A novel synthetic approach to isoindolobenzazepine alkaloid, chilenine, employing SmI2-mediated pinacolic coupling reaction

Article abstract of DOI:10.1016/S0040-4039(02)00881-X

Samarium(II) diiodide-mediated intramolecular reductive coupling reaction of phthalimides with N-formylated alkyl side chains is shown to afford dihydroxylated tricyclic lactams with 5-7-membered rings. This process was further applied for the preparation of an isoindolobenzazepine alkaloid, chilenine, by featuring the elaboration of the functionalized phthalimide derivative.

Full text of DOI:10.1016/S0040-4039(02)00881-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4667–4669
A novel synthetic approach to isoindolobenzazepine alkaloid,
chilenine, employing SmI2-mediated pinacolic coupling reaction
Hidemi Yoda,* Akira Nakahama, Tomomi Koketsu and Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Hamamatsu 432-8561, Japan
Received 8 April 2002; revised 22 April 2002; accepted 2 May 2002
Abstract—Samarium(II) diiodide-mediated intramolecular reductive coupling reaction of phthalimides with N-formylated alkyl
side chains is shown to afford dihydroxylated tricyclic lactams with 5–7-membered rings. This process was further applied for the
preparation of an isoindolobenzazepine alkaloid, chilenine, by featuring the elaboration of the functionalized phthalimide
derivative. © 2002 Elsevier Science Ltd. All rights reserved.
Chilenine (1) and lennoxamine (2) first found in the
plants of the Chilean Berberis species, Berberis empetri-
folia Lam and Berberis darwinii Hook, respectively, are
a new class of alkaloids belonging to the aporhoedane
series.1 Although biogenetically related to protoberber-
ines and usually classified as isoquinoline alkaloids,
they are distinguished by the presence of an isoin-
dolo[1,2-b][3]benzazepine unit embedded in their skele-
ton from the simple isoquinoline group. Due to the fact
that their structures incorporating the 3H-3-benz-
azepine moiety and equally an isoindolinone ring sys-
tem are architecturally sophisticated and possess the
real and potential biological properties,2 they have cap-
tured the interest as attractive and synthetically chal-
lenging targets.3 Synthetic strategies described up to
date, however, in general require multistep reactions or
crucial techniques and were not necessarily satisfactory.
On the other hand, as part of our work designed to
explore the use of cyclic imides, we have demonstrated
some significant stereoselective reactions4 and their
applications to the total syntheses of biologically active
natural products.5 In addition, recently, novel and
stereoselective methods for the preparation of hydroxy-
lactams via reductive coupling reactions mediated by
SmI2 have also been developed in this laboratory.6 The
purpose of the present communication is to describe the
result that N-functionalized phthalimide derivatives
underwent fast SmI2-induced intramolecular pinacol-
type coupling reaction, which in turn made it possible
to provide a new expeditious and practical opportunity
for the synthesis of an isoindolobenzazepine alkaloid,
chilenine.
OMe
OMe
O
O
MeO
MeO
N
N
HO
O
O
O
O
O
2: lennoxamine
1: chilenine
In formulating the synthetic plan for chilenine (1), we
envisioned that the benzazepine ring of significant pre-
cursor 3 would originate from the intramolecular cou-
pling reaction of 4, which could be divided into two
known fragments, acid ester 57 and bromopiperonal
(6),8 respectively (Scheme 1).
In advance, initial experiments have been performed on
the intramolecular coupling reaction in the presence of
SmI2 (2 equiv.) in THF at rt employing simple phthal-
imide derivatives 79 with N-formylated alkyl sub-
stituents. As shown in Scheme 2, it became apparent
that these conditions without additives brought about
the desired dihydroxylated tricyclic lactams 8 with 5–7-
membered rings in satisfactory yields, respectively.10
With these results in hand, we next focussed our atten-
tion on the synthesis of 1, an isoindolobenzazepine
natural product. The results from our survey are sum-
marized in Scheme 3. To begin with, the ethylene acetal
compound derived from bromopiperonal (6) was con-
verted into 9 via aromatic allylation,11 which underwent
dihydroxylation and oxidative cleavage of the olefinic
Keywords: SmI2; imide; coupling reaction; alkaloid; chilenine.
* Corresponding author. Tel.: +81 53 478 1150; fax: +81 53 478 1150;
e-mail: tchyoda@ipc.shizuoka.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00881-X

4668
H. Yoda et al. / Tetrahedron Letters 43 (2002) 4667–4669
OMe
MeO
COOEt
COOH
OMe
HO
O
OMe
O
MeO
MeO
N
5
6
N
1
O
O
O
HO
Br
OHC
O
O
OHC
3
4
O
O
Scheme 1.
O
N
O
SmI2 (2 equiv.)
N
CHO
n
n
THF, rt
HO
HO
O
8a: n = 1
8b: n = 2
8c: n = 3
7a: n = 1
7b: n = 2
7c: n = 3
y. 86%
y. 79%
y. 63%
Scheme 2.
HO
MPMO
O
O
O
a
b
6
O
O
O
9
10
OMe
OMe
O
O
MeO
MeO
c
d
e
N
O
N
H
5
O
O
O
11
12
OMe
OMPM
OMe
HO
O
N
O
MeO
OMe
MeO
Danishefsky et al.
O
N
MeO
N
f
O
HO
HO
O
O
O
OHC
O
O
4
cis:trans = 3:1
3
1: chilenine
O
O
Scheme 3. Reagents and conditions: (a) 1, HO(CH2)2OH, p-TsOH, toluene, reflux; quant.; 2, BuLi, ether, −60°C, then allyl
bromide; 63%; (b) 1, conc. HCl, ether; 2, NaBH4, MeOH; 78% (two steps); 3, MPMCl, Ag2O, CH3COOEt; 82%; 4, OsO4, NMO,
acetone–H2O (1:1), 5, NaIO4, ether–H2O (1:1), −5°C; 6, NaBH4, MeOH; 80% (three steps); (c) 1, MPMNH2, DCC, CH2Cl2; 78%;
2, CAN, CH3CN–H2O (9:1), −10°C; 65%; (d) (10), DEAD, PPh3, THF; 46%; (e) DDQ, CH2Cl2–H2O (10:1), −10°C; 54%; (f) SmI2
(3 equiv.), THF; 65%.
plete regioselectivity. The ratio of the two diastereomers
part followed by reduction to give the alcohol 10 in
high yield after successive reactions of deacetalization,
reduction, and MPM(p-methoxybenzyl)-protection. On
the other hand, acid ester 5 was submitted to coupling
reaction with MPM-amine to afford the cyclic imide
directly, which was then deprotected with cerium
ammonium nitrate (CAN), leading to the NH-imide 11.
Thus, reaction of 11 with the alcohol 10 prepared above
under Mitsunobu conditions proved to yield the con-
densation product 12 in moderate yield. When the
subsequent deprotection of the MPM-group in 12 was
effected by the use of DDQ, it was apparent that the
desired aldehyde intermediate 4 could be obtained
directly. Finally, SmI2-mediated intramolecular pina-
colic reaction of 4 was performed to give the crucial
coupling product 3 in 65% yield with fortunately com-
1
(cis:trans=3:1) was easily determined by H NMR.12
Since both of these isomers of 3 has already been
converted into 1 via the same enol acetate12 by Dan-
ishefsky et al.13 in high yield, the whole sequence of
reactions constitutes, in a formal sense, a total synthesis
of natural chilenine.
In summary, we have found SmI2-mediated intramolec-
ular coupling reaction of cyclic imides with aldehyde-
alkyl side chains to give some isoindolone derivatives
directly and accomplished the formal synthesis of
chilenine natural alkaloid employing this procedure.
This process provides an easily accessible alternative to
existing synthetic methods of isoindoloazepine
alkaloids.

H. Yoda et al. / Tetrahedron Letters 43 (2002) 4667–4669
4669
Acknowledgements
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This work was supported in part by a Grant-in-Aid
(No. 13640530) for Scientific Research from the Japan
Society for the Promotion of Science.
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