Lewis acid-promoted tandem desulfurization and hydroxylation of γ-phenylthio-substituted lactams: Novel synthetic strategy of isoindolobenzazepine alkaloid, chilenine

Article abstract of DOI:10.1016/j.tetlet.2003.09.204

Treatment of a variety of alicyclic and aromatic γ-phenylthio- substituted lactams with Lewis acids such as cuprous or cupric halides in aqueous solution at rt was found to undergo novel tandem desulfurization and hydroxylation reactions to generate γ-hydroxylated lactams without the ring-opened products in extremely high yields, respectively. This process was further applied to the total synthesis of an isoindolobenzazepine alkaloid, chilenine, by featuring the elaboration of the functionalized phthalimide derivative.

Full text of DOI:10.1016/j.tetlet.2003.09.204

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9057–9060
Lewis acid-promoted tandem desulfurization and hydroxylation
of g-phenylthio-substituted lactams: novel synthetic strategy of
isoindolobenzazepine alkaloid, chilenine
Hidemi Yoda,* Kei-ichi Inoue, Yasuaki Ujihara, Nobuyuki Mase and Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Hamamatsu 432-8561, Japan
Received 3 September 2003; revised 22 September 2003; accepted 24 September 2003
Abstract—Treatment of a variety of alicyclic and aromatic g-phenylthio-substituted lactams with Lewis acids such as cuprous or
cupric halides in aqueous solution at rt was found to undergo novel tandem desulfurization and hydroxylation reactions to
generate g-hydroxylated lactams without the ring-opened products in extremely high yields, respectively. This process was further
applied to the total synthesis of an isoindolobenzazepine alkaloid, chilenine, by featuring the elaboration of the functionalized
phthalimide derivative.
© 2003 Elsevier Ltd. All rights reserved.
Due to their well documented and useful structural
features for the synthesis of biologically active com-
pounds, there has been increasing interest in the utiliza-
tion of g-phenylthio-substituted lactams as crucial and
key intermediates. Thus, a number of efficient tech-
niques to utilize such compounds have been accom-
plished and many advantageous reports have appeared
for CꢀC bond formation, e.g. thionium/N-acyliminium
ion cyclization cascade,1a Lewis acid-mediated allyla-
tion,1b intramolecular radical cyclization,1c direct
replacement of the sulfur group by the alkyl function
employing organo-zinc reagents,1d and successive alky-
lation–desulfurization sequence for the introduction of
the alkyl side chain1e together with the well known
desulfurization protocol.1f,g In this connection recent
disclosures from this laboratory have demonstrated
SmI2-promoted tandem desulfurization and high ery-
thro-selective coupling reactions of aromatic lactams
with carbonyl compounds.2 Although significant pro-
gress, thus, has been made in advancing the versatility
of sulfur-substituted lactams, the lack of studies con-
cerning the reactivity toward simple Lewis acids is
surprising except the lactol type of compounds.3 Herein
we wish to report our successful efforts for the develop-
ment of novel Lewis acid-mediated tandem reaction of
phenylthio-substituted alicyclic and aromatic lactams in
aqueous media, leading to the g-hydroxylated products,
whose process was further applied to the convenient
total synthesis of isoindolobenzazepine natural product,
chilenine.
Initial experiments have been performed on tandem
desulfurization and hydroxylation reactions of simple
g-phenylthio-substituted alicyclic lactams 1 in the pres-
ence of a variety of Lewis acid-additives such as MgBr2,
SmCl3, or CeCl3 in aqueous solution (CH3CN–H2O=
9:1) at ambient temperature. The reactions, however,
did not proceed under any conditions and recovered the
starting material 1. Next, we examined the same type of
reactions employing another Lewis acids. The results
from our survey are summarized in Table 1. Whereas
the reactions with FeCl3 and CuI gave the desired
hydroxylated product 2, but in low yield, respectively
(entries 1, 2), use of CuCl or CuBr had a dramatic
effect on the rate and smoothly brought about the
target compound 2 in almost quantitative yields (entries
6–8) under these mild and readily available conditions.
We were delighted to find that the same beneficial
results were again obtained in reaction employing qua-
ternary substituted phenylthiolactams containing
aliphatic and aromatic alkyl side chains (entries 9,10)
by replacement of the solvent system from CH3CN–
H2O (9:1) to 1,4-dioxane–H2O (2:1) without by-prod-
ucts such as ring-opened ketoamides derived from 2.
As shown in Table 2, we further found that the use of
b-substituted and a,b-disubstituted g-phenylthiolactams
3 (entries 1, 2) as well as the aromatic one (entry 3)
underwent convenient reactions to afford the corre-
* Corresponding author. Tel.: +81-53-478-1150; fax: +81-53-478-1150;
e-mail: tchyoda@ipc.shizuoka.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.204

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H. Yoda et al. / Tetrahedron Letters 44 (2003) 9057–9060
Table 1. Tandem desulfurization and hydroxylation reactions of g-phenylthiolactams 1
Entry
n
R
Lewis acid
Conditionsa
Time (days)
Yield (%)b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
2
1
1
H
H
H
H
H
H
H
H
FeCl3
CuI
A
A
A
A
A
A
A
A
B
1
1
1
1
1
1
1
1
36
8
81
CAN
CuBr2
CuCl2
CuCl
CuBr
CuBr
CuBr
CuBr
65
>99
>99
>99
>99
84c
97c
CH3(CH2)3
C6H5
0.1
0.1
10
B
a Conditions A performed in CH3CN–H2O (9:1) and conditions B performed in 1,4-dioxane-H2O (2:1), respectively.
b Isolated yield.
c Reactions under conditions A gave the corresponding ring-opened ketoamides as a main product derived from the quaternary hydroxylactams
2 in 23% (R: butyl) and 53% (R: phenyl) yields, respectively.
Table 2. Tandem desulfurization and hydroxylation reactions of functionalized g-phenylthiolactams 3
Entry
R1
R2
R3
Conditionsa
Time (days)
Yield (%)b
1
2
3
4
5
6
7
8
9
H
OBn
OBn
H
H
H
A
A
A
B
B
B
B
A
A
3
1
1
1
1
1
1
0.1
0.1
>99d
>99d
98
OBnc
-C6H4-
H
H
OBn
OBn
OBn
OBn
OBnc
OBnc
CH3(CH2)3
C6H5
CH3(CH2)3
C6H5
CH3(CH2)3
C6H5
92d
90d
86d
98d
>99
>99
-C6H4-
-C6H4-
a Conditions A performed in CH3CN–H2O (9:1) and conditions B performed in 1,4-dioxane–H2O (4:1), respectively.
b Isolated yield.
c d.l-Tartaric acid-derived lactam 3 was used.
d Unfortunately, these reactions resulted in the almost non-stereoselective formation of 4 except the case of entry 1, which indicated the moderate
trans-selectivity (cis:trans (to the b-OBn group)=16:84, isolated ratio).
In light of the above outcome, we turned our attention
to the development of novel and convenient synthetic
method of isoindolobenzazepine alkaloid, chilenine (5),5
whose structure incorporating the 3H-3-benzazepine
moiety and equally an isoindolinone ring system is
architecturally sophisticated and possesses the real and
potential biological properties.6 As summarized in
Scheme 1, the functionalized imide 6 obtained from
3,4-dimethoxy-2-ethoxycarbonylbenzoic acid and bro-
mopiperonal based on our reported method,6f was
reduced with DIBAL-H7 at low temperature to provide
the hydroxylactam intermediate, which was quickly
treated with thiophenol under acidic conditions, leading
to the phenylthiolactam 7 in 61% yield (two steps)
sponding desulfurized hydroxylactams in quite high
yields, respectively. In addition, it will be particularly of
interest to note that a variety of both sterically more
hindered and unstable quaternary hydroxy-substituted
lactams 4 with b- or a,b-disubstituents4a–f could be
obtained again under these conditions (entries 4–9)
irrespective of their structures.
Thus, this procedure is applicable for the production of
a wide range of g-hydroxylated lactam derivatives and
provides an easily accessible alternative to the existing
synthetic method of these types of compounds, since, to
the best of our knowledge, one approach to the direct
preparation of g-hydroxylactams 2 or 4 through nucleo-
philic addition of organometallic reagents to cyclic
imides has been demonstrated.4
1
regioselectively (96:4, determined by H NMR). When
the deprotection of the MPM-group in 7 was per-
formed by the use of DDQ, the desired aldehyde

H. Yoda et al. / Tetrahedron Letters 44 (2003) 9057–9060
9059
Scheme 1. Reagents and conditions: (a) 1, DIBAL-H, THF, −78°C; 2, PhSH, BF3OEt2, CH2Cl2; 61% (two steps); (b) DDQ,
CH2Cl2–H2O (10:1); 97%; (c) LiHMDS, HMPA, THF, −78 to 0°C; 65%; (d) TPAP, NMO, CH2Cl2; 78%; (e) CuBr, CH3CN–H2O
(1:1); 83%.
derivative 8 could be obtained directly. This was succes-
sively effected by intramolecular cyclization reaction
under basic conditions to provide the corresponding
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This work was supported in part by a Grant-in-Aid
(No. 15550031) for Scientific Research from the Japan
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