Synthesis of 1-Substituted Isoquinolines by Heterocyclization of TosMIC Derivatives: Total Synthesis of Cassiarin A

Article abstract of DOI:10.1021/acs.orglett.6b01521

A new method for the synthesis of 1-substituted isoquinolines by a heterocyclization that involves α-benzyl TosMIC derivatives and different electrophiles has been developed. This methodology has been successfully applied to a total synthesis of cassiarin A, an alkaloid with potent antiplasmodial activity against Plasmodium falciparum.

Full text of DOI:10.1021/acs.orglett.6b01521

Letter
pubs.acs.org/OrgLett
Synthesis of 1‑Substituted Isoquinolines by Heterocyclization of
TosMIC Derivatives: Total Synthesis of Cassiarin A
Sara Gutierrez, Anna Coppola, David Sucunza,* Carolina Burgos, and Juan J. Vaquero*
́
́ ́ ́ ́
Departamento de Química Organica y Química Inorganica, Universidad de Alcala, Alcala de Henares 28871, Spain
S
* Supporting Information
ABSTRACT: A new method for the synthesis of 1-substituted isoquinolines by a heterocyclization that involves α-benzyl
TosMIC derivatives and different electrophiles has been developed. This methodology has been successfully applied to a total
synthesis of cassiarin A, an alkaloid with potent antiplasmodial activity against Plasmodium falciparum.
Scheme 1. General Approach to Isoquinoline Derivatives
and Retrosynthetic Pathway for Cassiarin A
soquinolines and their reduced derivatives can be found as
1
Isubstructures in many relevant natural products and fine
chemicals, such as pharmaceuticals2 and organic materials.3
Consequently, diverse synthetic methods for their preparation
have been developed.4 Classical synthetic routes, such as the
Pictet−Spengler,5 Bischler−Napieralski,6 and Pomeranz−
Fritsch7 reactions, suffer from some drawbacks, mainly the
use of harsh reaction conditions.8 For this reason, the
development of efficient methods for the preparation of these
important heterocycles is still of great interest.9
As part of a research project aimed at expanding tosylmethyl
isocyanide (TosMIC) chemistry10 to the preparation of six-
membered heterocycles,11 our group has very recently
developed a new method for the synthesis of isoquinolines
through a catalytic acid-mediated cyclization of α-benzyl
TosMIC derivatives.12 This cyclization takes place through an
electrophilic aromatic substitution process and works efficiently
when electron-donating substituents are present in the benzene
ring. Moreover, the validity of this new methodology has been
demonstrated by applying it in the total synthesis of
mansouramycin B.
We have explored this strategy in relation to a heterocycliza-
tion that involves α-benzyl TosMIC derivatives and different
electrophiles. This reaction takes advantage of the capacity of
isocyanides to act both as nucleophiles and electrophiles, which
means that cyclization of a TosMIC derivative by electrophilic
aromatic substitution and attack of the isocyanide to the
corresponding electrophile would occur as a tandem process.
The above approach proved to be successful, and we report
here a remarkable and effective synthesis of 1-substituted
isoquinolines. Moreover, we applied this new methodology to a
synthesis of the natural product cassiarin A (Scheme 1). This
aromatic alkaloid, which has a tricyclic skeleton, was isolated
from the leaves of Cassia siamea,13 a common plant in
Southeast Asia, and has attracted the widespread attention of
synthetic chemists14 and pharmacologists15 due to its potent
antiplasmodial activity against Plasmodium falciparum (IC50
0.005 μg/mL).13
Our initial attempts to carry out the heterocyclization of α-
benzyl TosMIC derivative 2a, which was obtained from
TosMIC in a single one-pot, phase-transfer catalyst (PTC)
process (Scheme 2),12 employed benzaldehyde as the electro-
phile. Different Lewis acids [AlCl3, AlEt2Cl, Yb(OTf)3] were
also added to the reaction to enhance the electrophilicity of the
Received: May 26, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01521
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Organic Letters
Letter
Once the best reaction conditions for the formation of 4a
had been identified (2 equiv of the electrophile, 2 equiv of
AlEt2Cl, CH2Cl2 as solvent, room temperature for 18 h), we
studied the reaction with other α-benzyl TosMIC derivatives
with electron-donating methoxy substituents in the benzene
ring, such as the previously described α-ethyl and α-allyl
compounds (2b and 2c, respectively)12 as well as with α-methyl
derivative 2d. The reaction was carried out in the presence of
different carbonyl electrophiles, namely an aromatic and an
alkylic aldehyde and three different ketones. In this way,
compounds 4b−h were formed in excellent yield (80−99%),
whereas 4i and 4j, obtained both in this process in the presence
of benzophenone, were isolated in more moderate yields
(Scheme 4).
Scheme 2. Synthesis of TosMIC Derivatives 2a−d
aldehyde. It was found that the use of AlCl3 or Yb(OTf)3 led to
the formation of 3-benzyl-6,7-dimethoxyisoquinoline 3a
following a known mechanism12 in which the aldehyde is not
involved (Table 1).
Scheme 4. Synthesis of 1-Substituted Isoquinolines 4a−j
Table 1. Optimization of the Reaction Conditions for 4a
Lewis acid
equiv
solvent
yield 3a/4a (%)
a
1
2
3
4
5
6
AlEt2Cl
AlEt2Cl
AlEt2Cl
AlEt2Cl
AlCl3
1.4
1.4
2.0
2.0
1.0
1.0
THF
0/0
CH3CN
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
0/35
0/37
0/80
55/0
43/0
Yb(OTf)3
a
Starting material was recovered.
Nevertheless, the use of AlEt2Cl in CH3CN afforded the
desired 1-substituted isoquinoline 4a as the only reaction
product. In this sense, when 2 equiv of this Lewis acid was used
with CH2Cl2 as solvent, the reaction achieved 80% yield.
This result was rationalized through a plausible mechanistic
hypothesis that involves cyclization of the TosMIC derivative
by an electrophilic aromatic substitution and attack of the
isocyanide to the aldehyde in a single process. The subsequent
elimination of p-toluenesulfonic acid would afford the final
product 4a (Scheme 3). It is noteworthy that this method is
only efficient when electron-donating substituents are present
in the benzene ring. Thus, the dibenzyl TosMIC derivative was
unable to produce the cyclization reaction.
In order to determine the scope of this new isoquinoline
synthesis, we tested the cyclization with other kinds of
electrophiles, including Michael acceptors, epoxides, aziridines
and halogenating agents. Attempts with the first two types of
reagents were unsuccessful. The addition to the α-benzyl
TosMIC derivative 2a of AlEt2Cl and tert-butyl acrylate, β-
nitrostyrene, or propylene oxide only led to the recovery of
starting material.
However, the reaction of 2a with N-tosylaziridine and
AlEt2Cl was successful and yielded isoquinoline 5a in 68%
yield. Similar results were obtained in the reaction of N-tosyl
aziridine and the α-benzyl TosMIC derivatives 2b−d (Scheme
5).
Scheme 3. Mechanistic Hypothesis for the Cyclization of 4a
The use of N-iodosuccinimide as the electrophile also led to
the desired heterocyclization. However, the addition of a Lewis
acid was not necessary in this case, and a second step was
required under strongly basic conditions (LiHMDS instead
NaHCO3) to promote the elimination of p-toluenesulfonic acid
and the corresponding aromatization. In this sense, the addition
of 2 equiv of NIS to the α-benzyl TosMIC derivative 2a and a
subsequent treatment at 0 °C with LiHMDS in tert-butyl
methyl ether solution yielded isoquinoline 6a in 96% yield.
B
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Scheme 5. Synthesis of 1-Substituted Isoquinolines 5a−d
Scheme 7. Total Synthesis of Cassiarin A
Similar satisfactory results were obtained in the reactions of
NIS and the α-benzyl TosMIC derivatives 2b and 2d (Scheme
6). The use of N-bromosuccinimide as the electrophile was also
tested, but the starting materials 2a and 2b decomposed in all
cases.
Scheme 6. Synthesis of 1-Substituted Isoquinolines 6a−c
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01521.
1
Experimental procedures and H and 13C NMR spectra
for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Finally, the validity of this new methodology was
demonstrated with a total synthesis of cassiarin A (8). The
key step in this synthesis was the formation of 1-iodoisoquino-
line 6d, which subsequently could be transformed into the
desired alkaloid (Scheme 7). The synthesis started with the
preparation of benzyl bromide 9,16 and this was used in the
preparation of α-benzyl TosMIC derivative 2e through a PTC
process. In this way, sequential addition to TosMIC of 9 and
methyl iodide in a single two-phase medium [CH2Cl2/NaOH
(40%)] afforded derivative 2e in 71% yield. This compound
was treated with 2 equiv of NIS to achieve cyclization and an
aqueous solution of NaOH to force the aromatization, with the
consequent formation of 1-iodoisoquinoline 6d in 86% yield.
Finally, Sonogashira coupling of 6d with in situ generated
propyne gave alkyne 7 in 87% yield. Compound 7 was
converted quantitatively into the natural product cassiarin A
(8) by treatment with 10% aq HCl in methanol.14b
In summary, a new method for the synthesis of 1-substituted
isoquinolines has been developed through a heterocyclization
that involves α-benzyl TosMIC derivatives and different
electrophiles. This reaction works efficiently when electron-
donating methoxy substituents are present in the benzene ring
and takes advantage of the capacity of isocyanides to act both as
a nucleophile and an electrophile. The validity of the new
methodology was demonstrated by applying it in a total
synthesis of cassiarin A (53% overall yield in four steps from
commercially available TosMIC).
*E-mail: david.sucunza@uah.es.
*E-mail: juanjose.vaquero@uah.es.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Spanish Ministerio de Economia y
Competitividad (project CTQ2014-52488-R), Instituto de
Salud Carlos III (FEDER funds, ISCIII RETIC REDINREN
■
́
RD012/20021/0014), and University of Alcala
CCG2014/EXP-031) is gratefully acknowledged. S. G. and A.
C. also thank the University of Alcala for their grants.
́
́
(project
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