, specific inhibitor of PI-PLC

Article abstract of DOI:10.1016/S0040-4020(00)00619-0

In order to establish the stereochemistry of akaterpin, a specific inhibitor of PI-PLC, cis-decalin 2 and trans-decalin 3 were prepared. Comparison of NMR spectra of 2 and 3 with those of akaterpin indicated that the upper decalin has a cis-fused structure. Based on the methodology developed here, synthesis of a potential intermediate 32 for the total synthesis of akaterpin was successfully achieved. Further, resolution of β,γ-unsaturated ketone 6 was accomplished using chiral sulfoxyimine. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00619-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 6467±6478
Synthesis of a Potential Key Intermediate of Akaterpin,
Speci®c Inhibitor of PI-PLC
Nobuyuki Kawai,a Yuko Fujibayashi,a Seiya Kuwabara,a Ken-ichi Takao,a,² Yasuharu Ijuinb and
Susumu Kobayashia,
*
aFaculty of Pharmaceutical Sciences, Science University of Tokyo, Ichigaya-Funagawara-machi, Shinjuku-ku, Tokyo 162-0826, Japan
bSagami Chemical Research Center, 4-4-1, Nishi-Ohnuma, Sagamihara, Kanagawa 229-0012, Japan
Received 5 June 2000; accepted 13 July 2000
AbstractÐIn order to establish the stereochemistry of akaterpin, a speci®c inhibitor of PI-PLC, cis-decalin 2 and trans-decalin 3 were
prepared. Comparison of NMR spectra of 2 and 3 with those of akaterpin indicated that the upper decalin has a cis-fused structure. Based on the
methodology developed here, synthesis of a potential intermediate 32 for the total synthesis of akaterpin was successfully achieved. Further,
resolution of b,g-unsaturated ketone 6 was accomplished using chiral sulfoxyimine. q 2000 Elsevier Science Ltd. All rights reserved.
Phosphatidylinositol (PI) turnover plays an important role in
the regulation of cell growth and differentiation.1 Among
several enzymes involved in PI turnover, PI-speci®c phos-
pholipase C (PI-PLC) hydrolyzes PIP2 into two important
biomolecules, diacylglycerol (DG) and inositol-1,4,5-
triphosphate (IP3). DG activates protein kinase C, and IP3
releases Ca21 from the endoplasmic reticulum to the cyto-
plasm. Further, PI-PLC is considered to be a rate-limiting
enzyme of PI-turnover; therefore, a selective inhibitor of
PI-PLC is considered to be quite useful as a tool for the
investigation of signal transduction as well as being of
medicinal importance. Akaterpin2 (1) isolated recently by
Umezawa as a speci®c inhibitor of PI-PLC from the marine
sponge Callyspongia sp. is the most potent inhibitor among
several compounds such as ¯uvirucin B23 and pholipeptin.4
Further, akaterpin was also found to inhibit neutral sphingo-
myelinase.
The planar structure of akaterpin containing two decalin
rings and a hydroquinone disulfate moiety was elucidated
by extensive NMR measurements, although the stereo-
chemistry has remained unknown. The relative stereo-
chemistry of the lower decalin moiety is the same as that
of mamanuthaquinone.5 However, even the relative con-
®guration of the upper decalin has not yet been established.
Being interested in the structure and biological activities of
akaterpin, we embarked on a synthetic study of akaterpin. In
a previous communication,6 we reported that the relative
stereochemistry of the upper decalin moiety was determined
to be cis by synthesizing cis-decalin 2 and trans-decalin 3.
This paper describes the details of the synthesis of cis-
decalin 2 and trans-decalin 3, and the synthesis of a key
intermediate for total synthesis of akaterpin. The resolution
of a key intermediate for cis-decalin is also presented
(Fig. 1).
Figure 1.
Keywords: akaterpin; cis-decalin; trans-decalin; intramolecular Diels±Alder reaction.
* Corresponding author. Tel.: 181-3-3260-8848; fax: 181-3-3260-8848; e-mail: kobayash@ps.kagu.sut.ac.jp
Present address: Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.
²
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00619-0

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N. Kawai et al. / Tetrahedron 56 (2000) 6467±6478
Scheme 1.
Since the relative stereochemistry of the upper decalin has
not been established, our initial efforts were focused on the
determination of the upper decalin moiety. For this purpose,
we decided to synthesize cis-decalin 2 and trans-decalin 3.
We expected that the spectroscopic comparison of the
synthesized decalins with natural akaterpin would provide
some information on the stereochemistry.
We then investigated the alkylation of b,g-unsaturated
ketone 6. When a THF solution of enone 6 was added to a
THF solution of LDA (Entry 1), no reaction occurred to
recover the enone 6. Then, we attempted methylation
under various conditions varying the base, solvent, and
order of addition. Some results are summarized in Table
1. We examined two procedures, Method A and B, which
are classi®ed according to the order of addition. Method A
means that enone 6 was added to a base in a solvent,
followed by the addition of MeI. Method B means that
base was added to enone 6, and MeI was ®nally added to
the above reaction mixture. As shown in Table 1, dienol 12
was isolated in most cases. The structure of the dienol 12
Synthesis of cis-Decalin 2
There are many cis-fused clerodane diterpenes such as
arenarol,7 popollohuanone E,8 and (^)-15,16-epoxy-cis-
cleroda-3,13(16),14-triene,9 and several excellent method-
ologies have been developed for the total synthesis of these
natural products.7±9 Our synthetic strategy for cis-decalin 2
is shown in Scheme 1. We envisaged that b,g-unsaturated
ketone 6 might undergo regio- and stereoselective alkyl-
ation to afford cis-decalin 5. Unsaturated ketone 6, in turn,
might be derived from trienal 7 through an intramolecular
Diels±Alder reaction.10
1
was determined by NMR measurement. Thus, in the H
NMR spectrum, an OH proton appeared at d 5.0 as a singlet
which disappeared on the addition of D2O. The IR spectrum
also supported the enol structure, showing no CvO absorp-
tion. Further, dienol 12 slowly converted to the enone 6 in
CHCl3. From these results, we determined the dienol struc-
ture although the isolation of dienol is not clear. After a
number of experiments, regio- and stereoselective methyl-
ation was accomplished by the treatment of 6 with
NaN[Si(CH3)3]2 as a base and MeI (Method B) to obtain
the methylated cis-decalin 5 in 83% yield. Regioselectivity
and stereoselectivity of the present methylation was excel-
lent, producing 5 as a single isomer. cis-Fused structure of 5
was con®rmed after transformation to the saturated ketone
4. Comparison of the results (entry 7, 9, 10) strongly indi-
cated that the choice of base and the order of addition are
critical in the present methylation.
At ®rst, the synthesis of the cis-decalin 2 (racemate) is
described. According to the procedure reported by
Marshall,10 trienal 7, prepared from 2,4-hexadienal in 6
steps, was treated with Et2AlCl to obtain 8 in 63% yield.
The structure of 8 was con®rmed by comparing the NMR
data with those reported by Marshall. After introducing the
aromatic moiety by Grignard reaction, dehydroxylation at
the benzylic hydroxyl group was examined. Direct dehy-
11
droxylation with LiAlH4±AlCl3 only resulted in the
Hydrogenation of 5 was next examined. The double bond is
sterically hindered, and resisted the hydrogenation using a
conventional method such as Pd±C under H2 atmosphere.
Hydrogenation proceeded when Pd(OH)2 was employed as
a catalyst. However, two saturated ketones were formed in
the hydrogenation. The major isomer was estimated to be
the desired 4, and the minor isomer was found to be 13,
formation of a complex mixture of products. However, the
combination of Et3SiH12 (1.3 equiv.) and CF3CO2H
(1.6 equiv.) was found to be effective giving 10 in 93%
yield. No reaction occurred when acetic acid was used
instead of CF3CO2H. The TBDMS group in 10 was cleaved
with HF, and the resulting alcohol 11 was oxidized with
PCC to obtain the key intermediate 6 (Scheme 2).
Scheme 2.

N. Kawai et al. / Tetrahedron 56 (2000) 6467±6478
6469
Table 1.
Entry
Method
A
Base (eq)
Solvent
THF
THF
THF±HMPA
t-BuOH
THF
THF±HMPA
THF
THF
THF
THF
Temp (8C)
5 (%)
12 (%)
1
2
3
4
5
6
7
8
9
10
LDA (1.2)
220
0
0
rt
0
0
rt
0
0
No reaction
t-BuOK (1.2)
t-BuOK (1.2)
t-BuOK (1.2)
KHMDS (1.0)
KHMDS (1.0)
NaHMDS (1.0)
t-BuOK (1.2)
KHMDS (1.0)
NaHMDS (1.0)
±
30
Decomposition
Decomposition
±
40
Decomposition
±
±
±
83
35
43
47
±
B
rt
epimer at C-40 (ca 5:1). The minor compound 13 is an
intermediate for the ®rst enantioselective synthesis of (1)-
arenarol by Terashima.7c The undesirable 13 might be
produced from 14 which would be formed by the isomer-
ization of 5 prior to the hydrogenation. Addition of Et3N
was not effective for the undesirable epimerization. Separa-
tion of the two isomers was dif®cult, and it was necessary to
achieve the hydrogenation without any accompanying
epimerization (Table 2).
newly introduced angular Me. Exomethylenation of 4 was
achieved by the CH2Br2±Zn±TiCl4 method developed by
Takai and Nozaki13 to obtain 15 in 89% yield. Conventional
Wittig reaction was not successful, probably due to the
steric congestion (Scheme 3).
With the complete cis-decalin skeleton in hand, the remain-
ing step was the demethylation of the hydroquinone moiety
and sulfurization. Demethylation of 15 was found to be very
dif®cult, although a number of alkylative and oxidative
demethylation methods have been developed. For example,
treatment with TMSI14 prepared in situ from TMSCl and
NaI resulted in the isomerization of exo ole®n into endo
ole®n. We also attempted various oxidative demethylation
methods using CAN, CrO3,15 and an Ag complex of picoline
dicarboxylic acid.16 Among them, treatment with CAN
afforded quinone in moderate yield (36%). The resulting
quinone was immediately reduced with Na2S2O4 to obtain
After a number of unsuccessful experiments, we ®nally
found that Raney-Ni hydrogenation proceeded without
accompaniment of the undesirable epimerization. During
hydrogenation of the carbon±carbon double bond, ketone
was also reduced, affording an epimeric mixture of cyclo-
hexanol; the crude mixture was oxidized with PCC to give 4
in 98% yield. The cis-decalin structure of 4 was con®rmed
by NOE. between benzylic methylene protons and the
Table 2.
Entry
Catalyst
Additive
Time (h)
Yield (%)
Ratio (4:13)
1
2
3
4
Pd±C
±
±
Et3N
±
24
24
24
6
No reaction
58
43
Decomposition
±
Pd(OH)2
Pd(OH)2
PtO2
5:1
4:1
±
Scheme 3.

6470
N. Kawai et al. / Tetrahedron 56 (2000) 6467±6478
Scheme 4.
the desired hydroquinone 16. Although the yields are not
satisfactory, the CAN±Na2S2O4 method was employed for
the synthesis of cis-decalin 2 and trans-decalin 3. For
further study towards the total synthesis of akaterpin,
other protecting groups such as benzyl and MOM groups
are to be employed (Scheme 4).
enone 20, and 4,5-syn stereochemistry was achieved by a
stereoselective hydrogenation of exo-methylene 18. Since
the primary purpose of our present study was the determina-
tion of the relative stereochemistry of the upper decalin, we
decided to follow the procedure developed for avarol and to
examine several hydrogenation methods expecting to obtain
the desired 4,5-anti isomer (Scheme 5).
Finally, hydroquinone 16 was reacted with an SO3´pyridine
complex17 in pyridine at 608C, followed by treatment with
Na2CO3 to complete the synthesis of cis-decalin 2. During the
sulfurization of hydroquinone, we found that mono-sulfuriza-
tion products were isolated when sulfurization was carried
out at room temperature. This ®nding will be useful for the
study of the structure±activity relationships of akaterpin.
According to the literature procedure, exo-methylene 18
was prepared from Wieland±Miescher ketone analog 21
and subjected to hydrogenation. Although hydrogenation
of 18 was reported to produce the 4,5-syn dimethyl isomer
predominantly,18 we attempted the hydrogenation of 18
under various conditions to achieve the reversal of stereo-
selectivity. However, the desired 4,5-trans isomer 22 was
best obtained in 28% yield by the treatment with Raney-Ni
under H2 atmosphere in EtOH. The major product (62%
yield) was an isomeric 4,5-cis isomer 23. The structure of
23 was determined by comparison of the 1H- and 13C NMR
data with those reported by Wiemer et al.18c Catalytic hydro-
genation over palladium catalysts gave an inseparable
mixture of the desired 22 and isomerized endo-ole®n 24
along with 23 (Scheme 6).
Synthesis of trans-Decalin 3
Most clerodane diterpenes have a trans-decalin structure.
Among them, avarol18 and avaron18 are structurally closely
related to our target compound 3. The difference from a
stereochemical point of view is that 4,5-dimethyl sub-
stituents are syn in avaron and avarol whereas anti in 3. In
the total synthesis of avarol by Wiemer et al.,18c the trans-
decalin skeleton was constructed by reductive alkylation of
Although we were not able to achieve the reversal of
Scheme 5.
Scheme 6.

N. Kawai et al. / Tetrahedron 56 (2000) 6467±6478
6471
Scheme 7.
Table 3.
Position
Akaterpin
1.15 d
1.03 s
4.76 br s
4.73 br s
3.32 d
2.40 d
7.30 d (2.4 Hz)
7.09 dd (2.4, 8.5 Hz)
7.38 d (8.5 Hz)
cis-Decalin 2
1.13 d
0.96 s
4.75 br s
4.67 br s
3.26 d
2.53 d
7.31 d (3.0 Hz)
7.08 dd (3.0, 8.9 Hz)
7.38 d (8.9 Hz)
Dd
trans-Decalin 3
1.17 d
0.89 s
4.52 br s
4.46 br s
3.34 d
2.33 d
7.34 d (3.0 Hz)
7.08 dd (3.0, 8.9 Hz)
7.38 d (8.9 Hz)
Dd
40-Me
20.02
20.07
20.01
20.06
20.06
10.13
10.01
20.01
0.00
10.02
20.14
20.24
20.27
10.02
20.07
10.04
20.01
0.00
50-Me
100-CH2
110
300
500
600
selectivity, we proceeded with the synthesis of trans-decalin
3. After deprotection of ethylene ketal in 22, the resulting
ketone 17 was converted to trans-decalin 3 by a similar
procedure to that for cis-decalin 2 (Scheme 7).
The NMR spectra of 2 and 3 were then compared with those
of akaterpin. Tables 3 and 4 show the representative data of
1H NMR (500 MHz, CD3OD) and 13C NMR (125 MHz,
CD3OD), respectively. As shown in Table 3, differences
in chemical shifts of the exomethylene protons (100-CH2)
are most diagnostic. Differences in the chemical shift of 100-
CH2 protons are 0.24 and 0.27 ppm in trans-decalin 3,
whereas, at most, 0.06 ppm in cis-decalin 2. These data
strongly indicate the cis con®guration of the upper decalin
of akaterpin. This conclusion was also supported by 13C
NMR spectra. Chemical shift differences of 50-Me, 60, 100
and 100-H2 in 3 are apparently larger than in 2.
Comparison of NMR of 2 and 3 with those of Akaterpin
We were thus able to synthesize both cis-decalin 2 and
trans-decalin 3 in a stereochemically unambiguous manner.
Table 4.
Position Akaterpin cis-Decalin 2 D ppm trans-Decalin 3 D ppm
Resolution of b,g-unsaturated ketone 6
10
44.1
38.6
16.5
43.1
25.2
47.0
22.4
25.7
34.0
153.4
42.6
39.1
16.5
41.3
25.4
47.0
23.2
26.1
21.5
10.5
0.0
21.8
10.2
0.0
10.8
10.4
-0.6
13.8
23.1
20.7
0.0
42.1
37.0
16.8
42.1
20.8
19.6
23.1
26.6
22.0
21.6
10.3
21.0
24.4
12.6
10.7
10.9
10.1
18.1
27.0
20.8
10.1
10.1
20.5
10.2
20.1
20.1
40
40-Me
50
Based on the above conclusion that the upper decalin moiety
of akaterpin has cis stereochemistry, we next attempted the
resolution of intermediates of cis-decalin. Since the absolute
stereochemistry was not determined, both enantiomers of
the upper decalin are required. Therefore, we employed a
resolution strategy rather than the alternative enantio-
selective approach. Resolution of b,g-unsaturated ketone
6 seemed most desirable because 6 might serve as a poten-
tial intermediate for the total synthesis of akaterpin. Thus,
the introduction of a lower decalin moiety into 6 might be
possible by either direct alkylation or a stepwise method.
Among several methodologies for the resolution of a
ketone, the use of chiral sulfoxyimine developed by
Johnson19 was found to be successful in our case. When
50-Me
60
70
80
90
33.4
34.1
100
157.2
106.3
36.6
150.1
135.4
125.2
149.9
120.3
123.2
161.5
102.4
36.5
150.2
135.3
124.6
150.1
120.3
123.1
100-CH2 109.4
110
100
200
300
400
500
600
37.3
150.1
135.2
125.1
149.9
120.4
123.2
10.2
10.1
0.0
20.1
0.0

6472
N. Kawai et al. / Tetrahedron 56 (2000) 6467±6478
Scheme 8.
These stereochemically established isomers 28 and 30 were
separately subjected to thermal elimination affording (2)-6
([a]Dˆ23.48 (c 1.02, CHCl3)) and (1)-6 ([a]Dˆ13.38 (c
0.57, CHCl3)), respectively. These enantiomers were
cleanly separated on HPLC using chiral column (Daicel
AD, eluent; n-hexane/i-PrOH: 9:1; ¯ow rate; 0.5 ml/min;
tR of (1)-6, 13 min; tR of (2)-6, 20 min). Thermal elimina-
tion of the remaining sulfoxyimine adducts 29 and 31 also
proceeded almost quantitatively to obtain (2)-6 and (1)-6,
respectively. Resolution of key intermediate 6 was thus
established (Scheme 9).
Introduction of Acetate Unit into 6 and Synthesis of a
Potential Key Intermediate 32
Figure 2.
We envisaged that cis-decalin 32 with an ethoxycarbonyl
group might serve as a potential intermediate for the synthe-
sis of akaterpin. One plausible approach might be the
construction of the lower decalin by intermolecular Diels±
Alder reaction reported by Danishefsky in the synthesis of
mamanuthaquinone.5 We then attempted introduction of an
acetate unit into 6 and transformation of the derived
cis-decalin into the key intermediate 32 (Scheme 10).
racemic unsaturated ketone 6 was reacted with lithio
derivative of (S)-(1)-27, four possible stereoisomers of
the sulfoxyimine adducts were isolated in total 88% yield.
These isomers were separated by chromatography on silica
gel, and the yield of each isomer is shown in Scheme 8.
Relative as well as absolute stereochemistry of each isomer
was established as follows: The structures of 28 and 30 were
determined by X-ray crystallographic analysis (Fig. 2).
Following the procedure developed above, alkylation of 6
was ®rst attempted. When ethyl bromoacetate was used as
Scheme 9.
Scheme 10.

N. Kawai et al. / Tetrahedron 56 (2000) 6467±6478
6473
Scheme 11.
an electrophile, O-alkylation product 36 was isolated in
83% yield along with a small amount of dienol 12.
However, the desired C-alkylation product 35 was obtained
in 90% yield when ethyl iodoacetate was employed as an
electrophile. The resulting unsaturated ketoester 35 was
reduced to saturated ketoester 37 with Raney Ni. In this
case, progress of hydrogenation was carefully monitored
by TLC in order to avoid the accompanying reduction of
the cyclohexanone part which resulted in the undesirable
formation of lactone. Finally, ketoester 37 was treated
with CH2Br2±Zn±TiCl4 to obtain the key intermediate 32
in high yield (Scheme 11).
from commercial sources and used without further puri®ca-
tion. Organic extracts were dried over sodium sulfate
(Na2SO4), ®ltered, and concentrated using a rotary evapora-
tor at ,408C bath temperature. Involatile oils and solids
were vacuum dried at ,2 mmHg.
trans-5a-(tert-Butyldimethylsilyloxy)-1a-[(2,5-dimethoxy-
phenyl)-hydroxymethyl]-1,2,4a,5,6,7,8,8a-octahydro-1b,
2a-dimethylnaphthalene (9). To a vigorously stirred
mixture of Mg turnings (0.78 g, 32 mmol) in 30 ml of
re¯uxing ether containing 0.3 ml of 1,2-dibromoethane
(1.4 mmol) was added, dropwise, a solution of 1-bromo-
2,5-dimethoxy benzene (3.5 g, 32 mmol) in 30 ml of THF
over 2 h. After the mixture was re¯uxed for 30 min and
cooled to 08C, a solution of trans-5a-(tert-Butyldimethyl-
silyloxy)-1,2,4a,5,6,7,8,8a-octahydro-1b,2a-dimethyl-
naphthalene-1a-carbaldehyde 8 (1.73 g, 5.36 mmol) in
17 ml of THF was added over 10 min with stirring. Thirty
minutes later, the excess reagent was quenched by the addi-
tion of MeOH (6 ml). The resulting solution was poured
through a glass-wool plug into a separatory funnel contain-
ing 100 ml of ether and 100 ml of saturated aqueous NH4Cl
solution. The aqueous phase was extracted with two addi-
tional 100 ml portions of ether. The combined extract was
washed with 200 ml of saturated aqueous NaCl solution,
dried and concentrated. The residue was puri®ed by
chromatography on 100 g of silica gel by using 1:30
Conclusion
In this paper, we have described that the upper decalin
moiety of akaterpin has a cis con®guration. We further
disclosed our efforts toward the total synthesis by achieving
the synthesis of the potential key intermediate 32.
Additional characteristic features described herein are (i)
cis-decalin 2 was synthesized by developing the regio- and
stereoselective methylation of b,g-unsaturated ketone 6, (ii)
resolution of b,g-unsaturated ketone 6 was accomplished
using a chiral sulfoxyimine method.
ether±hexane as eluent, affording
mixture, 2.34 g, 95%) as a colorless oil. IR (neat) 3506,
2929, 2856, 1494, 1463, 1254, 1218 cm21 1H NMR
9 (diastereomeric
Experimental
All 1H- and 13C NMR spectra were measured in CDCl3 with
TMS and the solvent peak as internal standards, and
recorded on a JEOL JMN-EX270 spectrometer or JEOL
JMN-GS£500. IR spectra were recorded on Horiba
FT-210 or Hitachi 215 infrared spectrometer. Mass spectra
(MS) were obtained on a Hitachi M-80 spectrometer.
Optical rotations were measured on a JASCO DIP-360
digital polarimeter. Column chromatography was carried
out on Fujisilisiachem K.K.BW-127ZH. Analytical thin-
layer chromatography (TLC) was performed on Merck
precoated silica gel HF254 plates, and compounds were
visualized by UV illumination (254 nm) or by heating to
1508C after spraying phosphomolybdic acid in ethanol.
Dry diethyl ether (Et2O) and tetrahydrofuran (THF) were
distilled from sodium-benzophenone ketyl, and dry benzene
(PhH) and dichloromethane (CH2Cl2) were distilled from
calcium hydride, respectively, under an inert atmosphere.
All other organic solvents and reagents were obtained
;
(270 MHz) d 0.03 (3H, s, Si±CH3), 0.04 (3H£1/2, s, Si±
CH3), 0.05 (3H£1/2, s, Si±CH3), 0.70 (3H£1/2, s, 1-CH3),
0.89 (3H, d, Jˆ6.9 Hz, 2-CH3), 0.90 (9H, s, t-Bu), 1.08
(3H£1/2, s, 1-CH3), 1.20±1.98 (8H, m, 2,4a,6,7,8-H),
2.15±2.27 (1H£1/2, m, 8a-H), 2.34±2.40 (1H£1/2, m, 8a-
H), 3.76 (3H£1/2, s, OCH3), 3.77 (3H£1/2, s, OCH3), 3.78
(3H£1/2, s, OCH3), 3.79 (3H£1/2, s, OCH3), 4.05 (1H, br.s,
5-H), 5.20±5.60 (3H, m, 3,4-H, CH±OH), 6.75±6.78 (2H,
m, 30,40-H), 7.21 (1H£1/2, d, Jˆ2.6 Hz, 60-H), 7.24 (1H£1/
2, d, Jˆ2.6 Hz, 60-H); MS m/z 460 (M1); High resolution
MS calcd for C27H44O4Si (M1) 460.3009, found 460.3007.
trans-5a-(tert-Butyldimethylsilyloxy)-1a-[(2,5-dimethoxy-
phenyl)-methyl]-1,2,4a,5,6,7,8,8a-octahydro-1b,2a-
dimethylnaphthalene (10). To a solution of 9 (0.94 g,
2.04 mmol) in 30 ml of dry CH2Cl2 were added 0.4 ml
(2.6 mmol) of triethylsilane and 0.24 ml (3.3 mmol) of

6474
N. Kawai et al. / Tetrahedron 56 (2000) 6467±6478
tri¯uoroacetic acid. The solution was stirred for 10 h at rt
under Ar gas and quenched by the addition of saturated
aqueous NaHCO3 solution (50 ml). The aqueous phase
was extracted with two 50 ml portions of ether. The
combined extract was washed with 100 ml of saturated
aqueous NaCl solution, dried and concentrated. The residue
was puri®ed by chromatography on 50 g of silica gel by
using 1:2 chloroform±hexane as eluent, affording 10
(0.84 g, 93%) of as a colorless oil. IR (neat) 2954, 2929,
(270 MHz) d 0.89 (3H, s, 1-CH3), 1.09 (3H, d, Jˆ6.9 Hz,
2-CH3), 1.43±1.97 (6H, m, 2,7,8,8a-H), 2.11±2.22 (1H, m,
6-H), 2.35±2.41 (1H, m, 6-H), 2.44 (1H, d, Jˆ13.9 Hz,
Ar-CHH), 2.87±2.92 (1H, m, 4a-H), 3.07 (1H, d,
Jˆ13.9 Hz, Ar-CHH), 3.76 (3H, s, OCH3), 3.77 (3H, s,
OCH3), 5.73±5.75 (2H, m, 3,4-H), 6.71 (1H, dd, Jˆ3.0,
8.9 Hz, 40-H), 6.79 (1H, d, Jˆ8.9 Hz, 30-H), 6.91 (1H, d,
Jˆ3.0 Hz, 60-H); 13C NMR (67.5 MHz) d 17.52, 24.94,
26.26, 32.67, 38.08, 39.27, 40.94, 43.81, 52.42, 55.54,
55.76, 110.53, 111.12, 117.41, 120.0, 129.13, 134.36,
152.47, 152.97, 211.78; MS m/z 328 (M1); High resolution
MS calcd for C21H28O3 (M1) 328.2036, found 328.2025.
1
2858, 1496, 1464, 1254, 1222 cm21; H NMR (270 MHz):
0.02 (3H, s, Si±CH3), 0.04 (3H, s, Si±CH3), 0.75 (3H, s,
1-CH3), 0.90 (9H, s, t-Bu), 1.10 (3H, d, Jˆ6.9 Hz, 2-CH3),
1.41±1.98 (9H, m, 2,4a,6,7,8,8a-H), 2.38 (1H, d,
Jˆ13.9 Hz, Ar-CHH), 3.03 (1H, d, Jˆ13.9 Hz, Ar-CHH),
3.75 (3H, s, OCH3), 3.76 (3H, s, OCH3), 4.02 (1H, br.s,
5-H), 5.20±5.24 (1H, m, 3 or 4-H), 5.55±5.64 (1H, m, 3
or 4-H), 6.68 (1H, dd, Jˆ3.0, 8.6 Hz, 40-H), 6.77 (1H, d,
Jˆ8.6 Hz, 30-H), 6.92 (1H, d, Jˆ3.0 Hz, 60-H); 13C NMR
(67.5 MHz) d 24.63, 14.16, 17.73, 18.11, 21.37, 25.64,
25.86, 32.18, 34.11, 34.72, 38.24, 38.46, 45.97, 55.53,
55.85, 71.23, 110.23, 111.14, 117.45, 128.09, 130.21,
132.99, 152.77, 152.94; MS m/z 444 (M1); High resolution
MS calcd for C27H44O3Si (M1) 444.3060, found 444.3062.
cis-1a-[(2,5-Dimethoxyphenyl)methyl]-1,2,4a,7,8,8a-
hexahydro-1b,2a,4aa-trimethyl-5(6H)-naphthalenone
(5). To a solution of 6 (1.02 g, 3.1 mmol) in 100 ml of dry
THF was added 3.1 ml (3.1 mmol) of NaN[Si(CH3)3]2 as a
1.0 M solution in THF at rt. The solution was stirred for
20 min at rt under Ar gas and then 3.4 ml (31 mmol) of
CH3I was added. After being stirred for 10 h at rt under
Ar, the reaction mixture was diluted by the addition of
H2O (20 ml). The aqueous phase was extracted with two
20 ml portions of AcOEt. The combined extract was washed
with 40 ml of saturated aqueous NaCl solution, dried and
concentrated. The residue was puri®ed by chromatography
on 30 g of silica gel by using 1:20 AcOEt±hexane as eluent,
affording 5 (883 mg, 83%) as a white solid. Mp 60±618C;
trans-1a-[(2,5-Dimethoxyphenyl)methyl]-1,2,4a,5,6,7,8,
8a-octahydro-1b,2a-dimethyl-5a-naphthalenol (11). To
a solution of 10 (0.24 g, 0.54 mmol) in 4 ml of CH3CN was
added 0.2 ml of 46% aqueous HF. The solution was stirred
for 20 h at rt and quenched by the addition of saturated
aqueous NaHCO3 solution (10 ml). The aqueous phase
was extracted with two 20 ml portions of AcOEt. The
combined extract was washed with 40 ml of saturated
aqueous NaCl solution, dried and concentrated. The residue
was puri®ed by chromatography on 20 g of silica gel by
using 1:5 ether±hexane as eluent, affording 11 (0.17 g,
95%) as a white solid. Mp 94±968C; IR (neat) 3456,
IR (neat) 2968, 2921, 2830, 1703, 1693, 1377, 1220 cm21
;
1H NMR (270 MHz) d 0.80 (3H, s, 1-CH3), 1.11 (3H, d,
Jˆ6.9 Hz, 2-CH3), 1.38 (3H, s, 4a-CH3), 1.85±2.35 (7H, m,
2,6,7,8,8a-H), 2.44 (1H, d, Jˆ13.5 Hz, Ar-CHH), 2.57±2.66
(1H, m, 6-H), 3.09 (1H, d, Jˆ13.5 Hz, Ar-CHH), 3.74 (3H,
s, OCH3), 3.75 (3H, s, OCH3), 5.68±5.79 (2H, m, 3,4-H),
6.70 (1H, dd, Jˆ3.0, 8.9 Hz, 40-H), 6.77 (1H, d, Jˆ8.9 Hz,
30-H), 6.84 (1H, d, Jˆ3.0 Hz, 60-H); MS m/z 342 (M1);
High resolution MS calcd for C22H30O3 (M1) 342.2193,
found 342.2189.
1
2931, 2870, 1497, 1458, 1226 cm21; H NMR (270 MHz):
0.79 (3H, s, 1-CH3), 1.14 (3H, d, Jˆ6.9 Hz, 2-CH3), 1.26±
2.03 (9H, m, 2,4a,6,7,8,8a-H), 2.40 (1H, d, Jˆ14.2 Hz,
Ar-CHH), 3.03 (1H, d, Jˆ14.2 Hz, Ar-CHH), 3.75 (3H, s,
OCH3), 3.76 (3H, s, OCH3), 4.05 (1H, br.s, 5-H), 5.30±5.34
(1H, m, 3 or 4-H), 5.78±5.82 (1H, m, 3 or 4-H), 6.69 (1H,
dd, Jˆ3.0, 8.9 Hz, 40-H), 6.78 (1H, d, Jˆ8.9 Hz, 30-H), 6.92
(1H, d, Jˆ3.0 Hz, 60-H); 13C NMR (67.5 MHz) d 17.68,
18.02, 21.29, 25.48, 32.22, 32.29, 34.77, 38.37, 38.49,
45.43, 55.51, 55.78, 0.49, 110.31, 11.14, 117.37, 126.02,
129.79, 136.46, 152.59, 152.92; MS m/z 330 (M1); High
resolution MS calcd for C21H30O3 (M1) 330.2193, found
330.2200.
cis-1a-[(2,5-Dimethoxyphenyl)methyl]-octahydro-1b,
2a,4aa-trimethyl-5(6H)-naphthalenone (4). To a solution
of 5 (10 mg, 30 mmol) in 1 ml of ethanol were added one
drop of Raney-Ni (W-4). This reaction mixture was stirred
for 12 h at rt under H2 gas, ®ltered through a celite-pad, and
then was concentrated in vacuo to give a crude product. To a
solution of PCC (25 mg, 116 mmmol) in 1 ml of CH2Cl2 was
added 50 mg of MS-3A powder and a solution of the crude
product (10 mg) in 3 ml of CH2Cl2 at 08C. This reaction
mixture was stirred for 1 h at rt, diluted by the addition of
ether (5 ml), and ®ltered through a short column of silica
gel. The column was eluted with excess ether. The
combined eluates were concentrated. The residue was puri-
®ed by chromatography on 1 g of silica gel by using 1:10
AcOEt±hexane as eluent, affording 4 (9.8 mg, 98%) as a
white solid. Mp 104±1088C; IR (neat) 2935, 2881, 1701,
1707, 1589, 1498, 1463, 1222 cm21; 1H NMR (270 MHz) d
0.82 (3H, s, 1-CH3), 1.07 (3H, d, Jˆ6.9 Hz, 2-CH3), 1.21±
1.39 (2H, m, 3-H), 1.34 (3H, s, 4a-CH3), 1.53±2.18 (8H, m,
2,4,7,8,8a-H), 2.06±2.34 (1H, m, 6-H), 2.44 (1H, d,
Jˆ13.5 Hz, Ar-CHH), 2.52±2.62 (1H, m, 6-H), 3.04 (1H,
d, Jˆ13.5 Hz, Ar-CHH), 3.75 (6H, s, OCH3£2), 6.69 (1H,
dd, Jˆ3.0, 8.9 Hz, 40-H), 6.76 (1H, d, Jˆ8.9 Hz, 30-H), 6.81
(1H, d, Jˆ3.0 Hz, 60-H); MS m/z 344 (M1); High resolution
MS calcd for C22H32O3 (M1) 344.2349, found 344.2350.
trans-1a-[(2,5-Dimethoxyphenyl)methyl]-1,2,4a,7,8,8a-
hexahydro-1b,2a-dimethyl-5(6H)-naphthalenone (6). To
a suspension of PCC (1.6 g, 5.8 mmol) in 48 ml of CH2Cl2
were added 3.2 g of MS-3A powder and a solution of 11
(1.05 g, 3.2 mmol) in 16 ml of CH2Cl2 at 08C. This reaction
mixture was stirred for 1 h at rt, diluted by the addition of
ether (30 ml), and ®ltered through a short column of silica
gel. The column was eluted with excess ether. The
combined eluates were concentrated in vacuo. The residue
was puri®ed by chromatography on 30 g of silica gel by
using 1:3 ether±hexane as eluent, affording 6 (1.02 g,
98%) as white solid. Mp 119±1218C; IR (neat) 2964,
1
2921, 2845, 1720, 1707, 1378, 1303, 1220 cm21; H NMR

N. Kawai et al. / Tetrahedron 56 (2000) 6467±6478
6475
cis-1a-[(2,5-Dimethoxyphenyl)methyl]-decahydro-1b,
2a,4aa-trimethyl-5-methylenenaphthalene (15). To a
suspension of Zn (800 mg, 12.5 mmol) in 5 ml of THF
were added 0.4 ml (5.8 mmol) of CH2Br2, 3.1 ml
(3.1 mmol) of TiCl4 as a 1.0 M solution in CH2Cl2 and a
solution of 4 (120 mg, 0.35 mmol) in 4.5 ml of THF at rt.
This reaction mixture was stirred for 1 h at rt, diluted by the
addition of ether (30 ml), and poured through a glass-wool
plug into a separator funnel containing 10 ml of ether and
10 ml of 1 N aqueous HCl solution. The aqueous phase was
extracted with two additional 10 ml portions of ether. The
combined extract was washed with 20 ml of saturated
aqueous NaCl solution, dried and concentrated. The residue
was puri®ed by chromatography on 10 g of silica gel by
using 1:25 AcOEt±hexane as eluent, affording 15
(106 mg, 89%) as a white solid. Mp 48±498C; IR (neat)
4 h at 808C under Ar gas, cooled to rt, and 2 ml of H2O and
200 mg of Na2CO3 were added. The reaction mixture was
stirred for 30 min at 608C and concentrated The residue was
puri®ed by chromatography on 1 g of silica gel by using 2:1
chloroform±methanol as eluent, affording 2 (8.1 mg, 50%)
as white solid. Mp.2408C; IR (neat) 3467, 2927, 2873,
1
1556, 1485, 1460, 1261, 1232 cm21; H NMR (500 MHz,
CD3OD) d 0.96 (3H, s, 1-CH3), 1.13 (3H, d, Jˆ6.9 Hz,
2-CH3), 1.25 (3H, s, 4a-CH3), 1.51±2.06 (10H, m,
2,3,4,7,8,8a-H), 2.14±2.20 (1H, m, 6-H), 2.40±2.50 (1H,
m, 6-H), 2.53 (1H, d, Jˆ14.0 Hz, Ar-CHH), 3.26 (1H, d,
Jˆ14.0 Hz, Ar-CHH), 4.67 (1H, br.s, 5 vCHH), 4.75 (1H,
br.s, 5 vCHH), 7.08 (1H, dd, Jˆ3.0, 8.9 Hz, 40-H), 7.31
(1H, d, Jˆ3.0 Hz, 60-H), 7.38 (1H, d, Jˆ8.9 Hz, 30-H); 13C
NMR (125 MHz, CD3OD) d 16.5 (2-CH3), 23.2 (8), 25.4
(1-CH3), 26.1 (7), 27.0 (3), 32.3 (4), 32.5 (4a-CH3), 33.4 (6),
36.6 (Ar-CH2), 39.1 (2), 41.3 (1), 42.6 (4a), 47.0 (8a),
106.3 (5 vCH2), 120.3 (40), 123.2 (30), 125.2 (60),
135.4 (10), 149.9 (50), 150.1 (20), 157.2 (5); FABMS m/z
541 (M1Na)1; High resolution FABMS calcd for
C21H28O8S2Na3 (M1Na)1 541.0918, found 541.0914.
2935, 2831, 1498, 1463, 1282, 1222 cm21 1H NMR
;
(270 MHz) d 0.92 (3H, s, 1-CH3), 1.09 (3H, d, Jˆ6.9 Hz,
2-CH3), 1.25 (3H, s, 4a-CH3), 1.41±1.92 (10H, m,
2,3,4,7,8,8a-H), 2.15±2.23 (1H, m, 6-H), 2.35±2.45 (1H,
m, 6-H), 2.42 (1H, d, Jˆ13.9 Hz, Ar-CHH), 3.04 (1H, d,
Jˆ13.9 Hz, Ar-CHH), 3.74 (3H, s, OCH3), 3.75 (3H, s,
OCH3), 4.69 (1H, br.s, 5 vCHH), 4.75 (1H, br.s, 5
vCHH), 6.67 (1H, dd, Jˆ3.0, 8.9 Hz, 40-H), 6.75 (1H, d,
Jˆ8.9 Hz, 30-H), 6.85 (1H, d, Jˆ3.0 Hz, 60-H); MS m/z 342
(M1); High resolution MS calcd for C23H34O2 (M1)
342.2557, found 342.2545.
trans-1a-[(2,5-Dimethoxyphenyl)methyl]-octahydro-1b,
2a,4ab-trimethyl-5(6H)-naphthalenone ethylene ketal
(22). To a solution of trans-1a-[(2,5-dimethoxy-phenyl)-
methyl]-octahydro-1b,4ab-dimethyl-2-methylene-5(6H)-
naphthalenone ethylene ketal (300 mg, 0.777 mmol) in
10 ml of ethanol were added two drops of Raney-Ni. This
reaction mixture was stirred for 12 h at rt under H2 gas,
®ltered through a celite-pad and concentrated. The residue
was puri®ed by chromatography on 40 g of silica gel by
using 1:20 AcOEt±hexane as eluent, affording 22 (83 mg,
28%) as a colorless oil and 188 mg (62%) of the stereo-
isomer 23. 22: IR (neat) 2950, 2879, 1497, 1466,
cis-1a-[(2,5-Dihydroxyphenyl)methyl]-decahydro-1b,
2a,4aa-trimethyl-5-methylenenaphthalene (16). To a
solution of 15 (44 mg, 0.128 mmol) in 9 ml of CH3CN
was added, dropwise, a solution of CAN (195 mg,
0.355 mmol) in 4.5 ml of H2O over 1 h. This solution was
stirred for 1 day at rt, diluted with 10 ml of H2O, and
extracted with 30 ml of ether. The extract was washed
with 30 ml of saturated aqueous NaCl solution, dried and
concentrated to give a crude product.
1
1224 cm21; H NMR (270 MHz) d 0.82 (3H, s, 1-CH3),
1.12 (3H, s, 4a-CH3), 1.18 (3H, d, Jˆ6.9 Hz, 2-CH3),
1.25±1.91 (12H, m, 2,3,4,6,7,8,8a-H), 2.28 (1H, d,
Jˆ13.9 Hz, ArCHH), 3.03 (1H, d, Jˆ13.9 Hz, ArCHH),
3.74 (3H, s, O±CH3), 3.75 (3H, s, O±CH3), 3.77±4.00
(4H, m, O-CH2), 6.67 (1H, dd, Jˆ3.0,8.9 Hz, 40-H), 6.75
(1H, d, Jˆ8.9 Hz, 30-H), 6.88 (1H, d, Jˆ3.0 Hz, 60-H); MS
m/z 388 (M1); High resolution MS calcd for C24H36O4 (M1)
388.2611, found 388.2602. 23: 1H NMR (270 MHz) d 0.81
(3H, s, 1-CH3), 0.94 (3H, d, Jˆ5.6 Hz, 2-CH3), 1.05 (3H, s,
4a-CH3), 1.20±1.71 (11H, m, 2,3,4,6,7,8-H), 1.94 (1H, d,
Jˆ13.6 Hz, 8a-H), 2.63 (2H, s, Ar-CH2), 3.78 (3H, s,
OCH3), 3.78 (3H, s, OCH3), 3.70±3.85 (4H, m, OCH2),
6.65±6.86 (3H, m, 30,40,60-H).
To a solution of the crude quinone in 3 ml of THF was
added a solution of Na2S2O4 (200 mg) in 1 ml of H2O.
The solution was stirred for 10 min at rt, diluted with 5 ml
of H2O, and extracted with 10 ml of AcOEt. The extract was
washed with 30 ml of saturated aqueous NaCl solution,
dried and concentrated. The residue was puri®ed by
chromatography on 5 g of silica gel by using 1:5 AcOEt±
hexane as eluent, affording 16 (10 mg, 25%) as a yellow oil.
IR (neat) 3481, 3417, 3373, 2956, 2873, 1635, 1452,
1
1215 cm21; H NMR (270 MHz) d 0.98 (3H, s, 1-CH3),
1.10 (3H, d, Jˆ6.9 Hz, 2-CH3), 1.26 (3H, s, 4a-CH3),
1.45±1.93 (10H, m, 2,3,4,7,8,8a-H), 2.14±2.23 (1H, m,
6-H), 2.35±2.45 (1H, m, 6-H), 2.39 (1H, d, Jˆ13.9 Hz,
Ar-CHH), 2.97 (1H, d, Jˆ13.9 Hz, Ar-CHH), 4.35±4.41
(2H, m, OH), 4.71 (1H, br.s, 5 vCHH), 4.77 (1H, br.s, 5
vCHH), 6.53 (1H, dd, Jˆ3.0, 8.9 Hz, 40-H), 6.61 (1H, d,
Jˆ8.9 Hz, 30-H), 6.75 (1H, d, Jˆ3.0 Hz, 60-H); MS m/z 314
(M1); High resolution MS calcd for C21H30O2 (M1)
314.2155, found 314.2163.
trans-1a-[(2,5-Dimethoxyphenyl)methyl]-octahydro-1b,
2a,4ab-trimethyl-5(6H)-naphthalenone (17). To a solu-
tion of 22 (55 mg, 0.142 mmol) in 10 ml of THF was
added a solution of 1 N aqueous HCl solution (5 ml). This
reaction mixture was stirred for 10 min at rt, and quenched
by the addition of saturated aqueous NaHCO3 solution
(10 ml). The aqueous phase was extracted with two 10 ml
portions of ether. The combined extract was washed with
20 ml of saturated aqueous NaCl solution, dried and concen-
trated. The residue was puri®ed by chromatography on 10 g
of silica gel by using 1:25 AcOEt±hexane as eluent, afford-
ing 17 (48 mg, 98%) as a colorless oil. IR (neat) 2950, 2833,
cis-1a-[(2,5-bis(Sodiumoxysulfonyloxy)phenyl]methyl-
decahydro-1b,2a,4aa-trimethyl-5-methylenenaphtha-
lene (2). To a solution of SO3´pyridine (26 mg, 64 mmol) in
1 ml of pyridine was added a solution of 16 (10 mg,
32 mmol) in 3 ml of pyridine. This solution was stirred for
1705, 1589, 1497, 1463, 1282, 1223 cm21
;
1H NMR
(270 MHz) d 0.93 (3H, s, 1-CH3), 1.15 (3H, s, 4a-CH3),

6476
N. Kawai et al. / Tetrahedron 56 (2000) 6467±6478
1.20 (3H, d, Jˆ6.9 Hz, 2-CH3), 1.22±2.10 (10H, m,
2,3,4,7,8,8a-H), 2.17±2.35 (1H, m, 6H), 2.28 (1H, d,
Jˆ13.9 Hz, ArCHH), 2.50±2.63 (1H, m, 6H), 3.03 (1H, d,
Jˆ13.9 Hz, Ar-CHH), 3.74 (3H, s, O±CH3), 3.75 (3H, s,
O-CH3), 6.67 (1H, dd, Jˆ3.0, 8.9 Hz, 40-H), 6.75 (1H, d,
Jˆ8.9 Hz, 30-H), 6.85 (1H, d, Jˆ3.0 Hz, 60-H); MS m/z 344
(M1); High resolution MS calcd for C22H32O3 (M1)
344.2349, found 344.2341.
resolution MS calcd for C21H30O2 (M1) 314.2244, found
314.2245.
trans-1a-[(2,5-bis(Sodiumoxysulfonyloxy)phenyl]methyl-
decahydro-1b,2a,4ab-trimethyl-5-methylenenaphtha-
lene (3). To a solution of SO3´pyridine (26 mg, 64 mmol) in
1 ml of pyridine was added a solution of 26 (10 mg,
32 mmol) in 3 ml of pyridine. The solution was stirred for
4 h at 808C under Ar gas, cooled to rt, and 2 ml of H2O and
200 mg of Na2CO3 were added. The reaction mixture was
stirred for 30 min at 608C and concentrated. The residue was
puri®ed by chromatography on 1 g of silica gel by using 2:1
chloroform±methanol as eluent, affording 3 (10 mg, 61%)
as white solid. Mp.2408C; IR (neat) 3471, 2931, 1564,
trans-1a-[(2,5-Dimethoxyphenyl)methyl]-decahydro-1b,
2a,4ab-trimethyl-5-methylenenaphthalene (25). To a
suspension of Zn (125 mg, 1.98 mmol) in 2 ml of THF
were added 45 ml (0.6 mmol) of CH2Br2, 0.48 ml
(0.48 mml) of TiCl4 as a 1.0 M solution in CH2Cl2, and a
solution of 17 (15 mg, 44 mmol) in 1.5 ml of THF at rt. This
reaction mixture was stirred for 1 h at rt, diluted by the
addition of ether (20 ml), and poured through a glass-wool
plug into a separatory funnel containing 10 ml of ether and
10 ml of 1N aqueous HCl solution. The aqueous phase was
extracted with two additional 10 ml portions of ether. The
combined extract was washed with 20 ml of saturated
aqueous NaCl solution, dried and concentrated. The residue
was puri®ed by chromatography on 1 g of silica gel by using
1:25 AcOEt±hexane as eluent, affording 25 (11.5 mg, 76%)
as a white solid. Mp 32±348C; IR (neat) 2941, 2831, 1498,
;
1485, 1380, 1257, 1232 cm21 1H NMR (500 MHz,
CD3OD) d 0.89 (3H, s, 1-CH3), 1.14 (3H, s, 4a-CH3), 1.17
(3H, d, Jˆ6.9 Hz, 2-CH3), 1.20±2.04 (10H, m, 2,3,4,7,8,8a-
H), 2.07±2.15 (1H, m, 6-H), 2.30±2.40 (1H, m, 6-H), 2.33
(1H, d, Jˆ14.0 Hz, ArCHH), 4.46 (1H, br.s, 5 vCHH), 4.52
(1H, br.s, 5 vCHH), 7.08 (1H, dd, Jˆ3.0, 8.9 Hz, 40-H),
7.34 (1H, d, Jˆ3.0 Hz, 60-H), 7.38 (1H, d, Jˆ8.9 Hz, 30-H);
13C NMR (125 MHz, CD3OD) d 16.8 (2-CH3), 20.8
(1-CH3), 22.5 (4a-CH3), 23.1 (8), 26.6 (7), 30.0 (3), 31.2
(4), 34.1 (6), 36.5 (Ar-CH2), 37.0 (2), 42.1 (1), 42.1 (4a),
49.6 (8a), 102.4 (5 vCH2), 120.3 (40), 123.1 (30), 124.6
(60), 135.3 (10), 150.1 (50), 150.2 (20), 161.5 (5); FABMS
m/z 541 (M1Na)1; High resolution FABMS calcd for
C21H28O8S2Na3 (M1Na)1 541.0955, found 541.0959.
1
1463, 1381, 1282, 1225 cm21; H NMR (270 MHz) d 0.86
(3H, s, 1-CH3), 1.12 (3H, s, 4a-CH3), 1.15 (3H, d, Jˆ6.9 Hz,
2-CH3), 1.22±1.98 (10H, m, 2,3,4,7,8,8a-H), 2.13±2.40
(2H, m, 6-H), 2.22 (1H, d, Jˆ13.9 Hz, ArCHH), 3.03 (1H,
d, Jˆ13.9 Hz, ArCHH), 3.74 (3H, s, O-CH3), 3.75 (3H, s,
O-CH3), 4.49 (1H, br.s, 5 vCHH), 4.54 (1H, br.s, 5
vCHH), 6.68 (1H, dd, Jˆ3.0, 8.9 Hz, 40-H), 6.75 (1H, d,
Jˆ8.9 Hz, 30-H), 6.88 (1H, d, Jˆ3.0 Hz, 60-H); MS m/z 342
(M1); High resolution MS calcd for C23H34O2 (M1)
342.2557, found 342.2564.
Optical resolution of ketone 6 by addition of sulfoxy-
imine
To a solution of (S)-(1)-N,S-dimethyl-S-phenylsulfoxy-
imine (71 mg, 0.4 mmol) in 4 ml of dry THF was added
0.4 ml (0.4 mmol) of n-BuLi as a 1.0 M solution in n-hexane
at 08C. The solution was stirred for 30 min at 08C under Ar
gas, and then ketone 6 (65 mg, 0.2 mmol) was added as a
solution of THF at 2788C. After being stirred for 1 h at
2788C under Ar, the reaction mixture was quenched by
the addition of sat NH4Cl aq. The aqueous phase was
extracted with two additional 10 ml portions of ether. The
combined extract was washed with 20 ml of saturated
aqueous NaCl solution, dried and concentrated. The residue
was puri®ed by chromatography on 10 g of silica gel by
using 1:25 AcOEt±hexane as eluent, affording 28 (42 mg,
43%) as a white solid, 29 (3 mg, 3%) as a white solid, 30
(25 mg, 27%) as a white solid, 31 (14 mg, 15%) as a white
solid.
trans-1a-[(2,5-Dihydroxyphenyl)methyl]-decahydro-1b,
2a,4ab-trimethyl-5-methylenenaphthalene (26). To a
solution of 25 (42 mg, 0.12 mmol) in 12 ml of CH3CN
was added, dropwise, a solution of CAN (134 mg,
0.246 mmol) in 6 ml of H2O over 1 h. This solution was
stirred for 1 day at rt, diluted with 10 ml of H2O, and
extracted with 30 ml of ether. The extract was washed
with 30 ml of saturated aqueous NaCl solution, dried and
concentrated to give a crude product.
To a solution of the crude quinone in 3 ml of THF was
added a solution of Na2S2O4 (200 mg) in 1 ml of H2O.
The solution was stirred for 10 min at rt, diluted with 5 ml
of H2O, and extracted with 10 ml of AcOEt. The extract was
washed with 30 ml of saturated aqueous NaCl solution,
dried and concentrated. The residue was puri®ed by
chromatography on 5 g of silica gel by using 1:5 AcOEt±
hexane as eluent, affording 26 (11 mg, 28%) as a yellow oil.
28. Mp 1638C; [a]2D3ˆ1578 (c 0.18, CHCl3); IR (neat) 3418,
2956, 1654, 1496, 1222, 1138 cm21; 1H NMR (270 MHz) d
0.73 (3H, s, 1-CH3), 1.16 (3H, d, Jˆ6.9 Hz, 2-CH3), 1.58±
2.09 (8H, m, 2,6,7,8,8a-H), 2.41 (1H, d, Jˆ13.8 Hz,
ArCHH), 2.60 (3H, s, N-CH3), 2.70±2.81 (1H, m, 4a-H),
2.90 (1H, d, Jˆ13.5 Hz, CHHS), 3.03 (1H, d, Jˆ13.8 Hz,
ArCHH), 3.73 (1H, d, Jˆ13.5 Hz, CHHS), 3.75 (6H, s,
OCH£32), 5.34±5.38 (1H, m, 4-H), 5.70±5.81 (1H, m,
3-H), 6.68 (1H, dd, Jˆ3.0, 8.9 Hz, 40-H), 6.76 (1H, d,
Jˆ8.9 Hz, 30-H), 6.90 (1H, d, Jˆ3.0 Hz, 60-H), 7.57±7.63
(3H, m, S-Ar), 7.86±7.90 (2H, m, S-Ar); MS m/z 497 (M1).
IR (neat) 3475, 2931, 1635, 1504, 1452, 1381, 1194 cm21
;
1H NMR (270 MHz) d 0.92 (3H, s, 1-CH3), 1.13 (3H, s,
4a-CH3), 1.16 (3H, d, Jˆ6.9 Hz, 2-CH3), 1.19±2.04 (10H,
m, 2,3,4,7,8,8a-H), 2.09±2.40 (2H, m, 6-H), 2.23 (1H, d,
Jˆ13.9 Hz, ArCHH), 2.91 (1H, d, Jˆ13.9 Hz, ArCHH),
4.34 (1H, br.s, OH), 4.39 (1H, br.s, OH), 4.50 (1H, br.s,
5 vCHH), 4.55 (1H, br.s, 5 vCHH), 6.54 (1H, dd, Jˆ3.0,
8.9 Hz, 40-H), 6.62 (1H, d, Jˆ8.9 Hz, 30-H), 6.78 (1H,
d, Jˆ3.0 Hz, 60-H); MS m/z 314 (M1); High
29. Mp 110±1148C; [a]D23ˆ1278 (c 0.08, CHCl3); IR (neat)
3421, 2931, 1654, 1496, 1222, 1138 cm21 1H NMR
;

N. Kawai et al. / Tetrahedron 56 (2000) 6467±6478
6477
(270 MHz) d 0.76 (3H, s, 1-CH3), 1.04 (3H, d, Jˆ6.9 Hz,
2-CH3), 1.20±2.08 (8H, m, 2,6,7,8,8a-H), 2.31 (1H, d,
Jˆ13.8 Hz, ArCHH), 2.77 (3H, s, N-CH3), 2.92 (1H, d,
Jˆ13.8 Hz, ArCHH), 3.32 (1H, d, Jˆ13.5 Hz, CHHS),
3.56 (1H, d, Jˆ13.5 Hz, CHHS), 3.70 (6H, s, OCH£32),
5.68±5.81 (2H, m, 3,4-H), 6.68 (1H, dd, Jˆ3.0, 8.9 Hz,
40-H), 6.74 (1H, d, Jˆ8.9 Hz, 30-H), 6.85 (1H, d,
Jˆ3.0 Hz, 60-H), 7.57±7.63 (3H, m, S-Ar), 7.86±7.90
(2H, m, S-Ar); MS m/z 497 (M1).
gel by using 1:15 AcOEt±hexane as eluent, affording 6
(135 mg, 97%) as a white solid.
A solution of 29 (14 mg, 29 mmol) in deoxygenated toluene
(3 ml) was heated 1208C in a sealed tube for 20 h, cooled,
and concentrated. The residue was puri®ed by chromato-
graphy on 1 g of silica gel by using 1:15 AcOEt±hexane
as eluent, affording 6 (9.2 mg, 97%) as a white solid. Mp
119±1218C; [a]Dˆ23.48 (c 1.02, CHCl3).
30. Mp 1678C; [a]2D3ˆ2458 (c 0.21, CHCl3); IR (neat) 3423,
2932, 1654, 1496, 1222, 1138 cm21; 1H NMR (270 MHz), d
0.78 (3H, s, 1-CH3), 0.93 (3H, d, Jˆ6.9 Hz, 2-CH3), 1.20±
2.08 (8H, m, 2,6,7,8,8a-H), 2.31 (1H, d, Jˆ13.8 Hz,
ArCHH), 2.60 (3H, s, N-CH3), 2.98 (1H, d, Jˆ13.8 Hz,
ArCHH), 3.23±3.25 (2H, m, CH2S), 3.73 (6H, s,
OCH3£2), 5.60±5.70 (1H, m, 3-H), 5.75±5.81 (1H, m,
4-H), 6.67 (1H, dd, Jˆ3.0, 8.9 Hz, 40-H), 6.75 (1H, d,
Jˆ8.9 Hz, 30-H), 6.86 (1H, d, Jˆ3.0 Hz, 60-H), 7.56±7.67
(3H, m, S-Ph), 7.87±7.92 (2H, m, S-Ph); MS m/z 497 (M1).
(1)-(1R,2S,4aS,5R,8aS)-trans-1b-[(2,5-Dimethoxyphenyl)-
methyl]-1,2,4a,7,8,8a-hexahydro-1a,2b-dimethyl-5(6H)-
naphthalenone ((1)-6). A solution of 30 (125 mg,
0.26 mmol) in deoxygenated toluene (15 ml) was heated
1208C in a sealed tube for 10 h, cooled, and concentrated.
The residue was puri®ed by chromatography on 10 g of
silica gel by using 1:15 AcOEt±hexane as eluent, affording
6 (82 mg, 96%) as a white solid.
A solution of 31 (70 mg, 0.15 mmol) in deoxygenated
toluene (10 ml) was heated 1208C in a sealed tube for
12 hrs, cooled, and concentrated. The residue was puri®ed
by chromatography on 10 g of silica gel by using 1:15
AcOEt±hexane as eluent, affording 6 (47 mg, 96%) as a
white solid. Mp 118±1208C, [a]Dˆ13.38 (c 0.57, CHCl3).
31. Mp 122±1248C; [a]D23ˆ2408 (c 2.16, CHCl3); IR (neat)
3401, 3019, 1497, 1215, 1136 cm21; 1H NMR (270 MHz), d
0.74 (3H, s, 1-CH3), 1.13 (3H, d, Jˆ6.9 Hz, 2-CH3), 1.61±
2.07 (8H, m, 2,6,7,8,8a-H), 2.30±2.36 (1H, m, 4a-H), 2.39
(1H, d, Jˆ13.8 Hz, ArCHH), 2.72 (3H, s, N-CH3), 2.99 (1H,
d, Jˆ13.8 Hz, ArCHH), 3.31 (1H, d, Jˆ14.2 Hz, CHHS),
3.73 (6H, s, OCH£32), 3.72 (1H, d, Jˆ14.2 Hz, CHHS),
5.47±5.51 (1H, m, 4-H), 5.74±5.81 (1H, m, 3-H), 6.68
(1H, dd, Jˆ3.0, 8.9 Hz, 40-H), 6.76 (1H, d, Jˆ8.9 Hz,
30-H), 6.90 (1H, d, Jˆ3.0 Hz, 60-H), 7.52±7.61 (3H, m,
S-Ar), 7.84±7.88 (2H, m, S-Ar); MS m/z 497 (M1).
cis-1a-[(2,5-Dimethoxyphenyl)methyl]-1,2,4a,7,8,8a-
hexahydro-1b,2a-dimethyl-4aa-(ethylcarboxylate)-
methyl-5(6H)-naphthalenone (35). To a solution of 6
(164 mg, 0.5 mmol) in 8 ml of dry THF was added 0.5 ml
(0.5 mmol) of NaN{Si(CH3)3}2 as a 1.0 M solution in THF
at rt. The solution was stirred for 20 min at rt under Ar gas
and then 0.165 ml (1.4 mmol) of ICH2CO2Et was added at
2788C. After being stirred for 1 h at 2788C under Ar, the
reaction mixture was diluted by the addition of H2O (4 ml).
The aqueous phase was extracted with two 10 ml portions of
AcOEt. The combined extract was washed with 10 ml of
saturated aqueous NaCl solution, dried and concentrated.
The residue was puri®ed by chromatography on 10 g of
silica gel by using 1:15 AcOEt±hexane as eluent, affording
35 (188 mg, 90%) as a white solid. Mp 30±348C; IR (neat)
2956, 2881, 2832, 1731, 1702, 1589, 1496, 1454, 1369,
X-Ray diffraction study
28. C29H39O4SN: colorless crystal (0.30£0.35£0.20 mm,
grown from dichloromethane), C29H39O4SN, M 497.70,
Ê
orthorhombic, space group P212121, aˆ18.236(4) A,
Ê
Ê
Ê
bˆ18.277(4) A, cˆ8.087(2) A, Vˆ2696(1) A, Zˆ4, Dˆ
1.23 g/cm3, F(000)ˆ1071, Tˆ293 K. A Mac Science
MXC18 diffractometer and graphite monochromated
Ê
CuKa radiation, lˆ1.54178 A, was used for all measure-
1
1336, 1218, 1051 cm21; H NMR (270 MHz) d 1.01 (3H,
ments. Cell constants and an orientation matrix for data
collection were obtained from a least-squares re®nement
using the setting angles of 20 carefully centered re¯ections.
s, 1-CH3), 1.09 (3H, d, Jˆ6.9 Hz, 2-CH3), 1.16 (3H, t,
Jˆ6.8 Hz, OCH2CH3),1.79±2.16 (5H, m, 2,7,8,8a-H),
2.27±2.34 (1H, m, 8a-H), 2.49±2.64 (2H, m, 6-H), 2.53
(1H, d, Jˆ15.1 Hz, ArCHH), 2.73 (1H, d, Jˆ15.6 Hz,
4a-CHH), 2.92 (1H, d, Jˆ15.1 Hz, ArCHH), 3.74 (3H, s,
O±CH3), 3.76 (3H, s, O±CH3), 3.88±4.05 (2H, m,
OCH2CH3), 5.47±5.51 (1H, m, 4-H), 5.69±5.72 (1H, m,
3-H), 6.67 (1H, dd, Jˆ3.0, 8.9 Hz, 40-H), 6.76 (1H, d,
Jˆ3.0 Hz, 60-H), 6.86 (1H, d, Jˆ8.9 Hz, 30-H); MS m/z
414 (M1); High resolution MS calcd for C25H34O5 (M1)
414.2406, found 414.2402.
30. C29H39O4SN: colorless crystal (0.40£0.30£0.44 mm,
grown from dichloromethane), C29H39O4SN, M 497.70,
Ê
orthorhombic, space group P212121, aˆ14.412(4) A,
Ê
Ê
Ê
bˆ21.788(5) A, cˆ8.619(3) A, Vˆ2706(1) A, Zˆ4, Dˆ
1.22 g/cm3, F(000)ˆ1071, Tˆ293 K. A Mac Science
MXC18 diffractometer and graphite monochromated
Ê
CuKa radiation, lˆ1.54178 A, was used for all measure-
ments. Cell constants and an orientation matrix for data
collection were obtained from a least-squares re®nement
using the setting angles of 20 carefully centered re¯ections.
cis-1a-[(2,5-Dimethoxyphenyl)methyl]-decahydro-1b,
2a-dimethyl-4aa-(ethylcarboxylate)methyl-5(6H)-
naphthalenone (37). To a solution of 35 (80 mg,
0.19 mmol) in 3 ml of ethanol was added ca. 90 mg of
Raney-Ni (W-4). This reaction mixture was stirred for
3days at rt under H2 gas, ®ltered through a celite-pad, and
then was concentrated and puri®ed by chromatography on
10 g of silica gel by using 1:10 AcOEt±hexane as eluent,
(2)-(1S,2R,4aR,5S,8aR)-trans-1a-[(2,5-Dimethoxyphenyl)-
methyl]-1,2,4a,7,8,8a-hexahydro-1b,2a-dimethyl-5(6H)-
naphthalenone ((2)-6). A solution of 28 (210 mg,
0.43 mmol) in deoxygenated toluene (15 ml) was heated
1208C in a sealed tube for 3 h, cooled, and concentrated.
The residue was puri®ed by chromatography on 1 g of silica

6478
N. Kawai et al. / Tetrahedron 56 (2000) 6467±6478
affording 37 (79 mg, 98%) as a white solid. Mp 42±458C;
References
1
IR (neat) 2929, 1726, 1461, 1272, 1122 cm21; H NMR
(270 MHz) d 0.86 (3H, s, 1-CH3), 1.00 (3H, d, Jˆ6.9 Hz,
2-CH3), 1.18 (3H, t, Jˆ6.8 Hz, OCH2CH3), 1.34±2.06
(10H, m, 2,3,4,7,8,8a-H), 2.54±2.58 (2H, m, 6-H), 2.59
(1H, d, Jˆ13.9 Hz, ArCHH), 2.90 (1H, d, Jˆ13.9 Hz,
ArCHH), 3.07 (1H, d, Jˆ16.3 Hz, 4a-CHH), 3.75 (6H, s,
O±CH£32), 3.97±4.05 (2H, m, OCH2CH3), 6.67 (1H, dd,
Jˆ3.0, 8.9 Hz, 40-H), 6.73 (1H, d, Jˆ3.0 Hz, 60-H), 6.75
(1H, d, Jˆ8.9 Hz, 30-H); MS m/z 416 (M1); High resolution
MS calcd for C25H36O5 (M1) 416.2563, found 416.2567.
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2a-dimethyl-4aa-(ethylcarboxylate)methyl-5-methyl-
enenaphthalene (32). To a suspension of Zn (183 mg,
2.8 mmol) in 5 ml of THF were added 66 ml (0.94 mmol)
of CH2Br2, 0.7 ml (0.7 mml) of TiCl4 as a 1.0 M solution in
CH2Cl2 and a solution of 37 (23 mg, 55 mmol) in 3 ml of
THF at rt. This reaction mixture was stirred for 1 h at rt,
diluted by the addition of ether (10 ml), and poured through
a glass-wool plug into a separatory funnel containing 5 ml
of ether and 10 ml of 1N aqueous HCl solution. The aqueous
phase was extracted with two additional 10 ml portions of
ether. The combined extract was washed with 20 ml of
saturated aqueous NaCl solution, dried and concentrated.
The residue was puri®ed by chromatography on 10 g of
silica gel by using 1:25 AcOEt±hexane as eluent, affording
32 (19 mg, 83%) as a white solid. Mp 55±578C; IR (neat)
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D. J. Org. Chem. 1990, 55, 4709±4711. (b) Anderson, J. C.;
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2958, 2854, 1720, 1641, 1498, 1222 cm21 1H NMR
;
(270 MHz) d 0.83 (3H, s, 1-CH3), 1.12 (3H, d, Jˆ 6.9 Hz,
2-CH3), 1.20 (3H, t, Jˆ6.8 Hz, OCH2CH3), 1.34±2.06 (12H,
m, 2,3,4,6,7,8,8a-H), 2.32 (1H, d, Jˆ13.9 Hz, ArCHH), 2.37
(1H, d, Jˆ16.3 Hz, 4a-CHH), 2.88 (1H, d, Jˆ13.9 Hz,
ArCHH), 3.07 (1H, d, Jˆ16.3 Hz, 4a-CHH), 3.75 (6H, s,
O-CH£32), 4.07 (2H, q, Jˆ6.9 Hz, OCH2CH3), 4.80 (2H, s,
CvCH2), 6.68 (1H, dd, Jˆ3.0, 8.9 Hz, 40-H), 6.75 (1H, d,
Jˆ3.0 Hz, 60-H), 6.83 (1H, d, Jˆ8.9 Hz, 30-H); MS m/z 414
(M1); High resolution MS calcd for C26H38O4 (M1)
414.2416, found 414.2412.
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Acknowledgements
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We thank Prof. Kazuo Umezawa (Keio University) for help-
ful discussions. We also thank Shin-Etsu Chemical Co. Ltd
for a generous donation of silyl compounds. This work was
supported in part by CREST, Japan Science and Technology
Corporation.