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Synthetic approaches to anti-hormonal steroids

Thomas, C.A.A. (1992). Synthetic approaches to anti-hormonal steroids. (Unpublished Doctoral thesis, City, University of London)

Abstract

The first section of this thesis presents a review of the literature on hormones and anti-hormones, with particular emphasis on the structures and functions of the naturally occurring male and female sex steroids and on the preparation and properties of their synthetic analogues which have been found to function as anti-hormones.

The second section of the thesis presents the results of a small project carried out to synthesise two 7-methylated derivatives of 19-nortestosterone for biological evaluation as potential anti-androgens. One of these, 17β-hydroxy-7- methylestra-4,6-dien-3-one, was prepared by the oxidation of 7α-methyl-19-nortestosterone, whereas hitherto oxidation had been successfully achieved only with the 7β-methyl isomer. 7β-methyl-19-nortestosterone, the second of the two methyl- steroids required, was synthesised in poor yield, along with the 7α-isomer, by conjugate methylcuprate addition to 6-dehydro-19-nortestosterone. The separation of the 7-methyl epimers proved to be difficult and was achieved by development of a preparative HPLC system using a large laboratory-made column.

The third section of the thesis describes the major part of the research work and concerns the development of a route for the synthesis of 11-aryl-A-nor steroids. These steroids have been designed to explore their potential as anti-progestins. It is demonstrated that a thallium-mediated ring contraction of steroidal 4-en-3-ones carrying an 11- keto group provides entry to a functionalised A-nor steroid skeleton which can then be arylated using organo1ithiurn reagents. Manipulation of the functionalities led to the successful synthesis of 11-phenyl-A-nor-5β-androst-11-ene- 2,17-dione, which should be a valuable intermediate for the generation of a set of 11-arylated A-nor steroids for biological evaluation.

Publication Type: Thesis (Doctoral)
Subjects: Q Science > QD Chemistry
Departments: School of Science & Technology
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