Synthesis of phenserine analogues and evaluation of their cholinesterase inhibitory activities

Article abstract of DOI:10.1016/j.bmc.2012.06.048

Phenserine is a potentially attractive drug for Alzheimer's disease. In order to further expand SAR study for inhibitions of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), the methyl group at the 3a-position of phenserine was replaced with an alkyl or alkenyl group, and its phenylcarbamoyl moiety was substituted at the o- or p-position. The synthetic methodology for these phenserine analogues includes the efficient cascade reactions for introduction of the 3a-substituent and assembly of the quaternary carbon center followed by reductive cyclization to the key pyrroloindoline structure. The bulkiness of the substituent at 3a-position of phenserine derivatives tends to reduce the inhibitory effect on AChE activity in the following order: methyl > ethyl > vinyl > propyl ≈ allyl > reverse-prenyl groups. Among the series synthesized, the 3a-ethyl derivative demonstrated the highest AChE selectivity. In construct, the 3a-reverse-prenyl derivative indicated modest BuChE selectivity.

Full text of DOI:10.1016/j.bmc.2012.06.048

Bioorganic & Medicinal Chemistry 20 (2012) 4901–4914
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of phenserine analogues and evaluation of their cholinesterase
inhibitory activities
Masashi Shinada a, Fuminori Narumi a, Yuji Osada a, Koji Matsumoto a, Takayasu Yoshida a,
b
b
Kazuhiro Higuchi a, Tomomi Kawasaki a, , Hiroyuki Tanaka , Mitsutoshi Satoh
⇑
a Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
b Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Phenserine is a potentially attractive drug for Alzheimer’s disease. In order to further expand SAR study
for inhibitions of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), the methyl group at the
3a-position of phenserine was replaced with an alkyl or alkenyl group, and its phenylcarbamoyl moiety
was substituted at the o- or p-position. The synthetic methodology for these phenserine analogues
includes the efficient cascade reactions for introduction of the 3a-substituent and assembly of the qua-
ternary carbon center followed by reductive cyclization to the key pyrroloindoline structure. The bulki-
ness of the substituent at 3a-position of phenserine derivatives tends to reduce the inhibitory effect on
AChE activity in the following order: methyl > ethyl > vinyl > propyl ꢀ allyl > reverse-prenyl groups.
Among the series synthesized, the 3a-ethyl derivative demonstrated the highest AChE selectivity. In con-
struct, the 3a-reverse-prenyl derivative indicated modest BuChE selectivity.
Received 28 May 2012
Revised 27 June 2012
Accepted 28 June 2012
Available online 6 July 2012
This work is dedicated to Dr. Masanori
SAKAMOTO, Professor Emeritus of Meiji
Pharmaceutical University, on the occasion
of his 77th birthday (KIJU)
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Phenserine
Enzyme inhibitor
Acetylcholinesterase
Butyrylcholinesterase
Substituent effect
1. Introduction
symptoms of AD and control its progression. The structure–activity
relationship (SAR) of phenserine analogues 2 has been developed
Alzheimer’s disease (AD) is the most common form of elderly-
onset dementia. Progressive AD is a neurodegenerative disease
characterized by deficiency of cholinergic neurotransmission,1 the
formation of senile plaques including amyloid-b peptide (Ab),2
and the development of neurofibrillary tangles.3 For enhancement
of cholinergic neurotransmission by increasing acetylcholine
(ACh) availability, development of selective acetylcholinesterase
inhibitors (AChEIs) created several medicines such as donepezil
and galantamine approved for AD treatment.4 These medicines
are prescribed to ease only AD symptoms, but they could not halt
the progress of dementia. The approved AD medicine rivastigmine5
and the experimental AD drug phenserine (1)6 show non-selective
inhibition of AChE and butyrylcholinesterase (BuChE). Since over-
expression of BuChE in neuritic amyloid b Ab plaques in AD brain
was observed,7 the presence of BuChE amplifies the toxicity of Ab.
On re-examining the non-selective ChEIs, phenserine (1) was found
to be the most attractive drug to show dual action–inhibition of
ChEs and reduction in the production of Ab precursor protein.8
Therefore, this drug has been expected to both ameliorate the
(Fig. 1); for example, tolserine (R = Me, R1 = 2-Me) indicated potent
cholinesterase inhibition with a high selectivity for AChE, while
cymserine (R = Me, R1 = 4-i-Pr) showed potent and selective BuChE
inhibition.9 A variety of N1- and N8-substituents (R2 and R3) in
phenserine (1), tolserine, and cymserine have also been well stud-
ied. However, to the best of our knowledge, there has been little re-
search on the synthesis and SAR of various 3a-substituted (R)
phenserine analogues.9–11 Recently, we have developed a concise
and efficient synthetic methodology for a series of pyrroloindole
alkaloids.12 On the basis of structural attractiveness and synthetic
accessibility, we began to investigate SAR of novel phenserine ana-
logues having a bulkier group (R) than methyl group at 3a-position
and a substituent (R1) on the phenyl moiety. Herein, we describe
the efficient and versatile synthesis of the phenserine analogues
3–13 and their biological evaluation.
2. Results and discussion
2.1. Chemistry
The syntheses of target compounds 3–13 was accomplished by
the synthesis of 3a-substituted pyrrolo[2,3-b]indolines 14 from 15
⇑
Corresponding author. Tel./fax: +81 42 495 8763.
E-mail address: kawasaki@my-pharm.ac.jp (T. Kawasaki).
0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2012.06.048

4902
M. Shinada et al. / Bioorg. Med. Chem. 20 (2012) 4901–4914
H
H
R1
N
N
Ph
O
O
Me
R
O
O
3a
N
N
N
R3
N
R2
Me
H
H
Me
(–)-1 phenserine
2
H
N
Ph
O
H
N
O
R1
O
O
R
N
O
N
Me
H
N
Me
N
( )-13
Me
H
Me
H
N
( )-3 R = CH2CH=CH2, R1 = H
Ph
O
R
( )-4 R = CH2CH=CH2, R1 = 4-i-Pr
( )-5 R = CH2CH=CH2, R1 = 4-Br
( )-6 R = CH2CH=CH2, R1 = 4-F
( )-7 R = CH2CH=CH2, R1 = 2-F
( )-8 R = n-Pr, R1 = H
O
N
N
Me
H
Me
( )-9 R = CH=CH2 R1 = H
(–)-3 R = CH2CH=CH2,
(–)-9 R = CH=CH2
( )-10 R = Et, R1 = H
( )-11 R = CMe2CH=CH2, R1 = H
( )-12 R = CMe2Et, R1 = H
(–)-10 R = Et
(–)-12 R = CMe2Et
Figure 1. Phenserine (1), its analogues 2 used in SAR of ChEIs: e.g. cymserine (R = R2 = R3 = Me, R1 = 4-i-Pr) and tolserine (R = R2 = R3 = Me, R1 = 2-Me), and target compounds
3–13.
using our previously developed methodology12,13 and the transfor-
mation of 14 to 3–13 according to the known procedure for phen-
serine (1)14 (Scheme 1).
The target compounds 9 and 10 were obtained by conversion of
the allyl group of 19 to both vinyl and ethyl groups (Scheme 4).
Thus, OsO4-oxidation of 19 followed by reduction gave alcohol
24. Subsequent arylselenation and oxidative elimination of 24
afforded 3-vinyloxindole 25. In the same way as ( )-3, synthesis
of vinyl derivative ( )-9 from 25 was achieved through hydrolysis,
condensation with methylamine, reductive cyclization, demethyla-
tion, and carbamoylation. The ethyl derivative ( )-10 was obtained
by hydrogenation of 9.
To synthesize the targets 11 and 12 with the bulky reverse-
prenyl group at the 3a-position (Scheme 5), methylamide 33 was
produced in 42% yield (six steps) from 16 and prenyl alcohol by
the procedure similar to the preparation of 21. Reduction of 33
with LiAlH4 proceeded with cyclization to give both pyrroloindo-
lin-2-one 34 and pyrroloindoline 35. The indolin-2-one 34 was
further reduced to afford 35 in 85% overall yield from 33. In the
case of 35, demethylation with BBr3 gave a miserable result due
to its acid lability. For this reason, the dihydro-derivative 12 was
prepared instead of 11. After hydrogenation of 35, demethylation
of 36 with BBr3 proceeded successfully, and subsequent carbamo-
ylation with phenyl isocyanate afforded the target ( )-12.
2.1.1. Synthesis of racemic compounds ( )-3–13
The key synthetic intermediate 22 for the target molecules 3–8
was obtained starting from 5-methoxy-1-acetylindolin-3-one (16)15
as shown in Scheme 2. Bromination of 16 at C2 followed by substitu-
tion with allyl alcohol afforded ether 17. The Horner–Wadsworth–
Emmons olefination of 17 with diethyl cyanomethylphosphonate in
the presence of t-BuOK at a low temperature proceeded with the cas-
cade of isomerization/deacylation/Claisen rearrangement to produce
oxindole 18 in 87% yield. Methylation of 18, followed by hydrolysis
of nitrile 19 and condensation of carboxylic acid 20 with methyl-
amine, gave methylamide 21 in 67% yield (three steps). The reductive
cyclization of 21 with LiAlH4 furnished the key pyrroloindoline 22.
Using conditions optimized by Brossi,14a sequential demethylation
of 22 with BBr3 and reaction with phenyl isocyanate were performed
to produce the allyl target ( )-3 in 76% yield (entry 1). To investigate
the role of the substituent on the aromatic ring, some analogues ( )-
4–7 were prepared in good yields from 22 using conditions reported
by Overman14b (entries 2–5). The propyl derivative ( )-8 was obtained
by hydrogenation of 3.
2.1.2. Synthesis of optically active compounds (ꢁ)-3, (ꢁ)-9, (ꢁ)-
10, (ꢁ)-12
The target 13 was prepared from 21. Thus, AlH3-reduction of 21
proceeded with cyclization to give 23, which was converted to ( )-
13 in the same manner as ( )-3 (Scheme 3).
To prepare the (3aR,8aR)-enantiomers (ꢁ)-3, (ꢁ)-9, (ꢁ)-10, and
(ꢁ)-12 having the same absolute configuration with (ꢁ)-phenserine
H
R1
N
MeO
O
MeO
R'
R
R
O
X
X
O
N
N
O
N
N
N
Me
Me
H
H
Me
Me
Ac
3-13 X = H2, O
14 X = H2, O
15
Scheme 1. Retrosynthetic approach to compounds 3–13.

M. Shinada et al. / Bioorg. Med. Chem. 20 (2012) 4901–4914
4903
MeO
MeO
MeO
MeO
MeO
O
O
CN
CN
c
d
a, b
e
O
O
O
N
N
N
N
H
Me
Ac
Ac
16
( )-17
( )-18
MeO
( )-19
MeO
CO2H
CONHMe
f
g
h, i or j
N
O
O
N
N
N
Me
H
Me
Me
Me
( )-20
( )-21
( )-22
yield
(%, 2 steps)
ArHN
PhHN
O
O
entry compd.
Ar
k
1
2
3
4
5
3
4
5
6
7
Ph
76
56
87
84
64
O
O
4-i-Pr-C6H4
4-Br-C6H4
4-F-C6H4
2-F-C6H4
N
N
N
N
Me
Me
H
H
Me
Me
( )-8
( )-3-7
Scheme 2. Reagents and conditions: (a) Br2, CH2Cl2, 0 °C, (b) allyl alcohol, MS 4A, MeCN, rt, 79% (2 steps); (c) (EtO)2P(O)CH2CN, t-BuOK, DMF, ꢁ78 °C to rt, 87%; (d) MeI, NaH,
DMF, 0 °C, 98%; (e) NaOH, MeOH, reflux, 85%; (f) EDC, C6F5OH, Et3N, THF, rt, then MeNH2, 81%; (g) LiAlH4, THF, reflux, 86%; (h) BBr3, CH2Cl2, 0 °C; (i) Na, Et2O, rt, then PhNCO,
entry 1; (j) NaH, THF, rt, then ArNCO, entries 2–5; (k) Pd/C, H2, rt, 96%.
PhHN
MeO
O
MeO
O
O
CONHMe
O
a
b, c
N
N
O
N
N
N
Me
Me
H
H
Me
Me
Me
( )-21
( )-23
( )-13
Scheme 3. Reagents and conditions: (a) AlH3ꢂEtNMe2, toluene/THF, ꢁ15 °C, 94%; (b) BBr3, CH2Cl2, 0 °C; (c) NaH, THF, rt, then PhNCO, 69% (2 steps).
OH
MeO
MeO
MeO
CN
CN
CN
c, d
e
a, b
O
O
O
N
N
N
Me
Me
Me
( )-25
( )-19
( )-24
MeO
MeO
MeO
CO2H
f
g
CONHMe
N
O
N
O
N
N
Me
H
Me
Me
Me
( )-27
( )-26
( )-28
PhHN
PhHN
O
O
O
O
j
h, i
N
N
N
N
Me
Me
H
H
Me
Me
( )-9
( )-10
Scheme 4. Reagents and conditions: (a) OsO4, NMO, MeCN, rt, then NaIO4, 1,4-dioxane–H2O, rt; (b) NaBH4, MeOH, 0 °C, 65% (2 steps); (c) o-nitrophenyl selenocyanate, n-
Bu3P, THF, rt; (d) H2O2, THF, rt, 73% (2 steps); (e) NaOH, MeOH, reflux, quant.; (f) EDC, C6F5OH, Et3N, THF, rt, then MeNH2, 90%; (g) LiAlH4, THF, reflux, 75%; (h) BBr3, CH2Cl2, rt;
(i) Na, Et2O, rt, then PhNCO, 57% (2 steps); (j) Pd/C, H2, EtOH, rt, 98%.
(1), the optical resolution of the respective carboxylic acids ( )-20,
( )-26, and ( )-32 through (R)-4-phenyloxazolin-2-one derivatives
37a–c was implemented (Scheme 6). The carboxylic acids ( )-20,
( )-26, and ( )-32 were condensed with (R)-4-phenyloxazolin-2-
one to give two diastereoisomers 37 and 38 (ca. 1:1). Hydrolysis of
oxazolin-2-one derivatives 38a–c with LiOH and H2O2 produced
(ꢁ)-20, (+)-26, and (ꢁ)-32 in 28–43% yield (three steps), respec-
tively.16 The optically pure (ꢁ)-3, (ꢁ)-9, (ꢁ)-10, and (ꢁ)-12 were ob-
tained from (ꢁ)-20, (+)-26, and (ꢁ)-32 in the same manner as the
racemic version.17

4904
M. Shinada et al. / Bioorg. Med. Chem. 20 (2012) 4901–4914
MeO
MeO
MeO
MeO
MeO
O
O
CN
CN
a, b
c
d
e
O
O
O
N
N
N
N
H
Me
Ac
Ac
16
( )-29
( )-30
( )-31
MeO
MeO
MeO
O
CO2H
f
CONHMe
g
+
N
N
O
O
N
N
N
N
Me
Me
H
H
Me
Me
Me
Me
( )-32
( )-33
( )-34
( )-35
h
PhHN
MeO
O
O
i
j, k
N
N
N
N
Me
Me
H
H
Me
Me
( )-36
( )-12
Scheme 5. Reagents and conditions: (a) Br2, CH2Cl2, 0 °C, (b) prenyl alcohol, MS 4A, MeCN, rt, 74% (2 steps); (c) (EtO)2P(O)CH2CN, t-BuOK, DMF, ꢁ78 °C to rt, 91%; (d) MeI,
NaH, DMF, rt, 75%; (e) NaOH, MeOH, reflux, 88%; (f) EDC, C6F5OH, Et3N, THF, rt, then MeNH2, 95%; (g) LiAlH4, THF, reflux, 34 (52%) and 35 (41%); (h) LiAlH4, THF, reflux, 85%; (i)
Pd/C, H2, rt, 99%; (j) BBr3, CH2Cl2, 0 °C; (k) Na, Et2O, rt, then PhNCO, 63% (2 steps).
2.2. Biological activity
of new compounds ( )-3–13 and phenserine (ꢁ)-1 are shown in
Table 1. A slight difference in the AChE inhibitory effect between
the alkenyl and alkyl groups at 3a-site [e.g. vinyl 9 vs ethyl 10 (en-
tries 7, 8)] was observed. A bulkier substituent (R) at the 3a-posi-
2.2.1. Inhibitory effects of racemic phenserine derivatives on
AChE and BuChE activity in vitro
The Ogura et al.18-modified spectrophotometric method of Ell-
man et al.19 was used to evaluate 10 racemic and four optically ac-
tive derivatives along with phenserine (ꢁ)-1 and physostigmine as
reference compounds. All of the test compounds inhibited the
activities of AChE and BuChE in a concentration-dependent manner
in 3 ꢃ 10ꢁ5 M (Fig. 2). The IC50 values for AChE and BuChE inhibition
tion of the phenserine derivatives tends to exert a weaker
inhibitory effect on AChE activity in the following order: methyl
(ꢁ)-1 > ethyl ( )-10 > vinyl ( )-9 > propyl ( )-8 ꢀ allyl ( )-3 > re-
verse-prenyl derivative ( )-12 (entries 1, 6–11). The inhibitory
activities of 4- and 2-fluoride derivatives ( )-6 and ( )-7 was
comparable to that of ( )-3 (entries 4, 5 vs 1), but 4-bromo- and
O
O
MeO
O
O
MeO
MeO
R
R
R
a
CO2H
N
N
+
O
O
O
Ph
Ph
N
O
O
N
N
Me
Me
Me
( )-20: R = -CH2CH=CH2
( )-26: R = -CH=CH2
( )-32: R = -CMe2CH=CH2
37a 46%
37b 36%
37c 48%
38a 42%
38b 34%
38c 48%
MeO
MeO
R
R
b
c
d
CO2H
CONHMe
38a-c
O
O
N
N
Me
Me
(–)-20 89%
(+)-26 78%
(–)-32 89%
(–)-21 72%
(+)-27 96%
(–)-33 94%
PhHN
MeO
O
R
R
X
f, g (for 3, 9)
O
N
N
h, f, g (for 12)
N
N
Me
Me
H
H
Me
Me
(–)-22 X = H2, 88%
(–)-28 X = H2, 78%
(–)-34 X = O, 81%
(–)-35 X = H2, 80%
(–)-3 R = -CH2CH=CH2, 72% (2 steps)
(–)-9 R = -CH=CH2, 96% (2 steps)
(–)-10 R = -Et, 99%
h
e
(–)-12 R = -CMe2Et, 50% (3 steps)
Scheme 6. Reagents and conditions: (a) EDC, C6F5OH, NEt3, rt, then (R)-(ꢁ)-4-phenylisoxazolin-2-one, n-BuLi or NaH, 0 °C; (b) LiOH, H2O2, THF, H2O, rt; (c) EDC, C6F5OH, NEt3,
THF, rt, then MeNH2; (d) LiAlH4, THF, reflux, 1 h; (e) LiAlH4, THF, rt, 0.5 h; (f) BBr3, CH2Cl2, rt; (g) Na, Et2O, rt, then PhNCO; (h) Pd/C,H2, EtOH, rt.

M. Shinada et al. / Bioorg. Med. Chem. 20 (2012) 4901–4914
4905
100
80
3. Conclusion
Physostigmine
(–)-1
Several series of phenserine analogues with an alkyl or alkenyl
group at the 3a-position were synthesized starting from 5-meth-
oxy-1-acetylindolon-3-one in the following key steps: the cascade
of olefination/isomerization/deacylation/Claisen rearrangement of
2-allyloxyindolin-3-ones to 3,3-disubstituted oxindoles, reductive
cyclization of 3-allyl-3-carbamoylmethyloxindoles to 3a-allyl-pyr-
rolo[2,3-b]indolines, the substituent variation at the allylic moiety,
and conventional carbamoylation. The phenserine analogues were
assessed by AChE and BuChE inhibition assays. The bulkiness of the
substituent at the 3a-position of phenserine analogues tends to re-
duce the inhibitory effect on AChE activity. Of the series synthe-
sized, the 3a-ethyl derivative demonstrated the highest AChE
selectivity. In construct, the 3a-reverse-prenyl derivative indicated
modest BuChE selectivity.
( )-10
( )-9
60
40
20
0
( )-13
( )-8
( )-3
( )-12
-10
-9
-8
-7
-6
-5
-4
Log (M)
100
80
Physostigmine
(–)-1
( )-10
( )-9
60
4. Experimental section
4.1. Chemistry
( )-13
( )-8
40
( )-3
20
0
( )-12
All melting points were measured on a Yanagimoto micro melt-
ing point apparatus and are uncorrected. Optical rotations were
obtained using a JASCO P-2200 polarimeter. Optical purities were
determined on a JASCO HPLC (PU-2089 plus, MD-2015 plus) instru-
ment equipped with Daisel Chemical chiral columns. CD spectra
were measured with JASCO J-820 equipment with distilled CH2Cl2
in 10 mm of quarts cell at 25 °C. IR spectra were recorded on a Shi-
madzu IRPrestige-21 spectrophotometer. 1H and 13C NMR spectra
were measured on a JEOL JNM-AL300 (300 MHz), JEOL JMN-
AL400 (400 MHz) or JEOL JNM-LA500 (500 MHz) spectrometer
with tetramethylsilane as an internal standard. J-Values are given
in Hertz. Mass spectra were recorded on a JEOL JMS-DX302 or JEOL
JMS 700 instrument with a direct inlet system. Elemental analysis
was performed using a Yanaco MT-6 elemental analyzer. Column
chromatography was carried out on silica gel [Kanto Chemical
-10
N
-9
-8
N
-7
-6
-5
-4
Log (M)
Figure 2. Effect of physostigmine, phenserine (ꢁ)-1 and phenserine derivatives ( )-
3–13 on rat brain AChE and rat plasma BuChE activity. Data are presented as
mean SE values from four experiments.
isopropyl derivatives ( )-5 and ( )-4 showed considerably poorer
inhibitory effects than 3 (entries 2, 3). The 2- or 4-substituent of
the phenyl ring of ( )-3 had little effect on AChE and BuChE inhib-
itory activity. In terms of AChE selectivity (BuChE/AChE ratio),
phenserine (ꢁ)-1 has the highest value of more than 1000-fold,
while ( )-3 and ( )-6–12 exhibit moderate selectivity for AChE
(>5.4 to 76-fold), respectively. The AChE inhibitory activity and
selectivity of lactam derivative ( )-13 was lower than that of amine
( )-3 (entries 1 vs 10).
Co. Inc. (Silica Gel 60N, Spherical, neutral 40–50
Ltd. gel (Silica Gel 60, 230–400 mesh)].
lm) and Merck
IC50 and AChE selectivity of optically active allyl (ꢁ)-3, vinyl
(ꢁ)-9, ethyl (ꢁ)-10 and reverse-prenyl derivatives (ꢁ)-12, phenser-
ine (ꢁ)-1 and (ꢁ)-physostigmine are shown in Table 2. The IC50
values for AChE inhibition of the optically active compounds were
lower than those of the racemic derivatives (Tables 1 vs 2). The
AChE selectivity of optically active derivatives tends to be higher
than that of the corresponding racemic derivatives. The effect of
substituent (R) on AChE inhibitory activity and selectivity has the
same tendency as the racemic version indicated above.
4.1.1. 1-Acetyl-2-allyloxy-5-methoxyindolin-3-one ( )-(17)
Under N2 atmosphere, to a solution of 16 (1.0 g, 4.9 mmol) in
CH2Cl2 (35 mL) was added a solution of Br2 in CH2Cl2 (11 mL,
1.0 M, 11 mmol) at 0 °C and the solution was stirred for 2 h. Start-
ing material consumption was determined by TLC, and the reaction
mixture was neutralized with satd. aqueous NaHCO3. The organic
layer was washed with brine and dried over MgSO4. The concen-
trated residue (1.4 g) was used without further purification. Under
Table 1
Inhibitory effects of racemic phenserine derivatives on rat brain AChE and rat plasma BuChE
Entry
Compound
R
IC50
(l
M)a
Selectivity
No.
R1
AChE
BuChE
BuChE/AChE
1
2
3
4
5
6
7
8
( )-3
( )-4
( )-5
( )-6
( )-7
( )-8
( )-9
( )-10
( )-12
( )-13
(ꢁ)-1
CH2@CHCH2–
CH2@CHCH2–
CH2@CHCH2–
CH2@CHCH2–
CH2@CHCH2–
n-Pr–
CH2@CH–
Et–
EtMe2C–
H
3.77 0.12
>10
>10
4.36 0.26
3.55 0.06
3.66 0.11
0.749 0.12
0.397 0.005
18.4 0.6
4.73 0.001
>100
>10
>10
>100
87.3 2.7
>100
>30
>27
—
—
>23
25
>27
>40
76
4-i-Pr
4-Br
4-F
2-F
H
H
H
H
H
ꢄ30
9
10
11
>100
65.3 5.4
ꢄ30
>5.4
14
1100
b
CH2@CHCH2-
Me–
H
0.0283 0.0013
a
Data are presented as mean SE values from 4 dose-response curves for each test compound.
Lactam compound.
b

4906
M. Shinada et al. / Bioorg. Med. Chem. 20 (2012) 4901–4914
Table 2
Inhibitory effects of optically active phenserine derivatives on rat brain AChE and rat plasma BuChE
Entry
Compound
R
IC50
(l
M)a
Selectivity
No.
R1
AChE
BuChE
BuChE/AChE
1
2
3
4
5
6
(ꢁ)-3
CH2@CHCH2–
CH2@CH–
Et–
EtMe2C–
Me–
H
H
H
H
H
1.26 0.06
>100
>79
65
97
>11
1100
5.3
(ꢁ)-9
0.644 0.005
0.373 0.008
9.50 0.71
0.0283 0.0013
0.0110 0.0050
41.9 1.2
36.2 0.8
>100
(ꢁ)-10
(ꢁ)-12
(ꢁ)-1
ꢄ30
(ꢁ)-Physostigmine
0.0584 0.0070
a
Data are presented as mean SE values from four dose-response curves for each test compound.
N2 atmosphere, to a suspension of above residue (1.4 g) and molec-
ular sieves 4A (6.9 g, powder) in CH3CN (50 mL) was added allyl
alcohol (1.6 mL, 24 mmol) and the mixture was stirred for 1 day.
The reaction mixture was filtrated through a Celite pad and con-
centrated under reduced pressure. The residue was purified by sil-
ica gel column chromatography (AcOEt/n-hexane = 1/2.5) to give
( )-17 (1.0 g, 79%) as pale yellow needles.
solution of ( )-18 (1.4 g, 5.9 mmol) in DMF (20 mL) with ice-bath
cooling. After 1 h stirring at room temperature, MeI (0.43 mL,
7.0 mmol) was added to the mixture with ice-bath cooling. After
15 min stirring at room temperature, water (100 mL) was added
to the reaction mixture. The mixture was extracted by Et2O. The or-
ganic layer was washed with brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (AcOEt/n-hexane = 1/1) to give ( )-
19 (1.5 g, 98%) as colorless crystals.
Mp: 99–102 °C (AcOEt); IR (CHCl3): 1726, 1682, 1489 cmꢁ1 1H
;
NMR (300 MHz, CDCl3): 2.38 (3H, s), 3.83 (3H, s), 4.05 (1H, ddt,
J = 11.9, 5.7, 1.2 Hz), 4.19 (1H, ddt, J = 11.9, 5.7, 1.2 Hz), 5.20 (1H,
ddt, J = 10.8, 2.5, 1.2 Hz), 5.24 (1H, s), 5.28 (1H, ddt, J = 17.4, 3.1,
1.2 Hz), 5.89 (1H, ddt, J = 17.4, 10.8, 5.7 Hz), 7.12 (1H, d,
J = 2.7 Hz), 7.25 (1H, dd, J = 9.0, 2.7 Hz), 8.41 (1H, d, J = 9.0 Hz);
13C NMR (100 MHz, CDCl3): 23.5, 55.8, 66.4, 85.7, 105.0, 118.4,
119.2, 123.0, 126.4, 132.5, 147.8, 156.4, 168.8, 194.6; MS (EI): m/
z (%) 262 (13), 261 (M+, 81), 218 (42), 205 (20), 191 (15), 178
(100), 162 (45), 150 (21), 106 (13), 43 (20), 41 (13); HRMS (EI):
m/z Calcd for C14H15NO4: 261.1001; Found: 261.1004; Anal. Calcd
for C14H15NO4: C, 64.36; H, 5.79; N, 5.36. Found: C, 64.11; H,
5.76; N, 5.28.
Mp: 115 °C (AcOEt/n-hexane); IR (CHCl3): 3020, 1713, 1603,
1498 cmꢁ1 1H NMR (300 MHz, CDCl3): d 2.62 (1H, dd, J = 13.5,
;
7.9 Hz), 2.64 (1H, d, J = 16.7 Hz), 2.68 (1H, dd, J = 13.5, 6.8 Hz),
2.74 (1H, d, J = 16.5 Hz), 3.20 (3H, s), 3.82 (3H, s), 5.04 (1H, dd,
J = 10.2, 1.8 Hz), 5.10 (1H, dd, J = 17.1, 1.8 Hz), 5.42 (1H, dddd,
J = 17.1, 10.2, 7.8, 6.9 Hz), 6.78 (1H, d, J = 8.4 Hz), 6.87 (1H, J = 8.4,
2.4 Hz), 7.06 (1H, d, J = 2.4 Hz); 13C NMR (75 MHz, CDCl3): d 24.9,
26.4, 40.2, 49.1, 55.8, 108.9, 110.9, 113.4, 116.3, 120.3, 130.1,
130.5, 136.6, 156.3, 175.9; MS (EI): m/z (%) 256 (M+, 48), 215
(100); HRMS (EI): m/z Calcd for C15H16N2O2: 256.1212; Found:
256.1211; Anal. Calcd. for C15H16N2O2: C, 70.29; H, 6.29; N,
10.93. Found: C, 70.58; H, 6.50; N, 10.80.
4.1.2. 2-(3-Allyl-5-methoxy-2-oxoindolin-3-yl)acetonitrile ( )-
(18)
4.1.4. 2-(3-Allyl-5-methoxy-1-methyl-2-oxoindolin-3-yl)acetic
acid ( )-(20)
Under N2 atmosphere, to a solution of t-BuOK (4.5 g, 41 mmol)
in DMF (48 mL) was added (EtO)2P(O)CH2CN (7.7 mL, 44 mmol) at
0 °C and the mixture was stirred at room temperature for 0.5 h.
After cooling at ꢁ78 °C, to the mixture was added slowly a solution
of ( )-17 (3.5 g, 14 mmol) in DMF (20 mL) at the same tempera-
ture. After consumption of ( )-17 (0.5 h), the stirred reaction mix-
ture was warmed to room temperature for 2 h. The reaction
mixture was diluted with Et2O, neutralized with 10% HCl and ex-
tracted with Et2O. The organic layer was washed with brine, dried
over MgSO4, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (AcOEt/n-hex-
ane = 1/1) to give ( )-18 (2.8 g, 87%) as colorless crystals.
Mp: 131.5–133.0 °C (AcOEt/n-hexane); IR (CHCl3): 3436, 2257,
To a solution of ( )-19 (1.3 g, 5.0 mmol) in MeOH (20 mL) was
added 35% aqueous NaOH (11 mL, 0.10 mol) and the mixture was
stirred under reflux for 3 days. The mixture was concentrated
and acidified with 1 N aqueous HCl and extracted with AcOEt.
The organic layer was dried over MgSO4 and concentrated to give
( )-20 (1.2 g, 85%) as a pale yellow oil.
IR (CHCl3): 3010, 1710, 1601, 1500 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): d 2.34–2.49 (2H, m), 2.64 (1H, d, J = 16.0 Hz), 2.80 (1H, d,
J = 16.0 Hz), 3.02 (3H, s), 3.75 (3H, s), 4.90 (1H, d, J = 10.2 Hz),
4.98 (1H, d, J = 16.2 Hz), 5.28–5.40 (1H, m), 6.66 (1H, d,
J = 8.4 Hz), 6.70–6.79 (2H, m), 9.88 (1H, br s); 13C NMR (75 MHz,
CDCl3): d 26.2, 41.1, 41.8, 50.2, 55.7, 108.3, 110.6, 112.1, 119.3,
131.4, 132.5, 137.3, 155.9, 174.4, 179.4; MS (EI): m/z (%) 275 (M+,
48), 191 (12), 190 (100), 174 (15); HRMS (EI): m/z Calcd for
1710, 1605, 1493 cmꢁ1 1H NMR (300 MHz, CDCl3): d 2.63 (1H,
;
dd, J = 15.4, 7.9 Hz), 2.69 (1H, dd, J = 15.4, 8.8 Hz), 2.69 (1H, d,
J = 16.7 Hz), 2.86 (1H, d, J = 16.7 Hz), 3.80 (3H, s), 5.03 (1H, dd,
J = 10.3, 1.3 Hz), 5.13 (1H, dd, J = 16.8, 1.3 Hz), 5.48 (1H, dddd,
J = 16.8, 10.3, 8.8, 7.9 Hz), 6.80 (1H, dd, J = 8.4, 2.4 Hz), 6.88 (1H,
J = 8.4 Hz), 7.00 (1H, d, J = 2.4 Hz), 9.25 (1H, br s); 13C NMR
(75 MHz, CDCl3): d 24.9, 40.2, 49.7, 55.8, 110.8, 110.9, 113.8,
116.3, 120.5, 130.4, 130.6, 133.7, 156.1, 178.8; MS (EI): m/z (%)
242 (M+, 59), 201 (100), 158 (28); HRMS (EI): m/z Calcd for
C
C
15H17NO4: 275.1158; Found: 275.1152; Anal. Calcd for
15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.27; H, 6.36;
N, 5.14.
4.1.5. 2-(3-Allyl-5-methoxy-1-methyl-2-oxoindolin-3-yl)-N-
methylacetamide ( )-(21) and (S)-derivative (ꢁ)-21
Under N2 atmosphere, to a solution of ( )-20 (0.20 g, 0.73 mmol)
in THF (10 mL) was added pentafluorophenol (0.40 g, 2.2 mmol),
Et3N (0.20 mL, 1.5 mmol), and EDCꢂHCl (0.21 g, 1.1 mmol). After
2 h stirring at room temperature, MeNH2 gas which was generated
by the reaction of aqueous MeNH2ꢂHCl and NaOH pellet, was bub-
bled through the reaction mixture. After consumption of mixed
anhydride, the reaction mixture was neutralized by 10% aqueous
HCl and extracted with Et2O. The organic layer was washed with
brine and dried over MgSO4. The concentrated residue was purified
C
C
14H14N2O2: 242.1055; Found: 242.1060; Anal. Calcd for
14H14N2O2: C, 69.41; H, 5.82; N, 11.56. Found: C, 69.28; H, 5.96;
N, 11.46.
4.1.3. 2-(3-Allyl-5-methoxy-1-methyl-2-oxoindolin-3-
yl)acetonitrile ( )-(19)
Under N2 atmosphere, to a suspension of NaH (0.28 g, 60%,
7.0 mmol, washed with n-hexane) in DMF (40 mL) was added a

M. Shinada et al. / Bioorg. Med. Chem. 20 (2012) 4901–4914
4907
by silica gel column chromatography (AcOEt/n-hexane = 1/1 to
100/0) to give ( )-21 (0.17 g, 81%) as colorless crystals.
Et2O and the solution was washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The residue was puri-
fied by silica gel column chromatography (CH2Cl2/MeOH = 20/1)
to give ( )-3 (0.17 g, 76%) as a white powder.
Mp: 131 °C (AcOEt/n-hexane); IR (CHCl3): 3462, 3030, 1690,
1603, 1499 cmꢁ1 1H NMR (300 MHz, CDCl3): d 2.52 (1H, dd,
;
J = 13.4, 7.1 Hz), 2.58 (1H, dd, J = 13.4, 7.1 Hz), 2.62 (1H, d,
J = 15.0 Hz), 2.63 (3H, d, J = 4.5 Hz), 2.80 (1H, d, J = 15.0 Hz), 3.20
(3H, s), 3.79 (3H, s), 4.94 (1H, d, J = 10.2 Hz), 4.99 (1H, dd,
J = 17.0 Hz), 5.40 (1H, ddt, J = 17.0, 10.2, 7.1 Hz), 6.36 (1H, br s),
6.73 (1H, d, J = 8.4 Hz), 6.80 (1H, J = 8.4, 2.4 Hz), 6.86 (1H, d,
J = 2.4 Hz); 13C NMR (100 MHz, CDCl3): d 26.3, 26.5, 41.4, 42.6,
50.6, 55.8, 108.3, 110.8, 112.2, 119.3, 131.3, 132.3, 136.7, 155.8,
169.3, 178.9; MS (EI): m/z (%) 288 (M+, 57), 216 (14), 215 (11),
191 (12), 190 (100), 174 (10); HRMS (EI): m/z Calcd for
Mp: 138–140 °C; IR (CHCl3): 3433, 2934, 1748, 1602, 1526 cm
ꢁ1
;
1H NMR (300 MHz, CDCl3): d 1.94 (1H, ddd, J = 11.9, 6.0,
3.5 Hz), 2.04 (1H, ddd, J = 11.9, 9.0, 6.6 Hz), 2.40 (1H, dd, J = 14.0,
8.5 Hz), 2.51 (3H, s), 2.61 (1H, dd, J = 14.0, 6.1 Hz), 2.61 (1H, ddd,
J = 9.4, 9.0, 6.0 Hz), 2.73 (1H, ddd, J = 9.4, 6.6, 3.5 Hz), 2.90 (3H, s),
4.22 (1H, s), 5.01–5.09 (2H, m), 5.58 (1H, dddd, J = 16.5, 10.1, 8.4,
6.1 Hz), 6.36 (1H, d, J = 8.4 Hz), 6.83 (1H, d, J = 2.4 Hz), 6.84 (1H,
br s), 6.87 (1H, dd, J = 8.4, 2.4 Hz), 7.09 (1H, t, J = 7.2 Hz), 7.33
(2H, d, J = 7.2 Hz), 7.44 (2H, d, J = 7.2 Hz); 13C NMR (100 MHz,
CDCl3): d 37.0, 37.9, 39.1, 44.4, 52.7, 56.7, 94.4, 106.5, 116.6,
117.8, 118.6, 120.5, 123.6, 129.0, 134.7, 135.5, 137.5, 142.4,
150.3; MS (EI): m/z (%) 363 (M+, 8), 244 (100), 203 (67), 188 (23),
160 (53), 119 (38), 91 (19); HRMS (EI): m/z Calcd for C22H25N3O2:
363.1947; Found: 363.1948.
C
C
16H20N2O3: 288.1474; Found: 288.1468; Anal. Calcd for
16H20N2O3: C, 66.65; H, 6.99; N, 9.72. Found: C, 66.60; H, 7.01;
N, 9.65.
Optically active compound (ꢁ)-21 was obtained from (ꢁ)-20 in
a procedure similar to that above. The enantiomer excess (>99% ee)
was determined by HPLC (CHIRALCEL OD, flow = 0.5 mL/min, i-
PrOH / n-hexane = 1/5). The spectral data of (ꢁ)-21 were identical
Optically active compound (ꢁ)-3 was obtained from (ꢁ)-22 in a
procedure similar to that above. The spectral data of (ꢁ)-3 were
identical to those of ( )-3, other than for specific optical rotation:
to those of ( )-21, other than for specific optical rotation: ½a D25
ꢁ1.4
ꢅ
(c 1.14, CHCl3).
½
a 2D5
ꢅ
ꢁ25.8 (c 0.96, CHCl3) and CD kmax (nm) [
De
(Mꢁ1 cmꢁ1)]
307 (ꢁ1.35), 268 (ꢁ3.09).
4.1.5.1. 3a-Allyl-5-methoxy-1,8-dimethyl-1,2,3,3a,8,8a-hexahy-
dropyrrolo[2,3-b]indole ( )-(22) and (S)-derivative (ꢁ)-
4.1.6. General procedure for preparation of carbamates ( )-4–7
Under N2 atmosphere, to a solution of ( )-22 (1.0 mmol) in
CH2Cl2 (10 mL) was added a BBr3 (4.9 mmol) at 0 °C. After 2 h stir-
ring, the reaction mixture was neutralized with satd aqueous NaH-
CO3. The mixture was extracted by AcOEt. The organic layer was
washed with brine, dried over MgSO4, and concentrated under re-
duced pressure. The residue was purified by silica gel column chro-
matography (CH2Cl2/MeOH = 10/1) to give 5-hydroxy derivative.
Under N2 atmosphere, to a mixture of above 5-hydroxy derivative
in THF (18 mL) added NaH (60%, 0.094 mmol) at room tempera-
ture. After stirring for 15 min, the corresponding arylisocyanate
(1.0 mmol) was added and stirred for 0.5 h. The concentrated res-
idue was dissolved in AcOEt and the solution was washed with
water and brine. The extract was dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (CH2Cl2/MeOH = 10/1) to give carba-
mate ( )-4-( )-7, respectively. The yields are listed in Scheme 2.
22.
Under N2 atmosphere, to a solution of ( )-21 (30 mg,
0.11 mmol) in THF (18 mL) was added LiAlH4 (1.1 mL, 1.0 M in
THF, 1.1 mmol) and the solution was stirred under reflux for
2.5 h. Excess LiAlH4 was quenched by THF/H2O (1:1) and filtered
through Celite pad. The filtrate was extracted with AcOEt and
washed with satd aqueous NaHCO3. The organic layer was dried
over MgSO4 and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (CH2Cl2/
MeOH = 20/1) to give ( )-22 (23 mg, 86%) as a pale yellow oil.
( )-22: IR (CHCl3): 2938, 1640, 1595, 1499 cmꢁ1 1H NMR
;
(300 MHz, CDCl3): d 1.91 (1H, ddd, J = 12.1, 6.0, 3.1 Hz), 2.05 (1H,
ddd, J = 12.1, 9.2, 6.8 Hz), 2.39 (1H, dd, J = 13.9, 8.4 Hz), 2.52 (3H,
s), 2.57 (1H, dd, J = 13.9, 5.9 Hz), 2.57 (1H, ddd, J = 7.8, 6.8,
6.0 Hz), 2.73 (1H, ddd, J = 9.2, 7.8, 3.1 Hz), 2.86 (3H, s), 3.74 (3H,
s), 4.16 (1H, s), 4.99–5.11 (2H, m), 5.58 (1H, dddd, J = 18.5, 10.1,
8.4, 5.9 Hz), 6.36 (1H, d, J = 8.4 Hz), 6.63–6.66 (2H, m); 13C NMR
(100 MHz, CDCl3): d 37.5, 38.0, 39.1, 44.4, 52.7, 56.1, 56.9, 94.6,
107.5, 110.1, 112.4, 117.6, 135.0, 136.0, 147.2, 152.8; MS (EI): m/
z (%) 258 (M+, 100), 243 (12), 217 (64), 202 (24), 187 (11), 174
(36); HRMS (EI): m/z Calcd for C16H22N2O: 258.1732; Found:
258.1737.
4.1.6.1.
o[2,3-b]indol-5-yl
(4).
IR (CHCl3): 3433, 1744, 1612, 1524, 1494 cmꢁ1
3a-Allyl-1,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrol-
(4-isopropylphenyl)carbamate
( )-
;
1H NMR
(300 MHz, CDCl3): d 1.23 (3H, s), 1.24 (3H, s), 1.93 (1H, ddd,
J = 11.9, 6.0, 3.3 Hz), 2.05 (1H, ddd, J = 11.9, 9.1, 6.6 Hz), 2.39 (1H,
dd, J = 14.0, 8.4 Hz), 2.50 (3H, s), 2.58 (1H, dd, J = 14.0, 5.8 Hz),
2.58 (1H, ddd, J = 9.4, 9.1, 6.0 Hz), 2.71 (1H, ddd, J = 9.4, 6.6,
3.3 Hz), 2.86 (1H, sep), 2.90 (3H, s), 4.23 (1H, s), 5.01–5.08 (2H,
m), 5.59 (1H, dddd, J = 16.5, 10.1, 8.4, 5.8 Hz), 6.35 (1H, d,
J = 8.4 Hz), 6.82 (1H, d, J = 2.3 Hz), 6.87 (1H, dd, J = 8.4, 2.3 Hz),
6.94 (1H, br s), 7.17 (2H, d, J = 8.4 Hz), 7.33 (2H, d, J = 8.4 Hz); 13C
NMR (68 MHz, CDCl3): d 24.0, 33.5, 37.0, 37.7, 39.0, 44.2, 52.6,
56.6, 94.4, 106.6, 116.7, 117.9, 118.9, 120.6, 127.0, 134.9, 135.3,
135.6, 142.6, 144.4, 150.5, 152.6; MS (EI): m/z (%) 405 (M+, 8),
245 (17), 244 (100), 203 (59), 188 (19), 187 (15), 161 (30), 160
(44), 146 (76), 128 (16); HRMS (EI): m/z Calcd for C25H31N3O2:
405.2416; Found: 405.2409.
Optically active compound (ꢁ)-22 was obtained from (ꢁ)-21 in
a procedure similar to that above. The spectral data of (ꢁ)-22 were
identical to those of ( )-22, other than for specific optical rotation:
½
a 2D5
ꢅ
ꢁ30.8 (c 1.05, CHCl3).
4.1.5.2. 3a-Allyl-1,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrol-
o[2,3-b]indol-5-yl phenylcarbamate ( )-(3) and (3aR,8aR)-deriv-
ative (ꢁ)-3. Under N2 atmosphere, to a solution of ( )-22
(0.16 g, 0.62 mmol) in CH2Cl2 (16 mL) was added a CH2Cl2 solution
of BBr3 (3.1 mL, 1.0 M, 3.1 mmol) at 0 °C. After 1.5 h stirring at
room temperature, the reaction mixture was concentrated. MeOH
(10 mL) was added to the residue and the mixture was stirred for
0.5 h. The mixture was added satd. NaHCO3 and extracted by
Et2O. The organic layer was washed with brine, dried over MgSO4,
and concentrated under reduced pressure to give crude alcohol.
Under N2 atmosphere, to a solution of above alcohol (0.15 g,
0.62 mmol) in Et2O (35 mL) added Na (3.3 mg, 0.14 mmol) at room
4.1.6.2.
o[2,3-b]indol-5-yl (4-bromophenyl)carbamate ( )-(5).
159–163 °C (AcOEt); IR (CHCl3): 3431, 1748, 1593, 1520,
1493 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.93 (1H, ddd, J = 3.3,
3a-Allyl-1,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrol-
Mp:
temperature. After stirring for 15 min, PhNCO (81
lL, 0.74 mmol)
;
was added and stirred for 0.5 h. The reaction mixture was filtrated
and the filtrate was concentrated. The residue was dissolved in
6.0, 9.6 Hz), 2.04 (1H, ddd, J = 6.6, 8.7, 12.0 Hz), 2.39 (1H, dd,
J = 8.4, 13.8 Hz), 2.50 (3H, s), 2.56 (1H, ddd, J = 6.0, 8.7, 9.9 Hz),

4908
M. Shinada et al. / Bioorg. Med. Chem. 20 (2012) 4901–4914
2.58 (1H, dd, J = 6.0, 13.8 Hz), 2.69 (1H, ddd, J = 3.3, 6.6, 9.9 Hz),
2.91 (3H, s), 4.22 (1H, s), 5.02–5.09 (2H, m), 5.59 (1H, dddd,
J = 6.0, 8.4, 10.2, 16.2 Hz), 6.35 (1H, d, J = 8.4 Hz), 6.81 (1H, d,
J = 2.4 Hz), 6.86 (1H, dd, J = 2.4, 8.4 Hz), 6.84–6.87 (1H, s), 7.32
(2H, d, J = 9.0 Hz), 7.42 (2H, d, J = 9.0 Hz); 13C NMR (68 MHz,
CDCl3): d 36.8, 37.8, 38.9, 44.2, 52.6, 56.6, 94.4, 106.5, 116.1,
116.6, 117.9, 120.3, 120.6, 132.0, 134.8, 135.8, 136.8, 142.3,
150.6, 152.4; MS (EI): m/z (%) 443 (2), 441 (M+, 2), 245 (17), 244
(100), 203 (63), 199 (43), 197 (44), 188 (20), 187 (15), 160 (44),
90 (16); HRMS (EI): m/z Calcd for C22H24BrN3O2: 441.1052; Found:
441.1051; Anal. Calcd for C22H24BrN3O2: C, 59.73; H, 5.47; N, 9.50;
Found: C, 59.47; H, 5.54; N, 9.37.
174 (26), 160 (59), 119 (37), 91 (19); HRMS (EI): m/z Calcd for
22H27N3O2: 365.2103; Found: 365.2110.
C
4.1.7.1. 3a-Allyl-5-methoxy-1,8-dimethyl-3,3a,8,8a-tetrahydro-
pyrrolo[2,3-b]indol-2(1H)-one ( )-(23). Under N2 atmo-
sphere, to a solution of ( )-21 (78 mg, 0.27 mmol) in THF (13 mL)
was added AlH3ꢂEtNMe2 (2.7 mL, 5.0 M in toluene, 1.4 mmol) at
ꢁ15 °C and the solution was stirred for 5 min. Excess AlH3ꢂEtNMe2
was quenched by THF/H2O (1:1) and filtered through Celite pad.
The filtrate was basified by satd aqueous NaHCO3 and extracted
with AcOEt. The organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (AcOEt/n-hex-
ane = 1/1) to give ( )-23 (69 mg, 94%).
4.1.6.3.
3a-Allyl-1,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrol-
Mp:
IR (CHCl3): 1682, 1499 cmꢁ1 1H NMR (300 MHz, CDCl3): d 2.41
;
o[2,3-b]indol-5-yl (4-fluorophenyl)carbamate ( )-(6).
(1H, dd, J = 8.2, 13.9 Hz), 2.54 (1H, dd, J = 6.1, 13.9 Hz), 2.63 (1H, d,
J = 17.2 Hz), 2.70 (1H, d, J = 17.2 Hz), 2.91 (3H, s), 2.99 (3H, s), 3.75
(3H, s), 4.62 (1H, s), 5.05–5.15 (2H, m), 5.46–5.60 (1H, m), 6.43 (1H,
d, J = 8.4 Hz), 6.65 (1H, d, J = 2.6 Hz), 6.71 (1H, dd, J = 2.6, 8.4 Hz);
13C NMR (76 MHz, CDCl3): d 28.0, 37.2, 42.3, 43.8, 49.7, 56.0,
90.5, 109.0, 110.3, 113.5, 119.1, 133.1, 135.5, 144.4, 153.8, 172.7;
MS (EI): m/z (%) 272 (M+, 100), 231 (60), 174 (38); HRMS (EI): m/
z Calcd for C16H20N2O2: 272.1525. Found: 272.1524.
170–181 °C (AcOEt); IR (CHCl3): 3433, 1746, 1526, 1510, 1493 cm
;
ꢁ1
1H NMR (300 MHz, CDCl3): d 1.92 (1H, ddd, J = 3.3, 6.0,
12.1 Hz), 2.04 (1H, ddd, J = 6.8, 9.0, 12.1 Hz), 2.39 (1H, dd, J = 8.5,
13.9 Hz), 2.50 (3H, s), 2.58 (1H, ddd, J = 6.0, 9.0, 9.6 Hz), 2.58 (1H,
dd, J = 5.9, 13.9 Hz), 2.70 (1H, ddd, J = 3.3, 6.8, 9.6 Hz), 4.22 (1H,
s), 5.01–5.09 (2H, m), 5.60 (1H, dddd, J = 5.9, 8.5, 10.0, 14.3 Hz),
6.35 (1H, d, J = 8.4 Hz), 6.81 (1H, d, J = 2.4 Hz), 6.86 (1H, dd,
J = 2.4, 8.4 Hz), 6.81–6.88 (1H, br s), 7.02 (2H, t, J = 8.6 Hz), 7.40
(2H, dd, J = 4.6, 8.6 Hz); MS (EI): m/z (%) 381 (M+, 5), 245 (17),
244 (100), 203 (63), 202 (12), 200 (14), 188 (21), 187 (15), 186
(11), 160 (45), 137 (40), 109 (19); HRMS (EI): m/z Calcd for
4.1.7.2.
3a-Allyl-1,8-dimethyl-2-oxo-1,2,3,3a,8,8a-hexahydro-
Under
pyrrolo[2,3-b]indol-5-yl phenylcarbamate ( )-(13).
N2 atmosphere, to a solution of ( )-23 (50 mg, 0.18 mmol) in
CH2Cl2 (1.8 mL) was added a BBr3 (0.17 mL, 1.8 mmol) at 0 °C. After
2 h stirring, the reaction mixture was neutralized with satd aque-
ous NaHCO3 and was extracted by CH2Cl2. The organic layer was
concentrated under reduced pressure and the residue was added
Et2O. The solution was washed with brine, dried over MgSO4, and
concentrated under reduced pressure to give crude phenol. Under
N2 atmosphere, to a mixture of above phenol (47 mg, 0.18 mmol)
in THF (4.0 mL) added NaH (8.7 mg, 60%, 0.22 mmol) at room tem-
C
22H24FN3O2: 381.1853; Found: 381.1855.
4.1.6.4.
o[2,3-b]indol-5-yl (2-fluorophenyl)carbamate ( )-(7).
120–124 °C (AcOEt); IR (CHCl3): 3433, 1749, 1535, 1497,
1456 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.94 (1H, ddd, J = 3.1,
3a-Allyl-1,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrol-
Mp:
;
6.1, 11.9 Hz), 2.06 (1H, ddd, J = 7.0, 8.8, 11.9 Hz), 2.40 (1H, dd,
J = 8.5, 14.0 Hz), 2.51 (3H, s), 2.57 (1H, ddd, J = 6.1, 8.8, 9.4 Hz),
2.60 (1H, dd, J = 5.9, 14.0 Hz), 2.71 (1H, ddd, J = 3.1, 7.0, 9.4 Hz),
2.90 (3H, s), 4.23 (1H, s), 5.02–5.09 (2H, m), 5.59 (1H, dddd,
J = 5.9, 8.5, 9.3, 17.0 Hz), 6.36 (1H, d, J = 8.3 Hz), 6.84 (1H, d,
J = 2.4 Hz), 6.88 (1H, ddd, J = 0.9, 2.4, 8.2 Hz), 6.93–7.16 (4H, m),
8.05–8.15 (1H, m); 13C NMR (68 MHz, CDCl3): d 36.8, 37.8, 38.9,
44.2, 52.6, 56.6, 94.4, 106.5, 114.7, 115.0, 116.5, 117.9, 120.5,
123.7, 124.7, 126.3, 134.8, 135.7, 142.3, 150.6, 152.2, 154.0; MS
(EI): m/z (%) 381 (M+, 8), 245 (17), 244 (100), 229 (10), 203 (64),
202 (13), 200 (14), 188 (20), 187 (16), 186 (11), 160 (46), 137
(43), 109 (18); HRMS (EI): m/z Calcd for C22H24FN3O2: 381.1853;
Found: 381.1844; Anal. Calcd for C22H24FN3O2: C, 69.27; H, 6.34;
N, 11.02; Found: C, 69.02; H, 6.50; N, 10.86.
perature. After stirring for 5 min, phenylisocyanate (24 lL,
0.22 mmol) was added and the solution was stirred for 15 min.
The concentrated residue was dissolved in AcOEt and the solution
was washed with water and brine. The extract was dried over
MgSO4, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (AcOEt/n-hex-
ane = 1/1 to 3/1) to give ( )-13 (47 mg, 69%) as a white powder.
Mp: 203–206 °C; IR (CHCl3): 3431, 1749, 1682, 1603, 1526,
1497 cmꢁ1 1H NMR (300 MHz, CDCl3): d 2.42 (1H, dd, J = 8.1,
;
13.8 Hz), 2.53 (1H, dd, J = 6.3, 13.8 Hz), 2.64 (1H, d, J = 17.1 Hz),
2.73 (1H, d, J = 17.1 Hz), 2.93 (3H, s), 3.04 (3H, s), 4.71 (1H, s),
5.09–5.15 (2H, m), 5.49–5.64 (1H, m), 6.44 (1H, d, J = 8.4 Hz),
6.86 (1H, br s), 6.87 (1H, d, J = 2.4 Hz), 6.95 (1H, dd, J = 2.4,
8.4 Hz), 7.09 (1H, t, J = 7.5 Hz), 7.30–7.46 (4H, m); 13C NMR
(68 MHz, CDCl3): d 28.4, 36.3, 42.2, 43.8, 49.4, 90.1, 107.8, 116.9,
118.6, 119.3, 121.7, 123.5, 128.9 (C2), 132.6, 134.7, 137.5, 143.2,
147.5, 152.3, 172.5; MS (EI): m/z (%) 377 (M+, 0.97), 258 (100),
217 (62), 176 (11), 160 (41), 119 (36), 91 (13); HRMS (EI): m/z
Calcd for C22H23N3O3: 377.1739; Found: 377.1738.
4.1.7. 1,8-Dimethyl-3a-propyl-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indol-5-yl phenylcarbamate ( )-(8)
To a solution of ( )-3 (50 mg, 0.14 mmol) in EtOH (3.0 mL) was
added 10% Pd/C (10 mg) and the solution was stirred vigorously at
room temperature under H2 bubbling for 3 h. The reaction mixture
was filtrated and concentrated. The residue was purified by silica
gel column chromatography (CH2Cl2/MeOH = 20/1) to give ( )-8
(48 mg, 96%) as a white powder.
4.1.8. 2-[3-(2-Hydroxyethyl)-5-methoxy-1-methyl-2-
Mp: 154–158 °C; IR (CHCl3): 3433, 1748, 1603, 1526, 1495 cm
oxoindolin-3-yl]acetonitrile ( )-(24)
ꢁ1
;
1H NMR (300 MHz, CDCl3): d 0.85 (3H, t, J = 7.2 Hz), 1.06–1.22
To a solution of ( )-19 (0.88 g, 3.4 mmol) in CH3CN (6.3 mL) was
added OsO4 (1.1 mL, 4% aq, 0.17 mmol) and NMO (1.6 mL, 50% aq,
6.8 mmol) and the mixture was stirred for 12 h at room tempera-
ture. The concentrated residue was dissolved in 1,4-dioxane/H2O
(2/1, 23 mL) and added NaIO4 (0.88 g, 4.1 mmol). After 10 min stir-
ring, the mixture was filtrated through by Celite pad and the fil-
trate was concentrated under reduced pressure. The mixture was
extracted with AcOEt. The organic layer was washed with brine
and dried over MgSO4. The concentrated residue was purified by
(2H, m), 1.59–1.75 (2H, m), 1.91–2.00 (2H, m), 2.52 (3H, s), 2.51–
2.59 (1H, m), 2.67–2.73 (1H, m), 2.91 (3H, s), 4.21 (1H, s), 6.35
(1H, d, J = 8.4 Hz), 6.78 (1H, d, J = 2.4 Hz), 6.87 (1H, dd, J = 8.4,
2.4 Hz), 7.07(1H, br s), 7.08 (1H, d, J = 7.4 Hz), 7.30 (2H, t,
J = 8.4 Hz), 7.42 (2H, d, J = 7.8 Hz); 13C NMR (100 MHz, CDCl3): d
14.7, 19.2, 36.9, 37.9, 39.6, 42.5, 52.6, 57.2, 94.8, 106.3, 116.4,
118.6, 120.3, 123.5, 128.9, 135.8, 137.5, 142.4, 150.2, 152.3; MS
(EI): m/z (%) 365 (M+, 6), 246 (100), 203 (29), 202 (32), 188 (25),

M. Shinada et al. / Bioorg. Med. Chem. 20 (2012) 4901–4914
4909
silica gel column chromatography (AcOEt/n-hexane = 1/1 to 100/0)
5.36 (1H, d, J = 10.5 Hz), 5.98 (1H, dd, J = 17.2, 10.5 Hz), 6.84 (1H,
d, J = 8.7 Hz), 6.91 (1H, dd, J = 8.7, 2.4 Hz), 7.09 (1H, d, J = 2.4 Hz);
13C NMR (100 MHz, CDCl3): d 25.5, 26.8, 52.0, 55.9, 109.3, 111.9,
113.8, 116.1, 118.7, 128.9, 133.9, 136.3, 156.2, 174.4; MS (EI): m/
z (%) 242 (M+, 53), 202 (100), 174 (17), 159 (10); HRMS (EI): m/z
Calcd for C14H14N2O2: 242.1056; Found: 242.1062; Anal. Calcd
for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56. Found: C, 69.38; H,
5.56; N, 11.45.
to give aldehyde (0.73 g, 83%) as a colorless oil.
IR (CHCl3): 3021, 2837, 2255, 1713, 1601, 1499 cmꢁ1 1H NMR
;
(300 MHz, CDCl3):
d 2.60 (1H, d, J = 16.5 Hz), 2.93 (1H, d,
J = 16.5 Hz), 3.09 (1H, d, J = 17.8 Hz), 3.26 (3H, s), 3.29 (1H, d,
J = 17.8 Hz), 3.80 (3H, s), 6.84 (1H, d, J = 8.4 Hz), 6.89 (1H, dd,
J = 8.4, 2.4 Hz), 7.04 (1H, d, J = 2.4 Hz), 9.51 (1H, s); 13C NMR
(100 MHz, CDCl3): d 26.1, 26.9, 45.8, 55.9, 109.3, 110.7, 113.7,
115.6, 129.3, 136.7, 156.2, 175.3, 196.2; MS (EI): m/z (%): 258
(M+, 64), 229 (47), 215 (11), 203 (10), 190 (100), 191 (12), 189
(13), 175 (13), 174 (24); HRMS (EI): m/z Calcd for C14H14N2O3:
258.1005; Found: 258.1003.
To a solution of aldehyde (1.5 g, 6.6 mmol) in MeOH (30 mL)
was added NaBH4 (2.5 g, 66 mmol) at 0 °C and the mixture was
stirred for 0.5 h at the same temperature. After addition of satd
aqueous NH4Cl, the mixture was stirred for 1 h and then concen-
trated under reduced pressure. The residue was extracted with
AcOEt and the organic layer was washed with brine and dried over
MgSO4. The concentrated residue was purified by silica gel column
chromatography (AcOEt/n-hexane = 1/1 to 100/0) to give ( )-24
(1.2 g, 78%) as colorless crystals.
4.1.10. 2-(5-Methoxy-1-methyl-2-oxo-3-vinylindolin-3-yl)acetic
acid ( )-(26)
A solution of ( )-25 (1.2 g, 4.7 mmol) in MeOH (47 mL) was
added 35% aqueous NaOH (8.1 mL, 71 mmol) and the mixture
was stirred under reflux for 3 days. The mixture was acidified with
1 N aqueous HCl and extracted with AcOEt. The organic layer was
dried over MgSO4 and concentrated to give ( )-26 (1.2 g, quant.) as
brownish powders.
IR (CHCl3): 3505, 3383, 3092, 3010, 1711, 1602, 1499 cmꢁ1 1H
;
NMR (300 MHz, CDCl3): d 2.89 (1H, d, J = 16.5 Hz), 3.15 (1H, d,
J = 16.5 Hz), 3.19 (3H, s), 3.79 (3H, s), 5.08 (1H, d, J = 17.4 Hz),
5.17 (1H, d, J = 10.3 Hz), 5.90 (1H, dd, J = 17.2, 10.3 Hz), 6.76–6.85
(3H, m); 13C NMR (100 MHz, CDCl3): d 26.8, 40.3, 52.8, 55.8,
108.9, 111.4, 112.7, 116.7, 130.7, 135.7, 136.9, 155.9, 172.8,
177.2; MS (EI): m/z (%) 261 (M+, 100), 246 (10), 202 (84), 174
(17); HRMS (EI): m/z Calcd for C14H15NO4: 261.1001; Found:
261.1000.
Mp: 102–106 °C (AcOEt); IR (CHCl3): 3599, 3445, 3021, 2941,
2253, 1705, 1601, 1499 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.94
;
(1H, br s), 2.17 (1H, dt, J = 14.3, 5.5 Hz), 2.26 (1H, ddd, J = 14.3,
7.7, 5.5 Hz), 2.62 (1H, d, J = 16.7 Hz), 2.91 (1H, d, J = 16.7 Hz), 3.22
(3H, s), 3.41–3.52 (1H, m), 3.58–3.67 (1H, m), 3.82 (3H, s), 6.82
(1H, d, J = 8.4 Hz), 6.88 (1H, dd, J = 8.4, 2.4 Hz), 7.04 (1H, d,
J = 2.4 Hz); 13C NMR (100 MHz, CDCl3): d 26.1, 26.8, 38.1, 47.9,
55.9, 58.7, 109.2, 110.7, 113.6, 116.2, 130.1, 136.4, 156.3, 176.9;
MS (EI): m/z (%) 260 (M+, 60), 190 (100), 174 (18); HRMS (EI): m/
z Calcd for C14H16N2O3: 260.1161; Found: 260.1163; Anal. Calcd
for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C, 64.76; H,
6.31; N, 10.85.
4.1.11. (5-Methoxy-1-methyl-2-oxo-3-vinylindolin-3-yl)-N-
methylacetamide ( )-(27) and (S)-derivative (+)-27
Under N2 atmosphere, to a solution of ( )-26 (1.2 g, 4.6 mmol)
in THF (46 mL) was added pentafluorophenol (1.3 g, 6.9 mmol),
Et3N (1.3 mL, 9.2 mmol), and EDCꢂHCl (1.3 g, 6.9 mmol). After 2 h
stirring, MeNH2 gas, which was generated by the reaction of aque-
ous MeNH2ꢂHCl and NaOH pellet, was bubbled through the reac-
tion mixture. After consumption of mixed anhydride, the reaction
mixture was neutralized by 10% aqueous HCl and extracted with
Et2O. The organic layer was washed with brine and dried over
MgSO4. The concentrated residue was purified by silica gel column
chromatography (AcOEt/n-hexane = 1/1 to 100/0) to give ( )-27
(1.1 g, 90%) as colorless crystals.
4.1.9. (5-Methoxy-1-methyl-2-oxo-3-vinylindolin-3-
yl)acetonitrile ( )-(25)
Under N2 atmosphere, to a solution of ( )-24 (1.7 g, 6.5 mmol)
and o-nitrophenyl selenocyanate (1.8 g, 7.8 mmol) in THF (65 mL)
was added tributylphosphine (2.0 mL, 7.8 mmol) and the solution
was stirred at room temperature for 1.5 h. The concentrated resi-
due was purified by silica gel column chromatography (AcOEt/n-
hexane = 1/1) to give arylselenide (2.3 g, 79%) as yellow
amorphous.
Mp: 122–124 °C (AcOEt); IR (CHCl3): 3460, 3312, 3009, 1690,
1603, 1499 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d 2.68 (3H, d,
J = 4.8 Hz), 2.86 (1H, d, J = 15.0 Hz), 2.95 (1H, d, J = 15.0 Hz), 3.22
(3H, s), 3.79 (3H, s), 5.08 (1H, d, J = 17.2 Hz), 5.15 (1H, d,
J = 10.5 Hz), 5.96 (1H, dd, J = 17.2, 10.5 Hz), 6.58 (1H, br s), 6.76
(1H, d, J = 8.4 Hz), 6.81 (1H, dd, J = 8.4, 2.4 Hz), 6.87 (1H, d,
J = 2.4 Hz); 13C NMR (100 MHz, CDCl3): d 26.2, 26.6, 42.2, 53.5,
55.7, 108.6, 111.4, 112.2, 116.0, 131.2, 136.3, 136.6, 155.7, 169.1,
177.3; MS (EI): m/z (%) 274 (M+, 100), 202 (71), 189 (13), 174
(15); HRMS (EI): m/z Calcd for C15H18N2O3: 274.1317; Found:
274.1319; Anal. Calcd for C15H18N2O3: C, 65.68; H, 6.61; N, 10.21.
Found: C, 65.80; H, 6.63; N, 10.15.
IR (CHCl3): 3021, 2255, 1707, 1593, 1516, 1499 cmꢁ1 1H NMR
;
(300 MHz, CDCl3): d 2.31–2.64 (4H, m), 2.62 (1H, d, J = 16.7 Hz),
2.85 (1H, d, J = 16.7 Hz), 3.28 (3H, s), 3.85 (3H, s), 6.87 (1H, d,
J = 8.4 Hz), 6.93 (1H, dd, J = 8.4, 2.4 Hz), 7.08 (1H, d, J = 2.4 Hz),
7.24–7.36 (2H, m), 7.53 (1H, ddd, J = 8.4, 7.7, 1.8 Hz), 8.29 (1H,
dd, J = 8.8, 1.8 Hz); 13C NMR (100 MHz, CDCl3): d 19.5, 25.9, 26.7,
35.2, 49.9, 55.9, 109.3, 110.6, 113.7, 115.8, 125.5, 126.3, 128.3,
129.0, 131.7, 133.6, 136.7, 146.5, 156.4, 175.2; MS (EI): m/z (%)
445 (M+, 72), 259 (11), 243 (15), 216 (100), 189 (83), 174 (15),
106 (13); HRMS (EI): m/z Calcd for C20H19N3O4Se: 445.0541;
Found: 445.0543.
Optically active compound (+)-27 was obtained from (+)-26 in a
procedure similar to that above. The spectral data of (+)-27 were
identical to those of ( )-26, other than for specific optical rotation:
To THF (2.4 mL) solution of arylselenide (0.11 g, 0.24 mmol)
was added 30% aqueous H2O2 (65
lL, 0.58 mmol) at 0 °C and the
½
a 2D3
+10.2 (c 1.66, CHCl3).
ꢅ
mixture was stirred for 12 h at room temperature. The mixture
was diluted with water and extracted with AcOEt. The organic
layer was washed with 3% aqueous sodium hydrogen sulfite and
brine. After dried over MgSO4, the solution was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (AcOEt/n-hexane = 1/1) to give ( )-25 (54 mg,
93%) as colorless needles.
4.1.12. 5-Methoxy-1,8-dimethyl-3a-vinyl-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole ( )-(28) and (3aR,8aR)-
derivative (ꢁ)-28
Under N2 atmosphere, to a solution of ( )-27 (0.37 g, 1.4 mmol)
in THF (50 mL) was added LiAlH4 (14 mL, 1.0 M in THF, 14 mmol)
and the solution was stirred under reflux for 3 h. Excess LiAlH4
was quenched by THF/H2O (1:1) and filtered through Celite pad.
The filtrate was extracted with AcOEt and washed with satd aque-
ous NaHCO3. The organic layer was dried over MgSO4 and
Mp: 68–72 °C; IR (CHCl3): 3016, 2255, 1713, 1601, 1499 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d 2.73 (1H, d, J = 16.7 Hz), 3.01 (1H, d,
J = 16.7 Hz), 3.22 (3H, s), 3.83 (3H, s), 5.25 (1H, d, J = 17.2 Hz),

4910
M. Shinada et al. / Bioorg. Med. Chem. 20 (2012) 4901–4914
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (CH2Cl2/MeOH = 20/1) to give
( )-28 (0.28 g, 75%) as a pale yellow oil.
Mp: 154–157 °C; IR (CHCl3): 3433, 1748, 1602, 1526, 1495 cm
1H NMR (300 MHz, CDCl3): d 0.77 (3H, t, J = 7.5 Hz), 1.69 (1H,
ꢁ1
;
dq, J = 16.1, 7.5 Hz), 1.81 (1H, dq, J = 16.1, 7.5 Hz), 1.91 (1H, ddd,
J = 12.0, 6.4, 3.5 Hz), 2.01 (1H, ddd, J = 12.0, 9.0, 6.4 Hz), 2.52 (3H,
s), 2.56 (1H, ddd, J = 9.8, 9.0, 6.4 Hz), 2.70 (1H, ddd, J = 9.8, 6.4,
3.5 Hz), 2.92 (3H, s), 4.18 (1H, s), 6.35 (1H, d, J = 8.4 Hz), 6.78
(1H, d, J = 2.4 Hz), 6.86 (1H, dd, J = 8.4, 2.4 Hz), 6.91 (1H, br s),
7.10 (1H, t, J = 7.5 Hz), 7.32 (2H, t, J = 7.5 Hz), 7.43 (2H, d,
J = 7.5 Hz); 13C NMR (100 MHz, CDCl3): d 10.2, 32.6, 36.9, 38.0,
39.4, 52.7, 57.6, 94.4, 106.3, 116.5, 118.6, 120.3, 123.5, 128.9,
135.5, 137.5, 142.4, 150.5, 152.5; MS (EI): m/z (%) 351 (M+, 9),
232 (100), 203 (22), 188 (45), 175 (16), 174 (29), 160 (47), 119
(36), 91 (15); HRMS (EI): m/z Calcd for C21H25N3O2: 351.1947;
Found: 351.1947.
IR (CHCl3): 2939, 1635, 1595, 1497 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): d 1.98 (1H, ddd, J = 12.1, 5.9, 3.7 Hz), 2.28 (1H, ddd,
J = 12.1, 9.4, 6.8 Hz), 2.52 (3H, s), 2.67 (1H, dt, J = 9.4, 5.9 Hz),
2.78 (1H, ddd, J = 9.4, 6.8, 3.7 Hz), 2.89 (3H, s), 3.74 (3H, s), 4.25
(1H, s), 5.04 (1H, d, J = 17.3 Hz), 5.09 (1H, d, J = 10.5 Hz), 6.09
(1H, dd, J = 17.3, 10.5 Hz), 6.38 (1H, d, J = 8.4 Hz), 6.60 (1H, d,
J = 2.6 Hz), 6.68 (1H, dd, J = 8.4, 2.6 Hz); 13C NMR (100 MHz, CDCl3):
d 37.8, 38.3, 38.6, 53.1, 56.1, 59.8, 97.1, 107.7, 111.2, 112.9, 113.0,
134.5, 142.7, 146.7, 152.8; MS (EI): m/z (%) 244 (M+, 100), 229 (17),
200 (37), 187 (13), 174 (22), 172 (15); HRMS (EI): m/z Calcd for
C15H20N2O: 244.1576; Found: 244.1578.
Optically active compound (ꢁ)-28 was obtained from (+)-27 in
Optically active compound (ꢁ)-10 was obtained from (ꢁ)-9 in a
procedure similar to that above. The spectral data of (ꢁ)-10 were
identical to those of ( )-10, other than for specific optical rotation:
a procedure similar to that above. The spectral data of (ꢁ)-28 were
identical to those of ( )-28, other than for specific optical rotation:
½
a 2D3
ꢅ
ꢁ15.0 (c 0.43, CHCl3).
½
a 2D3
ꢅ
ꢁ53.6 (c 1.02, CHCl3) and CD kmax (nm) [
De
(Mꢁ1 cmꢁ1)] 332
(0.43), 266 (ꢁ2.96).
4.1.13. 1,8-Dimethyl-3a-vinyl-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indol-5-yl phenylcarbamate ( )-(9) and
(3aR,8aR)-derivative (ꢁ)-9
4.1.15. 1-Acetyl-5-methoxy-2-(3-methylbut-2-enyloxy)indolin-
3-one ( )-(29)
Under N2 atmosphere, to a solution of ( )-28 (0.28 g, 1.2 mmol)
in CH2Cl2 (12 mL) was added BBr3 (0.55 mL, 5.8 mmol) at 0 °C.
After 1.5 h stirring at room temperature, the reaction mixture
was quenched with satd NaHCO3 and extracted by Et2O. The organ-
ic layer was washed with brine, dried over MgSO4, and concen-
trated under reduced pressure to give crude phenol. Under N2
atmosphere, to a solution of above phenol in Et2O (20 mL) added
Na (3.0 mg, 0.13 mmol) at room temperature. After stirring for
5 min, PhNCO (0.15 mL, 1.4 mmol) was added and stirred for
15 min. The reaction mixture was filtrated and the filtrate was con-
centrated. The residue was dissolved in Et2O and the solution was
washed with brine, dried over MgSO4, and concentrated under re-
duced pressure. The residue was purified by silica gel column chro-
matography (CH2Cl2/MeOH = 20/1) to give ( )-9 (0.23 g, 57%) as a
white powder.
Under N2 atmosphere, to a solution of 16 (2.5 g, 12 mmol) in
CH2Cl2 (70 mL) was added a solution of Br2 in CH2Cl2 (24 mL,
1.0 M, 24 mmol) at 0 °C and the solution was stirred for 1 h. Start-
ing material consumption was determined by TLC and the reaction
mixture was neutralized with satd aqueous NaHCO3. The organic
layer was washed with brine and dried over MgSO4. The concen-
trated residue was used without further purification. Under N2
atmosphere, a suspension of above residue and molecular sieves
4A (17 g, powder) in CH3CN (85 mL) was added prenyl alcohol
(6.2 mL, 61 mmol) and the mixture was stirred for 1 day. The reac-
tion mixture was filtrated and concentrated under reduced pres-
sure. The residue was purified by silica gel column
chromatography (AcOEt/n-hexane = 1/3) to give ( )-29 (2.7 g,
74%) as pale yellow needles.
Mp: 75–78 °C (AcOEt/n-hexane); IR (CHCl3): 1724, 1678, 1620,
Mp: 122–128 °C; IR (CHCl3): 3433, 2940, 1749, 1602, 1526,
1589, 1489 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.65 (3H, s), 1.71
;
1495 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d 1.99 (1H, ddd, J = 12.1,
(3H, s), 2.38 (3H, s), 3.83 (3H, s), 4.09 (1H, dd, J = 10.8, 7.5 Hz),
4.18 (1H, dd, J = 10.8, 7.5 Hz), 5.21 (1H, s), 5.32 (1H, tt, J = 7.5,
1.5 Hz), 7.14 (1H, d, J = 2.7 Hz), 7.25 (1H, dd, J = 8.4, 2.7 Hz), 8.43
(1H, d, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3): d 18.1, 23.6, 25.8,
55.8, 62.0, 85.6, 104.9, 119.1, 119.3, 123.2, 126.3, 139.6, 147.8,
156.4, 168.9, 195.1; MS (EI): m/z (%) 289 (M+, 13), 205 (17), 178
(100), 69 (12), 43 (8); HRMS (EI): m/z Calcd for C16H19NO4:
289.1314; Found: 289.1312; Anal. Calcd for C16H19NO4: C, 66.42;
H, 6.62; N, 4.84. Found: C, 66.46; H, 6.82; N, 4.83.
5.7, 3.9 Hz), 2.27 (1H, ddd, J = 12.1, 8.6, 7.0 Hz), 2.53 (3H, s),
2.66–2.81 (2H, m), 2.93 (3H, s), 4.32 (1H, s), 5.06 (1H, d,
J = 17.4 Hz), 5.09 (1H, d, J = 10.8 Hz), 6.08 (1H, dd, J = 17.4,
10.8 Hz), 6.38 (1H, d, J = 8.4 Hz), 6.79 (1H, d, J = 2.4 Hz), 6.89 (1H,
dd, J = 8.4, 2.4 Hz), 6.91 (1H, br s), 7.08 (1H, t, J = 7.2 Hz), 7.31
(2H, dd, J = 7.7, 7.2 Hz), 7.42 (2H, d, J = 7.7 Hz); 13C NMR
(100 MHz, CDCl3): d 36.6, 38.69, 38.72, 53.1, 59.5, 97.0, 106.5,
113.2, 117.8, 118.6, 120.8, 123.6, 128.9, 133.9, 137.5, 142.2,
142.4, 149.9, 152.6; MS (EI): m/z (%) 349 (M+, 3), 230 (100), 186
(47), 173 (20), 160 (25), 119 (50), 91 (19); HRMS (EI): m/z Calcd
for C21H23N3O2: 349.1790; Found: 349.1789.
4.1.16. 2-[5-Methoxy-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-
3-yl]acetonitrile ( )-(30)
Optically active compound (ꢁ)-9 was obtained from (ꢁ)-28 in a
procedure similar to that above. The spectral data of (ꢁ)-9 were
identical to those of ( )-9, other than for specific optical rotation:
Under N2 atmosphere, to a suspension of t-BuOK (0.58 g,
5.2 mmol) in DMF (10 mL) was added (EtO)2P(O)CH2CN (1.0 mL,
5.6 mmol) at 0 °C and the mixture was stirred at room temperature
for 1 h. After cooling at ꢁ78 °C, to the mixture was added ( )-29
(0.50 g, 1.7 mmol) and the solution was stirred at the same tem-
perature for 1 h. After consumption of ( )-29, the reaction mixture
was warmed to room temperature and stirred for 3 h. To the reac-
tion mixture was added H2O, neutralized with 10% HCl, and ex-
tracted with Et2O. The organic layer was washed with brine,
dried over MgSO4, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(AcOEt/n-hexane = 1/3) to give ( )-30 (0.43 g, 91%) as colorless
crystals.
½
a 2D3
ꢅ
ꢁ53.5 (c 1.07, CHCl3) and CD kmax (nm) [
De
(Mꢁ1 cmꢁ1)]
309 (ꢁ0.81), 276 (ꢁ0.53).
4.1.14. 1,8-Dimethyl-3a-ethyl-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indol-5-yl phenylcarbamate ( )-(10)
and (3aR,8aR)-derivative (ꢁ)-10
Under H2 atmosphere, to a solution of ( )-9 (0.14 g, 0.40 mmol)
in EtOH (4.0 mL) was added 10% Pd/C (10 mg, Aldrich) and the
solution was stirred vigorously at room temperature for 3 h. The
reaction mixture was filtrated with Celite pad and concentrated.
The residue was purified by silica gel column chromatography
(CH2Cl2/MeOH = 20/1) to give ( )-10 (0.14 g, 98%) as a white
powder.
Mp: 150 °C (AcOEt/n-hexane); IR (CHCl3): 3435, 2250, 1727,
1603 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.08 (3H, s), 1.17 (3H,
;
s), 2.81 (1H, d, J = 16.5 Hz), 3.00 (1H, d, J = 16.5 Hz), 3.80 (3H, s),

M. Shinada et al. / Bioorg. Med. Chem. 20 (2012) 4901–4914
4911
5.10 (1H, dd, J = 17.4, 0.9 Hz), 5.22 (1H, dd, J = 10.8, 0.9 Hz), 6.10
(1H, dd, J = 17.4, 10.8 Hz), 6.82–6.88 (3H, m), 7.78 (1H, br s); 13C
NMR (100 MHz, CDCl3): d 21.7, 22.01, 22.04, 41.6, 55.78, 55.84,
110.3, 113.1, 113.3, 115.2, 116.7, 129.4, 134.8, 141.6, 155.1,
178.2; MS (EI): m/z (%) 270 (M+, 16), 202 (100), 175 (86), 158
(10), 69 (49), 41 (14); HRMS (EI): m/z Calcd for C16H18N2O2:
and dried over MgSO4. The concentrated residue was purified by
silica gel column chromatography (AcOEt/n-hexane = 1/1 to 100/
0) to give ( )-33 (0.21 g, 95%) as colorless crystals.
Mp: 167 °C (AcOEt/n-hexane); IR (CHCl3): 3019, 1690, 1601,
1499 cmꢁ1 1H NMR (300 MHz, CDCl3): d 0.97 (3H, s), 1.10 (3H,
;
s), 2.51 (3H, d, J = 5.1 Hz), 2.64 (1H, d, J = 14.4 Hz), 3.02 (1H, d,
J = 14.4 Hz), 3.19 (3H, s), 3.78 (3H, s), 4.98 (1H, dd, J = 17.4,
1.2 Hz), 5.10 (1H, dd, J = 10.8, 1.2 Hz), 5.38 (1H, br s), 6.03 (1H,
dd, J = 17.4, 10.8 Hz), 6.68 (1H, d, J = 8.4 Hz), 6.76 (1H, d,
J = 2.4 Hz), 6.79 (1H, dd, J = 8.4, 2.4 Hz); 13C NMR (100 MHz, CDCl3):
d 21.8, 22.1, 26.2, 26.3, 38.8, 41.9, 55.8, 56.0, 107.4, 111.5, 113.3,
113.7, 130.9, 138.3, 143.0, 154.6, 169.6, 178.3; MS (EI): m/z (%)
316 (M+, 23), 248 (61), 190 (100), 189 (65), 174 (16); HRMS (EI):
m/z Calcd for C18H24N2O3: 316.1787; Found: 316.1783; Anal. Calcd
for C18H24N2O3: C, 68.33; H, 7.65; N, 8.85. Found: C, 68.13; H, 7.83;
N, 8.65.
270.1368; Found: 270.1366; Anal. Calcd for
C16H18N2O2: C,
71.09; H, 6.71; N, 10.36. Found: C, 71.22; H, 6.83; N, 10.10.
4.1.17. 2-[5-Methoxy-1-methyl-3-(2-methylbut-3-en-2-yl)-2-
oxoindolin-3-yl]acetonitrile ( )-(31)
Under N2 atmosphere, to a suspension of NaH (0.23 g, 60%,
5.7 mmol) in DMF (9.0 mL) was added ( )-30 (0.61 g, 2.3 mmol)
with cooling by ice bath. After 1 h stirring at room temperature,
MeI (0.42 mL, 6.8 mmol) was added to the mixture with ice-bath.
After 15 min stirring at room temperature, water (100 mL) was
added to the reaction mixture. The mixture was extracted by
Et2O. The organic layer was washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The residue was puri-
fied by silica gel column chromatography (AcOEt/n-hexane = 1/3)
to give ( )-31 (0.48 g, 75%) as colorless crystals.
Optically active compound (ꢁ)-33 was obtained from (ꢁ)-32 in
a procedure similar to that above. The enantiomer excess (>99% ee)
was determined by HPLC (CHIRALPAK AD, flow = 0.5 mL/min,
i-PrOH/n-hexane = 1/20). The spectral data of (ꢁ)-33 were identical
to those of ( )-32, other than for specific optical rotation: ½a D25
ꢅ
Mp: 180–184 °C (AcOEt/n-hexane); IR (CHCl3): 2250, 1705,
ꢁ90.2 (c 0.24, CHCl3).
1600, 1498 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.02 (3H, s), 1.14
;
(3H, s), 2.81 (1H, d, J = 16.2 Hz), 2.98 (1H, d, J = 16.2 Hz), 3.21
(3H, s) 3.81 (3H, s), 5.08 (1H, dd, J = 17.4, 0.9 Hz), 5.20 (1H, dd,
J = 10.8, 0.9 Hz), 6.06 (1H, dd, J = 10.8, 17.4 Hz), 6.78 (1H, d,
J = 8.4 Hz), 6.87 (1H, dd, J = 2.4, 8.4 Hz), 6.91 (1H, d, J = 2.4 Hz);
13C NMR (100 MHz, CDCl3): d 21.7, 22.0, 22.1, 26.4, 41.7, 55.3,
55.8, 108.3, 112.8, 113.5, 115.0, 116.6, 128.9, 137.7, 141.8, 155.3,
175.6; MS (EI): m/z (%) 284 (M+, 20), 216 (96), 189 (100), 174
(14), 69 (36), 41 (12); HRMS (EI): m/z Calcd for C17H20N2O2:
4.1.20. 1,8-Dimethyl-5-methoxy-3a-(2-methylbut-3-en-2-yl)-
3,3a,8,8a-tetrahydropyrrolo[2,3-b]indol-2(1H)-one ( )-(34), 1,8-
Dimethyl-5-methoxy-3a-(2-methylbut-3-en-2-yl)-1,2,3,3a,8,8a-
hexahydro pyrrolo[2,3-b]indole ( )-(35), and (3aR,8aR)-
derivatives (ꢁ)-34 and (ꢁ)-35
Under N2 atmosphere, to a solution of ( )-33 (0.50 g, 1.6 mmol)
in THF (100 mL) was added LiAlH4 (16 mL, 1.0 M in THF, 16 mmol)
and the solution was stirred under reflux for 10 h. Excess LiAlH4
was quenched by THF/H2O (1:1) and filtered through a Celite
pad. The filtrate was extracted with AcOEt and washed with satd
aqueous NaHCO3. The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (CH2Cl2/MeOH = 15/1) to give
( )-34 (0.25 g, 52%) as a colorless oil and ( )-35 (0.19 g, 41%) as a
pale yellow oil. Under N2 atmosphere, to a solution of ( )-34
(0.36 g, 1.2 mmol) in THF (20 mL) was added LiAlH4 (5.9 mL,
1.0 M in THF, 5.9 mmol) and the solution was stirred under reflux
for 1 h. The same work-up and purification procedure as that above
was applied to this reaction to give ( )-35 (0.29 g, 85%).
284.1525; Found: 284.1519; Anal. Calcd for
C17H20N2O2: C,
71.81; H, 7.09; N, 9.85. Found: C, 71.92; H, 7.19; N, 9.74.
4.1.18. 2-[5-Methoxy-1-methyl-3-(2-methylbut-3-en-2-yl)-2-
oxoindolin-3-yl]acetic acid ( )-(32)
A solution of ( )-31 (0.33 g, 1.2 mmol) in MeOH (29 mL) was
added 35% aqueous NaOH (1.7 mL, 15 mmol) and the mixture
was stirred under reflux for 3 days. The mixture was acidified with
1 N aqueous HCl and extracted with AcOEt. The organic layer was
dried over MgSO4 and concentrated to give ( )-32 (0.31 g, 88%) as a
pale yellow oil.
IR (CHCl3): 3501, 1709, 1601, 1500 cmꢁ1
;
1H NMR (300 MHz,
( )-34; IR (CHCl3): 3007, 2970, 2936, 1677, 1637, 1499 cmꢁ1; 1H
NMR (300 MHz, CDCl3): d 0.93 (3H, s), 1.04 (3H, s), 2.56 (1H, d,
J = 17.4 Hz), 2.85 (1H, d, J = 17.4 Hz), 2.86 (3H, s), 3.01 (3H, s),
3.74 (3H, s), 4.67 (1H, s), 5.05 (1H, dd, J = 17.2, 1.1 Hz), 5.11 (1H,
dd, J = 10.8, 1.1 Hz), 5.78 (1H, dd, J = 17.4, 10.8 Hz), 6.36 (1H, m),
6.71–6.74 (2H, m); 13C NMR (100 MHz, CDCl3): d 22.0, 22.9, 27.6,
36.4, 39.5, 40.9, 56.0, 56.3, 88.2, 108.3, 112.5, 113.4, 114.1, 133.7,
143.4, 144.5, 152.8, 172.2; MS (EI): m/z (%) 300 (M+, 36), 231
(100), 174 (50), 159 (8), 131 (6); HRMS (EI): m/z Calcd for
CDCl3): d 0.96 (3H, s), 1.10 (3H, s), 2.84 (1H, d, J = 16.2 Hz), 3.17
(1H, d, J = 16.2 Hz), 3.17 (3H, s), 3.78 (3H, s), 5.02 (1H, dd,
J = 17.4, 1.2 Hz), 5.12 (1H, dd, J = 10.8, 1.2 Hz), 6.01 (1H, dd,
J = 17.4, 10.8 Hz), 6.68 (1H, d, J = 8.4 Hz), 6.77 (1H, dd, J = 8.4,
2.4 Hz), 6.80 (1H, d, J = 2.4 Hz); 13C NMR (100 MHz, CDCl3): d
21.8, 21.9, 26.4, 36.8, 41.7, 54.8, 55.8, 107.6, 111.8, 112.7, 114.1,
130.6, 138.5, 142.5, 154.7, 174.8, 177.9; MS (EI): m/z (%) 303 (M+,
29), 235 (85), 190 (93), 189 (100), 174 (26), 69 (15); HRMS (EI):
m/z Calcd for C17H21NO4: 303.1471; Found: 303.1471; Anal. Calcd
for C17H21NO4: C, 67.31; H, 6.98; N, 4.62. Found: C, 67.40; H,
7.26; N, 4.45.
C
18H24N2O2: 300.1838; Found: 300.1841.
( )-35; IR (CHCl3): 1636, 1595, 1499 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): d 0.96 (3H, s) 1.01 (3H, s), 1.80 (1H, ddd, J = 11.8, 5.3,
2.9 Hz), 2.26 (1H, ddd, J = 11.8, 9.5, 6.6 Hz), 2.44 (3H, s), 2.44 (1H,
ddd, J = 9.5, 9.0, 5.3 Hz), 2.67 (1H, ddd, J = 9.0, 6.6, 2.9 Hz), 2.89
(3H, s), 3.73 (3H, s), 4.16 (1H, s), 5.01 (1H, dd, J = 17.4, 1.4 Hz),
5.07 (1H, dd, J = 10.8, 1.4 Hz), 5.96 (1H, dd, J = 17.4, 10.8 Hz), 6.31
(1H, d, J = 8.4 Hz), 6.66 (1H, dd, J = 8.4, 2.4 Hz), 6.73 (1H, d,
J = 2.4 Hz); MS (EI): m/z (%) 286 (M+, 34), 217 (100), 202 (14),
187 (7), 174 (24), 159 (6), 131 (5); HRMS (EI): m/z Calcd for
4.1.19. 2-[5-Methoxy-1-methyl-3-(2-methylbut-3-en-2-yl)-2-
oxoindolin-3-yl]-N-methylacetamide ( )-(33) and (S)-derivative
(ꢁ)-33
Under N2 atmosphere, to
a solution of ( )-32 (0.21 g,
0.70 mmol) in THF (10 mL) was added pentafluorophenol (0.39 g,
2.1 mmol), Et3N (0.20 mL, 1.1 mmol), and EDCꢂHCl (0.20 g,
1.1 mmol). After 2 h stirring, MeNH2 gas which was generated by
the reaction of aqueous MeNH2ꢂHCl and NaOH pellet) was bubbled
through the reaction mixture. After consumption of mixed anhy-
dride, the reaction mixture was neutralized by 10% aqueous HCl
and extracted with Et2O. The organic layer was washed with brine
C18H26N2O: 286.2045; Found: 286.2047.
Under N2 atmosphere, to a solution of (ꢁ)-33 (0.50 g, 1.6 mmol)
in THF (16 mL) was added LiAlH4 (16 mL, 1.0 M in THF, 16 mmol)
and the solution was stirred under reflux for 1 h. Excess LiAlH4
was quenched by THF/H2O (1:1) and filtered through a Celite

4912
M. Shinada et al. / Bioorg. Med. Chem. 20 (2012) 4901–4914
pad. The filtrate was extracted with AcOEt and washed with satd.
aqueous NaHCO3. The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (CH2Cl2/MeOH = 30/1) to give
(ꢁ)-34 (0.38 g, 81%) as a colorless oil. The spectral data of (ꢁ)-34
were identical to those of ( )-34, other than for specific optical
34.3, 36.0, 37.4, 37.9, 53.4, 65.7, 91.4, 105.6, 118.5, 118.6, 120.4,
123.5, 128.9, 134.3, 137.5, 141.7, 150.6, 152.3; MS (EI): m/z (%)
393 (M+, 4), 274 (68), 203 (100), 188 (14), 160 (40), 119 (25), 91
(12); HRMS (EI): m/z Calcd for C24H31N3O2: 393.2416; Found:
393.2423.
Optically active compound (ꢁ)-12 was obtained in three steps
from (ꢁ)-35 in a procedure similar to that above. The spectral data
of (ꢁ)-12 were identical to those of ( )-12, other than for specific
rotation: ½a 2D2
ꢁ108.7 (c 1.09, CHCl3).
ꢅ
Under N2 atmosphere, to a solution of (ꢁ)-34 (0.35 g, 1.2 mmol)
in THF (16 mL) was added LiAlH4 (3.5 mL, 1.0 M in THF, 3.5 mmol)
and the solution was stirred at room temperature for 0.5 h. Excess
LiAlH4 was quenched by THF/H2O (1:1) and filtered through a Cel-
ite pad. The filtrate was extracted with AcOEt and washed with
satd. aqueous NaHCO3. The organic layer was dried over MgSO4
and concentrated under reduced pressure. The residue was puri-
fied by silica gel column chromatography (CH2Cl2/MeOH = 20/1)
to give (ꢁ)-35 (0.27 g, 80%) as a pale yellow oil. The spectral data
of (ꢁ)-35 were identical to those of ( )-35, other than for specific
optical rotation: ½a D21
ꢅ
ꢁ85.1 (c 1.10, CHCl3) and CD kmax (nm) [
De
(Mꢁ1 cmꢁ1)] 312 (ꢁ1.95), 265 (ꢁ6.67).
4.1.23. General procedure for 3-{2-[(3R)-2-oxoindolin-3-
yl]acetyl}-4(R)-phenyloxazolidin-2-ones 37 and 3-{2-[(3S)-2-
oxoindolin-3-yl]acetyl}-4(R)-phenyloxazolidin-2-ones 38
Under N2 atmosphere, to a solution of ( )-20, ( )-26, ( )-32
(5 mmol) in THF (45 mL) was added pentafluorophenol (7.5 mmol),
Et3N (9.5 mmol), and EDCꢂHCl (7.5 mmol). After 2 h stirring, the
mixture was concentrated under reduced pressure and dissolved
in AcOEt. The solution was washed with satd aqueous Na2CO3
and dried over MgSO4. The filtrate was concentrated under reduced
pressure to give a crude ester. To a solution of (R)-(ꢁ)-4-phenyl-2-
oxazolidinone (5.5 mmol) in THF (37 mL) was added NaH (60%,
5.5 mmol, for 20 and 26) or n-BuLi (1.6 M in hexane, 5.5 mmol,
for 38) at 0 °C and the mixture was stirred for 2 h. To this solution
was added above crude ester and the mixture was stirred for 0.5 h.
After consumption of ester, the reaction mixture was neutralized
by 1 N aqueous HCl and extracted with Et2O. The organic layer
was washed with brine and dried over MgSO4. The concentrated
residue was purified by silica gel column chromatography
(AcOEt/n-hexane = 1/2) to give 37 and 38.
optical rotation: ½a D21
ꢁ78.4 (c 2.60, CHCl3).
ꢅ
4.1.21. 1,8-Dimethyl-5-methoxy-3a-tert-pentyl-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole ( )-(36)
Under H2 atmosphere, to
a solution of ( )-35 (0.21 g,
0.74 mmol) in EtOH (3.0 mL) was added 10% Pd/C (10 mg, Aldrich)
and the solution was stirred vigorously at room temperature for
3 h. The reaction mixture was filtrated with Celite pad and concen-
trated. The residue was purified by silica gel column chromatogra-
phy (CH2Cl2/MeOH = 20/1) to give ( )-36 (0.21 g, 99%) as a pale
yellow oil.
IR (CHCl3): 2968, 2938, 2880, 2831, 1593, 1499, 1427 cmꢁ1 1H
;
NMR (300 MHz, CDCl3): d 0.80 (3H, t, J = 7.6 Hz), 0.86 (3H, s), 0.90
(3H, s), 1.25 (2H, m), 1.80 (1H, ddd, J = 11.8, 5.3, 2.4 Hz), 2.26 (1H,
ddd, J = 11.8, 9.7, 6.4 Hz), 2.43 (1H, ddd, J = 9.7, 9.0, 5.3 Hz), 2.44
(3H, s), 2.70 (1H, ddd, J = 9.0, 6.4, 2.4 Hz), 2.90 (3H, s), 3.76 (3H,
s), 4.23 (1H, s), 6.29 (1H, d, J = 8.4 Hz), 6.65 (1H, dd, J = 8.4,
2.4 Hz), 6.72 (1H, d, J = 2.4 Hz); 13C NMR (100 MHz, CDCl3): d 8.6,
21.5, 21.7, 29.8, 34.3, 36.7, 37.1, 37.8, 53.2, 56.0, 65.7, 91.5,
106.2, 111.8, 112.7, 134.9, 147.6, 151.9; MS (EI): m/z (%) 288 (M+,
65), 217 (100), 202 (18), 187 (7), 174 (34), 160 (7), 131 (4); HRMS
(EI): m/z Calcd for C18H28N2O: 288.2202; Found: 288.2201.
4.1.23.1. 3-{2-[3(R)-Allyl-5-methoxy-1-methyl-2-oxoindolin-3-
yl]acetyl}-4(R)-phenyloxazolidin-2-one (37a) and 3-{2-[3(S)-
Allyl-5-methoxy-1-methyl-2-oxoindolin-3-yl]acetyl}-4(R)-phe-
nyloxazolidin-2-one (38a).
Carboxylic acid ( )-20 (1.2 g,
4.5 mmol), pentafluorophenol (1.2 g, 6.7 mmol), Et3N (1.2 mL,
8.9 mmol), EDCꢂHCl (1.3 g, 6.7 mmol), (R)-(ꢁ)-4-phenyl-2-oxazo-
lidinone (1.1 g, 6.7 mmol), and NaH (0.23 g, 60%, 5.8 mmol) gave
37a (0.86 g, 46%) as a pale yellow oil and 38a (0.80 g, 42%) as a pale
yellow oil.
4.1.22. 1,8-Dimethyl-3a-tert-pentyl-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indol-5-yl phenylcarbamate ( )-(12)
and (3aR,8aR)-derivative (ꢁ)-12
Compound 37a; IR (CHCl3): 1780, 1707, 1603, 1499 cmꢁ1 1H
;
NMR (300 MHz, CDCl3): d 2.47 (3H, dd, J = 13.2, 7.5 Hz), 2.53 (3H,
dd, J = 13.2, 7.0 Hz), 3.11 (3H, s), 3.35 (1H, d, J = 17.1 Hz), 3.77
(3H, s), 4.00 (1H, d, J = 17.1 Hz), 4.13 (1H, dd, J = 8.8, 3.3 Hz), 4.59
(1H, dd, J = 8.8, 8.6 Hz), 4.96 (1H, dd, J = 10.1 Hz), 5.01 (1H, dd,
J = 17.1 Hz), 5.26 (1H, dd, J = 8.6, 3.3 Hz), 5.44 (1H, dddd, J = 17.4,
10.1, 7.5, 7.0 Hz), 6.59 (1H, d, J = 8.4 Hz), 6.71 (1H, dd, J = 8.4,
2.4 Hz), 6.81 (1H, d, J = 2.4 Hz), 6.86–6.89 (2H, m), 7.18–7.21 (3H,
m); 13C NMR (100 MHz, CDCl3): d 26.4, 40.8, 42.4, 50.2, 55.8,
57.2, 70.0, 108.1, 109.9, 112.2, 119.4, 125.0, 128.0, 128.7, 131.1,
131.8, 137.6, 138.1, 153.5, 155.4, 168.3, 178.2; MS (EI): m/z (%)
420 (M+, 72), 216 (100), 174 (8); HRMS (EI): m/z Calcd for
Under N2 atmosphere, to
a solution of ( )-36 (55 mg,
0.19 mmol) in CH2Cl2 (6.3 mL) was added a CH2Cl2 solution of
BBr3 (0.59 mL, 6.3 mmol) at 0 °C. After 1.5 h stirring, the reaction
mixture was added satd NaHCO3 and extracted by Et2O. The organ-
ic layer was washed with brine, dried over MgSO4, and concen-
trated under reduced pressure to give crude phenol (51 mg).
Under N2 atmosphere, to a solution of above phenol (51 mg) in
Et2O (4.0 mL) added Na (3.0 mg, 0.13 mmol) at room temperature.
After stirring for 5 min, PhNCO (25 lL, 0.23 mmol) was added and
stirred for 15 min. The reaction mixture was filtrated and the fil-
trate was concentrated. The residue was dissolved in Et2O and
the solution was washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (CH2Cl2/MeOH = 20/1) to give
( )-12 (47 mg, 63%) as a white powder.
C
24H24N2O5: 420.1685. Found: 420.1689.
Compound 38a; IR (CHCl3): 3009, 1782, 1709, 1603, 1501 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d 2.45–2.55 (2H, m), 3.11 (3H, s), 3.34
(1H, d, J = 17.4 Hz), 3.77 (3H, s), 3.92 (1H, d, J = 17.4 Hz), 4.16
(1H, dd, J = 9.0, 3.3 Hz), 4.56 (1H, dd, J = 9.0, 8.7 Hz), 4.96–5.04
(2H, m), 5.20 (1H, dd, J = 8.7, 3.3 Hz), 5.42–5.46 (1H, m), 6.69–
6.79 (3H, m), 7.13–7.16 (2H, m), 7.28–7.33 (3H, m).
Mp: 143–147 °C; IR (CHCl3): 3433, 1748, 1603, 1526, 1497,
1443 cmꢁ1 1H NMR (300 MHz, CDCl3): d 0.80 (3H, t, J = 7.5 Hz),
;
0.86 (3H, s), 0.90 (3H, s), 1.14–1.38 (2H, m), 1.80 (1H, ddd,
J = 11.8, 5.3, 2.4 Hz), 2.25 (1H, ddd, J = 11.8, 9.7, 6.4 Hz), 2.45 (3H,
s), 2.46 (1H, ddd, J = 9.7, 9.0, 5.3 Hz), 2.68 (1H, ddd, J = 9.0, 6.4,
2.4 Hz), 2.94 (3H, s), 4.27 (1H, s), 6.29–6.32 (1H, m), 6.86–6.92
(3H, m), 7.08 (1H, t, J = 7.5 Hz), 7.31 (2H, t, J = 7.5 Hz), 7.43 (2H,
d, J = 7.5 Hz); 13C NMR (100 MHz, CDCl3): d 8.7, 21.5, 21.6, 29.8,
4.1.23.2. 3-{2-[5-Methoxy-1-methyl-2-oxo-3(S)-vinylindolin-3-
yl]acetyl}-4(R)-phenyloxazolidin-2-one (37b) and 3-{2-[5-Meth-
oxy-1-methyl-2-oxo-3(R)-vinylindolin-3-yl]acetyl}-4(R)-phenyl-
oxazolidin-2-one (38b).
Carboxylic acid ( )-26 (1.3 g, 5.0 mmol),
pentafluorophenol (1.4 g, 7.8 mmol), Et3N (1.4 mL, 10 mmol),
EDCꢂHCl (1.5 g, 7.8 mmol), (R)-(ꢁ)-4-phenyl-2-oxazolidinone

M. Shinada et al. / Bioorg. Med. Chem. 20 (2012) 4901–4914
4913
(1.3 g, 7.8 mmol), and NaH (0.31 g, 60%, 7.8 mmol) gave 37b (0.75 g,
36%) as colorless crystals and 38b (0.72 g, 34%) as a colorless oil.
(5); HRMS (EI): m/z Calcd for C26H28N2O5: 448.1998; Found:
448.2000.
37b; IR (CHCl3): 1782, 1705, 1605, 1499 cmꢁ1
;
1H NMR
(400 MHz, CDCl3): d 3.12 (3H, s), 3.53 (1H, d, J = 17.6 Hz), 3.75
(3H, s), 4.04 (1H, d, J = 16.9 Hz), 4.13 (1H, dd, J = 3.2, 8.8 Hz), 4.59
(1H, t, J = 8.8 Hz), 5.06 (1H, d, J = 17.2 Hz), 5.15 (1H, d,
J = 10.0 Hz), 5.27 (1H, dd, J = 3.6, 8.4 Hz), 5.91 (1H, dd, J = 10.4,
17.2 Hz), 6.62 (1H, d, J = 8.4 Hz), 6.73 (1H, dd, J = 2.8, 8.4 Hz),
6.78–6.81 (1H, m), 6.88–6.91 (2H, m), 7.16–7.22 (3H, m); 13C
NMR (100 MHz, CDCl3): d 26.7, 40.7, 53.3, 55.8, 57.2, 70.1, 108.6,
110.7, 112.6, 116.2, 125.0, 128.0, 128.7, 130.7, 136.6, 137.5,
138.1, 153.5, 155.4, 168.1, 176.7; MS (EI): m/z (%) 407 (25), 406
(M+, 100), 216 (16), 215 (12), 202 (55); HRMS (EI): m/z Calcd for
4.1.24. General procedure for (S)-2-(2-oxoindolin-3-yl)acetic
acids (ꢁ)-20, (+)-26, (ꢁ)-32
A mixture of 38 (1.0 mmol), 30% aqueous H2O2 (4.0 mmol) and
LiOHꢂH2O (2.0 mmol) in THF/H2O (2:1, 6–10 mL) was stirred at
room temperature for 3 days. The concentrated residue was basi-
fied with 10% aqueous Na2CO3 and washed with Et2O. The water
layer was then acidified with 20% aqueous HCl and extracted with
Et2O. The organic layer was dried over MgSO4 and concentrated to
give (ꢁ)-20, (+)-26, (ꢁ)-32.
C23H22N2O5: 406.1529; Found: 406.1522; ½a D23
ꢅ
ꢁ140.7 (c 2.33,
4.1.24.1.
yl)acetic acid (ꢁ)-(20).
(S)-2-(3-Allyl-5-methoxy-1-methyl-2-oxoindolin-3-
Oxazolidin-2-one 38a (0.80 g,
CHCl3).
Compound 38b; Mp: 166–168 °C (AcOEt/n-hexane); IR (CHCl3):
1.9 mmol), 30% aqueous H2O2 (0.75 mL, 7.6 mmol), and LiOHꢂH2O
(0.16 g, 3.8 mmol) in THF/H2O (2:1, 12 mL) gave (ꢁ)-20 (0.46 g,
89%). The spectral data of (ꢁ)-20 were identical to those of ( )-
1782, 1711, 1603, 1499 cmꢁ1 1H NMR (400 MHz, CDCl3): d 3.12
.
(3H, s), 3.54 (1H, d, J = 17.4 Hz), 3.80 (3H, s), 3.94 (1H, d,
J = 17.4 Hz), 4.16 (1H, dd, J = 3.6, 8.8 Hz), 4.56 (1H, t, J = 8.8 Hz),
5.06 (1H, d, J = 17.2 Hz), 5.15 (1H, d, J = 10.4 Hz), 5.20 (1H, dd,
J = 3.6, 8.4 Hz), 5.93 (1H, dd, J = 10.4, 17.2 Hz), 6.72–6.83 (3H,
m), 7.14 (2H, d, J = 6.4 Hz), 7.26–7.36 (3H, m); 13C NMR
(100 MHz, CDCl3): d 26.7, 41.1, 53.0, 55.8, 57.2, 70.1, 108.5,
111.0, 112.3, 116.1, 125.4, 128.4, 129.0, 131.2, 136.7, 137.6,
138.2, 153.6, 155.4, 168.1, 176.4; MS (EI): m/z (%) 406 (M+, 100),
20, other than for specific optical rotation: ½a D25
ꢅ
ꢁ11.0 (c 1.90,
CHCl3).
4.1.24.2.
(R)-2-(5-Methoxy-1-methyl-2-oxo-3-vinylindolin-3-
yl)acetic acid (+)-(26).
Oxazolidin-2-one 38b (0.70 g,
1.7 mmol), 30% aqueous H2O2 (0.78 mL, 6.9 mmol), and LiOHꢂH2O
(0.15 g, 3.5 mmol) in THF/H2O (2:1, 15 mL) gave (+)-26 (0.35 g,
216 (13), 202 (57); HRMS (EI): m/z Calcd for
C
23H22N2O5:
78%). The spectral data of (+)-26 were identical to those of ( )-
23
406.1529; Found: 406.1523; Anal. Calcd for
C
23H22N2O5: C,
26, other than for specific optical rotation: [
a]
D
+2.3 (c 2.46,
67.97; H, 5.46; N, 6.89. Found: C, 67.94; H, 5.66; N, 6.84; ½a D23
ꢅ
CHCl3).
ꢁ102.9 (c 1.18, CHCl3).
4.1.24.3.
2-[(R)-5-Methoxy-1-methyl-3-(2-methylbut-3-en-2-
Oxazolidin-2-
yl)-2-oxoindolin-3-yl]acetic acid (ꢁ)-(32).
4.1.23.3. 3-{2-[5-Methoxy-1-methyl-3(S)-(2-methylbut-3-en-2-
yl)-2-oxoindolin-3-yl]acetyl}-4(R)-phenyloxazolidin-2-one
(37c) and (R)-3-{2-[5-Methoxy-1-methyl-3(R)-(2-methylbut-3-
en-2-yl)-2-oxoindolin-3-yl]acetyl}-4(R)-phenyloxazolidin-2-
one 38c (1.4 g, 3.1 mmol), 30% aqueous H2O2 (1.3 mL, 13 mmol),
and LiOHꢂH2O (0.26 g, 6.2 mmol) in THF/H2O (2:1, 30 mL) gave
(ꢁ)-32 (0.83 g, 88%) as a pale yellow oil. The spectral data of (ꢁ)-
32 were identical to those of ( )-32 other than for specific optical
rotation: ½a 2D5
ꢅ
ꢁ80.1 (c 0.70, CHCl3).
one (38c).
Carboxylic acid ( )-32 (2.0 g, 6.7 mmol), pentaflu-
orophenol (1.8 g, 9.9 mmol), Et3N (1.8 mL, 13 mmol), EDCꢂHCl
(1.9 g, 9.9 mmol), (R)-(ꢁ)-4-phenyl-2-oxazolidinone (1.2 g,
7.2 mmol), and n-BuLi (4.6 mL, 1.6 M in hexane, 7.2 mmol) gave
37c (1.4 g, 48%) as a pale yellow oil and 38c (1.4 g, 48%) as a pale
yellow oil.
4.2. Biological methods
4.2.1. Animals
Male Wistar ST rats (8ꢁ10 weeks old) were purchased from
Sankyo Labo Service Co. (Tokyo, Japan) and given free access to
water and commercial food pellets (MF: Oriental Yeast Co., Tokyo,
Japan). They were kept in a temperature—(24 1 °C) and humid-
ity—(55 5%) controlled room with a 12-h day-night cycle. All
experiments were performed in accordance with the guidelines
of the Animal Research Committee of Toho University.
Compound 37c; IR (CHCl3): 3023, 3017, 1781, 1705, 1603, 1501,
1470 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.02 (3H, s), 1.13 (3H, s),
;
3.09 (3H, s), 3.39 (1H, d, J = 16.9 Hz), 3.76 (3H, s), 4.11 (1H, dd,
J = 8.4, 3.5 Hz), 4.19 (1H, d, J = 16.9 Hz), 4.57 (1H, dd, J = 8.6,
8.4 Hz), 5.04 (1H, dd, J = 17.4, 1.1 Hz), 5.13 (1H, dd, J = 10.8,
1.1 Hz), 5.21 (1H, dd, J = 8.6, 3.5 Hz), 6.05 (1H, dd, J = 17.4,
10.8 Hz), 6.52 (1H, d, J = 8.4 Hz), 6.67 (1H, dd, J = 8.4, 2.4 Hz),
6.76–6.79 (3H, m), 7.11–7.18 (2H, m); 13C NMR (100 MHz, CDCl3):
d 21.3, 21.9, 25.8, 36.9, 41.5, 54.9, 55.3, 56.7, 69.6, 107.2, 111.6,
111.7, 113.7, 124.4, 127.3, 128.1, 130.3, 137.9, 138.3, 142.3,
153.3, 154.2, 168.7, 177.5; MS (EI): m/z (%) 448 (M+, 33), 380
(98), 216 (100), 189 (64), 174 (22), 160 (8); HRMS (EI): m/z Calcd
for C26H28N2O5: 448.1998; Found: 448.2005.
4.2.2. Measurement of AChE and BuChE activities
Rat brain homogenates and plasma were used as the sources of
AChE and BuChE, respectively. Rat whole forebrain was homoge-
nized in 20 volumes of ice-cold 0.1 M phosphate buffer (pH 8.0
or 7.4) containing 0.5% Triton-X. The homogenate was centrifuged
at 1500ꢃg at 4 °C for 10 min and the supernatant was used as the
source of AChE. AChE and BuChE activities were measured using
the Ogura18 modified spectrophotometric method of Ellman19 with
acetylthiocholine iodide (AthCh) and butyrylthiocholine iodide
(ButhCh) as the substrates for AChE and BuChE, respectively. The
AChE assay mixture consisted of 0.1 M phosphate buffer
(2.75 mL), 10 mM 5,50-dithiobis(2-nitrobenzoic acid) (DTNB)
(0.10 mL), 75 mM AthCh (0.02 mL), ChE inhibitor (0.03 mL) and
brain homogenates (0.10 mL). The BuChE assay mixture consisted
of 0.1 M phosphate buffer (2.55 mL), 10 mM DTNB (0.10 mL),
150 mM ButhCh (0.02 mL), ChE inhibitor (0.03 mL) and plasma
(0.30 mL). After mixing for 1 min with agitation, changes in absor-
bance at 412 nm were continuously recorded for 2 min at 25 °C
Compound 38c; IR (CHCl3): 3023, 1781, 1709, 1601, 1538, 1518,
1500 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.00 (3H, s), 1.11 (3H, s),
;
3.07 (3H, s), 3.43 (1H, d, J = 12.9 Hz), 3.76 (3H, s), 4.05 (1H, dd,
J = 8.8, 3.4 Hz), 4.11 (1H, d, J = 12.9 Hz), 4.41 (1H, dd, J = 8.8,
8.5 Hz), 4.98 (1H, dd, J = 8.5, 3.4 Hz), 5.03 (1H, dd, J = 17.3,
0.9 Hz), 5.12 (1H, dd, J = 10.8, 0.9 Hz), 6.03 (1H, dd, J = 17.3,
10.8 Hz), 6.66 (1H, d, J = 8.3 Hz), 6.77 (1H, dd, J = 8.3, 2.3 Hz), 6.80
(1H, d, J = 2.3 Hz), 7.06 (2H, d, J = 6.4 Hz), 7.20–7.28 (3H, m); 13C
NMR (100 MHz, CDCl3): d 21.6, 22.2, 26.2, 37.5, 41.9, 55.1, 55.6,
57.0, 69.9, 107.4, 111.6, 112.1, 114.1, 125.2, 128.2, 128.7, 131.1,
138.1, 138.6, 142.4, 153.6, 154.5, 169.0, 177.7; MS (EI): m/z (%)
448 (M+, 31), 380 (99), 216 (100), 189 (66), 174 (22), 160 (8), 69

4914
M. Shinada et al. / Bioorg. Med. Chem. 20 (2012) 4901–4914
8. (a) Greig, N. H.; Sambamurti, K.; Yu, Q. S.; Brossi, A.; Bruinsma, G. B.; Lahiri, D.
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N. H. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 7605.
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Rapoport, S. I.; Brossi, A. Med. Chem. Res. 1992, 2, 238; (b) Pei, X.-F.; Yu, Q.-S.;
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F.; Greig, N. H. Aust. J. Chem. 1996, 49, 171; (d) Haung, A.; Kodanko, J. J.;
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using a spectrophotometer (Hitachi, Tokyo, Japan). The ChE activity
was determined as the change in absorbance during the last min-
ute. Each ChE inhibitor was mixed with brain homogenate (3:10, v/
v) or plasma (3:30, v/v) and incubated for 0.5 h at 37 °C. Aliquots of
0.13 or 0.33 mL of the preincubation mixture were used to assay
ChE activity.
4.2.3. Statistical analysis
IC50 values were determined by 4-parameter logistic regression
analysis using Stat View version 5.0 (SAS Institute Inc., Tokyo,
Japan). Differences at P < 0.05 were considered statistically
significant.
Acknowledgments
11. 3a-Phenyl derivative of phenserine was only synthesized, but its biological
activity was not reported: Pei, X. F.; Greig, N. H.; Brossi, A. Heterocycles 1998,
49, 437.
This work was supported by a Grant-in-Aid for Scientific
Research (C) (No. 21590028) and for the High-Tech Research
Center Project (S0801043) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan. We are grateful to
N. Eguchi, T. Koseki, and S. Kubota at the Analytical Center of
MPU for performing microanalysis and mass spectrometry.
12. (a) Kawasaki, T.; Ogawa, A.; Takashima, Y.; Sakamoto, M. Tetrahedron Lett.
2003, 44, 1591; (b) Kawasaki, T.; Shinada, M.; Kamimura, D.; Ohzono, M.;
Ogawa, A. Chem. Commun. 2006, 420; (c) Kawasaki, T.; Shinada, M.; Ohzono,
M.; Ogawa, A.; Terashima, R.; Sakamoto, M. J. Org. Chem. 2008, 73, 5959; (d)
Takiguchi, S.; Iizuka, T.; Kumakura, Y.; Murasaki, K.; Ban, N.; Higuchi, K.;
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Synth. Commun. 1999, 29, 3251.
16. The tentative assignment of the stereochemistry was based on comparison of
the specific rotations of the demethoxy compounds previously reported.12
17. The absolute configurations of (ꢁ)-3, (ꢁ)-9, (–)-10, and (ꢁ)-12 were suggested
by comparison of these CD spectra with that of (ꢁ)-phenserine (1): CD kmax
(nm) [De
(Mꢁ1 cmꢁ1)] 325 (0.65), 269 (–2.14).
18. Ogura, H.; Kosasa, T.; Kuriya, Y.; Yamanishi, Y. Methods Find. Exp. Clin.
Pharmacol. 2000, 22, 609.
19. Ellman, G. L.; Courtny, K. D.; Andres, V. Jr.; Feather-Stone, R. M. Biochem.
Pharmacol. 1961, 7, 88.