Total synthesis of (±)-hyrtiazepine

Article abstract of DOI:10.1016/j.tet.2011.01.029

The total synthesis of the azepinoindole alkaloid, (±)-hyrtiazepine, was achieved. Construction of the azepinoindole core structure was carried out by C-4 selective α-hydroxyalkylation of 5-hydroxyindole, introduction of serine at C-3 of the indole moiety, and intramolecular imination.

Full text of DOI:10.1016/j.tet.2011.01.029

Tetrahedron 67 (2011) 1805e1811
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Total synthesis of (ꢀ)-hyrtiazepine
,
b
a,
*
Fumihiro Ito a , Koichi Shudo , Kentaro Yamaguchi
*
a Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2101, Japan
b Research Foundation Itsuu Laboratory, 2-28-10 Tamagawa, Setagaya-ku, Tokyo 158-0094, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of the azepinoindole alkaloid, (ꢀ)-hyrtiazepine, was achieved. Construction of the
Received 22 December 2010
Received in revised form 11 January 2011
Accepted 12 January 2011
azepinoindole core structure was carried out by C-4 selective a-hydroxyalkylation of 5-hydroxyindole,
introduction of serine at C-3 of the indole moiety, and intramolecular imination.
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 15 January 2011
Keywords:
Total synthesis
Hyrtiazepine
ortho Selective a-hydroxyalkylation
1. Introduction
intermolecular
imination
ortho-selective
hydroxyalkylation
H
N
P
N
CO2H
N
Hyrtiazepine (1), an azepinoindole alkaloid, was initially isolated
from the marine sponge Hyrtios erectus by Bourguet-Kondracki and
co-workers in 2006.1 The unique heterocyclic structure of 1, which
includes two 5-hydroxyindoles and a seven-membered ring thought
to be a significant structure in medicinal chemistry, has prompted us
to investigate its total synthesis. To our knowledge, the total synthesis
RHN
O
HO
CO2P
PO
HO
PO
N
H
N
P
(
)-hyrtiazepine (1)
2
of 1 has not been achieved by any group so far. The ortho selective a-
hydroxyalkylation reaction reported by Nagata and Aoki in 19792 is
one of the versatile CeC bond forming reactions and its aromatic
version is the most useful method for the preparation of 2-
CHO
HO
MeO
(a
-hydroxyalkyl)phenols.3 Although the low regioselectivity for the
N
P
N
P
addition of a carbon unit is usuallyencountered by phenol derivatives
used as substrates, in the case of 5-hydroxyindole derivatives, a se-
lectivity at C-4 position of the indole is known.3b The selectivity is
dependent on the stability of the intermediate, similar to the Claisen
rearrangement observed in the case of 5-hydroxyindole.4 Therefore,
we attempted the first total synthesis of hyrtiazepine (1) from
3
4
Scheme 1. Retrosynthesis of (ꢀ)-hyrtiazepine (1).
a
-hydroxyalkylation, followed by intramolecular imination.5 We
envisioned that the application of this strategy would produce the
azepinoindole core of 1 effectively. We examined the -hydroxy-
5-hydroxyindole by using the ortho selective
a-hydroxyalkylation
reaction. Herein we report the total synthesis of (ꢀ)-hyrtiazepine (1).
a
alkylation of 5-hydroxyindoles 8a and
carbaldehydes 10a and b. These substrates for
b
with 3-methoxy-
-hydroxyalkylation
2. Results and discussion
a
were prepared from commercially available 5-hydroxyindole (5)
and 3-methoxyindolecarbaldehyde (9), respectively (Scheme 2). N-
Benzyl 5-hydroxyindole 8a was prepared according to the litera-
ture.6 On the other hand, N-tosyl 5-hydroxyindole 8b7 was prepared
as follows. After silylation of the hydroxyl group with TBSCl in DMF
and tosylation of 6 with TsCl in THF, resulting 7 was converted into
8b with 6 N HCl aq in THF in 78% yield from 5. Indolecarbaldehydes
The retrosynthesis is shown in Scheme 1. Construction of the
azepinoindole core structure was achieved by ortho selective
* Corresponding authors. Tel.: þ81 87 894 5111; fax: þ81 87 894 0181; e-mail
addresses: h-itoh@kph.bunri-u.ac.jp (F. Ito), yamaguchi@kph.bunri-u.ac.jp
(K. Yamaguchi).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.029

1806
F. Ito et al. / Tetrahedron 67 (2011) 1805e1811
HO
HO
TBSO
Ts
N
(c)
(a)
2'
N
P
H
N
H
N
P
5
8a: P = Bn
8b: P = Ts
3'
6: P = H
(b)
OH
7: P = Ts
8
H
H
CHO
CHO
4
O
H
3
MeO
(d) for 10a
(e) for 10b
MeO
H
5
N
P
N
6
H
N
9
10a: P = Bn
10b: P = Ts
Ts
Fig. 1. Selected HMBC correlations of phenol 12.
Scheme 2. Preparation of N-Ts 5-hydroxyindole 8b and carbaldehydes 10a and b.
Reagents and conditions: (a) TBSCl, imidazole, DMF, rt, 0.5 h; (b) TsCl, NaH, THF, rt, 2 h
(96%); (d) 6 N HCl aq, THF, reflux, 2 h (78% from 5); (d) BnBr, K2CO3, DMF, rt, 24 h
(96%); (e) TsCl, NaH, THF, rt, 3 h (94%).
MeO
MeO
10a8 and b were prepared by benzylation and tosylation in 96% and
94% yields, respectively.
NTs
NP
Next, the ortho selective a-hydroxyalkylation of 8a and b with
10a and b was examined (Table 1). In the case of N-benzyl protected
indoles, desired borate 11 or phenol 12 was not produced by the
HO
O
(b)
(d)
PO
MeO
(c)
a
-hydroxyalkylation (runs 1e3). In contrast, in the case of the tosyl
N
N
moiety as the protecting group in indole, desired 12 was obtained
in 77% yield from 8b (run 4). We thought that the complex mixtures
(runs 1e3) were produced by the activation at C-3 position of the
indole moiety by the benzyl group. The assignment of 12 was de-
termined from the HMBC correlations of both the aromatic protons
(H-6 and 20) with a carbon (C-8) and the proton (H-8) with carbons
(C-4, 5, and 30) (Fig. 1).
Ts
12: P = H
Ts
14: P = Ts
(a)
13: P = Me
15: P = H
MeO
Bn
N
Table 1
AcHN
CO2P
O
MeO
ortho Selective a-hydroxyalkylation of 5-hydroxyindoles 8 and indolecarbaldehydes
10
NBn
O
(f)
MeO
HO
MeO
N
H
N
MeO
MeO
O
P
N
P
8a: P = Bn
8b: P = Ts
16: P = Ts
18: P = H
(b)
(a)
NP
(e)
(g)
NP
HO
HO
Ph
CHO
17: P = H
19: P = Me
B
O
MeO
Scheme 3. Preparation of methyl ester 19. Reagents and conditions: (a) MeI, K2CO3,
DMF, rt, 2 h (75%); (b) IBX, DMSO, rt, 2 h (86%); (c) KOH, MeOH, rt, 0.5 h (92%); (d)
BnBr, K2CO3, DMF, rt, 2 h (98%); (e) KOH, MeOH, reflux, 3 h (84%); (f) serine, Ac2O,
AcOH, 80 ꢁC, 2 h (82%); (g) MeI, K2CO3, DMF, rt, 0.5 h (88%).
N
P
N
P
N
P
11
12
10a: P = Bn
10b: P = Ts
Table 2
Run
5-OH-indole
Carbaldehyde
Results
Intramolecular imination of methyl ester 19
1
2
3
4
8a
8a
8b
8b
10a
10b
10a
10b
Complex mixtures
Complex mixtures
Complex mixtures
77%
Bn
Bn
N
N
CO2Me
AcHN
N
CO2Me
reagent
O
MeO
MeO
Reagents and conditions: (a) PhB(OH)2, EtCO2H, toluene, reflux, 24 h; (b) 30% H2O2
aq, THF, 0 ꢁC, 0.5 h.
MeO
MeO
conditions
solvent
N
H
N
H
Substrate 19 for intramolecular imination5 was prepared as
follows (Scheme 3). After the phenolic hydroxyl group in 12 was
alkylated with MeI in DMF to afford alcohol 13 in 75% yield, the
second hydroxyl group was oxidized with IBX9 in DMSO to obtain
ketone 14 in 86% yield. After one tosyl group in 14 was removed
with KOH in MeOH at room temperature in 92% yield and resulting
15 was alkylated with BnBr in 98% yield, the remaining tosyl group
in 16 was removed in 84% yield. Finally, after carboxylic acid 18 was
obtained by the addition of serine under acidic conditions in 82%
yield,10 18 was converted into methyl ester 19 in 88% yield.11
We tried to perform the intramolecular imination under acidic
conditions (Table 2).5 Complex mixtures were obtained with TFA in
19
20
Run
Reagent
Solvent
Conditions
20
1
2
3
4
TFA
CH2Cl2
THF
MeOH
MeOH
rt 12 h
Complex mixtures
Complex mixtures
6 N HCl
6 N HCl
3 N HCl
Reflux 12 h
Reflux 12 h
Reflux 24 h
24%
40%
CH2Cl2 (run 1) and 6 N HCl aq in THF (run 2). However, desired
azepinoindole 20 was obtained with 6 N HCl aq in MeOH under
reflux in 24% yield (run 3). The assignment of 20 was determined
from the HMBC correlations of both the aromatic proton (H-20) and
the methine proton (H-4) with a carbon (C-6) (Fig. 2). Finally, the

F. Ito et al. / Tetrahedron 67 (2011) 1805e1811
1807
H
Bn
N
7'
H
2'
6
6'
5'
N1'
O
H
H
H
CO2Me
7'a
10
3
N
H
OH
4
2'
H
5
3'a
4
N
3'
2a
HO
6a
4'
MeO
H
H
6
H
H
H
8
6a
2
HO
N
H
7
9b
9a
2a
H
2
Fig. 2. Selected HMBC correlations of azepinoindole 20.
8
N
H
1
9
H
yield was improved to 40% yield by using 3 N HCl aq (run 4). Al-
though we were able to construct the azepinoindole core, all pro-
tecting groups, particularly the benzyl group, were not removed by
the trial based on deprotection of 20 with AlCl3 and BBr3 (Table 3).
H
Fig. 3. HMBC correlations of (ꢀ)-hyrtiazepine (1).
Table 3
Trials for debenzylation of 20
group at N-10 position, selective detosylation at N-1 position seems
difficult. Therefore, after all the tosyl groups in 14 were removed in
92% yield, resulting 22 was retosylated to afford 23 in 85% yield.
Then, carboxylic acid 24 was obtained in 68% yield using the same
method as that for preparing 17, and 24 was converted into methyl
ester 25a and ethyl ester 25b in 82% and 81% yields, respectively.11
Esters 25a and b were examined for potential use in the intra-
molecular imination with 3 N HCl aq. Although methyl ester 25a
gave desired 26a in low yield (23%) when MeOH was used as sol-
vent similar to 19, ethyl ester 25b gave 26b in 70% yield when EtOH
was used as solvent. In the case of imination of 25a in EtOH, ester
exchange occurred. Finally, with the removal of methyl groups and
ethyl ester in 26b with BBr3 in CH2Cl2 and the detosylation of 27
with K2CO3 in MeOH, the total synthesis of (ꢀ)-hyrtiazepine (1) was
achieved in 6.1% yield from 5-hydroxyindole (5). The spectral data,
including HMBC experiments (Fig. 3), were identical with those of
the natural product.
Bn
N
NP1
CO2Me
CO2P2
N
N
reagent
MeO
P2O
MeO
P2O
conditions
solvent
N
N
H
H
20
1: P1 = P2 = H
21: P1 = Bn, P2 = H
Run
Reagent
Solvent
Conditions
Results
1
2
AlCl3
BBr3
Toluene
CH2Cl2
Reflux 3 h
Reflux 2 h
Complex mixtures
21: 3%
Therefore, we exchanged the benzyl group with a tosyl group
(Scheme 4). Since carbonyl group at C-30 position activates tosyl
MeO
MeO
MeO
3. Conclusion
(a)
(b)
NTs
NH
NTs
(c)
O
O
O
We have achieved the first total synthesis of (ꢀ)-hyrtiazepine
MeO
MeO
MeO
(1) by the ortho selective
a-hydroxyalkylation of N-tosyl 5-
hydroxyindole 8b with N-tosyl 3-methoxyindolecarbaldehyde 10b
and the intramolecular imination of 25b in 22 steps from 5 and 20
steps from 9 in 6.1%, and 7.4% overall yields, respectively. Moreover,
N
N
H
N
H
Ts
22
14
23
Ts
N
it is suggested that the ortho selective a-hydroxyalkylation has high
Ts
N
CO2P2
selectivity for the C-4 position of 5-hydroxyindole derivatives and
is useful for the synthesis of 5-hydroxyindole derivatives, similar to
the Claisen rearrangement. Thus, our synthetic method could
provide an efficient route to various natural products having the
5-hydroxyindole core.
AcHN
O
N
CO2P
MeO
(d)
P1O
(f) for 25a
(g) for 25b
MeO
P1O
N
H
N
H
24: P = H
26a: P1
=
P2 = Me
(e)
26b: P1 = Me, P2 = Et
25a: P = Me
25b: P = Et
4. Experimental section
4.1. General
Ts
N
H
N
CO2H
CO2H
All melting points were measured on a Yanaco MP-500D and are
uncorrected. IR spectra were recorded on a JASCO FT/IR-6300
spectrophotometer; ATR¼attenuated total reflectance system. 1H
and 13C NMR spectra were recorded in CDCl3 unless otherwise
stated, on a JEOL JNM-ECP 400 and a Bruker 400 MHz with tetra-
methylsilane (TMS) as the internal reference. ESIMS was recorded
on a JEOL JMS-T100LC mass spectrometer. TLC Silica gel 60 F254 TLC
plates (Merck No. 5715) and NH plates (Fuji Silysia Chemical Ltd.,
No. TO 80817) were used and for column chromatography, spher-
N
N
(h)
(i)
HO
HO
HO
HO
N
N
H
H
27
( )-hyrtiazepine (1)
Scheme 4. Preparation of (ꢀ)-hyrtiazepine (1). Reagents and conditions: (a) KOH, THF,
MeOH, reflux, 0.5 h (92%); (b) TsCl, NEt3, CH2Cl2, rt, 2 h (85%); (c) serine, Ac2O, AcOH,
80 ꢁC, 2 h (68%); (d) MeI, K2CO3, DMF, rt, 2 h (81%); (e) EtI, K2CO3, DMF, rt, 2 h (82%); (f)
3 N HCl aq, MeOH, reflux, 20 h (23%); (g) 3 N HCl aq, EtOH, reflux, 20 h (70%); (h) BBr3,
CH2Cl2, reflux, 3 h; (i) K2CO3, MeOH, reflux, 4 h (52% from 26b).
ical silica gel 60 (particle size 63e210
mm, Kanto Chemical, No.
37565-84 for neutral) and NH silica gel (Fuji Silysia Chemical Ltd.,

1808
F. Ito et al. / Tetrahedron 67 (2011) 1805e1811
particle size 100e200 mesh, No. IO61280 and 200e350 mesh, No.
HU80502) were used.
(100 MHz)
d
: ꢂ4.5,18.2, 21.5, 25.7, 28.8 (CH3),109.0,111.1,114.1,118.1,
126.8, 127.1, 129.8, 130.0, 131.9, 135.3, 144.8, 152.0. HRESIMS: m/z
402.1535 (calcd for C21H28NO3SSi: 402.1559).
4.1.1. 1-Benzyl-5-methoxy-3-1H-indole-carbaldehyde (10a). Under
Ar, to a mixture of K2CO3 (332 mg, 2.40 mmol) and 9 (194 mg,
1.11 mmol) in DMF (2 mL), benzyl bromide (0.2 mL, 1.68 mmol) was
added. The reaction mixture was stirred at room temperature for
24 h. Then, the reaction mixture was poured into water and
extracted with AcOEt. The organic layer was washed with water and
brine, dried over Na2SO4, and evaporated in vacuo. The residue was
purified by SiO2-column chromatography (n-hexane/AcOEt¼1:1) to
give 10a as a colorless powder (283 mg, 96%). Mp: 96e97 ꢁC. IR (ATR,
4.1.5. 1-(Toluene-4-sulfonyl)-1H-indole-5-ol (8b). Under Ar, a mix-
ture of 5 (1.01 g, 7.59 mmol), imidazole (1.02 g, 15.0 mmol), and
tert-butyldimethylsilyl chloride (1.70 g, 11.3 mmol) in DMF (5 mL)
was stirred at room temperature for 0.5 h. The reaction mixture
was diluted with AcOEt, washed with water and brine, dried over
Na2SO4, and evaporated in vacuo. The residue was added to a mix-
ture of NaH (604 mg, 15.1 mmol, 60% in mineral oil) in THF (10 mL).
After the mixture was stirred at room temperature for 10 min, p-
toluenesulfonyl chloride (2.88 g, 15.1 mmol) was added and the
reaction mixture was stirred at room temperature for 2 h. The re-
action mixture was diluted with AcOEt, washed with water and
brine, dried over Na2SO4, and evaporated in vacuo. A solution of the
residue in THF (10 mL) and 6 N HCl aq (20 mL) was refluxed for 2 h.
After cooling to room temperature, the reaction mixture was di-
luted with AcOEt, washed with satd NaHCO3 aq and brine, dried
over Na2SO4, and evaporated in vacuo. The residue was purified by
SiO2-column chromatography (n-hexane/AcOEt¼5:1 to 1:1) to give
8b as a colorless solid (1.69 g, 78% from 5). Mp: 160e161 ꢁC. IR (ATR,
cmꢂ1): 1649.1H NMR (400 MHz)
d: 3.90 (3H, s), 5.33 (2H, s), 6.94 (1H,
dd, J¼8.8, 2.4 Hz), 7.16e7.19 (2H, m), 7.21 (1H, d, J¼8.8 Hz), 7.32e7.39
(3H, m), 7.67 (1H, s), 7.82 (1H, d, J¼2.4 Hz), 9.97 (1H, s). HRESIMS: m/z
266.1195 (calcd for C17H16NO2: 266.1181).
4.1.2. 5-Methoxy-1-(toluene-4-sulfonyl)-3-1H-indole-carbaldehyde
(10b). Under Ar, after a mixture of NaH (115 mg, 2.88 mmol, 60% in
mineral oil) and 9 (160 mg, 0.92 mmol) in THF (3 mL) was stirred at
room temperature for 10 min, p-toluenesulfonyl chloride (353 mg,
1.85 mmol) was added and the reaction mixture was stirred at
room temperature for 3 h. The reaction mixture was poured into
water and extracted with AcOEt. The organic layer was washed
with water and brine, dried over Na2SO4, and evaporated in vacuo.
The residue was purified by SiO2-column chromatography (n-
hexane/AcOEt¼5:1) to give 10b as a colorless powder (283 mg,
94%). Mp: 125e126 ꢁC. IR (ATR, cmꢂ1): 1673, 1366, 1162. 1H NMR
cmꢂ1): 3391, 1369, 1144. 1H NMR (400 MHz)
d: 2.34 (3H, s), 4.72
(1H, br s), 6.54 (1H, d, J¼3.6 Hz), 6.84 (1H, dd, J¼8.8, 2.4 Hz), 6.92
(1H, d, J¼2.4 Hz), 7.21 (2H, d, J¼8.2 Hz), 7.52 (1H, d, J¼3.6 Hz), 7.73
(2H, d, J¼8.2 Hz), 7.85 (1H, d, J¼8.8 Hz). HRESIMS: m/z 326.0224
(calcd for C15H13KNO3S: 326.0253).
(400 MHz)
7.28 (2H, d, J¼8.7 Hz), 7.70 (1H, d, J¼2.4 Hz), 7.82 (3H, d, J¼8.7 Hz),
8.16 (1H, s), 10.1 (1H, s). 13C NMR (100 MHz)
: 21.7, 55.8, 104.0,
114.1, 116.2, 122.3, 127.2, 127.3, 129.7, 130.3, 134.4, 136.6, 146.1, 157.8,
185.5. HRESIMS: m/z 352.0596 (calcd for C17H15NNaO4S: 352.0620).
d
: 2.37 (3H, s), 3.84 (3H, s), 7.00 (1H, dd, J¼8.7, 2.4 Hz),
4.1.6. 4-{Hydroxy-[5-methoxy-1-(toluene-4-sulfonyl)-1H-indol-3-
yl]-methyl}-1-(toluene-4-sulfonyl)-1H-indol-5-ol (12). A solution of
8b (324 mg, 1.13 mmol), 10b (540 mg, 1.64 mmol), benzeneboronic
acid (287 mg, 2.35 mmol), and propanoic acid (0.02 mL, 0.27 mmol)
in toluene (10 mL) was refluxed with azeotropic removal of water
using a DeaneStark type separator for 24 h. After evaporation of the
solvent, the residue was dissolved with CH2Cl2. The organic layer
was washed with satd NaHCO3 aq, water and brine, dried over
Na2SO4, and evaporated in vacuo. A mixture of the residue and 30%
H2O2 aq (3 mL) in THF (5 mL) was stirred at 0 ꢁC for 0.5 h. The re-
action mixture was poured into ice/water and extracted with
CH2Cl2. The organic layer was washed with sodium hydrogen sul-
fite solution and brine, dried over Na2SO4, and evaporated in vacuo.
The residue was purified by SiO2-column chromatography
(n-hexane/AcOEt¼2:1 to 1:1) to give 12 as a yellow powder
(534 mg, 77% from 8b). Mp: 115e118 ꢁC. IR (ATR, cmꢂ1): 3372, 1361,
d
4.1.3. 5-(tert-Butyl-dimethyl-silanyloxy)-1H-indole (6). Under Ar, a
mixture of 5 (2.98 g, 22.4 mmol), imidazole (3.36 g, 49.3 mmol), and
tert-butyldimethylsilyl chloride (3.57 g, 23.7 mmol) in DMF (20 mL)
was stirred at room temperature for 0.5 h. The reaction mixture was
diluted with AcOEt, washed with water and brine, dried over Na2SO4,
and evaporated in vacuo. The residue was purified by SiO2-column
chromatography(n-hexane/AcOEt¼0:1to10:1)togive6asacolorless
oil (5.54 g, quant.). IR (ATR, cmꢂ1): 3416. 1H NMR (400 MHz)
d: 0.21
(6H, s), 1.02 (9H, s), 6.45 (1H, ddd, J¼3.2, 2.1, 0.8 Hz), 6.78 (1H, dd,
J¼8.8, 2.5 Hz), 7.08 (1H, d, J¼2.5 Hz), 7.17 (1H, dd, J¼2.6, 2.6 Hz), 7.24
(1H, dd, J¼8.8, 0.8 Hz). 13C NMR (100 MHz)
d
: ꢂ4.43, 18.2, 25.8, 102.2,
1164. 1H NMR (400 MHz)
d: 2.32 (3H, s), 2.33 (3H, s), 3.34 (1H, br d,
110.1, 111.2, 116.3, 124.8, 128.5, 131.4, 149.3. HRESIMS: m/z 286.1011
J¼2.8 Hz), 3.65 (3H, s), 6.37 (1H, d, J¼3.6 Hz), 6.45 (1H, d, J¼2.8 Hz),
6.87 (1H, dd, J¼9.1, 2.5 Hz), 6.91 (1H, d, J¼9.2 Hz), 7.00 (1H, d,
J¼2.5 Hz), 7.14 (2H, br d, J¼8.3 Hz), 7.207 (1H, s), 7.212 (2H, br d,
J¼8.3 Hz), 7.40 (1H, d, J¼3.6 Hz), 7.58 (2H, d, J¼8.4 Hz), 7.71 (2H, d,
J¼8.4 Hz), 7.78 (1H, d, J¼9.1 Hz), 7.82 (1H, d, J¼9.2 Hz), 7.91 (1H, s).
(calcd for C14H21KNO1Si: 286.1030).
4.1.4. 5-(tert-Butyl-dimethyl-silanyloxy)-1-(toluene-4-sulfonyl)-1H-
indole (7). Under Ar, a mixture of 5 (5.20 g, 39.1 mmol), imidazole
(4.98 g, 73.1 mmol), and tert-butyldimethylsilyl chloride (8.51 g,
56.5 mmol) in DMF (30 mL) was stirred at room temperature for 1 h.
The reaction mixture was diluted with AcOEt, washed with water
and brine, dried over Na2SO4, and evaporated in vacuo. The residue
was added to a mixture of NaH (3.01 g, 75.3 mmol, 60% in mineral
oil) in THF (40 mL). After the mixture was stirred at room temper-
ature for 10 min, p-toluenesulfonyl chloride (14.0 g, 73.4 mmol) was
added and the reaction mixture was stirred at room temperature for
2 h. The reaction mixture was diluted with AcOEt, washed with
water and brine, dried over Na2SO4, and evaporated in vacuo. The
residue was purified by NH-column chromatography (n-hexane/
AcOEt¼5:1) to give 7 as colorless needles (15.1 g, 96% from 5). Mp:
13C NMR (100 MHz)
d: 21.62, 21.66, 55.6, 60.5, 68.1, 102.6, 106.4,
114.3, 114.6, 114.8, 115.2, 115.9, 123.3, 125.6, 126.8, 127.1, 129.1, 129.3,
129.8, 129.9, 130.1, 130.4, 134.9, 135.2, 145.1, 145.2, 152.2, 156.6.
HRESIMS: m/z 639.1250 (calcd for C32H28N2NaO7S2: 639.1236).
4.1.7. [5-Methoxy-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-[5-me-
thoxy-1-(toluene-4-sulfonyl)-1H-indol-4-yl]-methanol (13). Under
Ar, to a suspension of 12 (501 mg, 0.81 mmol) and K2CO3 (346 mg,
2.50 mmol) in DMF (5 mL) was added methyl iodide (0.07 mL,
1.12 mmol), and the mixture was stirred at room temperature for
2 h. The reaction mixture was poured into water and extracted with
AcOEt. The organic layer was washed with water and brine, dried
over Na2SO4, and evaporated in vacuo. The residue was purified by
NH-column chromatography (n-hexane/AcOEt¼5:1 to 1:1) to give
13 as a colorless powder (386 mg, 75%). Mp: 166e168 ꢁC. IR (ATR,
94e96 ꢁC. IR (ATR, cmꢂ1): 1366,1149.1H NMR (400 MHz)
d: 0.19 (6H,
s), 0.99 (9H, s), 2.34 (3H, s), 6.54 (1H, d, J¼3.8 Hz), 6.84 (1H, dd, J¼8.8,
2.4 Hz), 6.93 (1H, d, J¼2.4 Hz), 7.22 (1H, d, J¼8.0 Hz), 7.50 (1H, d,
J¼3.8 Hz), 7.73 (2H, d, J¼8.0 Hz), 7.83 (1H, d, J¼8.8 Hz). 13C NMR
cmꢂ1): 3126,1363,1170. 1H NMR (400 MHz)
d: 2.31 (6H, s), 3.47 (1H,

F. Ito et al. / Tetrahedron 67 (2011) 1805e1811
1809
br s), 3.61 (3H, s), 3.79 (3H, s), 6.44 (1H, d, J¼7.2 Hz), 6.72 (1H, d,
J¼3.6 Hz), 6.85 (1H, dd, J¼9.0, 2.4 Hz), 6.92 (1H, d, J¼2.4 Hz), 6.98
(1H, d, J¼9.2 Hz), 7.12 (2H, br d, J¼7.6 Hz), 7.18 (1H, s), 7.19 (2H, br d,
J¼7.6 Hz), 7.48 (1H, d, J¼3.6 Hz), 7.60 (2H, d, J¼8.4 Hz), 7.72 (2H, d,
J¼8.4 Hz), 7.82 (1H, d, J¼9.0 Hz), 7.93 (1H, d, J¼9.2 Hz). 13C NMR
115.0,117.3, 122.6, 126.7,126.8,127.5,127.9,128.1,128.9, 129.8, 129.9,
130.6, 132.0, 135.0, 135.7, 138.5, 145.1, 152.9, 156.7, 188.5. HRESIMS:
m/z 565.1798 (calcd for C33H29N2O5S: 565.1797).
4.1.11. (1-Benzyl-5-methoxy-1H-indol-3-yl)-(5-methoxy-1H-indol-
4-yl)-methanone (17). To a solution of 16 (2.29 g, 4.06 mmol) in THF
(10 mL) and MeOH (10 mL) was added KOH (1.01 g, 18.0 mmol), and
the mixture was refluxed for 3 h. After cooling to room tempera-
ture, the reaction mixture was poured into satd NH4Cl aq and
extracted with CH2Cl2. The organic layer was washed with water
and brine, dried over Na2SO4, and evaporated in vacuo. The residue
was purified by SiO2-column chromatography (n-hexane/
AcOEt¼1:1) to give 17 (1.40 g, 84%) as a colorless powder. Mp:
(100 MHz) d: 21.61, 21.64, 55.5, 56.6, 65.3, 102.9, 108.1, 109.8, 114.0,
114.1, 114.7, 121.1, 124.3, 125.8, 126.77, 126.78, 127.6, 129.8, 130.1,
130.36, 130.41, 130.42, 130.5, 135.2, 144.9, 145.2, 153.3, 156.4. HRE-
SIMS: m/z 653.1384 (calcd for C33H30N2NaO7S2: 653.1392).
4.1.8. [5-Methoxy-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-[5-me-
thoxy-1-(toluene-4-sulfonyl)-1H-indol-4-yl]-methanone (14). To
a
solution of 13 (1.20 g, 1.91 mmol) in DMSO (10 mL) was added IBX
(859 mg, 3.01 mmol), and the mixture was stirred at room tem-
perature for 2 h. The reaction mixture was poured into water and
filtered through a Celite pad. The reaction mixture was extracted
with CH2Cl2. The organic layer was washed with satd NaHCO3 aq
and brine, dried over Na2SO4, and evaporated in vacuo. The residue
was purified by SiO2-column chromatography (n-hexane/
acetone¼1:1 to 1:3) to give 14 (1.0 g, 86%) as a colorless powder.
Mp: 198e200 ꢁC. IR (ATR, cmꢂ1): 1644, 1368, 1173. 1H NMR
173e175 ꢁC. IR (ATR, cmꢂ1): 3320, 1585. 1H NMR (400 MHz)
d: 3.79
(3H, s), 3.91 (3H, s), 5.22 (2H, s), 6.44 (1H, ddd, J¼3.0, 2.2, 1.0 Hz),
6.89 (1H, dd, J¼8.8, 2.5 Hz), 6.99 (1H, d, J¼8.8 Hz), 7.07 (1H, dd,
J¼7.6, 1.6 Hz), 7.13 (1H, d, J¼8.8 Hz), 7.18 (1H, dd, J¼3.0, 3.0 Hz),
7.25e7.31 (3H, m), 7.40 (1H, dd, J¼8.8, 1.0 Hz), 7.45 (1H, s), 8.02 (1H,
d, J¼2.5 Hz), 8.20 (1H, br s). 13C NMR (100 MHz)
d: 51.1, 55.9, 58.1,
102.2, 104.1, 109.7, 111.2, 112.5, 114.0, 117.7, 122.2, 126.0, 126.8, 127.6,
127.8, 128.1, 129.0, 131.8, 132.1, 136.1, 138.9, 150.9, 156.6, 190.3.
HRESIMS: m/z 411.1683 (calcd for C26H23N2O3: 411.1709).
(400 MHz) d: 2.37 (6H, s), 3.77 (3H, s), 3.85 (3H, s), 6.49 (1H, d,
J¼4.0 Hz), 6.99 (1H, dd, J¼9.2, 2.5 Hz), 7.06 (1H, d, J¼9.2 Hz), 7.25
(2H, d, J¼8.0 Hz), 7.27 (2H, d, J¼8.0 Hz), 7.55 (1H, d, J¼4.0 Hz), 7.70
(2H, d, J¼7.2 Hz), 7.71 (1H, s), 7.77 (2H, d, J¼7.2 Hz), 7.82 (1H, d,
J¼9.2 Hz), 7.86 (1H, J¼2.5 Hz), 8.09 (1H, d, J¼9.2 Hz). 13C NMR
4.1.12. 2-Acetylamino-3-[4-(1-benzyl-5-methoxy-1H-indole-3-car-
bonyl)-5-methoxy-1H-indol-3-yl]-propionic acid (18). Under Ar, to
a mixture of 17 (1.09 g, 2.66 mmol) in AcOH (10 mL) and Ac2O
(100 MHz)
d
: 21.70, 21.72, 55.8, 56.9, 104.6, 108.1, 110.2, 114.1, 115.7,
(1.00 mL, 10.6 mmol) was added L-serine (446 mg, 4.25 mmol) and
116.3, 121.1, 121.9, 126.9, 127.2, 128.5, 128.9, 129.6, 130.08, 130.12,
130.2, 130.8, 134.7, 135.2, 135.8, 145.4, 145.9, 153.4, 157.8, 189.7.
HRESIMS: m/z 629.1420 (calcd for C33H29N2O7S2: 629.1416).
the solution was stirred for 2 h at 80 ꢁC. After cooling to room
temperature, the reaction mixture was diluted with Et2O and ad-
justed with 30% NaOH aq to pH 10. The partitioned water layer was
ice-cooled and then, the organic layer was diluted with additional
Et2O and extracted with 10% NaOH aq. The combined water layer
was acidified (pH 3) with 10% HCl aq and the water layer was
extracted with CH2Cl2. The organic layer was washed with water
and brine, dried over Na2SO4, and evaporated in vacuo. The residue
was purified by SiO2-column chromatography (CHCl3/MeOH¼10:1)
to give 18 (1.18 g, 82%) as a brownish powder. Mp: 146e149 ꢁC. IR
4.1.9. (5-Methoxy-1H-indol-3-yl)-[5-methoxy-1-(toluene-4-sulfo-
nyl)-1H-indol-4-yl]-methanone (15). To a solution of 14 (3.13 g,
4.98 mmol) in THF (40 mL) and MeOH (20 mL) was added KOH
(1.09 g, 19.4 mmol), and the mixture was stirred at room temper-
ature for 0.5 h. The reaction mixture was poured into satd NH4Cl aq
and extracted with CH2Cl2. The organic layer was washed with
water and brine, dried over Na2SO4, and evaporated in vacuo. The
residue was purified by SiO2-column chromatography (n-hexane/
AcOEt¼3:1 to 0:1) to give 15 (2.11 g, 92%) as a colorless amorphous
solid. Mp: 201e203 ꢁC. IR (ATR, cmꢂ1): 3137, 1591, 1369, 1139. 1H
(ATR, cmꢂ1): 3254, 1716, 1619. 1H NMR (400 MHz)
d: 1.82 (3H, s),
2.74 (1H, br s), 3.00 (1H, dd, J¼14.8, 4.0 Hz), 3.57 (3H, s), 3.75 (3H, s),
3.91 (3H, br s), 4.56 (1H, br s), 5.22 (2H, s), 6.89 (1H, d, J¼7.2 Hz),
6.96 (1H, d, J¼8.8 Hz), 7.01 (1H, s), 7.06 (2H, d, J¼6.0 Hz), 7.13 (1H, d,
J¼8.8 Hz), 7.23e7.31 (4H, m), 7.37 (1H, d, J¼8.8 Hz), 7.70 (1H, br s),
NMR (400 MHz) d: 2.35 (3H, s), 3.69 (3H, s), 3.81 (3H, s), 6.44 (1H, d,
J¼3.6 Hz), 6.86 (1H, dd, J¼8.8, 2.6 Hz), 6.98 (1H, d, J¼9.2 Hz), 7.19
(1H, d, J¼8.8 Hz), 7.22 (2H, d, J¼7.2 Hz), 7.25 (1H, d, J¼2.6 Hz), 7.46
(1H, d, J¼3.6 Hz), 7.72 (2H, d, J¼7.2 Hz), 7.85 (1H, d, J¼3.2 Hz), 7.98
8.63 (1H, br s). 13C NMR (100 MHz, CD3OD)
d: 21.0, 27.6, 50.4, 53.8,
54.8, 57.0, 103.8, 108.5, 109.6, 111.6, 112.5, 113.2, 118.2, 121.4, 124.7,
125.8, 126.8, 127.4, 127.6, 128.5, 132.5, 133.0, 136.5, 140.6, 150.0,
156.8, 171.7, 174.1, 193.6. HRESIMS: m/z 562.2003 (calcd for
C31H29N3NaO6: 562.1954).
(1H, d, J¼9.2 Hz), 9.21 (1H, br s). 13C NMR (100 MHz)
d: 21.7, 55.8,
57.0, 103.6, 108.2, 110.2, 112.5, 114.4, 115.1, 118.6, 122.6, 126.4, 126.9,
128.0, 129.8, 130.1, 130.5, 131.5, 135.1, 135.9, 145.3, 153.0, 156.6,
189.5. HRESIMS: m/z 475.1307 (calcd for C26H23N2O5S: 475.1328).
4.1.13. 2-Acetylamino-3-[4-(1-benzyl-5-methoxy-1H-indole-3-car-
bonyl)-5-methoxy-1H-indol-3-yl]-propionic acid methyl ester
(19). Under Ar, to a suspension of 18 (1.15 g, 2.14 mmol) and K2CO3
(541 mg, 3.91 mmol) in DMF (10 mL) was added methyl iodide
(0.26 mL, 4.18 mmol) and the mixture was stirred at room tem-
perature for 0.5 h. The reaction mixture was poured into 10% HCl aq
and extracted with CH2Cl2. The organic layer was washed with
water and brine, dried over Na2SO4, and evaporated in vacuo. The
residue was purified by SiO2-column chromatography (AcOEt only)
to give 19 as a colorless powder (1.04 g, 88%). Mp: 111e114 ꢁC. IR
4.1.10. (1-Benzyl-5-methoxy-1H-indol-3-yl)-[5-methoxy-1-(toluene-
4-sulfonyl)-1H-indol-4-yl]-methanone (16). Under Ar, to a suspen-
sion of 15 (1.91 g, 4.14 mmol) and K2CO3 (2.06 g, 14.9 mmol) in DMF
(15 mL) was added benzyl bromide (1.00 mL, 8.36 mmol), and the
mixture was stirred at room temperature for 2 h. The reaction
mixture was poured into water and extracted with AcOEt. The or-
ganic layer was washed with water and brine, dried over Na2SO4,
and evaporated in vacuo. The residue was purified by SiO2-column
chromatography (n-hexane/AcOEt¼2:1) to give 16 (2.29 g, 98%) as
a colorless powder. Mp: 200e202 ꢁC. IR (ATR, cmꢂ1): 1615, 1369,
(ATR, cmꢂ1): 3271, 1738, 1658. 1H NMR (400 MHz)
d: 1.82 (3H, s),
2.74 (1H, br s), 3.00 (1H, dd, J¼14.8, 4.0 Hz), 3.57 (3H, s), 3.75 (3H, s),
3.91 (3H, br s), 4.56 (1H, br s), 5.22 (2H, s), 6.89 (1H, d, J¼7.2 Hz),
6.96 (1H, d, J¼8.8 Hz), 7.01 (1H, s), 7.06 (2H, d, J¼6.0 Hz), 7.13 (1H, d,
J¼8.8 Hz), 7.23e7.31 (4H, m), 7.37 (1H, d, J¼8.8 Hz), 7.70 (1H, br s),
1167. 1H NMR (400 MHz)
d: 2.37 (3H, s), 3.76 (3H, s), 3.87 (3H, s),
5.22 (2H, s), 6.54 (1H, dd, J¼3.6, 0.8 Hz), 6.90 (1H, dd, J¼8.8, 2.4 Hz),
7.03 (1H, d, J¼8.8 Hz), 7.04e7.09 (2H, m), 7.15 (1H, d, J¼8.8 Hz), 7.24
(2H, d, J¼8.4 Hz), 7.27e7.32 (4H, m), 7.51 (1H, d, J¼3.6 Hz), 7.74 (2H,
d, J¼8.4 Hz), 7.90 (1H, br s), 8.01 (1H, dd, J¼8.8, 0.8 Hz). 13C NMR
8.08 (1H, br s), 8.63 (1H, br s). 13C NMR (100 MHz)
d: 23.0, 27.3, 51.3,
52.2, 55.7, 56.0, 58.1, 104.3, 109.0, 110.7, 111.5, 112.8, 114.1, 118.9,
121.6, 125.5, 125.9, 126.9, 127.6, 128.3, 129.1, 132.4, 135.9, 139.4,
(100 MHz) d: 21.6, 51.0, 55.8, 56.9, 103.9, 108.4, 110.1, 111.2, 114.1,

1810
F. Ito et al. / Tetrahedron 67 (2011) 1805e1811
150.3, 157.0, 171.3, 172.7, 193.4. HRESIMS: m/z 554.2317 (calcd for
C32H32N3O6: 554.2291).
(n-hexane/AcOEt¼1:1) to give 23 as a colorless amorphous solid
(3.40 g, 85%). Mp: 106e109 ꢁC. IR (ATR, cmꢂ1): 3334, 1631. 1H NMR
(400 MHz) d: 2.37 (3H, s), 3.79 (3H, s), 3.88 (3H, s), 6.37 (1H, ddd,
4.1.14. 6-(1-Benzyl-5-methoxy-1H-indol-3-yl)-7-methoxy-3,4-dihy-
dro-1H-azepino[5,4,3-cd]indole-4-carboxylic acid methyl ester (20). A
suspension of 19 (53.1 mg, 95.9 mM) in MeOH (2 mL) and 3 N HCl aq
(1 mL) was refluxed for 24 h. After cooling to room temperature, the
reaction mixture was poured into satd NaHCO3 aq. The water layer
was extracted with AcOEt. The organic layer was washed with brine,
dried over Na2SO4, and evaporated in vacuo. The residue was puri-
fied by NH-column chromatography (n-hexane/AcOEt¼1:1) to give
20 (19.1 mg, 40%) as a yellow powder. Mp: 130e132 ꢁC. IR (ATR,
J¼3.2, 2.0, 0.8 Hz), 7.00 (1H, dd, J¼8.8, 2.8 Hz), 7.01 (1H, d, J¼8.8 Hz),
7.22 (1H, d, J¼2.8 Hz), 7.25 (2H, d, J¼8.6 Hz), 7.49 (1H, dd, J¼8.8,
0.8 Hz), 7.73 (2H, d, J¼8.6 Hz), 7.83 (1H, d, J¼8.8 Hz), 7.84 (1H, s),
7.96 (1H, d, J¼2.8 Hz), 8.30 (1H, br s). 13C NMR (100 MHz)
d: 21.6,
55.7, 57.5, 101.8, 104.6, 109.1, 113.6, 114.0, 115.4, 120.2, 122.1, 126.4,
127.1, 127.4, 129.1, 129.5, 130.0, 131.7, 134.6, 135.9, 145.6, 151.4, 157.6,
191.1. HRESIMS: m/z 497.1159 (calcd for C26H22N2NaO5S: 497.1157).
4.1.18. 2-Acetylamino-3-{4-[5-methoxy-1-(toluene-4-sulfonyl)-1H-in-
dole-3-carbonyl]-5-methoxy-1H-indol-3-yl}-propionic acid (24). Under
Ar, to a mixture of 23 (405 mg, 0.85 mmol) in AcOH (4 mL) and Ac2O
cmꢂ1): 3301, 1724, 1584. 1H NMR (400 MHz)
d
: 3.27 (1H, dd, J¼15.2,
10.0 Hz), 3.45 (3H, s), 3.50 (1H, d, J¼15.2 Hz), 3.85 (3H, s), 3.90 (3H, s),
4.75 (1H, d, J¼10.0 Hz), 5.26 (2H, s), 6.82 (1H, dd, J¼8.8, 2.5 Hz), 6.91
(1H, d, J¼8.8 Hz), 7.05 (1H, s), 7.11 (2H, d, J¼6.4 Hz), 7.12 (1H, d,
J¼8.8 Hz), 7.16 (1H, s), 7.22e7.30 (3H, m), 7.40 (1H, d, J¼8.8 Hz), 7.73
(0.24 mL, 2.54 mmol) was added L-serine (144 mg, 1.37 mmol) and
the solution was stirred for 3 h at 80 ꢁC. After cooling to room tem-
perature, the reaction mixture was diluted with Et2O and adjusted
with 30% NaOH aq to pH 10. The partitioned water layer was ice-
cooled and then, the organic layer was diluted with additional Et2O
and extracted with 10% NaOH aq. The combined water layer was
acidified (pH 3) with 10% HCl aq and the water layer was extracted
with CH2Cl2. The organic layer was washed with water and brine,
dried over Na2SO4, and evaporated in vacuo. The residue was purified
by SiO2-column chromatography (CHCl3/MeOH¼10:1) to give 24
(348 mg, 68%) as a brownish powder. Mp: 149e151 ꢁC. IR (ATR,
(1H, d, J¼2.5 Hz), 8.09 (1H, br s). 13C NMR (100 MHz)
d: 31.0, 50.4,
52.3, 55.5, 57.5, 65.3, 103.5, 110.4,110.5,112.6,114.1, 114.2,115.4,117.8,
123.5, 126.7, 127.6, 127.7, 128.0, 128.8, 131.77, 131.81, 132.1, 137.6, 153.9,
155.0, 161.2, 174.8. HRESIMS: m/z 494.2078 (calcd for C30H28N3O4:
494.2080).
4.1.15. 6-[1-Benzyl-5-hydroxy-1H-indol-3-yl]-7-hydroxy-3,4-dihy-
dro-1H-azepino[5,4,3-cd]indole-4-carboxylic acid (21). Under Ar, to
a solution of 20 (143 mg, 0.29 mmol) in CH2Cl2 (1 mL) was added
1 M CH2Cl2 solution of BBr3 (3.00 mL, 3.00 mmol) at room tem-
perature. The reaction mixture was refluxed for 2 h. After cooling at
room temperature, ice and 1 N HCl aq were added to the reaction
mixture. The water layer was extracted with AcOEt. The organic
layer was washed with brine, dried over Na2SO4, and evaporated in
vacuo. The residue was purified by SiO2-column chromatography
(CHCl3/MeOH¼5:1) to give 21 (4.2 mg, 3%) as a yellow amorphous
cmꢂ1): 3254, 1716, 1619. 1H NMR (400 MHz, CD3OD)
d: 1.81 (3H, s),
2.35 (3H, s), 2.65 (1H, dd, J¼14.8, 10.0 Hz), 2.95 (1H, dd, J¼14.8,
4.8 Hz), 3.74 (3H, s), 3.83 (3H, s), 4.36 (1H, dd, J¼10.0, 4.8 Hz), 6.99
(1H, dd, J¼8.8, 2.5 Hz), 7.08 (1H, d, J¼8.8 Hz), 7.16 (1H, br s), 7.31 (2H,
d, J¼8.2 Hz), 7.52 (1H, d, J¼8.8 Hz), 7.77 (2H, d, J¼8.2 Hz), 7.79 (1H, s),
7.83 (1H, d, J¼8.8 Hz), 10.6 (0.6H, br s). 13C NMR (100 MHz, CD3OD)
d:
20.1, 20.8, 28.0, 53.1, 54.6, 56.6, 104.3, 107.9, 109.3, 113.3, 113.8, 114.7,
119.8, 123.0, 124.4, 126.1, 126.9, 128.5, 129.7, 129.9, 133.0, 134.2, 136.2,
146.1, 150.4, 157.8, 171.5, 173.7, 193.8. HRESIMS: m/z 604.1761 (calcd
for C31H30N8O6S: 604.1754).
solid. Mp: >300 ꢁC. 1H NMR (400 MHz, CD3OD)
d: 3.13 (1H, dd,
J¼14.8, 11.2 Hz), 3.69 (1H, d, J¼14.8 Hz), 4.39 (1H, d, J¼11.2 Hz), 5.44
(2H, s), 6.80 (1H, dd, J¼8.8, 2.4 Hz), 6.85 (1H, d, J¼8.8 Hz), 7.24e7.38
(9H, m), 7.65 (1H, d, J¼8.8 Hz), 7.99 (1H, s). 13C NMR (100 MHz,
4.1.19. 2-Acetylamino-3-{4-[5-methoxy-1-(toluene-4-sulfonyl)-1H-
indole-3-carbonyl]-5-methoxy-1H-indol-3-yl}-propionic acid methyl
ester (25a). Under Ar, to a suspension of 24 (407 mg, 0.67 mmol)
and K2CO3 (192 mg, 1.39 mmol) in DMF (4 mL) was added methyl
iodide (0.06 mL, 0.96 mmol) and the mixture was stirred at room
temperature for 3 h. The reaction mixture was poured into water
and extracted with AcOEt. The organic layer was washed with
water and brine, dried over Na2SO4, and evaporated in vacuo. The
residue was purified by SiO2-column chromatography (n-hexane/
AcOEt¼1:3 to 0:1) to give 25a as a yellow powder (338 mg, 81%).
Mp: 127e129 ꢁC. IR (ATR, cmꢂ1): 3258, 1737, 1636. 1H NMR
CD3OD) d: 33.4, 50.7, 103.9, 112.5, 112.6, 113.3, 121.2, 126.4, 126.9,
127.1, 127.7, 128.6, 131.3, 131.9, 136.2, 139.7, 154.5, 157.3, 197.0.
HRESIMS: m/z 452.1566 (calcd for C27H22N3O4: 452.1610).
4.1.16. [5-Methoxy-1H-indol-3-yl]-[5-methoxy-1H-indol-4-yl]-meth-
anone (22). A suspension of 14 (3.33 g, 5.29 mmol) and powdered
KOH (3.08 g, 54.9 mmol) in MeOH (30 mL) and THF (30 mL) was
refluxed for 2 h. After cooling to room temperature, the reaction
mixture was poured into 10% HCl aq and extracted with CH2Cl2. The
organic layer was washed with brine, dried over Na2SO4, and
evaporated in vacuo. The residue was purified by NH-column
chromatography (n-hexane/AcOEt¼1:4 to 0:1) to give 22 (1.46 g,
86%) as a colorless solid. Mp: 228e232 ꢁC. IR (ATR, cmꢂ1): 3738. 1H
(400 MHz)
d
: 1.85 (3H, s), 2.37 (3H, s), 2.65 (1H, dd, J¼15.2, 10.4 Hz),
2.92 (1H, dd, J¼15.2, 4.0 Hz), 3.50 (3H, s), 3.75 (3H, s), 3.90 (3H, s),
4.60 (1H, ddd, J¼10.4, 8.0, 4.0 Hz), 6.99 (1H, d, J¼8.8 Hz), 7.00 (1H,
dd, J¼9.2, 2.4 Hz), 7.08 (1H, d, J¼2.4 Hz), 7.25 (2H, d, J¼8.4 Hz), 7.45
(1H, d, J¼8.8 Hz), 7.73 (2H, d, J¼8.4 Hz), 7.77 (1H, s), 7.81 (1H, d,
NMR (400 MHz, DMSO) d: 3.69 (3H, s), 3.79 (3H, s), 6.06 (1H, ddd,
J¼2.8, 2.0, 0.8 Hz), 6.86 (1H, dd, J¼8.8, 2.8 Hz), 7.00 (1H, d, J¼8.8 Hz),
7.29 (1H, t, J¼2.8 Hz), 7.37 (1H, d, J¼8.8, 0.4 Hz), 7.41 (1H, d,
J¼2.8 Hz), 7.45 (1H, dd, J¼8.8, 0.8 Hz), 7.68 (1H, d, J¼2.0 Hz).13C NMR
J¼9.2 Hz), 7.90 (1H, br s). 13C NMR (100 MHz)
d: 21.6, 22.9, 27.5,
52.0, 54.4, 55.8, 57.4, 104.7, 108.5, 110.2, 113.4, 114.0, 115.5, 119.9,
123.0, 125.2, 125.7, 127.1, 128.5, 129.6, 130.1, 132.2, 134.4, 136.2,
145.8, 150.6, 157.8, 170.5, 172.3, 194.0. HRESIMS: m/z 640.1681
(calcd for C32H31N3NaO8S: 640.1730).
(100 MHz, DMSO) d: 55.9, 57.9, 100.4,103.6, 109.2, 113.1, 113.4,113.6,
118.0,122.0,126.9,127.3,127.6,132.2,132.3,136.8,150.0,156.1,190.5.
HRESIMS: m/z 321.1243 (calcd for C19H17N2O3: 321.1239).
4.1.17. [5-Methoxy-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-[5-me-
thoxy-1-1H-indol-4-yl]-methanone (23). Under Ar, to a solution of
22 (2.70 g, 8.43 mmol) and NEt3 (7.00 mL, 50.2 mmol) in CH2Cl2
(40 mL) was added TsCl (4.00 g, 21.0 mmol) and the mixture
was stirred at room temperature for 7 h. The reaction mixture was
poured into H2O and extracted with AcOEt. The organic layer was
washed with H2O and brine, dried over Na2SO4, and evaporated in
vacuo. The residue was purified by SiO2-column chromatography
4.1.20. 2-Acetylamino-3-{4-[5-methoxy-1-(toluene-4-sulfonyl)-1H-
indole-3-carbonyl]-5-methoxy-1H-indol-3-yl}-propionic acid ethyl
ester (25b). Under Ar, to a suspension of 24 (1.60 g, 2.65 mmol) and
K2CO3 (731 mg, 5.29 mmol) in DMF (20 mL) was added ethyl iodide
(0.37 mL, 4.63 mmol) and the mixture was stirred at room tem-
perature for 2 h. The reaction mixture was poured into 10% HCl aq
and extracted with CH2Cl2. The organic layer was washed with
water and brine, dried over Na2SO4, and evaporated in vacuo. The

F. Ito et al. / Tetrahedron 67 (2011) 1805e1811
1811
residue was purified by SiO2-column chromatography (n-hexane/
AcOEt¼1:3 to 0:1) to give 25b as a yellow powder (1.37 g, 82%). Mp:
a red amorphous solid. Mp: >300 ꢁC. IR (ATR, cmꢂ1): 3124, 1732,
1585. 1H NMR (400 MHz, CD3OD)
: 2.40 (3H, s), 6.56 (1H, s), 6.73
d
109e110 ꢁC. IR (ATR, cmꢂ1): 3313, 1734, 1644. 1H NMR (400 MHz)
d:
(1H, d, J¼8.8 Hz), 6.86 (1H, dd, J¼8.8, 2.4 Hz), 7.40 (2H, d, J¼8.0 Hz),
0.99 (3H, t, J¼7.6 Hz), 1.85 (3H, s), 2.35 (3H, s), 2.65 (1H, dd, J¼15.0,
10.4 Hz), 2.93 (1H, dd, J¼15.2, 4.3 Hz), 3.73 (3H, s), 3.87 (3H, s), 3.97
(2H, ddq, J¼7.6, 7.6, 3.6 Hz), 4.58 (1H, ddd, J¼10.4, 7.6, 4.3 Hz), 6.95
(1H, d, J¼8.8 Hz), 7.00 (1H, dd, J¼8.8, 2.4 Hz), 7.04 (1H, d, J¼2.4 Hz),
7.09 (1H, br s), 7.24 (2H, d, J¼8.4 Hz), 7.42 (1H, d, J¼8.8 Hz), 7.73 (2H,
d, J¼8.4 Hz), 7.79 (1H, s), 7.81 (1H, d, J¼8.8 Hz), 7.91 (1H, br s), 9.22
7.46 (1H, s), 7.77 (1H, d, J¼8.8 Hz), 7.80 (1H, d, J¼8.8 Hz), 7.92 (2H, d,
J¼8.0 Hz), 8.27 (1H, s). 13C NMR (100 MHz, CD3OD)
d: 20.4, 31.7,
60.8, 104.0, 111.8, 113.0, 114.5, 114.9, 124.5, 127.3, 127.7, 129.0, 129.6,
130.1, 130.9, 134.7, 146.3, 155.1, 160.8. HRESIMS: m/z 516.1208 (calcd
for C27H22N3O6S: 516.1229).
(1H, br d, J¼3.6 Hz). 13C NMR (100 MHz)
d
: 13.9, 21.6, 22.9, 27.6,
4.1.24. (ꢀ)-7-Hydroxy-6-(5-hydroxy-1H-indol-3-yl)-3,4-dihydro-1H-
azepino[5,4,3-cd]indole-4-carboxylic acid (hyrtiazepine) (1). Under Ar,
to a solution of 26b (342 mg, 0.60 mmol) in CH2Cl2 (1 mL) was added
1 M CH2Cl2 solution of BBr3 (3.00 mL, 3.00 mmol) at room temper-
ature. The reaction mixture was refluxed for 3 h. After cooling at
room temperature, ice and 1 N HCl aq were added to the reaction
mixture. The water layer was extracted with a mixed solvent (AcOEt/
MeOH¼10:1). The organic layer was washed with brine, dried over
Na2SO4, and evaporated in vacuo. Under Ar, the suspension of crude
27 and K2CO3 (713 mg, 5.16 mmol) in degassed dry MeOH (5 mL)
was refluxed for 3 h. After the reaction mixture was cooled at room
temperature, it was acidified with NH4Cl and filtered through a Celite
pad. After removal of the solvent, the residue was purified by SiO2-
column chromatography (CHCl3/MeOH¼5:1) to give 1 (113 mg, 52%
from 26b) as a yellow amorphous solid. Mp: 242e256 ꢁC (lit.,4 no
data). IR (ATR, cmꢂ1): 3166, 1726, 1617, 1580. 1H NMR (400 MHz,
54.6, 55.7, 57.4, 61.1, 104.7, 108.3, 109.6, 113.6, 114.0, 115.4, 119.7,
123.1, 125.1, 126.1, 127.1, 128.6, 129.7, 130.1, 132.3, 134.4, 136.3, 145.9,
150.5, 157.8, 170.8, 172.0, 194.2. HRESIMS: m/z 670.1627 (calcd for
C33H33KN3O8S: 670.1625).
4.1.21. 6-[5-Methoxy-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-7-me-
thoxy-3,4-dihydro-1H-azepino[5,4,3-cd]indole-4-carboxylicacidmethyl
ester (26a). A suspension of 25a (148 mg, 0.24 mmol)inMeOH (2 mL)
and 3 N HCl aq (2 mL) was refluxed for 20 h. After cooling to room
temperature, the reaction mixture was poured into satd NaHCO3 aq.
The water layer was extracted with AcOEt. The organic layer was
washed with brine, dried over Na2SO4, and evaporated in vacuo. The
residue was purified by NH-column chromatography (AcOEt only) to
give 26a (31.1 mg, 23%) as a yellow powder. Mp: 128e130 ꢁC. IR (ATR,
cmꢂ1): 3419,1732,1592.1H NMR (400 MHz)
d: 2.32 (3H, s), 3.17 (3H, s),
3.17 (1H, ddd, J¼15.2,10.0,1.2 Hz), 3.44 (3H, s), 3.49 (1H, d, J¼15.2 Hz),
3.81 (3H, s), 3.87 (3H, s), 4.68 (1H, d, J¼10.0 Hz), 6.93 (1H, dd, J¼9.0,
2.5 Hz), 6.93 (1H, d, J¼8.8 Hz), 7.05 (1H, s), 7.17 (2H, d, J¼8.2 Hz), 7.43
(1H, s), 7.44 (1H, d, J¼8.8 Hz), 7.65 (1H, d, J¼2.8 Hz), 7.72 (2H, d,
CD3OD)
d
: 3.13 (1H, br dd, J¼15.0,10.0 Hz), 3.66 (1H, br d, J¼15.0 Hz),
4.51 (1H, br d, J¼10.0 Hz), 6.83 (1H, dd, J¼8.8, 1.8 Hz), 6.84 (1H, d,
J¼8.8 Hz), 7.28 (1H, br s), 7.32 (1H, s), 7.36 (1H, d, J¼8.8 Hz), 7.66 (1H,
d, J¼8.8 Hz), 7.8 (1H, s). 13C NMR (100 MHz, CD3OD)
d: 32.8, 60.1,
J¼8.2 Hz), 7.87 (1H, d, J¼8.8 Hz), 8.24 (1H, br s).13C NMR (100 MHz)
d:
103.9, 104.8, 110.6, 112.3, 112.6, 113.5, 122.1, 126.0, 126.2, 126.8, 131.2,
132.3, 137.0, 154.0, 158.2, 167.4, 171.2. HRESIMS: m/z 362.1140 (calcd
for C20H16N3O4: 362.1141).
21.5, 30.5, 52.3, 55.3, 56.8, 65.5, 104.1, 109.9, 113.1, 114.0, 114.4, 114.77,
114.83, 123.7, 124.4, 126.9, 127.1, 128.0, 129.7, 129.8, 130.7, 131.5, 135.1,
144.9, 153.8, 156.8, 160.3, 174.1. HRESIMS: m/z 558.1741 (calcd for
C30H28N3O6S: 558.1699).
Supplementary data
4.1.22. 6-[5-Methoxy-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-7-me-
thoxy-3,4-dihydro-1H-azepino[5,4,3-cd]indole-4-carboxylic acid ethyl
ester (26b). A suspension of 25b (1.37 g, 2.17 mmol) in EtOH (15 mL)
and 3 N HCl aq (10 mL) was refluxed for 20 h. After cooling to room
temperature, the reaction mixture was poured into satd NaHCO3 aq.
The water layer was extracted with AcOEt. The organic layer was
washed with brine, dried over Na2SO4, and evaporated in vacuo. The
residue was purified by NH-column chromatography (AcOEt only) to
give 26b (865 mg, 70%) as a yellow powder. Mp: 124e126 ꢁC. IR (ATR,
Copies of 1H and 13C NMR spectra are provided. Supplementary
data associated with this article can be found in the online version
at doi:10.1016/j.tet.2011.01.029.
References and notes
1. Sauleau, P.; Martin, M. T.; Dau, M. E. T. H.; Youssef, D. T. A.; Bourguet-Kondracki,
M. L. J. Nat. Prod. 2006, 69, 1676e1679.
2. Nagata, W.; Aoki, T. Synthesis 1979, 365e368.
cmꢂ1): 3419, 1732, 1592. 1H NMR (400 MHz)
d: 0.99 (3H, t, J¼7.2 Hz),
ꢀ
3. (a) Genisson, Y.; Young, R. N. Tetrahedron Lett. 1994, 35, 7747e7750; (b) Bane-
ꢀ
rjee, A. K.; Cabrera, E. V. J. Chem. Res., Synop. 1998, 380e381; (c) Genisson, Y.;
2.33 (3H, s), 3.17 (1H, ddd, J¼15.6, 10.0, 1.6 Hz), 3.45 (3H, s), 3.49 (1H,
d, J¼15.6 Hz), 4.27e4.40 (2H, m), 4.66 (1H, d, J¼10.0 Hz), 6.93 (1H,
dd, J¼9.0, 2.5 Hz), 6.94 (1H, d, J¼8.8 Hz), 7.07 (1H, s), 7.18 (2H, d,
J¼8.2 Hz), 7.42 (1H, s), 7.45 (1H, d, J¼8.8 Hz), 7.67 (1H, d, J¼2.5 Hz),
7.72 (2H, d, J¼8.2 Hz), 7.87 (1H, d, J¼9.0 Hz), 8.14 (1H, br s). 13C NMR
Tyler, P. C.; Ball, R. G.; Young, R. N. J. Am. Chem. Soc. 2001, 123, 11381e11387; (d)
Turner, J. A.; Pernich, D. J. J. Agric. Food Chem. 2002, 50, 4554e4566; (e) Du-
fresne, C.; Cretney, D.; Lau, C. K.; Mascitti, V.; Tsou, N. Tetrahedron: Asymmetry
2002, 13, 1965e1967; (f) Urgaonkar, S.; Pierre, H. S. L.; Meir, I.; Lund, H.; Ray-
Chaudhuri, D.; Shaw, J. T. Org. Lett. 2005, 7, 5609e5612; (g) Wolf, S.; Zismann,
T.; Lunau, N.; Meier, C. Chem.dEur. J. 2009, 15, 7656e7664.
(100 MHz) d: 14.4, 21.5, 30.4, 55.5, 56.8, 61.1, 65.6, 104.8, 109.9, 113.2,
4. Koizumi, Y.; Kobayashi, H.; Wakimoto, T.; Furuta, T.; Fukuyama, T.; Kan, T. J. Am.
113.9, 114.0, 114.7, 115.0, 123.6, 124.4, 126.9, 127.2, 128.1, 129.7, 129.9,
130.7, 131.5, 135.2, 144.8, 153.8, 156.8, 160.1, 173.5. HRESIMS: m/z
572.1850 (calcd for C31H30N3O6S: 572.1855).
Chem. Soc. 2008, 130, 16854e16855.
5. von Strandtmann, M.; Cohen, M. P.; Shavel, J., Jr. J. Med. Chem. 1963, 6, 719e725.
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4.1.23. 6-[5-Hydroxy-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-7-
hydroxy-3,4-dihydro-1H-azepino[5,4,3-cd]indole-4-carboxylic acid
(27). Under Ar, to a solution of 26b (112 mg, 0.20 mmol) in CH2Cl2
(2 mL) was added 1 M CH2Cl2 solution of BBr3 (1.00 mL, 1.00 mmol)
at room temperature. The reaction mixture was refluxed for 2 h.
After cooling at room temperature, ice and 1 N HCl aq were added
to the reaction mixture. The water layer was extracted with AcOEt.
The organic layer was washed with brine, dried over Na2SO4, and
evaporated in vacuo. The residue was purified by SiO2-column
chromatography (CHCl3/MeOH¼5:1) to give 27 (81.0 mg, 80%) as
9. Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537e4538.
10. Yamada, Y.; Akiba, A.; Arima, S.; Okada, C.; Yoshida, K.; Itou, F.; Kai, T.; Satou, T.;
Takeda, K.; Harigaya, Y. Chem. Pharm. Bull. 2005, 53, 1277e1290.
11. Although enzymatic optical resolution of carboxylic acids 18 and 24 by
D
- and
L-aminoacylase was examined, optically active compounds were not
obtained.