Synthesis and structure activity relationships of ring D modified steroidal hormones

Doctoral Thesis


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University of Cape Town

The synthesis of steroidal 14α,16-methano, 14α,17-methano-, 14α,17-ethano- and 14α,17-propano estradiol analogues as well as 14α-alkyl and 14α-functionalised-alkyl estradiol analogues was investigated. Furthermore, the synthesis of 17β-hydroxy-17α, 14-(epoxymethano)androst-4-en-3-one was undertaken and acid-mediated rearrangement of the 14,17-etheno bridged testosterone analogue gave the 14,16-ethano analogue of androst-4-en-3,17-dione. Established ring D cycloaddition and oxidative cleavage methodology gave ring D 14α-formyl and 14α, 17α-diformyl compounds as key intermediates in the overall synthetic plan. Chemoselective- and stereoselective nucleophilic addition at C-14¹ of the 14α-formyl-3-methoxyestra-1,3,5(10)-trien-17-one provided access to 14α-alkyl- and 14α-alkyl-functionalised 19-norsteroids for elaboration toward 14α,17-propano- and 14α-alkylamide estradiol analogues. Synthesis of the 14α,17-methano bridged steroid was attainable indirectly through intramolecular pinacol coupling between the 17-oxo- and 14-formyl group of 14αformyl- 3-methoxyestra-1,3,5(10)-trien-17-one. The 14α, 16-methano bridged steroid was synthesised via base-mediated intramolecular cyclisation of 14-(toluene-p-sulfonyloxy)methyl-3-methoxyestra-1,3,5( 1 0)-trien-17-one. Novel compounds were characterised with the aid of high field NMR techniques. A X-ray crystal structure determination of the strained ring D 14α, 17-methano bridged estriol analogue corroborated its structure. The minimum energy conformation of novel estradiol analogues were superimposed on estradiol, and their least square fit values determined and discussed in relation to biological activity. These analogues will contribute toward defining the structural parameters responsible for certain pattern of hormonal activity, and hence, the ultimate goal of predictive drug design.

Includes bibliographical references.