Synthesis of the indoloazocine derivatives from a chiral indol amide-stabilized sulfur ylide

Article abstract of DOI:10.1016/j.tetlet.2013.03.068

We present here a synthetic route for the access to a series of diverse indoloazocine derivatives through selective epoxidation of chiral sulfonium salt 4, which reacts with diverse aromatic and aliphatic aldehydes to give trans-glycidic amides, followed by an intramolecular electrophilic aromatic substitution promoted by Cu(OTf)₂ giving the desired heterocyclic compound in a high chemical yield. Using this strategy, the total synthesis of (S,R)-(+)-norbalasubramide was achieved.

Full text of DOI:10.1016/j.tetlet.2013.03.068

Tetrahedron Letters 54 (2013) 2729–2732
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of the indoloazocine derivatives from a chiral indol
amide-stabilized sulfur ylide
Maira Juárez-Calderón a, David M. Aparicio a, Dino Gnecco a, Jorge R. Juárez a, Laura Orea a,
Angel Mendoza a, Fernando Sartillo-Piscil a, Esther del Olmo b, Joel L. Terán a,
⇑
a Centro de Química del Instituto de Ciencias y Centro de Investigación de la Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Edif. 103H, Complejo de
Ciencias, Pue., C.U. 72570 Puebla, Mexico
b Departamento de Química Farmacéutica, Facultad de Farmacia, CIETUS, Campus Unamuno, 37007 Salamanca, España
a r t i c l e i n f o
a b s t r a c t
Article history:
We present here a synthetic route for the access to a series of diverse indoloazocine derivatives through
selective epoxidation of chiral sulfonium salt 4, which reacts with diverse aromatic and aliphatic alde-
hydes to give trans-glycidic amides, followed by an intramolecular electrophilic aromatic substitution
promoted by Cu(OTf)2 giving the desired heterocyclic compound in a high chemical yield. Using this
strategy, the total synthesis of (S,R)-(+)-norbalasubramide was achieved.
Received 27 February 2013
Accepted 15 March 2013
Available online 24 March 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Selective epoxidation
trans-Epoxyamides
8-exo-tet ring-closing
Indoloazocine
Introduction
sulfur ylide derived from (R)-(+)-phenylethylamine are a valuable
starting material for the regiospecific synthesis of diverse 1,4-oxa-
The diverse pharmacological activity of a number of lactam
rings containing the indoloazocine moiety has motivated the
chemist to develop new synthetic strategies and methodologies
of this kind of important alkaloids1 like balasubramide, which is
characterized by an eight-membered lactam ring. Balasubramide
was isolated from Clausena indica and grows in the central moun-
tain rainforests in Sri Lanka.2
zepan-5-ones and morpholin-3-ones by an appropriate choice of
cyclization reaction conditions (Scheme 1).5
In our continuing interest on the application of this protocol, we
envision that this methodology could be applied to the synthesis of
norbalasubramide and some derivatives according to the next retro
synthetic analysis (Scheme 2).
Results and discussion
N
O
Chiral sulfonium salt 4 was synthesized in four steps. Firstly, 3-
(2-bromoethyl)-1H-indole was treated with (Boc)2O, triethyl-
amine, DMAP, in dichloromethane from 0 °C to room temperature
affording the N-Boc intermediate 1 in 97%.6 Next, compound 1 was
condensed with (S)-(À)-phenylethylamine in CH3CN, K2CO3 as a
base under reflux to give the corresponding amine 2 in 94%. Then,
compound 2 was treated with bromoacetyl bromide, K2CO3 in
chloroform at 0 °C giving the desired bromo acylamide 3 in 93%. Fi-
nally, 3 was condensed with dimethyl sulfide in dichloromethane
at room temperature giving the sulfonium salt 4 in 85% overall
yield (Scheme 3).
(R)
N
H
(S)
OH
Ph
(+)-balasubramide
Wang and co-workers3 reported the synthesis of (5R,6S)-
balasubramide through the intramolecular 8-endo-epoxy-arene
cyclization of (Z)-N-(phenylvinyl)oxiranecarboxamides. Kerr and
co-workers4 reported the synthesis of both antipodes of balasubra-
mide by the epoxidation of cinnamic acid, followed by coupling
with tryptamine giving the corresponding cinnamic amide. Finally,
Wang and Kerr used the intramolecular cyclization to obtain the
desired balasubramide in good overall yield.
With the sulfonium salt 4 in hand; we focused to explore the
epoxidation with benzaldehyde. When sulfonium salt 4 was trea-
ted with potassium tert-butoxide as the base in THF at room tem-
perature,7 for 12 h, total consumption of the starting material was
observed. The NMR spectra showed the presence of a E/Z rotameric
On the other hand, we recently reported that alkyl or aryl trans-
epoxyamides coming from a chiral non-racemic amide-stabilized
⇑
Corresponding author. Tel.: +52 222 229 5500x7277; fax: +52 222 229 5551.
E-mail address: joel.teran@correo.buap.mx (J.L. Terán).
mixture for each diastereomer of trans-epoxyamides8 and
a
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.068

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M. Juárez-Calderón et al. / Tetrahedron Letters 54 (2013) 2729–2732
OH
N
Ph
CH3
S
O
Br
RCHO
base
OH
7-endo-tet
Ring Closure
6-exo-tet
Ring Closure
O
O
O
R
R
N
Ph
CH3
HO
N
Ph
CH3
N
Ph
CH3
HO
O
R
O
O
[1,4]-oxazepan-5-one
trans-epoxyamides
morpholin-3-one
R = Ar, Alk
Scheme 1. Regiospecific ring closure of trans-epoxyamides.
CH3
CH3
N
N
Ph
Ph
NH
O
O
O
N
Boc
O
N
Boc
N
H
asymmetric
epoxydation
S
OH
Ph
Ph
Br
norbalasubramide
5
4
Scheme 2. Retrosynthetic analysis.
from 0 °C to room temperature with several aromatic and aliphatic
aldehydes (Scheme 4).
CH3
Br
Br
N
H
As the separation of the trans-diastereomeric mixture proved to
be difficult at this stage, the intramolecular opening of the oxirane
ring of the diastereomeric mixture 5(a+b) by an 8-exo-tet ring-
closing with diverse Brønsted and Lewis Acids was investigated.
The use of trifluoroacetic acid gave only the deprotection of N-
Boc group. Other Lewis acids as PTSA resulted in the degradation
of starting material. Then, activation with various Lewis acids
was investigated. We were pleased to observe that cyclization took
place in the presence of copper(II)triflate, CH3CN as a solvent at
room temperature producing the eight-membered lactam as the
sole regioisomer in a 90% chemical yield. Diastereoisomers were
easily separated at this stage by chromatographic purification
(yielding; 12a, 50% and 12b, 40%) (Scheme 4).
Ph
i
ii
N
H
N
Boc
N
Boc
2
1
iii
CH3
CH3
N
N
Ph
Ph
iv
O
O
N
Boc
N
Br
S
Boc
Br
The major diastereoisomer was crystallized, and then the X-ray
analysis diffraction showed the unequivocal configuration as S and
R at C-5 and C-6, respectively (Fig. 1).9
The 8-exo-tet ring-closing with all trans-epoxyamides was then
investigated (Table 2).
4
3
Scheme 3. Reagents and conditions: (i) (Boc)2O (2 equiv), Et3N (2 equiv), DMAP
(0.1 equiv), CH2Cl2, 0 °C–rt, 12 h, 97%;11 (ii) (S)-(À)-phenylethylamine (2 equiv),
K2CO3, CH3CN, reflux, 4 h, 94%; (iii) bromoacetyl bromide (1 equiv), K2CO3 (3 equiv),
CHCl3, 0 °C, 1 h, 93%; (iv) dimethyl sulfide (3 equiv), CH2Cl2, rt, 18 h, quantitative.
The intramolecular ring opening of oxirane with epoxyamides
coming from nitro benzaldehydes, 2,6-dichlorobenzaldehyde and
aliphatic aldehydes under optimized conditions, gave only traces
of the corresponding bicyclic compounds, however when the reac-
tion was performed at reflux temperature in dichloromethane,
bicyclic compounds were obtained in good to excellent yield. The
use of epoxyamides 6(a+b) and 9(a+b) (Table 2, entries 1 and 4) re-
sulted in a cyclization of only one of the two diastereoisomers.10
This result could be explained because of the presence of a substi-
tuent in the ortho position which may represent a combination of
unfavorable steric and electronic effects. The same result was ob-
tained when epoxyamides coming from aliphatic aldehydes were
reacted with Cu(OTf)2, giving the cyclization of one the two diaste-
reoisomers (Table 2, entries 5 and 6).
bicyclic compound tetrahydroazepino-indole in a 7:3 ratio, respec-
tively, (Table 1, entry 1).
We next tested the epoxidation reaction using KOH as base in
THF at room temperature affording the mixture of trans-epoxya-
mides 5(a+b) and the corresponding tetrahydroazepino-indole in
traces (Table 1, entry 2). These conditions proved not be effective
with aromatic aldehydes containing a deactivating group at the
aromatic ring. In this case, a mixture of trans-epoxyamides and tet-
rahydroazepin-indole in a 50:50 ratio was observed (Table 1, entry
3). Finally, exclusive formation of trans-epoxyamides was obtained
when sulfonium salt 4 was treated with DBU in dichloromethane,

M. Juárez-Calderón et al. / Tetrahedron Letters 54 (2013) 2729–2732
2731
Table 1
Epoxidation of sulfonium salt 4 with diverse aromatic and aliphatic aldehydes
Ph
N
O
CH3
CH3
Ph
H3C
O
N
Ph
N
base, solvent
R
+
O
R
O
RCHO,temperature
N
S
N
Boc
N
Boc
Boc
Br
4
trans-epoxyamides
5-alkyliden/arylidene-
tetrahydroazepinoindole
Entry
R
Base
Solvent
Temp (°C)
Time (h)
Comb yielda (%)
Ratio
1
2
3
4
5
6
7
8
9
–C6H5
–C6H5
2-O2NC6H4
–C6H5
–C6H5
2-O2NC6H4
3-O2NC6H4
4-O2NC6H4
Et
t-BuOK
KOH
KOH
DBU
DBU
DBU
DBU
DBU
DBU
DBU
THF
THF
THF
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25
25
25
0–25
0–25
0–25
0–25
0–25
0–25
0–25
12
12
12
10
10
8
12
12
12
12
60
92
42
92
85
98
83
95
65
60
7:3
9:1
50:50
10:0
10:0
10:0
10:0
10:0
10:0
10:0
10
Pr
The epoxidation reactions were performed with 2 equiv for aromatic aldehydes and 4 equiv for aliphatic aldehydes.
a
Isolated yield of diastereomeric mixture of trans-epoxyamides.
Table 2
Intramolecular cyclization via epoxide ring opening
Ph
N
Ph
H3C
N
O
O
H3C
Ph
O
H3C
H3C
O
O
Ph
O
N
Cu(OTf)2, 30 mol%
CH3CN, rt, 20min
N
Ph
R
(S)
OH
OH
N
(R) R
Ph
N
Boc
N
N
Boc
Boc
Boc
Cu(OTf)220mol%
CH2Cl2,reflux,time
12(a+b)
5(a+b)
trans-epoxyamides
+
+
Ph
N
H3C
O
Ph
O
H3C
O
N
Scheme 4. 8-exo-Tet ring closing catalyzed by Cu(OTf)2.
R
(R)
OH
(S)
N
R
N
Boc
Boc
diastereomeric mixture of
diastereomeric mixture of
byciclic lactams
O
H
trans-epoxyamides
HO (S)
Me
Ph
(S)
N
Ph
Entry
R
trans-Epoxyamides
Time (h)
Product
Yield (%)
(R)
O
1
2
3
4
5
6
2-O2NC6H4
3-O2NC6H4
4-O2NC6H4
2,6-ClC6H3
Et
6(a+b)
7(a+b)
8(a+b)
9(a+b)
10(a+b)
11(a+b)
18
18
12
8
24
24
13a
40
N
95a
98a
45
O
14(a+b)
15(a+b)
16a
17a
18a
45
30
Pr
a
Figure 1. X-ray crystal structure of 12a.
Isolated yield of diastereomeric mixture. All reactions were performed at reflux
temperature.
H3C
H3C
Ph
Ph
O
N (S)
NH
N(S)
TBAF
Birch
O
O
(S)
(S)
(R)
(S)
CH2Cl2, rt
(R)
(R)
OH
OH
OH
N
H
N
H
N
Boc
Ph
Ph
Ph
12a
(+)-norbalasubramide
19a
Scheme 5.

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M. Juárez-Calderón et al. / Tetrahedron Letters 54 (2013) 2729–2732
Finally, the synthesis of the (+)-norbalasubramide was per-
References and notes
formed starting from bicyclic lactam 12a in two steps. Firstly, com-
pound 12a was treated with tetra-n-butylammonium fluoride
(TBAF) giving the unprotected indol 19a in 80%. Next, a debenzyla-
tion reaction was performed, under Birch conditions, obtained the
desired (+)-norbalasubramide in 85%. ([
(Scheme 5).
In summary, we proved that chiral non-racemic amide-stabi-
lized sulfur ylide 4 is a valuable starting material for the prepara-
tion of indoloazocine skeleton, and represents the first example
in which it is possible obtain diverse balasubramide analogous.
This new, versatile, and scalable access to both enantiomers opens
the route to the pharmacological investigation of these promising
compounds as well as the design of analogs.
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D + 2.9 (c 0.2, CHCl3)11
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Acknowledgments
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We are grateful to CONACyT (Project No. 154104) for financial
support, M.J.C. thanks to CONACyT for the scholarship (17503).
We thank R. López-González and O.H. Rodríguez-Matsui for their
technical assistance.
8. The exclusive formation of trans adducts was confirmed by the magnitude of
its coupling constants of the epoxides (J = 2.1 and 1.6 Hz).
9. Crystal structure was deposited at the CCDC 926646.
Supplementary data
10. We assumed that the indoloazocine obtained have the configuration (S,R) at C-
5 and C-6, respectively, because it has the same chemical shift of the methyl
group (around 1.5 ppm) compared with the indoloazocine 12a.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
03.068.
11. For (À)-norbalasubramide: [
a]D À 2.5 (c 0.2, CHCl3). Zheng, C.; Li, Y.; Yang, Y.;
Wang, H.; Cui, H.; Zhang, J.; Zhao, G. Adv. Synth. Catal. 2009, 351, 1685.