The synthesis and structural examination of 3alpha, 5-cyclo-5alpha-androstane steroids.
Gibb, Bruce Clark
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The work described in this thesis is based on the synthesis and structural examination of several cyclosteroids. The a-aromatic steroid 3a, 5-cyclo-5c-androstan-6beta-ol- 17-one was used as a lead compound in an attempt to produce, in particular, the 17a-ethynyl derivative, the 6beta-methyl derivative and the 7a-hydroxy, 6beta-methyl derivative. Full experimental details of the various routes are provided. Xray crystallography, along with standard spectroscopic techniques, were utilised in structural determinations. To complement these techniques molecular mechanics were also utilised to predict spectroscopic results and to structurally define the products. The biological significance of steroids with respect to contraception is outlined and the chemistry of the cyclopropane ring discussed. A critical evaluation of the synthesis of cyclopropane steroids and the alkylation of steroids has been made. The objectives and methodologies behind recent innovations are discussed. An improved synthesis of the lead compound, from dehydroepiandrosterone, was achieved. The chemical and spectral implications of the introduction of a-aromaticity into the steroid nucleus is discussed. The synthesis of the ethynyl derivative, was achieved in increasing yields by four different routes. Synthesis of the 6beta-methyl derivative was considered via four different pathways. Three of these routes gave the important 6-methylene precursor but insufficient quantities prevented the formation of the desired molecule. Formation of the 7a-hydroxy, 6beta-methyl derivative, as well as its 6beta-hydroxy, 7a-methyl isomer has been accomplished. However, instability of the epoxide precursor resulted in low yields. Two novel single crystal X-ray structures have been elucidated and X-ray powder diffraction data obtained on a third. Results of the two determinations have been published. The accurate geometrical details of these compounds formed a basis for subsequent molecular mechanics calculations. Molecular modelling was used to aid product identification, determine theoretical product stability, i. e., potential reaction outcome and to support spectroscopic data.