Synthesis of calothrixins and its analogs using FeCl3-mediated domino reaction protocol

Article abstract of DOI:10.1021/ol4015738

A novel one pot synthesis of calothrixin B and its analogs is achieved involving an FeCl₃-mediated domino reaction of enamines in dry DMF at reflux. Alternatively, the enamines upon interaction with CuBr₂ in DMF at reflux led to the

Full text of DOI:10.1021/ol4015738

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Synthesis of Calothrixins and Its Analogs
Using FeCl3‑Mediated Domino Reaction
Protocol
Bose Muthu Ramalingam, Velu Saravanan, and Arasambattu K. Mohanakrishnan*
Department of Organic Chemistry, School of Chemistry, University of Madras,
Guindy Campus Chennai 600 025, Tamil Nadu, India
mohanakrishnan@unom.ac.in
Received June 7, 2013
ABSTRACT
A novel one pot synthesis of calothrixin B and its analogs is achieved involving an FeCl3-mediated domino reaction of enamines in dry DMF at
reflux. Alternatively, the enamines upon interaction with CuBr2 in DMF at reflux led to the formation of 1-phenylsulfony-2-(20-nitroaryl)-4-
hydroxycarbazole-3-carbaldehydes in excellent yields.
Ellipticine 1, a pyrido[4,3-b]carbazole alkaloid, has been
well explored for its anticancer properties (Figure 1).1 The
synthesis of a quino[4,3-b]carbazole 2, a benzo- analog of
ellipticine isreported fromthislaboratoryby using thermal
electrocyclization as a key step.2 Subsequently, Rickard
et al.3 isolated calothrixin A 3 and calothrixin B 4 from
Calothrix cyanobacterium. The carbazoloquinones 3 and 4
exhibit potent antimalarial activity, anticancer properties,
and inhibition of RNA polymerase.3,4 The promising
biological activity of calothrixins prompted several groups
to explore their synthesis. Ross Kelly et al.5 reported the
first synthesis of calothrixin A and B through the
attachment of a N-protected indole-3-carboxaldehyde
with N,N-diethylquinoline-4-carboxamide involving a di-
rected lithiation protocol.
€
(1) (a) Knolker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303–
€
4427. (b) Schmidt, A. W.; Reddy, K. R.; Knolker, H.-J. Chem. Rev. 2012,
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(2) Mohanakrishnan, A. K.; Srinivasan, P. C. J. Org. Chem. 1995, 60,
1939–1946.
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N. M.; Kirk, J.; Kirk, K.; Saliba, K. J.; Smith, G. D. Tetrahedron 1999,
55, 13513–13520.
Figure 1. Structures of pyrido[4,3-b]carbazoles.
(4) (a) Bernardo, P. H.; Chai, C. L. L.; Heath, G. A.; Mahon, P. J.;
Smith, G. D.; Waring, P.; Wilkes, B. A. J. Med. Chem. 2004, 47, 4958–
4963. (b) Bernardo, P. H.; Chai, C. L. L.; Le Guen, M.; Smith, G. D.;
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Hatae, N.; Iwamura, N.; Tohyama, S.; Nobuhiro, J.; Hibino, S. Bioorg.
Med. Chem. Lett. 2012, 22, 4762–4764.
Synthetic pathways outlined to date for calothrixins are
prominently based on carbazole intermediates employ-
ing either a regioselective hetero DielsꢀAlder reaction6
(5) Kelly, T. R.; Zhao, Y.; Cavero, M.; Torneiro, M. Org. Lett. 2000,
2, 3735–3737.
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r
10.1021/ol4015738
XXXX American Chemical Society

or Pd-mediated intramolecular arylation.7ꢀ9 Substituted
quinolines and indoles are the starting material for calo-
thrixins which involve lithiation,5,10 FriedelꢀCrafts acyla-
tion followed by cyclization,11 and allene-mediated electro-
cyclization.12 Moody and co-workers achieved the synthesis
of calothrixins involving a biomimetic protocol.13
Despite, the many multistep synthesis procedures avail-
able, there remains a need for an efficient route that will
more readily provide diverse calothrixin analogues for
biological screening.
We have recently outlined the synthesis of carbazoles
involving an in situ generated enamine14 as well as a Lewis
acid mediated domino reaction.15 In further continuation
of our work on carbazole alkaloids,16 we report herein a
novel synthesis of calothrixin B and its analogs using a
Lewis acid mediated domino reaction strategy. The meth-
odology involves a Lewis acid mediated cyclization of an
enamine 6 followed by reductive cyclization, hydrolysis,
and oxidation of carbazole 7 to afford the target com-
pound 8 (Scheme 1).
Our synthesis route began with allylic bromination
of 1-phenylsulfonyl-3-acetyl-2-methylindole 914b using an
NBS and a catalytic amount of AIBN in CCl4 at reflux
(Scheme 2). The Lewis acid mediated Arbuzov reaction17
of resulting bromo compound 10 with triethyl phosphite in
the presence of 20 mol % anhydrous ZnBr2 at room
temperature led to phosphonate ester 11. Contrary to
our expectation, the WittigꢀHorner reaction of the phos-
phonate ester 11 with 2-nitrobenzaldehyde using NaH in
dry THF led to the isolation of bis(2-nitrophenyl)vinylene
12. An attempt to control the undesirable condensation
reaction using K2CO3 as a base in THF was also found to
be problematic, providing only the divinylindole 12 as a
major product (Scheme 2).
Scheme 2. WittigꢀHorner Reaction of Phosphonate Ester 11
Scheme 1. Schematic Pathway for Calothrixins
Next, we turned our attention to employing the Wittig
reaction toprocure the required 1-phenylsulfonyl-3-acetyl-
2-(20nitrophenyl)vinylindole. Accordingly, the bromo com-
pound 10 upon refluxing with triphenylphosphine in dry
THF followed by the reaction of resulting phosphonium
salt with K2CO3 in dry DCM at room temperature led to
the isolation of a stable ylide 13. As expected the ylide 13
upon refluxing with 2-nitroaryl aldehydes 14aꢀg in dry
DCM/1,2-DCE furnished 2-nitroarylvinylenes 15aꢀg in
good yields (Scheme 3).
(7) Bhosale, S. M.; Gawade, R. L.; Puranik, V. G.; Kusurkar, R. S.
Tetrahedron Lett. 2012, 53, 2894–2896.
(8) (a) Abe, T.; Ikeda, T.; Yanada, R.; Ishikura, M. Org. Lett. 2011,
13, 3356–3359. (b) Abe, T.; Ikeda, T.; Choshi, T.; Hibino, S.; Hatae, N.;
Toyata, E.; Yanada, R.; Ishikura, M. Eur. J. Org. Chem. 2012, 5018–
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2807.
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(11) (a) Bernardo, P. H.; Chai, C. L. L.; Elix, J. A. Tetrahedron Lett.
2002, 43, 2939–2940. (b) Bernardo, P. H.; Chai, C. L. L. J. Org. Chem.
2003, 68, 8906–8909.
(12) (a) Tohyama, S.; Choshi, T.; Matsumoto, K.; Yamabuki, A.;
Ikegata, K.; Nobuhiro, J.; Hibino, S. Tetrahedron Lett. 2005, 46, 5263–
5264. (b) Yamabuki, A.; Fujinawa, H.; Choshi, T.; Tohyama, S.;
Matsumoto, K.; Ohmura, K.; Nobuhiro, J.; Hibino, S. Tetrahedron
Lett. 2006, 47, 5859–5861.
(13) McErlean, C. S. P.; Sperry, J.; Blake, A. J.; Moody, C. J.
Tetrahedron 2007, 63, 10963–10970.
(14) (a) Mohanakrishnan, A. K.; Balamurugan, R. Tetrahedron Lett.
2005,46, 4045–4048. (b) Sureshbabu, R.; Balamurugan, R.; Mohanakrishnan,
A. K. Tetrahedron 2009, 65, 3582–3591. (c) Sureshbabu, R.; Mohanakrishnan,
A. K. J. Het. Chem. 2012, 49, 913–918.
A subsequent reaction of the 3-acetyl-2-nitroarylviny-
lenes 15aꢀg with DMF DMA in the presence of 50 mol %
3
glycocyamine18 as a catalyst at 100 °C for 3ꢀ4 h followed
by aqueous workup furnished the respective enamines
16aꢀg as yellow/orange solids (Scheme 4).
As a representative case, thermal electrocyclization of
the enamine 16a was carried out in refluxing xylenes
without any success. However, when the electrocycliza-
tion of the enamine 16a was performed with 1 equiv
of ZnBr2 in xylenes at reflux for 24 h following workup,
(15) (a) Dhayalan, V.; Arul Clement, J.; Jagan, R.; Mohanakrishnan,
A. K. Eur. J. Org. Chem. 2009, 4, 531–546. (b) Sureshbabu, R.;
Saravanan, V.; Dhayalan, V.; Mohanakrishnan, A. K. Eur. J. Org.
Chem. 2011, 922–935. (c) Sivasakthikumaran, R.; Nandakumar, M.;
Mohanakrishnan, A. K. J. Org. Chem. 2012, 77, 9053–9071.
(16) Gobi Rajeshwaran, G.; Mohanakrishnan, A. K. Org. Lett. 2011,
13, 1418–1421.
(17) Gobi Rajeshwaran, G.; Nandakumar, M.; Sureshbabu, R.;
Mohanakrishnan, A. K. Org. Lett. 2011, 13, 1270–1273.
(18) Bindal, S.; Kumar, D.; Kommi, D. N.; Bhatiya, S.; Chakraborti,
A. K. Synthesis 2011, 12, 1930–1935.
B
Org. Lett., Vol. XX, No. XX, XXXX

Use of 3 equiv of ZnBr2 in xylenes at reflux slightly
enhanced the yield of the carbazole 17a (entry 2). Rela-
tively, carbazole formation was found to be better and
faster in DMF than xylenes confirming the involvement of
ionic intermediates. Among the Lewis acids employed, the
maximum yield for the carbazole 17a was obtained using
CuBr2 (entries 4, 8, and 9). Surprisingly, the electrocycliza-
tion reaction was found to be successful even under moder-
ate temperatures affording the carbazole 17a in 75% yield
(entry 9). Finally, the use of 1 equiv of FeCl3 in DMF at
reflux for 1 h led to the isolation of 17a in low yield (entry 10).
Scheme 3. Synthesis of 2-Nitroarylvinylene Using Wittig Reaction
Table 1. Effect of Catalyst on Lewis Acid Mediated Cyclization
of Enamine 16a
yield
entry
catalyst
condition
(%)a
1
2
1 equiv of ZnBr2
3 equiv of ZnBr2
1 equiv of InBr3
1 equiv of CuBr2
1 equiv of ZnBr2
1 equiv of InBr3
1 equiv of CeCl3
1 equiv of CuBr2
1 equiv of CuBr2
1 equiv of FeCl3
xylenes, ref, 24 h
xylenes, ref, 24 h
xylenes, ref, 24 h
xylenes, ref, 6 h
DMF, ref, 16 h
DMF, ref, 18 h
DMF, ref, 8 h
50
55
35
73
63
60
65
89
75
10
3
4
5
6
7
8
DMF, ref, 1 h
Scheme 4. Preparation of Enamine 16aꢀg Using DMF DMA
3
9
1,2-DCE, ref, 6 h
DMF, ref, 3 h
10
a Isolated yields of carbazole 17a.
Having established a facile transformation of the en-
amine 16a into the carbazole 17a using CuBr2, adopting
similar conditions, the rest of the enamines 16bꢀg were
also converted into the respective 4-hydroxycarbazoles
17bꢀg in excellent yields (Scheme 6). The structures of
1
the 4-hydroxycarbazoles 17aꢀg were confirmed by H
NMR, 13C NMR, and HRMS analyses. As a representa-
tive case, the structure of the carbazole 17d was confirmed
by a single crystal X-ray analysis.19
Scheme 6. CuBr2-Mediated Domino Reaction of Enamines
16bꢀg
2-(20-nitroaryl)-4-hydroxy carbazole-3-carbaldehyde 17a
was isolated in 50% yield (Scheme 5).
Scheme 5. Lewis Acid Mediated Cyclization of Enamine 16a
The Lewis acid mediated cyclization of the enamine 16a
was then carried out using different Lewis acids, and the
results obtained are presented in Table 1. In general, the
reaction was found tobesuccessful withall theLewis acids.
The low yield formation of carbazole 17a using FeCl3
(Table 1, entry 10) prompted us to study the reaction in a
Org. Lett., Vol. XX, No. XX, XXXX
C

detailed manner. It should be noted that under these
conditions the enamine 16a was fully consumed.
phenylsulfonyl group led to the target compounds 4/
18bꢀf (Scheme 8). The observed cleavage of the N-
phenylsulfonyl group can be visualized through the
nucleophilic addition of a dimethylamide anion which was
formed during reductive cyclization of the intermediate B.
Alternatively, the coordination of FeCl3 with oxygen
atoms of sulfonyl and carbazoloquinone units followed by
nucleophilic addition of the chloride anion may also sup-
port cleavage of the N-phenylsulfonyl group.
Additionally, the TLC analysis of the crude product
indicatedthe formation ofpolarcomponentsinaddition to
the aldehyde 17a. Further, the enamine 16g which is
lackingaNO2 functioncanbeconvertedintotherespective
4-hydroxycarbazole 17g using 1 equiv of FeCl3 in DMF at
reflux for 1 h in 76% yield.
To our delight, the reaction of enamine 16a with 3 equiv
of FeCl3 in DMF at reflux for 3 h followed by workup led
to the isolation calothrixin B 4 in 65% yield (Scheme 7).
Under identical conditions, the enamines 16bꢀf also con-
verted into the corresponding carbazoloquinones 18bꢀf in
good yields. The structures of the calothrixins B 4, 18bꢀf
Finally, as a representative case, the calothrixin B 4 was
converted into calothrixin A 3 using an excess of m-CPBA
in DCM at reflux.5
1
were confirmed by H NMR, 13C NMR, and HRMS
Scheme 8. Mechanistic Hypothesis for Calothrixins 4/18bꢀf
analyses.
Scheme 7. FeCl3-Mediated Cyclization of Enamines 16aꢀf
In summary, a novel one pot synthesis of calothrixins
and its analogs is achieved involving an FeCl3-mediated
domino reaction of the enamines as a key step. The FeCl3-
mediated domino reaction protocol reported herein af-
forded calothrixin B and its analogs in an overall yield of
39ꢀ50%. Studies on antimalarial as well as anticancer
activities of calothrixins and their analogs are in progress,
and the results will be reported in due course.
To our knowledge, this type of domino reaction which
comprises electrocyclization, reductive cyclization, and
oxidation followed by cleavage of the phenylsulfonyl
group is highly unprecedented.
Acknowledgment. Financial assistance from the Coun-
cil of Scientific Industrial Research (CSIR) and University
Grants Commission (UGC) New Delhi is acknowledged.
The authors thank DST-FIST for the high-resolution
NMR facility. A.K.M. thanks Dr. Jacob M. Hooker,
Harward Medical School, MA for critical reading of the
manuscript. B.M.R. thanks CSIR, New Delhi for a JRF
fellowship. V.S. thanks UGC for a fellowship.
It should be mentioned that the reaction of 4-hydroxy-2-
o-nitrophenylcarbazole-3-carbaldehyde 17a with FeCl3 in
DMF at reflux failed to produce calothrixin B 4. This
clearly confirms the involvement of low valent iron as the
transient species in the reduction of the nitro group.
Mechanistically, the reaction of enamine with FeCl3 gen-
erates a triene intermediate A, which upon electrocycliza-
tion followed by oxidation led to the 4-hydroxycarbazole
iminium ion B. Obviously, the FeCl/HCl-mediated reduc-
tion of the nitro group followed by an intramolecular
cyclization led to a quinoline moiety. The hydroxy-
quinoline upon oxidation followed by cleavage of the
Supporting Information Available. Experimental pro-
1
cedure along with characterization data, H, 13C NMR
spectra of all new compounds, ORTEP diagram and CIF
file for 17d. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) Structure was confirmed by single-crystal X-ray data. CCDC
number for carbazole 17d: 937225 (see the Supporting Information).
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX