A synthesis of calothrixin B

Article abstract of DOI:10.1055/s-2004-834831

A new short and efficient synthesis of calothrixin B is reported. The key reaction is a hetero-Diels-Alder reaction between 3-bromo-9H-carbazole-1,4-dione and a 'push-pull' 2-aza-1,3-diene.

Full text of DOI:10.1055/s-2004-834831

2
612
LETTER
A Synthesis of Calothrixin B
A
D
S
ynthesis of Cal
r
othrixin
iB
ssa Sissouma, Sylvain C. Collet, André Y. Guingant*
Laboratoire de Synthèse Organique, UMR CNRS 6513, FR CNRS 2465, Faculté des Sciences et des Techniques, 2, rue de la Houssinière,
BP 92208, 44322 Nantes Cedex 03, France
Fax +33(2)51125402; E-mail: guingant@chimie.univ-nantes.fr
Received 29 July 2004
Hetero-Diels–Alder reaction
Abstract: A new short and efficient synthesis of calothrixin B is
O
NMe2
reported. The key reaction is a hetero-Diels–Alder reaction between
O
3
-bromo-9H-carbazole-1,4-dione and a ‘push-pull’ 2-aza-1,3-di-
N
N
Br
ene.
N
+
H
Key words: calothrixin B, hetero-Diels–Alder reaction, 2-aza-1,3-
diene, natural product
N
O
Bn
O
O
Calothrixin B 1
2
3
Calothrixin B (1) and its N-oxide derivative (calothrixin
A) are natural products obtained in 1999 from the cell ex-
1
tracts of Calothrix cyanobacteria. These metabolites dis-
O
play impressive in vitro cytotoxicity against HeLa cancer
cells in the nanomolar range and also inhibit the growth of
a chloroquine-resistant strain of the malaria parasite
N
N
2
Plasmodium falciparum. The calothrixins feature an
Bn
O
amazing and unprecedented indolo[3,2-j]phenanthridine
framework which, in addition to their remarkable biolog-
ical activities, makes them interesting targets for synthetic
organic chemists. We report herein on a new and efficient
O
4
Scheme 1 Synthetic strategy to calothrixin B.
3
synthesis of calothrixin B which is inspired by our recent
these conditions, 9a could be cleanly accessed in 94% iso-
lated yield. Conversion of 9a into 3-bromo-9H-carbazole-
,4-dione (2) was first attempted under the conditions of
the Grunwell reaction, e.g. treatment with an excess of
NBS (4 equiv) in acetic acid. Although this protocol
proved successful, compound 2 was accompanied by a
results obtained in the field of angucycline aza-ana-
4
logues. Based on these results, we thus believed that a
1
hetero-Diels–Alder reaction between 3-bromo-9H-carba-
zole-1,4-dione (2) and ‘push-pull’ 2-aza-1,3-diene 3
would allow to assemble the core of the natural product in
one single operation as depicted in Scheme 1. Following
this strategy, the expected Diels–Alder adduct 4 could be
used to access 1 after oxidation state adjustment and in-
dole nitrogen protecting group removal.
5
6
product of over-bromination, 10, from which it could be
separated by column chromatography only with difficulty
(
60% isolated yield).
4
Looking for a more convenient route to 2, which would
avoid the formation of the undesirable 10, 9a was exposed
to half an equivalent of NBS to afford the 9-benzyl-3-
Since we already synthesised diene 3, the first synthetic
task was to prepare the bromo-activated dienophile 2
Scheme 2). Toward this end, commercially available car-
bazole 5 was exposed to the action of DDQ in THF–H O
to form the 1,2,3,9-tetrahydro-carbazol-4-one (6), which
was next protected under the form of a N-benzyl deriva-
tive 7. Full aromatisation of 7 to give the 9-benzyl-9H-
7
(
bromo-9H-carbazol-4-ol (11) in 80% yield (based on
2
8
reacting 9a). Its transformation into the desired 2 was
subsequently accomplished by treatment with diacetoxy-
iodobenzene as shown in Scheme 3.
carbazol-4-ol (9a) could be accomplished in the presence With both diene 3 and dienophile 2 in hand, we were in a
of Pd/C in diphenyl ether at 250 °C. However, a major position to effect the key [4+2] cycloaddition reaction. As
drawback of this procedure was the concomitant forma- anticipated, stirring both entities in acetonitrile at 40 °C
tion of the N-debenzylated product 9b (ratio 1:1).
for 48 hours delivered the aza-angucycline-like adduct 4
in 80% yield.9 Having synthesised this key element, fi-
nal modifications to reach the calothrixin B seemed rela-
tively easy to achieve. First, aromatisation of 4 into 12
was accomplished in 73% yield by heating at 250 °C in
diphenyl ether for 15 minutes. In contrast to the behaviour
of compound 7, no trace of N-debenzylated product was
detected in that case. Excision of the superfluous hydroxyl
group to give N-benzyl calothrixin B (14) was efficiently
,10
Therefore, we came to favour a two-step procedure con-
sisting of the formation of a-keto sulfoxide 8 (not isolat-
ed) followed by its easy aromatisation in THF at reflux. In
SYNLETT 2004, No. 14, pp 2612–2614
2
2
.1
1
.2
0
0
4
Advanced online publication: 20.10.2004
DOI: 10.1055/s-2004-834831; Art ID: D21404ST
©
Georg Thieme Verlag Stuttgart · New York

LETTER
A Synthesis of Calothrixin B
2613
O
O
SOPh
i
iii
N
N
Z
N
H
Bn
5
6 Z = H
Z = Bn
8
ii
7
HO
O
O
Br
Br
Br
iv
+
N
N
Bn
N
O
O
R
Bn
9
a R = Bn
2
10
9
b R = H
Scheme 2 Synthesis of dienophile 2 (first route). Reagents and conditions: (i) DDQ, THF–H O, 0 °C, (91%); (ii) NaH, DMF, BnBr, 0–20 °C,
2
(
92%); (iii) NaH, THF, PhSO Me, 20 °C then reflux, (94%); (iv) NBS (4 equiv), HOAc, 20 °C (2: 60%).
2
HO
HO
O
Br
Br
ii
i
N
N
N
O
Bn
Bn
Bn
9
a
11
2
Scheme 3 Synthesis of dienophile 2 (second route). Reagents and conditions: (i) NBS (0.5 equiv), MeCN, 20 °C, (80%); (ii) DAIB, HOAc–
TFA, 20–50 °C, (96%).
O
O
O
i
N
ii
N
iv
4
1
N
N
Bn
Bn
O
HO
R
1
2
13 R = OTf
4 R = H
iii
1
Scheme 4 The final steps to calothrixin B. Reagents and conditions: (i) Pd/C 10%, PhOPh, 250 °C, 15 min, (73%); (ii) TfOTf, Et N, CH Cl ,
3
2
2
–
78 °C to 20 °C, (100%); (iii) Pd(PPh ) , dioxane, 60 °C, (95%); (iv) AlCl (5 equiv), Ph-H, reflux, 2 h, (57%).
3
4
3
accomplished in a two-step operation involving triflate Acknowledgment
formation (→ 13) and subsequent palladium-mediated re-
The support of the ‘Région des Pays de la Loire’ (CER 2000-2006)
is gratefully acknowledged. D.S is thankful to the AUF (Agence
Universitaire pour la Francophonie) for a Postdoctoral Fellowship.
1
1
duction. The remaining N-debenzylation step proved
unexpectedly difficult. After numerous experiments we
finally found that it could be achieved in 57% isolated
yield by exposure of 14 to an excess of AlCl in benzene
at reflux (Scheme 4).
3
1
2
References
(
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.
In conclusion, a convergent and efficient synthesis of
calothrixin B has been achieved. A key feature of this syn-
thesis includes a [4+2] cycloaddition between 3-bromo-
(
2) (a) Doan, N. T.; Rickards, R. W.; Rothschild, J. M.; Smith,
G. D. J. Appl. Phycol. 2000, 12, 409. (b) Doan, N. T.;
Stewart, P. R.; Smith, G. D. FEMS Microbiol. Lett. 2001,
196, 135.
9
H-carbazole-1,4-dione (2) and 2-aza-1,3-diene (3) for
the regioselective construction of the five-ring framework
of the natural product. We believe that the developed
chemistry could facilitate the synthesis of a small library
of structural analogues of calothrixin B for biological
evaluation.
(3) Previous syntheses of calothrixins A and B: (a) Kelly, T. R.;
Zhao, Y.; Cavero, M.; Torneiro, M. Org. Lett. 2000, 2,
3735. (b) Bernardo, P. H.; Chai, C. L. L.; Elix, J. A.
Tetrahedron Lett. 2002, 43, 2939. (c) Bernardo, P. H.; Chai,
C. L. L. J. Org. Chem. 2003, 68, 8906.
Synlett 2004, No. 14, 2612–2614 © Thieme Stuttgart · New York

2
614
D. Sissouma et al.
LETTER
(
4) Collet, S. C.; Rémi, J. F.; Cariou, C.; Laïb, S.; Guingant, A.
a solution of 9-benzyl-3-bromo-9H-carbazole-1,4-dione 2
(0.55 mmol) in dry MeCN (4 mL) was added at r.t. with
stirring. After 48 h at 40 °C, the solvent was removed under
reduced pressure. The residue was purified by silica gel
chromatography (CH Cl –EtOAc = 95:5) to give the
Y.; Wu, N. Q.; Dujardin, G. Tetrahedron Lett. 2004, 45,
4
911.
5) Heinzman, S. W.; Grunwell, J. R. Tetrahedron Lett. 1980,
1, 4305.
(
(
(
(
2
2
2
6) The position of the bromine atom on the phenyl ring has not
yet been established with certainty.
7) Poumaroux, A.; Bouaziz, Z.; Domard, M.; Fillion, H.
Heterocycles 1997, 43, 585.
cycloadduct 4 as an orange powder (80% yield); mp 118 °C.
1
H NMR (300 MHz, CDCl ): d = 2.27 (quint, 2 H, J = 6.6
3
Hz, CH ), 2.93 (t, 2 H, J = 6.6 Hz, CH ), 3.18 (t, 2 H, J = 6.6
2
2
Hz, CH ), 5.89 (s, 2 H, CH N), 7.20–7.32 (m, 5 H, H-Ar),
2
2
8) 9-Benzyl-3-bromo-9H-carbazole-1,4-dione (2): red
7.40–7.47 (m, 3 H, H-Ar), 8.43 (d, 1 H, J = 7.8 Hz, H-Ar),
1
13
needles; mp 208 °C. H NMR (300 MHz, CDCl ): d = 5.84
9.41 (s, 1 H, CH=N). C NMR (75 MHz, CDCl ): d = 21.4,
3
3
(
s, 2 H, CH N), 7.14 (d, 2 H, J = 7.6 Hz, H-Ar), 7.17 (s, 1 H,
33.1, 39.2, 48.6, 111.7, 118.4, 123.6, 123.9, 125.1, 126.8,
127.0 (2 C), 128.0, 128.1, 128.2, 128.9 (2 C), 135.6, 136.0,
140.0, 140.7, 150.3, 168.2, 177.5, 179.3, 198.3. FT-IR
2
CH=), 7.26–7.29 (m, 3 H, H-Ar), 7.37–7.46 (m, 3 H, H-Ar),
1
3
8
.31 (d, 1 H, J = 7.6 Hz, H-Ar). C NMR (100 MHz,
–
1
CDCl ): d = 48.4, 111.8, 116.4, 123.4, 124.4, 125.3, 126.9 (2
(KBr): 3041, 2958, 1702, 1666, 1569, 1509, 743 cm . MS
3
+
C), 127.7, 128.1, 129.0 (2 C), 133.3, 136.0, 137.4, 139.3,
(EI, 70 eV): m/z (%) = 406 (100) [M ], 378 (21), 315 (6), 287
1
1
3
40.4, 175.2, 178.2. FT-IR (KBr): 3036, 1663, 1646, 1583,
(2), 91 (93). HRMS (EI): m/z calcd for C H N O :
406.1317. Found: 406.133 [M ].
2
6
18
2
3
–1
+
81
+
518 cm . MS (EI, 70 eV): m/z (%) = 367 (11) [M , Br],
+
79
65 (11) [M , Br], 91 (100). HRMS (EI): m/z calcd for
(10) Compound 4 was formed along with the product arising
from the addition of dimethylamine to 2 (13%).
(11) (a) Hirota, K.; Isobe, Y.; Maki, Y. J. Chem. Soc., Perkin
Trans. 1 1989, 2513. (b) Cacchi, S.; Ciattini, P. G.; Morera,
E.; Ortar, G. Tetrahedron Lett. 1986, 27, 5541.
79
+
C H NO Br: 365.0051. Found: 365.006 [M ].
19
12
2
(
9) At this stage, the regioselectivity of the cycloaddition could
not be determined by inspection of NMR data. The structure
of adduct 4 was tentatively assigned on the basis of the usual
4
bromine directing effect and confirmed later by the
obtention of calothrixin B.
(12) Murakami, Y.; Watanabe, T.; Kobayashi, A.; Yokoyama, Y.
Synthesis 1984, 738.
Experimental Procedure for the Synthesis of 12-Benzyl-
2,3,4,7,12,13-hexahydro-1H-indolo[3,2-j]phen-
anthridine-1,7,13-trione (4):
To a solution of diene 3 (0.60 mmol) in dry MeCN (4 mL),
Synlett 2004, No. 14, 2612–2614 © Thieme Stuttgart · New York