Total synthesis of the marine pyridoacridine alkaloid sebastianine A

Article abstract of DOI:10.1016/S0040-4039(03)00320-4

The synthesis of the marine alkaloid sebastianine A and of a regioisomer has been accomplished via hetero-Diels-Alder reaction of indole-4,7-dione or N-tosylindole-4,7-dione with trifluoroacetamidocinnamaldehyde dimethylhydrazone, and subsequent cyclisati

Full text of DOI:10.1016/S0040-4039(03)00320-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2473–2475
Total synthesis of the marine pyridoacridine alkaloid
sebastianine A
Laurent Legentil, Jean Bastide and Evelyne Delfourne*
Centre de Phytopharmacie, UMR-CNRS 5054, Universite´ de Perpignan, 52 Avenue de Villeneuve, 66860 Perpignan Cedex,
France
Received 24 January 2003; revised 3 February 2003; accepted 3 February 2003
Abstract—The synthesis of the marine alkaloid sebastianine A and of a regioisomer has been accomplished via hetero-Diels–Alder
reaction of indole-4,7-dione or N-tosylindole-4,7-dione with trifluoroacetamidocinnamaldehyde dimethylhydrazone, and subse-
quent cyclisation in alkaline conditions. © 2003 Elsevier Science Ltd. All rights reserved.
9 and 10, respectively.6 The protective group of 10 was
Pyrido[4,3,2-mn]acridine alkaloids represent a group of
cleaved to give indole-4,7-dione 11.7
natural products isolated from marine source, many of
which exhibit significant biological properties including
tumor toxicity and fungal growth inhibition.1 In 1998,
The hetero-Diels–Alder reactions with both dienophiles
9 and 11 in refluxing toluene afforded in low yield after
Plubrukarn and Davidson2 reported the isolation and
structure elucidation of arnoamines A (1) and B (2), the
first members of the pyridoacridine family that possess
a pyrrole ring fused to the pyridoacridine ring system,
and for which we proposed an original synthesis.3
Recently, two other pyridoacridine alkaloids, sebastia-
nine A (3) and B (4) presenting the same structural
features were described by Torres et al., from the
ascidian Cystodytes delle Chiaijei4 (Fig. 1).
aromatisation by MnO2 (8 and 6%, respectively) a
mixture of the two regioisomers 12a/12b and 13a/13b.
The tosylindoloquinone 9 gave compound 12b as the
major isomer (12a/12b being 5/95) whereas with indole-
4,7-dione, isomer 13a predominated (13a/13b being 60/
40). This reversal of regioselectivity when changing the
We report herein, the first total synthesis of sebastia-
nine A and of its regioisomer 5 using hetero-Diels–
Alder reaction.
Two hetero-Diels–Alder cycloaddition involving N-
tosylindole-4,7-dione
dienophile, and o-trifluoroacetamidocinnamaldehyde
9 or indole-4,7-dione 11 as
dimethylhydrazone as diene were investigated (Scheme
1).
The two dienophiles 9 and 11 were obtained starting
from 4,7-dimethoxyindole 6, itself prepared from 2,5-
dimethoxybenzaldehyde according to the three-step
procedure previously described by Beneteau and
Besson.5 Two protective groups: tosyl and BOC were
introduced to compound 6, and the protected indoles 7
and 8 were oxidised by CAN into the indole-4,7-diones
* Corresponding author. Tel.: +33-468-662251; fax: +33-468-662223;
e-mail: delfourn@univ-perp.fr
Figure 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00320-4

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L. Legentil et al. / Tetrahedron Letters 44 (2003) 2473–2475
Scheme 1. Reagents and conditions: (a) KOH, pTsCl, THF, 1 h, (67%); (b) NaH, BOC2O, THF, rt, 30 min (95%); (c) CAN,
CH3CN/H2O (4:1), rt, 30 min (R=Ts, 100%, R=BOC, 90%); (d) TFA, CH2Cl2, rt, 2 h (100%); (e) toluene, reflux, 12 h (R=Ts,
8%, R=H, 6%); (f) 1N NaOH, CH2Cl2, 2 h (13a, 85%, 12b, 92%); (g) 1N NaOH, CH2Cl2, 12 h (14a, 95%, 14b, 98%).
nature of the substituent on the indolic nitrogen was
previously reported by Barret et al. in hetero-Diels–
Alder reactions involving indoloquinones and croton-
aldehyde dimethylhydrazone as the diene.8 They
studied the structure assignement of each isomer in
2D-NMR experiments (HMQC and HMBC) conclud-
ing that the unsubstituted quinones afforded a regioiso-
mers whereas b isomers were obtained with quinones
bearing an electronwithdrawing substituent on the
nitrogen. Based on the same regioselectivity for the
cycloaddition of o-trifluoroacetamidocinnamaldehyde
dimethylhydrazone, we propose structure a to be the
major isomer in the reaction involving dienophile 11
whereas structure b is the major isomer in the reaction
with dienophile 9. The Diels–Alder adducts 13a and
12b were subsequently cyclised in alkaline conditions to
give the corresponding pentacyclic compounds 3 and 59
in 85 and 92% yield, respectively. It has to be noted
that in the case of the tosyl-derivative 12b, the tosyl
pentacyclic derivative 14b was intermediately obtained
by shortening the time of the reaction. As we have
previously reported in the case of quinolinic or iso-
quinolinic derivatives.10 the proton close to the imino-
quinone function in isomer 5 (H11) shows a deshielding
effect related to the same proton in isomer 3 (H9) which
confirms the structure assignement established for the
Diels–Alder adducts.
compound 3 proving the structure of sebastianine A.
The synthesis of sebastianine B is currently in progress.
References
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9. 11H - 7,11,12 - Triazabenzo[de]cyclopenta[a]anthracen - 8-
one, 3: yellow solid, mp >260°C. MS m/z (%): 271 (100);
243 (37); 215 (21); 188 (14). 1H NMR (400 MHz, DMSO-
d6): l 7.00 (d, 1H, J=2.6 Hz); 7.48 (d, 1H, J=2.6 Hz);
7.79 (t, 1H, J=8.0 Hz); 7.94 (t, 1H, J=8.0 Hz); 8.18 (d,
1H, J=8.1 Hz); 8.88 (d, 1H, J=8.1 Hz); 8.96 (d, 1H,
J=5.2 Hz); 9.19 (d, 1H, J=5.2 Hz); 12.83 (s, 1H). 13C
The spectroscopic data of 3 and 5, obtained in the same
solvent conditions, were compared with the values
reported for the natural product sebastianine A. The
values of the natural product were similar with those of

L. Legentil et al. / Tetrahedron Letters 44 (2003) 2473–2475
2475
NMR (100 MHz, DMSO-d6) 106.95; 117.72; 120.28;
121.90; 124.63; 128.63; 129.53; 130.17; 130.41; 131.54;
132.19; 137.67; 145.84; 149.05 (2C); 149.76; 172.58.
9H-7,9,12-Triazabenzo[de]cyclopenta[a]anthracen-8-one,
5: orange solid, mp >260°C. MS m/z (%): 271 (100); 243
Hz); 8.18 (dd, 1H, J=7.0 and 1.1 Hz); 8.89 (dd, 1H,
J=7.0 and 1.1 Hz); 8.95 (d, 1H, J=5.6 Hz); 9.18 (d, 1H,
J=5.6 Hz); 12.88 (s, 1H). 13C NMR (100 MHz, DMSO-
d6) 108.44; 117.32; 120.11; 122.12; 124.79; 125.24; 126.17;
128.72; 130.07; 132.35; 135.28; 137.59; 145.22; 145.55;
149.09; 149.88; 178.38.
1
(51); 215 (16); 188 (15). H NMR (400 MHz, DMSO-d6):
10. Brahic, C.; Darro, F.; Belloir, M.; Bastide, J.; Kiss, R.;
Delfourne, E. Bioorg. Med. Chem. 2002, 10, 2845–2853.
l 6.76 (d, 1H, J=2.8 Hz); 7.27 (d, 1H, J=2.8 Hz); 7.82
(td, 1H, J=7.0 and 1.1 Hz); 7.96 (td, 1H, J=7.0 and 1.1