Concise total synthesis of calothrixins A and B

Article abstract of DOI:10.1021/ol201107a

The concise total synthesis of calothrixins A and B has been accomplished by utilizing the one-pot formation of hexatriene as a key intermediate via the palladium-catalyzed tandem cyclization/cross-coupling reaction of triethyl(indol-2-yl)borate. In anoth

Full text of DOI:10.1021/ol201107a

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3356–3359
Concise Total Synthesis of
Calothrixins A and B
Takumi Abe,† Toshiaki Ikeda,† Reiko Yanada,‡ and
Minoru Ishikura*,†
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido,
Ishikari-Tobetsu, Hokkaido 061-0293, Japan, and Faculty of Pharmaceutical Sciences,
Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112,
Japan
ishikura@hoku-iryo-u.ac.jp
Received April 27, 2011
ABSTRACT
The concise total synthesis of calothrixins A and B has been accomplished by utilizing the one-pot formation of hexatriene as a key intermediate
via the palladium-catalyzed tandem cyclization/cross-coupling reaction of triethyl(indol-2-yl)borate. In another key transformation, the indolo-
[3,2-j]phenanthridine core was prepared in high yield via Cu(I)-mediated 6π-electrocyclization.
Calothrixins A (1) and B (2), first isolated from cyano-
bacterium of the genus Calothrix in 1999,1 are character-
ized by a unique indolo[3,2-j]phenanthridine core, bearing
indole, quinoline, and quinone moieties (Figure 1). Both 1
and 2 inhibit the chloroquinone-resistant strain of malaria
parasitePlasmodium falciparum and showantiproliferative
properties against several cancer cell lines as well as human
DNA topoisomerase I poisoning activity.2 Owing to their
intriguing structural features and potential biological
activity, 1 and 2 are attractive targets for total synth-
esis. Beginning with the first total synthesis employing
ortholithiation methods by Kelly in 2000,3 several ap-
proaches to synthesizing 1 and 2 have been developed,4
including the biomimetic total synthesis of 2 reported
independently by Hibino’s and Moody’s groups.5
In our ongoing studies of trialkyl(indol-2-yl)borates,6
we previously found that indolylborates show high reactiv-
ity in palladium-catalyzed cross-coupling reactions, such as
(4) (a) For a review, see: Choshi, T.; Hibino, S. Heterocycles 2009, 77,
85–97. (b) Tohyama, S.; Choshi, T.; Matsumoto, K.; Yamabuki, A.;
Hieda, Y.; Nobuhiro, J.; Hibino, S. Heterocycles 2010, 82, 397–416. (c)
Bennasar, M. -L.; Roca, T.; Ferrando, F. Org. Lett. 2006, 8, 561–564. (d)
Bernardo, P. H.; Chai, C. L. L. J. Org. Chem. 2003, 68, 8906–8909. (e)
Bernardo, P. H.; Chai, C. L. L.; Elix, J. A. Tetrahedron Lett. 2002, 43,
2939–2940. (f) Sissouma, D.; Maingot, L.; Collet, S.; Guingant, A.
J. Org. Chem. 2006, 71, 8434–8389. (g) Tohyama, S.; Choshi, T.;
Matsumoto, K.; Yamabuki, A.; Ikegata, K.; Nobuhiro, J.; Hibino, S.
Tetrahedron Lett. 2005, 46, 5263–5264.
(5) (a) McErlean, C. S. P.; Sperry, J.; Blake, A. J.; Moody, C. J.
Tetrahedron 2007, 63, 10963–10970. (b) Sperry, J.; McErlean, C. S. P.;
Slawin, A. M. Z.; Moody, C. J. Tetrahedron Lett. 2007, 48, 231–234. (c)
Yamabuki, A.; Fujinawa, H.; Choshi, T.; Tohyama, S.; Matsumoto, K.;
Ohnuma, K.; Nobuhiro, J.; Hibino, S. Tetrahedron Lett. 2006, 47, 5859–
5861.
† Health Sciences University of Hokkaido.
‡ Hiroshima International University.
(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.
(2) (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) Khan, Q. A.; Lu, J.; Hecht, S. M. J. Nat. Prod. 2009, 72, 438–
442.
(3) Kelly, T. R.; Zhao, Y.; Cavero, M.; Torneiro, M. Org. Lett. 2000,
2, 3735–3737.
(6) For a review, see: Ishikura, M. Heterocycles 2011, 83, 247–273.
r
10.1021/ol201107a
Published on Web 05/31/2011
2011 American Chemical Society

Scheme 2. Prepation of Vinyl Bromide 7
Figure 1. Calothrixins A (1) and B (2).
carbonylative cross-coupling7 and tandem cyclization/
cross-coupling reactions,8 although tetravalent organobor-
on compounds (ate complexes) have proven to be less
practical for the palladium-catalyzed cross-coupling reac-
tions.9 Herein, we describe a new approach to synthesizing 1
and 2 via the palladium-catalyzed tandem cyclization/cross-
coupling reaction of triethyl(indol-2-yl)borate; this ap-
proach employs one-pot construction of a hexatriene as a
key intermediate in building the indolophenanthridine core.
The retrosynthetic analysis of 2 is shown in Scheme 1. We
envisioned that the palladium-catalyzed cyclization/cross-
coupling reaction of indolylborate 6 (generated in situ from
the corresponding indole) with bromide 7 could be used to
generate hexatriene 5 in a one-pot procedure, and that 5
could then be easily transformed into the indolophenanthri-
dine 4 through 6π-elecrocyclization. Subsequently, 4 would
be converted into calothrixin B (2) through quinone 3.
2-iodoaniline with 2-(prop-2-yn-1-yloxy)tetrahydro-2H-
pyran in the presence of PdCl2(PPh3)2 (3 mol %) and
CuI (10 mol %) in Et2NH at 40 °C for 1 h easily produced 8
in 80% yield. N-Acetylation of 8 with AcCl in CH2Cl2
afforded amide 9 in 85% yield, and the subsequent
Table 1. Palladium-Catalyzed Tandem
Cyclization/Cross-Coupling Reaction of 6 with 7
Scheme 1. Retrosynthetic Analysis of Calothrixin B (2)
yield (%)b
entry
conditionsa
5
11
1
2
Pd(OAc)2 (5 mol %), 0.5 h
Pd(OAc)2 (5 mol %), P(o-tol)3 (10 mol %),
0.5 h
42
55
5
8
3
4
5
6
PdCl2[P(o-tol)3]2 (5 mol %), 0.5 h
PdCl2(PPh3)2 (5 mol %), 2 h
Pd2(dba)3•CHCl3 (2.5 mol %)
Pd2(dba)3•CHCl3 (2.5 mol %),
PPh3 (10 mol %), 0.5 h
60
20
50
18
8
7
6
7
The preparation of the requisite bromide 7 is outlined
in Scheme 2. The Sonogashira coupling reaction of
7
Pd2(dba)3•CHCl3 (2.5 mol %),
P(o-tol)3 (10 mol %), 0.5 h
68
5
(7) Ishikura, M.; Terashima, M. J. Org. Chem. 1994, 59, 2634–2637.
(8) Ishikura, M.; Takahashi, N.; Yamada, K.; Yanada, R. Tetrahe-
dron 2006, 62, 11580–11591.
(9) (a) Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A. J. Am.
Chem. Soc. 1985, 107, 972–980. (b) Negishi, E.; Takahashi, T.; Baba, S.;
van Horn, D. E.; Okukado, N. J. Am. Chem. Soc. 1987, 109, 2393–2401.
(c) Sharma, S.; Oehlschlager, A. C. Tetrahedron Lett. 1988, 29, 261–264.
a Borate 6 [derived in situ from 10 (2 mmol), n-BuLi (2.4 mmol), and
BEt3 (2.4 mmol) in THF under an argon atmosphere] was treated with
bromide 7 (1 mmol) in the presence of a Pd complex (5 mol %). b Isolated
yield based on 7.
Org. Lett., Vol. 13, No. 13, 2011
3357

treatment of 9 with NaH and 2,3-dibromopropene in THF
gave bromide 7 in 80% yield.
The synthesis of 2 began with the palladium-catalyzed
tandem cyclization/cross-coupling reaction of indolylbo-
rate 6 with 7.
The treatment of 6 [generated in situ from 1-methoxyin-
dole (10) and n-BuLi in THF, followed by treatment with
BEt3] with7in the presence of a palladium complex (5 mol %)
in THF at 60 °C under an argon atmosphere produced triene
5 and a small amount of vinyl indole 11 (Table 1).
(entry 7); 5 was obtained in 18% and 50% yields in the
presence of Pd2(dba)3•CHCl3 (2.5 mol %) with and without
PPh3, respectively (entries 5 and 6).
The proposed catalytic cycle is shown in Scheme 3. The
coordination of the bulky P(o-tol)3 ligand to Pd shifts the
equilibrium between tetracoordinate complex A and tricoor-
dinate complex B toward the less crowded complex B.10 The
transfer of the indole ring from indolylborate 6 to the Pd of
complex B promptly occurs, leading to 5 via complex C.
Scheme 4. Total Synthesis of Calothrixins A (1) and B (2)
Scheme 3. Catalytic Cycle
Catalyst evaluation revealed that the presence of a bulky
P(o-tol)3 ligand was important for the successful Pd-cata-
lyzed cross-coupling reaction of 6 with 7. When the reac-
tion was carried out using Pd(OAc)2 (5 mol %), 5 was
obtained in 42% yield along with a small amount of 11
(5%) (entry 1). The combination of Pd(OAc)2 with 2P-
(o-tol)3 increased the yield of 5 to 55% (entry 2). As
compared with the reaction using PdCl2[P(o-tol)3]2 that
produced 5 in 60% yield, the reaction using PdCl2(PPh3)2
was slower and produced 5 in a low yield of 20% (entries 3
and 4). The reaction using Pd2(dba)3•CHCl3 (2.5 mol %) in
conjunction with P(o-tol)3 (10 mol %) resulted in the highest
yield of 5 (68%) along with a small amount of 11 (5%)
After removal of the O-THP group of 5 with CSA
(camphorsulfonic acid) in MeOH/CH2Cl2 (5:1), the con-
struction of indolophenanthridine 4 via cyclization of
hexatriene 12 was investigated (Scheme 4). As our previous
work in this area indicated that 12 should photochemically
cyclize to 4, the irradiation of 12 with a high-pressure
mercury lamp in benzene was first carried out.11 However,
the reaction producedonly a complex mixture. Inaddition,
the thermal reaction was attempted to convert 12 to 4,
(10) (a) Paul, F.; Patt, J.; Hartwig, J. F. Organometallics 1995, 14,
3030–3039. (b) Amator, C.; Jutand, A. J. Organomet. Chem. 1999, 576,
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Helv. Chim. Acta 2008, 91, 1828–1837.
3358
Org. Lett., Vol. 13, No. 13, 2011

without success. Although many examples of 6π-electro-
cyclization have been reported,12 we sought out the
feasibility of the Lewis acid mediated cyclization se-
quence.13 After screening various Lewis acids such as
In(OTf)3, [IrCpCl2]2, ZnBr2, and TiCl4, we found that a
(CuOTf)2•toluene complex was effective in promoting the
proposed cyclization. Treating 12 with the (CuOTf)2•tol-
uene complex (1 equiv) in MeCN at room temperature for
1 h produced 4 in 83% yield. Moreover, the reaction
worked well using a catalytic amount of the (CuOTf)2•tol-
uene complex (10 mol %) in MeCN under reflux for 16 h,
giving 4 in 72% yield. Althoughthere are some examples of
CuOTf-mediated olefin photocycloaddition reactions,14 to
our knowledge, use of Cu(OTf) as a mediator for 6π-
electrocyclization is unprecedented.
this stage, we found that Dakin oxidation15 of 13 [30%
H2O2, (PhSe)2 (10 mol %), and then 10% NaOH under
O2] led to the one-pot production of quinone 3 in 53%
yield and aldehyde 14 in 18% yield, accompanied by in
situ N-Ac deprotection and oxidation. Aldehyde 14 was
transformed into 3 in 67% yield by oxidation with
(PhSe)2 (30 mol %) and 30% H2O2 in CH2Cl2 at
room temperature for 48 h. Finally, the N-OMe group
of 3 was easily removed by catalytic hydrogenation
over 10% Pd/C in AcOEt, providing calothrixin B (2) in
85% yield. Furthermore, the oxidation of 2 by treat-
ment with dimethyl dioxirane,16 prepared in situ from
oxone and acetone in the presence of K2CO3, at room
temperature for 16 h gave calothrixin A (1) in 70%
yield.
With pentacycle 4 in hand, the subsequent conversion of
4 to calothrixin B (2) was achieved in a three-step sequence
(Scheme 4). The oxidation of the primary alcohol of 4 with
PCC in CH2Cl2 readily gave aldehyde 13 in 80% yield. At
In summary, we have demonstrated a new approach to
synthesizing calothrixins A (1) and B (2) through the
palladium-catalyzedtandemcyclization/cross-couplingre-
action of indolylborate 6 by taking advantage of the one-
pot generation of the key intermediate 5 for constructing
indolophenanthridine 4. In addition, the unprecedented
use of CuOTf for the 6π-elecrocyclization of 12 to 4 was
developed. Further synthetic studies of this cross-coupling
protocol are in progress.
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Walton, M. C.; Hsung, R. P.; Schwab, J. H.; Yu, X. Org. Lett. 2010, 12,
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Acknowledgment. This work was supported in part by
the Ministry of Education, Culture, Sports, Sciences and
Technology of Japan through a Grant-in Aid for Scientific
Research (No. 22590010).
Supporting Information Available. Experimental pro-
cedures and characterization data for products and iso-
lated intermediates. This material is available free of
charge via the Internet at http://pubs.acs.org.
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