A new radical-based route to calothrixin B

Article abstract of DOI:10.1021/ol052600e

A high-yielding totally regioselective intramolecular homolytic acylation of a quinoline ring constitutes the key step in a new synthesis of the pentacyclic indolo[3,2-j]phenanthridine alkaloid calothrixin B.

Full text of DOI:10.1021/ol052600e

ORGANIC
LETTERS
2006
Vol. 8, No. 4
561-564
A New Radical-Based Route to
Calothrixin B
M.-Llu1ısa Bennasar,* Toma`s Roca, and Francesc Ferrando
Laboratory of Organic Chemistry, Faculty of Pharmacy, UniVersity of Barcelona,
Barcelona 08028, Spain
bennasar@ub.edu
Received October 27, 2005
ABSTRACT
A high-yielding totally regioselective intramolecular homolytic acylation of a quinoline ring constitutes the key step in a new synthesis of the
pentacyclic indolo[3,2-j]phenanthridine alkaloid calothrixin B.
Calothrixin B and its N-oxide derivative (calothrixin A) are
quinone-based natural products isolated in 1999 from the
cyanobacteria Calothrix1 that display potent antimalarial and
anticancer properties.2 Owing to their striking biological
activities as well as their pentacyclic indolo[3,2-j]phenan-
thridine skeleton, unprecedented among natural products,3
calothrixins have attracted the synthetic interest of several
research groups. Thus, four syntheses of calothrixins have
been reported to date relying on the strategies depicted in
Figure 1. In 2000, Kelly et al.4 and two years later Chai et
al.5 synthesized calothrixin B and A by taking advantage of
elegant metalation techniques, inspired in earlier syntheses
of ellipticine quinones,6 to assemble the indole and the
quinoline nucleus (last bond formed C12a-C13, bond a). More
recently, Guingant et al.7 and Hibino et al.8 accomplished
the synthesis of calothrixin B by means of completely
different strategies, such as a hetero-Diels-Alder reaction
(bonds C6-C6a and C13a-C13b, bonds b) and a final formation
of the quinoline ring from an appropriately substituted
carbazole (bond C5-C6, bond c), respectively. In this context,
we envisaged an alternative approach to the pentacyclic
skeleton of calothrixin B, in which the central carbocyclic
ring would be closed in the last synthetic steps by homolytic
acylation of the 4-position of the quinoline ring (bond formed
C13-C13a, bond d). In this manner, an electron-deficient
quinoline ring would react with a nucleophilic acyl radical,9
which could be considered as the umpolung of the intramo-
lecular Friedel-Crafts acylation.
Intramolecular homolytic aromatic substitutions by nu-
cleophilic carbon-centered radicals have become an important
(1) Rickards, R. W.; Rothschild, J. M.; Willis, A. C.; de Chazal, N. M.;
Kirk, J.; Saliba, K. J.; Smith, G. D. Tetrahedron 1999, 55, 13513-13520.
(2) Bernardo, P. H.; Chai, C. L. L.; Heath, G. A.; Mahon, P. J.; Simith,
G. D.; Waring, P.; Wilkes, B. A. J. Med. Chem. 2004, 47, 4958-4963 and
references therein.
(3) For a previous approach to the pentacyclic system of calothrixins,
see: Mohanakrishnan, A. K.; Srinivasan, P. C. J. Org. Chem. 1995, 60,
1939-1946.
(4) Kelly, T. R.; Zhao, Y.; Cavero, M.; Torneiro, M. Org. Lett. 2000, 2,
3735-3737.
(5) (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.
(6) (a) Watanabe, M.; Snieckus, V. J. Am. Chem. Soc. 1980, 102, 1457-
1460. (b) Ketcha, D. M.; Gribble, G. W. J. Org. Chem. 1985, 50, 5451-
5457.
Figure 1. Calothrixins. Synthetic strategies.
10.1021/ol052600e CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/25/2006

tool for the construction of otherwise quite inaccessible
substituted heterocycles.10,11 However, to our knowledge, the
use of quinolines as substrates in intramolecular processes
has been limited to the reaction with aryl radicals under
reductive (tributyltin hydride) conditions.12 In fact, most
reported examples deal with intermolecular reactions con-
ducted in acidic media under oxidative protocols.13
Scheme 1. Preparation of the Radical Precursors
In the past few years, we have been studying the generation
of 2-indolylacyl radicals from the corresponding phenyl
selenoesters and their reaction with alkenes under reductive
conditions.14 Cyclization upon aromatic rings was also
possible,15 but under nonreductive (hexabutylditin/hν) condi-
tions, producing benzocarbazolediones16 and ellipticine quino-
nes17 in moderate yields. Based on these results, we expected
that the related quinoline-containing radicals would partici-
pate in similar cyclizations, ultimately leading to the carba-
zoledione moiety characteristic of calothrixin B.
Our investigation began with the preparation of selenoester
8, a model radical precursor bearing the required (3-
quinolyl)methyl moiety connected to the indole 3-position.18
This compound was easily accessible from N-methylindole
1 as depicted in Scheme 1. Chemoselective reaction with
3-lithio-2-bromoquinoline, followed by triethylsilane reduc-
tion of the resulting carbinol provided 2-bromoquinoline 3,
which was converted into methyl ester 5 upon reduction.
Subsequent hydrolysis of 5, followed by phenylselenation
of the respective carboxylic acid gave the target compound
8.
(7) Sissouma, D.; Collet, S. C.; Guingant, A. Y. Synlett 2004, 2612-
2614.
(8) Tohyama, S.; Choschi, T.; Matsumoto, K.; Yamabuki, A.; Ikegata,
K.; Nobuhiro, J.; Hibino, S. Tetrahedron Lett. 2005, 46, 5263-5264.
(9) For reviews on acyl radicals, see: (a) Ryu, I.; Sonoda, N.; Curran
D. P. Chem. ReV. 1996, 96, 177-194. (b) Chatgilialoglu, C.; Crich, D.;
Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99, 1991-2069.
(10) For reviews, see: (a) Studer, A.; Bossart, M. In Radicals in Organic
Synthesis; Renaud, P.; Sibi, M. P., Eds; Wiley-VCH: Weinheim, 2001;
Vol. 2, pp 62-80. (b) Bowman, W. R.; Fletcher, A. J.; Potts, G. B. S. J.
Chem. Soc., Perkin Trans. 1 2002, 2747-2762.
(11) For more recent representative leading references, see: (a) Menes-
Arzate, M.; Mart´ınez, R.; Cruz-Almanza, R.; Muchowski, J. M.; Osornio,
Y. M.; Miranda, L. D. J. Org. Chem. 2004, 69, 4001-4004. (b) Bacque´,
E.; El Qacemi, M.; Zard, S. Z. Org. Lett. 2004, 6, 3671-3674. (c) Nu´n˜ez,
A.; Sa´nchez, A.; Burgos, C.; Alvarez-Builla, J. Tetrahedron 2004, 60, 6217-
6224. (d) Ohno, H.; Iwasaki, H.; Eguchi, T.; Tanaka, T. Chem. Commun.
2004, 2228-2229. (e) Allin, S. M.; Bowman, W. R.; Elsegood, M. R. J.;
McKee, V.; Karim, R.; Rahman, S. S. Tetrahedron 2005, 61, 2689-2696.
(f) Murphy, J. A.; Tripoli, R.; Khan, T. A.; Mali, U. W. Org. Lett. 2005, 7,
3287-3289. (g) Crich, D.; Patel, M. Org. Lett. 2005, 7, 3625-3628. (h)
Taniguchi, T.; Iwasaki, K.; Uchiyama, M.; Tamura, O.; Ishibashi, H. Org.
Lett. 2005, 7, 4389-4390.
(12) (a) Harrowven, D. C.; Sutton, B. J.; Coulton, S. Tetrahedron Lett.
2001, 42, 2907-2910. (b) Harrowven, D. C.; Sutton, B. J.; Coulton, S.
Tetrahedron 2002, 58, 3387-3400. For a review, see: (c) Harrowven, D.
C.; Sutton, B. J. In Progress in Heterocyclic Chemistry; Gribble, G. W.,
Joule, J. A., Eds.; Elsevier: Amsterdam, 2004; Vol. 16, pp 27-53.
(13) (a) Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28,
489-519. (b) Minisci, F.; Fontana, F.; Pianese, G.; Yan, Y. M. J. Org.
Chem. 1993, 58, 4207-4211. (c) Minisci, F.; Recupero, F.; Ceccheto, A.;
Punta, C.; Gambarotti, C.; Fontana, F.; Pedulli, G. F. J. Heterocycl. Chem.
2003, 40, 325-328.
N-Methylselenoester 8 was first allowed to react under
conditions similar to those reported in our earlier work, i.e.,
with n-Bu6Sn2 under 300 W sun lamp irradiation. However,
after irradiation and heating at 80 °C for 24 h, we obtained
a complex reaction mixture of unidentified products, the
expected quinone only being detected in trace amounts. As
this disappointing result might be related with an increased
reactivity of the quinoline with respect to the pyridine or
phenyl rings, we turned to reductive conditions, hoping that
the cyclization would now be fast enough to avoid the
premature reduction of the initially formed acyl radical. We
were pleased to find that treatment of selenoester 8 with tris-
(trimethylsilyl)silane19 (TTMSS) and azobisisobutyronitrile
(AIBN, 2.5 molar equiv) at 80 °C for 8 h led to the
calothrixin-related pentacycle 10 in 65% isolated yield
(Scheme 2). The rather surprising structure of 10, incorporat-
ing the 2-cyano-2-propyl moiety of the initiator, was
Scheme 2. Cyclization in the N-Methyl Series
(14) (a) Bennasar, M.-L.; Roca, T.; Griera, R.; Bosch, J. Org. Lett. 2001,
3, 1697-1700. (b) Bennasar, M.-L.; Roca, T.; Griera, R.; Bosch, J. J. Org.
Chem. 2001, 66, 7547-7551. (c) Bennasar, M.-L.; Roca, T.; Ferrando, F.
Org. Lett. 2004, 6, 759-762.
(15) For previous cyclizations of acyl radicals upon indoles and pyrroles
under n-Bu3SnH-AIBN conditions, see: (a) Miranda, L. D.; Cruz-Almanza,
R.; Pavo´n, M.; Alva, E.; Muchowski, J. M. Tetrahedron Lett. 1999, 40,
7153-7157. (b) Allin, S. M.; Barton, W. R. S.; Bowman, W. R.; McInally,
T. Tetrahedron Lett. 2001, 42, 7887-7890.
(16) Bennasar, M.-L.; Roca, T.; Ferrando, F. Tetrahedron. Lett. 2004,
45, 5605-5609.
(17) Bennasar, M.-L.; Roca, T.; Ferrando, F. J. Org. Chem. 2005, 70,
9077-9080.
(18) The placement of a carbonyl group in the tether chain was discarded
as it would probably diminish the reactivity of the acyl radical.
562
Org. Lett., Vol. 8, No. 4, 2006

established by a combination of HSQC and HMBC experi-
ments. As expected, 10 could be converted into N-methyl-
calothrixin (11) by treatment with KOH in MeOH, through
a process involving a gramine-type nucleophilic substitution
(elimination-addition via a 3-alkylideneindolenine) and the
spontaneous oxidation of the resulting carbinol (95% yield).
Formation of pentacycle 10 was consistent with the radical
addition-rearomatization-overoxidation sequence depicted
in Scheme 3. Thus, the initially formed radical A, coming
In the above sequential events leading to 10, TTMSS
would only participate in the initial generation of the
2-indolylacyl radicals. So, we wondered if we could promote
a metal-free23 homolytic sequence in the presence of AIBN
acting as the oxidant, accomplishing the initial homolysis
of the C-Se bond under simple irradiation.9,24 Our reasoning
proved to be correct as cyclization did take place when
selenoester 8 and AIBN were irradiated (300 W sun lamp)
at 80 °C in benzene.25 Consumption of the starting product
required longer reaction times (12 h) than under the above
reductive conditions and the slow addition of higher amounts
of the reagent (0.5 molar equiv every 1.5 h up to a total of
4 molar equiv).26 Interestingly, after the extractive workup
Scheme 3. Probable Mechanism
1
the crude reaction product was shown by H NMR to be a
1:1 mixture of the pentacycle 10 and N-methylcalothrixin
(11), thus indicating that complete oxidation to the quinone
system had taken place under the reaction conditions.
Treatment of this mixture with KOH in MeOH as above
allowed the isolation of 11 in 75% overall yield from 8.
At this point, access to the natural product calothrixin B
required the extension of the chemistry outlined above to a
radical precursor suitably protected at the indole nitrogen.
To this end, we focused our attention on N-(methoxymethyl)-
selenoester 9, which was prepared from indole 2 by a
synthetic route parallel to that previously used in the model
series (Scheme 1). The overall yield through synthetic
intermediates 4, 6, and 7 was 42%.
To our delight, N-MOM-substituted 2-indolylacyl radicals
generated from selenoester 9 under reductive conditions
(TTMSS, AIBN, 2 molar equiv, 80 °C, 4 h) underwent
cyclization with an even higher efficiency than their N-methyl
counterparts. Nevertheless, the reaction followed a different
course since pentacyclic phenol 12, a fully aromatic tauto-
meric form of D (R ) MOM, Scheme 3) was isolated in a
yield as high as 90% (Scheme 4).27 The reaction was clean
Scheme 4. Synthesis of Calothrixin B
from the abstraction of the phenylseleno group by the silyl
radical, undergoes regioselective cyclization upon the 4-posi-
tion of the quinoline ring to give the azacyclohexadienyl
radical B. Considering the numerous precedents of homolytic
aromatic substitutions under apparently reductive condi-
tions,10,11 this radical (or the tautomeric benzhydryl radical
C) is probably oxidized by hydrogen-atom abstraction at the
hands of the initiator AIBN.20,21 A new hydrogen-atom
abstraction at the doubly benzylic position of pentacycle D,
for instance by 2-cyano-2-propyl radicals, would lead to the
radical E, which would be intercepted by AIBN.22
and showed no indication of byproducts coming from either
the alternative mode of addition at the quinoline 2-position
or overoxidation. On the other hand, upon application of the
(19) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188-194.
(20) For a discussion, see: Beckwith, A. L. J.; Bowry, V. W.; Bowman,
W. R.; Mann, E.; Parr, J.; Storey, J. M. D. Angew. Chem., Int. Ed. 2004,
43, 95-98 and references therein.
(21) Azo compounds have been shown to abstract hydrogen from the
benzhydryl radical to yield benzophenone and hydrazines: Engel, P. S.;
Wu, W.-X. J. Am. Chem. Soc. 1989, 111, 1830-1835.
(22) For the isolation of AIBN-containing byproducts in related radical
cyclizations, see: (a) Bennasar, M.-L.; Roca, T.; Griera, R.; Bassa, M.;
Bosch, J. J. Org. Chem. 2002, 67, 6268-6271. (b) See also ref 14b.
Org. Lett., Vol. 8, No. 4, 2006
563

AIBN/sun lamp irradiation protocol phenol 12 was also
isolated as the only product, although in a lower yield (50%).
Clearly, AIBN (or 2-cyano-2-propyl radicals) is not able
to overoxidize the initially formed cyclization product in this
series, i.e., phenol 12, which would be in the most favored
tautomeric form, perhaps because of the establishment of a
hydrogen bond between the hydroxy and methoxy group.
From the synthetic standpoint, this was not a serious
limitation since phenol 12 could be converted in a nearly
quantitative yield into N-MOM calothrixin (13), a known
immediate precursor of calothrixin B,4,5 by mild oxidation
with molecular oxygen in basic medium.28
In conclusion, we have shown that the cyclization of 3-(3-
quinolyl)methyl-2-indolylacyl radicals under TTMSS-AIBN
conditions provides an efficient synthetic entry to calothrixin-
related pentacycles, which are obtained in a different
oxidation state depending on the substitution at the indole
nitrogen. The reactions can also be performed under a new
metal-free protocol that illustrates the determinant role of
AIBN in homolytic aromatic substitutions. Starting from
N-MOM substrates, we have accomplished a new synthesis
of calothrixin B, thus highlighting the strong potential of
cyclizations of 2-indolylacyl radicals upon aromatic systems
for the construction of polycyclic indole compounds.
(23) Baguley, P. A.; Walton, J. C. Angew. Chem., Int. Ed. 1998, 37,
3072-3082.
Acknowledgment. Financial support from the Ministerio
de Ciencia y Tecnolog´ıa (MCYT-FEDER, Spain) through
Project No. BQU2003-04967-C-02-02 is gratefully acknowl-
edged. F.F. also thanks the University of Barcelona for a
grant.
(24) For the generation of acyl radicals by photolysis of acyl tellurides,
see: Crich, D.; Chen, C.; Hwang, J.-T.; Yuan, H.; Papadatos, A.; Walter,
R. I. J. Am. Chem. Soc. 1994, 116, 8937-8951.
(25) No cyclization was observed when selenoester 8 was irradiated at
80 °C without AIBN or when heated in the presence of AIBN without
irradiation.
(26) The half-life for decomposition of AIBN is 2 h at 80 °C: Walling,
C. Tetrahedron 1985, 41, 3887-3900.
Supporting Information Available: Experimental details
and spectroscopic and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(27) The use of n-Bu3SnH instead of TTMSS led to phenol 12 in a lower
yield (70%).
(28) For related oxidations in basic medium, see: (a) Asche, C.; Frank,
W.; Albert, A.; Kucklaender, U. Bioorg. Med. Chem. 2005, 13, 819-837.
(b) Tao, Z.-F.; Sowin, T. J.; Lin, N.-H. Tetrahedron Lett. 2005, 46, 7615-
7618.
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