Isoquinoline Synthesis by Heterocyclization of Tosylmethyl Isocyanide Derivatives: Total Synthesis of Mansouramycin B

Article abstract of DOI:10.1021/ol5032624

A new method for the synthesis of isoquinolines through a catalytic acid-mediated cyclization of α-benzyl TosMIC derivatives has been developed. This methodology has been successfully applied to the total synthesis of mansouramycin B. This is the first total synthesis of this compound to be reported in the literature. (Figure Presented).

Full text of DOI:10.1021/ol5032624

Letter
pubs.acs.org/OrgLett
Isoquinoline Synthesis by Heterocyclization of Tosylmethyl
Isocyanide Derivatives: Total Synthesis of Mansouramycin B
Anna Coppola, David Sucunza,* Carolina Burgos, and Juan J. Vaquero*
́ ́ ́ ́
Departamento de Química Organica y Química Inorganica, Universidad de Alcala, 28871 Alcala de Henares, Madrid, Spain
*
S Supporting Information
ABSTRACT: A new method for the synthesis of isoquino-
lines through a catalytic acid-mediated cyclization of α-benzyl
TosMIC derivatives has been developed. This methodology
has been successfully applied to the total synthesis of
mansouramycin B. This is the first total synthesis of this
compound to be reported in the literature.
he isoquinoline core is an important structural motif that
Scheme 1. General Approach to Isoquinoline Derivatives
and Retrosynthetic Pathway for Mansouramycin B
1
T
is found in many natural products, pharmaceutically
2
3
relevant molecules, and organic materials. Due to the
significance of this core, diverse synthetic methods for its
4
preparation have been developed. Classically, isoquinolines
5
have been synthesized using the Pictet−Spengler, Bischler−
6
7
Napieralski, and Pomeranz−Fritsch reactions. However, these
methods are often limited due to the use of harsh reaction
8
conditions. For this reason, the development of efficient
methods for the preparation of isoquinoline derivatives is of
great interest and recently reported annulation reactions to
generate the isoquinoline system are promoted by different
metallic catalysts such as rhodium (I and III), manganese, and
9
palladium.
10
Tosylmethyl isocyanide (TosMIC) is a densely function-
alized building block with three groups that can engage in a
multitude of reactions, although its most important application
1
3
with an IC value up to 0.089 μM for lung cancer. Due to the
50
11
biological importance of this group of alkaloids, the first total
synthesis of mansouramycin D has recently been published.
However, the successful synthesis of mansouramycin B has not
been reported to date.
has been in the synthesis of five-membered heterocycles.
In the course of our research aimed at expanding TosMIC
14
12
chemistry to the preparation of six-membered heterocycles,
we attempted the heterocyclization reaction of bromobenzyl
TosMIC derivatives in the presence of t-BuLi. However, the
expected isoquinoline derivative was not obtained, and an
unexpected rearrangement gave 2-vinylbenzonitriles in high
First, it was necessary to synthesize suitable TosMIC
derivatives to explore catalytic acid-mediated cyclization. The
preparation of the corresponding α-benzyl α-alkyl TosMIC
derivatives 2a−h was achieved by the addition of two different
alkyl groups in a single one-pot phase transfer catalyst (PTC)
process. It was found that TosMIC reagent 1 reacted
sequentially with two different alkyl halides in a single two-
phase medium [CH Cl /NaOH (40%)] in the presence of
1
2a
yields.
Here, we report a successful approach to the
isoquinoline system from α-benzyl TosMIC derivatives that
are able to undergo an annulation reaction to give isoquinolines
under metal-free conditions. The heterocyclization occurs on
substrates bearing electron-donating substituents in the
benzene ring under catalytic acid conditions.
Moreover, in order to prove the validity of this new
methodology, we have applied it in the first total synthesis of
mansouramycin B (Scheme 1). This alkaloid belongs to the
mansouramycin family, a group of five isoquinolinequinones
isolated in 2009 from the marine-derived Streptomyces sp.
isolate Mei37. These compounds have shown cytotoxicity
against 36 cancer cell lines and were found to have significant
activity against nonsmall cell lung cancer, breast cancer,
melanoma, and prostate cancer cells. Specifically, high
cytotoxicity was shown against many human cancer cell lines,
2
2
12a
tetrabutylammonium iodide (TBAI) as catalyst.
The first
addition of 1 equiv of the substituted benzyl bromide to
TosMIC at 0 °C, to avoid the formation of dibenzyl derivatives,
was followed by a second addition of a simple alkyl halide at
room temperature. This process gave isonitriles 2a−h in high
yields (Table 1). α-Benzyl α-phenyl TosMIC derivative 2i was
obtained in 85% yield by addition of 3,4-dimethoxybenzyl
15
bromide to tosylbenzyl isocyanide in the presence of n-BuLi.
Received: November 10, 2014
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5032624 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
16
Table 1. Synthesis of TosMIC Derivatives 2a−h
process. The subsequent elimination of p-toluenesulfonic
acid would afford isoquinoline 3a (Scheme 2). This mechanistic
Scheme 2. Mechanistic Hypothesis for the Cyclization of 2a
R1
R2
R3
Et
yield (%)
compd
1
2
3
4
5
6
7
8
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
73
70
78
70
68
2a
2b
2c
2d
2e
2f
Bn
allyl
Et
OCH O
2
OCH O
Bn
Et
2
a
OCH3
OCH3
NBn2
H
H
H
67
a
Bn
Et
72
2g
2h
60
a
These reactions were carried out in NaOH (30%) solution at 0 °C
during the first addition.
hypothesis was tested by adding to 2a catalytic amounts of
different Brønsted and Lewis acids (Table 2, entries 5−11).
Isoquinoline 3a was the only product of these reactions, and
this result confirmed our assumption.
With the aim of finding an efficient method to obtain
isoquinolines from the TosMIC derivatives, α-3,4-dimethox-
ybenzyl α-ethyl TosMIC 2a was selected to study the viability
of the planned cyclization reaction (Table 2). Initial attempts
From the experiments listed in Table 2, it was found that
treatment with 0.1 equiv of trifluoroacetic acid in CH Cl at
2
2
Table 2. Optimization of the Reaction Conditions for 3a
room temperature was the best condition for the cyclization of
TosMIC derivative 2a. In this way, isoquinoline 3a was
obtained in 73% yield. It is worth noting that this reaction was
also tested using different metals as catalysts (Ag, Cu, Au,
entries 12−14) but the reaction did not take place under these
conditions.
catalyst
equiv
solvent
CH Cl
time (h)
yield (%)
In order to determine the scope of this new isoquinoline
synthesis, the best conditions achieved for the cyclization of 2a
were applied to other α-benzyl TosMIC derivatives. As a
general conclusion, it was found that this method is efficient
when electron-donating substituents are present in the benzene
ring. The isoquinolines successfully obtained with this method-
ology are listed in Table 3. First, the catalytic acid-mediated
cyclization was tested with different α-alkyl or aryl α-3,4-
dimethoxybenzyl TosMIC derivatives, which gave in all cases
the expected isoquinolines in high yields (entries 1−3, 15).
However, if a substituent was not present in the C3 position of
the isoquinoline, the elimination of p-toluenesulfonic acid did
not occur and the tosyl group remained in the final product.
In the next step, the substituents present in the benzene ring
were changed. The results showed that cyclizations on benzene
derivatives with electron-withdrawing substituents, such as
halogens, or those without a substituent did not take place. For
this reason, the subsequent investigations were focused on
benzenes with electron-donating substituents (entries 4−14).
α-Piperonyl TosMIC derivatives 2d and 2e underwent the
cyclization to give high yields, although it was necessary to
lower the temperature of the reaction medium (entries 4−6).
In α-3-methoxybenzyl TosMIC derivatives, cyclization was also
successful despite the formation of a small amount of the other
possible regioisomer of the reaction (3-alkyl-8-methoxyisoqui-
nolines). In an effort to improve the selectivity of these
reactions, the cyclization was tested at different temperatures. It
was found that the selectivity of the reaction increased on
decreasing the temperature, with the best reaction conditions
achieved at −30 °C (entries 7−12). Finally, reaction of α-3-
dibenzylaminobenzyl TosMIC derivative 2h with catalytic
1
2
3
4
5
6
7
8
9
1
1
1
1
1
CH COCl
1
18
24
48
48
24
18
48
18
48
18
18
24
24
24
31
40
36
35
25
73
3
2
2
2
tBuCOCl
tBuCOCl
tBuCOCl
CF SO H
1
CH Cl
2
1
THF
1
CH CN
3
0.1
0.1
0.3
1
CH Cl
3
3
2
2
2
2
2
2
2
2
2
2
2
CF CO H
CH Cl
3
2
2
a
AlEt Cl
CH Cl
0
2
2
a
AlEt Cl
CH Cl
0
2
2
Yt(OTf)3
0.3
0.1
0.3
0.3
0.1
0.1
CH Cl
2
69
a
0
1
2
3
4
AlCl3
CH Cl
22
2
AlCl3
CH Cl
2
69
a
AgBF4
CH Cl
2
0
a
CuI
CH Cl
0
2
a
[P(Ph) ]AuCl
CH Cl
0
3
2
a
Starting material was recovered.
were carried out using acyl halides because there are examples
of the reaction of isocyanides with acyl halides to provide α-
ketoimidoyl halides, which can undergo silver(I)-mediated
11
cyclizations to form 1-acyl-3,4-dihydroisoquinolines. Thus,
derivative 2a was treated with 1 equiv of acetyl chloride, but
instead of the expected acylimidoyl chloride, isoquinoline 3a
was obtained as the main isolated product (Table 2, entry 1).
The same result was obtained on treatment of 2a with pivaloyl
chloride in different solvents (entries 2−4), with the best yield
obtained in CH Cl .
2
2
These results were rationalized as being due to the presence
in the reaction medium of tiny amounts of hydrogen chloride,
which could force an acid-mediated cyclization of TosMIC
derivative 2a by an electrophilic aromatic substitution
B
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Organic Letters
Letter
Table 3. Synthesis of Isoquinolines 3a−i
isoquinoline 3j was converted to the alkaloid 4 by reaction with
trichloroisocyanuric acid (TCCA) in H O/HCl at room
2
temperature followed by the addition of methylamine in
18
ethanol. In this way, mansouramycin B was obtained in 75%
yield (23% overall yield).
In summary, a new method for the synthesis of isoquinolines
through a catalytic acid-mediated cyclization of α-benzyl
TosMIC derivatives has been developed. This cyclization
takes place through an electrophilic aromatic substitution
process and works efficiently when electron-donating sub-
stituents are present in the benzene ring. The validity of the
new methodology was demonstrated by applying it in the total
synthesis of mansouramycin B (23% overall yield in three steps
from commercially available TosMIC). This is the first
synthesis of this compound to be reported in the literature.
Work is in progress to explore the potential of this reaction in
the formation of more complex isoquinolines and to improve
the synthesis of other relevant bioactive and pharmacologically
interesting compounds.
a
R1
R2
R3
Et
T (°C)
yield (%)
73 (0)
compd
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
rt
rt
3a
3b
3c
3d
3d
3e
3f
Bn
allyl
Et
88 (0)
80 (0)
24 (0)
75 (0)
73 (0)
70 (23)
82 (8)
68 (6)
70 (16)
73 (6)
68 (5)
0 (0)
rt
OCH O
rt
2
OCH O
Et
−30
−30
rt
2
OCH O
Bn
Et
2
OCH3
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
NBn2
Et
−30
−78
rt
3f
H
Et
3f
0
1
2
3
4
5
H
Bn
Bn
Bn
Et
3g
3g
3g
3h
3h
3i
H
−30
−78
rt
H
H
b
NBn2
H
Et
rt
60 (0) (AlCl3)
ASSOCIATED CONTENT
Supporting Information
■
OCH3
OCH3
Ph
rt
80 (0)
*
S
a
The first number refers to the yield of the major regioisomer (3a−i);
the number in parentheses refers to the yield of the minor regioisomer.
This reaction was carried out with AlCl3 (0.3 equiv) instead of
1
13
Experimental procedures and H and C NMR spectra for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
b
CF CO H.
3
2
trifluoroacetic acid led to a complex mixture of products, but
the same derivative was converted to isoquinoline 3h in 60%
AUTHOR INFORMATION
Corresponding Authors
■
*
*
yield on using 0.3 equiv of AlCl (entries 13 and 14).
3
E-mail: david.sucunza@uah.es.
E-mail: juanjose.vaquero@uah.es.
The validity of this new methodology was demonstrated with
the total synthesis of mansouramycin B (4). The key step in
this synthesis is the formation of isoquinoline 3j, which can
subsequently be transformed into the desired alkaloid (Scheme
Notes
The authors declare no competing financial interest.
3). Thus, the synthesis started with the preparation of TosMIC
ACKNOWLEDGMENTS
■
Scheme 3. Synthesis of Mansouramycin B
́
Financial support from the Spanish Ministerio de Economia y
Competitividad (project CTQ2011-24715), Instituto de Salud
Carlos III (REDinREN, RD12/0021/0014), and University of
́
Alcala (project CCG2013/EXP-036) is gratefully acknowl-
edged. A.C. also thanks the University of Alcala for her grant.
́
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