Synthetic studies on indolocarbazoles: Total synthesis of staurosporine aglycon

Article abstract of DOI:10.1021/ol200094b

A synthesis of staurosporine aglycon and its analogs was achieved in a 28-36% overall yield starting from 2-methylindole. The prominent key steps for the synthesis of the indolocarbazole alkaloids involved electrocyclization and nitrene insertion reactions.

Full text of DOI:10.1021/ol200094b

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1418–1421
Synthetic Studies on Indolocarbazoles:
Total Synthesis of Staurosporine Aglycon
Ganesan Gobi Rajeshwaran 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 January 12, 2011
ABSTRACT
A synthesis of staurosporine aglycon and its analogs was achieved in a 28-36% overall yield starting from 2-methylindole. The prominent key
steps for the synthesis of the indolocarbazole alkaloids involved electrocyclization and nitrene insertion reactions.
Indolocarbazole alkaloids, which are obtained from
either soil organisms or marine sources, contain an indolo-
[2,3-a]carbazole core.1 Of these, staurosporine 1, a meta-
bolite from Streptomyces, is an ATP competitive inhibitor
which is highly potent against protein kinase C (PKC)
(IC50 = 1 nM)2 as well as an inhibitor of cyclin B/CDK1.3
Thus, Staurosporine has become an important lead
structure for the development of novel PKC inhibitors
such as compounds 2 and 3, which have shown higher
selectivity for PKC. These compounds also have anti-
tumor properties against various human cancer cell
lines.4 Another compound, in this important class is
rebeccamycin 4, which exhibits topoisomerase I inhibi-
tory activity (Figure 1).5
as a new class of D1/CDK4 as well as JAK3 inhibitors.7 In
addition to the biological activities, the indolocarbazole
analogs are also being explored for their optical applica-
tions such as FET and OTFT and also for solar cells.8
Prompted by the PKC and cyclin-dependent kinase
activity of indolocarbazoles, several approaches for
the synthesis of these alkaloids have been developed.1,6
(3) Rialet, V.; Meijer, L. Anticancer Res. 1991, 11, 1581–1590.
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Muller, M.; Caravatti, G.; Matter, A. Int. J. Cancer 1989, 43, 851–856.
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H.; Ohkubo, M. J. Med. Chem. 2009, 52, 3225–3237. (b) Teicher, B. A.
Biochem. Pharmacol. 2008, 75, 1262–1271. (c) Pommier, Y. Nat. Rev.
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A structure-activity relationship profile of related mole-
cules demonstrated that edotecarin 5 and its analogs are
more potent and specific topoisomerase I inhibitors than
rebeccamycin.6 Recently, 6-substituted indolocarbazole
aglycons 6 and their simplified analogs were characterized
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r
10.1021/ol200094b
Published on Web 02/22/2011
2011 American Chemical Society

cyclization using Pd-catalysts,11 and acid-catalyzed cy-
clization followed by aromatization.12 The synthesis
of indolocarbazoles has also been achieved through
nitrene13 and carbene14 insertion reactions and through
ring-closing metathesis.15 Recently, Orito and co-work-
ers achieved the staurosporinone framework by the
reduction of a 5-cyano indolo[2,3-a]carbazole followed
by a Pd-mediated carbonylation reaction.16 Howard-
Jones and Walls established a biosynthetic route to
staurosporine and rebeccamycin aglycons from chro-
mopyrrolic acid.17
It is important to bear in mind that most of the indolo-
carbazoles, which exhibit potent biological activities, have
substituents on the benzene portion of the core. Despite the
synthetic efforts for indolocarbazoles mentioned above,
there remains a need for a flexible and efficient route.
Previously, we reported the synthesis of quino[4,3-b]carba-
zole analogs,18 a precursor of calothrixin19 which involved
a thermal electrocyclization in the key step. In a continua-
tion of these synthetic studies on carbazole analogs,20 we
report herein our results on the assembly of an unsymme-
trical indolocarbazole framework from 2-methylindole.
This methodology involves thermal electrocyclization of
2,3-divinylindole 7 followed by allylic bromination and
amidation to give 9. The carbazole 9 was subjected to a
nitrene insertion reaction followed by hydrolysis to afford
the target compound 10 (Scheme 1).
Figure 1. Structures of biologically important indolocarbazoles.
€
Recently, Knolker and Reddy extensively reviewed the
synthesis and biological activity of carbazole alkaloids,
wherein different synthetic strategies for indolocarba-
zole alkaloids were discussed.9 The synthesis proto-
cols outlined to date for indolocarbazoles are based
on readily available bisindolylmaleimides and involve
electrocyclization under photochemical conditions,10
Scheme 1. Schematic Pathway for Staurosporine Aglycon
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Org. Lett., Vol. 13, No. 6, 2011
1419

Our synthesis of the desired 2-nitroarylcarbazole is
illustrated in Scheme 2. Reaction of 2-methylindole 11
2,3-divinylindoles 17a-f as yellow solids, which, upon
refluxing in xylene in the presence of 10% Pd-C, under-
went smooth electrocyclization followed by aromatization
to afford 2-nitroarylcarbazoles 18a-f. The structures of
carbazoles 18c, 18e, and 18f were confirmed by single
crystal X-ray analyses.23
Scheme 2. Synthesis of 2-Nitroarylcarbazoles
Scheme 3. Synthesis of Stauorsporine Aglycon
Withthe2-nitroarylcarbazoles inhand, furthersynthetic
elaboration was accomplished according toScheme 3. This
began by boiling a dilute solution of each 4-methylcarba-
zole18a-ewith2-3 equivofNBSinthe presenceofAIBN
to obtain the bromomethylcarbazoles 19a-e in good
yields. It should be noted that the allylic bromination of
4-methyl carbazole 18f was complicated by the preferential
bromination at the methylenedioxy unit. Reaction of
bromomethylcarbazoles 19a-e with aq. NH3 in dry
THF under reflux conditions underwent amination fol-
lowed by intramolecular cyclization to give amides 20a-e.
The reaction of 2-nitroarylcarbazoles 20a-e with triethyl-
phosphite using o-DCB as a solvent under reflux for 12 h
effected final ring closure and thus afforded indolocarba-
zoles 21a-e in excellent yields.
with ethylacetoacetate in the presence of 20 mol % FeCl3
furnished vinylindole 12 in 93% yield.21 Phenylsulfonyla-
tion of 12 under PTC conditions22 gave compound 13,
which could be preferentially brominated at the allylic
position using 1.1 equiv of NBS in the presence of catalytic
amounts of AIBN in CCl4 at reflux. Bromo compound 14,
which was isolated as a thick brown liquid, underwent a
Michaelis-Arbuzov reaction with triethylphosphite at 170 °C
for 2 h followed by workup to give phosphonate ester 15,
which was elaborated using a Wittig-Horner reaction
with 2-nitroarylaldehydes 16a-f. This was accomp-
lished using NaH as a base in dry THF and furnished
(16) Wada, Y.; Nagasaki, H.; Tokuda, M.; Orito, K. J. Org. Chem.
2007, 72, 2008–2014.
It should be noted that during the triethylphosphite-
mediated nitrene insertion of the 2-nitroarylcarbazoles
20a-e, we did not observe any N-ethylation as reported
by Moody and co-workers.13g Moreover, the ring closure
proceeded in quantitative yields compared to Moody’s
work wherein a low yield (37%) was reported. The ex-
cellent yield obtained in the present case might be due to
the nitrene insertion taking place meta- to the amide
carbonyl unlike Moody’s work wherein a similar reaction
proceeded at the para-position to the amide. Finally, the
cleavage of the phenylsulfonyl in 21a-e using K2CO3 in
MeOH-THF under reflux led to the formation of staur-
osporine aglycons 22a-e as brown solids. The structures
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(23) Structures of carbazoles were confirmed by single-crystal X-ray
data. CCDC numbers for 18c, 18e, and 18f are 804433, 805205, and
805204, respectively (see the Supporting Information).
1420
Org. Lett., Vol. 13, No. 6, 2011

the presence of a Lewis acid are outlined in Scheme 4.
Attempts to perform triethylphosphite-mediated nitrene
insertion of 2-nitroarylcarbazole 20a at 90-95 °C in the
presence of ZnBr2 led to a complex mixture. However, the
interaction of carbazoles 18a,b and 23a,b with triethyl-
phosphite in the presence of 1 equiv of ZnBr2 at 90-95 °C
for 12-15 h led to the formation of the respective
indolocarbazoles 24a-d in 85-91% yields. Next, the
Wittig-Horner reaction of 2-indolylmethylphospho-
nate ester 15/25 with 2-azidobenzaldehyde24 led to the
formation of the corresponding 2-azidophenylvinylin-
dole 26a/26b as a yellow solid. Upon refluxing a solu-
tion of 2-azidophenylvinylindole 26a/26b in o-DCB in
the presence of 10% Pd-C, indolocarbazole 24c/24a
were formed through consecutive electrocyclization and
nitrene insertion.
Scheme 4. Synthesis of Indolocarbazoles
In conclusion, a facile synthesis of staurosporine
aglycon and related indolocarbazole analogs was achi-
eved through thermal electrocyclization and nitrene
insertion reactions. For the first time, triethylpho-
sphite-mediated nitrene insertion of 2-nitroarylcarba-
zole was performed at a moderate temperature using
anhydrous ZnBr2 as a catalyst. An alternative protocol
for the synthesis of indolocarbazoles involving concur-
rent electrocyclization followed by nitrene insertion was
also achieved.
Acknowledgment. Financial assistance from the De-
partment of Science and Technology (DST) New Delhi is
acknowledged. The authors thank DST-FIST for the high-
resolution NMR facility. A.K.M. thanks Dr. Jacob M.
Hooker for critical reading of the manuscript. G.G.R.
thanks CSIR, New Delhi for an SRF fellowship.
of the indolocarbazoles 22a-e were confirmed by 1H
NMR, 13C NMR, and HRMS analyses.
Having assembled an indolocarbazole framework, our
results on triethylphosphite-mediated nitrene insertion in
Supporting Information Available. Experimental pro-
cedure along with characterization data, 1H and 13C
NMR spectra of all new compounds and HRMS spectra
of 22a-e, CIF files, and ORTEP diagrams. This material
is available free of charge via the Internet at http://pubs.
acs.org.
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5606.
Org. Lett., Vol. 13, No. 6, 2011
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