Pd-catalyzed imine cyclization: Synthesis of antimalarial natural products aplidiopsamine A, marinoquinoline A, and their potential hybrid nclite-M1

Article abstract of DOI:10.1021/ol302676v

Palladium-catalyzed cyclization of imines has been developed to construct the extremely rare 3H-pyrrolo[2,3-c]quinoline ring system for diversity oriented first total synthesis of antimalarial marine natural product Aplidiopsamine A as well as synthesis o

Full text of DOI:10.1021/ol302676v

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5804–5807
Pd-Catalyzed Imine Cyclization: Synthesis
of Antimalarial Natural Products
Aplidiopsamine A, Marinoquinoline A, and
Their Potential Hybrid NCLite-M1
Jyoti P. Mahajan, Yogeshwar R. Suryawanshi, and Santosh B. Mhaske*
Division of Organic Chemistry, National Chemical Laboratory (CSIR-NCL),
Pune 411 008, India
sb.mhaske@ncl.res.in
Received September 27, 2012
ABSTRACT
Palladium-catalyzed cyclization of imines has been developed to construct the extremely rare 3H-pyrrolo[2,3-c]quinoline ring system for diversity
oriented first total synthesis of antimalarial marine natural product Aplidiopsamine A as well as synthesis of Marinoquinoline A and potential
natural product hybrid NCLite-M1.
Alkaloids are an important class of pharmacophores en-
compassing a wide range of biological properties. Particu-
larly, indole, β-carboline, quinazolinone, or quinoline alka-
loids have been demonstrated to possess potent antimalarial
activity. Natural products such as febrifugine1 and quinine2
alkaloids are well-known antimalarial drugs (Figure 1).
Isolation and bioactivity studies of natural products
from plants, bacteria, fungi, and marine organisms in search
of novel antimalarial lead structures have led to several drugs
and drug candidates.1,3 However, the malaria parasite devel-
Figure 1. Renowned antimalarial drugs of plant origin.
ops resistance to drugs owing to its highly adaptive nature;
hence alternative drugs with novel structures and diverse
mechanisms of action are always needed to treat resistant
strains of Plasmodium.
Recently, Carroll et al. reported4 isolation, structure eluci-
dation, and bioactivity studies of an important polyaromatic
(1) Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Angew.
Chem., Int. Ed. 2003, 42, 5274–5293.
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Qinghaosu; ASM Press: Washington, D.C., 2010; ISBN 978-1555815431. (b)
Figure 2. Marine natural products with high antimalarial activ-
Kaur, K.; Jain, M.; Kaur, T.; Jain, R. Bioorg. Med. Chem. 2009, 17, 3229–3256.
ity and minimal toxicity.4À6
(4) Carroll, A. R.; Duffy, S.; Avery, V. M. J. Org. Chem. 2010, 75,
8291–8294.
r
10.1021/ol302676v
Published on Web 10/24/2012
2012 American Chemical Society

Scheme 1. Total Synthesis of Natural Products Marinoquinoline A and Aplidiopsamine A
alkaloid Aplidiopsamine A (Figure 2) from the temperate
Australian ascidian Aplidiopsis confluata. It is the first
alkaloid to possess the tricyclic aromatic substructure
3H-pyrrolo[2,3-c]quinoline conjugated to an adenine and
exhibit significant inhibition of growth of chloroquine re-
sistant and sensitive strains of the malaria parasite Plasmo-
dium falciparum. The other natural product Marinoquinoline
A (Figure 2) isolated from a novel marine gliding bacterium
Rapidithrix thailandica possessing the unique 3H-pyrrolo-
[2,3-c]quinoline ring system was reported5 by Plubrukarn
et al. Very recently five new natural products, Marinoquino-
line BÀF (Figure 2), with this unprecedented moiety have
been reported.6
Total synthesis of Aplidiopsamine A and Marinoquino-
line D and F is not known hitherto, whereas the total syn-
thesis of Marinoquinoline AÀC and E has been reported7
very recently. In view of the reported4À6 high antimalarial
activity and minimal toxicity toward human cells, they
represent novel lead structures that could be further devel-
oped into antimalarial drugs; hence a diversity oriented
practical synthetic approach is essential for their SAR
studies. This prompted us to initiate studies toward the
total synthesis of marine natural products Aplidiopsamine
A, Marinoquinoline AÀF, and their potential analogues.
These natural products have 3H-pyrrolo[2,3-c]quinoline
core structure. Several attempts using well-known methods
starting from a variety of suitable starting materials could
not furnish the expected core structure.8À12 We then
designed a diversity oriented synthesis of the core using
regioselective metal-catalyzed intramolecular CÀC bond
formation as a key step. Presented herein is the successful
application of this protocol for the first total synthesis of
antimalarial marine natural product Aplidiopsamine A as
well as synthesis of Marinoquinoline A and their potential
natural product hybrid NCLite-M1.
The synthesis (Scheme 1) began with pyrrole, which was
converted to ketone 1 in two steps with good yields.13 The
next step, imine formation between 2-iodoaniline and
ketone 1, required several attempts using various reagents
and reaction conditions.14 Finally refluxing iodoaniline,
˚
pyrrole 1, p-toluene sulfonic acid, and freshly activated 4 A
molecular sieves in dry toluene with the aid of a DeanÀ
Stark apparatus provided imine 2 in 80% yield.
The novel and key transformation of the planned syn-
thetic route to the above-mentioned natural products is the
intramolecular cyclization of imine 2. Our first attempt
(Table 1, entry 1) using a neocuproine-KOtBu promoted
intramolecular cross-coupling15 reaction gave a trace
amount of expected product 3. Transition-metal-catalyzed
inter-/intramolecular cross-coupling reactions have been
used in the synthesis of several bioactive natural products
and evolved as a powerful tool in organic synthesis;16
however its application for imine cyclization to furnish
natural products has not been reported. The second
attempt (Table 1, entry 2) using 10 mol % of Pd(OAc)2
satisfyingly provided the expected product 3 in 51% yield.
(5) (a) Sangnoi, Y.; Sakulkeo, O.; Yuenyongsawad, S.; Kanjana-opas,
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Org. Lett., Vol. 14, No. 22, 2012
5805

Table 1. Optimization Studies on Cyclization of Iodo-Imine 2 to Pyrroloquinoline 3a
Pd(OAc)2, ligand, base, solvent
2
3
f
entry
catalyst (equiv)
ligand (equiv)
base (equiv)
solvent
temp
time
yield
01
02
03
04
05
06
07
08
09
10
11
12
À
neocuproine (0.50)
PPh3 (0.20)
PPh3 (0.40)
PPh3 (0.40)
PPh3 (0.20)
PCy3 (0.08)
PCy3 (0.08)
PCy3 (0.20)
PPh3 (0.10)
PPh3 (0.06)
PPh3 (0.04)
PPh3 (0.02)
KOtBu (2.5)
Ag2CO3 (2.0)
Ag2CO3 (4.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Cs2CO3 (2.0)
K2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (1.0)
Ag2CO3 (0.6)
Ag2CO3 (0.4)
Ag2CO3 (0.2)
benzene
DMF
100 °C
100 °C
100 °C
reflux
reflux
110 °C
110 °C
110 °C
120 °C
120 °C
18 h
02 h
02 h
04 h
03 h
24 h
24 h
24 h
07 h
08 h
10 h
24 h
trace
51%
64%
63%
91%
23%
35%
31%
90%
89%
93%
72%
Pd(OAc)2 (0.10)
Pd(OAc)2 (0.20)
Pd(OAc)2 (0.20)
Pd(OAc)2 (0.10)
Pd(OAc)2 (0.04)
Pd(OAc)2 (0.04)
Pd(OAc)2 (0.10)
Pd(OAc)2 (0.05)
Pd(OAc)2 (0.03)
Pd(OAc)2 (0.02)
Pd(OAc)2 (0.01)
DMF
THF
1,4-dioxane
THF
DMF
DMF
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
120 o
120 °C
C
a Reactions shown in entries 1 and 6À12 were carried out in a sealed tube.
Scheme 2. Proposed Mechanism for Imine Cyclization
Scheme 3. Synthesis of Natural Product Hybrid NCLite-M1
Optimization of the protocol was tried by varying molar
ratios, ligand, base, solvent, temperature, and time (Table 1,
entries 3À12). Out of several permutations and combina-
tions tried, the reaction conditions shown in Table 1, entry 5
(10 mol % Pd(OAc)2, no sealed tube) and Table 1, entry 11
(2 mol % Pd(OAc)2, using sealed tube) proved to be the
best, providing a 91% and 93% yield respectively. Thus, a
facile Pd-catalyzed intramolecular CÀC bond formation
protocol for the construction of pyrroloquinolines was
developed. Base-induced deprotection of the phenylsulfo-
nyl moiety from pyrroloquinoline 3 in methanolÀK2CO3
provided Marinoquinoline A in 96% yield, thus complet-
ing its total synthesis in three steps (Scheme 1). A plausible
mechanism for Pd-catalyzed imine cyclization is depicted
in Scheme 2.
Using the same reaction sequence Marinoquinoline BÀF
and theiranaloguescanbepreparedfrom related ketones.13
For the synthesis of Aplidiopsamine A our initial attempts
to brominate pyrroloquinoline 3 using NBS and radical
initiators such as AIBN, ABCN, etc. provided a maximum
30% yield of bromide 4, but it could be improved to 75%
by BPO-catayzed NBS bromination. The reaction of bro-
mide 4 with adenine in DMFÀK2CO3 at 50 °C provided a
complex reaction mixture; however treatment with 6-chloro-
purine under the same conditions provided 5 in 70% yield.
Treatment of pyrroloquinoline 5 in a saturated methanolic
solution of ammonia in a sealed tube at 150 °C provided
Aplidiopsamine A in 69% yield, thus, completing its first
total synthesis (Scheme 1). The spectral and analytical data
of the synthesized Aplidiopsamine A and Marinoquinoline
A were in complete agreement with the reported data.4,5
Synthesis of Marinoquinoline BÀD should be also pos-
sible by reacting the appropriate Grignard reagent with
bromide 4.
Application of the diversity oriented intermediate 4 for
the synthesis of potential analogues was exemplified by the
synthesis of a natural product hybrid analogue named
NCLite-M1. It was synthesized (Scheme 3) in two steps
from the intermediate 4. Thus, treatment of quinazolinone
(6) with compound 4 in the presence of K2CO3 gave
quinazolinone 7 in 73% yield. Deprotection of 7 using
methanol and K2CO3 furnished NCLite-M1 in 90% yield.
Likewise, several other nucleophiles can be reacted with
the intermediate 4 to generate combinatorial libraries for
SAR studies in search of novel drug entities.
The Pd-catalyzed imine cyclization protocol developed
herein was applied on various imines (Table 2, entries
1À6). Entry1providesmethylsulfonyl protectedderivative
of Marinoquinoline A, and entry 2 provides an efficient
access to a chlorinated analogue of Marinoquinoline A.
Entry 3 is intersting since it provides a positional isomer of
phenylsulfonyl protected Marinoquinoline A. Entires 4
and 5 smoothly provide phenanthridine alkaloids in good
5806
Org. Lett., Vol. 14, No. 22, 2012

Table 2. Generalization Studies of the Optimized Pd-Catalyzed Intramolecular Imine Cyclization Protocola
a Reaction condition: imine substrate (1 equiv), Pd(OAc)2 (0.02 equiv), PPh3 (0.04 equiv), Ag2CO3 (0.4 equiv), 1,4-dioxane, sealed tube, 120 °C.
yields. Interestingly during these investigations a metho-
dology on Pd-catalyzed CÀH activation/CÀC bond for-
mation to construct phenanthridines was reported17 by
Li et al. The CÀC bond cyclization in the case of entry 6
followed a different path and furnished the indole alkaloid
probably via an enamine intermediate.18
In conclusion, we have demonstrated a diversity ori-
ented practical approach for the first total synthesis of
Aplidiopsamine A as well as synthesis of Marinoquinoline
A and the potential natural product hybrid analogue
NCLite-M1. An efficient regioselective intramolecular
Pd-catalyzed CÀC bond forming reaction was developed
to construct a 3H-pyrrolo[2,3-c]quinoline core structure.
Application of the protocol to other imines also provided
interesting alkaloids as well as analogues of Marinoquino-
line A. Total synthesis of Marinoquinoline BÀF and syn-
thesis of Aplidiopsamine A and NCLite-M1 analogues in
search of novel antimalarial drug candidates are underway.
Acknowledgment. J.P.M. thanks CSIR, New Delhi for
the Research fellowship. S.B.M. thanks DST, New Delhi
for the Ramanujan Fellowship award and DST-SERC
FAST-Track research grant.
Supporting Information Available. Experimental de-
tails, analytical and spectral data, and copies of NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Peng, J.; Chen, T.; Chen, C.; Li, B. J. Org. Chem. 2011, 76, 9507–
9513.
(18) Shi, Z.; Glorius, F Angew. Chem., Int. Ed. 2012, 51, 9220–9222.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
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