New synthesis of pyridoacridines based on an intramolecular aza-Diels-Alder reaction followed by an unprecedented rearrangement

Article abstract of DOI:10.1039/a905234h

The synthesis of pyridoacridines related to the ascididemins can be performed by an intramolecular aza-Diels-Alder cycloaddition of an α,β-unsaturated hydrazone to a quinone followed by an unprecedented rearrangement to yield benzo- or pyrido-[b]acridine-

Full text of DOI:10.1039/a905234h

New synthesis of pyridoacridines based on an intramolecular aza-Diels–Alder
reaction followed by an unprecedented rearrangement†
Juan M. Cuerva,‡ Diego J. Cárdenas and Antonio M. Echavarren*
Departamento de Química Orgánica, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
E-mail: anton.echavarren@uam.es
Received (in Liverpool, UK) 24th June 1999, Accepted 29th July 1999
The synthesis of pyridoacridines related to the ascididemins
can be performed by an intramolecular aza-Diels–Alder
cycloaddition of an a,b-unsaturated hydrazone to a quinone
followed by an unprecedented rearrangement to yield benzo-
or pyrido-[b]acridine-6,11-diones.
The intramolecular cycloaddition of 5a–c was examined as
part of a projected synthesis of the alkaloid meridine1c,10 and
related compounds (Scheme 2). These aminoquinones were
readily available by the addition of the aniline 33 to 4a or 4b in
MeOH at 23 °C the presence of CeCl3·7H2O (0.1 equiv) (70%
for 4a, 48% for 4b).11 On the other hand, a hydroxy group in the
position 4 of quinolinequinone directs the nucleophilic attack of
aniline derivatives allowing the synthesis of adducts 5d–e with
the opposite regioselectivity.12
After much experimentation, the desired cycloadditions were
realised by trifluoroacetylation of the amines of 5a,b (NaH,
TFAA, 3 equiv. each, THF, 23 °C) followed by replacement of
THF by CH2Cl2 and addition of excess TFA (23 °C, 1 h) to
furnish quinones 6a (45%) and 6b (47%),13 respectively. Under
these conditions, the intermediate cycloadducts, which could
not be isolated, suffer elimination of the trifluoroacetamides to
form the quinone chromophores.
Pyridoacridine alkaloids of marine origin, such as amphimedine
and the ascididemins (1a–c),1 have attracted much attention due
to their structural novelty and cytotoxic properties.2,3 Strategies
based on Diels–Alder azacycloadditions are amongst the most
conceptually simple and potentially general approaches for the
synthesis of these heterocycles.2,4 However, the practical
realisation of these schemes has been hampered by the lack of
suitable reactivity of 4-substituted 1-azadienes towards
1,4-quinones.4–6
Herein we report a new approach for the synthesis of
heterocycles 2a–b7,8 related to the ascididemins (1a–c) based
on an intramolecular aza-Diels–Alder reaction of 1-dimethyla-
mino-1-azadienes9 followed by an unprecedented rearrange-
ment which occurs under oxidative conditions. The bond
connectivity achieved between azadiene 34 and 1,4-naph-
thoquinones 4a,b in the cycloaddition–rearrangement is shown
in Scheme 1. This scheme is formally equivalent to an
intermolecular cycloaddition of diene 3 with the corresponding
1,2-naphthoquinones.
Scheme 1
† Dedicated to Professor Jose´ Elguero on the occasion of his 65th
birthday.
‡ Current address: Departamento de Química Orgánica, Facultad de
Química, Universidad de Granada, Spain.
Scheme 2
Chem. Commun., 1999, 1721–1722
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Notes and references
1 Isolation: (a) Ascididemin: J. Kobayashi, J. Cheng, H. Nakamura, Y.
Ohizumi, Y. Hirata, T. Sasaki, T. Ohta and S. Nozoe, Tetrahedron Lett.,
1988, 29, 1177; (b) 2-bromoascididemin (2-bromoleptoclidinininone):
J. J. Bloor and F. J. Schmitz, J. Am. Chem. Soc. 1987, 109, 6134;
11-Hidroxyascididemin (c): F. Schmitz, F. S. DeGuzman, M. B.
Hossain and D. van der Helm, J. Org. Chem., 1991, 56, 804.
2 Reviews: T. F. Molinski, Chem. Rev., 1993, 93, 1825; B. S. Davidson,
Chem. Rev. 1993, 93, 1771; A. M. Echavarren, in Advances in Nitrogen
Heterocycles, ed. C. J. Moody, JAI Press, Greenwich, 1996, vol. 2. ch.
5.
3 Indeed, we have found that analogue 2b is highly cytotoxic in vitro to
mouse lymphoma (P-388), human lung carcinoma (A-549), human
colon carcinoma (HT-29), and human melanoma (MEL-28) (IC50
values of 0.01, 0.0012, 0.005 and 0.0025 mg ml21, respectively).
4 A. M. Echavarren, J. Org. Chem., 1990, 55, 4255.
5 J. M. Cuerva and A. M. Echavarren, Synlett, 1997, 173; M. C. Carreño,
J. M. Cuerva, Ribagorda and A. M. Echavarren, Angew. Chem., Int. Ed.,
1999, 38, 1449.
6 The first step of a synthesis of the alkaloid meridine is a Diels–Alder
cycloaddition of the nitro analogue of 3 which proceeds in low yield
(6%): Y. Kitahara, F. Tamura and A. Kubo, Chem. Pharm. Bull. 1994,
42, 1363; S. Nakahara, Y. Tanaka and A. Kubo, Heterocycles, 1996, 43,
2113; a similar reaction was used for the synthesis of cistodamine: Y.
Kitahara, F. Tamura and A. Kubo, Tetrahedron Lett. 1997, 38, 4441.
Alternative synthesis of aromatized adducts: P. Molina, A. Pastor and
M. Villaplana, Tetrahedron 1995, 51, 1265.
7 Previous synthesis of 2a: J. R. Peterson, J. K. Zjawiony, S. Liu, C. D.
Hupfford, A. M. Clark and R. D. Rogers, J. Med. Chem., 1992, 35,
4069.
8 Synthesis of another regioisomer of 1a and 2b: E. Gómez-Bengoa and
A. M. Echavarren, J. Org. Chem., 1991, 56, 3497.
9 Intramolecular cycloaddition of 1-dimethylamino-1-azadienes: N.
Bushby, C. J. Moody, D. A. Riddick and I. R. Waldron, Chem.
Commun., 1999, 793; R. E. Dolle, W. P. Armstrong, A. N. Shaw and R.
Novelli, Tetrahedron Lett., 1988, 29, 6349.
10 P. J. McCarthy, T. P. Pitts, G. P. Gunawardana, M. Kelly-Borges and
S. A. Pomponi, J. Nat. Prod., 1992, 55, 1664.
Scheme 3
Much to our surprise, 6a was cleanly transformed into
tetracycle 7a14 by heating with acid (1+1 10% aq HCl–
1,4-dioxane, reflux; 94%). Quinone 7a could also be obtained
directly from 5a by thermolysis (xylene, reflux; 55%) or by
treatment with TFA (23 °C; 68%).15 Under these latter
conditions, heterocyclic quinone 7b was similarly obtained
from 5b (66%).13 Scheme 3 suggests a possible mechanism for
these remarkable transformations in which the dimethylhy-
drazine and two carbons are lost under relatively mild
conditions. Accordingly, a 6-endo-trig cyclization of the
trifluoroacetamide (from 6a,b) or the amine (via 6c,d formed in
situ from 5a,b) onto the quinone double bond with concomitant
(or subsequent) transacylation would lead to intermediates 8,
which may undergo aromatization to form a pyridine ring by a
Grob-type fragmentation to give acetylene and the hydrazine
derivative. The first step of this process, nucleophilic addition–
elimination on a quinone, is somewhat reminiscent of the so-
called mitomycin rearrangement.16
According to the hypothetical equilibrium of Scheme 3,
oxidation of intermediate 8 could yield a precursor of
tetracycles related to the ascididemins (1). In the event,
treatment of 6a,b with excess MnO2 in CH2Cl2 at 23 °C
smoothly led to tetracycles 9a,b in quantitative yield as single
isomers. The rearrangement also takes place in the presence of
DDQ or CAN as the oxidants. A trans configuration was
assigned for the alkenyl portion of these derivatives on the basis
of a vicinal coupling constant of 15.5 Hz. However, the
configuration around the enamine nitrogen was not rigorously
assigned. Reaction of 9a,b with NH4Cl and NaOAc in EtOH
under refluxing conditions gave pentacyclic 2a4 (93%) and 2b
(84%).13 After examining several hydrazone and oxime deriva-
tives,17 we found that thermolysis of phenylhydrazone 5c
directly furnished 2a (refluxing xylene, 40%), probably through
intermediate 10a. In fact, related tetracyclic derivative 10b
could be isolated in 54% yield by thermolysis of 5b in
xylene.
11 Hydrazones 5c–e were obtained in three steps by: (i) reaction of the
quinolinequinone with o-aminocinnamol (CeCl3·7H2O, MeOH, 23 °C);
(ii) oxidation of the allyl alcohol to the aldehyde with PCC or MnO2;
(iii) condensation of the aldehyde with the hydrazine.
12 By using the reaction pathway outlined in Scheme 2, adducts 5d–e could
be converted into 11-hydroxyascididemin (1c).
13 Yield based on unrecovered starting material.
14 A. Ettienne and A. Staehelin, Bull. Soc. Chim. Fr., 1954, 748; V. Zanker
and F. Mader, Chem. Ber., 1960, 93, 850. 2-Chloro derivative: M. Prato,
G. Scorrano, M. Stivanello, P. Tecilla and V. Lucchini, Gazz. Chim.
Ital., 1987, 117, 325.
15 Quinone 5a was quantitatively converted into 7a and N,N-dimethylhy-
drazine at 50–55 °C (3+1 benzene-d6–TFA-d solution, sealed NMR
tube). In addition, a small signal at 1.8 ppm attributable to dissolved
acetylene was also observed.
16 M. Kono, Y. Saitoh, K. Shirahata, Y. Arai and S. Ishii, J. Am. Chem.
Soc., 1987, 109, 7224; T. Fukuyama and L. Yang, J. Am. Chem. Soc.,
1987, 109, 7881; T. Fukuyama and L. Yang, J. Am. Chem. Soc., 1989,
111, 8303.
17 The methoxime and diphenylhydrazone analogues of 5a afforded 7a
after being treated with TFA.
In summary, a highly concise synthesis of heterocycles 2a,b
has been developed based on an intramolecular aza-Diels–Alder
cycloaddition followed by a novel rearrangement in which the
aminoaryl formally undergoes a 1,2-shift.
This work was supported by the DGES (Project PB97-
0002-C2-02). We acknowledge the Instituto Biomar, S.A., for
the data in ref. 3.
Communication 9/05234H
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Chem. Commun., 1999, 1721–1722