An efficient total synthesis of calothrixin B

Article abstract of DOI:10.1016/j.tetlet.2012.03.131

An efficient synthesis of calothrixin B (2) is demonstrated starting from 9H-carbazol-4-ol, having two one-pot reaction sequences as key steps. As a novel observation, DMF-methanol was shown to be a hydride donor for reduction of aldehyde to alcohol. Unexpectedly, nucleophilic substitution of benzyloxy by methoxy group was observed.

Full text of DOI:10.1016/j.tetlet.2012.03.131

Tetrahedron Letters 53 (2012) 2894–2896
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Tetrahedron Letters
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An efficient total synthesis of calothrixin B
Shrikar M. Bhosale a, Rupesh L. Gawade b, Vedavati G. Puranik b, Radhika S. Kusurkar a,
⇑
a Department of Chemistry, University of Pune, Pune 411 007, India
b National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of calothrixin B (2) is demonstrated starting from 9H-carbazol-4-ol, having two
one-pot reaction sequences as key steps. As a novel observation, DMF–methanol was shown to be a
hydride donor for reduction of aldehyde to alcohol. Unexpectedly, nucleophilic substitution of benzyloxy
by methoxy group was observed.
Received 17 March 2012
Revised 29 March 2012
Accepted 30 March 2012
Available online 4 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Calothrixin B
DMF–methanol
CAN
Hydride donor
O
O
O
O
O
In 1999, Rickards and co-workers reported two new carbazole
alkaloids, calothrixin A and B (Fig. 1) which were isolated from
the cell extract of cyanobacteria Calothrix species.1 These natural
products show unique indolo[3,2-j]phenanthridine skeleton which
bears indole, quinone, and quinoline moieties. Calothrixin A and B
exhibit important biological activities such as anti-malarial, anti-
cancer and they inhibit RNA polymerase activity.2 In addition, cal-
othrixin A appears to induce intracellular formation of reactive
oxygen species.3 Due to the unique ring system and potent biolog-
ical activities several groups have been attracted toward the syn-
thesis of calothrixins using various approaches.4 In continuation
with our interest in the synthesis of naturally occurring heterocy-
clic alkaloids,5 we herein report a new and efficient route for the
synthesis of calothrixin B from simple and easily available starting
material.
N
N
N
N
Ph
Ph
Calothrixin B (2)
Calothrixin A (1)
Figure 1. Calothrixin A (1) and B (2).
and appearance of methylene protons at 4.69 and two methoxy
groups at 3.84 and 3.87 d in 1H NMR. In this one-pot reaction
sequence bromine and benzyloxy were replaced by methoxy
groups and subsequently aldehyde was reduced to alcohol. To
investigate the source of hydride for reduction, the reaction was
carried out in methanol instead of DMF under the same conditions.
The reaction failed to give any reduced product and starting mate-
rial was recovered after refluxing for 10 h. Similar results were ob-
served in the reaction using DMSO instead of DMF even at 120 °C.
It was shown that the reduction took place in the absence of CuI.
These results indicated that DMF is required for reduction and
CuI for nucleophilic substitution of Br. During the search of the hy-
dride source, literature survey revealed that (i) the base-catalyzed
decomposition of DMF leads to the formation of carbon monoxide
and dimethylamine,6 (ii) dry carbon monoxide gas and methanol in
the presence of strong base gave methyl formate7 which acts as
hydride donor.8 From the above literature information and exper-
imental proofs DMF–methanol system was shown to be the hy-
dride source for reduction of aldehyde to alcohol.
The synthesis started with formylation of 9H-carbazole-4-ol4c 3,
which gave ortho and para formylated products in 3:1 ratio, respec-
tively (Scheme 1). ortho Formylated compound 4 was initially bro-
minated to compound 6 using NBS in quantitative yield. Further,
both –NH and –OH groups of compound 6 were protected by ben-
zyl group in 96% yield. Having protected bromo aldehyde 7 in
hand, attempt was made to replace bromine by methoxy group.
Thus, the reaction of aldehyde 7 in dry DMF with sodium methox-
ide in methanol and CuI for 5 h at 120 °C, furnished compound 8 in
80% yield by nucleophilic substitution of –Br as well as benzyloxy
group. By continuing the reaction for 10 h, alcohol 9 was produced
by complete consumption of starting compound 7 in 77% yield.
Formation of 9 was confirmed by the absence of aldehydic proton
Further, alcohol 9 (Scheme 2) was directly treated with o-iodo-
aniline in the presence of catalytic amount of pTSA under reflux
condition in THF for 15 min to get product 10 in 83% yield. N-acyl-
ation with acetyl chloride and triethylamine in DCM resulted in the
⇑
Corresponding author.
E-mail address: rsk@chem.unipune.ernet.in (R.S. Kusurkar).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.131

S. M. Bhosale et al. / Tetrahedron Letters 53 (2012) 2894–2896
2895
Figure 2. ORTEP diagram of compound 12.
OH
OH
OH
b
CHO
a
N
N
H
N
H
CHO
H
3
5
4
OH
3:1
OCH2Ph
CHO
OCH3
CHO
CHO
c
4
d
N
H
N
N
Br
Br
OCH3
Ph
Ph
6
7
8
e
OCH3
OH
N
OCH3
Ph
9
Scheme 1. Reagents and conditions: (a) DMF, POCl3, 0 °C–30 min, rt–3 h, 94%; (b) NBS, DMF, rt–2 h, 95%; (c) NaH, DMF, 0 °C–30 min, BnBr, rt–2 h, 96%; (d) NaOCH3, CuI, DMF,
5 h, 120 °C; (e) NaOCH3, CuI, DMF, 10 h,120 °C.
formation of compound 11. Treatment of 11 with Pd(OAc)2, PPh3,
and K2CO3 furnished cyclized product 12 in 90% yield. Surprisingly,
CH2 at C6 in the expected structure 12 was not observed in 1H and
13C NMR spectra. Structure 12 was confirmed by single crystal
X-ray analysis9 (Fig. 2) where CH2 at C6 was observed. This behav-
ior can be attributed to the presence of acetyl group attached to the
nitrogen on the six membered ring of compound 12. Further
temperature dependent NMR studies are in progress.
Subsequently, compound 12 was converted to quinone using
CAN at 0 °C however, interestingly deacylation and aromatization
took place along with quinone formation with 80% yield in a single
step reaction to furnish compound 13. Deacylation by using CAN is
not reported earlier. Finally, deprotection of benzyl group of com-
pound 13 led to the formation of calothrixin B (2). 1H and 13C NMR
data were exactly matching with that of the earlier reported
compounds 13 and 2.

2896
S. M. Bhosale et al. / Tetrahedron Letters 53 (2012) 2894–2896
OMe
OMe
OMe
OMe
OMe
O
O
OH
NH
a
b
N
I
N
N
I
N
OMe
10
Ph
Ph
Ph
Ph
9
11
c
O
O
OMe
N
e
N
d
N
N
N
H
N
O
O
2
Ph
OMe
13
12
Scheme 2. Reagents and conditions: (a) o-iodoaniline, cat p-TSA, THF, reflux, 15 min, 83%; (b) AcCl, Et3N, DCM, 2 h, rt, 96%; (c) Pd(OAc)210 mol %, PPh3 30 mol %, K2CO3
2 equiv, reflux, 7 h, 90%; (d) CAN, 0 °C, 15 min, CH3CN/H2O, 3:1, 80%; (e) Pd(OH)2, H2, CH3OH, 4 h, 65%.
2. (a) Bernardo, P. H.; Chai, C. L. L.; Heath, G. A.; Mahon, P. J.; Smith, G. D.; Waring,
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biologically active calothrixin B was established with good overall
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yield. This approach involves two one pot reaction sequences.
Unprecedented use of DMF–MeOH as a source of hydride for the
reduction of aldehyde to ketone and nucleophilic substitution of
benzyloxy by methoxy group were the novel observations during
the present work. Ceric ammonium nitrate has been used for the
first time as a reagent for deacylation at room temperature.
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Acknowledgements
We are grateful to Mrs. J.P. Chaudhari for NMR spectra and Ms.
Deepanjali for IR spectra. S.M.B. is thankful to the CSIR, New Delhi
for financial support.
Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
03.131.
9. Crystallographic data for structure 12 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos. CCDC 862004.
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: +44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.Uk).
References and notes
1. Rickards, R. W.; Rothschild, J. M.; Willis, A. C.; de Chazal, N. M.; Kirk, J.; Kirk, K.;
Saliba, K. J.; Smith, G. D. Tetrahedron 1999, 55, 13513–13520.