Synthesis of a calothrixin B isomer with a novel 7H-indolo[2,3-j] phenanthridine-7,13(8H)-dione structure

Article abstract of DOI:10.1055/s-2007-1000933

Synthesis of an N-protected 2-bromo- 1H-carbazole-1,4(9H)-dione is reported for the first time. We took full advantage of the high polarization and electrophilic properties of this new compound to engage it in a regioselective hetero-Diels-Alder reaction. The resultant cycloadduct was next transformed to an isomer of the naturally occurring calothrixin B displaying a new 7H-indolo[2,3-j]phenanthridine-7,13(8H)-dione structure. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000933

LETTER
263
Synthesis of a Calothrixin B Isomer with a Novel 7H-Indolo[2,3-j]phenanthri-
dine-7,13(8H)-dione Structure
Synthesis of
a
C
u
a
lothrixin B
c
Isome
r
ie Maingot,a Frédéric Thuaud,a Drissa Sissouma,a,b Sylvain Collet,*a André Guingant,*a Michel Evainc
a
Laboratoire de Synthèse Organique (LSO), Faculté des Sciences et des Techniques, Université de Nantes, Nantes Atlantique Universités,
CNRS, UMR CNRS 6513, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France
Fax +33(2)51125402; E-mail: Sylvain.Collet@univ-nantes.fr; E-mail: Andre.Guingant@univ-nantes.fr
Laboratoire de Chimie Organique Structurale, UFR SSMT, Université de Cocody-Abidjan, Ivory Coast
Institut des Matériaux Jean Rouxel, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 03, France
b
c
Received 10 September 2007
quence.4 It may be added that the same motif can be found
embedded in a structurally more complex orange dye.5
Abstract: Synthesis of an N-protected 2-bromo-1H-carbazole-
1,4(9H)-dione is reported for the first time. We took full advantage
of the high polarization and electrophilic properties of this new
compound to engage it in a regioselective hetero-Diels–Alder reac-
tion. The resultant cycloadduct was next transformed to an isomer
of the naturally occurring calothrixin B displaying a new 7H-indo-
lo[2,3-j]phenanthridine-7,13(8H)-dione structure.
The most salient feature of our calothrixin B synthesis2d,g
was a fully regioselective hetero-Diels–Alder cycloaddi-
tion between a 3-bromo-1H-carbazole-1,4(9H)-dione 4
and the ‘push–pull’ diene 5. By analogy, we thus thought
that a similar strategy based on the cycloaddition reaction
of a 2-bromo-1H-carbazole-1,4(9H)-dione 6 with diene 5
would be well suited to reach the targeted calothrixin iso-
mer 2. Herein, we describe the synthesis of the yet un-
known dienophiles 6a and 6b and the transformation of
6b to 2 following the retrosynthetic plan shown in
Scheme 1.
Key words: 2-bromo-1H-carbazole-1,4(9H)-dione, hetero-Diels–
Alder reaction, 7H-indolo[2,3-j]phenanthridine-7,13(8H)-dione,
calothrixin B isomer
Calothrixins A and B (1a, 1b; Figure 1) were first report-
ed in 1999 as antiproliferative agents from the strains of
Calothrix cyanobacterium (a blue-green alga) and shown
to have an indolo[3,2-j]phenanthridine core structure on
the basis of their spectroscopic data.1 Owing to their bio-
logical properties and their unusual structure, there has
been much interest in these alkaloids and several total
syntheses have recently appeared.2 As part of an ongoing
research project in the quest for novel analogues to im-
prove the spectrum of activity of these alkaloids, we be-
came interested in the synthesis of the calothrixin B
isomer 2 which features a 7H-indolo[2,3-j]phenanthri-
dine-7,13(8H)-dione structure. To the best of our knowl-
edge such a structure has not yet been synthesized;
however, two examples of the preparation of the 12H-in-
dolo[3,2-j]phenanthridine ring 3 have been already re-
ported, one based on an electrocyclization reaction,3 the
other on a Diels–Alder cycloaddition–lactamization se-
Our initial approach to 2 is outlined in Scheme 2, where a
benzyl protecting group had been chosen to temporarily
mask the indole nitrogen atom. As shown in Scheme 2,
compound 6a was easily prepared from the 9-benzyl-9H-
carbazol-4-ol (8), itself prepared in a three-step sequence
from the commercially available carbazole (7).2d Its reac-
tion with diene 5 led to the expected addition product 10
in 73% yield. Although the transformation of this adduct
to compound 13 could be accomplished uneventfully fol-
lowing a route, which, at the same time, proved successful
to prepare the N-benzyl-protected calothrixine B,2d efforts
to deprotect the indole nitrogen atom to give 2 in practical
yield remained unfruitful.
Because of this failure, we were led to reconsider the
choice of the indole nitrogen protecting group and we
X
O
O
N
N
O
N
O
N
N
H
H
H
1a calothrixin A (X = NO)
1b calothrixin B (X = N)
2
3
Figure 1
SYNLETT 2008, No. 2, pp 0263–0267
x
x.
x
x.
2
0
0
7
Advanced online publication: 21.12.2007
DOI: 10.1055/s-2007-1000933; Art ID: D28407ST
© Georg Thieme Verlag Stuttgart · New York

264
L. Maingot et al.
LETTER
Me
N
Me
Br
O
N
O
N
O
+
N
PG
O
N
O
O
H
4a (PG = Bn)
1b
5
4b (PG = Cbz)
O
Br
O
+
N
N
O
N
PG
N
O
N
Me
Me
H
2
(PG = protecting group)
6a (PG = Bn)
5
6b (PG = Cbz)
Scheme 1
O
O
HO
Br
ref. 2d
ii
i
N
H
O
O
N
N
N
Bn
Bn
Bn
7
8
9
6a
HO
O
O
R
O
O
N
N
N
iii
iv
v
O
O
N
N
O
N
Bn
Bn
Bn
11
10
12 R = OTf
13 R = H
vi
Scheme 2 Reagents and conditions: (i) PhI(OCOCF3)2 (3 equiv), MeCN–H2O, 2 h, 40 °C, 75%; (ii) Br2, AcOH, 20 min, 20 °C then ice-water;
crude solid taken up in EtOH, 1 h, reflux, 70%; (iii) 6a + 5 (1 equiv each), MeCN, 40 °C, 48 h, 73%; (iv) 10% Pd/C (0.25 equiv), PhOPh, 1 h,
reflux, 73%; (v) TfOTf (1.2 equiv), Et3N (5 equiv), CH2Cl2, 1 h, –78 °C; (vi) Pd(PPh3)4 (0.04 equiv), Et3N (4 equiv), HCO2H (2.7 equiv), di-
oxane, reflux, 30 min, 81% (two steps).
thought that a more labile Cbz group could be a useful al- this transformation, all attempts led to mixtures of 4b and
ternative to the initially chosen benzyl group. The synthe- 6b in ratios ranging from 1:1 to ca. 1:2.6
sis of the new key intermediate 6b was first envisaged
following a reaction sequence similar to that we used for
the preparation of 6a (Scheme 3). Thus, the benzyl 4-hy-
Consequently, we turned our attention to an alternative
strategy involving bromination of the N-Cbz-protected
9H-carbazol-1-ol 21. Scheme 4 outlines our successful
droxy-9H-carbazole-9-carboxylate (14), prepared from
approach to this compound. First of all, N-Cbz protection
carbazole (7),2g was first oxidized to the benzyl 1,4-dioxo-
of the 2,3,4,9-tetrahydro-1H-carbazol-1-one (18), effi-
1,4-dihydro-9H-carbazole-9-carboxylate (15) by expo-
ciently prepared from 4-(1H-indol-3-yl)butanoic acid
sure to phenyliodoso trifluoroacetate in aqueous acetoni-
(17),7 afforded compound 19 which was next fully arom-
atized following a two-step procedure to give the required
trile. Bromination of 15 led to the expected formation of
the dibromo adduct 16. However, and in sharp contrast
21 via the seleno intermediate 20. Finally, when submitted
with its N-benzyl analogue, subsequent efforts to achieve
to the Grunwell reaction conditions,8 21 led to the re-
a regioselective b-elimination of HBr met with little suc-
quired 6b9 (33% overall yield) whose structure was fully
cess. Indeed, irrespective of the conditions used to effect
ascertained by a single crystal X-ray analysis10 (Figure 2).
Synlett 2008, No. 2, 263–267 © Thieme Stuttgart · New York

LETTER
Synthesis of a Calothrixin B Isomer
265
Br
O
O
HO
Br
iii
ii
i
4b + 6b
O
O
N
N
N
Cbz
Cbz
Cbz
14
15
16
Scheme 3 Reagents and conditions: (i) PhI(OCOCF3)2 (3 equiv), MeCN–H2O, 1 h, 20 °C, 84%; (ii) Br2 (1 equiv), AcOH, 20 min, 20 °C then
ice-water and filtration of the precipitate (→ 16), quant.; (iii) see ref. 6.
i
ii
iii
CO2H
O
O
N
N
H
N
H
Cbz
17
18
19
O
Br
SePh
iv
v
OH
N
O
O
N
N
Cbz
Cbz
Cbz
20
21
6b
Scheme 4 Reagents and conditions: (i) PPA (15 equiv), toluene, reflux, 5 h, 98%; (ii) 18, NaH (1.3 equiv), DMF, 0 °C, 1 h then ClCO2Bn,
1 h, 20 °C, 90%; (iii) 19, THF, –78 °C then LiHMDS (1.3 equiv), 15 min, then PhSeCl (1.2 equiv) in THF, –78 °C; (iv) crude 20, CH2Cl2, 0 °C
then H2O2 (3 equiv), 30 min, 65% (two steps); (v) NBS (5 equiv), AcOH–H2O (1:2), 70 °C, then 21 in AcOH, 70 °C, 1.5 h, 60%.
Proceeding on to reach the targeted 2 we next reacted 6b 5.5% global yield. The most salient features of this syn-
with diene 5. After heating in chloroform at 50 °C for 18 thesis include a hetero-Diels–Alder reaction to assemble
hours, the 3,4-dihydro-2H-indolo[2,3-j]phenanthridine- the five-ring framework of the molecule and the prepara-
1,7,13(8H)-trione (22)11–14 could be isolated in 70% yield tion and use of a new 2-bromo-1H-carbazole-1,4(9H)-di-
(Scheme 5). It is noteworthy that cleavage of the N-Cbz one dienophile protected by an easily removed N-Cbz
protecting group occurred in the course of the reaction.15 group. Preliminary evaluation of in vitro cytotoxic effects
The final steps of the synthesis were accomplished as against MCF-7 and KB human cancer cell lines were real-
shown in Scheme 5. Chemoselective O-triflation provid- ized for compounds 10 and 13. It is interesting to note that
ed enol triflate 23 along with phenol triflate 24. Treatment compound 13 displays an activity of the same order as that
of this mixture with DDQ afforded 24 in 55% overall showed by its N-benzyl calothrixin B isomer (IC50 ≈ 0.1
yield. Finally, reduction of triflate 24, following the pro- mM) and that both 10 and 13 display a similar activity.
cedure reported by Cacchi et al.,16 provided the calothrix- Moreover, compound 10 and its N-debenzylated analogue
in isomer 2.17
are equally cytotoxic, the same being true for the corre-
sponding calothrixin B synthetic intermediates. It thus ap-
pears that deprotection of the indole nitrogen and full
aromatization of the Diels–Alder adducts are not key
transformations to get significant cytotoxicities.
In conclusion, a synthesis of a calothrixin B isomer, fea-
turing a new 7H-indolo[2,3-j]phenanthridine-7,13(8H)-
dione structure, has been achieved in 11 steps and in ca.
O
TfO
O
TfO
O
O
N
N
N
+
i
iv
ii
6b +
5
2
O
O
O
N
H
N
H
N
H
22
23
24
iii
Scheme 5 Reagents and conditions: (i) 5 (1.5 equiv), CHCl3, 20 °C, then 6b in CHCl3, 50 °C, 18 h, 70%; (ii) 22, THF–HMPA (2.5:1),
–78 °C, LiHMDS (2.5 equiv), 1 h, then PhNTf2 (1.5 equiv) in THF, 1 h, –78 °C; (iii) 23 + 24, DDQ (2 equiv), dioxane, reflux, 2 h, 55% (two
steps); (iv) 24, dioxane, 20 °C, then Et3N (4 equiv), Pd(PPh3)4 (0.04 equiv), HCO2H (2.7 equiv), reflux, 4 h, 50%.
Synlett 2008, No. 2, 263–267 © Thieme Stuttgart · New York

266
L. Maingot et al.
LETTER
71.0 (OCH2Ph), 114.5 (C-3), 122.8 (quaternary C), 123.2
(quaternary C), 123.4 (CHAr), 126.1 (CHAr), 128.8 (2 ×
CHAr), 129.2 (3 × CHAr), 129.7 (CHAr), 133.6 (quaternary
C), 133.8 (quaternary C), 137.6 (quaternary C + CHAr),
138.8 (quaternary C), 149.9 (NCO), 170.2 (C-1), 181.2 (C-
4). FT-IR (KBr): 3300, 3054, 1755, 1682, 1654 cm–1. MS
+
(CI, NH3): m/z (%) = 427 [M + NH4 , 79Br], 410 [M + H+,
79Br], 366, 332, 145, 91. HRMS (EI): m/z calcd for
C20H12BrNO4: 408.9950; found: 408.9954.
(10) C20H12BrNO4: The data set was collected on a Nonius-
Bruker Kappa CCD diffractometer, using the Mo–KL2,3
radiation. C20H12BrNO4 (M = 410.2): triclinic, space group
P1, Dc = 1.660 g cm–3, a = 7.1218(3), b = 9.6798(4), c =
13.2182(7) Å, a = 72.048(3)°, b = 84.294(6)°, g = 71.184(5)°,
V = 820.54(7) Å3, Z = 2, l = 0.71069 Å, m = 2.532 mm–1,
T = 150 K, R(F2) = 0.0547 for 3460 observed reflections
[I > 2 s(I)] and Rw(F2) = 0.1183 for all 4692 reflections. The
data have been deposited with the Cambridge
Crystallographic Data Centre, CCDC No. 654172.
(11) The orientation of addition of 6b to 5 is governed by the
bromo substituent. We have already observed such an effect
in previous works.12 First observations were reported by
Cameron et al.13
Figure 2
(12) (a) Collet, S.; Rémi, J. F.; Cariou, C.; Laïb, S.; Guingant, A.;
Nguyen, Q. V.; Dujardin, G. Tetrahedron Lett. 2004, 45,
4911. (b) Nguyen, Q. V.; Dujardin, G.; Collet, S.; Raiber, E.-
A.; Guingant, A.; Evain, M. Tetrahedron Lett. 2005, 46,
7669.
(13) Cameron, D. W.; Feutrill, G. I.; McKay, P. G. Aust. J. Chem.
1982, 35, 2095.
Acknowledgment
We wish to thank Julien Baudon for preliminary experiments and
Dr. Thierry Cresteil (CNRS, ISCN, Gif sur Yvette) for IC50 deter-
minations.
(14) 3,4-Dihydro-2H-indolo[2,3-j]phenanthridine-1,7,13
(8H)-trione (22): To a stirred solution of diene 5 (250 mg,
1.47 mmol) in anhydrous CHCl3 (5 mL) at r.t was added a
solution of dienophile 6b (400 mg, 0.98 mmol) in anhydrous
CHCl3 (8 mL). After the mixture was heated at 50 °C for 18
h, it was cooled to r.t. and concentrated in vacuo. The residue
was purified by column chromatography on silica gel
(elution with EtOAc–hexanes, 1:1) to give the cycloadduct
22 (215 mg, 0.68 mmol, 70%) as an orange-red solid: mp
>300 °C (CHCl3–hexanes) (dec.). 1H NMR (300 MHz,
DMSO): d = 2.20 (quint, J = 6.3 Hz, 2 H, H-3), 2.91 (t, J =
6.6 Hz, 2 H, H-2), 3.12 (t, J = 6.0 Hz, 2 H, H-4), 7.42 (t, J =
7.5 Hz, 1 H, H-10 or H-11), 7.52 (t, J = 7.5 Hz, 1 H, H-11 or
H-10), 7.65 (d, J = 8.4 Hz, 1 H, H-9), 8.12 (d, J = 7.8 Hz, 1
H, H-12), 9.20 (s, 1 H, H-6), 13.27 (br s, 1 H, NH). 13C NMR
(75 MHz, DMSO): d = 21.5 (C-3), 33.0 (C-4), 39.4 (C-2),
114.6 (C-9), 118.7 (quaternary C), 122.8 (CHAr), 124.2
(quaternary C), 124.8 (CHAr), 126.7 (quaternary C), 128.0
(CHAr), 129.8 (quaternary C), 136.7 (quaternary C), 139.0
(quaternary C), 141.4 (quaternary C), 149.3 (C-6), 169.2 (C-
7), 176.7 (C-4a), 179.0 (C-13), 199.0 (C-1). FT-IR (KBr):
3287, 2954, 1685, 1655, 1653 cm–1. MS (EI, 70 eV): m/z
(%) = 316 (60) [M+], 288 (100), 260 (21), 232 (11), 203 (24),
177 (24), 115 (24). HRMS (EI): m/z calcd for C19H12N2O3:
316.0848; found: 316.0849.
References and Notes
(1) Rickards, R. W.; Rothschild, J. M.; Willis, A. C.; de Chazal,
N. M.; Kirk, K.; Saliba, K. J.; Smith, G. D. Tetrahedron
1999, 55, 13513.
(2) (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. (d) Sissouma,
D.; Collet, S.; Guingant, A. Synlett 2004, 2612.
(e) Tohyama, S.; Tominari, C.; Matsumoto, K.; Yamabuki,
A.; Ikegata, K.; Nobuhiro, J.; Hibino, S. Tetrahedron Lett.
2005, 46, 5263. (f) Bennasar, M. L.; Roca, T.; Ferrando, F.
Org. Lett. 2006, 8, 561. (g) Sissouma, D.; Maingot, L.;
Collet, S.; Guingant, A. J. Org. Chem. 2006, 71, 8384.
(3) Elango, S.; Srinivasan, P. C. Tetrahedron Lett. 1993, 34,
1347.
(4) Mohanakrishnan, A. K.; Srinivasan, P. C. J. Org. Chem.
1995, 60, 1939.
(5) Wick, A. K. Helv. Chim. Acta 1966, 49, 1755.
(6) Conditions tested from 16 for HBr b-elimination: EtOH,
reflux, 1.5 h (4b:6b = 1.5:1); CHCl3, MgBr2 (1 equiv), 40 °C,
4 h (4b:6b = 2:1); SiO2 (4b:6b = 1:1); EtOH, BF3·Et2O,
55 °C, 2 h (4b:6b = 1:1.5).
(7) Maertens, F.; Van den Bogaert, A.; Compernolle, F.;
Hoornaert, G. J. Eur. J. Org. Chem. 2004, 4648.
(8) (a) Heinzman, S. W.; Grunwell, J. R. Tetrahedron Lett.
1980, 21, 4305. (b) See also: Jung, M. E.; Hagenah, J. A.
J. Org. Chem. 1983, 48, 5359.
(9) Benzyl 2-Bromo-1,4-dioxo-1H-carbazole-9(4H)-
carboxylate (6b): orange solid; mp 148 °C. 1H NMR (300
MHz, CDCl3): d = 5.53 (s, 2 H, OCH2Ph), 7.23 (s, 1 H, H-3),
7.30–7.70 (m, 7 H, HAr), 7.99 (d, J = 8.4 Hz, 1 H, H-8), 8.28
(d, J = 7.5 Hz, 1 H, H-5). 13C NMR (75 MHz, CDCl3): d =
Compound 22 and its regioisomer, arising from the
cycloaddition of 4b to diene 5 (a precursor of calothrixin
B),2g display distinguishable NMR signals (Dd = 0.06 ppm).
(15) Isolation of benzyl dimethylcarbamate, next to 22,
demonstrates that the N–Cbz bond cleavage resulted from
the attack of Me2NH·HBr generated in the course of the
Diels–Alder primary adduct aromatization process.
(16) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1986, 27, 5541.
Synlett 2008, No. 2, 263–267 © Thieme Stuttgart · New York

LETTER
Synthesis of a Calothrixin B Isomer
267
(17) 8H-Indolo[2,3-j]phenanthridine-7,13-dione (2): red solid;
mp >350 °C. 1H NMR (300 MHz, DMSO): d = 7.35 (t, J =
7.2 Hz, 1 H, HAr), 7.43 (t, J = 7.2 Hz, 1 H, HAr), 7.56 (d, J =
8.4 Hz, 1 H, HAr), 7.81 (t, J = 7.6 Hz, 1 H, HAr), 7.91 (t, J =
7.6 Hz, 1 H, HAr), 8.10 (d, J = 8.4 Hz, 1 H, HAr), 8.20 (d, J =
8.0 Hz, 1 H, HAr), 9.50 (s, 1 H, H-6), 9.65 (d, J = 8.4 Hz, 1
H, HAr), 13.10 (br s, 1 H, NH). 13C NMR (75 MHz, DMSO):
d = 114.0 (CHAr), 118.5 (quaternary C), 122.3 (CHAr), 123.0
(quaternary C), 124.0 (2 × quaternary C), 124.3 (CHAr),
127.1 (CHAr), 127.9 (CHAr), 129.7 (CHAr), 129.9 (CHAr),
131.8 (CHAr), 134.1 (quaternary C), 135.4 (quaternary C),
138.4 (quaternary C), 146.9 (CHAr), 151.8 (quaternary C),
177.6 (C-7), 186.7 (C-13). FT-IR (KBr): 3444, 1659, 1535
cm–1. MS (EI, 70 eV): m/z (%) = 298 (100) [M+], 270 (55),
242 (26), 241 (26), 214 (38). HRMS (EI): m/z calcd for
C19H10N2O2: 298.0742; found: 298.0743.
Synlett 2008, No. 2, 263–267 © Thieme Stuttgart · New York

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