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

Abstract

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-6,11-diones.

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, 16134; (c) 11-Hidroxyascididemin: F. Schmitz, F. S. DeGuzman, M. B. Hossain and D. van der Helm, J. Org. Chem., 1991, 56, 804.
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3. Indeed, we have found that analogue 2b is highly cytotoxic in vitro 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 µg ml^–1, respectively).
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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.
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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.
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15. Quinone 5a was quantitatively converted into 7a and N,N-dimethylhydrazine 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.
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17. The methoxime and diphenylhydrazone analogues of 5a afforded 7a after being treated with TFA.