Formal total synthesis of calothrixin B and its N-benzyl analogues

Article abstract of DOI:10.1039/c5ra18120h

A formal total synthesis of calothrixin B and its N-benzyl analogues has been accomplished from (2-chlorophenyl)boronic acid, 8-bromophenanthridine-7,10-dione and benzylamines. The synthesis involves Suzuki cross-coupling and copper-catalyzed domino reactions to generate N-benzylcalothrixins in good to moderate yields.

Full text of DOI:10.1039/c5ra18120h

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DOI: 10.1039/C5RA18120H
Formal Total Synthesis of Calothrixin B and Its N-Benzyl Analogues
Nagarajan Ramkumar and Rajagopal Nagarajan*
School of Chemistry, University of Hyderabad, Hyderabad-500046, India.
O
O
N
Br
B(OH)2
Cl
2 steps
N
N
H2N
O
O
R
R
9 examples
46-86% yield
A formal total synthesis of Calothrixin B and its N-benzyl analogues has been reported from
(2-chlorophenyl)boronic acid, 8-bromophenanthridine-dione and benzylamines.

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Formal Total Synthesis of Calothrixin B and Its N-Benzyl Analogues
Nagarajan Ramkumar and Rajagopal Nagarajan*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
formal total synthesis of Calothrixin B
and its N-benzyl intramolecular arylation,7 FeCl3-mediated domino reaction,8
analogues has been accomplished from (2-chlorophenyl)boronic thermal electrocyclization,9 oxidative radical reaction,10
acid, 8-bromophenanthridine-7,10-dione and benzylamines. The Pb(OAc)4-mediated rearrangement11 and Pd-mediated
synthesis involves Suzuki cross-coupling and copper-catalyzed multiple cross-coupling reaction.12 We have also reported two
domino reactions to generate N-benzylcalothrixins in good to total syntheses of Calothrixin B using Pd-catalyzed cross-
moderate yields.
coupling/C‒H activation13 and Friedel‒Crafts hydroxyalkylation
followed by a ketone directed ortho-lithiation strategies.14
Calothrixin A (
1) and B (2) are pentacyclic quinones which
belong to the family of quinolino[4,3-b]carbazole alkaloids (Fig.
1).1 These alkaloids were isolated from the strain of Calothrix
cyanobacteria in 1999 by Rickards and co-workers.2 They show
potent activity against malaria parasites and human cancer
cells.2,3 Due to their valuable biological activities as well as
their unique structural scaffold, novel among natural products,
calothrixins have drawn much attention from medicinal and
synthetic chemists.4
O
H2N
R
O
Copper-catalyzed
domino reaction
N
N
Cl
N
Ullmann type
N-arylation
O
7
O
8a-i
C-H amination
R
9a-i
Suzuki cross-coupling
B(OH)2
OMe O
O
Br
Br
(i) Reduction
(ii) Oxidation
NMOM
N
Cl
OMe
O
5
6
3
O
O
O
N
N
Scheme 1. Retrosynthetic analysis to N-benzylcalothrixins
N
H
N
H
The Suzuki coupling reaction has been frequently used in
syntheses of complex natural products.15 Copper-catalyzed
domino reactions are one of the most useful synthetic method
for the construction of heterocyclic compounds.16
Benzylamines are widely used as a starting material in several
copper-catalyzed domino reactions for the production of
O
O
Calothrixin A (1)
Figure 1. Structures of Calothrixin A (
Calothrixin B (2)
1) and B (2)
In 2009, Hibino and co-workers extensively reviewed the
synthesis of calothrixins in which they described six total
syntheses and two biomimetic routes.5 Several synthetic
routes have been developed later for the synthesis of
calothrixins and its analogues, comprising of Pd-catalyzed
tandem cyclization/cross-coupling reaction followed by
various N-heterocycles.17 N-Alkylated calothrixins show
a
promising antimalarial activity.18 In particular, the activity of N-
benzylcalothrixins has never been reported till date due to the
lack of synthetic routes available for their direct synthesis.
Therefore, we herein report a facile route to synthesize a
series of N-benzylcalothrixins by exploiting Suzuki cross-
coupling and copper-catalyzed domino reaction through
Ullmann type N-arylation and C‒H amination, starting from
readily available starting materials (2-chlorophenyl)boronic
copper-catalyzed
electrocyclization,6
Pd-mediated
School of Chemistry, University of Hyderabad, Hyderabad-500046, India.
E-mail: rnsc@uohyd.ernet.in (Dr. R. Nagarajan); Fax: +91 40-23012460
Electronic Supplementary Information (ESI) available: Experimental procedures
and copies of 1H, 13C NMR and Mass spectra for all compounds. See acid, benzylamines and 8-bromophenanthridine-7,10-dione.
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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The retrosynthetic approach for the synthesis of N-benzylated with benzylamine 8a proceeded smoothly in the presence of
calothrixins is described in Scheme 1. Two key reactions are 10 mol% Cu powder and 20 mol% CuO as a catalyst, t-BuOK (2
o
utilized to construct the target compounds; (i) copper- equiv.) as a base and NMP as a solvent at 140 C for 6 h under
catalyzed domino reaction of intermediate
benzylamines, (ii) Suzuki cross-coupling reaction of (2- 78% yield.
chlorophenyl)boronic acid and 8-bromophenanthridine-7,10-
7
with nitrogen atmosphere, which gave N-benzylcalothrixin 9a in
6
dione
5
. The compound
5
could be synthesized from a known
8-bromo-7,10-dimethoxy-5-
synthetic
precursor
(methoxymethyl)phenanthridin-6(5H)-one
previously used for the synthesis of calothrixin B.19
The synthesis of a starting material 8-bromophenanthridine-
7,10-dione began from a known derivative, 8-bromo-7,10-
dimethoxy-5-(methoxymethyl)phenanthridin-6(5H)-one
which was synthesized according to the procedure reported by
Chai and co-workers (Scheme 2).19 In turn, the compound
was converted into in two steps by standard
transformations. Reduction of
with LiAlH4 in THF at 0 oC for 2
h afforded , which was not isolated from the reaction
mixture. After the work up process, the crude mixture
containing was treated with CAN in CH3CN/H2O (2:1) at room
temperature for 2 h gave required 8-bromophenanthridine-
3
which was
O
NH2
N
O
Cu (10 mol%)
CuO (20mol%)
N
Cl
N
5
t-BuOK, NMP, N2
140 oC, 6-10 h
O
R
O
3
8a-i
7
9a-i
R
3
O
O
O
5
N
N
N
3
4
N
N
N
O
O
O
4
Me
MeO
O
9a, 78%, 6 h
9b, 76%, 6 h
9c, 81%, 6 h
7,10-dione
compound
5
in 78% yield over 2 steps. With required starting
in hand, we proceeded Suzuki cross-coupling
O
5
N
N
reaction with commercially available (2-chlorophenyl)boronic
acid as a coupling partner (Scheme 2). The coupled product
6
7
N
N
O
O
was obtained in 84% yield, on carrying out this reaction using
10 mol% Pd(PPh3)4, K2CO3 (2 equiv.) in DMF at 140 oC for 8 h.
Cl
F
9d, 63%, 8 h
9e
, 58%, 8 h
O
O
N
N
OMe
O
OMe
Br
CAN
CH3CN/H2O (2:1)
Br
NMOM
N
N
N
LiAlH4, THF
O
O
0
oC, 2 h
0 oC to rt, 2 h
2 steps, 78%
OMe
OMe
MeO
Cl
Cl
3
4
OMe
9g, 46%, 10 h
9f
, 6 h, 86%
N
(not isolated)
O
O
O
O
N
Pd(PPh3)4
K2CO3, DMF
Br
B(OH)2
N
N
Cl
N
140 oC, 8 h, 84%
N
O
Cl
O
O
O
6
5
7
Br
OMe
9h, 80%, 6 h
9i, 68%, 8 h
Scheme 2. Synthesis of 8-(2-chlorophenyl)phenanthridine-7,10-dione (7)
Scheme 3. Copper-catalyzed domino synthesis of N-benzylcalothrixins (9a-i
)
Next, we focused on copper-catalyzed domino reaction of the
coupled product with benzylamines (Scheme 3). Initially, we
7
tried out various reaction conditions to find out an optimal,
high yielding catalyst system for the copper-catalyzed domino
reaction. In order to obtain a suitable reaction condition,
different copper salts like CuBr, CuCl, CuCl2, CuBr2, CuO, Cu2O,
CuI, Cu(OAc)2.H2O, Cu(OTf)2 and combination of Cu powder
(electrolytic) with these copper salts as catalysts, and K2CO3,
Cs2CO3, AcOK, K3PO4, NaOH and t-BuOK as bases, and DMF,
DMA, DMSO, NMP, ethylene glycol, toluene and dioxane as
solvents at different temperatures under inert atmosphere
O
O
N
N
AlCl3, anisole
100 oC, 8 h
68%
N
N
H
O
O
Calothrixin B 2
9f
MeO
OMe
Scheme 4. Synthesis of Calothrixin B (2)
were examined. Out of which, we found that the reaction of
7
2 | J. Name., 2012, 00, 1-3
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Sperry, A. J. Blake and C. J. Moody, Tetrahedron 2007, 63
10963; (n) J. Sperry, C. S. P. McErlean, A. M. Z. Slawin and C.
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,
With this optimized condition, we were able to synthesize a
series of N-benzylcalothrixins 9b-i by varying substituents in
benzylamines 8b-i. The compound 9f was obtained in a
maximum yield of 86% and the compound 9g in moderate
yield of 46%, when we used benzylamines 8f and 8g
5
6
T. Choshi and S. Hibino, Heterocycles 2009, 77, 85.
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(a) S. M. Bhosale, R. L. Gawade, V. G. Puranik and R. S.
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2 was obtained by the N-
deprotection of the derivative 9f using 5 equiv. of AlCl3 in
anisole at 100 oC with an overall yield of 36.1% in 5 steps from
7
the known precursor 3 (Scheme 4).
8
9
B. M. Ramalingam, V. Saravanan and A. K. Mohanakrishnan,
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In summary, we have developed a simple and efficient route
Tetrahedron 2014, 70, 5928.
11 D. H. Dethe and G. M. Murhade, Eur. J. Org. Chem., 2014,
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12 S. A. Kaliyaperumal, S. Banerjee and U. K., S. Kumar, Org.
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the first example of constructing
a
series of N-
benzylcalothrixins using Suzuki cross-coupling and copper-
catalyzed domino reaction protocols, starting from
commercially available benzylamines, (2-chlorophenyl)boronic
acid, and 8-bromophenanthridine-7,10-dione in good yields.
13 N. Ramkumar and R. Nagarajan, J. Org. Chem., 2013, 78
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