Stereoselective synthesis of cis and trans-fused 3a-aryloctahydroindoles using cyclization of N-vinylic α-(methylthio)acetamides: synthesis of (-)-mesembrane

Article abstract of DOI:10.1016/j.tet.2007.03.153

Treatment of N-(2-arylcyclohex-1-en-1-yl)-α-(methylthio)acetamides with N-chlorosuccinimide (NCS) gave 3a-aryl-2,3,3a,4,5,6-hexahydro-3-(methylthio)indol-2-ones. Desulfurization of the cyclization products followed by a catalytic hydrogenation of the resu

Full text of DOI:10.1016/j.tet.2007.03.153

Tetrahedron 63 (2007) 4865–4873
Stereoselective synthesis of cis and trans-fused
3a-aryloctahydroindoles using cyclization of N-vinylic
a-(methylthio)acetamides: synthesis of (L)-mesembrane
*
Miho Saito, Jun-ichi Matsuo and Hiroyuki Ishibashi
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kanazawa 920-1192, Japan
Received 19 February 2007; revised 23 March 2007; accepted 23 March 2007
Available online 30 March 2007
Abstract—Treatment of N-(2-arylcyclohex-1-en-1-yl)-a-(methylthio)acetamides with N-chlorosuccinimide (NCS) gave 3a-aryl-2,3,3a,4,
5,6-hexahydro-3-(methylthio)indol-2-ones. Desulfurization of the cyclization products followed by a catalytic hydrogenation of the resulting
hexahydroindol-2-ones gave predominantly or exclusively trans-fused octahydroindol-2-ones. On the other hand, reduction of the desulfur-
ization products with Et3SiH in CF3CO2H exclusively provided cis-fused octahydroindol-2-ones. A chiral induction of N-[2-(3,4-dimethoxy)-
phenylcyclohex-1-en-1-yl]-a-(methylthio)acetamide having an (R)-1-(1-naphthyl)ethyl group on the nitrogen atom led to the synthesis of
(ꢀ)-mesembrane and (ꢀ)-trans-mesembrane.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
We have been interested in the application of this method to
the synthesis of 3a-aryloctahydroindoles such as (ꢂ)-me-
sembrane (cis-13) using the cyclization of a-chlorosulfide
8 giving 10. We report here that a-(methylthio)acetamide
6, when treated with N-chlorosuccinimide (NCS), gives no
a-chlorosulfide 8 but directly affords the desired cyclization
product, 3a-arylhexahydroindol-2-one 10, the reduction of
which provides a new method for the synthesis of (ꢂ)-me-
sembrane (cis-13) and its isomer trans-13. Stereoselective
synthesis of (ꢀ)-mesembrane (29) and (ꢀ)-trans-mesem-
brane (33) using cyclization of enamide 22 having a chiral
auxiliary on the nitrogen atom is also described.3
Carbon–carbon bond-forming reactions of a-chlorosulfides
with external or internal alkenic bonds, which are generally
performed in the presence of Lewis acid, have emerged as
a valuable tool in organic synthesis.1 For example, a-chloro-
sulfides gave ene reaction products and [3++2], [4++2], and
[2++4] polar cycloaddition products with external alkenes,
and olefin cyclization products with internal alkenic bonds.
We previously reported that N-vinylic a-chloro-a-(methyl-
thio)acetamide 1 underwent cyclization at 100 ꢁC in the ab-
sence of Lewis acid to give the product 3 in 30% yield
(Scheme 1).2 This cyclization can be explained in terms of
a high nucleophilic nature of the alkenic bond of enamide
1 giving the intermediacy of acyliminium ion 2. Dehydro-
chlorination of 2 followed by migration of the alkenic
bond would afford 3.
2. Results and discussion
2.1. Synthesis of ( )-mesembrane and ( )-trans-
mesembrane
Ph
Cl–
SMe
O
Ph
SMe
O
Ph
SMe
Cl
O
We began our investigation by examining the cyclization of
N-(2-arylcyclohex-1-en-1-yl)-a-chloro-a-(methylthio)acet-
amide 8 (Scheme 2). The requisite a-(methylthio)acetamide
6 was prepared in 52% yield by condensation of 2-(3,4-di-
methoxyphenyl)cyclohexanone4 and methylamine followed
by acylation of the resulting imine 4 with (methylthio)acetyl
chloride (5).5
100 °C
+
N
N
PMB
3
N
PMB
1
PMB
2
PMB = p-methoxybenzyl
Scheme 1.
Treatment of sulfide 6 with N-chlorosuccinimide (NCS) in
CCl4 at room temperature gave the cyclization product,
3-(methylthio)hexahydroindol-2-one 10, in 48% yield as a
single stereoisomer. No expected a-chlorosulfide 8 was
Keywords: (ꢀ)-Mesembrane; 3a-Aryloctahydroindole; Triethylsilane; a-
Chloro-a-(methylthio)acetamide; N-Chlorosuccinimide.
* Corresponding author. Tel.: +81 76 234 4474; fax: +81 76 234 4476;
e-mail: isibasi@p.kanazawa-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.153

4866
M. Saito et al. / Tetrahedron 63 (2007) 4865–4873
OMe
OMe
OMe
OMe
O
OMe
MeS
Cl
OMe
MeNH2
MS 4A
5
NCS
SMe
toluene
110 °C, 17 h
sealed tube
CCl4
rt, 2.5 h
PhNMe2, DMAP
toluene
0 °C to rt, 10 min
N
Me
O
N
Me
O
6 (52%)
4
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
+
Raney Ni
SMe
SMe
Cl
O
SMe
SMe
+
3a
Cl–
O
EtOH
reflux, 3 h
N
Me
N
Me
N
N
Me
O
O
Cl–
Me
9
8
10 (48%)
7
OMe
OMe
OMe
OMe
OMe
OMe
OMe
O
OMe
OMe
O
OMe
LiAlH4
H2, PtO2
AcOH
rt, 1.5 h
+
+
THF
reflux
10 min
N
N
H
O
N
H
N
H
N
H
Me
11 (87%)
Me
Me
Me
Me
( )-trans-
trans-12
cis-12
( )-mesembrane
(cis-13, 29%)
mesembrane
(trans-13, 53%)
(90%, trans-12/cis-12 = 2:1, inseparable)
Scheme 2.
obtained. The cyclization of 6 to 10 can be best explained by
rapid intramolecular nucleophilic attack of an electron-rich
alkenic bond of 7 on the thionium ion, which is an interme-
diate for the formation of a-chlorosulfide 8 from 6. Depro-
tonation of the resulting iminium ion 9 would afford 10.
An alternative mechanism for the formation of 9 may
involve a rapid intramolecular SN2-type substitution of a-
chlorosulfide 8. Stereochemistry of the MeS group of 10
was tentatively assigned to be trans to the neighboring 3,4-
dimethoxyphenyl group as depicted in Scheme 2.6 Desul-
furization of compound 10 with Raney nickel gave 11 in
87% yield. A subsequent catalytic hydrogenation of com-
pound 11 in the presence of PtO2 in acetic acid gave an
inseparable ca. 2:1 mixture of trans-fused octahydroindol-
2-one trans-12 and its isomer cis-12 in 90% combined yield.
A subsequent LiAlH4 reduction of the mixture gave (ꢂ)-
trans-mesembrane (trans-13)7d and (ꢂ)-mesembrane (cis-
13)7 in 53% and 29% yields, respectively.
Miller and his co-workers8 reported that catalytic hydroge-
nation of compound 14 with PtO2 in acetic acid gave almost
exclusively trans-fused compound trans-15a as a result of
steric hindrance of an angular methyl group of 14, which
caused the metal to preferentially bind to the opposite face
of the methyl group (Scheme 3). They also reported that
treatment of 14 with Et3SiH in CF3CO2H (TFA) predomi-
nantly gave cis-fused compound cis-15 together with
trans-fused compound trans-15 in a ratio of ca. 2:1.
We then treated 11 with Et3SiH in TFA to give cis-fused 3a-
aryloctahydroindol-2-one cis-12 as a sole product (Scheme
4). A subsequent reduction of cis-12 with LiAlH4 gave
(ꢂ)-mesembrane (cis-13).
The stereochemical outcome of the catalytic hydrogenation
of 11 can be explained in a manner similar to that described
for 14. Binding of the metal to the opposite face of the aryl
PtO2-AcOH
or
Et3SiH-TFA
+
O
N
H
O
N
H
O
N
H
H
H
14
trans-15
cis-15
PtO2-AcOH: trans/cis = 98:2
Et3SiH-TFA: trans/cis = 1:2
Scheme 3.

M. Saito et al. / Tetrahedron 63 (2007) 4865–4873
4867
Et3SiH
LiAlH4
synthesis of (ꢀ)-mesembrane (29) exploiting a chiral induc-
tion of compound having a chiral auxiliary on the nitrogen
atom.
cis-12
11
cis-13
CF3CO2H
rt, 5 min
(quant.)
THF
reflux, 10 min
(quant.)
a-(Methylthio)acetamide 19a having an (R)-1-phenylethyl
group was prepared in 55% yield by condensation of 2-phe-
nylcyclohexanone and (R)-1-phenylethylamine followed by
acylation of the resulting imine 18a with acid chloride 5
(Scheme 6). When compound 19a was treated with NCS,
compound 20a was obtained in 69% yield as a ca. 5:3 mix-
ture of two stereoisomers of over four possible diastereoiso-
mers. The MeS groups of the mixture of 20a were probably
trans to the phenyl group in a manner similar to that shown in
Scheme 2. This result indicated that the chiral induction of
enamide 19a, having a 1-phenylethyl group on the nitrogen
atom, was ca. 5:3. Desulfurization of 20a gave a ca. 5:3
mixture of two diastereoisomers of 21a in 89% yield.
Scheme 4.
group at C3a so as to form 16 gave trans-fused compound
trans-12 (Scheme 5).
Pt
Ar
Ar
H
O
O
PtO2
7a NMe
NMe
N
Me
11
O
O
Ar
Ar
16
trans-12
O
O
+
H
H
NMe
7a H
N
Me
Et3SiH
CF3CO2H
H
H
Our attention was next turned to enamide 19b having an (R)-
1-(1-naphthyl)ethyl group on the nitrogen atom. Treatment
of 19b with NCS gave two products, 20b1 and 20b2, in
40% and 18% yields, respectively. This result showed that
the chiral induction of 19b was ca. 2:1, indicating that the
1-(1-naphthyl)ethyl group was preferable to the 1-phenyl-
ethyl group as a chiral auxiliary on the nitrogen atom. Desul-
furization of 20b1 and 20b2 gave diastereomeric isomers
21b1 and 21b2 in 78% and 55% yields, respectively.
N
Me
11
Ar
Ar
cis-12
H
SiEt3
17
Ar = 2-(3,4-dimethoxyphenyl)
Scheme 5.
On the other hand, the reactive intermediate for the reduction
of Et3SiH in TFA might be the acyliminium ion 17 (Scheme
5). The literature8 indicated that reduction of 14 with steri-
cally more demanding di-tert-butylmethylsilane increased
the amount of cis-15 (trans-15/cis-15, 1:57) more than in the
case of reduction with triethylsilane (trans-15/cis-15, 1:2),
and we therefore speculated that an equatorial attack of hy-
dride of silane onto the acyliminium ion 17 occurred to give
cis-fused compound cis-12 in order to avoid 1,3-diaxial
interaction in a chair conformation of 17.
2.3. Synthesis of (L)-mesembrane and (L)-trans-
mesembrane
We then examined the cyclization of compound 22 having an
1-(1-naphthyl)ethyl group on the nitrogen atom for the syn-
thesis of (ꢀ)-mesembrane. Treatment of 22 with NCS gave
an inseparable ca. 2:1 mixture of the cyclization products 23
in 59% yield (Scheme 7). As mentioned above, formation of
23 from 22 can be considered to proceed, in formal sense,
through the thionium ion such as 7 (Scheme 2), and there-
fore, Pummerer rearrangement of sulfoxide 24 via the inter-
mediacy of thionium ion 25 was next examined. Sulfide 22
2.2. Studies on chiral induction
Being encouraged by the success of obtaining (ꢂ)-mesem-
brane (cis-13) using cyclization of 6, we next examined
O
Ar
H
Me
MeS
Cl
SMe
5
H2N
cat. TsOH
toluene
reflux, 5 h
PhNMe2, DMAP
toluene
0 °C to 60 °C, 12 h
N
H
N
O
O
Me
Ar
Me
Ar
H
19a (55%)
19b (45%)
18a,b
a: Ar = Ph
b: Ar = 1-Naphthyl
SMe
NCS
CCl4
rt, 30 min
Raney Ni
EtOH
reflux, 30 min
N
H
O
N
H
O
Me
Ar
Me
Ar
21a (89%, 5:3)
21b1 (78%), 21b2 (55%)
20a (69%, 5:3)
20b1 (40%), 20b2 (18%)
Scheme 6.

4868
M. Saito et al. / Tetrahedron 63 (2007) 4865–4873
OMe
OMe
OMe
OMe
SMe
SMe
NCS
3a
CCl4
rt, 1 h
N
O
N
O
Me
1-Naph
Me
1-Naph
H
22
H
23
(59%, 2:1)
OMe
OMe
OMe
+
O
SMe
SMe
–OCOCF3
MCPBA
(CF3CO)2O
23
22
CH2Cl2
0 °C, 1 h
CH2Cl2
0 °C, 5 min
(30%, 3:1)
N
O
N
O
Me
1-Naph
Me
1-Naph
H
H
24
25
Scheme 7.
was oxidized with m-chloroperbenzoic acid (MCPBA) and
the resulting sulfoxide 24 was treated with trifluoroacetic an-
hydride (TFAA) in CH2Cl2 at 0 ꢁC to give 23 as a mixture of
two diastereoisomers in a ratio of 3:1 and in 30% yield based
on 22. The major isomer of 23 was identical with that ob-
tained by the treatment of 22 with NCS. The diastereoselec-
tivity for the formation of 23 by Pummerer reaction of
sulfoxide 24 was slightly improved more than that by treat-
ment of sulfide 22 with NCS. This was probably due to the
reaction temperature employed. The reaction of sulfoxide
24 with TFAA could be carried out at 0 ꢁC,9 whereas the cy-
clization of 22 by treatment with NCS did not occur at 0 ꢁC.
product. The absolute configurations of 27a and 27b were
confirmed by transforming 27a to (ꢀ)-mesembrane (29).
The major isomer 27a was reduced with LiAlH4 to give
amine 28 in 97% yield. Hydrogenolysis of amine 28 in the
presence of Pd(OH)2/C followed by N-methylation with
HCHO/NaBH3(CN) gave (ꢀ)-mesembrane (29)10 {[a]D
ꢀ15.6, lit.11 [a]D ꢀ15.2} in 84% yield. Therefore, the
absolute stereochemistry of the aryl group at the C3a-
position of the major isomer of 23 (or 26) was found to be
S-configuration.
On the other hand, catalytic hydrogenation of 26 in the
presence of PtO2 in acetic acid gave trans-fused octahy-
droindol-2-one 30a as a major product and its isomer 30b
as a minor product, together with a small quantity of com-
pound 31, whose naphthalene rings were partially reduced
(Scheme 9).
Desulfurization of 23 gave a diastereoisomeric mixture of
hexahydroindol-2-ones 26 in 94% yield (Scheme 8). A sub-
sequent reduction of 26 with Et3SiH gave octahydroindol-2-
one 27a as a major product and its isomer 27b as a minor
OMe
OMe
OMe
OMe
OMe
OMe
Raney Ni
Et3SiH
3a
+
23
EtOH
reflux, 1 h
CF3CO2H
rt, 1 h
(2:1)
N
O
N
H
O
N
H
O
Me
1-Naph
Me
1-Naph
Me
1-Naph
H
26
H
27a
H
27b
(33%)
(94%, 2:1)
(63%)
OMe
OMe
OMe
1) H2
OMe
Pd(OH)2/C
MeOH
rt, 24 h
LiAlH4
27a
THF
reflux
2) HCHO/
NaBH3(CN)
MeOH
N
H
N
Me
H
rt, 5 min
Me
1-Naph
H
29 (84%)
(–)-mesembrane
28
(97%)
Scheme 8.

M. Saito et al. / Tetrahedron 63 (2007) 4865–4873
OMe
4869
OMe
OMe
method was applied to the chiral induction of N-[2-(3,4-
dimethoxy)phenylcyclohex-1-en-1-yl]-a-(methylthio)acet-
amide having a 1-(1-naphthyl)ethyl group on the nitrogen
atom, which led to the synthesis of (ꢀ)-mesembrane and
(ꢀ)-trans-mesembrane.
OMe
O
OMe
OMe
H2, PtO2
+
+
26
AcOH
rt, 14 h
N
H
N
H
O
N
O
Me
Me
Me
H
H
H
4. Experimental
4.1. General
30a (54%)
30b (21%)
31 (4%)
Melting points are uncorrected. Infrared (IR) spectra were
recorded on a Shimadzu FTIR-8100 spectrophotometer. 1H
NMR and 13C NMR spectra were measured with a JEOL
JNM-GSX 500 or a JEOL JNM-EX 270 spectrometer. d
values quoted are relative to tetramethylsilane. High resolu-
tion mass spectra (HRMS) were obtained with a JEOL JMS-
SX-102A mass spectrometer. Column chromatography was
performed using silica gel 60N (Kanto Kagaku Co., Ltd.,
spherical, neutral, 63–210 mm). Thin layer chromatography
was carried out on silica gel Wakogel B-5F.
Scheme 9.
The trans-stereochemistry of the major isomer 30a was con-
firmed by the following conversion into (ꢀ)-trans-mesem-
brane (33). LiAlH4 reduction of 30a gave amine 32 in
74% yield (Scheme 10). Hydrogenolysis of 32 in the pres-
ence of Pd(OH)2/C followed by N-methylation of the result-
ing amine gave (ꢀ)-trans-mesembrane (33) in 71% yield
based on 32. The spectral data of enantiopure (ꢀ)-trans-
mesembrane thus obtained were in accord with those
reported for (ꢂ)-trans-mesembrane.7d
4.1.1. N-[2-(3,4-Dimethoxyphenyl)cyclohexen-1-yl]-N-
methyl-a-(methylthio)acetamide (6). Gaseous methyl-
amine was bubbled to a solution of 2-(3,4-dimethoxyphe-
nyl)cyclohexanone (500 mg, 2.13 mmol) in toluene (4 ml)
OMe
OMe
OMe
1) H2 (15 atm)
ꢁ
Pd(OH)2/C
MeOH
OMe
˚
containing MS 4 A (ca. 1 g) at ꢀ78 C for 5 min, and
the mixture was heated in a sealed tube at 110 ꢁC for 17 h.
After removal of excess methylamine, N,N-dimethylaniline
(774 mg, 6.39 mmol) and 4-dimethylaminopyridine (26 mg,
0.21 mmol) were added to the residual solution, and a solu-
tion of a-(methylthio)acetyl chloride (399 mg, 3.2 mmol) in
toluene (5 mL) was added dropwise at 0 ꢁC. The mixture
was stirred at room temperature for 10 min, and the reaction
mixture was washed with a saturated NH4Cl solution and
brine. The organic layer was dried (MgSO4) and concen-
trated, and the crude material was purified by column chro-
matography on silica gel (hexane/AcOEt, 10:1/5:1/2:1)
to give 6 (371 mg, 52%) as a colorless oil. IR (CHCl3) n
rt, 12 d
LiAlH4
30a
THF
reflux, 1 h
2) HCHO/
N
H
H
Me
NaBH3(CN)
MeOH
N
Me
H
rt, 15 min
33 (71%)
(–)-trans-mesembrane
32 (74%)
Scheme 10.
The trans-stereochemistry of another isomer 30b was de-
duced from a comparison of the coupling constants (J¼13.2,
3.4 Hz) of the 7a-hydrogen atom with that (J¼12.7, 2.9 Hz)
of trans-isomer 30a. The cis-compounds 27a and 27b have
the coupling constants J¼8.6, 5.5 Hz and 9.0, 5.9 Hz, re-
spectively. An absolute configuration of 31 was tentatively
assigned as shown in Scheme 9.
1636 cmꢀ1; H NMR (270 MHz, CDCl3) d 1.74–1.90 (4H,
1
m), 2.05–2.59 (4H, m), 2.13 (3H, s), 2.85 (1H, d,
J¼14.3 Hz), 2.97 (3H, s), 3.29 (1H, d, J¼14.3 Hz), 3.85
(6H, s), 6.63–6.82 (3H, m); 13C NMR (67.8 MHz, CDCl3)
d 16.4, 22.6, 22.8, 28.6, 31.1, 34.7, 35.0, 55.7, 55.9, 110.4,
111.1, 119.2, 132.7, 135.1, 135.4, 148.2, 148.7, 168.6;
HRMS calcd for C18H25NO3S: 335.1555, found: 335.1555.
Catalytic hydrogenation of 11 (Scheme 2) gave a ca. 2:1
mixture of trans and cis-fused compounds trans-12 and
cis-12, whereas a similar hydrogenation of 26 (Scheme 9)
gave only trans-fused compounds 30a and 30b. It seemed
that the bulkiness of the 1-(1-naphthylethyl) group of 26
prevents binding of the metal to the same face of the aryl
group at C3a.
4.1.2. (3R*,3aR*)-2,3,3a,4,5,6-Hexahydro-3a-(3,4-di-
methoxyphenyl)-1-methyl-3-(methylthio)indol-2-one
(10). N-Chlorosuccinimide (124 mg, 0.93 mmol) was added
by portions to a solution of 6 (300 mg, 0.89 mmol) in CCl4
(10 mL) at 0 ꢁC, and the mixture was stirred at room temper-
ature for 2.5 h. The precipitated succinimide was filtered off,
the filtrate was concentrated, and the residue was purified by
column chromatography on silica gel (hexane/AcOEt,
10:1/5:1/2:1) to give 10 (124 mg, 48%) as a colorless
3. Conclusion
1
We revealed that N-(2-arylcyclohex-1-en-1-yl)-a-(methyl-
thio)acetamides, when treated with N-chlorosuccinimide,
underwent cyclization to afford 1,2,3a,4,5,6-hexahydro-3a-
aryl-3-(methylthio)indol-2-ones. Stereoselective synthesis
of cis and trans-fused octahydroindol-2-ones was performed
by reduction of desulfurized hexahydroindol-2-ones with
Et3SiH and by catalytic hydrogenation, respectively. The
oil. IR (CHCl3) n 1719, 1682 cmꢀ1; H NMR (500 MHz,
CDCl3) d 1.24–1.36 (1H, m), 1.64–1.76 (2H, m), 1.82 (3H,
s), 2.12–2.18 (2H, m), 2.67 (1H, dt, J¼12.8, 3.1 Hz), 3.09
(3H, s), 3.52 (1H, s), 3.85 (3H, s), 3.86 (3H, s), 5.07 (1H,
t, J¼3.4 Hz), 6.72 (1H, dd, J¼2.4, 8.5 Hz), 6.76 (1H, d,
J¼8.6 Hz), 6.76 (1H, d, J¼1.8 Hz); 13C NMR (67.8 MHz,
CDCl3) d 14.8, 18.4, 22.9, 26.4, 34.0, 49.1, 55.7, 55.8,

4870
M. Saito et al. / Tetrahedron 63 (2007) 4865–4873
59.0, 100.1, 110.5, 111.6, 120.5, 132.5, 143.4, 148.1, 148.3,
171.1; HRMS calcd for C18H23NO3S: 333.1399, found:
333.1401.
J¼8.6 Hz), 7.28 (1H, dd, J¼2.1, 8.6 Hz), 7.59 (1H, d,
J¼2.1 Hz); 13C NMR (125 MHz, CDCl3) d 22.3, 24.2,
25.7, 38.0, 40.0, 41.5, 48.9, 53.3, 55.7, 55.9, 76.8, 110.6,
113.2, 120.9, 138.2, 146.4, 148.3; HRMS calcd for
C17H25NO2: 275.1885, found: 275.1883.
4.1.3. 2,3,3a,4,5,6-Hexahydro-3a-(3,4-dimethoxyphenyl)-
1-methylindol-2-one (11). Raney nickel (W-2) (ca. 500 mg)
was added to a solution of 10 (120 mg, 0.36 mmol) in EtOH
(2.5 mL), and the mixture was heated under reflux for 3 h.
The Raney nickel was filtered off, the filtrate was concen-
trated, and the residue was purified by column chromato-
graphy on silica gel (hexane/AcOEt, 10:1/5:1/2:1) to
give 11 (90 mg, 87%) as a colorless oil. IR (CHCl3) n
The second eluent gave cis-13 (5 mg, 29%) as a colorless oil.
IR (CHCl3) n 1520 cmꢀ1 1H NMR (270 MHz, CDCl3)
;
d 1.12–1.96 (10H, m), 2.25–2.37 (1H, m), 2.33 (3H, s),
2.59 (1H, br s), 3.26 (1H, td, J¼9.1, 4.8 Hz), 3.87 (3H, s),
3.89 (3H, s), 6.81 (1H, d, J¼8.2 Hz), 6.89–6.94 (2H, m);
13C NMR (67.8 MHz, CDCl3) d 20.4, 22.9, 23.6, 36.0,
40.6, 41.0, 47.5, 54.3, 55.8, 55.9, 68.7, 110.7, 110.8,
118.9, 140.2, 146.9, 148.6; HRMS calcd for C17H25NO2:
275.1885, found: 275.1888.
1717, 1678 cmꢀ1 1H NMR (500 MHz, CDCl3) d 1.16–
;
1.30 (1H, m), 1.56–1.66 (1H, m), 1.79 (1H, td, J¼13.3,
2.7 Hz), 2.11–2.25 (3H, m), 2.64 (1H, d, J¼16.2 Hz), 2.77
(1H, d, J¼16.2 Hz), 2.99 (3H, s), 3.85 (6H, s), 5.13 (1H, t,
J¼3.7 Hz), 6.77 (3H, s); 13C NMR (125 MHz, CDCl3)
d 18.2, 22.6, 26.0, 35.7, 45.6, 46.9, 55.8, 55.9, 100.0,
110.3, 110.8, 119.3, 137.9, 144.1, 147.7, 148.8, 173.0;
HRMS calcd for C17H21NO3: 287.1522, found: 287.1524.
4.1.5. (3aR*,7aR*)-3a-(3,4-Dimethoxyphenyl)-1-methyl-
octahydroindol-2-one (cis-12): reduction of 11 with
Et3SiH. A mixture of 11 (20 mg, 0.07 mmol) and triethyl-
silane (16 mg, 0.14 mmol) in trifluoroacetic acid (0.3 mL)
was stirred at room temperature for 5 min. The reaction mix-
ture was concentrated, and the residue was purified by thin
layer chromatography on silica gel (hexane/AcOEt, 1:4) to
give cis-12 (20 mg, quant.) as a colorless oil. IR (CHCl3) n
4.1.4. (3aR*,7aS*)-3a-(3,4-Dimethoxyphenyl)-1-methyl-
octahydroindole [( )-trans-mesembrane] (trans-13) and
(3aR*,7aR*)-3a-(3,4-dimethoxyphenyl)-1-methyloctahy-
droindole [( )-mesembrane] (cis-13). A mixture of 11
(20 mg, 0.07 mmol) and platinum dioxide (2.5 mg,
0.01 mmol) in acetic acid (0.5 mL) was stirred at room tem-
perature for 1.5 h under a hydrogen atmosphere. The catalyst
was filtered off, the filtrate was concentrated, and the residue
was purified by thin layer chromatography on silica gel
(hexane/AcOEt, 1:4) to give an inseparable mixture of
(3aR*,7aS*)-3a-(3,4-dimethoxyphenyl)-1-methyloctahy-
droindol-2-one (trans-12) and its (3aR*,7aR*)-isomer (cis-
12) (18 mg, 90%) in a ratio of 2:1 (determined by 1H
NMR spectroscopy) as a colorless oil. IR (CHCl3) n
1
1678 cmꢀ1; H NMR (270 MHz, CDCl3) d 1.26–2.05 (8H,
m), 2.50 (2H, br s), 2.86 (3H, s), 3.88 (3H, s), 3.89 (3H, s),
3.92 (1H, t, J¼3.7 Hz), 6.81–6.73 (3H, m); 13C NMR
(67.8 MHz, CDCl3) d 20.3, 21.6, 24.6, 26.9, 34.8, 42.8,
48.1, 55.9, 56.0, 62.2, 110.3, 111.0, 118.7, 137.1, 147.6,
148.9, 174.3; HRMS calcd for C17H23NO3: 289.1678,
found: 289.1680.
4.1.6. (3aR*,7aR*)-3a-(3,4-Dimethoxyphenyl)-1-methyl-
octahydroindole [( )-mesembrane] (cis-13). To a solution
of LiAlH4 (14 mg, 0.37 mmol) in dry THF (0.3 mL) was
added dropwise a solution of cis-12 (18 mg, 0.062 mmol)
in dry THF (1 mL) at 0 ꢁC, and the mixture was heated under
reflux for 10 min. After work-up as described above for the
preparation of trans-13 and cis-13 from the mixture of trans-
12 and cis-12 (Section 4.1.4), the crude material was purified
by thin layer chromatography on silica gel (CHCl3/MeOH/
isopropylamine, 80:1:2) to give cis-13 (17 mg, quant.) as a
colorless oil. The spectral data of this compound were in ac-
cord with those of (ꢂ)-mesembrane obtained above (Section
4.1.4).
1
1682 cmꢀ1; H NMR (500 MHz, CDCl3) d 1.26–2.15 (22/
3H, m, for trans-12 and cis-12), 2.34 (1Hꢃ2/3, d,
J¼15.3 Hz, for trans-12), 2.42 (1Hꢃ2/3, d, J¼15.3 Hz, for
trans-12), 2.48 (1Hꢃ1/3, d, J¼16.4 Hz, for cis-12), 2.51
(1Hꢃ1/3, d, J¼16.4 Hz, for cis-12), 2.58 (1Hꢃ2/3, br d,
J¼13.4 Hz, for trans-12), 2.85 (3Hꢃ1/3, s, for cis-12),
2.90 (3Hꢃ2/3, s, for trans-12), 3.53 (1Hꢃ2/3, dd, J¼13.3,
3.3 Hz, for trans-12), 3.83 (3Hꢃ2/3, s, for trans-12), 3.85
(3Hꢃ2/3, s, for trans-12), 3.88 (3Hꢃ1/3, s, for cis-12),
3.89 (3Hꢃ1/3, s, for cis-12), 3.91 (1Hꢃ1/3, t, J¼3.7 Hz,
for cis-12), 6.77–6.91 (3H, m, for trans-12 and cis-12);
HRMS calcd for C17H23NO3: 289.1678, found: 289.1674.
4.1.7. N-[2-(3,4-Dimethoxyphenyl)cyclohexen-1-yl]-a-
(methylthio)-N-[(R)-1-(1-naphthyl)ethyl]acetamide (22).
A mixture of 2-(3,4-dimethoxyphenyl)cyclohexanone (1 g,
4.3 mmol), (R)-1-naphthylethylamine (805 mg, 4.7 mmol),
and p-toluenesulfonic acid monohydrate (82 mg,
0.43 mmol) in toluene (15 mL) was heated under reflux
with azeotropic removal of water for 6 h. After cooling the
reaction mixture, N,N-dimethylaniline (1.56 g, 12.9 mmol),
4-dimethylaminopyridine (53 mg, 0.43 mmol), and a solu-
tion of a-(methylthio)acetyl chloride (959 mg, 7.7 mmol)
in toluene (30 mL) were added at 0 ꢁC, and the mixture was
stirred at 60 ꢁC for 13 h. The reaction mixture was washed
with a saturated NH4Cl solution, brine, dried (MgSO4), and
concentrated. The crude material was purified by column
chromatography on silica gel (hexane/AcOEt, 7:1) to give
22 (1.05 g, 52%) as a yellow amorphous. IR (CHCl3) n
A solution of the mixture of trans-12 and cis-12 (18 mg,
0.062 mmol) obtained above in dry THF (1 mL) was added
dropwise to a solution of LiAlH4 (14 mg, 0.37 mmol) in dry
THF (0.3 mL) at 0 ꢁC, and the mixture was heated under re-
flux for 10 min. The reaction mixture was quenched by the
successive addition of water (14 mL), aqueous NaOH solu-
tion (15%) (14 mL), water (28 mL), and THF (1 mL). After
filtration, the filtrate was concentrated, and the residue was
purified by thin layer chromatography on silica gel
(CHCl3/MeOH/isopropylamine, 80:1:2). The first eluent
gave trans-13 (9 mg, 53%) as a colorless oil. IR (CHCl3) n
1
1514 cmꢀ1; H NMR (270 MHz, CDCl3) d 1.12–1.77 (9H,
m), 2.17 (1H, dd, J¼10.7, 4.4 Hz), 2.26 (1H, td, J¼10.2,
2.9 Hz), 2.36 (3H, s), 2.55–2.60 (1H, m), 3.08 (1H, dt,
J¼10.1, 8.1 Hz), 3.85 (3H, s), 3.86 (3H, s), 6.79 (1H, d,
1
1730, 1628 cmꢀ1; H NMR (500 MHz, CDCl3) d 0.7–2.6

M. Saito et al. / Tetrahedron 63 (2007) 4865–4873
4871
(8H, m), 1.02 (3Hꢃ3/8, d, J¼7.1 Hz), 1.61 (3Hꢃ5/8, d,
J¼7.1 Hz), 2.33 (3Hꢃ5/8, s), 2.45 (3Hꢃ3/8, s), 3.39
(1Hꢃ5/8, d, J¼13.9 Hz), 3.50 (1Hꢃ3/8, d, J¼13.9 Hz),
3.55 (1Hꢃ5/8, d, J¼13.9 Hz), 3.62 (3Hꢃ3/8, s), 3.63
(1Hꢃ3/8, d, J¼13.9 Hz), 3.67 (3Hꢃ3/8, s), 3.91 (3Hꢃ5/8,
s), 3.93 (3Hꢃ5/8, s), 5.79 (1Hꢃ3/8, d, J¼2.0 Hz), 5.87
(1Hꢃ3/8, dd, J¼8.3, 2.0 Hz), 6.02 (1Hꢃ3/8, d, J¼8.3 Hz),
6.37 (1Hꢃ5/8, q, J¼7.1 Hz), 6.48 (1Hꢃ3/8, q, J¼7.1 Hz),
6.77 (1Hꢃ5/8, d, J¼2.0 Hz), 6.83 (1Hꢃ5/8, dd, J¼8.3,
2.0 Hz), 6.89 (1Hꢃ5/8, d, J¼8.3 Hz), 7.20–8.05 (7H, m).
Anal. Calcd for C29H33NO3S: C, 73.23; H, 6.99; N, 2.94.
Found: C, 72.96; H, 7.12; N, 2.86.
amorphous. IR (CHCl3) n 1709, 1667 cmꢀ1
;
1H NMR
(500 MHz, CDCl3) d 0.83–2.10 (6H, m), 1.90 (3H, d,
J¼7.1 Hz), 2.65 (1Hꢃ2/3, d, J¼15.6 Hz), 2.69 (1Hꢃ1/3,
d, J¼16.1 Hz), 2.86 (1Hꢃ2/3, d, J¼15.6 Hz), 2.91 (1Hꢃ1/
3, d, J¼16.1 Hz), 3.34 (3Hꢃ1/3, s), 3.70 (3Hꢃ1/3, s), 3.81
(3Hꢃ2/3, s), 3.86 (3Hꢃ2/3, s), 4.91 (1Hꢃ2/3, t, J¼
9.6 Hz), 5.19 (1Hꢃ1/3, t, J¼9.6 Hz), 5.75 (1Hꢃ1/3, dd,
J¼8.2, 2.3 Hz), 5.98 (1Hꢃ1/3, d, J¼8.2 Hz), 6.20 (1Hꢃ2/3,
q, J¼7.2 Hz), 6.26 (1Hꢃ1/3, q, J¼6.0 Hz), 6.28 (1Hꢃ1/3, d,
J¼2.4 Hz), 6.78 (1Hꢃ2/3, d, J¼8.3 Hz), 6.83 (1Hꢃ2/3, d,
J¼2.0 Hz), 6.86 (1Hꢃ2/3, dd, J¼8.3, 2.2 Hz), 7.13–8.12
(7H, m); HRMS calcd for C28H29NO3: 427.2148, found:
427.2144.
4.1.8. 2,3,3a,4,5,6-Hexahydro-3a-(3,4-dimethoxyphenyl)-
3-methylthio-1-[(R)-1-(1-naphthyl)ethyl]indol-2-one
(23): by reaction of 22 and NCS. N-Chlorosuccinimide
(294 mg, 2.2 mmol) was added by portions to a solution of
22 (1 g, 2.2 mmol) in CCl4 (40 mL) at 0 ꢁC, and the mixture
was stirred at room temperature for 1 h. The precipitated
succinimide was filtered off, the filtrate was concentrated,
and the residue was purified by column chromatography
on silica gel (hexane/AcOEt, 6:1) to give a ca. 2:1 mixture
of two diastereoisomers of 23 (610 mg, 59%) as a yellow
4.1.11. (3aS,7aS)-3a-(3,4-Dimethoxyphenyl)-1-[(R)-1-(1-
naphthyl)ethyl]octahydroindol-2-one (27a) and
(3aR,7aR)-3a-(3,4-dimethoxyphenyl)-1-[(R)-1-(1-naph-
thyl)ethyl]octahydroindol-2-one (27b). Triethylsilane
(16 mg, 0.14 mmol) was added to a solution of a 2:1 diaste-
reoisomeric mixture of 26 (30 mg, 0.07 mmol) in trifluoro-
acetic acid (0.3 mL) at room temperature, and the stirring
was continued for 1 h. The reaction mixture was concen-
trated, and the residue was purified by column chromato-
graphy on silica gel (hexane/AcOEt, 10:1/5:1/3:1/
1:1). The first eluent gave 27a (19 mg, 63%) as a white
amorphous. [a]2D6 +65.6 (c 2.19, CHCl3); IR (CHCl3) n
amorphous. IR (CHCl3) 1713, 1673 cmꢀ1
;
1H NMR
(500 MHz, CDCl3) d 0.9–1.9 (6H, m), 1.86 (3Hꢃ1/3, s),
1.96 (3Hꢃ2/3, s), 2.05 (3Hꢃ2/3, d, J¼7.1 Hz), 2.52 (1Hꢃ
1/3, dt, J¼12.3, 3.2 Hz), 2.57 (1Hꢃ2/3, dt, J¼12.7, 3.4 Hz),
3.51 (1Hꢃ2/3, s), 3.52 (3Hꢃ1/3, s), 3.59 (1Hꢃ1/3, s), 3.67
(3Hꢃ1/3, s), 3.73 (3Hꢃ2/3, s), 3.83 (3Hꢃ2/3, s), 4.97 (1Hꢃ
2/3, t, J¼3.8 Hz), 5.21 (1Hꢃ1/3, t, J¼3.9 Hz), 5.70 (1Hꢃ
1/3, d, J¼8.3 Hz), 5.85 (1Hꢃ1/3, d, J¼8.3 Hz), 6.29
(1Hꢃ2/3, q, J¼7.0 Hz), 6.40 (1Hꢃ1/3, q, J¼7.1 Hz), 6.69
(1Hꢃ2/3, d, J¼8.5 Hz), 6.76 (1Hꢃ1/3, d, J¼2.2 Hz), 6.86
(1Hꢃ2/3, dd, J¼8.5, 2.2 Hz), 6.92 (1Hꢃ2/3, d, J¼2.2 Hz),
7.37–7.55 (3H, m), 7.74–7.92 (3 H, m), 8.00 (1Hꢃ1/3,
d J¼8.5 Hz), 8.09 (1Hꢃ2/3, d, J¼8.3 Hz). Anal. Calcd for
C29H31NO3S: C, 73.54; H, 6.60; N, 2.96. Found: C, 73.51;
H, 6.94; N, 2.88.
1
1665 cmꢀ1; H NMR (500 MHz, CDCl3) d 0.47–0.52 (1H,
m), 0.68–0.94 (3H, m), 1.1–1.2 (1H, m), 1.12 (3H, d,
J¼6.7 Hz), 1.37–1.42 (1H, m), 1.66–1.80 (2H, m), 2.62
(1H, d, J¼16.5 Hz), 2.80 (1H, d, J¼16.5 Hz), 3.55 (1H,
dd, J¼8.6, 5.5 Hz), 3.89 (3H, s), 3.93 (3H, s), 6.07 (1H,
q, J¼6.9 Hz), 6.85 (1H, d, J¼8.5 Hz), 6.91 (1H, d,
J¼1.8 Hz), 6.98 (1H, dd, J¼8.5, 2.4 Hz), 7.39–7.58 (4H,
m), 7.78–7.84, (2H, m), 8.22 (1H, d, J¼8.5 Hz); 13C NMR
(125 MHz, CDCl3) d 15.7, 21.6, 22.1, 29.0, 35.5, 39.8,
45.26, 45.29, 55.9, 56.2, 61.6, 110.2, 110.9, 118.6, 123.6,
124.0, 124.8, 125.8, 126.7, 128.5, 128.6, 132.3, 133.4,
136.5, 139.2, 147.8, 148.8, 173.1; HRMS calcd for
C28H31NO3: 429.2304, found: 429.2302.
4.1.9. Compound 23 by the reaction of 24 and TFAA.
m-Chloroperbenzoic acid (65%) (56 mg, 0.21 mmol) was
added to a solution of 22 (100 mg, 0.21 mmol) in CH2Cl2
(6 mL) at 0 ꢁC over 1 h, and the mixture was stirred at the
same temperature for 1 h. The reaction mixture was washed
with aqueous 10% Na2S2O3 solution and aqueous NaHCO3
solution and dried. Trifluoroacetic anhydride (TFAA)
(88 mg, 0.42 mmol) was added to a solution of thus obtained
crude 24 in CH2Cl2 (3.2 mL) at 0 ꢁC, and the mixture was
stirred at the same temperature for 5 min. The reaction mix-
ture was washed with aqueous NaHCO3 solution, dried, con-
centrated, and the crude material was purified by column
chromatography on silica gel (hexane/AcOEt, 3:2) to give 23
(30 mg, 30%) as a ca. 3:1 mixture of the diastereoisomers.
The second eluent gave 27b (10 mg, 33%) as a white amor-
phous. [a]2D5 ꢀ73.0 (c 0.78, CHCl3); IR (CHCl3) n
1
1663 cmꢀ1; H NMR (500 MHz, CDCl3) d 1.15–1.23 (1H,
m), 1.38–1.73 (6H, m), 1.72 (3H, d, J¼7.1 Hz), 2.00–2.07
(1H, m), 2.67 (1H, d, J¼16.4 Hz), 2.81 (1H, d,
J¼16.4 Hz), 2.97 (1H, dd, J¼9.0, 5.9 Hz), 3.45 (3H, s),
3.76 (3H, s), 5.99 (1H, q, J¼7.1 Hz), 6.11 (1H, d,
J¼2.4 Hz), 6.26 (1H, d, J¼8.3 Hz), 6.36 (1H, dd, J¼8.3,
2.4 Hz), 7.01–7.04 (1H, m), 7.30–7.45 (3H, m), 7.54 (1H,
d, J¼7.1 Hz), 7.72 (1H, d, J¼8.3 Hz), 7.76 (1H, d,
J¼8.3 Hz); 13C NMR (125 MHz, CDCl3) d 18.5, 21.8,
22.5, 30.9, 36.4, 39.7, 44.5, 46.3, 55.3, 55.4, 61.5, 108.8,
109.9, 117.2, 122.9, 123.7, 124.3, 125.4, 126.1, 127.8,
128.6, 131.5, 133.3, 134.4, 138.2, 147.1, 148.1, 173.1.
Anal. Calcd for C28H31NO3: C, 78.29; H, 7.27; N, 3.26.
Found: C, 78.26; H, 7.36; N, 3.21.
4.1.10. 2,3,3a,4,5,6-Hexahydro-3a-(3,4-dimethoxy-
phenyl)-1-[(R)-1-(1-naphthyl)ethyl]indol-2-one (26). Ra-
ney nickel (W-2) (ca. 1.5 g) was added to a solution of a
2:1 diastereoisomeric mixture of 23 (300 mg, 0.63 mmol)
in EtOH (7 mL), and the mixture was heated under reflux
for 1 h. The Raney nickel was filtered off, the filtrate was
concentrated, and the residue was purified by column chro-
matography on silica gel (hexane/AcOEt, 3:1) to give a 2:1
diastereoisomeric mixture of 26 (280 mg, 94%) as a white
4.1.12. (3aS,7aS)-3a-(3,4-Dimethoxyphenyl)-1-[(R)-1-(1-
naphthyl)ethyl]octahydroindole (28). To a solution of
LiAlH4 (87 mg, 0.42 mmol) in dry THF (2 mL) was added
dropwise a solution of 27a (165 mg, 2.28 mmol) in dry
THF (7 mL) at 0 ꢁC, and the mixture was heated under reflux
for 1 h. After work-up as described above for the preparation

4872
M. Saito et al. / Tetrahedron 63 (2007) 4865–4873
of trans-13 and cis-13, the crude material was purified by
column chromatography on silica gel (hexane/AcOEt/iso-
propylamine, 90:9:1/75:24:1) to give 28 (153 mg, 97%)
as a colorless oil. [a]D26 ꢀ4.9 (c 0.47, MeOH); IR (CHCl3)
25.3, 30.3, 36.6, 45.0, 46.2, 47.0, 55.5, 55.8, 55.9, 103.6,
110.5, 110.6, 119.5, 124.5, 125.3, 128.9, 136.0, 137.25,
137.32, 137.7, 140.7, 147.5, 148.4, 172.5. HRMS calcd for
C28H33NO3: 431.2461, found: 431.2464.
n 1518 cmꢀ1 1H NMR (500 MHz, CDCl3) d 0.97–1.05
;
(1H, m), 1.37–1.76 (7H, m), 1.39 (3H, d, J¼6.7 Hz), 2.11–
2.20 (2H, m), 2.88–2.94 (1H, m), 3.05–3.08 (1H, m), 3.20
(1H, dd, J¼15.3, 9.2 Hz), 3.74 (3H, s), 3.91 (3H, s), 4.42
(1H, q, J¼6.7 Hz), 6.80–6.84 (2H, m), 6.94 (1H, dd,
J¼2.4, 8.5 Hz), 7.23–7.25 (1H, m), 7.32–7.41 (3H, m),
7.68 (1H, d, J¼7.9 Hz), 7.79 (1H, d, J¼8.5 Hz), 8.19 (1H,
d, J¼8.5 Hz); 13C NMR (125 MHz, CDCl3) d 21.9, 22.4,
23.0, 23.7, 32.0, 36.3, 47.4, 48.8, 55.8, 55.9, 63.1, 110.3,
110.4, 118.1, 124.4, 124.5, 125.0, 125.1, 125.2, 127.0,
128.4, 131.3, 134.0, 141.4, 142.4, 146.8, 148.4; HRMS calcd
for C28H33NO2: 415.2511, found: 415.2515.
The second eluent gave 30a (22 mg, 54%) as a white
amorphous. [a]2D5 ꢀ92.4 (c 0.61, CHCl3); IR (CHCl3) n
1673 cmꢀ1; 1H NMR d 0.95–2.20 (12H, m), 2.81 (3H, d, J¼
7.1 Hz), 2.35 (1H, d, J¼15.1 Hz), 2.40 (1H, d, J¼15.1 Hz),
2.52 (1H, br d, J¼13.4 Hz), 2.75 (1H, dt, J¼16.6, 4.5 Hz),
2.80–2.88 (2H, m), 3.09 (1H, dd, J¼12.7, 2.9 Hz), 3.85
(3H, s), 3.86 (3H, s), 5.56 (1H, q, J¼7.1 Hz), 6.80 (1H, d,
J¼8.5 Hz), 7.00–7.15 (4H, m), 7.33 (1H, d, J¼7.8 Hz);
13C NMR (67.8 MHz, CDCl3) d 20.1, 21.7, 22.8, 23.2,
24.4, 25.3, 26.3, 30.2, 36.1, 45.6, 47.5, 48.8, 55.8, 56.2,
67.9, 111.2, 111.5, 120.1, 124.9, 125.0, 129.0, 135.8,
136.6, 136.7, 137.6, 147.2, 148.7, 174.5; HRMS calcd for
C28H35NO3: 433.2617, found: 433.2616.
4.1.13. (3aS,7aS)-3a-(3,4-Dimethoxyphenyl)-1-methyl-
octahydroindole [(L)-mesembrane] (29). A mixture of
28 (149 mg, 0.35 mmol) and Pd(OH)2/C (33 mg) in MeOH
(5.5 mL) was stirred at room temperature for 24 h under a
hydrogen atmosphere. The catalyst was filtered off, and
the filtrate was concentrated to give (3aS,7aS)-3a-(3,4-di-
methoxyphenyl)octahydroindole. A mixture of this material
and aqueous HCHO solution (37%, 0.33 mL, 4.08 mmol)
and NaBH3(CN) (214 mg, 3.4 mmol) in MeOH (8 mL) was
stirred at room temperature for 5 min, and the reaction mix-
ture was concentrated. The residue was purified by thin layer
chromatography on silica gel (CH2Cl2/MeOH/isopropyl-
amine, 80:1:2) to give 29 (83 mg, 84%) as a colorless oil.
[a]D28 ꢀ15.6 (c 1.15, MeOH); IR (CHCl3) n 1520 cmꢀ1; 1H
NMR (500 MHz, CDCl3) d 1.12–1.21 (1H, m), 1.34–1.61
(4H, m), 1.76–1.95 (5H, m), 2.27–2.32 (1H, m), 2.32 (3H,
s), 2.57 (1H, br s), 3.25 (1H, dt, J¼9.2, 4.9 Hz), 3.87 (3H, s),
3.89 (3H, s), 6.81 (1H, J¼8.5 Hz), 6.90 (1H, d, J¼2.4 Hz),
6.92 (1H, dd, J¼2.1, 8.2 Hz); 13C NMR (500 MHz,
CDCl3) d 20.3, 22.9, 23.7, 36.0, 40.6, 41.0, 47.5, 54.3,
55.8, 55.9, 68.6, 110.7, 110.8, 118.9, 140.2, 146.8, 148.6;
HRMS calcd for C17H25NO2: 275.1885, found: 275.1888.
The third eluent gave 30b (8.6 mg, 21%) as a colorless crys-
tal. [a]2D6 +102.4 (c 0.30, CHCl3); mp 199.5–200 ꢁC (hexane/
1
AcOEt); IR (CHCl3) n 1674 cmꢀ1; H NMR (500 MHz,
CDCl3) d 0.94–1.04 (1H, m), 1.32–1.43 (2H, m), 1.56–
1.78 (7H, m), 1.69 (3H, d, J¼7.1 Hz), 1.98–2.01 (1H, m),
2.41 (1H, d, J¼15.5 Hz), 2.45–2.50 (1H, m), 2.46 (1H, d,
J¼15.1 Hz), 2.62–2.68 (1H, m), 2.77–2.87 (3H, m), 3.63
(1H, dd, J¼13.2, 3.4 Hz), 3.73 (3H, s), 3.81 (3H, s), 5.53
(1H, q, J¼7.1 Hz), 6.58 (2H, d, J¼1.0 Hz), 6.77 (1H, s),
7.05–7.16 (2H, m), 7.30 (1H, d, J¼7.3 Hz); 13C NMR
(67.8 Hz, CDCl3) d 16.8, 21.5, 22.6, 23.2, 24.2, 25.5, 25.8,
30.5, 37.2, 45.4, 47.4, 49.9, 55.7, 56.1, 67.0, 110.3, 111.9,
121.3, 124.7, 124.8, 128.8, 135.5, 136.5, 137.7, 138.5,
147.1, 148.9, 175.0. Anal. Calcd for C28H35NO3: C, 77.56;
H, 8.14; N, 3.23. Found: C, 77.40; H, 8.17; N, 3.25.
4.1.15. (3aS,7aR)-3a-(3,4-Dimethoxyphenyl)-1-[(R)-1-
(1,2,3,4-tetrahydronaphthalen-5-yl)ethyl]octahydroin-
dole (32). To a solution of LiAlH4 (96 mg, 0.42 mmol) in dry
THF (2 mL) was added dropwise a solution of 30a (180 mg,
0.42 mmol) in dry THF (8 mL) at 0 ꢁC, and the mixture was
heated under reflux for 1 h. After work-up as described
above for the preparation of trans-13 and cis-13, the crude
material was purified by column chromatography on silica
gel (hexane/AcOEt, 20:1) to give 32 (130 mg, 74%) as a
colorless oil. [a]2D6 ꢀ138.7 (c 0.33, MeOH); IR (CHCl3) n
4.1.14. (3aS,7aR)-3a-(3,4-Dimethoxyphenyl)-1-[(R)-1-
(1,2,3,4-tetrahydronaphthalen-5-yl)ethyl]octahydroin-
dol-2-one (30a), (3aR,7aS)-3a-(3,4-dimethoxyphenyl)-1-
[(R)-1-(1,2,3,4-tetrahydronaphthalen-5-yl)ethyl]octahy-
droindol-2-one (30b), and (R)-2,3,3a,4,5,6-hexahydro-3a-
(3,4-dimethoxyphenyl)-1-[(R)-1-(1,2,3,4-tetrahydro-
naphthalen-5-yl)ethyl]indol-2-one (31). Platinum dioxide
(5 mg, 0.02 mmol) was added to a solution of a 2:1 dia-
stereoisomeric mixture of 26 (40 mg, 0.094 mmol) in acetic
acid (1 mL) at room temperature under a hydrogen atmo-
sphere, and the stirring was continued for 14 h. The catalyst
was filtered off, the filtrate was concentrated, and the residue
was purified by thin layer chromatography on silica gel (hex-
ane/AcOEt, 3:1). The first eluent gave 31 (1.6 mg, 4%) as
a colorless oil. [a]2D6 +170.9 (c 0.27, MeOH); IR (CHCl3) n
1514 cmꢀ1 1H NMR (500 MHz, CDCl3) d 1.15–1.87
;
(13H, m), 1.32 (3H, d, J¼6.6 Hz), 2.56–2.64 (2H, m), 2.71
(1H, dd, J¼11.6, 3.5 Hz), 2.76–2.84 (4H, m), 3.09 (1H, dt,
J¼10.2, 5.9 Hz), 3.76 (3H, s), 3.84 (3H, s), 4.20 (1H, q, J¼
6.5 Hz), 6.75 (1H, d, J¼8.5 Hz), 6.94 (1H, d, J¼7.3 Hz),
7.05 (1H, t, J¼7.6 Hz), 7.24 (1H, dd, J¼2.2, 8.5 Hz), 7.29
(1H, d, J¼7.5 Hz), 7.62 (1H, d, J¼2.2 Hz); 13C NMR
(125 MHz, CDCl3) d 13.5, 22.3, 22.8, 23.5, 25.0, 25.7,
25.9, 30.4, 37.9, 40.3, 44.5, 48.7, 53.0, 55.7, 55.9, 72.6,
110.5, 113.5, 120.6, 124.1, 124.7, 127.6, 134.4, 137.0,
138.1, 143.5, 146.3, 148.0. HRMS calcd for C28H37NO2:
419.2824, found: 419.2829.
1709, 1667 cmꢀ1 1H NMR (270 MHz, CDCl3) d 0.88–
;
2.16 (11H, m), 1.72 (3H, d, J¼7.3 Hz), 2.50 (1H, dt,
J¼17.2, 5.6 Hz), 2.66 (1H, d, J¼16.2 Hz), 2.75–2.83 (2H,
m), 2.95 (1H, d, J¼16.2 Hz), 3.61 (3H, s), 3.82 (H, s),
5.27 (1H, t, J¼3.6 Hz), 5.63 (1H, q, J¼7.7 Hz), 6.36 (1H,
dd, J¼2.1, 8.3 Hz), 6.54 (1H, d, J¼2.1 Hz), 6.62 (1H, d,
J¼8.2 Hz), 7.04–7.21 (2H, m), 7.39 (1H, d, J¼7.7 Hz);
13C NMR (125 MHz, CDCl3) d 16.6, 17.3, 22.3, 22.8,
4.1.16. (3aS,7aR)-3a-(3,4-Dimethoxyphenyl)octahy-
droindole [(L)-trans-mesembrane] (33). A mixture of 32
(60 mg, 0.14 mmol) and Pd(OH)2/C (15 mg) in MeOH
(1.5 mL) was stirred at room temperature for 12 days under a
hydrogen atmosphere. The catalyst was filtered off, and the

M. Saito et al. / Tetrahedron 63 (2007) 4865–4873
4873
2. Ishibashi, H.; Nakaharu, T.; Nishimura, M.; Nishikawa, A.;
Kameoka, C.; Ikeda, M. Tetrahedron 1995, 51, 2929.
3. For a portion of this work, see: Saito, M.; Matsuo, J.;
Uchiyama, M.; Ishibashi, H. Heterocycles 2006, 69, 69.
4. (a) Lotspeish, J. F.; Karichhoff, S. J. Org. Chem. 1966, 31,
2183; (b) Beagmann, D. E.; Pappo, R.; Ginsburg, D. J.
J. Chem. Soc. 1950, 1369.
filtrate was concentrated to give (3aS,7aS)-3a-(3,4-di-
methoxyphenyl)octahydroindole. A mixture of this material,
aqueous HCHO solution (37%, 0.094 mL, 1.15 mmol), and
NaBH3(CN) (60 mg, 0.96 mmol) in MeOH (8 mL) was
stirred at room temperature for 15 min. The mixture was
concentrated, and the residue was purified by thin layer chro-
matography on silica gel (CHCl3/MeOH/isopropylamine,
80:1:2) to give 33 (23 mg, 71%) as a colorless oil. [a]D28
5. Mooradian, A.; Cavallito, C. J.; Bergman, A. J.; Lawson, E. J.;
Suter, C. M. J. Am. Chem. Soc. 1949, 71, 3372.
ꢀ105.8 (c 0.32, MeOH); IR (CHCl3) n 1514 cmꢀ1
;
1H
6. Chlorine atom transfer cyclization of a-chloro-N-methyl-a-
(methylthio)-N-(2-phenylcyclohex-1-en-3-yl)acetamide with
RuCl2(PPh3)3 gave a compound having a trans-configuration
between the methylthio group and the phenyl group, see:
Ishibashi, H.; Uemura, N.; Nakatani, H.; Okazaki, M.;
Sato, T.; Nakamura, N.; Ikeda, M. J. Org. Chem. 1993, 58,
2360.
7. For synthesis of (ꢂ)-mesembrane and (ꢂ)-trans-mesembrane,
see: (a) Oh-ishi, T.; Kugita, H. Tetrahedron Lett. 1968, 5455;
(b) Oh-ishi, T.; Kugita, H. Chem. Pharm. Bull. 1970, 18, 291;
(c) Nagashima, H.; Ara, K.; Wakamatsu, H.; Itoh, K.
J. Chem. Soc., Chem. Commun. 1985, 518; (d) Pearson,
W. H.; Szura, D. P.; Postich, M. J. J. Am. Chem. Soc. 1992,
114, 1329; (e) Iwamatsu, S.; Matsubara, K.; Nagashima, H.
J. Org. Chem. 1999, 64, 9625; (f) Padwa, A.; Brodney,
M. A.; Dimitroff, M.; Liu, B.; Wu, T. J. Org. Chem. 2001,
66, 3119.
NMR (500 MHz, CDCl3) d 1.13–1.79 (9H, m), 2.17 (1H,
dd, J¼11.6, 3.7 Hz), 2.25 (1H, td, J¼10.4, 2.4 Hz), 2.37
(3H, s), 2.57–2.62 (1H, m), 3.08 (1H, dd, J¼18.3, 7.9 Hz),
3.84 (3H, s), 3.85 (3H, s), 6.79 (1H, d, J¼8.6 Hz), 7.28
(1H, dd, J¼8.5, 2.4 Hz), 7.59 (1H, d, J¼2.4 Hz); 13C
NMR (125 MHz, CDCl3) d 22.2, 24.2, 25.7, 38.0, 40.0,
41.5, 48.9, 53.3, 55.7, 55.9, 76.8, 110.6, 113.2, 120.9, 138.1,
146.4, 148.3; HRMS calcd for C17H25NO2: 275.1885,
found: 275.1884.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
8. Miller, R. A.; Humphrey, G. R.; Thompson, A. S. Tetrahedron
Lett. 1995, 36, 7949.
Supplementary data
9. Pummerer reaction of sulfoxide 24 with TFAA could also be
carried out at ꢀ78 ꢁC, but the yield of 23 was very low and
the diastereoselectivity for the formation of 23 was almost
the same as that at 0 ꢁC.
Experimental procedure for the preparation of 19a, 20a, 21a,
19b, 20b1, 20b2, 21b1, and 21b2; 1H NMR spectra of 29 and
33. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2007.03.153.
10. For isolation of (ꢀ)-mesembrane, see: (a) Capps, T. M.;
Hargrave, K. D.; Jeffs, P. W.; McPhail, A. T. J. Chem. Soc.,
Perkin Trans. 2 1977, 1098. For total synthesis of (ꢀ)-mesem-
brane, see: (b) Mori, M.; Kuroda, S.; Zhang, C.-S.; Sato, Y.
J. Org. Chem. 1997, 62, 3263.
References and notes
1. For reviews, see: (a) Ishibashi, H.; Ikeda, M. J. Synth. Org.
Chem. Jpn. 1989, 47, 330; (b) Ishibashi, H.; Ikeda, M. Rev.
Heteroatom. Chem. 1992, 7, 191.
11. Popelak, A.; Lettenbaur, G.; Haak, E.; Springer, H.
Naturwissenschaften 1960, 47, 231.