Enantioselective total synthesis of (S)-(+)-lennoxamine through asymmetric hydrogenation mediated by l-proline-tetrazole ruthenium catalyst

Article abstract of DOI:10.1016/j.tetlet.2012.05.033

A novel asymmetric synthetic strategy to prepare isoindolobenzazepine based lennoxamine alkaloid has been achieved in high ee% starting from 2-(benzo[d][1,3]dioxol-5-yl)ethanamine and 1-(chloromethyl)-2,3-dimethoxybenzene in 5 steps and with a 34% overall yield. The potentiality of this route involved the Bischler-Napieralsky cyclization that leads to tetracyclic indolinium skeleton, generation of chiral center through asymmetric hydrogen-transfer reaction employing l-proline-tetrazole as chiral ligand with Ru/Ir/Rh, and anodic oxidation as the key steps in the synthesis.

Full text of DOI:10.1016/j.tetlet.2012.05.033

Tetrahedron Letters 53 (2012) 3672–3675
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective total synthesis of (S)-(+)-lennoxamine through asymmetric
hydrogenation mediated by L-proline-tetrazole ruthenium catalyst
Yaneris Mirabal-Gallardo a, Johanna Piérola a, Nagula Shankaraiah b, Leonardo S. Santos a,
⇑
a Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, University of Talca, Talca, PO Box 747, Chile
b Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel asymmetric synthetic strategy to prepare isoindolobenzazepine based lennoxamine alkaloid has
been achieved in high ee% starting from 2-(benzo[d][1,3]dioxol-5-yl)ethanamine and 1-(chloromethyl)-
2,3-dimethoxybenzene in 5 steps and with a 34% overall yield. The potentiality of this route involved the
Bischler–Napieralsky cyclization that leads to tetracyclic indolinium skeleton, generation of chiral center
Received 18 April 2012
Revised 3 May 2012
Accepted 4 May 2012
Available online 12 May 2012
through asymmetric hydrogen-transfer reaction employing
L
-proline-tetrazole as chiral ligand with
Ru/Ir/Rh, and anodic oxidation as the key steps in the synthesis.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Isoindolobenzazepine
Chilenamine
Asymmetric hydrogenation reaction
Anodic oxidation
The framework of polycyclic isoindolobenzazepine, tetrahydro-
isoquinoline, and isoindolinones has gained considerable interest
in the last decade due to their extensive biological profiles. These
entities of tetracyclic ring containing alkaloids are well known in
nature, as exemplified by lennoxamine (1), chilenine (2), and neuv-
amine (3) (Fig. 1). Lennoxamine is a class of isoindolobenzazepine
alkaloid, belonging to the aporhoedane series, and was extracted
from the Chilean plant Berberis darwinii.1 The distinctive structural
features of lennoxamine ring system fused with an aromatic moi-
ety, have rendered this molecule attractive and a synthetically
challenging target, particularly from a stereoselective perspective.
Therefore, numerous methods have been developed to prepare the
natural product lennoxamine2 but the synthetic routes employed
did not consider stereoselectivity. More recently, Kise et al. re-
ported an elegant approach to reach lennoxamine via electroreduc-
tive intramolecular coupling reaction.3
A current challenge in synthetic organic chemistry is the devel-
opment of new methods that allow the regio- and stereoselectivi-
ties in organic molecules. In continuing efforts, a number of
asymmetric catalytic processes have aimed to create a chiral center
that can be allowed concise routes for the total synthesis of
bioactive natural products and pharmaceuticals.4 Comins et al.
have reported the first enantioselective synthetic route to
(+)-lennoxamine via chiral auxiliary based on anionic alkylation.5
In connection with our interest in developing new synthetic
routes,6 we pursued the development of an efficient methodology
for the stereoselective synthesis of optically active lennoxamine
alkaloid by employing chiral Rh(I), Ir(I), or Ru(II) complexes, which
have been formed with
strategy to lennoxamine was inspired by the highly regioselective
-N-anodic oxidation that we have employed and optimized in
L-proline-tetrazole ligand. This innovative
a
b-carboline system, which correctly positioned a carbonyl group
into the pyrrolo ring in the synthesis of (–)-quinolactacin B.6b
Moreover, the basis for developing this ring system, which
represents
a
conformationally constrained variant of the
isoindolobenzazepine nucleus is also a key step. In this context,
we report a complementary synthetic approach to the preparation
of the natural product (+)-lennoxamine. The feasibility of the route
has been further emphasized by anodic oxidation to assemble the
OMe
OMe
OMe
OMe
E
O
HO
O
O
O
D
A
B
C
N
N
O
O
O
(
S
)-(+)-lennoxamine (1)
chilenine (2)
O
O
N
O
OMe
OMe
nuevamine (3)
Figure 1. Structurally significant isoindolobenzazepine type alkaloids 1–3.
⇑
Corresponding author.
E-mail address: lssantos@utalca.cl (L.S. Santos).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.033

Y. Mirabal-Gallardo et al. / Tetrahedron Letters 53 (2012) 3672–3675
3673
ing the sequence depicted in Scheme 1, 2-(benzo[d][1,3]dioxol-
5-yl)ethanamine was converted into amide by treating with
trifluoroacetic anhydride affording 5 in 87% yield. Then, the pream-
ble of methylene chloride moiety to 5 employed formaldehyde
followed by the treatment with HCl at –20 °C that gave 6 in 96%
yield. The key lactam intermediate 8 was successfully achieved
by the replacement of chloro functionality with cyano group using
NaCN, aqueous NaOH treatment, and then coupling with EDC/
HOBt. The crude lactam 8 in CH2Cl2 was acidified with diluted
HCl, washed with H2O, dried, evaporated, and obtained in 72%
yield. Subsequent coupling of 8 and 9 with NaH in dry DMF gave
10 in moderate yield (75%).9 Next, the amide was subjected to
Bischler–Napieralsky cyclization with POCl3 achieving imine 11
in 85% yield. Having prepared imine 11, the next stage was set to
introduce the required chiral center through the asymmetric
hydrogenation reaction. Herein, we set up several model experi-
ments in different reaction conditions between imine 11 and a
variety of metals such as Ru, Ir, and Rh which are in complexation
OMe
OMe
OMe
OMe
O
O
O
O
+
N
N
O
(S
)-(+)-lennoxamine; 1
11
Cl
O
NH2
O
OMe
OMe
O
O
+
NH
O
4
8
9
Figure 2. Retrosynthetic analysis of optically active (S)-(+)-lennoxamine (1)
alkaloid.
with
L
-proline-tetrazole acting as a chiral ligand to accomplish bet-
-Proline-tetrazole chiral ligand has
specific hydroxyl group followed by soft oxidation process leading
to the targeted natural product (+)-1.
ter yields and improved %ee.
L
been efficiently prepared in our laboratory in gram scale by a pre-
viously reported method,10 as depicted in Scheme 2. The Ru (12a)
based hydrogenation reaction was successfully performed with
HCO2H/Et3N at 0 °C in DMF for 12 h producing 13 in 85% yield
and 92–94% ee.1,11,12 Compound 13 is also a known alkaloid:
Chilenamine. The formation of catalyst 12a was probed by
ESI(+)-MS experiments. The ESI mass spectra showed the presence
of the species [12a+H]+ (m/z 410), which is the proposed active
species for the asymmetric hydrogenation process. Furthermore,
[12a+Na]+ (m/z 432) and [12a+K]+ (m/z 448) were also identified
and characterized by ESI-MS/MS. The species [12aꢀCl]+ of m/z
374 was rationalized to be formed by in-source CID during the
electrospray ionization process. Similarly, the other hydrogenation
reactions with Ir and Rh catalysts also afforded yields of 78%
(92–96% ee) and 80% (90–92% ee), respectively through reaction
conditions employing EtOH as solvent, 5 bar H2 at 55 °C for 4 h.
After successful chirality insertion in the isoindolobenzazepine
The retrosynthetic analysis for the basic framework of 1 is de-
picted in Figure 2, and features the asymmetric hydrogen-transfer
reaction employing various chiral catalysts and anodic oxidation as
the key step. Although demonstrated as a useful synthetic method,
these types of asymmetric reductions remain to be fully explored
in the arena of total syntheses of alkaloid natural products.7,8 The
key intermediate 8 was obtained in five steps from commercially
available 2-(benzo[d][1,3]dioxol-5-yl)ethanamine (4). Next, inter-
mediate 8 and 1-(chloromethyl)-2,3-dimethoxybenzene (9) gave
the iminium ion 11 that is the key intermediate to test the asym-
metric hydrogenation reaction employing catalyst 12a–c. Finally,
anodic oxidation followed by treatment with TPAP/NMO produces
(+)-1 in high ee%. In this work, the use of a new catalyst was tested
and the data compared with the asymmetric Noyori hydrogenation
reaction, showing the feasibility of high scale chiral induction in
imines to produce tetracyclic moieties.
The synthetic strategy is based on the introduction of chirality
in the tetracyclic ring system through the iminium ion 11. Follow-
moiety, it was explored for the a
-oxidation of 1313,14 through
anodic oxidation to introduce the hydroxyl-group. Previously, we
i) HCOH
NH2
NHCOCF3
NHCOCF3
O
O
O
O
O
O
(CF3CO)2O
87%
ii) HCl
−20 οC
96%
Cl
4
5
8
6
NaCN/DMSO
91%
OMe
O
MeO
O
O
O
i) NaOH
EtOH:H2O
Cl
NHCOCF3
O
O
N
O
O
9
NH
CN
ii) EDC/HOBt
72%
NaH/DMF
75%
MeO
10
7
MeO
POCl3-MeCN, rt
85%
N
N
OMe
OMe
OMe
OMe
OMe
i) Pt/W, 2e−
CH2Cl2
N
M
L
N
L
N
12a−c
OMe
O
O
O
O
ii)TPAP/NMO
63%
Ru, HCO2H,
Et3N, DMF
N+
N
N
O
O
O
0
oC, 1 h
or
13
11
(S)-(+)-lennoxamine; 1
Ir/Rh, EtOH
12a; M = Ru, 85%, 92−94% ee
12b; M = Ir, 78%, 92−96% ee
12c; M = Rh, 80%, 90−92% ee
5 bar H2, 55 oC, 4 h
Scheme 1. New Ru/Ir/Rh catalyst 12 based on L-proline-tetrazole chiral ligand 19 for the asymmetric induction in the total synthesis of (S)-(+)-lennoxamine.

3674
Y. Mirabal-Gallardo et al. / Tetrahedron Letters 53 (2012) 3672–3675
Cl
N
N
NH4HCO3
(Boc)2O
NaN3
ZnBr2
Cl
N
Cl
NH2
N
Cbz-protection
N
N
18
CO2H
14
CO2H
CN
N
H
N
N
N
N
Py cat.
MeCN
DMF
H2O
O
HN
2-propanol
Cbz
Cbz
15
16
Cbz
Cbz
17
N
N
ML2
H2, Pd/C
N
N
N
N
N
L
N
N
HN
19
H
M
H2O/AcOH
Et3N, DMF
70 oC, 1 h
L
12a-c
Scheme 2. Straightforward synthesis of L-proline-tetrazole chiral ligand 19, and ESI(+)-MS of the Ru-catalyst obtained by the reaction of (p-cyRuCl)2 and 19.
evaluated the feasibility of the oxidation route through model
experiments in the total synthesis of (ꢀ)-Quinolactacin B6b that
would in turn be generated by electrochemically functionalizing13
the corresponding natural product (+)-1. Thus, with the electro-
chemical approach optimized we performed the reaction with
compound 13. As expected by previous model studies, the anodic
oxidation proceeded smoothly at ꢀ78 °C giving the desired hydro-
xy-isoindolobenzazepine intermediate. The expected regioselectiv-
References and notes
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ring system has been extensively studied.14 The mechanism be-
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In summary, a new asymmetric route has been developed for
the construction of the chiral center in isoindolone core of iso-
indolobenzazepine alkaloid, by employing asymmetric catalysis
reaction. Our strategy allowed the use of L-proline tetrazole as chi-
ral ligand to obtain (+)-Lennoxamine skeleton in high ee% after five
9. Analytical data for compound 10: Mp 185–186 °C. FTIR (KBr film): 1644,
1510 cmꢀ1 1H NMR (300 MHz, CDCl3): d 2.83 (t, J 6.0 Hz, 2H), 3.58 (t, J 6.0 Hz,
.
steps in 34% overall yield from 8 and 9.
2H), 3.83 (s, 2H), 3.84 (s, 3H), 3.87 (s, 3H), 4.56 (s, 2H), 5.91 (s, 2H), 6.47 (s, 1H),
6.70 (s, 1H), 6.80–7.02 (m, 3H). HRMS, ESI(+)-MS: Cacld for [C20H21NO5 + H]+
356.1498. Found 356.1502.
Acknowledgments
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FONDECYT 1110022 (LSS) and ‘‘Programa de Doctorado menc-
ión Investigación y Desarrollo de Productos Bioactivos (YMG)’’
are gratefully acknowledged. We thank Professor Dr. Felipe Laurie
for further corrections in the manuscript.
11. Analytical data for intermediate 13: ½a D20
ꢁ
+13 (c 0.5, CHCl3). Mp 178–180 °C (lit.
180–181 °C).1,12 FTIR (KBr film): 2822, 2775, 2750, 1621, 1505 cmꢀ1
.
1H NMR
(300 MHz, CDCl3): d 2.44–3.52 (m, 7H), 2.62 (dd, J 13.0 and 4.0 Hz, 1H), 3.82 (s,
3H), 3.87 (s, 3H), 4.36 (d, J 13.0 Hz, 1 H), 5.91 (s, 2H), 6.66 (s, 1H), 6.73 (2s, 2),

Y. Mirabal-Gallardo et al. / Tetrahedron Letters 53 (2012) 3672–3675
3675
6.80 (d, J 7.9 Hz, 1H), 6.86 (d, J 7.9 Hz, 1H). HRMS, ESI(+)-MS: Calcd for
[C20H21NO4+H]+ 340.1549. Found 340.1554.
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;
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NMR (300 MHz, CDCl3): d 2.74–2.94 (m, 4H); 3.10 (dd, J 14.0 and 2.0 Hz, 1H),
3.91 (s, 3H), 4.09 (s, 3H), 4.27 (dd, J 10.5, 2.0 Hz, 1H), 4.68–4.77 (m, 1H), 5.92 (d,
J 1.7 Hz, 1H), 5.94 (d, J 1.7 Hz, 1H), 6.68 (s, 1H), 6.77 (s, 1H), 7.11 (d, J 8.1 Hz,
1H), 7.17 (d, J 8.1 Hz, 1H). 13C NMR (300 MHz, CDCl3): d 36.0, 41.0, 42.7, 56.6,
60.3, 62.4, 101.0, 110.3, 110.4, 116.1, 117.0, 124.3, 131.0, 134.7, 138.2, 146.1,
146.4, 147.3, 152.6, 165.0. HRMS, ESI(+)-MS: Calcd for [C20H19NO5 +H]+
354.1341. Found 354.1345.