Divergent total synthesis of the natural antimalarial marinoquinolines A, B, C, e and unnatural analogues

Article abstract of DOI:10.1016/j.tetlet.2012.06.115

A new synthetic route to marinoquinolines was developed, allowing the synthesis of several structurally related compounds from a common key intermediate. Four natural marinoquinolines (A, B, C and E) and nine unnatural new analogues were prepared by this strategy, which features a Heck-Matsuda reaction in pure water and the Pictet-Spengler reaction as key steps.

Full text of DOI:10.1016/j.tetlet.2012.06.115

Tetrahedron Letters 53 (2012) 4836–4840
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Divergent total synthesis of the natural antimalarial marinoquinolines A, B, C,
E and unnatural analogues
⇑
Cristiane Storck Schwalm, Carlos Roque D. Correia
Instituto de Química, Universidade Estadual de Campinas, UNICAMP, 13084-917 Campinas, São Paulo, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A new synthetic route to marinoquinolines was developed, allowing the synthesis of several structurally
related compounds from a common key intermediate. Four natural marinoquinolines (A, B, C and E) and
nine unnatural new analogues were prepared by this strategy, which features a Heck–Matsuda reaction
in pure water and the Pictet–Spengler reaction as key steps.
Received 8 June 2012
Revised 23 June 2012
Accepted 26 June 2012
Available online 2 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Marinoquinolines
Antimalarial
Heck–Matsuda reactions
Pictet–Spengler
Introduction
3-quinolyl hydrazone derivatives,7–9 and the palladium catalyzed
annulations of amino halogenated quinolines.10 Both strategies re-
The 3H-pyrrolo[2,3-c]quinoline system is a rather rare struc-
tural motif among natural products and was first reported in mari-
noquinoline A (1a), a strong inhibitor of acetilcholinesterase
quire the use of appropriate substituted starting materials for the
synthesis of the desired compound. Molina and co-workers
described the preparation of 4-substituted 3H-pyrrolo[2,3-c]quino-
line-2-carboxylates through the condensation of ethyl azidoacetate
with the appropriate 4-formylquinoline, available from o-(1-meth-
ylethenyl)aniline by acylation, cyclization, and formylation.11 More
recently, Yao and co-workers accomplished the total synthesis of
marinoquinolines A, B, and C through the condensation of TosMIC
(IC50 = 4.9 lM) isolated from the marine gliding bacteria Rapidi-
thrix thailandica, in 2006 (Fig. 1).1,2 More recently, along with mari-
noquinoline A, five other derivatives — the marinoquinolines B–F
(1b–f) — were isolated from Ohtaekwangia kribbensis.3 All of these
compounds displayed moderate cytotoxicity against four different
cancer cell lines, as well as promising activities against resistant
and an
a,b-unsaturated ester under basic conditions to prepare
Plasmodium falciparum K1 (IC50 ranging from 1.7 to 15
l
M). The
the pyrrole moiety and a Morgan–Walls reaction with the appropri-
ate aroyl chloride to construct the substituted quinoline ring as the
key steps.12 However, in these two approaches at least three reac-
tion steps are required to complete the synthesis of each different
compound after the introduction of the appropriate substituent.
Herein we describe a novel and concise divergent total synthe-
sis of marinoquinoline derivatives by means of the Pictet–Spengler
reaction of the key arylpyrrole derivative 4 with the appropriate
aldehyde, followed by in situ aromatization (Scheme 1). The aryl-
pyrrole 4 is derived from the nitro compound 5, which was pre-
pared via the Heck–Matsuda reaction between the N-protected
3-pyrroline 6 and the aryldiazonium salt 7 as the key step, a strat-
egy previously developed in our research group.13
other two known natural products displaying this interesting motif
are the trigonoine B (2), isolated from the leaves of Trigonostemon
lii,4 and aplidiopsamine A (3), isolated from Aplidiopsis confluata.5
This latter compound also displays high antimalarial activity, with
IC50 values of 1.65 and 1.47 lM for chloroquine resistant and sen-
sitive Plasmodium falciparum strains, respectively, while exhibiting
minimal toxicity toward human cells.
As these natural products display a 4-substituted pyrroloquino-
line moiety, a synthetic strategy allowing for a late introduction of
the highly variable 4-substituent is desirable. This strategy could
lead to a variety of structurally diverse analogues from a common
precursor in a rapid fashion, which is an important feature for fu-
ture biological activity studies.
Among the reported synthetic strategies available for the
construction of the pyrroloquinoline system are the cyclization of
Results and discussion
Aiming at the synthesis of the 3-arylpyrrole intermediate 5, we
first performed the Heck–Matsuda reaction between 3-pyrroline 6
and the ortho-nitro benzenediazonium salt 7. Surprisingly, when
⇑
Corresponding author. Tel.: +55 19 3521 3086.
E-mail address: roque@iqm.unicamp.br (Carlos Roque D. Correia).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.115

C. S. Schwalm, Carlos Roque D. Correia / Tetrahedron Letters 53 (2012) 4836–4840
4837
9
9a
1
6
5a
9b
2
N
N
N
N
3a
N
H
N
H
4
R
H
N
O
N
N
Marinoquinolines A-F (1a-f)
N
NH2
Aplidiopsamine (3)
1a: R = CH3
1d:
1e:
1f:
R = p-OH-benzyl
R = 3-indolyl
N
1b:
R = CH2CH(CH3)2
Trigonoine B (2)
1c: R = benzyl
R = indole-3-carbonyl
Figure 1. 3H-pyrrolo[2,3-c]quinoline containing natural products.6
6
NH2
NO2
N
[H]
RCHO
CO2Et
+
[O]
N
N
H
N2BF4
N
N
R
7
H
H
Marinoquinoline
derivatives
4
5
NO2
Scheme 1. Retrosynthetic analysis.
NO2
NO2
NO2
Pd(OAc)2, 4 mol%
+
TFAA
N
2,4-Lut
PhMe,Δ
CO2Et
N
N2BF4
H2O, r.t.
OH
CO2Et
N
CO2Et
6
7
8
9 (61-66%
over 2 steps)
Scheme 2. Synthesis of enecarbamate 9 by the HM reaction.
NH2
NO2
NO2
NO2
DDQ
NaOH
Pd/C
PhMe, Δ
MeOH, r.t.
MeOH
r.t.
H
2 (1 atm)
sealed tube
N
H
N
N
N
CO2Et
CO2Et
H
9
5 (93-98%)
4 (91-94%)
10
(92-96%)
Scheme 3. Conversion of 9 into the pyrrolylaniline 4.
NH2
O
[O]
Pictet-Spengler
HN
N
+
H
N
H
N
H
N
H
4
11
12
Marinoquinoline A (1a)
Scheme 4. Preparation of marinoquinoline A through a Pictet–Spengler reaction followed by in situ aromatization.
the conditions already described by us for the reaction of 6 with
another aryldiazonium salts were employed — Pd(OAc)2 as the pal-
ladium source in acetonitrile and water as the solvent13 — only
decomposition products were observed. Remarkably, the use of
pure water as solvent led to complete conversion and formation
of lactamol 8,14 which was immediately dehydrated to afford the
desired aryl enecarbamate 9 in 61–66% yield for the two steps
(Scheme 2).
The 4-aryl enecarbamate 9 was subjected to aromatization
with DDQ in toluene, leading to the corresponding arylpyrrole
10 in high yields (92–96%, Scheme 3). The 3-arylpyrrole 10 was
then deprotected under basic methanolic conditions to afford
the free arylpyrrole 5 in excellent yields, which was then reduced
in the presence of Pd/C and H2 leading to the key intermediate 4
in high yields with an overall yield of ꢀ83% from enecarbamate
9.15

4838
C. S. Schwalm, Carlos Roque D. Correia / Tetrahedron Letters 53 (2012) 4836–4840
Table 1
It is worth mentioning that in the latter three step sequence
compounds 10 and 5 were employed in their crude form. Only
compound 4 was subjected to chromatographic purification at
the end of the sequence. By this synthetic route we were able to
prepare up to 3 grams of the pyrrolylaniline 4 without any obser-
vable decrease in yields.
With pyrrolylaniline 4 in hand, the steps required for the syn-
thesis of marinoquinolines were the Pictet–Spengler reaction with
the appropriate aldehyde followed by aromatization. In this partic-
ular case, we envisioned that both transformations could be
achieved in a single reaction step, since the in situ aromatization
of the Pictet–Spengler adduct is often described when arylamines
are involved.16–24
Pictet–Spengler conditions tested for the reaction between pyrrolylaniline 4 and
acetaldehyde
Entry Conditionsa
Conversion. (%)b 1a (%)b
1
2
TFA (2 equiv), MgSO4, CH2Cl2, rt, 6 h
AlCl3 10%, THF, benzotriazole, rt, 10 h
p-TSA 10%, toluene, 140 °C, 6 h
66
24
32
89
25
5
11
27
50
3
4c
5
TFA (2 equiv), MgSO4, CH2Cl2, rt, 18 h
TFA (2 equiv), MgSO4, CH2Cl2, 60 °C, 3 h 100
a
All reactions performed using 1.2 equiv of acetaldehyde.
Determined by 1H NMR of the crude reaction mixture, using styrene as the
b
internal standard.
c
17% of the non-aromatized primary adduct 12 also observed.
NH2
TFA (2 equiv.)
O
MgSO4 (250 mg/mmol)
N
+
H
R
CH2Cl2, 0,15 M
N
H
60 oC, sealed tube, 3h
R
N
H
4
1.2 equiv.
1a
: R = Me (46%)
R = Bu (50%)
i
1b:
1c:
R = benzyl (27%)
1e:
R = 3-indolyl (26%)
Scheme 5. Synthesis of the natural marinoquinolines A, B, C and E.
Table 2
Pictet–Spengler reactions of 4 with different aldehydes
NH2
TFA (2 equiv.)
O
MgSO4 (250 mg/mmol)
N
+
H
R
CH2Cl2, 0,15 M
r.t., 6 h
N
H
N
H
R
4
13a-i (1.2 equiv.)
14a-i
Entry
1
Aldehyde
Product
Yielda (%)
55
O
13a
13b
14a
H
O
H
2
3
14b
14c
62
45
(Me)2N
O
13c
13d
H
H
MeO
MeO
O
O
4
5
14d
14e
58
63
OMe
OMe
MeO
MeO
H
13e

C. S. Schwalm, Carlos Roque D. Correia / Tetrahedron Letters 53 (2012) 4836–4840
4839
Table 2 (continued)
Entry
Aldehyde
Product
Yielda (%)
O
O
13f
H
H
6
7
14f
53
51
Cl
13g
14g
Br
O
H
13h
13i
8
14h
14i
43
44
O2N
O
9
H
a
Isolated yields after column chromatography. Complete conversion observed in all the cases, except for entry 9.
Firstly, we investigated the preparation of marinoquinoline A,
through the reaction of the pyrrolylaniline 4 with acetaldehyde
(11, Scheme 4).
For this transformation we initially employed different Pictet–
Spengler reaction conditions (Table 1, entries 1–3). The direct for-
mation of the expected marinoquinoline A (1a) was indeed ob-
served, but in all the cases the starting material was not totally
consumed. In the best case, the product 1a was formed in 25% yield
with only 66% conversion (entry 1).
Conclusions
This work describes a new synthetic route for natural and
unnatural marinoquinolines, featuring a Heck–Matsuda arylation
in pure water and the Pictet–Spengler reaction as the key steps.
Through the present approach, four natural marinoquinolines (A,
B, C, and E) and nine unnatural analogues were prepared in a rapid
and straightforward fashion, with overall yields ranging from 14 to
33% over a total of 6 steps.
Since the use of the TFA/CH2Cl2 system appeared to be the most
promising, we performed other experiments under similar condi-
tions. In the first case, we increased the reaction time, but com-
plete conversion was not achieved even after 16 h of reaction
(entry 4). Next we submitted the reaction mixture to moderate
heating, using a sealed tube (entry 5). In this case, the total con-
sumption of the starting material was observed. After 3 h the de-
sired product was formed in 50% yield (determined by 1H NMR)
and isolated in 46% yield after column chromatography. Several
other minor modifications such as changes in the concentration,
time, or stoichiometry of the reaction did not lead to any improve-
ment in the observed yields.
With these results in hand, we extended the conditions de-
scribed in entry 5 for the preparation of marinoquinolines B, C,
and E, all derived from the reaction of pyrrolylaniline 4 with com-
mercially available aldehydes (Scheme 5). Although all these natu-
ral products could be indeed prepared, they were isolated only in
modest to moderate yields.
The vast majority of the examples of the Pictet–Spengler
reaction involves the employment of aromatic aldehydes as
electrophiles. Therefore, we investigated the reaction of the
pyrrolylaniline 4 with benzaldehyde (13a). In this case, com-
plete conversion of the pyrrolylaniline was achieved with no
need for heating. Under these milder conditions using TFA
and MgSO4 in CH2Cl2 at room temperature the corresponding
marinoquinoline 14a was obtained in 55% isolated yield (Table
2, entry 1).
Several substituted benzaldehydes were subjected to the same
reaction conditions. Both electron donating and withdrawing
groups in the benzaldehyde were tolerated, leading to the corre-
sponding marinoquinolines in moderate yields (entries 1–8, Table
2). Propionaldehyde (13i) was also employed under this condition,
but as observed previously with acetaldehyde, complete conver-
sion of 4 was not achieved in this case (entry 9).
Acknowledgments
The authors thank the Brazilian National Research Council
(CNPq), the Coordination for the Improvement of Higher Education
Personnel (CAPES) and the Research Supporting Foundation of the
State of São Paulo (FAPESP) for fellowships and financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
06.115.
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