Convenient synthesis of spiroindole derivatives via palladium-catalyzed cyclization of propargyl chlorides

Article abstract of DOI:10.1016/j.tet.2015.05.006

Abstract Herein, we report the palladium-catalyzed cyclization reactions of indoles bearing a propargyl chloride side chain at their 3-position. In the presence of an external nucleophile, such as a sulfonamide or malonate, indoles bearing a propargyl gro

Full text of DOI:10.1016/j.tet.2015.05.006

Accepted Manuscript
Convenient synthesis of spiroindole derivatives via palladium-catalyzed cyclization of
propargyl chlorides
Akira Iwata, Shinsuke Inuki, Shinya Oishi, Nobutaka Fujii, Hiroaki Ohno
PII:
S0040-4020(15)00647-X
10.1016/j.tet.2015.05.006
TET 26723
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 March 2015
Revised Date: 23 April 2015
Accepted Date: 1 May 2015
Please cite this article as: Iwata A, Inuki S, Oishi S, Fujii N, Ohno H, Convenient synthesis of spiroindole
derivatives via palladium-catalyzed cyclization of propargyl chlorides, Tetrahedron (2015), doi: 10.1016/
j.tet.2015.05.006.
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Convenient synthesis of spiroindole
derivatives via palladium-catalyzed
cyclization of propargyl chlorides
Leave this area blank for abstract info.
Akira Iwata, Shinsuke Inuki, Shinya Oishi , Nobutaka Fujii, Hiroaki Ohno
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
EtO2C
EtO2C
CO2Et
CO2Et
CO2Et
EtO2C
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
dppb, TsNH2, Cs2CO3
dppe, BnNH2, Cs2CO3
THF, rt
THF, 60 oC
N
N
N
H
H
H
Ts
N
(±)
Cl

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Convenient synthesis of spiroindole derivatives via palladium-catalyzed cyclization of
propargyl chlorides
Akira Iwata , Shinsuke Inuki,† Shinya Oishi , Nobutaka Fujii , Hiroaki Ohno
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein, we report the palladium-catalyzed cyclization reactions of indoles bearing a propargyl
chloride side chain at their 3-position. In the presence of an external nucleophile, such as a
sulfonamides or malonate, indoles bearing a propargyl group at their 3-position gave fused
tetracyclic spiroindolines preferentially. However, in the absence of an external nucleophile, the
same substrates afforded spiroindoles. Our attempts to develop a catalytic asymmetric
spirocyclization onto a propargylpalladium species are also presented in this paper.
Available online
Keywords:
palladium
2015 Elsevier Ltd. All rights reserved
.
spiroindole
cascade cyclization
catalytic asymmetric reaction
1. Introduction
(Scheme 1, eq. 1, path a). We also expected that running the
same reaction without using an external nucleophile would
promote β-hydride elimination (path b) to produce spiroindoles
bearing a conjugated diene moiety (eq. 2).
The palladium-catalyzed reactions of propargyl compounds
provide efficient approaches for the formation of carbon-carbon
and carbon-heteroatom bonds.1 The pioneering work of Tsuji and
co-workers revealed that double nucleophilic additions proceeded
at the central and terminal carbons of the propargylic moiety
when soft carbon- or oxo-nucleophiles were employed.2 This
chemistry is particularly useful for the construction of carbo- and
heterocyclic frameworks, including furans,3 cyclobutanes,4
indenes,5 cyclopentanones,6 cyclic carbonates,7 benzofurans,8 and
indoles,9 especially when it is used in combination with an inter-
or intramolecular nucleophilic addition reaction as the
terminating step.
EtO2C
CO2Et
EtO2C
CO2Et
a
(1)
N
H
NuH2
Nu
N
H
H
Cl
[Pd]
CO2Et
EtO2C
CO2Et
H
EtO2C
b
b
Spirocyclic compounds are currently attracting considerable
interest in organic chemistry because of their unique molecular
structure and diverse biological activities.10 In particular, enantio-
enriched spiroindoles and spiroindolines represent important
structural motifs that can be found in a wide range of biologically
active natural products and synthetic compounds.11 As part of our
ongoing efforts towards the construction of heterocyclic
frameworks based on the palladium-catalyzed reactions of
propargyl/allenic compounds, we recently became interested in
the intramolecular nucleophilic addition reactions of indoles as a
strategy for the synthesis of spiroindoles. It was envisaged that
this strategy would provide facile access to tetracyclic
spiroindolines when it was used in combination with the
intermolecular nucleophilic cyclization of an external nucleophile
———
(2)
Pd+Ln
N
N
a
NuH
Scheme 1. Our concept: palladium-catalyzed spirocyclization of
indole-based propargyl compounds
In 2013, Hamada and co-workers reported the development of
a palladium-catalyzed intramolecular spirocyclization of phenol-
based propargylic carbonates (Scheme 2, eq. 3).12 When
tryptamine-derived carbonates were used, this reaction produced
spiroindoles bearing an azepine moiety. Immediately after our
communication in 2014,13 the groups of Rawal14a and You14b
Corresponding author. Tel.: +81-75-753-4571; fax: +81-75-753-4570; e-mail: hohno@pharm.kyoto-u.ac.jp
Corresponding author. Tel.: +81-75-753-4551; fax: +81-75-753-4570; e-mail: nfujii@pharm.kyoto-u.ac.jp

2
Tetrahedron
ACCEPTED MANUSCRIPT
independently reported the intermolecular reactions of indole-
Scheme 3. Preparation of substrates 5a−c. (a) diethyl malonate,
based dual nucleophiles and propargyl carbonates as general
strategies for the synthesis of spiroindoles (eq. 4). In this paper,
we report the full details of our recent investigations into
construction of tetracyclic spiroindolines (eq. 1) and conjugated
diene-type spiroindoles (eq. 2) via the palladium-catalyzed
cyclization of propargyl chlorides. Our attempts to achieve a
catalytic asymmetric spirocyclization onto a propargylpalladium
species have also been presented.
ethyl propiolate, Et2O, rt; (b) BrCH2C≡CCH2OTBS, NaH, THF,
0 °C to rt; (c) TBAF, THF, 0 °C; (d) NCS, PPh3, CH2Cl2, rt; (e)
ClCO2Me, pyridine, CH2Cl2, 0 °C; (f) TrisCl, DMAP, CH2Cl2,
then CuBr·Me2S, LiBr, THF, 50 °C; (g) 1, ethyl propiolate, Et2O,
rt.
Our studies began with a series of screening experiments to
identify the optimal reaction conditions using propargyl chloride
5a as a model substrate (Table 1). The reaction of 5a with 5
mol % Pd(PPh3)4, TsNH2 and Cs2CO3 in THF gave spiroindole
9a, the β-hydride elimination product, in only 20% yield (entry
1). When the reaction was conducted in the presence of 5 mol %
Hamada and Nemoto12
MeO2C CO2Me
CO2Me
CO2Me
Pd(dba)2
and
the
bidentate
ligand
1,1′-
[Pd]
(3)
bis(diphenylphosphino)ferrocene (dppf), the desired reaction
proceeded smoothly to afford the tetracyclic spiroindoline 8a in
47% yield (entry 2). A variety of different inorganic bases
(entries 3–5), ligands (entries 6–10) and solvents (entries 11–13)
were also screened against the reaction, and the results revealed
that the use of 1,4-bis(diphenylphosphino)butane (dppb) as the
ligand with Cs2CO3 as the base in THF gave the best results, with
compound 8a being isolated in ca. 72% yield (entry 9). However,
the main problem with these conditions was found to be poor
reproducibility. Operating under the assumption that the poor
reproducibility of these conditions was related to the purity of
Pd(dba)2, we investigated the use of Pd2(dba)3·CHCl3 following
its recrystallization from CHCl3.17 This change afforded the
desired product 8a in 72% yield reproducibly (entry 14).
HO
O
OCO2Me
Rawal14a and You14b
NuH
Nu
[Pd]
(4)
OCO2R
Nu = NR14a or C(CO2R)2
R
R
N
N
H
14b
Scheme 2. Related palladium-catalyzed spirocyclization reaction
using propargyl compounds
2. Results and discussion
With the optimized conditions in hand, we proceeded to
examine the performance of the reaction in the presence of a
variety of different nucleophiles. The results are summarized in
Table 1 (entries 15–19) and Scheme 4. The reaction with
sulfonamides (e.g., PhSO2NH2, MtsNH2, NsNH2, and MsNH2)
gave the corresponding tetracyclic spiroindolines 8b–e in
moderate yields (entries 15–18). In contrast, benzylamine was
found to be inert as the external nucleophile, with the β-hydride
elimination product 9a being isolated as the major product (entry
19). Interestingly, the use of dimethyl malonate as the
nucleophile resulted in the formation of the regioisomeric
spiroindoline 10a (17%) and spiroindole 9a (15%) as shown in
Scheme 4. The use of acetyl acetone, which is a more acidic
carbon nucleophile than dimethyl malonate, led to an increase in
the yield of spiroindoline 10b (50%), along with spiroindole 9a
(20%).
The route used for the preparation of substrates 5a−c is shown
in Scheme 3. In accordance with a literature procedure,15 gramine
(1) was converted to the corresponding malonate 2. The
subsequent alkylation of 2 followed by a desilylation reaction
afforded propargyl alcohol 4. Substrates 5a and 5b were obtained
by the reaction of 4 with NCS/PPh3 or ClCO2Me/pyridine,
respectively. Bromoallene 5c was prepared from propargyl
alcohol 6 using an established procedure for the formation of
bromoallenes.16 The treatment of 6 with TrisCl (Tris = 2,4,6-
triisopropylbenzenesulfonyl) and DMAP gave the corresponding
sulfonate, which was converted to bromoallene 7 by treatment
with CuBr·SMe2 in the presence of LiBr. Finally, the
introduction of the indole unit to 7 was achieved by its reaction
with gramine (1) in the presence of ethyl propiolate to give
bromoallene 5c. The other substrates were also prepared in the
same manner (see Supplementary material).
EtO2C
EtO2C
EtO2C
CO2Et
CO2Et
EtO2C
E
E
E
E
N
+
R
(a)
(b)
N
N
H
79%
53%
N
H
H
O
N
H
N
N
R
O
Cl
H
5a
10a (R = OMe) (17%)
10b (R = Me) (50%)
9a (15%)
9a (20%)
OTBS
1
2 (E = CO2Et)
3
E
E
E
E
Scheme 4. Reaction with carbon nucleophiles. Reaction
conditions: Pd2(dba)3·CHCl3 (2.5 mol %), dppb (10 mol %),
Cs2CO3 and CH2(COR)2 in THF at rt.
(c)
(d) or (e)
92% (d)
82% (e)
88%
N
N
H
H
OH
4
X
5a
(X = Cl)
5b (X = OCO2Me)
It is well known that bromoallenes are the synthetic
equivalents of propargyl compounds including chlorides and
carbonates in palladium-catalyzed transformations.18 With this in
mind, we examined the reactions of propargyl carbonate 5b and
bromoallene 5c (Scheme 5). Unfortunately, these reactions gave
the desired spiroindoline 8a in only 8–14% yield. These results
therefore demonstrated that substrates of this type are less
effective for this reaction than propargyl chloride 5a.
E
E
E
OH
E
(f)
63%
(g)
E
E
•
Br
N
H
64%
•
6
7
5c
(E = CO2Et)
Br

3
EtO2C
ACCEPTED MANUSCRIPT
EtO2C
CO2Et
CO2Et
CO2Et
EtO2C
+
N
N
H
N
H
H
Ts
N
OCO Me
(±)-8a (14%)
9a (6%)
(0%)
5b
5c
2
•
(8%)
Br
Scheme 5. Reaction of carbonate 5b and bromoallene 5c.
Reaction conditions: Pd2(dba)3·CHCl3 (2.5 mol %), dppb (10
mol %), TsNH2 and Cs2CO3 in THF at rt.
Table 1. Optimization of the reaction conditions and the reaction with various nitrogen nucleophiles.
EtO2C
Pd cat.
ligand (10 mol %)
RNH2, base (2 equiv)
CO2Et
EtO2C
CO2Et
CO2Et
EtO2C
+
N
H
solvent
N
R
N
H
H
N
Cl
5a
8a–f
9a
(±)-
% yielda (product)
9a
temp
(°C)
time
(h)
entry
Pd (mol %)
ligand
RNH2 (equiv)
Base
solvent (M)
8
1
2
Pd(PPh3)4 (5)
Pd(dba)2 (5)
(PPh3)
dppfb
dppf
TsNH2 (1)
TsNH2 (1)
Cs2CO3
Cs2CO3
K2CO3
THF (0.1)
THF (0.1)
60
50
50
60
60
60
60
50
rt
24
0.5
3
0
20
5
47 (8a)
15 (8a)
0
3
Pd(dba)2 (5)
TsNH2 (1)
THF (0.1)
6
4
Pd(dba)2 (5)
dppf
TsNH2 (1)
CaCO3
NaHCO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
THF (0.1)
24
24
24
7
0
5
Pd(dba)2 (5)
dppf
TsNH2 (1)
THF (0.1)
0
0
6
Pd(dba)2 (5)
dppmc
dpped
dpppe
dppbf
dpppeg
dppb
dppb
dppb
dppb
dppb
dppb
dppb
dppb
dppb
TsNH2 (1)
THF (0.1)
0
17
62
6
7
Pd(dba)2 (5)
TsNH2 (1)
THF (0.1)
22 (8a)
29 (8a)
ca. 72 (8a)
37 (8a)
ca. 13 (8a)
ca. 59 (8a)
ca. 54 (8a)
72 (8a)
64 (8b)
55 (8c)
43 (8d)
68 (8e)
8
Pd(dba)2 (5)
TsNH2 (1)
THF (0.1)
1
9
Pd(dba)2 (5)
TsNH2 (1)
THF (0.1)
2.5
5
3
10
11
12
13
14
15
16
17
18
Pd(dba)2 (5)
TsNH2 (1)
THF (0.1)
50
70
rt
2
Pd(dba)2 (5)
TsNH2 (1)
dioxane (0.1)
DMF (0.1)
CH3CN (0.1)
THF (0.067)
THF (0.067)
THF (0.067)
THF (0.067)
THF (0.067)
THF (0.067)
20
2.5
2
3
Pd(dba)2 (5)
TsNH2 (1)
1
Pd(dba)2 (5)
TsNH2 (1)
40
rt
1
Pd2(dba)3·CHCl3 (2.5)
Pd2(dba)3·CHCl3 (2.5)
Pd2(dba)3·CHCl3 (2.5)
Pd2(dba)3·CHCl3 (2.5)
Pd2(dba)3·CHCl3 (2.5)
Pd2(dba)3·CHCl3 (2.5)
TsNH2 (1.5)
PhSO2NH2 (1.5)
MtsNH2h (1.5)
NsNH2 (1.5)
MsNH2 (1.5)
3
5
rt
5
6
rt
3.5
2
9
60
60
60
15
10
54
24
7
19
BnNH2 (1.5)
0 (8f)
a
b
c
d
e
Isolated yields.
1,1'-bis(diphenylphosphino)ferrocene
bis(diphenylphosphino)methane.
1,2-bis(diphenylphosphino)ethane.
1,3-
bis(diphenylphosphino)propane. f 1,4-bis(diphenylphosphino)butane. g 1,5-bis(diphenylphosphino)pentane. h Mts = 2,4,6-trimethylbenzenesulfonyl.
We next examined the scope and limitations of the reaction
using a series of different indole substrates (Table 2). N-
Substituted indoles 5d and 5e did not produce the spirocyclic
products (entries 1 and 2). In contrast, indoles bearing an
electron-withdrawing fluorine group (5f) or electron-donating
methoxy group (5h) at their 5-position reacted smoothly under
the optimized conditions to give the desired products 8i and 8k in
good yields (entries 3 and 5). However, when compound 5g
bearing a bromine group at the 5-position of the indole was used
as a substrate, a slightly lower yield (43%) of spiroindoline 8j
was observed. The lower yield observed in this case was
attributed to side reaction(s) involving the aryl bromide moiety of
the substrate, as well as the aryl bromide of the product 8j.
We then turned our attention to the selective synthesis of the
β-elimination product 9 (Table 3). It was envisaged that 9 could
be efficiently produced under the same reaction conditions in the
absence of an external nucleophile. This assumption was based
on the results of our previous reaction, where the use of 1,2-
bis(diphenylphosphino)ethane (dppe) as
a ligand afforded
spiroindole 9a as the major product in 62% yield (Table 1, entry
7). Contrary to our expectation, the treatment of 5a with
Pd2(dba)3·CHCl3 (2.5 mol %) and dppe (10 mol %) in the

4
Tetrahedron
BnNH2 (1.5)/
Cs2CO3 (2)
BnNH2 (1.5)/
Cs2CO3 (2)
BnNH2 (0.2)/
Cs2CO3 (2)
BnNH2 (1.5)/
Cs2CO3 (2)
presence of Cs2CO3 (2 equiv) at 70 °C afforded the desired
ACCEPTED MANUSCRIPT
6
7
8
5a
5a
5a
5/10
5/10
5/10
55
60
60
24
3
33 (9a)
68 (9a)
45 (9a)
product 9a in only 7% yield (Table 3, entry 1). Based on this
disappointing result, we carefully examined the reaction
parameters and screened a series of bases against the reaction
(entries 2–6), including Cs2CO3, Et3N, (i-Pr)2NEt (DIPEA) and
BnNH2 at 50–55 °C. Among them, a combination of BnNH2 and
Cs2CO3 gave a better result (33%, entry 6) than the reaction using
Cs2CO3 alone (entry 1). Furthermore, the reaction temperature
had a significant impact on the yield of 9a. For example, the
reaction reached completion within 3 h at a slightly elevated
temperature (60 °C) to afford the desired product in 68% yield
(Table 3, entry 7). Lowering the loading of BnNH2 (entry 8,
45%) or increasing the loading of the catalyst (entry 9, 64%) did
not improve the yield of 9a. It is noteworthy that the reaction
involving the use of BnNH2 as the only base afforded only a trace
amount of 9a (entry 10). Under the optimized conditions,
substituted indoles 5f and 5h afforded spiroindoles 9b and 9d,
respectively, in moderate to good yields (entries 11 and 13).
Furthermore, the brominated substrate 5g reacted under these
conditions to 9c, albeit in a lower yield (40%, entry 12).
4
9
5a
5a
5f
10/20
10/20
5/10
60
60
60
3
24
3
64 (9a)
trace (9a)
56 (9b)
10
11
BnNH2 (2)
BnNH2 (1.5)/
Cs2CO3 (2)
BnNH2 (1.5)/
Cs2CO3 (2)
BnNH2 (1.5)/
Cs2CO3 (2)
12
13
5g
5h
5/10
5/10
60
60
3
3
40 (9c)
74 (9d)
a Isolated yields.
E
E
E
E
Pd+Ln
Pd(0)
E
E
N
8
N
N
H
H
Table 2. Reaction of various indoles.a
Nu
base
Cl
A
5a
(E = CO2Et)
EtO2C
EtO2C
R2
CO2Et
CO2Et
CO2Et
R2
EtO2C
D'
b'
R2
E
E
E
E
E
H
c
E
+
N
N
N
R1
H
Pd+Ln
Ts
N
R1
c
b
Cl
b
Nu
a
5d–h
8g–k
9a–d
% yield (product)b
(±)-
N
E
N
9a
N
NuH
B
D
β
-hydride elimination
temp
(°C)
time
(h)
entry subst.
R1
R2
a
8
9
E
E
HB
HA
E
1
2
3
4
5
5d
5e
5f
Boc
Me
H
H
H
60
60
rt
24
24
3
0 (8g)
0 (8h)
71 (8i)
43 (8j)
71 (8k)
0 (9a)
0 (9a)
5 (9b)
6 (9c)
20 (9d)
E
E
Pd+Ln
e
F
d
Nu
e
Nu
N
N
H
(±)-
N
H
d
H
H
Nu
H
5g
5h
H
Br
60
rt
3
8
C
10
(±)-
H
OMe
2.5
a
Reactions were carried out using propargyl chloride 5d–h with
Figure 1. Proposed mechanism for palladium-catalyzed cascade
cyclization.
Pd2(dba)3·CHCl3 (2.5 mol %), dppb (10 mol %), Cs2CO3 (2 equiv) and TsNH2
(1.5 equiv) in THF (0.067 M). b Isolated yields.
Table 3 Synthesis of spiroindoles 9a–d.
A plausible mechanism for the cascade cyclization is shown in
Figure 1. Briefly, propargyl chloride would initially react with a
palladium catalyst to give the η3-propargylpalladium complex
A.1c,18 Intramolecular nucleophilic addition of the indole to the
central carbon atom of the η3-propargylpalladium A would give
η3-allylpalladium complex B.19 Deprotonation at the indole
nitrogen would be necessary for this step, considering that the N-
substituted substrates 5d and 5e did not react under the optimized
reaction conditions (Table 2, entries 1 and 2). The tetracyclic
EtO2C
CO2Et
CO2Et
R
Pd2(dba)3·CHCl3
dppe, base
EtO2C
R
THF
N
H
N
Cl
5a
5f
(R = H), (R = F)
9a
9b
(R = H), (R = F)
9c (R = Br), 9d (R = OMe)
5g (R = Br), 5h (R = OMe)
spiroindolines
8 and 10 would then be formed by the
[Pd]/dppe
entry subst.
temp
(°C)
time
(h)
% yield a
(product)
intermolecular nucleophilic attack of the external nucleophile via
path a and/or b. Path a represents the first intermolecular
nucleophilic attack on the imine carbon, which would be
followed by the allylic substitution reaction of intermediate C.
Depending on which carbons of the allylic moiety in C
participated in the cyclization (path d vs. e), the regioisomeric
products 8 and 10 would be formed. Path b would occur to give
intermediate D if the intermolecular allylic substitution reaction
dominated over the addition of the nucleophile to the imine, with
spiroindoline 10 being formed as the major product. In this step,
the occurrence of an intermolecular reaction at the more hindered
base (equiv)
(mol %)
1
2
3
5a
5a
5a
5/10
5/10
5/10
Cs2CO3 (2)
Et3N (2)
70
55
55
4
24
24
7
3
4
(9a)
(9a)
(9a)
DIPEA (2)
Et3N (1.5)/
Cs2CO3 (2)
DIPEA (1.5)/
Cs2CO3 (2)
4
5
5a
5a
5/10
5/10
55
55
24
20
11 (9a)
21 (9a)

5
22 (34)
carbon (path b') would be another possible pathway. In contrast,
ACCEPTED MANUSCRIPT
4
(R)-BINAP
BnNH2
BnNH2
4
6
-
-
β-hydride elimination from B would produce diene 9a (path c).
When a sulfonamide was used as the external nucleophile,
tetracyclic spiroindoline 8 was obtained without producing any of
the regioisomeric spiroindoline 10. This regioselectivity was
most likely affected by steric hindrance during the reactions
involved in path a, in that the product 10 as well as the transition
state from C to 10 would be destabilized by unfavorable steric
interactions between the indole proton at the 4-position (HA) and
the flagpole hydrogen (HB) of the cyclohexene moiety. In
contrast, the reaction using carbon nucleophile would favor the
formation of regioisomer 10 (Scheme 4). This can be explained
by considering both the sterically congested and soft
characteristics of the carbon nucleophiles. Thus, the sterically
hindered imine carbon (having a quaternary carbon at the
neighboring position) would induce the nucleophilic attack of the
soft carbon nucleophiles at the η3-allylpalladium moiety of B to
form 10 via intermediate D (path b).20
ca. 34%
5
(S)-SYNPHOS
(40)
6
(R)-SEGPHOS
(R)-DM-SEGPHOS
(R)-DIFLUORPHOS
(R)-SEGPHOS
BnNH2
BnNH2
6
4
-
12 (53)
24 (51)
5.5 (34)
14 (73)
15 (71)
4 (77)
7
-
8
BnNH2 24
-
9
TsNH2
24
14
20
24 (56)
38 (65)
16 (30)
TsNH2,
H2O e
TsNH2,
H2O e
10
11
(R)-SEGPHOS
(R)-DM-SEGPHOS
a
Reactions were carried out using propargyl chloride 5a with
Pd2(dba)3 CHCl3 (2.5 mol %), chiral ligand (10 mol %), Cs2CO3 (2 equiv) and
other reagent (1.5 equiv) in THF (0.067 M). b One of the enantiomers of 8a is
·
c
d
shown in the Scheme. Isolated yields. Determined by HPLC analysis
(Chiralcel IC-3) e Reaction was carried out with addition of H2O (1 equiv).
Finally, we attempted to carry out a catalytic asymmetric
version of the current reaction. To the best of our knowledge,
only two catalytic asymmetric reactions have been reported to
date for the propargylpalladium chemistry. Rawal et al.14a
reported an asymmetric version of the aforementioned
intermolecular spirocyclization of a tryptamine-derived substrate
(Scheme 2, eq 4) and obtained the spiroindole (Nu = NR) in 16%
ee using (R)-BINAP. You et al.14b found that (R)-SEGPHOS
showed more efficient asymmetric induction, affording the
corresponding spiroindole [Nu = C(CO2Et)2] in 52% ee. The
enantio-determining step in these reactions would be the allylic
substitution step, where the chiral spirocenter would be formed
by the nucleophilic reaction of the indole moiety. We screened a
series of chiral ligands against β-hydride elimination reaction to
PPh2
PPh2
N
O
O
PPh2
PPh2
PPh2
(R)-QUINAP
(S,S)-DIOP
(R)-CHIRAPHOS
O
O
F
F
O
O
PPh2
PPh2
PPh2
PPh2
O
O
PPh2
PPh2
F
F
O
O
(R)-BINAP
(R)-DIFLUORPHOS
(S)-SYNPHOS
produce spiroindole 9a (Table 4, entries 1–8). When (R)-
O
O
SEGPHOS and (R)-DM-SEGPHOS were used, these reactions
produced spiroindole 9a with better enantioselectivities (51–53%
ee, entries 6 and 7), although the yields of 9a were unsatisfactory
(12–24%). We thus proceeded to examine the synthesis of
tetracyclic spiroindoline 8a using (R)-SEGPHOS and (R)-DM-
SEGPHOS. Fortunately, the palladium-catalyzed reaction of 5a
with TsNH2 in the presence of H2O (1 equiv) using (R)-
SEGPHOS gave the tetracyclic spiroindoline 8a (38% yield) and
spiroindole 9a (15% yield) with moderate enantioselectivities
(65–71% ee, entry 10). It should be noted that the addition of
H2O to the reaction was necessary for a high level of
reproducibility. This result therefore highlights the great potential
of a propargylpalladium complex in terms of its use in catalytic
asymmetric reactions.
O
O
O
PAr2
PPh2
PPh2
Ar =
PAr2
O
O
O
(R)-DM-SEGPHOS
(R)-SEGPHOS
3. Conclusion
In conclusion, we have developed the palladium-catalyzed
spirocyclization of propargyl chlorides using an external
nucleophile for the divergent synthesis of tetracyclic
spiroindolines. When this reaction was conducted in the absence
of an appropriate external nucleophile, it gave the corresponding
spiroindoles through β-hydride elimination. The regioselectivity
of this reaction was found to be dependent on the external
nucleophiles employed in the reaction. We have also investigated
an asymmetric version of this reaction to produce spiroindole
derivatives in 65–71% ee. This methodology would provide a
novel approach to biologically active spiroindole derivatives.
Table 4. Optimization of the catalytic asymmetric reaction
conditions. a,b
EtO2C
CO2Et
EtO2C
CO2Et
CO2Et
Ts
EtO2C
+
N
N
H
N
H
H
N
4. Experimental
Cl
5a
8a
9a
General Methods.
% yieldc (% ee)d
other
time
entry
chiral ligand
All reactions under argon atmosphere were performed using
syringe-septum cap techniques and all glassware was dried in an
oven at 80 °C for 2 h prior to use. For flash chromatography,
silica gel (Wakosil C-200E: Wako Pure Chemical Industries,
Ltd) or NH2 silica gel (Chromatorex NH-DM1020: Fuji Silysia
Chemical Ltd.) was employed. Thin layer chromatography was
reagent
(h)
8a
9a
1
2
3
(R)-QUINAP
(S,S)-DIOP
BnNH2
5
-
trace
BnNH2
BnNH2
3.5
7
-
-
mixture
13 (13)
(R)-CHIRAPHOS

6
Tetrahedron
performed on Merck TLC silica gel 60 F254 or Wako NH2 silica
PrOH at 0.75 mL/min, t1 = 16.03 min (major enantiomer), t2 =
ACCEPTED MANUSCRIPT
gel 60 F254 plate (layer thickness 0.25 mm), which were
developed using standard visualizing agents: UV fluorescence
(254 nm) and anisaldehyde with heating. Melting points were
measured by a hot stage melting point apparatus (uncorrected).
1H NMR spectra were recorded using a JEOL AL-400 or JEOL
ECA-500 spectrometer, and chemical shifts are reported in δ
(ppm) relative to TMS as internal standard. 13C NMR spectra
were recorded using a JEOL AL-400 or JEOL ECA-500
39.26 min (minor enantiomer)]}.
Diethyl 2-[(1H-indol-3-yl)methyl]-2-(4-chlorobut-2-yn-1-
yl)malonate (5a).
1
Brown oil; IR (neat): 3409 (NH), 2242 (C≡C), 1729 (C=O); H
NMR (500 MHz, CDCl3) δ 1.23 (t, J = 7.3 Hz, 6H), 2.83 (t, J =
2.2 Hz, 2H), 3.57 (s, 2H), 4.10-4.25 (m, 6H), 7.03 (d, J = 2.4 Hz,
1H), 7.09 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H), 7.16 (ddd, J = 8.0, 7.1,
1.0 Hz, 1H), 7.32 (dd, J = 8.0, 1.0 Hz, 1H), 7.66 (dd, J = 8.0, 1.0
Hz, 1H), 8.08 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 14.0
(2C), 23.1, 27.3, 30.8, 58.2, 61.7 (2C), 78.3, 82.9, 109.6, 111.0,
118.9, 119.5, 122.0, 123.4, 128.1, 135.8, 170.1 (2C). HRMS
(FAB) calcd C20H21ClNO4: [M – H]–, 374.1165; found: [M – H]–,
374.1168.
1
spectrometer and referenced to the residual solvent signal. H
NMR spectra are tabulated as follows: chemical shift,
multiplicity (b = broad, s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), number of protons, and coupling
constant(s). Exact mass (HRMS) spectra were recorded on a
JMS-HX/HX 110A mass spectrometer. Infrared (IR) spectra
were obtained on a JASCO FT/IR-4100 FT-IR spectrometer with
JASCO ATR PRO410-S.
Diethyl 11-methylene-1-tosyl-2,3,10,10a-tetrahydro-1H-2,5a-
methanoazepino[2,3-b]indole-4,4(5H)-dicarboxylate (8a).
Colorless solid; mp 164–165 °C; IR (neat): 3361 (NH), 1729
General procedure for the synthesis of tetracyclic
spiroindolines (8).
1
(C=O); H NMR (500 MHz, CDCl3) δ 1.24 (t, J = 7.1 Hz, 3H),
To a stirred mixture of 5a (30 mg, 0.080 mmol) and TsNH2 (20.5
mg, 0.12 mmol) in THF were added Pd2(dba)3·CHCl3 (2.1 mg,
3.9 µmol, 2.5 mol %), dppb (3.4 mg, 8.0 µmol, 10 mol %), and
Cs2CO3 (52 mg, 0.16 mmol) at room temperature under argon.
The mixture was stirred for 3 h at this temperature, and H2O was
added to the mixture. The whole was extracted with EtOAc. The
extract was washed with H2O, brine and dried over MgSO4. The
filtrate was concentrated under reduced pressure to give an oily
residue, which was purified by flash chromatography over NH2
silica gel with n-hexane–EtOAc (8:1) to give 8a (29.3 mg, 72%
yield) and 9a (1.4 mg, 5.2% yield).
1.35 (t, J = 7.1 Hz, 3H), 2.38 (s, 3H), 2.40 (d, J = 13.7 Hz, 1H),
2.48 (d, J = 13.7 Hz, 1H), 3.22 (d, J = 13.7 Hz, 2H), 4.09-4.10
(m, 1H), 4.13-4.39 (m, 4H), 4.44 (s, 1H), 4.66 (d, J = 4.1 Hz,
1H), 4.76 (s, 1H), 6.05 (d, J = 4.6 Hz, 1H), 6.64 (d, J = 7.8 Hz,
1H), 6.82 (dd, J = 7.8, 7.8 Hz, 1H), 7.07-7.15 (m, 2H), 7.25 (d, J
= 8.2 Hz, 2H), 7.86 (d, J = 8.2 Hz, 2H); 13C NMR (125 MHz,
CDCl3) δ 13.9 (2C), 21.4, 37.7, 39.9, 52.3, 57.7, 61.3, 62.1, 62.6,
84.0, 103.4, 110.7, 119.3, 122.9, 127.4 (3C), 129.0, 129.6 (2C),
137.6, 143.2, 148.8, 151.7, 170.9, 171.3. HRMS (FAB) calcd
C27H30N2O6S: [M+], 510.1825; found: [M+], 510.1832.
Diethyl 2-methylenespiro[cyclohexane-1,3’-indol]-3-ene-5,5-
dicarboxylate (9a).
Yellow oil; IR (neat): 1732 (C=O); H NMR (500 MHz, CDCl3)
General procedure for the synthesis of spiroindoles (9).
1
To a stirred mixture of 5a (30 mg, 0.080 mmol) and BnNH2 (13
µL, 0.12 mmol) in THF were added Pd2(dba)3·CHCl3 (2.1 mg,
3.9 µmol, 2.5 mol %), dppe (3.2 mg, 8.0 µmol, 10 mol %), and
Cs2CO3 (52 mg, 0.16 mmol) at 60 °C under argon. The mixture
was stirred for 3 h at this temperature, and H2O was added to the
mixture. The whole was extracted with EtOAc. The extract was
washed with H2O, brine and dried over MgSO4. The filtrate was
concentrated under reduced pressure to give an oily residue,
which was purified by flash chromatography over silica gel with
n-hexane–EtOAc (9:1 to 8:1) to give 9a (18.5 mg, 68% yield).
δ 1.22-1.28 (m, 6H), 2.37 (d, J = 14.3 Hz, 1H), 2.72 (d, J = 14.3
Hz, 1H), 4.16-4.30 (m, 4H), 4.56 (s, 1H), 4.87 (s, 1H), 6.18 (d, J
= 10.3 Hz, 1H), 6.57 (d, J = 10.3 Hz, 1H), 7.27-7.35 (m, 2H),
7.37-7.43 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.95 (s, 1H); 13C
NMR (125 MHz, CDCl3) δ 13.9 (2C), 35.0, 55.5, 60.8, 62.3 (2C),
114.8, 121.5, 122.9, 125.4, 126.5, 128.5, 131.6, 137.6, 141.3,
155.4, 169.8, 170.1, 173.9. HRMS (FAB) calcd C20H22NO4: [M +
H]+, 340.1549; found: [M + H]+, 340.1555.
2,2-Diethyl 6,6-dimethyl 3,5,6a,7-tetrahydro-1H-indeno[1,7a-
b]indole-2,2,6,6-tetracarboxylate (10a).
Yellow oil; IR (neat): 1735 (C=O); H NMR (500 MHz, CDCl3)
Asymmetric synthesis of spiroindoline (8a) and spiroindole
(9a).
1
δ 1.13 (t, J = 7.2 Hz, 3H), 1.23-1.28 (m, 3H), 2.53 (d, J = 14.9
Hz, 1H), 2.66-2.90 (m, 5H), 3.68 (s, 3H), 3.73 (s, 3H), 4.00-4.34
(m, 5H), 4.76 (s, 1H), 5.70-5.76 (m, 1H), 6.53 (d, J = 8.0 Hz,
1H), 6.67 (dd, J = 8.0, 8.0 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.99
(dd, J = 8.0, 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 13.8,
13.9, 29.6, 29.7, 38.6, 39.9, 52.6, 52.9, 53.9, 54.7, 61.5, 65.6.,
74.2, 109.4, 118.0, 119.4, 123.6, 128.2, 135.0, 140.9, 149.6,
169.3, 170.6, 171.0, 171.8. HRMS (FAB) calcd C25H29NO8:
[M+], 471.1893; found: [M+] , 471.1901.
To a stirred mixture of 5a (30 mg, 0.080 mmol), TsNH2 (20.5
mg, 0.12 mmol) and H2O (1.4µl, 0.080) in THF were added
Pd2(dba)3·CHCl3 (2.1 mg, 3.9 µmol, 2.5 mol %), (R)-SEGPHOS
(4.9 mg, 8.0 µmol, 10 mol %), and Cs2CO3 (52 mg, 0.16 mmol)at
60 °C under argon. The mixture was stirred for 14 h at this
temperature, and H2O was added to the mixture. The whole was
extracted with EtOAc. The extract was washed with H2O, brine
and dried over MgSO4. The filtrate was concentrated under
reduced pressure to give an oily residue, which was purified by
flash chromatography over NH2 silica gel with n-hexane–EtOAc
(10:1 to 8:1) to give 8a (15.7 mg, 38% yield, 65% ee [HPLC,
Chiralcel-IC-3 column eluting with 65:35 n-hexane/i-PrOH at
0.75 mL/min, t1 = 17.98 min (major enantiomer), t2 = 26.74 min
(minor enantiomer)]} and 9a {4.1 mg, 15% yield and 71% ee
[HPLC, Chiralcel-IC-3 column eluting with 65:35 n-hexane/i-
Diethyl 6,6-diacetyl 5,6,6a,7-tetrahydro-1H-indeno[1,7a-
b]indole-2,2(3H)-dicarboxylate (10b).
1
Yellow oil; IR (neat): 3406 (NH), 1728 (C=O); H NMR (500
MHz, CDCl3) δ 1.15 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H),
2.01 (s, 3H), 2.18 (s, 3H), 2.37 (d, J = 14.7 Hz, 1H), 2.64-2.73
(m, 3H), 2.84-2.91 (m, 2H), 4.04-4.20 (m, 4H), 4.43 (br s, 1H),

7
16. (a) Montury, M.; Goré, J. Synth. Commun. 1980, 10, 873. (b) Elsevier,
4.83 (s, 1H), 5.70-5.75 (m, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.70
(dd, J = 8.0, 8.0 Hz, 1H), 6.91 (dd, J = 8.0, 1.1 Hz, 1H), 7.00
(ddd, J = 8.0, 8.0, 1.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
13.8, 13.9, 26.3, 28.8, 29.5, 36.3, 40.4, 54.2, 55.0, 61.6 (2C),
73.3., 79.5, 110.2, 117.6, 119.8, 123.4, 128.3, 136.0, 141.1,
149.4, 170.8, 171.7, 203.1, 204.8. HRMS (FAB) calcd
C25H29NO6: [M+], 439.1995; found: [M+], 439.2000.
ACCEPTED MANUSCRIPT
C. J.; Meijer, J.; Tadema, G.; Stehouwer, P. M.; Bos, H. J. T.; Vermeer,
P. J. Org. Chem. 1982, 47, 2194.
17. Pd2(dba)3･CHCl3 is one of the most efficient palladium(0) sources, see:
Zalesskiy, S. S.; Ananikov, V. P. Organometallics 2012, 31, 2302.
18. (a) Ohno, H.; Hamaguchi, H.; Ohata, M.; Tanaka, T. Angew. Chem., Int.
Ed. 2003, 42, 1749. (b) Ohno, H.; Hamaguchi, H.; Ohata, M.; Kosaka,
S.; Tanaka, T. J. Am. Chem. Soc. 2004, 126, 8744. For selected related
works reported by our group, see: (c) Ohno, H.; Okano, A.; Kosaka, S.;
Tsukamoto, K.; Ohata, M.; Ishihara, K.; Maeda, H.; Tanaka, T.; Fujii, N.
Org. Lett. 2008, 10, 1171. (d) Inuki, S.; Yoshimitsu, Y.; Oishi, S.; Fujii,
N.; Ohno, H. Org. Lett. 2009, 11, 4478. (e) Okano, A.; Oishi, S.;
Tanaka, T.; Fujii, N.; Ohno, H. J. Org. Chem. 2010, 75, 3396. (f)
Yoshimitsu, Y.; Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2013,
15, 3046.
19. For a recent review on related catalytic dearomatization reactions, see:
Zhuo, C.-X.; Zhang, W.; You, S.-L. Angew. Chem. Int. Ed. 2012, 51,
12662.
20. At present, formation of 10 through intermediate C (path e) cannot be
completely excluded. We performed an additional experiment with a
separately prepared propargyl tosylamide (SN2 adduct from 5a) to
confirm that this reaction does not proceed via the first SN2 reaction. In
addition, the tetracyclic spiroindolines 8a was not obtained from the
elimination product 9a under the reaction conditions.
Acknowledgement
This work was supported by
a
Grant-in-Aid for the
Encouragement of Young Scientists (A) from JSPS, Japan;
Platform for Drug Design, Discovery, and Development from
MEXT, Japan; research Grants from Takeda Science Foundation.
A.I. and S.I. are grateful for Research Fellowships from the Japan
Society for the Promotion of Science (JSPS) for Young Scientists.
References and Foot notes
†
Current address: Department of Chemistry, Faculty of Science and
Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama,
Kanagama 223-8522, Japan
Supplementary Material
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ACCEPTED MANUSCRIPT
Supplementary Material
Convenient synthesis of spiroindole derivatives via palladium-catalyzed
cyclization of propargyl chlorides
Iwata Akira, Shinsuke Inuki, Shinya Oishi, Nobutaka Fujii,* and Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku,
Kyoto 606-8501, Japan
E-mail: hohno@pharm.kyoto-u.ac.jp; nfujii@pharm.kyoto-u.ac.jp
Table of contents
Optimization of reaction conditions ···················································································· S2
Experimental section ······································································································ S3
NMR spectra ················································································································ S12
HPLC chart ·················································································································· S39
S1

ACCEPTED MANUSCRIPT
Optimization of reaction conditions
(Equivalents and concentrations of TsNH2 and Cs2CO3)
Pd2(dba)3·CHCl3
(2.5 mol %)
EtO2C
CO2Et
CO2Et
EtO2C
EtO2C
dppb (10 mol %)
TsNH2, Cs2CO3
CO2Et
+
solvent, rt
N
N
H
N
N
H
Ts
Cl
5a
8a
9a
% yield a
entry
TsNH2 (equiv)
Cs2CO3 (equiv)
solvent (M)
8a
9a
1
2
3
4
5
TsNH2 (1)
TsNH2 (1.5)
TsNH2 (1.5)
TsNH2 (1.5)
TsNH2 (1.5)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (1)
Cs2CO3 (2)
Cs2CO3 (1)
THF (0.1)
THF (0.1)
59
68
69
72
61
7
4
5
5
9
THF (0.1)
THF (0.067)
THF (0.067)
a Isolated yields.
S2

ACCEPTED MANUSCRIPT
Experimental Section
Preparation of the substrates.
The known compounds S2 (R = H,1 Br,2 OMe1), S3 (R =H, Br, OMe),3 S4 (R =H, Br, OMe)3 and 63 were
prepared according to the literature procedure.
1 Jones, D. T.; Artman, G. D.; Williams, R. M. Tetrahedron Lett. 2007, 48, 1291.
2 Bandini, M.; Eichholzer, A. Angew. Chem. Int. Ed. 2009, 48, 9533.
3 Cera, G.; Crispino, P.; Monari, M.; Bandini, M. Chem. Commun. 2011, 47, 7803.
4 Miyake, Y.; Endo, S.; Moriyama, T.; Sakata, K.; Nishibayashi, Y. Angew. Chem. Int. Ed. 2013, 52, 1758.
General procedure for the synthesis of malonates S2.
CO2Et
CO2Et
R
diethyl malonate
ethyl propiolate
R
N
Et2O
N
N
H
H
S2
S1
To a stirred mixture of S1 (R = H, F, Br, or OMe; 5.20 mmol) and diethyl malonate (4.85 mmol) in Et2O (2.6
mL) was added dropwise ethyl propiolate (5.20 mmol) at room temperature. The mixture was stirred for 45 min at
this temperature, followed by quenching with H2O. The whole was extracted with Et2O. The extract was washed
successively with H2O and brine, and dried over MgSO4. The filtrate was concentrated under reduced pressure to
give an oily residue, which was purified by flash chromatography over silica gel with n-hexane–EtOAc (8:1) to
give the corresponding S2 as a pale yellow needle. The NMR spectra of the known compounds (R = H,1 Br,2 and
OMe1) were identical with those of previous report.
Diethyl 2-[(5-fluoro-1H-indol-3-yl)methyl]malonate (S2; R = F).
1
Pale yellow needle (1.27 g, 77% yield): mp 60–61 °C; IR (neat): 3410 (NH), 1726 (C=O); H NMR (500 MHz,
CDCl3)  1.21 (t, J = 7.2 Hz, 6H), 3.33 (d, J = 7.7 Hz, 2H), 3.72 (t, J = 7.7 Hz, 1H), 4.12-4.20 (m, 4H), 6.93 (ddd, J
= 9.2, 9.2, 2.5 Hz, 1H), 7.09 (d, J = 2.3 Hz, 1H), 7.23-7.26 (m, 2H), 8.00 (br s, 1H); 13C NMR (125 MHz, CDCl3) 
13.9 (2C), 24.4, 52.9, 61.4 (2C), 103.5 (d, J = 24.0 Hz), 110.4 (d, J = 26.4 Hz), 111.8 (d, J = 9.6 Hz), 112.3 (d, J = 4.8
Hz) 124.4, 127.5 (d, J = 9.6 Hz), 132.6, 157.8 (d, J = 235 Hz), 169.2 (2C). Anal. Calcd for C16H18FNO4: C, 62.53; H,
5.90; N, 4.56. Found: C, 62.41; H, 5.93; N, 4.50.
General procedure for the synthesis of malonates S3.
EtO2C
CO2Et
CO2Et
CO2Et
R
R
Br
NaH
+
THF, 0 °C to rt
N
OTBS
N
H
H
OTBS
S3
S2
propargyl bromide 1
S3

ACCEPTED MANUSCRIPT
To a solution of S2 (R = H, F, Br, or OMe; 3.71 mmol) in THF was added NaH (60% suspension in mineral oil; 7.42
mmol) at 0 °C. The suspension was stirred for 30 min at 0 °C, then propargyl bromide 1 (4.45 mmol) in THF was
added dropwise. The reaction was warmed up to room temperature and stirred for 2 h, followed by quenching with
H2O. The whole was extracted with EtOAc. The extract was washed successively with H2O and brine, and dried
over MgSO4. The filtrate was concentrated under reduced pressure to give an oily residue, which was purified by
flash chromatography over silica gel with n-hexane–EtOAc (5:1) to give the corresponding S3 as a colorless oil.
The NMR spectra of the known compounds (R = H, Br, and OMe) were identical with those of previous report.3
Diethyl 2-{4-[(tert-butyldimethylsilyl)oxy]but-2-yn-1-yl}-2-[(5-fluoro-1H-indol-3-yl)methyl]malonate (S3; R =
F).
Colorless oil (682 mg, 38%): IR (neat): 3387 (NH), 2332 (CC), 1736 (C=O); 1H NMR (500 MHz, CDCl3)  0.14
(s, 6H), 0.92 (s, 9H), 1.23 (t, J = 7.0 Hz, 6H), 2.81 (t, J = 2.1 Hz, 2H), 3.51 (s, 2H), 4.10-4.22 (m, 4H), 4.37 (t, J =
2.1 Hz, 2H), 6.90 (ddd, J = 9.0, 9.0, 2.5 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 7.21 (dd, J = 9.0, 4.3 Hz, 1H), 7.29 (dd, J
= 9.9, 2.5 Hz, 1H), 8.12 (br s, 1H); 13C NMR (125 MHz, CDCl3)  –5.2 (2C), 13.9 (2C), 18.3, 23.1, 25.8 (3C), 27.3,
51.8, 58.0, 61.6 (2C), 80.2, 82.4, 103.8 (d, J = 24.0 Hz), 110.0 (d, J = 4.8 Hz), 110.4 (d, J = 26.4 Hz), 111.6 (d, J = 9.6
Hz), 125.3, 128.5 (d, J = 9.6 Hz), 132.3, 157.9 (d, J = 234 Hz), 170.1 (2C). HRMS (FAB) calcd C26H36FNO5Si: [M+],
489.2347; found: [M+], 489.2350.
General procedure for the synthesis of propargyl alcohols S4.
EtO2C
EtO2C
CO2Et
CO2Et
R
R
TBAF
THF, 0 °C
N
N
H
H
OTBS
S3
OH
S4
To a stirred solution of S3 (1.30 mmol) in THF was added TBAF (1.00 M solution in THF; 1.43 mL, 1.43
mmol) at 0 °C. The mixture was stirred for 1.5 h at this temperature and quenched by addition of saturated NH4Cl.
The whole was extracted with EtOAc. The extract was washed with H2O and brine, and dried over MgSO4. The
filtrate was concentrated under reduced pressure to give an oily residue, which was purified by flash
chromatography over silica gel with n-hexane–EtOAc (3:1) to give the corresponding S4 as a pale yellow oil. The
NMR spectra of the known compounds (R = H, Br, and OMe) were identical with those of previous report.3
Diethyl 2-[(5-fluoro-1H-indol-3-yl)methyl]-2-(4-hydroxybut-2-yn-1-yl)malonate (S4; R = F).
Yellow oil (485 mg, 99% yield): IR (neat): 3410 (NH), 3403 (OH), 2254 (CC), 1720 (C=O); 1H NMR (500 MHz,
CDCl3)  1.24 (t, J = 7.2 Hz, 6H), 1.97 (s, 1H), 2.80 (s, 2H), 3.51 (s, 2H), 4.11-4.25 (m, 4H), 4.31 (s, 2H), 6.90
(ddd, J = 8.9, 8.9, 2.5 Hz, 1H), 7.08 (d, J = 2.3 Hz, 1H), 7.22 (dd, J = 8.9, 4.4 Hz, 1H), 7.29 (dd, J = 10.0, 2.5 Hz,
1H), 8.19 (br s, 1H); 13C NMR (125 MHz, CDCl3)  13.9 (2C), 23.1, 27.3, 51.2, 58.0, 61.7 (2C), 81.4, 82.2, 103.7
S4

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(d, J = 23.0 Hz), 109.7 (d, J = 4.8 Hz), 110.4 (d, J = 25.9 Hz), 111.7 (d, J = 10.5 Hz), 125.4, 128.5 (d, J = 11.5 Hz),
132.3, 157.9 (d, J = 235 Hz), 170.2 (2C). HRMS (FAB) calcd C20H22FNO5: [M+], 375.1482; found: [M+], 375.1478.
General procedure for the synthesis of propargyl chloride 5a and 5f-h.
EtO2C
EtO2C
CO2Et
CO2Et
R
R
NCS, PPh3
CH2Cl2
N
N
H
H
OH
S4
Cl
5a
5f
(R = H), (R = F)
5g (R = Br), 5h (R = OMe)
To a stirred mixture of a propargyl alcohol S4 (1.0 equiv) and PPh3 (1.5 equiv) in CH2Cl2 was added NCS (1.2
equiv) in CH2Cl2 at room temperature. The mixture was stirred for 1.5–3 h at this temperature and quenched by
addition of H2O. The whole was extracted with EtOAc. The extract was washed with H2O, brine and dried over
MgSO4. The filtrate was concentrated under reduced pressure to give an oily residue, which was purified by flash
chromatography over silica gel to give the corresponding propargyl chloride 5.
Diethyl 2-(4-chlorobut-2-yn-1-yl)-2-[(5-fluoro-1H-indol-3-yl)methyl]malonate (5f).
EtO2C
CO2Et
F
Brown oil. Flash chromatography: n-hexane–EtOAc = 5:1. Yield = 87%.
IR (neat): 3407 (NH), 2238 (CC), 1727 (C=O); 1H NMR (500 MHz, CDCl3)  1.25 (t, J
= 7.4 Hz, 6H), 2.82 (t, J = 2.3 Hz, 2H), 3.51 (s, 2H), 4.13-4.24 (m, 6H), 6.90 (ddd, J =
9.0, 9.0, 2.5 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 7.21 (dd, J = 9.0, 4.3 Hz, 1H), 7.29 (dd, J
= 9.0, 2.5 Hz, 1H), 8.17 (br s, 1H); 13C NMR (125 MHz, CDCl3)  13.9 (2C), 23.1, 27.4,
N
H
Cl
5f
30.7, 58.0, 61.8 (2C), 78.6, 82.7, 103.8 (d, J = 24.0 Hz), 109.7 (d, J = 4.8 Hz), 110.5 (d, J = 26.4 Hz), 111.7 (d, J = 9.6
Hz), 125.3, 128.5 (d, J = 9.6 Hz), 132.3, 157.9 (d, J = 235 Hz), 170.0 (2C). HRMS (FAB) calcd C20H21ClFNO4: [M+],
393.1143; found: [M+], 393.1147.
Diethyl 2-[(5-bromo-1H-indol-3-yl)methyl]-2-(4-chlorobut-2-yn-1-yl)malonate (5g).
EtO2C
CO2Et
Br
Brown oil. Flash chromatography: n-hexane–EtOAc = 4:1. Yield = 73%.
IR (neat): 3384 (NH), 2238 (CC), 1727 (C=O); 1H NMR (500 MHz, CDCl3)  1.27 (t,
J = 7.2 Hz, 6H), 2.80 (t, J = 2.3 Hz, 2H), 3.52 (s, 2H), 4.15-4.25 (m, 6H), 7.06 (d, J =
2.4 Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 7.23 (dd, J = 8.6, 1.9 Hz, 1H), 7.75 (d, J = 1.9 Hz,
1H), 8.17 (br s, 1H); 13C NMR (125 MHz, CDCl3)  14.0 (2C), 23.1, 27.2, 30.7, 57.8,
N
H
Cl
5g
61.9 (2C), 78.7, 82.6, 109.3, 112.5, 112.9, 121.5, 124.8, 124.9, 129.7, 134.4, 169.9 (2C). HRMS (FAB) calcd
C20H21BrClNO4: [M+], 453.0342; found: [M+], 453.0345.
S5

ACCEPTED MANUSCRIPT
Diethyl 2-(4-chlorobut-2-yn-1-yl)-2-[(5-methoxy-1H-indol-3-yl)methyl]malonate
EtO2C
CO2Et
MeO
(5h).
Brown oil. Flash chromatography: n-hexane–EtOAc = 4:1. Yield = 70%.
N
1
H
IR (neat): 3417 (NH), 2239 (CC), 1732 (C=O); H NMR (500 MHz, CDCl3)  1.23
Cl
(t, J = 7.0 Hz, 6H), 2.85 (t, J = 2.0 Hz, 2H), 3.53 (s, 2H), 3.86 (s, 3H), 4.14-4.24 (m,
5h
6H), 6.83 (dd, J = 8.9, 2.5 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H), 7.15 (d, J = 2.5 Hz, 1H),
7.20 (d, J = 8.9 Hz, 1H), 8.00 (br s, 1H); 13C NMR (125 MHz, CDCl3)  14.0 (2C), 23.1, 27.4, 30.7, 55.9, 58.5,
61.7 (2C), 78.3, 83.1, 100.5, 109.4, 111.8, 112.6, 124.1, 128.6, 131.0, 154.2, 170.0 (2C). HRMS (FAB) calcd
C21H24ClNO5: [M+], 405.1343; found: [M+], 405.1345.
EtO2C
EtO2C
CO2Et
CO2Et
ClCO2Me, pyridine
CH2Cl2, 0 °C
N
N
H
H
OCO2Me
5b
OH
4
Diethyl 2-[(1H-indol-3-yl)methyl]-2-{4-[(methoxycarbonyl)oxy]but-2-yn-1-yl}malonate (5b).
To a stirred mixture of 4 (50 mg, 0.135 mmol), pyridine (33 μL, 0.41 mmol) in CH2Cl2 (675 μL) was added
ClCO2Me (14 μL, 0.20 mmol) at 0 °C. The mixture was stirred for 30 min at this temperature and quenched by
addition of saturated NH4Cl. The whole was extracted with Et2O. The extract was washed with H2O, 1 N HCl, brine
and dried over MgSO4. The filtrate was concentrated under reduced pressure to give an oily residue, which was
purified by flash chromatography over silica gel with n-hexane–EtOAc (4:1) to give 5b as a brown oil (47.5 mg,
82% yield): IR (neat): 3407 (NH), 2252 (CC), 1731 (C=O); 1H NMR (500 MHz, CDCl3)  1.22 (t, J = 6.8 Hz, 6H),
2.82 (t, J = 2.3 Hz, 2H), 3.56 (s, 2H), 3.82 (s, 3H), 4.10-4.23 (m, 4H), 4.78 (t, J = 2.3 Hz, 2H), 7.01 (d, J = 2.3 Hz,
1H), 7.09 (ddd, J = 8.0, 8.0, 1.0 Hz, 1H), 7.15 (ddd, J = 8.0, 8.0, 1.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.63 (d, J =
8.0 Hz, 1H), 8.14 (br s, 1H); 13C NMR (125 MHz, CDCl3)  13.9 (2C), 23.0, 27.3, 55.1, 55.9, 58.1, 61.6 (2C), 77.3,
83.7, 109.5, 110.0, 118.8, 119.4, 122.0, 123.5, 128.1, 135.8, 155.2, 170.0 (2C). HRMS (FAB) calcd C22H25NO7: [M
– H]–, 414.1558; found: [M – H]–, 414.1564.
i) TrisCl, DMAP
EtO2C
EtO2C
OH
CH2Cl2
EtO2C
EtO2C
•
Br
ii) CuBr·Me2S, LiBr
THF, 50 ºC
6
7
Diethyl 2-(4-bromobuta-2,3-dien-1-yl)malonate (7)
To a stirred mixture of 6 (410 mg, 1.8 mmol) and TrisCl (1.36 g, 4.5 mmol) in CH2Cl2 (41 mL) was added DMAP
(770 mg, 6.3 mmol) at room temperature. The mixture was stirred for 3 h at this temperature. Concentration of the
mixture under reduced pressure followed by rapid filtration through a short pad of silica gel with Et2O to give a
crude sulfonate, which was used without further purification. CuBr·SMe2 (1.10 g, 5.4 mmol) and LiBr (465 mg,
S6

ACCEPTED MANUSCRIPT
0.373 mmol) were dissolved in THF (18 mL) at room temperature under argon, and the mixture was stirred for 30
min at this temperature. To this mixture was added a solution of the above crude sulfonate in THF (26 mL) at room
temperature. The mixture was allowed to warm to 50 °C and stirred at this temperature for 1.5 h, which was
quenched by addition of saturated NH4Cl and 28% NH4OH. The whole was extracted with EtOAc. The extract was
washed with H2O and brine and dried over MgSO4. The filtrate was concentrated under reduced pressure to give an
oily residue, which was purified by flash chromatography over silica gel with n-hexane–EtOAc (30:1) to give 7 as a
colorless oil (330 mg, 63% yield): IR (neat): 1958 (C=C=C), 1732 (C=O); 1H NMR (500 MHz, CDCl3)  1.26-1.31
(m, 6H), 2.73-2.78 (m, 2H), 3.52 (t, J = 7.4 Hz, 1H), 4.18-4.27 (m, 4H), 5.45 (dd, J = 12.6, 5.7 Hz, 1H), 6.00 (ddd,
J = 5.7, 2.4, 2.4 Hz, 1H); 13C NMR (125 MHz, CDCl3)  14.0 (2C), 21.2, 50.8, 61.7 (2C), 73.7, 97.3, 168.4, 168.5,
202.3; HRMS (FAB) calcd C11H16BrNO4: [M + H]+, 291.0232; found: [M + H]+, 291.0227.
EtO2C
CO2Et
N
EtO2C
EtO2C
ethyl propiolate
Et2O
+
•
Br
N
•
N
H
H
Br
1
5c
7
Diethyl 2-(4-bromobuta-2,3-dien-1-yl)-2-[(1H-indol-3-yl)methyl]malonate (5c).
To a stirred mixture of 7 (286 mg, 1.13 mmol) and 1 (306 mg, 1.05 mmol) in Et2O (1.1 mL) was added
dropwise ethyl propiolate (115 μL, 1.13 mmol) at room temperature. The mixture was stirred for 5 h at this
temperature, followed by quenching with H2O. The whole was extracted with EtOAc. The extract was washed
successively with H2O and brine, and dried over MgSO4. The filtrate was concentrated under reduced pressure to
give an oily residue, which was purified by flash chromatography over silica gel with n-hexane–EtOAc (8:1 to 5:1)
to give 5c as a brown oil (285 mg, 64% yield): IR (neat): 3393 (NH), 1957 (C=C=C), 1720 (C=O); 1H NMR (400
MHz, CDCl3)  1.18-1.24 (m, 6H), 2.75-2.77 (m, 2H), 3.42-3.52 (m, 2H), 4.10-4.22 (m, 4H), 5.34-5.41 (m, 1H),
5.92-5.97 (m, 1H), 7.03 (d, J = 2.3 Hz, 1H), 7.10 (dd, J = 8.0, 8.0 Hz, 1H), 7.17 (dd, J = 8.0, 8.0 Hz, 1H), 7.33 (d, J
= 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 8.05 (br s, 1H); 13C NMR (125 MHz, CDCl3)  13.9 (2C), 28.0, 31.9, 58.6,
61.5 (2C), 72.4, 95.7, 109.5, 111.1, 118.7, 119.4, 121.9, 123.4, 128.0, 135.7, 170.7 (2C), 203.6. HRMS (FAB) calcd
C20H22BrNO4: [M+], 419.0732; found: [M+], 419.0724.
EtO2C
EtO2C
CO2Et
CO2Et
Boc2O, Et3N
DMAP
N
N
CH2Cl2
H
Boc
Cl
Cl
5d
5a
Diethyl 2-{[1-(tert-butoxycarbony)-1H-indol-3-yl]methyl}-2-(4-chlorobut-2-yn-1-yl)malonate (5d).
To a stirred mixture of 5a (100 mg, 0.27 mmol), DMAP (3.2 mg, 0.027 mmol) and Et3N (46 μL, 0.32 mmol)
in CH2Cl2 (2.6 mL) was added Boc2O (70 mg, 0.32 mmol) at room temperature. The mixture was stirred for 30 min
S7

ACCEPTED MANUSCRIPT
at this temperature and quenched by addition of H2O. The whole was extracted with EtOAc. The extract was
washed with H2O, brine and dried over MgSO4. The filtrate was concentrated under reduced pressure to give an
oily residue, which was purified by flash chromatography over silica gel with n-hexane–EtOAc (10:1) to give 5d as
a colorless oil (91.0 mg, 72% yield): IR (neat): 1733 (C=O); 1H NMR (500 MHz, CDCl3)  1.26 (t, J = 7.3 Hz, 6H),
1.66 (s, 9H), 2.83 (t, J = 2.2 Hz, 2H), 3.49 (s, 2H), 4.14-4.25 (m, 6H), 7.22 (ddd, J = 7.6, 7.6, 1.0 Hz, 1H), 7.29
(ddd, J = 7.6, 7.6, 1.0 Hz, 1H), 7.41 (s, 1H), 7.63 (dd, J = 7.6, 1.0 Hz, 1H), 8.05-8.14 (br m, 1H); 13C NMR (125
MHz, CDCl3)  14.0 (2C), 23.2, 26.9, 28.2 (3C), 30.7, 57.9, 61.9 (2C), 78.7, 82.6, 83.7, 114.4, 115.2, 119.1, 122.5,
124.4, 124.9, 131.0, 135.1, 149.6, 169.7 (2C). HRMS (FAB) calcd C25H30ClNO6: [M+], 475.1762; found: [M+],
475.1758.
EtO2C
EtO2C
CO2Et
CO2Et
Me2SO4
KOH
N
N
DMF
H
Me
Cl
Cl
5e
5a
Diethyl 2-(4-chlorobut-2-yn-1-yl)-2-[(1-methyl-1H-indol-3-yl)methyl]malonate (5e).
To a stirred mixture of 5a (183 mg, 0.49 mmol) and KOH (64 mg, 0.97 mmol) in DMF (4.8 mL) was added
Me2SO4 (92 μL, 0.32 mmol) at room temperature. The mixture was stirred for 3.5 h at this temperature and
quenched by addition of H2O. The whole was extracted with EtOAc. The extract was washed with H2O, brine and
dried over MgSO4. The filtrate was concentrated under reduced pressure to give an oily residue, which was purified
by flash chromatography over silica gel with n-hexane–EtOAc (6:1) to give 5e as a pale yellow oil (100 mg, 53%
yield): IR (neat): 2252 (CC), 1735 (C=O); 1H NMR (500 MHz, CDCl3)  1.24 (t, J = 7.2 Hz, 6H), 2.83 (t, J = 2.3
Hz, 2H), 3.54 (s, 2H), 3.72 (s, 3H), 4.11-4.24 (m, 6H), 6.87 (s, 1H), 7.08 (ddd, J = 7.6, 7.6, 1.1 Hz, 1H), 7.18 (ddd,
J = 7.6, 7.6, 1.1 Hz, 1H), 7.23-7.26 (m, 1H), 7.63 (d, J = 7.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)  14.0 (2C),
23.1, 27.3, 30.8, 32.7, 58.2, 61.6 (2C), 78.2, 83.0, 107.8, 109.1, 118.9 (2C), 121.5, 128.1, 128.6, 136.6, 169.7 (2C).
HRMS (FAB) calcd C21H24ClNO4: [M+], 389.1394; found: [M+], 389.1390.
EtO2C
Diethyl 11-methylene-1-(phenylsulfonyl)-2,3,10,10a-tetrahydro-1H-2,5a-methanoazep-
ino[2,3-b]indole-4,4(5H)-dicarboxylate (8b).
CO2Et
SO2Ph
IR (neat): 3355 (NH), 1727 (C=O); 1H NMR (500 MHz, CDCl3)  1.24 (t, J = 7.2 Hz, 3H),
1.35 (t, J = 7.2 Hz, 3H), 2.41 (d, J = 13.6 Hz, 1H), 2.49 (d, J = 13.6 Hz, 1H), 3.21-3.27 (m,
2H), 4.10-4.12 (m, 1H), 4.13-4.40 (m, 4H), 4.46 (s, 1H), 4.67 (d, J = 4.0 Hz, 1H), 4.77 (s,
N
N
H
8b
1H), 6.07 (d, J = 4.0 Hz, 1H), 6.65 (d, J = 7.7 Hz, 1H), 6.83 (dd, J = 7.7, 7.7 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 7.14
(dd, J = 7.7, 7.7 Hz, 1H), 7.43-7.55 (m, 3H), 7.99 (d, J = 8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3)  13.9 (2C),
37.7, 39.9, 52.3, 57.7, 61.3, 62.1, 62.6, 84.0, 103.6, 110.8, 119.4, 122.9, 127.3 (2C), 127.4, 128.9 (2C), 129.0, 132.5,
140.5, 148.8, 151.6, 170.9, 171.2. HRMS (FAB) calcd C26H28N2O6S: [M+], 496.1668; found: [M+], 496.1668.
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ACCEPTED MANUSCRIPT
EtO2C
Diethyl 1-(mesitylsulfonyl)-11-methylene-2,3,10,10a-tetrahydro-1H-2,5a-methanoazep-
ino[2,3-b]indole-4,4(5H)-dicarboxylate (8c).
CO2Et
Mts
IR (neat): 3377 (NH), 1728 (C=O); 1H NMR (500 MHz, CDCl3)  1.22-1.28 (m, 6H), 2.31
(s, 3H), 2.38 (d, J = 14.5 Hz, 1H), 2.64 (s, 6H), 2.73 (dd, J = 13.7, 2.9 Hz, 1H), 3.08 (dd, J
= 14.5, 2.9 Hz, 1H), 3.21 (d, J = 13.7 Hz, 1H), 4.02 (d, J = 4.0 Hz, 1H), 4.10-4.33 (m, 4H),
N
N
H
8c
4.37 (t, J = 2.9 Hz, 1H), 4.52 (s, 1H), 4.92 (s, 1H), 5.98 (d, J = 4.0 Hz, 1H), 6.46 (d, J = 8.0 Hz, 1H), 6.76 (dd, J =
8.0, 8.0 Hz, 1H), 6.95 (s, 2H), 7.03-7.09 (m, 2H); 13C NMR (125 MHz, CDCl3)  13.7, 13.9, 21.0, 23.1 (2C), 38.6,
39.4, 51.5, 58.0, 62.0, 62.3, 62.4, 82.8, 103.7, 109.9, 118.6, 122.8, 126.8, 128.9, 132.0 (2C), 133.9, 140.2 (2C),
142.6, 148.9, 151.4, 170.9, 171.5. HRMS (FAB) calcd C29H34N2O6S: [M+], 538.2138; found: [M+], 538.2142.
Diethyl 11-methylene-1-[(2-nitrophenyl)sulfonyl]-2,3,10,10a-tetrahydro-1H-2,5a-meth-
EtO2C
CO2Et
anoazepino[2,3-b]indole-4,4(5H)-dicarboxylate (8d).
The reaction was performed for 2 h at 60 °C.
N
Ns
IR (neat): 3372 (NH), 1728 (C=O); 1H NMR (500 MHz, CDCl3)  1.24 (t, J = 7.2 Hz, 3H),
N
H
1.31 (t, J = 7.2 Hz, 3H), 2.46-2.51 (m, 2H), 3.23-3.32 (m, 2H), 4.10-4.40 (m, 5H), 4.57 (s,
8d
1H), 4.66 (d, J = 4.6 Hz, 1H), 4.95 (s, 1H), 6.07 (d, J = 4.6 Hz, 1H), 6.63 (d, J = 8.0 Hz,
1H), 6.86 (dd, J = 7.4, 7.4 Hz, 1H), 7.12-7.17 (m, 2H), 7.59-7.71 (m, 3H), 8.18 (dd, J = 7.4, 1.7 Hz, 1H); 13C NMR
(125 MHz, CDCl3)  13.8, 14.0, 37.8, 39.9, 52.3, 57.9, 62.3, 62.6, 62.8, 84.0, 104.3, 111.0, 119.8, 123.0, 124.4,
127.3, 129.1, 129.5, 132.1, 133.1, 134.6, 148.5, 148.9, 151.5, 170.8, 171.1. HRMS (FAB) calcd C26H27N3O8S: [M+],
541.1519; found: [M+], 541.1511.
Diethyl 11-methylene-1-(methylsulfonyl)-2,3,10,10a-tetrahydro-1H-2,5a-methanoazep-
ino[2,3-b]indole-4,4(5H)-dicarboxylate (8e).
EtO2C
CO2Et
Ms
The reaction was performed for 24 h at 60 °C.
N
N
IR (neat): 3345 (NH), 1728 (C=O); 1H NMR (500 MHz, CDCl3)  1.24 (t, J = 7.2 Hz, 3H),
1.33 (t, J = 7.2 Hz, 3H), 2.43-2.48 (m, 2H), 2.98 (s, 3H), 3.20-3.26 (m, 2H), 4.11-4.33 (m,
4H), 4.35-4.37 (m, 1H), 4.50 (s, 1H), 4.55 (d, J = 4.6 Hz, 1H), 4.96 (s, 1H), 5.78 (d, J = 4.6
H
8e
Hz, 1H), 6.67 (d, J = 7.4 Hz, 1H), 6.87 (dd, J = 7.4, 7.4 Hz, 1H), 7.10-7.17 (m, 2H); 13C NMR (125 MHz, CDCl3) 
13.9, 14.0, 37.5, 40.5, 40.6, 52.6, 58.2, 61.8, 62.2, 62.6, 84.0, 103.4, 111.2, 119.8, 122.9, 127.8, 129.1, 148.6, 152.1,
170.7, 171.2. HRMS (FAB) calcd C21H26N2O6S: [M+], 434.1512; found: [M+], 434.1512.
Diethyl 7-fluoro-11-methylene-1-tosyl-2,3,10,10a-tetrahydro-1H-2,5a-methanoazepi-
no[2,3-b]indole-4,4(5H)-dicarboxylate (8i).
EtO2C
CO2Et
F
IR (neat): 3345 (NH), 1730 (C=O); 1H NMR (500 MHz, CDCl3)  1.24 (t, J = 7.7 Hz, 3H),
1.35 (t, J = 7.7 Hz, 3H), 2.32 (d, J = 13.7 Hz, 1H), 2.39 (s, 3H), 2.48 (d, J = 14.9 Hz, 1H),
3.20-3.23 (m, 2H), 4.09-4.11 (m, 1H), 4.13-4.41 (m, 4H), 4.46 (s, 1H), 4.55 (d, J = 4.0 Hz,
1H), 4.79 (s, 1H), 6.07 (d, J = 4.6 Hz, 1H), 6.55 (dd, J = 8.0, 4.3 Hz, 1H), 6.80-6.86 (m,
N
Ts
N
H
8i
S9

ACCEPTED MANUSCRIPT
2H), 7.25 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3)  13.8, 14.0, 21.5, 37.6, 39.9,
52.2, 57.7, 61.2, 62.2, 62.7, 84.4, 103.6, 110.6 (d, J = 22.8 Hz), 111.2 (d, J = 8.4 Hz), 115.1 (d, J = 25.2 Hz), 127.4
(2C), 128.9 (d, J = 10.8 Hz), 129.6 (2C), 137.5, 143.3, 144.7, 151.3, 157.1 (d, J = 243.5 Hz), 170.9, 171.11. HRMS
(FAB) calcd C27H29FN2O6S: [M+], 528.1730; found: [M+], 528.1724.
Diethyl 5’-fluoro-2-methylenespiro[cyclohexane-1,3’-indol]-3-ene-5,5-dicarboxylate (9b).
IR (neat): 1731 (C=O); 1H NMR (500 MHz, CDCl3)  1.23-1.30 (m, 6H), 2.39 (d, J = 14.3 Hz,
1H), 2.66 (d, J = 14.3 Hz, 1H), 4.18-4.30 (m, 4H), 4.58 (s, 1H), 4.90 (s, 1H), 6.19 (d, J = 9.7 Hz,
1H), 6.56 (d, J = 9.7 Hz, 1H), 7.02 (dd, J = 8.0, 2.2 Hz, 1H), 7.08 (ddd, J = 8.6, 8.0, 2.2 Hz, 1H),
7.60 (dd, J = 8.6, 4.6 Hz, 1H), 7.91 (s, 1H); 13C NMR (125 MHz, CDCl3)  13.9, 14.0, 34.8,
55.3, 61.3, 62.4 (2C), 110.7 (d, J = 25.2 Hz), 115.0, 115.3 (d, J = 2.5 Hz), 122.4 (d, J = 9.6 Hz),
CO2Et
EtO2C
F
N
9b
125.4, 131.4, 137.1, 143.4, 151.4, 161.7 (d, J = 245.9 Hz), 170.0 (2C), 173.8. HRMS (FAB) calcd C20H21FNO4: [M
+ H]+, 358.1455; found: [M + H]+, 358.1447.
Diethyl 7-bromo-11-methylene-1-tosyl-2,3,10,10a-tetrahydro-1H-2,5a-methanoaze-
pino[2,3-b]indole-4,4(5H)-dicarboxylate (8j).
EtO2C
CO2Et
Br
The reaction was performed for 3 h at 60 °C.
N
Ts
N
1
IR (neat): 3364 (NH), 1730 (C=O); H NMR (500 MHz, CDCl3)  1.25 (t, J = 7.2 Hz,
H
3H), 1.34 (t, J = 7.2 Hz, 3H), 2.32 (d, J = 13.7 Hz, 1H), 2.39 (s, 3H), 2.48 (d, J = 12.6 Hz,
1H), 3.17-3.23 (m, 2H), 4.10 (s, 1H), 4.12-4.38 (m, 4H), 4.49 (s, 1H), 4.65 (d, J = 4.6 Hz,
8j
1H), 4.79 (s, 1H), 6.06 (d, J = 4.6 Hz, 1H), 6.52 (d, J = 8.3 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.3, 2.0
Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3)  13.8, 14.0, 21.5, 37.5,
39.8, 52.2, 57.6, 61.2, 62.2, 62.6, 84.1, 103.7, 111.0, 119.3, 126.0, 127.3 (2C), 129.0, 129.6 (2C), 129.7, 137.4,
143.3, 147.9, 151.1, 170.8, 171.0. HRMS (FAB) calcd C27H29BrN2O6S: [M+], 588.0930; found: [M+], 588.0926.
Diethyl 5’-bromo-2-methylenespiro[cyclohexane-1,3’-indol]-3-ene-5,5-dicarboxylate (9c).
IR (neat): 1729 (C=O); 1H NMR (500 MHz, CDCl3)  1.23-1.30 (m, 6H), 2.40 (d, J = 14.3 Hz,
1H), 2.65 (d, J = 14.3 Hz, 1H), 4.19-4.28 (m, 4H), 4.59 (s, 1H), 4.91 (s, 1H), 6.19 (d, J = 10.3
Hz, 1H), 6.56 (d, J = 10.3 Hz, 1H), 7.43-7.45 (m, 1H), 7.51-7.53 (m, 2H), 7.92 (s, 1H); 13C
NMR (125 MHz, CDCl3)  14.0 (2C), 34.7, 55.3, 61.1, 62.4, 62.5, 115.1, 120.4, 122.9, 125.5,
126.4, 131.3, 131.7, 136.8, 143.6, 154.4, 169.6, 169.9, 174.4. HRMS (FAB) calcd
CO2Et
EtO2C
Br
N
9c
C20H21BrNO4: [M + H]+, 418.0654; found: [M + H]+, 418.0650.
Diethyl 7-methoxy-11-methylene-1-tosyl-2,3,10,10a-tetrahydro-1H-2,5a-methano-
EtO2C
CO2Et
MeO
azepino[2,3-b]indole-4,4(5H)-dicarboxylate (8k).
IR (neat): 3352 (NH), 1731 (C=O); 1H NMR (500 MHz, CDCl3)  1.24 (t, J = 7.2 Hz,
3H), 1.35 (t, J = 7.2 Hz, 3H), 2.35 (d, J = 13.7 Hz, 1H), 2.38 (s, 3H), 2.46 (dd, J = 14.9,
1.7 Hz, 1H), 3.20-3.26 (m, 2H), 3.77 (s, 3H), 4.08-4.11 (m, 1H), 4.13-4.39 (m, 4H),
N
Ts
N
H
8k
S10

ACCEPTED MANUSCRIPT
4.44 (d, J = 5.2 Hz, 1H), 4.47 (s, 1H), 4.77 (s, 1H), 6.03 (d, J = 5.2 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.67-6.71 (m,
2H), 7.25 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3)  13.9, 14.0, 21.5, 37.7, 40.0,
52.3, 56.0, 57.9, 61.3, 62.1, 62.6, 84.3, 103.4, 110.1, 111.2, 113.6, 127.4 (2C), 128.8, 129.6 (2C), 137.6, 142.4,
143.1, 151.6, 153.7, 170.9, 171.3. HRMS (FAB) calcd C28H32N2O7S: [M+], 540.1930; found: [M+], 540.1935.
Diethyl 5’-methoxy-2-methylenespiro[cyclohexane-1,3’-indol]-3-ene-5,5-dicarboxylate
(9d).
EtO2C
EtO2C
1
MeO
IR (neat): 1732 (C=O); H NMR (500 MHz, CDCl3)  1.22-1.30 (m, 6H), 2.38 (d, J = 14.3
Hz, 1H), 2.68 (d, J = 14.3 Hz, 1H), 3.84 (s, 3H), 4.19-4.27 (m, 4H), 4.58 (s, 1H), 4.89 (s,
1H), 6.17 (d, J = 10.3 Hz, 1H), 6.56 (d, J = 10.3 Hz, 1H), 6.86 (d, J = 2.6 Hz, 1H), 6.90 (dd,
J = 8.6, 2.6 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.82 (s, 1H); 13C NMR (125 MHz, CDCl3) 
N
9d
13.9 (2C), 25.8, 35.2, 55.5, 55.7, 60.9, 62.3, 109.1, 113.6, 114.9, 121.9, 125.3, 131.6, 137.8, 143.0, 149.0, 158.9,
169.8, 170.1, 171.9. HRMS (FAB) calcd C21H24NO5: [M + H]+, 370.1654; found: [M + H]+, 370.1653.
S11

ACCEPTED MANUSCRIPT
C:\Documents and Settings\Hirotaka Kamitani\ƒfƒXƒNƒgƒbƒv\ƒXƒsƒƒCƒ“ƒh[ƒ‹@˜_•¶\‚m‚l‚q\F-ƒƒ`ƒ“\dataE-158-sai-2.als
DFILE dataE-158-sai-2.als
COMNT single_pulse
DATIM 2013-06-21 13:18:46
OBNUC 1H
EXMOD single_pulse.ex2
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
500.16 MHz
2.41 KHz
6.01 Hz
52428
7507.39 Hz
8
6.9835 sec
5.0000 sec
6.50 usec
PW1
IRNUC 1H
CTEMP
SLVNT CDCL3
EXREF
BF
25.4 c
0.00 ppm
0.12 Hz
50
8.00
7.25 7.10 6.956.904.204.154.103.753.703.353.301.20
RGAIN
CO2Et
CO2Et
F
N
H
S2
PPM
8
6
4
2
0
C:\Documents and Settings\Hirotaka Kamitani\ƒfƒXƒNƒgƒbƒv\ƒXƒsƒƒCƒ“ƒh[ƒ‹@˜_•¶\‚m‚l‚q\F-ƒƒ`ƒ“\E-158--BCM-data-1.als
DFILE E-158--BCM-data-1.als
COMNT single pulse decoupled gated NOE
DATIM 2013-01-15 15:29:47
OBNUC 13C
EXMOD single_pulse_dec
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
125.77 MHz
7.87 KHz
4.21 Hz
26214
31446.06 Hz
688
0.8336 sec
2.0000 sec
3.73 usec
PW1
IRNUC 1H
CTEMP
26.2 c
SLVNT CDCL3
EXREF
BF
77.00 ppm
0.12 Hz
58
RGAIN
CO2Et
CO2Et
F
N
H
S2
PPM
200
175
150
125
100
75
50
25
0
S12

ACCEPTED MANUSCRIPT
\\Corelabo\40.Iwata\ƒvƒƒpƒ‹ƒMƒ‹‚o‚„•¶Œ£@Šâ“c@•ª—Þ@{‘‚«‚©‚¯ƒf[ƒ^\NMR\‚m‚l‚q\‚e-‚s‚a‚r\data E-160-1.als
DFILE data E-160-1.als
COMNT single_pulse
DATIM 2013-04-04 23:52:33
OBNUC 1H
EXMOD single_pulse.ex2
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
500.16 MHz
2.41 KHz
6.01 Hz
52428
7507.39 Hz
8
6.9835 sec
5.0000 sec
6.50 usec
PW1
IRNUC 1H
CTEMP
SLVNT CDCL3
EXREF
BF
25.3 c
0.00 ppm
0.12 Hz
38
8.15 8.10
7.30
7.20 7.10
6.90 4.40 4.35
4.20 4.15 4.10
3.50
2.80
1.25 0.95 0.90 0.15
RGAIN
EtO2
C
CO2Et
F
N
H
OTBS
S3
PPM
8
6
4
2
0
\\Corelabo\40.Iwata\ƒvƒƒpƒ‹ƒMƒ‹‚o‚„•¶Œ£@Šâ“c@•ª—Þ@{‘‚«‚©‚¯ƒf[ƒ^\NMR\‚m‚l‚q\‚e-‚s‚a‚r\data E-160 bcm-1.als
DFILE data E-160 bcm-1.als
COMNT single pulse decoupled gated NOE
DATIM 2013-04-05 03:04:19
OBNUC 13C
EXMOD single_pulse_dec
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
125.77 MHz
7.87 KHz
4.21 Hz
26214
31446.06 Hz
4048
0.8336 sec
2.0000 sec
3.73 usec
PW1
IRNUC 1H
CTEMP
25.6 c
SLVNT CDCL3
EXREF
BF
77.00 ppm
0.12 Hz
58
RGAIN
EtO2
C
CO2Et
F
N
H
OTBS
S3
PPM
200
175
150
125
100
75
50
25
0
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ACCEPTED MANUSCRIPT
\\Corelabo\40.Iwata\ƒvƒƒpƒ‹ƒMƒ‹‚o‚„•¶Œ£@Šâ“c@•ª—Þ@{‘‚«‚©‚¯ƒf[ƒ^\NMR\‚m‚l‚q\‚e|‚n‚g\data E-162-1.als
DFILE data E-162-1.als
COMNT single_pulse
DATIM 2013-04-04 09:27:30
OBNUC 1H
EXMOD single_pulse.ex2
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
500.16 MHz
2.41 KHz
6.01 Hz
52428
7507.39 Hz
8
6.9835 sec
5.0000 sec
6.50 usec
PW1
IRNUC 1H
CTEMP
SLVNT CDCL3
EXREF
BF
25.2 c
0.00 ppm
0.12 Hz
42
8.20 8.15 7.30
7.20
6.90
4.30 4.25 4.20 4.15 4.10
3.50
2.80
2.00 1.95
1.25 1.20
RGAIN
EtO2
C
CO2Et
F
N
H
OH
S4
PPM
8
6
4
2
0
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DFILE E-162_Carbon-1-1.als
COMNT single pulse decoupled gated NOE
DATIM 2013-01-17 10:23:53
OBNUC 13C
EXMOD carbon.jxp
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
100.53 MHz
5.35 KHz
5.86 Hz
26214
25125.63 Hz
400
1.0433 sec
2.0000 sec
3.00 usec
PW1
IRNUC 1H
CTEMP
26.3 c
SLVNT CDCL3
EXREF
BF
77.00 ppm
0.12 Hz
60
RGAIN
EtO2
C
CO2Et
F
N
H
OH
S4
PPM
0
200
175
150
125
100
75
50
25
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ACCEPTED MANUSCRIPT
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DFILE data-E-17_Proton-1-1.als
COMNT single_pulse
DATIM 2013-04-03 13:30:43
OBNUC 1H
EXMOD single_pulse.ex2
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
500.16 MHz
2.41 KHz
6.01 Hz
52428
7507.39 Hz
8
6.9835 sec
5.0000 sec
6.50 usec
PW1
IRNUC 1H
CTEMP
SLVNT CDCL3
EXREF
BF
24.8 c
0.00 ppm
0.12 Hz
40
8.10 8.075.65
7.40 7.30
7.20
4.20 4.15
3.50 2.85 2.801.65 1.25
RGAIN
EtO2
C
CO2Et
N
H
Cl
5a
PPM
8
6
4
2
0
\\Corelabo\40.Iwata\ƒvƒƒpƒ‹ƒMƒ‹‚o‚„•¶Œ£@Šâ“c@•ª—Þ@{‘‚«‚©‚¯ƒf[ƒ^\NMR\‚m‚l‚q\‚g‘Ì\data E-172 bcm-1.als
DFILE data E-172 bcm-1.als
COMNT single pulse decoupled gated NOE
DATIM 2013-04-02 15:41:46
OBNUC 13C
EXMOD single_pulse_dec
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
125.77 MHz
7.87 KHz
4.21 Hz
26214
31446.06 Hz
883
0.8336 sec
2.0000 sec
3.73 usec
PW1
IRNUC 1H
CTEMP
25.3 c
SLVNT CDCL3
EXREF
BF
77.00 ppm
0.12 Hz
56
RGAIN
EtO2
C
CO2Et
N
H
Cl
5a
PPM
0
200
175
150
125
100
75
50
25
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ACCEPTED MANUSCRIPT
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DFILE data carbonate-1.als
COMNT single_pulse
DATIM 2013-05-10 15:29:01
OBNUC 1H
EXMOD single_pulse.ex2
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
500.16 MHz
2.41 KHz
6.01 Hz
13107
7507.39 Hz
8
1.7459 sec
5.0000 sec
6.50 usec
PW1
IRNUC 1H
CTEMP
SLVNT CDCL3
EXREF
BF
25.5 c
0.00 ppm
0.12 Hz
38
8.15
7.65
7.30
7.15 7.10
7.00
4.20 4.15 4.10
3.55
1.25 1.20
RGAIN
EtO2
C
CO2Et
N
H
OCO2Me
5b
PPM
8
6
4
2
0
\\Corelabo\40.Iwata\ƒvƒƒpƒ‹ƒMƒ‹‚o‚„•¶Œ£@Šâ“c@•ª—Þ@{‘‚«‚©‚¯ƒf[ƒ^\NMR\‚m‚l‚q\ƒJƒ‹ƒ{ƒi[ƒg\data carbonate bcm-1.als
DFILE data carbonate bcm-1.als
COMNT single pulse decoupled gated NOE
DATIM 2013-05-10 15:58:49
OBNUC 13C
EXMOD single_pulse_dec
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
125.77 MHz
7.87 KHz
4.21 Hz
26214
31446.06 Hz
616
0.8336 sec
2.0000 sec
3.73 usec
PW1
IRNUC 1H
CTEMP
26.2 c
SLVNT CDCL3
EXREF
BF
77.00 ppm
0.12 Hz
56
RGAIN
EtO2
C
CO2Et
N
H
OCO2Me
5b
PPM
200
175
150
125
100
75
50
25
0
S16

ACCEPTED MANUSCRIPT
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DFILE F-105-data-1.als
COMNT single_pulse
DATIM 2013-07-13 13:25:56
OBNUC 1H
EXMOD single_pulse.ex2
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
500.16 MHz
2.41 KHz
6.01 Hz
52428
7507.39 Hz
4
6.9835 sec
5.0000 sec
6.50 usec
PW1
IRNUC 1H
CTEMP
SLVNT CDCL3
EXREF
BF
25.0 c
0.00 ppm
0.12 Hz
40
6.00 5.45
4.25 4.20
3.50 2.80 2.751.30
RGAIN
EtO2
C
EtO2C
•
Br
7
PPM
8
6
4
2
0
\\Corelabo\40.Iwata\ƒvƒƒpƒ‹ƒMƒ‹‚o‚„•¶Œ£@Šâ“c@•ª—Þ@{‘‚«‚©‚¯ƒf[ƒ^\NMR\‚m‚l‚q\7 ƒuƒƒ‚ƒAƒŒƒ“\F-105-data bcm-1.als
DFILE F-105-data bcm-1.als
COMNT single pulse decoupled gated NOE
DATIM 2013-07-13 13:42:20
OBNUC 13C
EXMOD single_pulse_dec
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
125.77 MHz
7.87 KHz
4.21 Hz
26214
31446.06 Hz
333
0.8336 sec
2.0000 sec
3.73 usec
PW1
IRNUC 1H
CTEMP
25.4 c
SLVNT CDCL3
EXREF
BF
77.00 ppm
0.12 Hz
52
RGAIN
EtO2
C
EtO2C
•
Br
7
PPM
200
150
100
50
0
S17

ACCEPTED MANUSCRIPT
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DFILE E-179-2_Proton-1-1.als
COMNT single_pulse
DATIM 2013-02-07 10:02:40
OBNUC 1H
EXMOD proton.jxp
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
399.78 MHz
4.19 KHz
7.29 Hz
13107
7598.78 Hz
8
1.7249 sec
5.0000 sec
4.65 usec
PW1
IRNUC 1H
CTEMP
SLVNT CDCL3
EXREF
BF
25.2 c
0.00 ppm
0.12 Hz
52
8.05
7.575.35
7.157.10
5.955.405.35 4.204.154.103.503.45
2.751.251.20
RGAIN
EtO2
C
CO2Et
N
•
H
Br
5c
PPM
8
6
4
2
0
\\Corelabo\40.Iwata\ƒvƒƒpƒ‹ƒMƒ‹‚o‚„•¶Œ£@Šâ“c@•ª—Þ@{‘‚«‚©‚¯ƒf[ƒ^\NMR\‚m‚l‚q\5c ƒuƒƒ‚ƒAƒŒƒ“\data E-179-2 sai bcm-1.als
DFILE data E-179-2 sai bcm-1.als
COMNT single pulse decoupled gated NOE
DATIM 2013-05-11 14:08:34
OBNUC 13C
EXMOD single_pulse_dec
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
125.77 MHz
7.87 KHz
4.21 Hz
26214
31446.06 Hz
344
0.8336 sec
2.0000 sec
3.73 usec
PW1
IRNUC 1H
CTEMP
25.8 c
SLVNT CDCL3
EXREF
BF
77.00 ppm
0.12 Hz
56
RGAIN
EtO2
C
CO2Et
N
•
H
Br
5c
PPM
200
150
100
50
0
S18

ACCEPTED MANUSCRIPT
\\Corelabo\40.Iwata\ƒvƒƒpƒ‹ƒMƒ‹‚o‚„•¶Œ£@Šâ“c@•ª—Þ@{‘‚«‚©‚¯ƒf[ƒ^\NMR\‚m‚l‚q\5d ‚a‚‚ƒ‘Ì\data-E-17_Proton-1-1.als
DFILE data-E-17_Proton-1-1.als
COMNT single_pulse
DATIM 2013-04-03 13:30:43
OBNUC 1H
EXMOD single_pulse.ex2
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
500.16 MHz
2.41 KHz
6.01 Hz
52428
7507.39 Hz
8
6.9835 sec
5.0000 sec
6.50 usec
PW1
IRNUC 1H
CTEMP
SLVNT CDCL3
EXREF
BF
24.8 c
0.00 ppm
0.12 Hz
40
8.10 8.075.65 7.60 7.40 7.30
7.20
4.20
3.50 2.85
1.65
1.25
RGAIN
EtO2
C
CO2Et
N
Boc
Cl
5d
PPM
8
6
4
2
0
\\Corelabo\40.Iwata\ƒvƒƒpƒ‹ƒMƒ‹‚o‚„•¶Œ£@Šâ“c@•ª—Þ@{‘‚«‚©‚¯ƒf[ƒ^\NMR\‚m‚l‚q\5d ‚a‚‚ƒ‘Ì\data F-42-bcm.als
DFILE data F-42-bcm.als
COMNT single pulse decoupled gated NOE
DATIM 2013-04-17 08:00:08
OBNUC 13C
EXMOD single_pulse_dec
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
125.77 MHz
7.87 KHz
4.21 Hz
26214
31446.06 Hz
2400
0.8336 sec
2.0000 sec
3.73 usec
PW1
IRNUC 1H
CTEMP
25.7 c
SLVNT CDCL3
EXREF
BF
0.00 ppm
0.12 Hz
60
RGAIN
EtO2
C
CO2Et
N
Boc
Cl
5d
PPM
200
175
150
125
100
75
50
25
0
S19

ACCEPTED MANUSCRIPT
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DFILE data-E-119-1.als
COMNT single_pulse
DATIM 2013-04-03 19:01:25
OBNUC 1H
EXMOD single_pulse.ex2
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
500.16 MHz
2.41 KHz
6.01 Hz
13107
7507.39 Hz
8
1.7459 sec
5.0000 sec
6.50 usec
PW1
IRNUC 1H
CTEMP
SLVNT CDCL3
EXREF
BF
24.9 c
0.00 ppm
0.12 Hz
34
7.257.20 7.10
4.25 4.20 4.15
3.70 3.55 2.85 2.80 1.25
RGAIN
EtO2C
CO2Et
N
Me
Cl
5e
PPM
8
6
4
2
0
\\Corelabo\40.Iwata\ƒvƒƒpƒ‹ƒMƒ‹‚o‚„•¶Œ£@Šâ“c@•ª—Þ@{‘‚«‚©‚¯ƒf[ƒ^\NMR\‚m‚l‚q\5e‚l‚…‘Ì\data-E-119 bcm-1.als
DFILE data-E-119 bcm-1.als
COMNT single pulse decoupled gated NOE
DATIM 2013-04-03 19:08:42
OBNUC 13C
EXMOD single_pulse_dec
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
125.77 MHz
7.87 KHz
4.21 Hz
26214
31446.06 Hz
142
0.8336 sec
2.0000 sec
3.73 usec
PW1
IRNUC 1H
CTEMP
25.2 c
SLVNT CDCL3
EXREF
BF
77.00 ppm
0.12 Hz
54
RGAIN
EtO2C
CO2Et
N
Me
Cl
5e
PPM
200
175
150
125
100
75
50
25
0
S20

ACCEPTED MANUSCRIPT
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DFILE e-163-3-1.als
COMNT single_pulse
DATIM 2013-01-23 15:50:46
OBNUC 1H
EXMOD single_pulse.ex2
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
500.16 MHz
2.41 KHz
6.01 Hz
13107
7507.39 Hz
8
1.7459 sec
5.0000 sec
6.90 usec
PW1
IRNUC 1H
CTEMP
SLVNT CDCL3
EXREF
BF
27.3 c
0.00 ppm
0.12 Hz
30
8.208.157.30 7.20
6.90 4.254.204.154.10 3.502.852.80 1.25
RGAIN
EtO2C
CO2Et
F
N
H
Cl
5f
PPM
8
6
4
2
0
\\Corelabo\40.Iwata\ƒvƒƒpƒ‹ƒMƒ‹‚o‚„•¶Œ£@Šâ“c@•ª—Þ@{‘‚«‚©‚¯ƒf[ƒ^\NMR\‚m‚l‚q\5f ‚e‘Ì\e-163-3 BCM -1.als
DFILE e-163-3 BCM -1.als
COMNT single pulse decoupled gated NOE
DATIM 2013-01-23 16:13:22
OBNUC 13C
EXMOD single_pulse_dec
OBFRQ
OBSET
OBFIN
POINT
FREQU
SCANS
ACQTM
PD
125.77 MHz
7.87 KHz
4.21 Hz
26214
31446.06 Hz
466
0.8336 sec
2.0000 sec
3.73 usec
PW1
IRNUC 1H
CTEMP
27.7 c
SLVNT CDCL3
EXREF
BF
77.00 ppm
0.12 Hz
54
RGAIN
EtO2C
CO2Et
F
N
H
Cl
5f
PPM
200
175
150
125
100
75
50
25
0
S21