C4 Pictet-Spengler Reactions for the Synthesis of Core Structures in Hyrtiazepine Alkaloids

Article abstract of DOI:10.1055/s-0036-1588438

The hyrtiazepine alkaloids are a family of bisindole natural products that have the azepinoindole backbone. We developed a biomimetic approach by constructing the azepinoindole core in a one-pot manner through 1,4-diazabicyclo[2.2.2]octane/2,2,2-trifluoroethanol (DABCO/TFE) promoted Pictet-Spengler reaction onto the C-4 position of tryptophan. This strategy allowed the synthesis of common key structures of these families. The key intermediate can be converted into the 3 H -pyrano[2,3- b:5,6- e ′]diindol intermediate present in hyrtimomines A and B, as well as the azepinoindole core present in fargesine..

Full text of DOI:10.1055/s-0036-1588438

SYNTHESIS
0
0
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9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–J
special topic
A
en
T. Abe et al.
Special Topic
Synthesis
C4 Pictet–Spengler Reactions for the Synthesis of Core Structures
in Hyrtiazepine Alkaloids
Takumi Abe*
0
0
0
0
0-
0
0
3
1-
7
2
9
1-
0
9
7
OAc
Tomohiro Haruyama
Koji Yamada*
CO2Me
AcHN
OBn
C4 Pictet–Spengler
N
4 steps
Faculty of Pharmaceutical Sciences, Health Sciences Uni-
versity of Hokkaido, Ishikari-tobetsu, Hokkaido 061-0293,
Japan
abe-t@hoku-iryo-u.ac.jp
kyamada@hoku-iryo-u.ac.jp
CO2Me
BnO
H2N
O
CO2Me
H
N
NH
C4
Ts
N
CHO
DABCO
TFE
hyrtimonine B core
CO2Me
HO
HO
+
reflux
N
H
N
N
H
Published as part of the Special Topic Modern Cyclization
Strategies in Synthesis
N
one-pot!!
Ts
H
3 steps
HO
hyrtiazepine core
TFE: 2,2,2-trifluoroethanol
N
H
fargesine core
Received: 10.03.2017
Accepted after revision: 04.05.2017
Published online: 07.06.2017
indole ring affords hyrtiazepine. After the formation of
hyrtiazepine, a cascade sequence would occur. Thus, oxida-
tion sequences could afford hyrtinadines C, D and hyrtimo-
mine C, whereas hyrtimomines A and B would be produced
by an intramolecular oxa-Michael addition of hyrtiazepine.
Previously, we reported a base-promoted C-4 Pictet–
Spengler reaction of serotonines, which enable azepinoin-
doles to be afforded in one pot.6 Furthermore, the concise
synthesis of (±)-aurantioclavine was also accomplished in
DOI: 10.1055/s-0036-1588438; Art ID: ss-2017-c0153-st
Abstract The hyrtiazepine alkaloids are a family of bisindole natural
products that have the azepinoindole backbone. We developed a bio-
mimetic approach by constructing the azepinoindole core in a one-pot
manner through 1,4-diazabicyclo[2.2.2]octane/2,2,2-trifluoroethanol
(DABCO/TFE) promoted Pictet–Spengler reaction onto the C-4 position
of tryptophan. This strategy allowed the synthesis of common key
structures of these families. The key intermediate can be converted into
the 3H-pyrano[2,3-b:5,6-e′]diindol intermediate present in hyrtimomi-
nes A and B, as well as the azepinoindole core present in fargesine.
OH
OH
OH
Key words Pictet–Spengler reaction, indole alkaloids, azepinoindoles,
biomimetic synthesis, cyclizations, stereoselectivities
CO2H
CO2H
H
H
HN
HO
N
N
N
N
N
The hyrtiazepine alkaloids, hyrtiazepine,1 hyrtimomine
A–C,2a and F,2b and hyrtinadine C and D,3 are a family of bis-
indole natural products containing azepinoindole core
structures (Figure 1). These bisindoles display promising bi-
ological activity, such as cytotoxity against human epider-
moid carcinoma KB cells and muline leukemia L1210 cells,2a
and antimicrobial3 activities. Their complex structure and
interesting biological properties has prompted investiga-
tions on the synthesis of these alkaloids.4 Ito and Yamagu-
chi reported the first total synthesis of (±)-hyrtiazepine by
using ortho-selective α-hydroxyalkylation/intramolecular
imine formation.5 Given their complexity, to date, there is
no precedent for the total synthesis of these natural prod-
ucts except for Ito and Yamaguchi’s milestone.
The structural relationship between these natural prod-
ucts inspired us to develop a biomimetic strategy for their
synthesis. These alkaloids can plausibly be biosynthesized
by the oxidative Pictet–Spengler reaction (Scheme 1). First,
a condensation of tryptophan and 5-hydroxy-indole-3-
carbaldehyde affords the iminium ion. Subsequently, an ox-
idative Pictet–Spengler reaction at the C-4 position of the
O
O
N
N
N
H
H
H
(–)-hyrtiazepine
OH
hyrtimomine A
OH
(–)-hyrtimomine B
OH
CO2H
OMe
CO2H
OH
HN
HN
HO
N
N
N
HN
O
HO
HO
N
N
N
H
H
H
hyrtimomine C
(–)-hyrtinadine C
OH
(–)-hyrtinadine D
O
O
N
HN
HO
O
N
H
hyrtimomine F
Figure 1 Members of the hyrtiazepine family
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

B
T. Abe et al.
Special Topic
Synthesis
only three steps from Nb-benzyl-serotonine and alkylalde-
hydes by using this strategy.7 Recently, we reported the first
synthesis of the azepinoindole alkaloid hyrtioreticulins C
and D through a base-promoted C-4 Pictet–Spengler reac-
tion between tryptophan and acetaldehyde.8 Although
these results demonstrated that such a biomimetic cascade
toward hyrtiazepines was possible, there were a few chal-
lenges in the synthesis of these alkaloids. To obtain azepi-
noindoles from the C-4 Pictet–Spengler reaction, the reac-
tion with tryptophan and 5-hydroxyindole-3-carbaldehyde
must proceed smoothly. However, in the preliminary exper-
iments, this scenario would not be easy to achieve under
the previously reported conditions.6–8 Therefore, alternative
and appropriate reaction conditions for the C-4 Pictet–
Spengler reaction would be necessary to supply a common
hyrtiazepine core structure. As an outgrowth of our investi-
gations in the area of indole alkaloids,9 we envisioned that
the C-4 Pictet–Spengler reaction of tryptophans with 5-hy-
droxyindole-3-carbaldehydes would allow a concise ap-
proach to these alkaloids under new reaction conditions.
Given that we envisioned a biomimetic approach, we
started our venture by preparing the starting materials.
Thus, we synthesized tryptophan methyl ester 6 from tryp-
tophan by following a reported procedure;10 the other
starting materials, indole-3-carbaldehydes, were synthe-
sized from 5-hydroxyindole (1) (Scheme 2). First, com-
pound 1 was reacted with BnBr in the presence of K2CO3
and N,N-dimethylformamide (DMF) under reflux condi-
tions, which led to the formation of O-protected indole 2.11
Next, treatment of 2 with Vilsmeier–Haack reagent12 at
room temperature furnished the desired aldehyde 4a.13 The
latter was transformed into 4b14 and 4c by using TsCl and
(Boc)2O, respectively. The N-methoxyindole 5 was obtained
from 2, via indoline 315 followed by Somei oxidation16 using
Na2WO4 and methylation. Finally, the Vilsmeier–Haack re-
action of 5 afforded the desired aldehyde 4d.
OH
CO2H
HN
H
N
H2N
+
CO2H
HO
CHO
HO
+
HO
N
N
H
H
N
H
oxidative
C4 Pictet–Spengler
OH
N
OH
OH
intra-
CO2H
CO2H
molecular
oxa-Michael
addition
H
N
H
HN
N
N
N
HO
O
O
– CO2
N
H
N
N
H
H
(–)-hyrtiazepine
(–)-hyrtimomine B
hyrtimomine A
[O]
[O]
OH
OH
CO2H
N
CO2H
OH
HN
HO
HN
HO
N
OMe
[O]
N
N
– CO2
H
H
(–)-hyrtinadine C
(–)-hyrtinadine D
OH
N
HN
HO
O
[O]
– CO2
N
H
hyrtimomine C
With the starting materials in hand, we next set out to
investigate the reaction between tryptophan 6 and alde-
hyde 4b (Scheme 3). Initially, 6 and 4b were subjected to
the previously reported reaction conditions (MeOH/Et3N
under microwave irradiation).8 Unfortunately, unexpected
4a was mainly produced via detosylation under basic condi-
tions, and neither the desired azepinoindole 7 nor β-carbo-
line 8 could be obtained.
Having encountered difficulties in obtaining 7, we in-
vestigated the use of milder reaction conditions that were
compatible with aldehyde 4b (Table 1). To our delight, con-
ducting the reaction in MeOH at reflux afforded the desired
azepinoindole 7 in 29% yield (cis/trans = 0:100), along with
8 in 4% yield (cis/trans = 75:25) and unstable imine 9 in 8%
yield (entry 1). Among the various bases screened, 1,4-
diazabicyclo[2.2.2]octane (DABCO) was most effective (en-
tries 2–4). However, although the yield increased, the dia-
stereoselectivity dropped off significantly. The cis stereo-
Scheme 1 Biosynthesis of the azepinoindole alkaloids
1
chemistry of 7a was established by H NOE experiments,
which revealed a strong NOE interaction (Figure 2). To im-
prove the diastereoselectivity, we probed the solvents in
the reaction (entries 5–8). However, none of the attempts
were successful. For example, when MeOH was replaced
with DMF, imine 9 was mainly isolated (entry 5). Among
these solvents, alcohols seemed to be diastereoselective
(entries 7 and 8). At this stage, we hypothesized that the C-
4 Pictet–Spengler reaction would be promoted if a corre-
sponding iminium ion derived from 9 could be stabilized.
Based on our hypothesis and on previous reports,17 we
next conducted a polar solvent screen. Among the solvents
examined, 2,2,2-trifluoroethanol (TFE)17 resulted in the for-
mation of 7b in 74% yield with high diastereoselectivity (Ta-
ble 1, entry 9).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

C
T. Abe et al.
Special Topic
Synthesis
Furthermore, the use of a combination of DABCO and
TFE provided 7b in 84% yield as the only product (Table 1,
entry 10). TFE has several unique properties,18 which in-
clude high polarity, high ionization power,19 high ability to
make hydrogen bonds,20 and low nucleophilicity.21 These
properties of TFE would enhance the reactivity of the imin-
ium ion in the C-4 Pictet–Spengler reaction.
To confirm the origin of diastereoselectivity, we carried
out isomerization experiments (Scheme 4). Subjecting the
cis-isomer to the reaction in MeOH under reflux conditions
led to the production of the trans-isomer in 87% yield. This
sequence would be initiated by retro-Mannich reaction,
forming the quinodimehane intermediate 10.
HO
N
H
1
BnBr, K2CO3
DMF, reflux
91%
BnO
BnO
NaBH3CN
AcOH
84%
N
N
H
H
2
3
1) 30% H2O2
Na2WO4⋅2H2O
2) Me2SO4, K2CO3
POCl3, DMF
81%
45%
The intramolecular Mannich reaction then afforded the
trans-isomer via intermediate 11B. Due to steric repulsion
at 11A, the thermodynamically unstable cis-isomer is not
dominant in the Pictet–Spengler reaction at the C-4 posi-
tion of the indole ring. These trends are similar to the
majority of the syntheses of clavicipitic acids,22 except for
Piersanti’s cis-selective synthesis using Rh(I)-catalyzed in-
tramolecular 1,2-additions of boronic acids to imines.23
These results suggests that the high trans-diastereoselectiv-
ity would result from isomerization under reflux condi-
tions. However, in these isomerization experiments, the cis-
diastereoselectivity22 could not be explained (Table 1, entry
4). To obtain some clues for the origin of this cis-diastereo-
selectivity, further investigations must be conducted.
We then investigated the protective group on the indole
nitrogen on 4 under the optimized conditions (Table 2). No
reaction occurred in the absence of a protective group on
the indole nitrogen atom (entry 1). In the case of the elec-
tron-withdrawing group, the desired products 7b and 7d
were obtained in 85% and 66% yield, respectively (entries 2
and 3). No product could be obtained when N-methoxyal-
dehyde 4d was used (entry 4).
BnO
BnO
CHO
N
H
N
4a
TsCl, NaOH
Bu4NBr
76%
5
OMe
Boc2O, NaOH
Bu4NBr
50%
POCl3, DMF
94%
BnO
BnO
BnO
CHO
CHO
CHO
N
N
N
Ts
Boc
OMe
4b
4c
4d
Scheme 2 Synthesis of 3-formylindoles
CO2Me
H2N
BnO
CHO
Et3N–MeOH (1:1, v/v)
HO
+
microwave irradiation (50 W)
reflux, 6 h
N
N
H
Ts
6
4b
OBn
CO2Me
NH
HO
CO2Me
+
BnO
H
N
CHO
Ts
N
+
N
H
HO
N
H
OBn
OBn
H2N
OBn
OBn
4a
N
N
H
7a: cis
8a: cis
8b: trans
CO2Me
MeOH
CO2Me
CO2Me
Ts
H
N
H
N
Ts
Ts
Ts
N
N
N
7b: trans
0%
55%
0%
O
HO
HO
reflux
87%
Scheme 3 Attempted synthesis of azepinoindole 7 by using our previ-
ously developed conditions
N
N
N
H
H
H
7b
10
7a
unfavor
favor
OBn
NOE
H
Ar
HN
HN
H
O
Ar
H
O
H
H
H
Ts
H
N
N
N
H
N
H
CO2Me
MeO2C
6
4
MeO2C
11A
HO
11B
N
H
Scheme 4 Isomerization of 7a into 7b via 10 and possible origin of
diastereoselectivity
(4S,6S)-7a
Figure 2 1H NOE experiments with 7a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

D
T. Abe et al.
Special Topic
Synthesis
Table 1 Reaction of 6 with Aldehyde 4b for the Construction of Hyrtiazepine Skeleton
OBn
CO2Me
H2N
CO2Me
NH
CO2Me
HO
CO2Me
H
HO
Ts
BnO
N
CHO
N
base, solvent
reflux, 24 h
N
HO
OBn
+
+
+
N
HO
H
N
H
N
OBn
N
H
Ts
N
N
N
H
6
4b
7a: cis
7b: trans
8a: cis
8b: trans
9
Ts
Ts
Entry
Base
–
Solvent
Yields (%)a
7 (cis/trans)b
8 (cis/trans)b
9
6
1
2
MeOH
MeOH
MeOH
MeOH
DMF
29 (0:100)
56 (39:61)
37 (35:65)
39 (72:28)
–
4 (75:25)
8
18
15
60
31
26
32
49
40
7
DABCO
–
–
–
3
Et3N
–
4
DIEA
–
–
5
–
12 (58:42)
16 (53:47)
7 (34:66)
10 (32:68)
–
54
17
14
12
9
6
–
MeCN
EtOH
iPrOH
TFE
5 (25:75)
7 (0:100)
22 (12:88)
74 (0:100)
85 (1:99)
7
–
8
–
9
–
10
DABCO
TFE
–
–
–
a Isolated yield.
b Determined by 1H NMR spectroscopic analysis.
With the precursor 7b in hand, we planned to use the
approach for the synthesis of the hyrtiazepine cores
(Scheme 5). The tosyl group on the indole nitrogen was re-
moved by using magnesium powder in MeOH24 to provide
amine 7c in 73% yield. Subsequent reduction with 10% Pd-C
and hydrogen gas provided phenol 12 in 70% yield.
With 12 in hand, we then turned our attention to the
synthesis of hyrtiazepine using an unprecedented late-stage
imine formation of azepinoindoles. We attempted to realize
this strategy by employing the oxidation conditions, but all
failed. 5-Hydroxyindole was mainly obtained via retro-
Mannich type fragmentation.
Next, the azepinoindole intermediate 12 was used to
test the formation of the alkylidene indolenine core present
in hyrtiazepine alkaloids such as hyrtimomines A and B. In-
tensive investigations provided a solution for this problem.
Thus, intermediate 12, on exposure to TfOH in the presence
of 10% Pd-C at room temperature, followed by acetylation,
afforded the desired pyranodiindole 13 in 47% yield through
an intramolecular oxa-Michael addition/ring opening of the
azepane ring (Scheme 5). This is the first example of the
synthesis of 3H-pyrano[2,3-b:5,6-e′]diindol. We also tried
to synthesize hyrtimonime B from 12 without cleaving the
C–N bond of the azepine-ring according to the precedents
for the hemiaminal formation.25 However, all attempts
failed to obtain hyrtimonime B.
During the attempted synthesis of hyrtimonine B, we
encountered an unexpected reaction. The treatment of
compound 12 in MeOH under reflux conditions afforded an
unstable cyclic imine 14 in 61% yield through retro-Man-
nich reaction. This framework is present in azepinoindole
alkaloids such as fargesine26 and cimitrypazepine.27
Finally, the imine formation of model substrate 15 was
investigated because of the difficulty encountered in the
imine formation of 12 (Scheme 6). Disappointingly, the
imine formation could not be achieved and decomposition
Table 2 Reaction of 6 with Aldehydes 4
OBn
CO2Me
CO2Me
H
R
H2N
N
N
DABCO
TFE
BnO
CHO
HO
+
HO
reflux
N
R
N
N
H
H
6
4
7
Entry
4
R
Time (h)
7
R
Yield (%)a
1
2
3
4
4a
H
24
4
7c
7b
7d
7e
H
0
85
66
0
4b
4c
4d
Ts
Ts
Boc
OMe
4
Boc
OMe
24
a Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

E
T. Abe et al.
Special Topic
Synthesis
OH
OH
N
OH
OBn
OBn
CO2Me
CO2H
CO2H
N
CO2Me
CO2Me
H
N
H
N
H
HN
HN
Ts
N
the late-stage
imine formation
HN
HN
N
Mg, MeOH
73%
H2, Pd–C
OH
HO
HO
MeOH
70%
HO
HO
HO
N
N
N
H
N
N
H
H
H
H
12
7b
7c
(–)-hyrtiazepine
(–)-hyrtinadine C
OH
H
hemiaminal formation without ring opening
CO2Me
HN
N
HO
HO
N
H
OH
OH
OAc
N
12
H
O–
Me
CO2Me
+
Me
CO2H
CO2Me
H
H
AcHN
N
N
N
N
N
N
N
N
1. TfOH, Pd–C
MeOH
MeOH
HO
O
O
HO
HO
O
2. Ac2O
reflux
61%
N
N
H
N
N
N
N
H
H
H
47% (2 steps)
H
H
cimitrypazepine
fargesine
(–)-hyrtimomine B
13
14
hyrtimomine A
Scheme 5 Synthesis of diverse hyrtiazepine alkaloid core structures from the common intermediate 7b
of 15 was observed. To avoid the decomposition, milder
conditions for imine formations were also attempted. To
our surprise, enamine 17 was obtained when the Stahl’s ox-
idation conditions were applied.28 These results suggest
that it is difficult to accomplish the synthesis of hyrtiaze-
pine by the late-stage imine formation strategy.
phan. The common intermediate can be converted into the
alkylidene indolenine core present in hyrtimomines A and
B, as well as the azepinoindole core present in fargesine and
cimitrypazepine. We found that the imine formation of aze-
pinoindoles is difficult to achieve. Our campaign for the to-
tal synthesis of hyrtiazepine alkaloids using the C-4 Pictet–
Spengler reaction is in progress and the results will be re-
ported in due course.
CO2Me
CO2Me
H
N
N
oxidation conditions
HO
HO
Optical rotations were recorded with a JASCO P-2200 polarimeter.
Melting points were recorded with a Yamato MP21 and are uncor-
rected. IR spectra were measured with a Shimadzu IRAffinity-1 spec-
trometer and absorbance bands are reported in wavenumbers (cm–1).
NMR experiments were performed with a JEOL JNM-ECA500 (500
MHz) spectrometer. Chemical shifts in 1H and 13C NMR are expressed
in ppm (δ). All 13C NMR spectra were determined with complete pro-
ton decoupling. Column chromatography and Flash column chroma-
tography were performed on silica gel (Silica Gel 60N, Kanto Chemical
Co., Ltd.). High-resolution MS spectra were recorded with Micromass
AutoSpec 3100 and JEOL JMS-T100LP mass spectrometers. Microwave
irradiation was performed with a Green-Motif I (IMCR-25003) mono-
mode microwave reactor (IDX Corporation). All microwave irradiation
experiments were carried out in glass tubes with microwave power at
50 W. All reagents were obtained from commercial suppliers and
used without further purification.
N
N
H
H
16
15
unexpected enamine formation
CO2Me
H
N
phd (5 mol %), ZnI2 (1 mol%)
PPTS (15 mol%)
O2 balloon
HO
DMF–MeCN (1/2, v/v), r.t., 100 h
N
O
O
H
17
22%
N
N
phd: 1,10-phenanthroline-5,6-dione
Scheme 6 Attempted imine formation using model substrate 15
5-Benzyloxy-1H-indole (2)11
In conclusion, we have developed a biomimetic ap-
proach employing a C-4 Pictet–Spengler reaction using
DABCO and TFE that provides access to the azepinoindole
core in a one-pot operation. The key feature in this reaction
is biomimetic cyclizations onto the C-4 position of trypto-
Benzylbromide (2.0 mL, 16.8 mmol) and K2CO3 (3.1 g, 22.5 mmol)
were added to a solution of 5-hydroxyindole 1 (2.0 g, 15.0 mmol) in
DMF (10 mL) and the mixture was stirred and heated at reflux. After
24 h, the mixture was cooled to r.t. and the reaction was quenched
with 10% aq HCl. The mixture was extracted with EtOAc (3 × 50 mL),
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

F
T. Abe et al.
Special Topic
Synthesis
washed with H2O (30 mL) and brine (2 × 20 mL), and dried over
MgSO4. The solvent was removed and the residue was purified by sili-
ca gel column chromatography (EtOAc/hexane, 1:6) to give 2.
tert-Butyl 5-Benzyloxy-3-formyl-1H-indole-1-carboxylate (4c)
Tetrabutylammonium bromide (97 mg, 0.3 mmol) was added to a
solution of 4a (48 mg, 0.19 mmol) and 50% aq NaOH (2 mL) in CH2Cl2
(2 mL). After stirring at r.t. for 10 min, di-tert-butyl dicarbonate (84
mg, 0.38 mmol) was added and the mixture was stirred at r.t. for 8 h.
The mixture was diluted with EtOAc (50 mL) and washed with H2O
(15 mL) and brine (2 × 10 mL), and dried over MgSO4. The solvent was
removed, and the residue was purified by silica gel column chroma-
tography (EtOAc–hexane, 1:10) to give 4c.
Yield: 3 g (91%); colorless solid; mp 97–100 °C (CHCl3).
IR (CHCl3): 3483, 1626, 1581, 1477, 1452, 1281, 1153 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.03 (br. s, 1 H), 7.52 (d, J = 7.5 Hz, 2 H),
7.43 (t, J = 7.5 Hz, 2 H), 7.36 (t, J = 7.5 Hz, 1 H), 7.27 (d, J = 8.6 Hz, 1 H),
7.24 (d, J = 2.3 Hz, 1 H), 7.15 (t, J = 2.8 Hz, 1 H), 6.99 (dd, J = 8.6, 2.3 Hz,
1 H), 6.51 (t, J = 2.3 Hz, 1 H), 5.15 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 153.5, 137.8, 131.3, 128.7, 128.4,
127.9, 127.7, 125.1, 113.2, 111.9, 104.1, 102.5, 71.1.
Yield: 34 mg (50%); colorless solid; mp 248–249 °C (CHCl3–hexane).
IR (CHCl3): 1744, 1674, 1454, 1256, 1148, 1088 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 10.06 (s, 1 H), 8.19 (s, 1 H), 8.02 (d, J =
9.2 Hz, 1 H), 7.88 (d, J = 2.3 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 2 H), 7.40 (t, J =
8.0 Hz, 2 H), 7.33 (t, J = 7.5 Hz, 1 H), 7.09 (dd, J = 9.2, 2.8 Hz, 1 H), 5.14
(s, 2 H), 1.70 (s, 9 H).
HRMS (EI): m/z [M+] calcd for C15H13NO: 223.0997; found: 223.1028.
5-Benzyloxy-1H-indole-3-carboxaldehyde (4a)13
Phosphoryl chloride (0.4 mL, 4.3 mmol) was added to DMF (2.7 mL) at
–30 °C and the mixture was stirred at r.t. for 0.5 h. A solution of 2 (536
mg, 2.4 mmol) in DMF (3 mL) was added and the mixture was stirred
at r.t. for 1 h. The mixture was cooled to 0 °C and the reaction was
quenched with 10% aq NaOH, and stirred at r.t. for 0.5 h. The mixture
was neutralized with 10% aq HCl, and the resulting precipitate was
separated by filtration, washed with H2O, and dried under vacuum to
give 4a.
13C NMR (125 MHz, CDCl3): δ = 186.0, 156.5, 148.8, 137.0, 136.9,
130.7, 128.7, 128.1, 127.8, 127.1, 121.4, 116.2, 116.1, 105.3, 85.7, 70.6,
28.2.
HRMS (EI): m/z [M+] calcd for C21H21NO4: 351.1471; found: 351.1475.
5-Benzyloxyindoline (3)15
NaBH3CN (602 mg, 9.1 mmol) was added to a solution of 2 (1.0 g, 4.5
mmol) in AcOH (50 mL). After stirring at r.t. for 10 min, the mixture
was cooled to 0 °C and the reaction was quenched with H2O (50 mL)
and 40% aq NaOH. The mixture was extracted with EtOAc (3 × 50 mL),
washed with H2O (30 mL) and brine (2 × 20 mL), and dried over
MgSO4. The solvent was removed, and the residue was purified by sil-
ica gel column chromatography (CHCl3–MeOH–29% NH4OH, 46:1:0.1)
to give 3.
Yield: 489 mg (81%); colorless solid; mp 242–244 °C (CHCl3).
IR (KBr): 3152, 1632, 1616, 1585, 1522, 1493, 1479, 1468, 1449, 1395,
1261, 1204, 1140 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 12.01 (br. s, 1 H), 9.85 (s, 1 H), 8.19
(d, J = 1.9 Hz, 1 H), 7.65 (d, J = 2.3 Hz, 1 H), 7.45 (d, J = 8.1 Hz, 2 H),
7.34–7.40 (m, 3 H), 7.29 (t, J = 6.9 Hz, 1 H), 6.93 (dd, J = 8.6, 2.3 Hz,
1 H), 5.09 (s, 2 H).
13C NMR (125 MHz, DMSO-d6): δ = 185.3, 155.2, 139.2, 138.0, 132.6,
128.9, 128.2, 128.1, 125.4, 118.6, 114.3, 113.8, 104.6, 70.1.
Yield: 844 mg (84%); pale-yellow oil.
IR (CHCl3): 1492, 1140 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.43 (d, J = 7.5 Hz, 2 H), 7.38 (t, J =
7.5 Hz, 2 H), 7.31 (t, J = 7.5 Hz, 1 H), 6.84 (t, J = 2.8 Hz, 1 H), 6.67 (dd,
J = 8.6, 2.8 Hz, 1 H), 6.58 (d, J = 8.1 Hz, 1 H), 4.99 (s, 2 H), 3.53 (t, J =
8.3 Hz, 2 H), 3.01 (t, J = 8.2 Hz, 2 H).
HRMS (EI): m/z [M+] calcd for C16H13NO2: 251.0946; found: 251.0942.
5-Benzyloxy-1-tosyl-1H-indole-3-carboxaldehyde (4b)14
Tetrabutylammonium bromide (97 mg, 0.3 mmol) was added to a
solution of 4a (251 mg, 1.0 mmol) and 50% aq NaOH (2 mL) in CH2Cl2
(2 mL). After stirring at r.t. for 10 min, TsCl (210 mg, 1.1 mmol) was
added and the mixture was stirred at r.t. for 0.5 h. The mixture was
diluted with EtOAc (50 mL) and washed with H2O (15 mL) and brine
(2 × 10 mL), and dried over MgSO4. The solvent was removed, and the
residue was purified by silica gel column chromatography (CHCl3) to
give 4b.
13C NMR (125 MHz, CDCl3): δ = 152.8, 145.7, 137.8, 131.2, 128.6,
127.9, 127.6, 113.5, 112.8, 110.1, 71.1, 47.9, 30.5.
HRMS (ESI): m/z [MH+]: calcd for C15H16NO: 226.1232; found
226.1186.
5-Benzyloxy-1-methoxy-1H-indole (5)
A solution of 30% H2O2 (510 mg, 4.5 mmol) in MeOH (1 mL) was add-
ed to a mixture of 3 (100 mg, 0.45 mmol) and Na2WO4·2H2O (31 mg,
0.09 mmol) in MeOH–H2O (8:1 v/v, 4.5 mL) at 0 °C under stirring at r.t.
After 15 min, a solution of K2CO3 (315 mg, 2.3 mmol) and dimethyl
sulfate (121 mg, 0.9 mmol) in MeOH (1 mL) was added to the mixture.
After stirring at r.t. for 0.5 h, the reaction was quenched with H2O (30
mL) and the mixture was extracted with CHCl3 (3 × 50 mL), washed
with H2O (30 mL) and brine (2 × 20 mL), and dried over MgSO4. The
solvent was removed, and the residue was purified by silica gel col-
umn chromatography (EtOAc–hexane, 1:5) to give 5.
Yield: 308 mg (76%); colorless solid; mp 170–171 °C (EtOAc–hexane).
IR (CHCl3): 1678, 1541, 1476, 1450, 1383, 1177 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 10.01 (s, 1 H), 8.79 (s, 1 H), 7.94 (d,
J = 8.6 Hz, 1 H), 7.83 (d, J = 9.2 Hz, 1 H), 7.64 (d, J = 2.3 Hz, 1 H), 7.39–
7.43 (m, 4 H), 7.34 (t, J = 7.4 Hz, 2 H), 7.28 (t, J = 7.4 Hz, 1 H), 7.10 (dd,
J = 9.2, 2.3 Hz, 2 H), 5.09 (s, 2 H), 2.30 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): δ = 187.3, 156.8, 147.0, 139.5, 137.4,
133.9, 131.1, 129.5, 129.0, 128.4, 128.2, 127.7, 127.4, 122.0, 116.3,
114.7, 105.7, 70.2, 21.6.
Yield: 51 mg (45%); colorless solid; mp 56–58 °C (CHCl3–hexane).
HRMS (EI): m/z [M+] calcd for C23H19NO4S2: 405.1035; found:
405.1005.
IR (CHCl3): 1460, 1144 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.48 (d, J = 7.5 Hz, 2 H), 7.40 (t, J =
7.5 Hz, 2 H), 7.32–7.36 (m, 2 H), 7.24 (d, J = 3.4 Hz, 1 H), 7.14 (d, J =
2.3 Hz, 1 H), 7.01 (dd, J = 9.2, 2.3 Hz, 1 H), 6.27 (dd, J = 3.5, 1.2 Hz,
1 H), 5.11 (s, 2 H), 4.07 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

G
T. Abe et al.
Special Topic
Synthesis
13C NMR (125 MHz, CDCl3): δ = 153.7, 137.7, 128.6, 127.9, 127.6,
127.6, 124.8, 123.7, 113.6, 109.2, 104.5, 97.7, 71.0, 66.0.
HRMS (ESI): m/z [MNa+] calcd for C16H15NO2Na: 276.1001; found:
276.0986.
13C NMR (125 MHz, CDCl3): δ = 174.3, 155.5, 146.5, 145.1, 137.0,
135.0, 132.5, 130.5, 130.2, 130.0, 128.6, 128.0, 127.7, 126.9, 126.2,
125.5, 124.7, 122.8, 119.5, 115.1, 114.6, 113.6, 112.9, 110.0, 104.1,
70.2, 59.8, 55.3, 52.4, 34.0, 21.7.
HRMS (ESI): m/z [MH+] calcd for C35H32N3O6S: 622.2012; found:
622.2012.
5-Benzyloxy-1-methoxy-1H-indole-3-carboxaldehyde (4d)
Phosphoryl chloride (0.24 mL, 2.6 mmol) was added to DMF (1.5 mL)
at –30 °C and the solution was stirred at r.t. for 0.5 h. A solution of
5(321 mg, 1.3 mmol) in DMF (0.5 mL) was added and the mixture was
stirred at r.t. for 1 h. The mixture was cooled to 0 °C and the reaction
was quenched with 10% aq NaOH, and stirred at r.t. for 0.5 h. The mix-
ture was extracted with EtOAc (3 × 50 mL), washed with H2O (30 mL)
and brine (2 × 20 mL), and dried over MgSO4. The solvent was re-
moved, and the residue was purified by silica gel column chromatog-
raphy (EtOAc–hexane, 1:2) to give 4d.
Methyl (4S,6R)-6-(5-Benzyloxy-1-tosyl-1H-indol-3-yl)-7-hydroxy-
3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-4-carboxylate (7b)
24
Colorless solid; mp 138–141 °C (CHCl3–hexane); [α]D = –5.6 (c =
0.11 in MeOH).
IR (CHCl3): 3484, 1734, 1460, 1371, 1172 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.07 (br. s, 1 H), 7.81 (d, J = 9.2 Hz, 1 H),
7.54 (d, J = 8.0 Hz, 2 H), 7.45 (d, J = 7.4 Hz, 2 H), 7.39 (t, J = 7.5 Hz, 2 H),
7.31–7.34 (m, 2 H), 7.21 (d, J = 8.6 Hz, 1 H), 7.15 (d, J = 8.0 Hz, 2 H),
7.05 (s, 1 H), 6.98 (dd, J = 9.1, 2.3 Hz, 1 H), 6.79 (s, 1 H), 6.75 (d, J =
8.6 Hz, 1 H), 6.07 (s, 1 H), 5.02 (s, 2 H), 3.66 (dd, J = 12.3, 2.8 Hz, 1 H),
3.52 (s, 3 H), 3.43 (dd, J = 16.0, 2.8 Hz, 1 H), 3.02 (dd, J = 15.5, 12.6 Hz,
1 H), 2.32 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 174.5, 155.9, 145.2, 144.7, 137.2,
134.8, 132.7, 131.3, 131.0, 129.8, 128.7, 128.1, 127.8, 127.1, 126.7,
126.1, 123.5, 122.9, 120.7, 115.0, 114.9, 112.7, 112.5, 110.8, 104.2,
70.6, 54.9, 53.1, 52.1, 34.3, 21.6.
Yield: 334 mg (94%); colorless solid; mp 108–109 °C (CHCl3–hexane).
IR (CHCl3): 1661, 1458, 1368, 1103 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 9.90 (s, 1 H), 7.91 (d, J = 2.3 Hz, 1 H),
7.82 (s, 1 H), 7.49 (d, J = 6.9 Hz, 2 H), 7.40 (t, J = 7.4 Hz, 2 H), 7.37 (d, J =
9.2 Hz, 1 H), 7.33 (t, J = 7.5 Hz, 1 H), 7.09 (dd, J = 9.2, 2.3 Hz, 1 H), 5.14
(s, 2 H), 4.16 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 185.2, 156.3, 137.1, 131.8, 128.7,
128.1, 127.8, 122.5, 116.0, 113.8, 109.8, 104.7, 70.7, 67.1.
HRMS (ESI): m/z [MH+] calcd for C35H32N3O6S: 622.2012; found:
622.2036.
HRMS (ESI): m/z [MNa+] calcd for C17H15NNaO3: 304.0950; found:
304.0901.
Methyl (1S,3S)-1-(5-Benzyloxy-1-tosyl-1H-indol-3-yl)-6-hydroxy-
2,3,4,9-tetrahydro-9H-β-carboline-3-carboxylate (8a)
Pictet–Spengler Reaction of 6 with 4 under Microwave Irradiation
(Scheme 3)
24
Colorless solid; mp 132–137 °C (CHCl3–hexane); [α]D = –20.0 (c =
To a solution of tryptophan 6 (47 mg, 0.2 mmol) in Et3N–MeOH (1:1,
v/v, 2 mL), 4b (89 mg, 0.22 mmol) was added and the mixture was
stirred for 5 min at r.t. The mixture was heated under reflux for 6 h
using microwave irradiation (50 W). After the mixture had cooled,
the mixture was evaporated. The residue was purified by silica gel
column chromatography (CHCl3–MeOH, 2:1) to give 4a.
0.11 in MeOH).
IR (CHCl3): 3456, 1736, 1597, 1452, 1372, 1171 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.85 (d, J = 9.2 Hz, 1 H), 7.76 (d, J =
8.0 Hz, 2 H), 7.61 (s, 1 H), 7.37 (s, 1 H), 7.21–7.27 (m, 7 H), 6.99 (d, J =
8.6 Hz, 1 H), 6.95 (dd, J = 9.2, 2.3 Hz, 1 H), 6.92 (d, J = 2.3 Hz, 1 H), 6.75
(d, J = 2.3 Hz, 1 H), 6.71 (dd, J = 8.6, 2.3 Hz, 1 H), 5.41 (s, 1 H,), 4.76 (s,
2 H), 3.95 (dd, J = 10.9, 4.0 Hz, 1 H), 3.78 (s, 3 H), 3.13 (dd, J = 13.8,
4.0 Hz, 1 H), 2.88 (ddd, J = 14.9, 11.5, 2.3 Hz, 1 H), 2.36 (s, 3 H).
Yield: 28 mg (55%).
Pictet–Spengler Reaction of 6 with 4; Typical Procedure (Table 1)
13C NMR (125 MHz, CDCl3): δ = 173.1, 155.5, 149.7, 145.3, 136.8,
135.1, 134.5, 131.4, 130.4, 130.1, 129.9, 128.6, 127.9, 127.9, 127.5,
127.0, 125.8, 121.2, 115.1, 114.6, 111.8, 111.6, 108.1, 104.2, 103.1,
70.4, 56.9, 52.4, 50.8, 25.7, 21.7.
HRMS (ESI): m/z [MH+] calcd for C35H32N3O6S: 622.2012; found:
622.2009.
To a solution of 6 (47 mg, 0.2 mmol) in MeOH (2 mL), 4b (89 mg, 0.22
mmol) was added. After stirring at reflux for 24 h, the mixture was
cooled to r.t. and concentrated in vacuo. The residue was purified by
silica gel column chromatography (CHCl3–MeOH–29% NH4OH,
46:1:0.1) to give 7(36 mg, 29% yield),8(5 mg, 4% yield), and9 (10 mg,
8% yield). Analytical samples7a, 7b, 8a and8b were obtained by fur-
ther purification using silica gel column chromatography (CHCl3–
MeOH–29% NH4OH, 46:1:0.1).
Methyl (1R,3S)-1-(5-Benzyloxy-1-tosyl-1H-indol-3-yl)-6-hydroxy-
2,3,4,9-tetrahydro-9H-β-carboline-3-carboxylate (8b)
Methyl (4S,6S)-6-(5-Benzyloxy-1-tosyl-1H-indol-3-yl)-7-hydroxy-
3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-4-carboxylate (7a)
Colorless solid; mp 108–111 °C (CHCl3–hexane); [α]D24 = 4.5 (c = 0.10
24
Colorless solid; mp 129–132 °C (CHCl3–hexane); [α]D = –6.9 (c =
0.11 in MeOH).
IR (CHCl3): 3462, 1734, 1597, 1452, 1371, 1173 cm–1
.
in MeOH).
1H NMR (500 MHz, CDCl3): δ = 7.83 (d, J = 9.2 Hz, 1 H), 7.70 (d, J =
8.6 Hz, 2 H), 7.60 (s, 1 H), 7.27–7.32 (m, 6 H), 7.19 (d, J = 8.6 Hz, 2 H),
7.00 (d, J = 8.6 Hz, 1 H), 6.98 (dd, J = 9.2, 2.9 Hz, 1 H), 6.89 (d, J =
2.3 Hz, 1 H), 6.85 (br. s, 1 H), 6.69 (dd, J = 9.2, 2.3 Hz, 1 H), 5.57 (s,
1 H), 4.81 (s, 2 H), 3.85 (t, J = 6.3 Hz, 1 H), 3.68 (s, 3 H), 3.07 (dd, J =
15.5, 5.2 Hz, 1 H), 3.00 (dd, J = 14.9, 6.9 Hz, 1 H), 2.32 (s, 3 H).
IR (CHCl3): 3480, 1757, 1452, 1371, 1171 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.12 (br. s, 1 H), 7.80 (d,J = 9.2 Hz, 1 H),
7.69 (d, J = 8.6 Hz, 2 H), 7.48 (s, 1 H), 7.25–7.34 (m, 5 H), 7.20 (d, J =
8.0 Hz, 2 H), 7.12 (d, J = 8.5 Hz, 2 H), 7.02 (s, 1 H), 6.92 (dd, J = 9.2,
2.5 Hz, 1 H), 6.87 (d, J = 2.5 Hz, 1 H), 6.64 (d, J = 8.5 Hz, 1 H), 5.72 (s,
1 H), 4.74 (s, 2 H), 3.93 (dd, J = 12.0, 2.3 Hz, 1 H), 3.67 (s, 3 H), 3.41
(dd, J = 14.9, 2.3 Hz, 1 H), 3.11 (dd, J = 14.9, 12.9 Hz, 1 H), 2.32 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

H
T. Abe et al.
Special Topic
Synthesis
13C NMR (125 MHz, CDCl3): δ = 174.2, 155.6, 149.8, 145.2, 136.9,
135.0, 133.2, 131.4, 130.4, 130.2, 130.0, 128.6, 128.0, 127.7, 126.9,
125.8, 123.0, 115.0, 114.8, 111.8, 107.8, 103.7, 103.3, 70.4, 53.0, 52.3,
47.2, 24.6, 21.7.
13C NMR (125 MHz, CDCl3): δ = 174.8, 155.1, 149.9, 145.3, 137.4,
132.7, 130.9, 130.6, 128.6, 128.0, 127.7, 126.1, 122.8, 121.1, 120.6,
116.0, 114.5, 112.9, 112.5, 110.6, 104.2, 83.9, 70.6, 55.1, 53.2, 52.2,
34.3, 28.3.
HRMS (ESI): m/z [MH+] calcd for C35H32N3O6S: 622.2012; found:
HRMS (ESI): m/z [MH+] calcd for C33H34N3O6: 568.2448; found:
622.2007.
568.2434.
Methyl N-(5-Benzyloxy-1-tosyl-1H-indol-3-yl)methylene-5-hy-
droxytryptophanate (9)
Methyl (4S,6R)-6-(5-Benzyloxy-1H-indol-3-yl)-7-hydroxy-3,4,5,6-
tetrahydro-1H-azepino[5,4,3-cd]indole-4-carboxylate (7c)
24
Colorless solid; mp 97–102 °C (CHCl3–hexane); [α]D = –147.6 (c =
0.10 in MeOH).
Magnesium turnings (242 mg, 10 mmol) was added to a solution of
7b (250 mg, 0.4 mmol) in MeOH (20 mL). After stirring at r.t. for 1 h
under N2 atmosphere, the mixture was quenched by addition of sat.
aq NH4Cl (50 mL). The mixture was extracted with EtOAc (3 × 50 mL),
washed with brine (2 × 20 mL), and dried over MgSO4. The solvent
was removed, and the residue was purified by silica gel column chro-
matography (EtOAc–hexane, 1:2) to give 7c.
IR (CHCl3): 3480, 1736, 1641, 1450, 1379, 1173 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.96 (br. d, J = 2.3 Hz, 1 H), 7.91 (s, 1 H),
7.84 (br. s, 1 H), 7.81 (d, J = 9.2 Hz, 1 H),7.70 (d, J = 8.6 Hz, 2 H), 7.60
(br. s, 1 H), 7.46 (d, J = 7.5 Hz, 2 H), 7.37 (t, J = 7.5 Hz, 2 H), 7.29 (t, J =
7.5 Hz, 1 H), 7.19 (d,J = 8.6 Hz, 2 H), 7.10 (d, J = 8.6 Hz, 1 H), 7.03 (dd,
J = 9.2, 2.9 Hz, 1 H), 6.92 (d, J= 2.3 Hz, 1 H), 6.83 (d, J = 2.3 Hz, 1 H),
6.66 (dd, J = 8.6, 2.3 Hz, 1 H), 5.09 (dd, J = 18.3, 12.1 Hz, 2 H), 4.12 (dd,
J = 8.6, 4.5 Hz, 1 H), 3.74 (s, 3 H), 3.43 (dd, J = 14.3, 4.6 Hz, 1 H), 3.19
(dd, J = 14.3, 8.6 Hz, 1 H), 2.33 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 172.9, 156.6, 156.1, 149.5, 145.5,
137.2, 134.9, 131.4, 130.8, 130.1, 130.1, 129.0, 128.7, 128.1, 127.8,
127.0, 124.6, 119.9, 115.6, 114.2, 111.9, 111.8, 111.0, 106.7, 103.7,
74.3, 70.5, 52.3, 29.9, 21.7.
Yield: 137 mg (73%); colorless solid; mp 127–129 °C (CHCl3–MeOH);
[α]D24 = –2.1 (c = 0.11 in MeOH).
IR (CHCl3): 3478, 1732, 1583, 1483, 1454, 1439, 1192 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 10.46 (br s, 1 H), 10.31 (br s, 1 H),
7.98 (s, 1 H), 7.41 (d, J = 7.5 Hz, 2 H), 7.37 (t, J = 7.5 Hz, 2 H), 7.29 (t, J =
7.5 Hz, 1 H), 7.15 (br s, 1 H), 7.13 (d, J= 9.2 Hz, 1 H), 7.05 (d, J= 8.6 Hz,
1 H), 7.00 (s, 1 H), 6.69 (dd, J = 9.2, 2.3 Hz, 1 H), 6.61 (d, J = 8.6 Hz,
1 H), 6.22 (s, 1 H), 6.05 (s, 1 H), 4.69 (dd, J = 21.2, 12.6 Hz, 2 H), 3.68
(dd, J = 12.1, 2.9 Hz, 1 H), 3.48 (s, 3 H), 3.26 (dd, J = 15.5, 2.9 Hz, 1 H),
2.85 (dd, J = 15.5, 12.0 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 175.3, 152.3, 146.1, 138.3, 132.5,
132.1, 128.9, 128.2, 128.2, 127.8, 126.9, 125.9, 123.2, 122.3, 116.6,
112.3, 111.9, 111.6, 111.5, 109.9, 103.7, 70.2, 55.3, 53.2, 52.1, 34.8.
HRMS (ESI): m/z [MH+] calcd for C35H32N3O6S: 622.2012; found:
622.2005.
Isomerization of cis-Isomer 7a to trans-Isomer 7b
After a solution of7a (19 mg, 0.03 mmol) in MeOH (3 mL) was stirred
and heated at reflux for 30 h, the mixture was cooled to r.t. and con-
centrated in vacuo. The residue was purified by silica gel column
chromatography (CHCl3–MeOH–29% NH4OH, 46:1:0.1) to give 7b.
HRMS (ESI): m/z [MH+] calcd for C28H26N3O4: 468.1923; found:
468.1911.
Methyl (4S,6R)-6-(5-Hydroxy-1H-indol-3-yl)-7-hydroxy-3,4,5,6-
tetrahydro-1H-azepino[5,4,3-cd]indole-4-carboxylate (12)
Yield: 16 mg (87%).
10% Pd-C (49 mg, 0.05 mmol) was added to a solution of 7c (50 mg,
0.1 mmol) in MeOH (5 mL). After stirring at r.t. for 0.5 h under H2 at-
mosphere, the mixture was filtered through a pad of Celite and the
precipitates were washed with MeOH. The solvent was removed, and
the residue was purified by silica gel column chromatography (CHCl3–
MeOH–29% NH4OH, 46:1:0.1) to give 12.
Base-Promotedtrans-Selective Pictet–Spengler Reaction of 6 with
4; Typical Procedure
1,4-Diazabicyclo[2.2.2]octane (67 mg, 0.6 mmol) was added to a mix-
ture of 6 (47 mg, 0.2 mmol) and 4c (77 mg, 0.22 mmol) in 2,2,2-triflu-
oroethanol (2 mL). After stirring at reflux for 4 h, the mixture was
cooled to r.t. and concentrated in vacuo. The residue was purified by
silica gel column chromatography (CHCl3–MeOH–29% NH4OH,
46:1:0.1) to give 7d.
Yield: 28 mg (70%); colorless solid; mp 159–160 °C (CHCl3–MeOH);
[α]D24 = 19.1 (c = 0.11 in MeOH).
IR (CHCl3): 3418, 1732, 1483, 1454, 1437, 1192 cm–1
.
Yield: 75 mg (66%).
1H NMR (500 MHz, DMSO-d6): δ = 10.42 (br. s, 1 H), 10.09 (br. s, 1 H),
8.29 (s, 1 H), 7.92 (s, 1 H), 7.03 (d, J = 8.0 Hz, 1 H), 6.97 (br. s, 1 H), 6.59
(d, J = 8.6 Hz, 1 H), 6.53 (dd, J = 8.6, 2.3 Hz, 1 H), 6.04 (d, J = 1.7 Hz,
1 H), 6.00 (s, 1 H), 3.71 (dd, J = 11.5, 2.9 Hz, 1 H), 3.49 (s, 3 H), 3.25
(dd, J = 14.9, 2.9 Hz, 1 H), 2.83 (dd,J = 14.9, 12.6 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 175.1, 150.6, 146.1, 132.3, 132.0,
128.2, 127.0, 125.5, 123.0, 122.6, 116.1, 111.8, 111.8, 111.6, 111.6,
109.8, 104.4, 55.3, 53.1, 52.0, 34.6.
Methyl (4S,6R)-6-(5-Benzyloxy-1-tert-butoxycarbonyl-1H-indol-3-
yl)-7-hydroxy-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-4-
carboxylate (7d)
Yield: 75 mg (66%); colorless solid; mp 133–135 °C (CHCl3–hexane);
[α]D24 = 5.2 (c = 0.11 in MeOH).
IR (CHCl3): 3480, 1723, 1381, 1157 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.09 (br. s, 1 H), 7.90 (br. s, 1 H), 7.48
(d, J = 7.5 Hz, 2 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.31–7.37 (m, 2 H), 7.15 (d,
J = 8.0 Hz, 1 H), 6.97–6.99 (m, 2 H,), 6.93 (br. s, 1 H), 6.73 (d, J = 8.6 Hz,
1 H), 6.13 (s, 1 H), 5.05 (s, 2 H), 3.88 (dd, J = 12.6, 2.9 Hz, 1 H), 3.58 (s,
3 H), 3.48 (dd, J = 15.5, 2.9 Hz, 1 H), 3.06 (ddd, J = 14.9, 12.6, 1.1 Hz,
1 H), 1.58 (s, 9 H).
HRMS (ESI): m/z [MH+] calcd for C21H20N3O4: 378.1454; found:
378.1429.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

I
T. Abe et al.
Special Topic
Synthesis
Methyl (S)-2-Acetamino-3-(10-acetoxy-3H-pyrano[2,3-b:5,6-e′]di-
IR (CHCl3): 3478, 1732, 1438 cm–1
.
indol-1-yl)propanoate (13)
1H NMR (500 MHz, DMSO-d6): δ = 10.63 (d, J = 2.3 Hz, 1 H), 8.31 (s,
1 H), 7.13 (t, J = 7.5 Hz, 2 H), 7.06–7.09 (m, 1 H), 7.06 (d, J = 8.6 Hz,
1 H), 7.02 (br. s, 1 H), 6.93 (d, J = 7.5 Hz, 2 H), 6.59 (d, J = 8.6 Hz, 1 H),
5.78 (s, 1 H), 3.53 (s, 3 H), 3.36 (dd, J = 12.6, 2.3 Hz, 1 H), 3.22 (dd, J =
15.5, 2.3 Hz, 1 H), 2.82 (ddd, J = 15.5, 12.6, 1.2 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 174.8, 146.4, 144.1, 132.0, 128.8,
128.1, 127.1, 126.7, 123.3, 120.0, 111.4, 111.4, 110.4, 59.2, 55.3, 52.3,
34.4.
Compound 12 (38.0 mg, 0.10 mmol) was added to a suspension of
10% Pd-C (53.2 mg, 0.05 mmol) and TfOH ( 0.02 mL, 0.23 mmol) in
MeOH (4 mL) under N2 atmosphere. After stirring at r.t. for 20 h, the
mixture was filtered and the precipitates were washed with MeOH,
and evaporated in vacuo. Ac2O (0.05 mL, 0.53 mmol), Et3N (0.08 mL,
0.58 mmol) and DMAP (14.0 mg, 0.01 mmol) were added to a solution
of obtained crude product in THF (2 mL). After stirring at r.t. for 2 h,
the reaction was quenched with H2O. The mixture was extracted with
EtOAc (3 × 10 mL), washed with brine (10 mL), and dried over K2CO3.
The solvent was removed, and the residue was purified by silica gel
column chromatography (CHCl3–MeOH–29% NH4OH, 46:3:0.3) to
give 14.
HRMS (ESI): m/z [MH+] calcd for C19H19N2O3: 323.1396; found:
323.1367.
Methyl (R)-7-Hydroxy-6-phenyl-5,6-dihydro-1H-azepino[5,4,3-
cd]indole-4-carboxylate (17)
Yield: 22 mg (47%); orange solid; mp 280–285 °C (CHCl3–hexane);
[α]D24 = –23.6 [c = 0.10 in MeOH–TFA, 99:1, v/v)].
To a solution of 5 mol% 1,10-phenanthroline-5,6-dione (phd, 2 mg,
0.01 mmol), 2.5 mol% ZnI2 (1.6 mg, 0.005 mmol), and 15 mol% PPTS
(7.5 mg, 0.03 mmol) in DMF (1 mL) and MeCN (2 mL) was added 15
(65 mg, 0.2 mmol). After stirring at r.t. for 100 h under an O2 atmo-
sphere (1 atm), the mixture was concentrated in vacuo, and the resi-
due was purified by silica gel column chromatography (EtOAc–hex-
ane, 1:2) to give 17.
IR (CHCl3): 1740, 1647, 1427, 1319, 1184 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 11.62 (br. s, 1 H), 9.35 (s, 1 H), 8.50
(d, J = 7.5 Hz, 1 H), 7.98 (d, J = 2.3 Hz, 1 H), 7.83 (d, J = 8.6 Hz, 1 H),
7.56 (d, J = 9.2 Hz, 1 H), 7.55 (d, J = 8.6 Hz, 1 H), 7.45 (d, J = 2.3 Hz,
1 H), 7.21 (dd, J = 8.6, 2.3 Hz, 1 H), 4.65—4.69 (m, 1 H), 3.64 (s, 3 H),
3.55 (dd, J = 15.5, 5.8 Hz, 1 H), 2.94 (dd, J = 15.5, 8.6 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 172.7, 170.4, 170.3, 164.5, 150.2,
148.2, 145.7, 133.4, 130.6, 128.3, 124.5, 123.0, 123.0, 122.4, 119.1,
117.8, 115.8, 112.1, 111.9, 111.8, 53.4, 52.6, 29.7, 22.9, 21.4.
Yield: 14 mg (22%); colorless solid; mp 260–266 °C (CHCl3–hexane);
[α]D24 = 165.6 (c = 0.10 in MeOH).
IR (KBr): 3314, 1667, 1632, 1462, 1427, 1246 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 11.17 (d, J = 1.7 Hz, 1 H), 8.73 (s,
1 H), 7.39 (d, J = 2.9 Hz, 1 H), 7.11 (d, J = 8.6 Hz, 1 H), 7.06 (t, J = 7.5 Hz,
2 H), 6.98—7.02 (m, 1 H), 6.89 (d, J = 7.5 Hz, 2 H), 6.78 (d, J = 1.7 Hz,
1 H), 6.68 (d, J = 8.6 Hz, 1 H), 6.03 (d, J = 6.3 Hz, 1 H), 5.83 (dd, J = 6.3,
1.7 Hz, 1 H), 3.61 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): δ = 167.1, 146.5, 145.2, 131.6, 128.2,
128.2, 128.0, 126.9, 126.4, 125.9, 119.4, 113.8, 112.3, 111.1, 110.9,
56.6, 52.4.
HRMS (ESI): m/z [MH+] calcd for C25H25N3O6: 462.1665; found:
460.1527.
Methyl (S)-7-Hydroxy-3,4-dihydro-1H-azepino[5,4,3-cd]indole-4-
carboxylate (14)
A solution of 12 (18.6 mg, 0.05 mmol) in MeOH (2.5 mL) was heated
at reflux for 10 h. The mixture was cooled to r.t. and concentrated in
vacuo, and the residue was purified by silica gel column chromatog-
raphy (CHCl3–MeOH–29% NH4OH, 46:3:0.3) to give 1(4 mg, 53% yield)
and 14.
HRMS (ESI): m/z [MH+] calcd for C19H17N2O3: 321.1239; found:
321.1256.
Yield: 7 mg (61%); yellow solid; mp 136–140 °C (CHCl3–hexane);
[α]D24 = –10.8 [c = 0.02 in MeOH–TFA, 99:1, v/v)].
IR (KBr): 3198, 1742, 1609, 1435, 1252, 1231, 1165 cm–1
Acknowledgment
.
1H NMR (500 MHz, DMSO-d6): δ = 10.71 (br. s, 1 H), 8.42 (br. s, 1 H),
7.24 (d, J = 9.2 Hz, 1 H), 6.97 (s, 1 H), 6.37 (br. d, J = 7.5 Hz, 1 H), 4.31
(d, J = 7.5 Hz, 1 H), 3.64 (s, 3 H), 3.23 (d, J = 15.5 Hz, 1 H), 2.94 (dd, J =
15.5, 8.1 Hz, 1 H).
This work was financially supported by a Grant-in-Aid for Young Sci-
entists (B) (Grant No. 16K18849 for T. A.) from the Japan Society for
the Promotion of Science (JSPS).
13C NMR (125 MHz, DMSO-d6): δ = 172.6, 154.9, .8, 125.3, 122.5,
121.4, 115.9, 4.0, 110.1, 62.6, 52.5, 31.1.
Supporting Information
HRMS (ESI): m/z [MH+] calcd for C13H13N2O3: 245.0926; found:
Supporting information for this article is available online at
245.0923.
https://doi.org/10.1055/s-0036-1588438.
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Methyl (4S,6R)-7-Hydroxy-6-phenyl-3,4,5,6-tetrahydro-1H-azepi-
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References
1,4-Diazabicyclo[2.2.2]octane (70 mg, 0.6 mmol) was added to a mix-
ture of 6 (468 mg, 2 mmol) and benzaldehyde (0.6 mL, 6 mmol) in
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ture was cooled to r.t. and concentrated in vacuo, and the residue was
purified by silica gel column chromatography (EtOAc–hexane, 1:1) to
give 15.
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Special Topic
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J