Synthetic studies of decursivine derivatives: Preparation of key indole alkaloids via α-hydroxyalkylation

Article abstract of DOI:10.1016/j.tet.2012.03.026

2-Hydroxyacetyl indole modified at C-3 position was prepared with an eye to developing a total synthesis of decursivine derivatives (decursivine, serotobenine, moschaminindolol, and flavumindole). The indole was prepared through a sequence of oxalyl chlor

Full text of DOI:10.1016/j.tet.2012.03.026

Tetrahedron 68 (2012) 3708e3716
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic studies of decursivine derivatives: preparation of key indole alkaloids
via a-hydroxyalkylation
*
Fumihiro Ito, Kentaro Yamaguchi
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Hydroxyacetyl indole modified at C-3 position was prepared with an eye to developing a total syn-
thesis of decursivine derivatives (decursivine, serotobenine, moschaminindolol, and flavumindole). The
indole was prepared through a sequence of oxalyl chloride introduction at C-3 position of indole and acid
chloride reduction with tributyltin hydride. In addition, we report a novel synthesis of fully function-
Received 25 January 2012
Received in revised form 8 March 2012
Accepted 8 March 2012
Available online 15 March 2012
alized Uhle’s ketone via ortho-selective a-hydroxyalkylation.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
ortho-Selective
Indole alkaloid
Uhle’s ketone
a-hydroxyalkylation
1. Introduction
versatile CeC bond forming reactions for the synthesis of indole
alkaloids having an oxygen function at C-5 position of the indole
ring. We attempted to synthesize decursivine derivatives, including
decursivine (1), serotobenine (2), moschaminindolol (3), and fla-
vumindole (4), from 5-hydroxyindole. In this study, we achieved the
preparation of key intermediate 5 for use in the synthesis of
decursivine derivatives through the following reactions: insertion of
(þ)-Decursivine (1) is an optically active natural pentacyclic
indole alkaloid originally isolated from the leaves and stems of
Rhaphidophora decursiva Schott (Araceae) by Fong and co-workers
in 2002.1 It showed antimalarial activity with IC50 values of 3.93
and 4.41 mg/mL against the D6 and W2 clones of Plasmodium fal-
ciparum, respectively. Decursivine is structurally related to seroto-
benine (2),2 moschaminindolol (3),3 and flavumindole (4).4
Serotobenine (2) and flavumindole (4) have a unique tetracyclic
skeleton that includes an indole, an eight-membered ring, and
benzylaldehyde at C-4 position of 5-hydroxyindole by a-hydrox-
yalkylation, and modification of C-3 position of indole (Scheme 1).
Moreover, we describe the novel synthesis of highly functionalized
a
dihydrobenzofuran. Moschaminindolol (3) has an identical
structure except the furan ring. Unlike 1, natural 2, 3, and 4 are not
active against P. falciparum. However, these derivatives, including 1,
are challenging synthetic targets. Leduc and Kerr reported the first
synthesis of (ꢀ)-decursivine (1).5 Recently, Mascal and co-workers
and Jia’s and co-workers independently introduced an expedient
synthesis of (ꢀ)-decursivine (1) via the Witkop photocyclization,6
and Li’s group7 accomplished the asymmetric total synthesis of
(þ)-decursivine (1). Jia’s group also extended this methodology to
the synthesis of (ꢀ)-serotobenine (2).6b In the meantime,
Fukuyama and co-workers reported the first synthesis of
(ꢁ)-serotobenine (2).8
We have reported the total synthesis of hyrtiazepine by using
ortho-selective
work, weshowthatortho-selective
a
-hydroxyalkylation as the key reaction.9 In this
a-hydroxyalkylationis one of the
* Corresponding author. Tel.: þ81 87 894 5111; fax: þ81 87 894 0181; e-mail
address: yamaguchi@kph.bunri-u.ac.jp (K. Yamaguchi).
Fig. 1. Structures of decursivine and its related compounds.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.026

F. Ito, K. Yamaguchi / Tetrahedron 68 (2012) 3708e3716
3709
BnO
MeO
ortho-selective
BnO
MeO
BnO
MeO
modification
α
-hydroxyalkylation
of C-3 position
HO
O
O
OH
7
decursivine derivatives
HO
BnO
O
HO
N
N
N
Ts
Bn
Ts
8
5
6
OBn
OBn
BnO
MeO
O
MeO
MeO
OH
R
O
O
R
O
BnO
BnO
BnO
O
N
H
N
N
Bn
H
10a: R = NHBn
10b: R = OMe
9
11a: R = NHBn
11b: R = OMe
Uhle's ketone derivatives
Scheme 1. Retrosynthesis of decursivine and Uhle’s ketone derivatives by ortho-selective a-hydroxyalkylation.
6-benzyloxy-5-aryl-1,3-dihydro-benzo[cd]indole-3-one 9 from 5
and 6-benzyloxy-4-aryl-1,5-dihydro-benzo[cd]indole-5-one 10
from 11. The benzo[cd]indole core is important to construct ergot
alkaloid, such as lysergic acid. Notably, after 3,4-dihydro-6-
hydroxybenz[cd]indol-5(1H)-one (Uhle’s ketone), which is the key
intermediate in the synthesis of pharmacologically active lysergic
acid, was synthesized from6-chloro-2-nitrotoluene in eight steps by
Uhle in 1949,10 the synthesis of Uhle’s ketone derivatives, including
6-alkoxy-Uhle’s ketone, has been widely carried out11 (Fig. 1).
converted from enol form into keto form. Although various con-
ditions were examined, ester 15 did not tautomerize to keto form.
Thus, we looked instead into the possibility of the reaction of
benzylaldehyde 7 and 5-hydroxyindole 8. Desired 6 was prepared
in 80% yield from 5-hydroxyindole 8,9 which, in turn, was prepared
from indole 17; and benzylaldehyde 7,15 which was prepared from
benzaldehyde 12, by means of Nagata and Aoki’s method13 (Scheme
3). Although Citterio’s conditions14 were examined, 8 did not react
with 7 under those conditions, because Lewis acid consumed for
elimination of protecting group of 7. Structure assignment of 6 was
accomplished on the basis of HMBCeNMR correlations of (H-6)
with (C7), (H-20 and H-60) with (C8), (H-8) with (C4, C20, and C60),
and (H-7) with (C5 and C3a) (Fig. 2).
2. Results and discussion
We attempted to synthesize methyl ester 16 by the a-hydrox-
Next, the phenolic hydroxyl group in 6 was alkylated with
benzyl bromide in DMF to afford alcohol 18 in 83% yield, and the
second hydroxyl group was acylated with acetyl chloride and pyr-
idine in CH2Cl2 in 94% yield (Scheme 4). Then, we tried to exchange
yalkylation reaction of 5-hydroxyindole 8 with ester 16 (Table 1).
Methyl ester 15 was prepared from benzaldehyde 12 and hydantoin
(Scheme 2).12 However,
a-hydroxyalkylation did not occur under
Nagata’s conditions using boronic acid (run 1)13 or Citterio’s con-
ditions using Lewis acid (run 2).14 It was because ester 15 was not
OMe
OMe
ref 15)
BnO
MeO
(a) then (b)
BnO
BnO
Table 1
Trials of ortho-selective
a
-hydroxyalkylation
Solvent
CHO
CHO
OH
12
7
Run
1
Reagent
Condition
Result
HO
1. PhB(OH)2, EtCO2H
2. H2O2
1. Toluene
2. THF
1. Reflux, 20 h
No reaction
HO
HO
ref 9)
2. 0 ꢂC, 0.5 h
N
2
TiCl4
CH2Cl2
0
ꢂC, 1.0 h
No reaction
Ts
N
H
N
6
Ts
17
8
Scheme 3. Synthesis of 6 by
a-hydroxyalkylation. Reagents and conditions: (a) Et-
OMe
(a)
CO2H, PhB(OH)2, toluene, reflux, 20 h; (b) H2O2, THF, 0 ꢂC, 0.5 h (80%).
OMe
O
BnO
(b)
BnO
NH
O
OBn
MeO
CHO
N
H
12
13
BnO
MeO
6'
7
2'
OMe
OH
H
H
8
BnO
(c)
8
see
OH
CO2Me
H
O
H
H
Table 1
CO2R
HO
4
14: R = H
HO
N
15: R = Me
3a
5
Ts
16
N
H
Scheme 2. Preparation of methyl ester 15 and trials for ortho-selective
a-hydrox-
6
Ts
yalkylation. Reagents and conditions: (a) hydantoin, EtOH/H2O, reflux, 12 h (72%); (b)
20% NaOH aq, DMSO, 140 ꢂC, 2 h (93%); (c) AcCl, MeOH, reflux, 12 h (26%).
Fig. 2. Selected HMBC correlations of 6.

3710
BnO
F. Ito, K. Yamaguchi / Tetrahedron 68 (2012) 3708e3716
BnO
MeO
BnO
MeO
Table 3
Trials for modification of C-3 position of indoles 22, 24, and 26
MeO
TMSCN
see
BnO
BnO
2
(c)
OP
CN
R
Table 2
MeO
MeO
1
P O
BnO
BnO
(COCl)2, THF
0.5 h, rt
BnHN
X
O
O
X
N
N
N
H
Ts
Ts
1
2
20
then, BnNH2
21: R = CONH (not obtained)
22: R = CN (74%)
2
6: P = P = H
BnO
BnO
(a)
(b)
1
2
18: P = Bn; P = H
N
H
N
H
1
2
22: X = H, CN
24: X = O
26: X = H, OAc
27: X = H, CN
19: P = Bn; P = Ac
11a: X = O
28: X = H, OAc
Scheme 4. Preparation of nitrile 22. Reagents and conditions: (a) BnBr, K2CO3, DMF, rt,
2 h (83%); (b) AcCl, pyridine, CH2Cl2, 2 h (94%); (c) KOH, THF/MeOH, reflux, 0.5 h (74%).
Run
Substrate
X
Result
Trace
11a: 74%
1
2
3
22
24
26
(H, CN)
(O)
(H, OAc)
the acetate group in 19 with a cyano group by using trimethylsilyl
16
cyanide. When K2CO3 and TBAF17 were used as the additive, no
Trace
reaction took place (Table 2, runs 1 and 2). On the other hand, when
such boron reagents as B(C6F5)318 and BF3$OEt2 were used,19 nitrile
20 was obtained in 41% and 83% yields, respectively (runs 3 and 4).
However, hydrolysis of the cyano group did not occur under basic
conditions and indole 22 was obtained in 74% yield. Although
various conditions were attempted, the cyano group could not be
hydrolyzed. Therefore, we tried to modify the C-3 position of in-
doles 22, 24, and 26.
amide 11a with
a-bromonitromethane gave 10a, which was
obtained by cyclization at the benzyl position and the carbonyl
group of 11a, in ca. 35% yield (including impurities). Thus, we tried
to modify 24 by using reagents other than oxalyl chloride.
Under Vilsmier conditions with N,N-dimethylamide derivative22
and FriedeleCrafts conditions with bromo acetylbromide,23 com-
plex mixtures were obtained (Table 4, runs 1e3). Although various
conditions were examined, oxalyl chloride only reacted at C-3 po-
sition. Thus, acid chloride, which was prepared with oxalyl chloride
and indole 24, was reduced with excess tributyltin hydride24 to
obtain 31c in 56% yield (run 4). In addition, the hydroxyl group of
31c was acetylated in 89% yield and the nitrogen of indole in 32 was
benzylated (89% yield) and deacetylated to obtain 5 (96% yield,
Scheme 7). When a tosyl group was used, the acetyl group was not
removed selectively.
Finally, we attempted to perform the novel synthesis of the 4-
aryl-1H-benz[cd]indole core by using amide 11a under basic con-
ditions (Table 5). At first, under the conditions shown in Scheme 6,
treatment with triethylamine did not give 10a (run 1). Next, use of
THF as the solvent under reflux conditions did not give 10a either
(run 2). On the other hand, when t-BuOK, a strong inorganic base,
was used, 10a was obtained in 53% yield (run 3). In addition, the
yield was slightly increased when K2CO3, a mild inorganic base, was
used (run 4). These reactions hardly proceeded at room tempera-
ture. The moderate yield of 10a is due to the partial trapping by
silica gel used in column chromatography.
Table 2
Trials for preparation of nitrile 20
Run
Additive
Solvent
Condition
Result
1
2
3
4
K2CO3
TBAF
B(C6F5)3
BF3$OEt2
CH3CN
THF
CH3CN
CH2Cl2
Reflux, 6.0 h
Reflux, 6.0 h
rt to reflux, 3.0 h
ꢁ20 ꢂC, 0.5 h
No reaction
No reaction
41%
83%
Indoles 24 and 26 were prepared as follows (Scheme 5). After
alcohol 18 was oxidized with IBX20 in DMSO to obtain ketone 23 in
95% yield, the tosyl group of 23 was removed with KOH in 81%
yield. The carbonyl group of 24 was reduced with NaBH4 in 89%
yield and a second hydroxyl group was acylated with acetyl chlo-
ride and pyridine in CH2Cl2 to obtain 26 in 75% yield.
BnO
MeO
BnO
MeO
BnO
MeO
(a)
(b)
OH
O
O
BnO
BnO
BnO
Further trials were conducted in which K2CO3 and THF were
used as the base and the solvent, respectively (Table 6). In the case
of oxo-acetate 11b, which was prepared with oxalyl chloride and
methanol in 73% yield, ester 10b was obtained in 87% yield (run 2).
The reaction of alcohol 31c proceeded slowly under the same
conditions and after 12 h, a complex mixture was obtained (run 3).
Similarly, in the case of N-protected alcohol 5, desired cyclized
compound was not obtained (run 4). However, when the strong
base t-BuOK was used, 9 was obtained in 24% yield (run 5). The
assignment of 9 was based on the HMBC correlations of (H-2) with
(C3), (H-20 and H-60) with (C100), (H-100) with (C4 and C20), and (H-7
and H-100) with (C5 and C5a) (Fig. 3). In order to synthesize Uhle’s
ketone derivative, an electron-withdrawing group adjacent to the
carbonyl group is required.
N
N
N
H
Ts
Ts
18
23
24
BnO
BnO
MeO
MeO
(d)
(c)
OH
OAc
BnO
BnO
N
H
N
H
25
26
Scheme 5. Preparation of ketone 24 and acetate 26. Reagents and conditions: (a) IBX,
DMSO, rt, 2 h (95%); (b) KOH, THF/MeOH, reflux, 0.5 h (81%); (c) NaBH4, THF/MeOH,
8 h, rt, (89%); (d) AcCl, pyridine, CH2Cl2, 2 h (75%).
We also tried to modify the C-3 position of indoles 22, 24, and 26
with oxalyl chloride and benzyl amine in THF (Table 3). Although
indole 24 gave desired amide 11a in 74% yield (run 2), indoles 22
and 26 did not furnish target amides 27 and 28 (runs 1 and 3).
Next, we attempted to construct an eight-membered ring
3. Conclusion
In conclusion, with an eye to achieving the total synthesis of
decursivine derivatives, we have accomplished the synthesis of key
intermediate 5, which possesses a 2-hydroxyacetyl unit that is
necessary for the construction of the eight-membered ring as 5 can
hardly construct a six-membered ring under basic conditions. The
through the alkylation of amide 11a with a-bromonitromethane by
the intramolecular Henry reaction21 (Scheme 6). However, al-
though the mild organic base triethylamine was used, treatment of

F. Ito, K. Yamaguchi / Tetrahedron 68 (2012) 3708e3716
3711
OBn
BnO
BnO
MeO
BnO
MeO
MeO
O
MeO
O2N
O
NO2
Bn
N
BrCH2NO2
NEt3
O
BnHN
NBn
O
CONHBn
O
O
O
CH2Cl2
rt
24 h
BnO
BnO
BnO
BnO
O
O
N
H
N
H
N
N
H
H
11a
29
30 (not obtained)
10a (ca. 35%)
Scheme 6. Trial for construction of eight-membered ring by intramolecular Henry reaction.
Table 5
Table 4
Trials for preparation of 6-benzyloxy-Uhle’s ketone 10a
Trials for modification of C-3 position of indole 24
OBn
MeO
Run
1
Reagent
Solvent Condition
R
Result
BnO
MeO
O
d
0
ꢂC to rt, 0.5 h
CH2Br
Complex mixture
Br
Br
O
AlCl3
O
base
CONHBn
O
CONHBn
solvent
BnO
BnO
O
condition
2
Toluene 100 ꢂC, 0.5 h
CH2Br
Complex mixture
Br
pyridine
Br
N
H
N
H
O
11a
10a
Phth
3
4
Dioxane Reflux, 2.0 h
CH2Phth Complex mixture
Me2N
POCl3
Run
Base
Solvent
Condition
rt, 24 h
Reflux, 5.0 h
Reflux, 2.0 h
Reflux, 2.0 h
Yield (%)
1
2
3
4
NEt3
NEt3
t-BuOK
K2CO3
CH2Cl2
THF
THF
Trace
Trace
53
(CoCl)2 Bu3SnH THF
rt, 0.5 h then rt, 12 h CH2OH 31c: 56%
THF
58
BnO
BnO
MeO
Table 6
MeO
Preparation of 6-benzyloxy-Uhle’s ketones
see
(a)
O
O
R
OBn
OBn
BnO
MeO
Table 4
O
MeO
MeO
O
BnO
BnO
OH
N
H
N
O
base
H
R
O
R
24
31a: R = CH2Phth
31b: R = CH2Br
31c: R = CH2OH
THF
reflux
BnO
BnO
BnO
O
N
P
N
P
N
BnO
BnO
MeO
Bn
9
MeO
Run
Substrate
R
P
Base
Time (h)
Result
(d)
AcO
HO
O
O
1
2
3
4
5
11a
11b
31c
5
CONHBn
CO2Me
CH2OH
CH2OH
CH2OH
H
H
H
Bn
Bn
K2CO3
K2CO3
K2CO3
K2CO3
t-BuOK
2.0
2.0
12
12
2.0
10a: 58%
10b: 87%
Complex mixture
Complex mixture
9: 24%
BnO
BnO
O
O
N
P
N
5
Bn
32: P = H
5
(b)
(c)
33: P = Bn
34: P = Ts
OBn
Scheme 7. Preparation of indole 5. Reagents and conditions: (a) AcCl, pyridine, CH2Cl2,
ꢂC, 0.5 h (89%); (b) BnBr, K2CO3, DMF, rt, 2 h (89%); (c) TsCl, NEt3, CH2Cl2, 0 ꢂC, 1 h
(77%); (d) H2O2, K2CO3, THF, rt, 2.0 h (96%).
MeO
H
H
0
6'
2'
H
1'
OH
4
eight-membered ring is constructed by using the 2-hydroxyacetyl
group of 5 (Scheme 8). Moreover, we have developed a novel
method for the preparation of 1H-benz[cd]indole derivatives
O
3
1''
5
H
5a
BnO
through the ortho-selective a-hydroxyalkylation of benzylaldehyde
H
2
7 with N-Ts-5-hydroxyindole 8. Intermediates 5, 11a, and 11b are
useful for the synthesis of various indole alkaloids, such as decur-
sivine and Uhle’s ketone derivatives. It is noteworthy that 3-oxo-
and 5-oxo-Uhle’s ketone derivatives were prepared selectively
N
7
H
Bn
H
Fig. 3. Selected HMBC correlations of 9.

3712
F. Ito, K. Yamaguchi / Tetrahedron 68 (2012) 3708e3716
from the corresponding intermediates. New approaches to the
construction of eight-membered rings and the furan structure
followed by the total synthesis of decursivine derivatives are under
investigation.
70.5, 110.8, 113.8, 114.0, 123.1, 128.48, 128.50, 128.9, 129.1, 137.7,
140.9, 147.9, 149.3, 167.1. HRESIMS: m/z 323.0893 (calcd for
C17H16NaO5: 323.0890).
4.1.3. 3-(4-Benzyloxy-3-methoxy-phenyl)-2-hydroxy-acrylic
acid
methyl ester (15). Under Ar, acetyl chloride (0.1 mL,1.41 mmol) was
added to a dry MeOH (5 mL) solution of 14 (219 mg, 0.729 mmol).
After stirring for 12 h, the reaction mixture was evaporated in vacuo.
The residue was purified by SiO2 column chromatography (n-hex-
ane/ethyl acetate¼5:1) to give 15 (59 mg, 26%) as a colorless powder.
Mp: 103e105 ꢂC. IR (ATR, cmꢁ1): 3423, 1748, 1687, 1510. 1H NMR
BnO
MeO
BnO
MeO
BnO
MeO
O2N
O
NO2
H
N
NH
HO
O
O
BnO
BnO
BnO
O
O
N
N
N
(400 MHz) d: 3.91, 3.93 (each 3H, s), 5.19 (2H, s), 6.37 (1H, br s), 6.49
Bn
Bn
Bn
35
36
5
(1H, s), 6.89 (1H, d, J¼8.4 Hz), 7.20 (1H, dd, J¼8.4, 2.0 Hz), 7.30 (1H, t,
Scheme 8. Future plane of eight-membered ring by intramolecular Henry reaction.
J¼7.2 Hz), 7.37 (2H, t, J¼7.2 Hz), 7.44 (2H, d, J¼7.2 Hz), 7.50 (1H, d,
J¼2.0 Hz). 13C NMR (100 MHz)
d: 53.2, 55.9, 70.8, 111.4, 113.2, 113.5,
123.3,127.2,127.6,127.9,128.6,128.7,136.9,137.8,148.2,149.3,166.8.
4. Experimental section
4.1. General
HRESIMS: m/z 337.1049 (calcd for C18H18NaO5: 337.1046).
4.1.4. (4-Benzyloxy-3-methoxy-phenyl)-acetaldehyde (7). Under Ar,
t-BuOK (13.8 g, 123 mmol) was added to a suspension of benzalde-
hyde 12 (14.9 g, 61.5 mmol) and (methoxymethyl)triphenylphos-
phonium chloride (25.3 g, 73.9 mmol) in THF (200 mL) at 0 ꢂC. After
stirring at room temperature for 2 h, the reaction mixture was
poured into satd NH4Cl aq and extracted with ethyl acetate. The
organic layer was washed with satd NH4Cl aq and brine, dried over
Na2SO4, and evaporated in vacuo. The THF (200 mL) and 2 N HCl aq
(80 mL) solution of the residue was refluxed at 1 h. After cooling
down to room temperature, the reaction mixturewas extracted with
ethyl acetate. 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/ethyl
acetate¼3:1 to 2:1) to give 7 (13.1 g, 83%) as a colorless oil. IR (ATR,
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
specified, on a JEOL JNM-ECP 400 and a Bruker 400 MHz with
tetramethylsilane (TMS) as the internal reference. ESIMS were
recorded on a JEOL JMS-T100LC mass spectrometer and a Bruker
Daltonics apex-Qe 9.4T FT ICR 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 chroma-
tography, spherical silica gel 60 (particle size 63e210 mm, Kanto
Chemical, No. 37565-84 for neutral) and NH silica gel (Fuji Silysia
Chemical Ltd., particle size 100e200 mesh, No. IO61280 and
200e350 mesh, No. HU80502) were used.
cmꢁ1): 1720, 1511. 1H NMR (400 MHz)
d
: 3.62 (2H, d, J¼2.4 Hz), 6.71
(1H, dd, J¼8.0, 2.0 Hz), 6.74 (1H, d, J¼2.0 Hz), 6.88 (1H, d, J¼8.0 Hz),
7.31 (1H, t, J¼7.2 Hz), 7.38 (2H, t, J¼7.2 Hz), 7.45 (2H, d, J¼7.2 Hz), 9.73
4.1.1. 5-(4-Benzyloxy-3-methoxybenzylidene)-imidazolidine-2,4-
dione (13). Hydantoin (3.07 g, 30.6 mmol) was dissolved in 40 mL
of water at 70 ꢂC with stirring. After complete dissolution, the pH of
the mixture was adjusted to 7.0 with satd NaHCO3 aq Ethanolamine
(3.0 mL, 49.7 mmol) was added and the temperature of the reaction
mixture was increased to 90 ꢂC. After aldehyde 12 was heated with
EtOH (50 mL) until complete dissolution, it was added to the re-
action mixture. The temperature was raised to 120 ꢂC and the re-
action mixture was refluxed at that temperature for 12 h. After
cooling to room temperature, the precipitate was filtered. The
residue was washed with H2O/EtOH (5:1) to give 13 (5.03 g, 72%) as
a colorless powder. This product was used without further purifi-
cation. Mp: 251e253 ꢂC. IR (ATR, cmꢁ1): 3143, 1754, 1710. 1H NMR
(1H, t, J¼2.4 Hz). 13C NMR (100 MHz)
d: 50.2, 56.0, 71.1, 113.2, 114.5,
121.8, 124.7, 127.2, 127.9, 128.6, 137.1, 147.6, 150.1, 199.5.
4.1.5. 4-[2-(4-Benzyloxy-3-methoxy-phenyl)-1-hydroxy-ethyl]-1-
(toluene-4-sulfonyl)-1H-indol-5-ol (6). A suspension of indole 8
(7.93 g, 27.6 mmol), benzylaldehyde 7 (13.5 g, 52.5 mmol), phe-
nylboronic acid (6.60 g, 54.2 mmol), and propionic acid (2.0 mL,
26.7 mmol) in dry toluene (200 mL) was refluxed for 20 h with
a DeaneStark trap. After cooling to room temperature, the reaction
mixture was evaporated in vacuo. After 30% H2O2 aq (30 mL) was
added to a THF (200 mL) solution of the residue at 0 ꢂC, the whole
was stirred for 0.5 h. The mixture was poured into 20% Na2S2O3 aq
and extracted with ethyl acetate. The organic layer was washed
with 20% Na2S2O3 aq and brine, dried over Na2SO4, and evaporated
in vacuo. The residue was purified by SiO2 column chromatography
(chloroform/ethyl acetate¼10:1) to give 6 (12.0 g, 80%) as a yellow
powder. Mp: 60e62 ꢂC. IR (ATR, cmꢁ1): 3464, 3354, 1510. 1H NMR
(400 MHz, DMSO) d: 3.82 (3H, s), 5.11 (2H, s), 6.37 (1H, s), 7.03 (1H,
d, J¼8.0 Hz), 7.14 (1H, d, J¼1.6 Hz), 7.15 (1H, dd, J¼8.0, 1.6 Hz), 7.32
(1H, t, J¼7.2 Hz), 7.35 (2H, t, J¼7.2 Hz), 7.43 (2H, d, J¼7.2 Hz), 10.48
(1H, s). 13C NMR (100 MHz, DMSO)
d: 56.2, 70.2, 109.6, 113.3, 113.9,
123.3, 126.4, 126.7, 128.3, 128.4, 128.9, 137.3, 148.7, 149.5, 156.2,
166.1. HRESIMS: m/z 347.1012 (calcd for C18H16N2NaO4: 347.1002).
(400 MHz)
d
: 2.34 (3H, s), 2.83 (1H, br d, J¼2.0 Hz), 3.02 (2H, d,
J¼7.6 Hz), 3.73 (3H, s), 5.12 (2H, s), 5.28 (1H, t, J¼7.6 Hz), 6.36 (1H,
dd, J¼3.6, 0.4 Hz), 6.59 (1H, d, J¼2.0 Hz), 6.68 (1H, dd, J¼8.0, 2.0 Hz),
6.79 (1H, d, J¼8.0 Hz), 6.89 (1H, d, J¼8.8 Hz), 7.21 (2H, d, J¼8.2 Hz),
7.29 (1H, t, J¼6.8 Hz), 7.37 (2H, t, J¼6.8 Hz), 7.42 (2H, d, J¼6.8 Hz),
7.45 (1H, d, J¼3.6 Hz), 7.72 (2H, d, J¼8.2 Hz), 7.77 (1H, d, J¼8.8 Hz),
4.1.2. 3-(4-Benzyloxy-3-methoxyphenyl)-2-hydroxyacrylic
acid
(14). DMSO (10 mL) and 20% NaOH aq (20 mL) solution of 13
(4.00 g, 12.3 mmol) were stirred for 2 h at 140 ꢂC. After cooling to
room temperature, 6 N HCl aq was added at 0 ꢂC. The precipitate
was filtered and washed with 1 N HCl aq and n-hexane to give 14
(3.44 g, 93%) as a colorless powder. This product was used without
further purification. Mp: 156e164 ꢂC. IR (ATR, cmꢁ1): 3394, 3323,
8.13 (1H, s). 13C NMR (100 MHz)
d: 21.8, 43.4, 56.2, 71.3, 74.5, 106.1,
113.4, 114.0, 114.6, 115.8, 116.8, 121.6, 127.0, 127.2, 127.5, 128.1, 128.8,
128.9, 129.2, 130.1, 130.3, 135.4, 137.3, 145.1, 147.5, 150.0, 152.1.
HRESIMS: m/z 566.1637 (calcd for C31H29NNaO6S: 566.1613).
1694. 1H NMR (400 MHz, DMSO-d6)
d: 3.75 (3H, s), 5.08 (2H, s), 6.36
(1H, s), 7.02 (1H, d, J¼8.4 Hz), 7.28 (1H, dd, J¼8.4, 2.0 Hz), 7.32 (1H, t,
4.1.6. 2-(4-Benzyloxy-3-methoxy-phenyl)-1-[5-benzyloxy-1-(tolu-
ene-4-sulfonyl)-1H-indol-4-yl]-ethanol (18). Under Ar, benzyl bro-
mide (0.2 mL, 1.68 mmol) was added to a suspension of indole 6
J¼7.2 Hz), 7.38 (1H, t, J¼7.2 Hz), 7.43 (2H, d, J¼7.2 Hz), 7.44 (1H, d,
J¼2.0 Hz), 8.99 (1H, br s). 13C NMR (100 MHz, DMSO-d6)
d: 56.1,

F. Ito, K. Yamaguchi / Tetrahedron 68 (2012) 3708e3716
3713
(517 mg, 0.950 mmol) and K2CO3 (283 mg, 2.04 mmol) in DMF
(5 mL). After the whole was stirred for 2 h at room temperature, the
mixture was poured into water and extracted with ethyl acetate.
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/ethyl acetate¼3:1 to 1:1) to
give 18 (502 mg, 83%) as a yellow powder. Mp: 57e59 ꢂC. IR (ATR,
MeOH¼2:1 (20 mL) was refluxed for 0.5 h. After cooling to room
temperature, the reaction mixture was poured into 1 N HCl aq and
extracted with ethyl acetate. The organic layer was washed with
brine, dried over Na2SO4, and evaporated in vacuo. The residue was
purified by SiO2 column chromatography (n-hexane/ethyl
acetate¼2:1) to give 22 (674 mg, 74%) as a colorless powder. Mp:
52e54 ꢂC. IR (ATR, cmꢁ1): 3367, 2238, 1511. 1H NMR (400 MHz)
d:
cmꢁ1): 3532, 1509. 1H NMR (400 MHz)
d
: 2.35 (3H, s), 2.80 (1H, d,
3.12 (1H, dd, J¼13.6, 7.2 Hz), 3.31 (1H, dd, J¼13.6, 8.4 Hz), 3.64 (3H,
s), 4.76 (1H, dd, J¼8.4, 7.2 Hz), 4.93, 5.04 (each 1H, d, J¼11.6 Hz), 5.10
(2H, s), 6.53 (1H, d, J¼2.0 Hz), 6.62 (1H, dd, J¼8.2, 2.0 Hz), 6.75 (1H,
d, J¼8.2 Hz), 6.76 (1H, br s), 6.93 (1H, d, J¼8.8 Hz), 7.26e7.37 (13H,
J¼6.6 Hz), 3.02 (2H, d, J¼6.6 Hz), 3.58 (3H, s), 5.00, 5.04 (each 1H, d,
J¼11.8 Hz), 5.09 (2H, s), 5.37 (1H, q, J¼6.6 Hz), 6.44 (1H, d, J¼2.0 Hz),
6.54 (1H, dd, J¼8.4, 2.0 Hz), 6.70 (1H, d, J¼8.4 Hz), 6.81 (1H, dd,
J¼3.6, 0.6 Hz), 7.00 (1H, d, J¼8.8 Hz), 7.22 (2H, d, J¼8.4 Hz),
7.23e7.43 (10H, m), 7.50 (1H, d, J¼3.6 Hz), 7.72 (2H, d, J¼8.4 Hz),
m), 8.21 (1H, br s). 13C NMR (100 MHz)
d: 32.0, 39.0, 55.9, 71.3, 72.4,
101.3, 110.1, 111.7, 113.0, 114.2, 114.4, 121.3, 121.4, 126.2, 127.1, 127.5,
127.6, 128.0, 128.1, 128.7, 128.8, 131.0, 131.9, 137.4, 137.6, 147.4, 149.6,
149.8. HRESIMS: m/z 511.2024 (calcd for C32H28N2NaO3: 511.1998).
7.85 (1H, dd, J¼8.8, 0.6 Hz). 13C NMR (100 MHz)
d: 21.5, 43.8, 55.7,
71.1, 71.5, 108.5, 110.6, 112.9, 113.0, 114.1, 121.4, 123.3, 126.8, 127.1,
127.2, 127.5, 127.8, 128.1, 128.5, 128.7, 129.8, 130.1, 130.3, 131.5, 135.2,
136.8, 137.3, 144.8, 149.4, 151.9. HRESIMS: m/z 656.2070 (calcd for
C38H35NNaO6S: 656.2083).
4.1.10. 2-(4-Benzyloxy-3-methoxy-phenyl)-1-[5-benzyloxy-1-(tolu-
ene-4-sulfonyl)-1H-indol-4-yl]-ethanone
(23). IBX
(1.23
g,
4.40 mmol) was added to a DMSO (20 mL) solution of indole 18
(1.77 g, 2.79 mmol) and the whole was stirred for 2 h at room
temperature. After adding water to the reaction mixture, the whole
was filtered through Celite pad and the filtrate was extracted with
CH2Cl2. The organic layer was washed with satd NaHCO3 aq, water,
and brine, dried over Na2SO4, and evaporated in vacuo to give 23
(1.68 g, 95%) as a yellow powder. This product was used without
further purification. Mp: 51e52 ꢂC. IR (ATR, cmꢁ1): 1723, 1512. 1H
4.1.7. 2-(4-Benzyloxy-3-methoxy-phenyl)-1-[5-benzyloxy-1-(tolu-
ene-4-sulfonyl)-1H-indol-4-yl]-ethyl acetate (19). Under Ar, acetyl
chloride (0.5 mL, 7.03 mmol) and pyridine (0.6 mL, 7.45 mmol)
were added to a CH2Cl2 (20 mL) solution of indole 18 (2.05 g,
3.23 mmol) at 0 ꢂC. After stirring for 2 h, the reaction mixture was
poured into 1 N HCl aq and extracted with ethyl acetate. The or-
ganic layer was washed with 1 N HCl aq and brine, dried over
Na2SO4, and evaporated in vacuo. The residue was purified by NH
column chromatography (n-hexane/ethyl acetate¼3:1) to give 19
(2.04 g, 94%) as a colorless powder. Mp: 54e56 ꢂC. IR (ATR, cmꢁ1):
NMR (400 MHz) d: 2.36, 3.71 (each 3H, s), 4.23, 5.10, 5.18 (2H, s),
6.55 (1H, dd, J¼8.2, 2.0 Hz), 6.64 (1H, d, J¼2.0 Hz), 6.73 (1H, d,
J¼8.2 Hz), 6.87 (1H, dd, J¼3.6, 0.8 Hz), 7.03 (1H, d, J¼9.0 Hz), 7.22
(2H, d, J¼8.2 Hz), 7.27e7.42 (10H, m), 7.56 (1H, d, J¼3.6 Hz), 7.72
1736. 1H NMR (400 MHz)
d: 2.00, 2.36 (each 3H, s), 3.05 (1H, dd,
J¼13.6, 6.4 Hz), 3.15 (1H, dd, J¼13.6, 7.6 Hz), 3.51 (3H, s), 4.86, 5.02
(each 1H, d, J¼11.6 Hz), 5.06 (2H, s), 6.38 (1H, d, J¼2.0 Hz), 6.45 (1H,
dd, J¼8.0, 2.0 Hz), 6.64 (1H, dd, J¼7.6, 6.4 Hz), 6.65 (1H, d, J¼8.0 Hz),
6.87 (1H, dd, J¼3.6, 0.4 Hz), 6.91 (1H, d, J¼9.2 Hz), 7.24 (2H, d,
J¼8.0 Hz), 7.27e7.43 (10H, m), 7.55 (1H, d, J¼3.6 Hz), 7.75 (2H, d,
(2H, d, J¼8.2 Hz), 8.03 (1H, dd, J¼9.0, 0.8 Hz). 13C NMR (100 MHz)
d:
21.6, 50.3, 55.8, 71.1, 71.8, 109.0, 110.7, 113.3, 114.0, 117.2, 120.9, 121.8,
126.8, 127.2, 127.6, 127.7, 128.0, 128.3, 128.5, 128.8, 128.9, 129.9,
130.1, 131.2, 135.1, 136.3, 137.3, 145.1, 147.0, 149.4, 154.1, 201.4.
HRESIMS: m/z 654.1957 (calcd for C38H33NNaO6S: 654.1926).
J¼8.0 Hz), 7.83 (1H, dd, J¼9.2, 0.4 Hz). 13C NMR (100 MHz)
d: 21.3,
21.8, 40.8, 55.8, 71.2, 71.8,108.7,111.4, 113.2,113.6,114.0,120.9,121.7,
127.1, 127.3, 127.4, 127.5, 127.96, 127.98, 128.7, 129.8, 130.1, 130.5,
130.6, 135.4, 137.48, 137.51, 145.1, 146.9, 149.4, 152.1, 170.2. HRE-
SIMS: m/z 698.2156 (calcd for C40H37NNaO7S: 698.2188).
4.1.11. 1-(5-Benzyloxy-1H-indol-4-yl)-2-(4-benzyloxy-3-methoxy-
phenyl)-ethanone (24). A suspension of indole 23 (700 mg,
1.11 mmol) and potassium hydroxide (200 mg, 3.56 mmol) in THF/
MeOH¼5:2 (7 mL) was refluxed for 0.5 h. After cooling to room
temperature, the reaction mixture poured into 1 N HCl aq and
extracted with ethyl acetate. The organic layer was washed with
brine, dried over Na2SO4, and evaporated in vacuo. The residue was
purified by NH column chromatography (n-hexane/ethyl
acetate¼1:1) to give 24 (429 mg, 81%) as a colorless powder. Mp:
4.1.8. 3-(4-Benzyloxy-3-methoxy-phenyl)-2-[5-benzyloxy-1-(tolu-
ene-4-sulfonyl)-1H-indol-4-yl]-propionitrile (20). Under Ar, trime-
thylsilyl cyanide (0.06 mL, 0.480 mmol) and boron trifluoride
etherate (0.06 mL, 0.486 mmol) were added to a CH2Cl2 (20 mL)
solution of indole 19 (200 mg, 0.296 mmol) at ꢁ20 ꢂC. After the re-
action mixture was stirred for 0.5 h, satd NaHCO3 aq was added at
ꢁ20 ꢂC. The mixture was extracted with ethyl acetate. 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/ethyl acetate¼2:1) to give 20 (156 mg,
83%)as acolorlesspowder. Mp:64e66 ꢂC. IR (ATR, cmꢁ1):2237,1512,
52e54 ꢂC. IR (ATR, cmꢁ1): 3350, 1653, 1511. 1H NMR (400 MHz)
d:
3.75 (3H, s), 4.34, 5.10, 5.19 (each 2H, s), 6.64 (1H, dd, J¼8.4, 2.0 Hz),
6.73 (1H, d, J¼2.0 Hz), 6.77 (1H, d, J¼8.4 Hz), 6.85 (1H, ddd, J¼3.2,
2.0, 1.2 Hz), 6.95 (1H, d, J¼8.8 Hz), 7.23 (1H, t, J¼3.2 Hz), 7.28e7.46
(11H, m), 8.24 (1H, br s). 13C NMR (100 MHz)
d: 50.5, 55.8, 71.1, 72.4,
103.3, 109.5, 113.4, 113.9, 115.1, 120.1, 121.8, 127.3, 127.6, 127.7, 128.1,
128.5, 128.7, 128.8, 131.7, 137.0, 137.4, 146.8, 149.3, 152.6, 202.0.
HRESIMS: m/z 500.1812 (calcd for C31H27NNaO4: 500.1838).
1138. 1H NMR (400 MHz)
d: 2.36 (3H, s), 3.03, 3.18 (each 1H, dd,
J¼13.2, 7.6 Hz), 3.55 (3H, s), 4.66 (1H, t, J¼7.6 Hz), 4.92, 5.03 (each 1H,
d, J¼11.2 Hz), 5.10 (2H, s), 6.39 (1H, d, J¼2.0 Hz), 6.48 (1H, dd, J¼8.0,
2.0 Hz), 6.68 (1H, d, J¼8.0 Hz), 6.83 (1H, d, J¼3.6 Hz), 6.98 (1H, d,
J¼9.2 Hz), 7.24 (2H, d, J¼8.0 Hz), 7.25e7.43 (10H, m), 7.59 (1H, d,
J¼3.6 Hz), 7.75 (2H, d, J¼8.0 Hz), 7.91 (1H, dd, J¼9.2, 0.8 Hz).13C NMR
4.1.12. 1-(5-Benzyloxy-1H-indol-4-yl)-2-(4-benzyloxy-3-methoxy-
phenyl)-ethanol (25). Under Ar, sodium borohydride (892 mg,
23.6 mmol) and MeOH (10 mL) were added to a THF (20 mL) so-
lution of indole 24 (2.06 g, 4.31 mmol). After stirring at room
temperature for 8 h, the reaction mixture was poured into 1 N HCl
aq and extracted with ethyl acetate. The organic layer was washed
with 1 N HCl aq and brine, dried over Na2SO4, and evaporated in
vacuo. The residue was purified by SiO2 column chromatography
(n-hexane/ethyl acetate¼1:1) to give 25 (1.84 g, 89%) as a colorless
powder. Mp: 47e49 ꢂC. IR (ATR, cmꢁ1): 3434, 1511. 1H NMR
(100 MHz) d: 21.8, 31.5, 39.1, 55.9, 71.2, 71.7, 107.0, 110.8,112.9,114.2,
114.3, 115.1, 120.8, 121.4, 127.0, 127.4, 127.6, 128.0, 128.2, 128.4, 128.7,
128.9,130.1,130.2,130.5,135.2,136.8,137.3,145.3,147.5,149.6,152.1.
HRESIMS: m/z 665.2064 (calcd for C39H34N2NaO5S: 665.2086).
4.1.9. 3-(4-Benzyloxy-3-methoxy-phenyl)-2-(5-benzyloxy-1H-indol-
4-yl)-propionitrile (22). A suspension of potassium hydroxide
(507 mg, 9.04 mmol) and indole 20 (1.20 g, 1.87 mmol) in THF/
(400 MHz)
d
: 3.14 (1H, dd, J¼13.6, 5.8 Hz), 3.19 (1H, s), 3.20 (1H, dd,
J¼13.6, 8.0 Hz), 3.68 (3H, s), 5.00, 5.03 (each 1H, d, J¼11.6 Hz), 5.11

3714
F. Ito, K. Yamaguchi / Tetrahedron 68 (2012) 3708e3716
(2H, s), 5.51 (1H, dd, J¼13.2, 5.8 Hz), 6.58 (1H, d, J¼1.6 Hz),
6.64e6.67 (2H, m), 6.77 (1H, d, J¼8.0 Hz), 6.96 (1H, d, J¼8.8 Hz), 7.15
(1H, t, J¼2.8 Hz), 7.23 (1H, dd, J¼8.8, 0.4 Hz), 7.27e7.44 (13H, m),
72.2, 111.1, 112.9, 113.6, 114.1, 114.7, 121.1, 123.0, 124.2, 127.5, 127.8,
127.97, 128.01, 128.3, 128.7, 128.8, 132.3, 133.7, 137.0, 137.5, 147.2,
149.5, 151.3, 191.7, 205.4. HRESIMS: m/z 558.1889 (calcd for
8.19 (1H, br s). 13C NMR (100 MHz)
d: 43.7, 55.7, 71.1, 72.0, 72.3,
C33H29NNaO6: 558.1893).
101.7, 110.1, 110.4, 113.3, 114.0, 121.5, 122.5, 125.3, 126.7, 127.3, 127.6,
127.7,128.0,128.5,128.6,131.9,132.4,137.4,137.5,146.6,149.3,149.7.
HRESIMS: m/z 502.1962 (calcd for C31H29NNaO4: 502.1994).
4.1.16. 2-{5-Benzyloxy-4-[2-(4-benzyloxy-3-methoxy-phenyl)-ace-
tyl]-1H-indol-3-yl}-2-oxo-ethyl acetate (32). Under Ar, acetyl chlo-
ride (0.7 mL, 9.85 mmol) and pyridine (0.8 mL, 10.1 mmol) were
added to a CH2Cl2 (30 mL) solution of indole 31c (1.80 g, 3.36 mmol)
at 0 ꢂC. After stirring for 0.5 h at 0 ꢂC, the reaction mixture was
poured into 1 N HCl aq and extracted with ethyl acetate. The or-
ganic layer was washed with 1 N HCl aq and brine, dried over
Na2SO4, and evaporated in vacuo. The residue was purified by SiO2
column chromatography (n-hexane/ethyl acetate¼1:1 to 1:5) to
give 32 (1.72 g, 89%) as a colorless powder. Mp: 63e65 ꢂC. IR (ATR,
4.1.13. 1-(5-Benzyloxy-1H-indol-4-yl)-2-(4-benzyloxy-3-methoxy-
phenyl)-ethyl acetate (26). Under Ar, acetyl chloride (0.06 mL,
0.844 mmol) and pyridine (0.08 mL, 0.993 mmol) were added to
a CH2Cl2 (20 mL) solution of indole 25 (203 mg, 0.424 mmol) at 0 ꢂC.
After stirring for 2 h, the reaction mixture was poured into 1 N HCl
aq and extracted with ethyl acetate. The organic layer was washed
with 1 N HCl aq and brine, dried over Na2SO4, and evaporated in
vacuo. The residue was purified by NH column chromatography (n-
hexane/ethyl acetate¼2:1) to give 26 (167 g, 75%) as a colorless
powder. Mp: 47e49 ꢂC. IR (ATR, cmꢁ1): 3380, 1729, 1511. 1H NMR
cmꢁ1): 3258, 1744, 1703, 1661, 1512. 1H NMR (400 MHz)
d: 2.13, 3.72
(each 3H, s), 4.23, 4.87, 5.00, 5.06, 6.76 (each 2H, s), 6.86 (1H, d,
J¼8.8 Hz), 6.97 (1H, s), 7.08 (1H, d, J¼8.8 Hz), 7.26e7.42 (11H, m),
(400 MHz)
d
: 2.03 (3H, s), 3.18 (1H, dd, J¼13.6, 6.0 Hz), 3.30 (1H, dd,
10.1 (1H, d, J¼2.8 Hz). 13C NMR (100 MHz)
d: 20.7, 51.3, 55.8, 65.5,
J¼13.6, 8.0 Hz), 3.63 (3H, s), 4.89, 5.07 (each 1H, d, J¼12.0 Hz), 5.10
(2H, s), 6.58 (1H, d, J¼2.0 Hz), 6.60 (1H, dd, J¼8.0, 2.0 Hz), 6.71 (1H,
d, J¼8.0 Hz), 6.75 (1H, dd, J¼8.0, 6.0 Hz), 6.80 (1H, ddd, J¼2.8, 2.0,
0.8 Hz), 6.90 (1H, d, J¼8.8 Hz), 7.21 (1H, t, J¼2.8 Hz), 7.22 (1H, dd,
J¼8.8, 0.8 Hz), 7.28e7.46 (10H, m), 8.14 (1H, br s). 13C NMR
71.1, 72.0, 110.7, 113.1, 113.6, 113.7, 114.6, 121.0, 122.8, 123.8, 127.4,
127.5, 127.8, 127.95, 128.04, 128.5, 128.6, 132.2, 134.0, 136.9, 137.3,
146.9, 149.2, 150.9, 170.7, 186.1, 205.1. HRESIMS: m/z 600.2006
(calcd for C35H31NNaO7: 600.1998).
(100 MHz)
d
: 21.1, 40.4, 55.7, 71.1, 72.4, 72.8, 102.4, 111.0, 111.03,
4.1.17. 2-[5-Benzyloxy-4-[2-(4-benzyloxy-3-methoxy-phenyl)-ace-
tyl]-1-benzyl-1H-indol-3-yl]-2-oxo-ethyl acetate (33). Under Ar,
benzyl bromide (0.45 mL, 3.78 mmol) was added to a DMF (5 mL)
suspension of indole 32 (1.14 g, 1.97 mmol) and K2CO3 (743 mg,
5.38 mmol). After stirring for 2 h at room temperature, the reaction
mixture was poured into 1 N HCl aq and extracted with ethyl ac-
etate. 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/ethyl acetate¼1:1) to give
33 (1.17 g, 89%) as a yellow powder. Mp: 58e60 ꢂC. IR (ATR, cmꢁ1):
113.1, 113.8, 120.2, 121.6, 125.1, 126.1, 127.3, 127.4, 127.6, 127.7, 128.4,
128.5, 131.3, 132.2, 137.4, 138.0, 146.6, 149.2, 149.7, 170.3. HRESIMS:
m/z 544.2108 (calcd for C33H31NNaO5: 544.2100).
4.1.14. N-Benzyl-2-{5-benzyloxy-4-[2-(4-benzyloxy-3-methoxy-phe-
nyl)-acetyl]-1H-indol-3-yl}-2-oxo-acetamide (11a). Under Ar, oxalyl
chloride (0.05mL, 0.582mmol) was addedtoa THF(2 mL) solutionof
indole 24 (200 mg, 0.419 mmol) at room temperature. After stirring
the reaction mixture for 1 h, benzyl amine (0.1 mL, 0.916 mmol) was
added. The whole was stirred at room temperature for 10 min. Then,
the reaction mixture was poured into satd NH4Cl aq and extracted
with ethyl acetate. The organic layer was washed with satd NH4Cl aq
and brine, dried over Na2SO4, and evaporated in vacuo. The residue
was purified by SiO2 column chromatography (n-hexane/ethyl
acetate¼1:1 to 0:1) to give 11a (197 mg, 74%) as a yellow powder.
Mp: 73e75 ꢂC. IR (ATR, cmꢁ1): 3289,1678,1630. 1H NMR (400 MHz)
1744, 1709, 1668, 1512. 1H NMR (400 MHz)
d: 2.17, 3.74 (each 3H, s),
4.28, 5.05, 5.08, 5.13, 5.33, 6.77 (each 2H, s), 6.98 (1H, d, J¼8.8 Hz),
6.99 (1H, s), 7.15 (2H, dd, J¼7.2, 1.6 Hz), 7.23 (1H, d, J¼8.8 Hz),
7.27e7.45 (13H, m), 7.81 (1H, s). 13C NMR (100 MHz)
d: 20.7, 51.0,
51.1, 55.7, 65.8, 71.1, 72.3, 111.4, 111.5, 113.6, 113.8, 114.5, 122.4, 122.7,
125.5, 127.0, 127.3, 127.5, 127.6, 128.0, 128.2, 128.45, 128.54, 129.2,
132.8, 135.1, 135.4, 136.9, 137.6, 146.7, 149.1, 151.6, 170.5, 185.5, 202.7.
HRESIMS: m/z 690.2521 (calcd for C42H37NNaO9S: 690.2468).
d
: 3.60 (3H, s), 4.24 (2H, s), 4.49 (2H, d, J¼6.0 Hz), 5.01, 5.06 (each 2H,
s), 6.75 (1H, s), 6.83 (1H, s), 6.89 (1H, d, J¼8.8 Hz), 7.18 (1H, d,
J¼8.8 Hz), 7.25e7.41 (15H, m), 7.84 (1H, t, J¼6.0 Hz), 8.93 (1H, d,
4.1.18. 2-[5-Benzyloxy-4-[2-(4-benzyloxy-3-methoxy-phenyl)-ace-
tyl]-1-(toluene-4-sulfonyl)-1H-indol-3-yl]-2-oxo-ethyl acetate (34).
Under Ar, NEt3 (0.7 mL, 5.02 mmol) was added to a CH2Cl2 (5 mL)
suspension of indole 32 (954 mg, 1.65 mmol) and tosyl chloride
(594 mg, 3.12 mmol) at 0 ꢂC. After stirring for 1 h at 0 ꢂC, the re-
action mixture was poured into 1 N HCl aq and extracted with ethyl
acetate. 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/ethyl acetate¼1:1) to give
34 (932 mg, 77%) as a colorless powder. Mp: 69e71 ꢂC. IR (ATR,
J¼3.6 Hz), 9.81 (1H, d, J¼3.6 Hz). 13C NMR (100 MHz)
d: 43.6, 51.8,
55.8, 71.3, 72.3, 111.1, 113.1, 113.6, 114.1, 114.5, 122.6, 122.9, 124.8,
127.5, 127.8, 127.91, 127.94, 128.1, 128.2, 128.7, 128.8, 129.0, 129.1,
131.9, 137.0, 137.5, 137.6, 140.6, 147.1, 149.4, 151.9, 162.6, 179.0, 204.5.
HRESIMS: m/z 661.2302 (calcd for C40H34N2NaO6: 661.2315).
4.1.15. 1-[5-Benzyloxy-3-(2-hydroxy-acetyl)-1H-indol-4-yl]-2-(4-
benzyloxy-3-methoxy-phenyl)-ethanone (31c). Under Ar, oxalyl
chloride (0.45 mL, 5.24 mmol) was added to a THF (40 mL) solution
of indole 24 (1.97 g, 4.12 mmol) at room temperature. After stirring
the reaction mixture for 1 h, tributyltin hydride (5.0 mL, 19.1 mmol)
was added. The reaction mixture was stirred at room temperature
for 12 h and then poured into 1 N HCl aq and extracted with ethyl
acetate. The organic layer was washed with 1 N HCl aq and brine,
dried over Na2SO4, and evaporated in vacuo. The residue was pu-
rified by SiO2 column chromatography (n-hexane/ethyl
acetate¼1:10) to give 31c (1.23 g, 56%) as a yellow powder. Mp:
74e76 ꢂC. IR (ATR, cmꢁ1): 3218, 1700, 1647, 1511. 1H NMR (400 MHz)
cmꢁ1): 1746, 1691, 1512. 1H NMR (400 MHz)
d: 2.20, 2.41, 3.74 (each
3H, s), 4.23, 5.07, 5.11, 5.12 (each 2H, s), 6.69 (1H, dd, J¼8.0, 1.8 Hz),
6.76 (1H, d, J¼8.0 Hz), 6.90 (1H, d, J¼1.8 Hz), 7.09 (1H, d, J¼9.2 Hz),
7.28e7.39 (10H, m), 7.43 (2H, d, J¼7.2 Hz), 7.81 (2H, d, J¼8.4 Hz),
7.93 (1H, d, J¼9.2 Hz), 8.28 (1H, s). 13C NMR (100 MHz)
d: 20.6, 21.7,
50.6, 55.7, 66.0, 71.1, 71.9, 112.4, 113.8, 114.4, 114.5, 118.2, 122.5,
123.8, 125.4, 127.18, 127.24, 127.5, 127.6, 127.7, 128.2, 128.5, 128.7,
130.0, 130.4, 132.7, 134.1, 136.3, 137.5, 146.4, 146.9, 149.2, 152.9,
170.3, 186.9, 201.8. HRESIMS: m/z 754.2149 (calcd for
C42H37NNaO9S: 754.2087).
d: 3.71 (3H, s), 4.27, 4.37, 5.04, 5.06 (each 2H, s), 6.70 (1H, d,
J¼8.0 Hz), 6.80 (1H, dd, J¼8.0, 2.0 Hz), 6.90 (1H, d, J¼2.0 Hz), 6.92
(1H, d, J¼8.8 Hz), 7.18 (1H, d, J¼8.8 Hz), 7.24 (1H, br s), 7.27e7.42
4.1.19. 1-[5-Benzyloxy-3-(2-hydroxy-acetyl)-1-benzyl-1H-indol-4-
yl]-2-(4-benzyloxy-3-methoxy-phenyl)-ethanone (5). 30% H2O2 aq
(10H, m), 9.82 (1H, s). 13C NMR (100 MHz)
d: 51.6, 56.0, 64.5, 71.3,

F. Ito, K. Yamaguchi / Tetrahedron 68 (2012) 3708e3716
3715
(20 mL) was added to a THF (10 mL) suspension of indole 33
(867 mg, 1.30 mmol) and K2CO3 (856 mg, 6.19 mmol). After stirring
for 2 h at room temperature, the reaction mixture was poured into
1 N HCl aq and extracted with ethyl acetate. 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/ethyl acetate¼1:2) to give 5 (778 mg, 96%) as a yellow
powder. Mp: 60e61 ꢂC. IR (ATR, cmꢁ1): 3060, 1706, 1650, 1511. 1H
The residue was purified by SiO2 column chromatography (chlo-
roform/ethyl acetate¼5:1) to give 10b (169 mg, 87%) as a yellow
amorphous solid. Mp: 219e220 ꢂC. IR (ATR, cmꢁ1): 3189, 1718, 1616,
1579. 1H NMR (400 MHz, DMSO-d6)
d: 3.62, 3.74 (each 3H, s), 5.11,
5.31 (each 2H, s), 6.70 (1H, dd, J¼8.4, 2.0 Hz), 6.82 (1H, d, J¼2.0 Hz),
7.02, 7.23 (each 1H, d, J¼8.4 Hz), 7.28e7.42 (6H, m), 7.47, 7.59 (each
2H, d, J¼7.2 Hz), 7.84 (1H, d, J¼8.4 Hz), 8.06 (1H, d, J¼2.8 Hz). 13C
NMR (100 MHz, DMSO-d6) d: 52.7, 56.3, 70.6, 70.9, 108.4, 111.4,
NMR (400 MHz)
d
: 3.61 (1H, br s), 3.74 (3H, s), 4.29, 4.61, 5.06, 5.13,
113.5, 114.9, 115.0, 120.5, 122.9, 127.5, 127.7, 128.2, 128.4, 128.5,
129.0, 129.1, 130.2, 130.8, 132.1, 134.3, 136.9, 137.85, 137.93, 147.7,
148.9, 156.7, 167.9, 180.9. HRESIMS: m/z 546.1879 (calcd for
C34H28NO6: 546.1917).
5.32 (each 2H, s), 6.79 (1H, d, J¼8.4 Hz), 6.82 (1H, dd, J¼8.4, 1.6 Hz),
6.91 (1H, d, J¼1.6 Hz), 7.00 (1H, d, J¼9.2 Hz), 7.13 (2H, dd, J¼7.6,
1.8 Hz), 7.27e7.45 (13H, m), 7.76 (1H, s). 13C NMR (100 MHz)
d:
51.39, 51.43, 56.0, 64.8, 71.3, 72.5, 111.6, 111.9, 112.8, 114.2, 114.6,
122.4, 122.9, 125.6, 127.1, 127.5, 127.7, 127.9, 128.16, 128.23, 128.66,
128.72, 128.8, 129.4, 133.1, 135.2, 135.7, 137.0, 137.8, 147.1, 149.5,
151.9, 191.1, 203.1. HRESIMS: m/z 648.2359 (calcd for C40H35NNaO6:
648.2362).
4.1.23. 1-Benzyl-6-benzyloxy-5-(4-benzyloxy-3-methoxy-benzyl)-4-
hydroxy-1H-benzo[cd]indole-3-one (9). Under Ar, a THF (2 mL)
suspension of t-BuOK (92 mg, 0.820 mmol) and indole 5 (207 mg,
0.331 mmol) was refluxed for 2 h. After cooling to room tempera-
ture, the reaction mixture was poured into satd NH4Cl aq and
extracted with ethyl acetate. The organic layer was washed with
brine, dried over Na2SO4, and evaporated in vacuo. The residue was
purified by SiO2 column chromatography (chloroform/ethyl
acetate¼5:1) to give 9 (48 mg, 24%) as a yellow powder. Mp:
4.1.20. 6-Benzyloxy-4-(4-benzyloxy-3-methoxy-phenyl)-5-oxo-1,5-
dihydro-benzo[cd]indole-3-carboxylic acid benzylamide (10a).
Under Ar, a THF (1 mL) suspension of K2CO3 (42.0 mg, 0.304 mmol)
and indole 11a (100 mg, 0.157 mmol) was refluxed for 2 h. After
cooling down to room temperature, the reaction mixture was
poured into 1 N HCl aq and extracted with ethyl acetate. The or-
ganic layer was washed with brine, dried over Na2SO4, and evap-
orated in vacuo. The residue was purified by SiO2 column
chromatography (n-hexane/ethyl acetate¼1:10) to give 10a
(56.0 mg, 58%) as a yellow powder. Mp: 100e103 ꢂC. IR (ATR, cmꢁ1):
65e67 ꢂC. IR (ATR, cmꢁ1): 3300, 1599. 1H NMR (400 MHz)
d: 3.68
(3H, s), 4.50 (2H, s), 5.08 (4H, s), 5.41 (2H, s), 6.57 (1H, dd, J¼8.2,
1.8 Hz), 6.66 (1H, d, J¼8.2 Hz), 6.80 (1H, d, J¼1.8 Hz), 6.90 (1H, d,
J¼8.8 Hz), 7.17e7.22 (4H, m), 7.26 (1H, d, J¼8.8 Hz), 7.27e7.38 (10H,
m), 7.41 (2H, d, J¼6.8 Hz), 8.12 (1H, s). 13C NMR (100 MHz)
d: 33.0,
52.1, 56.1, 71.4, 71.6, 110.8, 112.8, 112.90, 112.92, 113.5, 114.3, 120.2,
122.4, 123.5, 127.4, 127.6, 127.7, 127.8, 128.2, 128.6, 128.8, 128.9,
129.2, 129.4, 134.3, 134.8, 135.3, 136.7, 137.9, 146.4, 149.6, 151.0,
155.3, 173.0. HRESIMS: m/z 630.2268 (calcd for C40H33NNaO5:
630.2251).
3412, 3178, 1631, 1583, 1534. 1H NMR (400 MHz)
d: 3.69 (3H, s), 4.24
(2H, d, J¼5.6 Hz), 5.07, 5.24 (each 2H, s), 5.86 (1H, t, J¼5.6 Hz), 6.79
(1H, d, J¼8.4 Hz), 6.81e6.84 (3H, m), 6.85 (1H, dd, J¼8.4, 1.8 Hz),
6.93 (1H, d, J¼1.8 Hz), 7.17e7.38 (9H, m), 7.45, 7.49 (each 2H, d,
J¼6.8 Hz), 7.66 (1H, s). 13C NMR (100 MHz)
d: 44.1, 56.2, 71.1, 71.5,
109.9, 110.8, 113.8, 114.3, 115.0, 119.9, 123.0, 127.2, 127.5, 127.68,
127.71, 127.8, 127.9, 128.1, 128.70, 128.72, 128.8, 129.8, 131.7, 135.7,
136.8, 137.2, 137.3, 137.9, 148.3, 149.8, 157.1, 167.5, 182.5. HRESIMS:
m/z 621.2368 (calcd for C40H33N2O5: 621.2390).
References and notes
1. Zhang, H.; Qiu, S.; Tamez, P.; Tan, G. T.; Aydogmus, Z.; Hung, N. V.; Cuong, N. M.;
Angerhofer, C.; Soejarto, D. D.; Pezzuto, J. M.; Fong, H. H. S. Pharm. Biol. 2002, 40,
221e224.
2. Sato, H.; Kawagishi, H.; Nishimura, T.; Yoneyama, S.; Yoshimoto, Y.; Sakamura,
S.; Furusaki, A.; Katsuragi, S.; Matsumoto, T. Agric. Biol. Chem. 1985, 49,
2969e2974.
4.1.21. {5-Benzyloxy-4-[2-(4-benzyloxy-3-methoxy-phenyl)-acetyl]-
1H-indol-3-yl}-oxo-acetic acid methyl ester (11b). Under Ar, oxalyl
chloride (0.2 mL, 2.33 mmol) was added to a THF (2 mL) solution of
indole 24 (305 mg, 0.639 mmol) at room temperature. After stirring
for 1 h, dry methanol (10 mL) was added to the reaction mixture.
After the whole was stirred at room temperature for 10 min, the
reaction mixture was poured into satd NaHCO3 aq and extracted
with ethyl acetate. 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/
ethyl acetate¼1:1 to 0:1) to give 11b (264 mg, 73%) as a yellow
powder. Mp: 65e68 ꢂC. IR (ATR, cmꢁ1): 3267, 1729, 1642, 1510. 1H
3. Sarker, S. D.; Savchenko, T.; Whiting, P.; Sik, V.; Dinan, L. Nat. Prod. Lett. 1997, 9,
189e199.
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4. Ndongo, J. T.; Shaaban, M.; Mbing, J. N.; Bikobo, D. N.; Atchade, A. T.; Pegnyemb,
D. E.; Laatsch, H. Phytochemistry 2010, 71, 1872e1878.
5. Leduc, A. B.; Kerr, M. A. Eur. J. Org. Chem. 2007, 237e240.
6. (a) Mascal, M.; Modes, K. V.; Durmus, A. Angew. Chem., Int. Ed. 2011, 50,
4445e4446; (b) Qin, H.; Xu, Z.; Cui, Y.; Jia, Y. Angew. Chem., Int. Ed. 2011, 50,
4447e4449.
7. Sun, D.; Zhao, Q.; Li, C. Org. Lett. 2011, 13, 5302e5305.
8. Koizumi, Y.; Kobayashi, H.; Wakimoto, T.; Furuta, T.; Fukuyama, T.; Kan, T. J. Am.
Chem. Soc. 2008, 130, 16854e16855.
9. Ito, F.; Shudo, K.; Yamaguchi, K. Tetrahedron 2011, 67, 1805e1811.
10. Uhle, F. C. J. Am. Chem. Soc. 1949, 71, 761e766.
11. (a) Ponticello, G. S.; Baldwin, J. J.; Lumma, P. K.; McClure, D. E. J. Org. Chem. 1980,
45, 4236e4238; (b) Meyer, M. D.; Kruse, L. J. Org. Chem. 1984, 49, 3195e3199; (c)
Teranishi, K.; Hayashi, S.; Nakatsuka, S.; Goto, T. Tetrahedron Lett. 1994, 35,
8173e8176; (d) Teranishi, K.; Hayashi, S.; Nakatsuka, S.; Goto, T. Synthesis 1995,
506e508.
12. (a) Thenmozhiyal, J. C.; Wong, P. T.-H.; Chui, W.-K. J. Med. Chem. 2004, 47,
1527e1535; (b) Raap, J.; Nieuwenhuis, S.; Creemers, A.; Hexspoor, S.; Kragl, U.;
Lugtenburg, J. Eur. J. Org. Chem. 1999, 2609e2621; (c) Beattie, J. K.; McErlean, C.
S. P.; Phippen, C. B. W. Chem.dEur. J. 2010, 16, 8972e8974.
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NMR (400 MHz) d: 3.67, 3.84 (each 3H, s), 4.29, 5.01, 5.03 (each 2H,
s), 6.71 (1H, d, J¼8.2 Hz), 6.78 (1H, dd, J¼8.2, 2.0 Hz), 6.87 (1H, d,
J¼2.0 Hz), 6.88, 7.16 (each 1H, d, J¼8.6 Hz), 7.26e7.40 (10H, m), 8.08,
10.1 (each 1H, d, J¼3.6 Hz). 13C NMR (100 MHz)
d: 51.6, 52.9, 56.0,
71.3, 72.2, 111.2, 113.6, 114.0, 114.7, 121.9, 123.0, 124.5, 127.5, 127.8,
127.9, 128.1, 128.3, 128.7, 128.8, 132.4, 136.9, 137.6, 139.5, 147.1, 149.4,
151.9, 163.7, 176.9, 204.9. HRESIMS: m/z 586.1831 (calcd for
C34H29NNaO7: 586.1842).
14. Citterio, A.; Gandolfi, M.; Piccolo, O.; Filippini, L.; Tinucci, L.; Valoti, E. Synthesis
1984, 760e763.
15. Tran, V. H.; Kantharaj, R.; Roufogalis, B. D.; Duke, C. C. J. Org. Chem. 2006,
2970e2976.
4.1.22. 6-Benzyloxy-4-(4-benzyloxy-3-methoxy-phenyl)-5-oxo-1,5-
dihydro-benzo[cd]indole-3-carboxylic acid methyl ester (10b). Under
Ar, a THF (2 mL) suspension of K2CO3 (147 mg, 1.06 mmol) and
indole 11b (201 mg, 0.357 mmol) was refluxed for 2 h. After cooling
down to room temperature, the reaction mixture was poured into
1 N HCl aq and extracted with chloroform. The organic layer was
washed with brine, dried over Na2SO4, and evaporated in vacuo.
16. Yabe, O.; Mizufune, H.; Ikemoto, T. Synlett 2009, 1291e1294.
17. Konno, H.; Toshiro, E.; Hinoda, N. Synthesis 2003, 2161e2164.
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ꢀ
19. Bonini, B.-F.; Giordano, L.; Fochi, M.; Comes-Franchini, M.; Bernardi, L.; Capito,
E.; Ricci, A. Tetrahedron: Asymmetry 2004, 15, 1043e1051.
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771e785.

3716
F. Ito, K. Yamaguchi / Tetrahedron 68 (2012) 3708e3716
21. (a) Nakagawa, K.; Aoki, N.; Mukaiyama, H.; Somei, M. Heterocycles 1992, 34,
2269e2275; (b) Cueva, J. P.; Nichols, D. E. Synthesis 2009, 715e720.
22. Kreisberg, J. D.; Magnus, P.; Mclver, E. G. Tetrahedron Lett. 2001, 42,
627e629.
23. (a) Deng, W.-P.; Nam, G.; Fan, J.; Kirk, K. L. J. Org. Chem. 2003, 68, 2798e2802;
(b) Strekowski, L.; Aken, K. V.; Gulevich, Y. J. Heterocycl. Chem. 2000, 37,
1495e1499.
24. Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 13179e13184.