The synthesis of 8-hydroxyellipticine and related compounds.

  • David Maxwell Dolman

Student thesis: Doctoral ThesisPhD


The ellipticine alkaloids or pyrido [4,3-b] carbazoles have been found to be effective against various forms of cancer, in particular leukemia, and as these compounds exhibit a low toxicity in mammals a great deal of work has been devoted to their synthesis and pharmacological testing. 9-Hydroxyellipticine has proved to be the most effective and interest in other hydroxyl derivatives naturally followed. This work is largely concerned with the synthesis of the new derivative 8-hydroxyellipticine. Of the various known methods for preparing pyrido [4,3-b] carbazoles we chose a procedure developed at an earlier time in this laboratory. This involves a Grignard condensation between an appropriately substituted indolylmagnesium bromide and a haloethylpyridine to give the corresponding indolyl- pyridylethane. Subsequent manipulations of the pyridine ring then lead to ring closure and aromatization. This method demands the preparation of suitably protected 6-hydroxyindoles on a relatively large scale, and a great deal of labour was devoted towards the development of satisfactory routes for this purpose. Finally this was achieved, and the rest of the synthesis carried out, with appropriate modifications, to give 8-hydroxyellipticine. During the course of our work Professor J.P. Rosazza of the University of Iowa isolated 8-hydroxyellipticine in small quantity, as an ellipticine metabolite of the micro-organism Aspergillus alliaceus. Thus, our synthesis served to provide larger quantities and to confirm the original structural assignment. We next turned our attention to a consideration of methods for the direct electrophilic substitution of various groups into the ellipticine skeleton. This hitherto neglected area proved fruitful and 9-bromo and 9-nitro ellipticines were prepared by a much simpler and higher yielding route than any previously used. An attempt was also made to modify and improve the potentially useful ellipticine synthesis first carried out by Stillwell at Harvard University. The synthesis in its original form gave disappointingly low yields and we sought to improve this. An unexpected result of this, was the isolation of a new pyridine derivative from one of the reactions in our proposed route, but we were unable to complete this last topic due to lack of time. However, a possible method of achieving this is presented. The thesis begins with a brief discussion of the occurrence and isolation of the ellipticines, and this is followed by a review of the various published syntheses of pyrido [4,3-b] carbazoles. In view of the recent interest in the metabolism of ellipticine these experiments are also discussed. As so much work with these compounds has been aimed at achieving clinically useful derivatives this thesis concludes with a summary of the pharmacology of ellipticine derivatives.
Date of Award1982
Original languageEnglish
Awarding Institution
  • University of Bath

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