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Synthesis of amino estratrienes as peptidomimetics

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posted on 18.12.2012, 16:32 by Jonathan P. Eddolls
This thesis describes the synthetic routes investigated in order to prepare amino estratrienes as potential small molecule mimics of endogenous opioid peptides. 3-Hydroxy-17 a-aminoestra-1,3,5(1 O)-triene was prepared from estra-1,3,5 (1 0)-trien-3,17p-diol by formation of the sulphonate ester 3-benzyloxy-1713- mesyloxyestra-1,3,5(1 O)-triene, displacement of the mesylate ester group with azide anion to give 3-benzyloxy-17a-azidoestra-1,3,5(10)-triene, followed by catalytic hydrogenation. As an altemative to hydrogenation, the Staudinger reaction was performed on the 17 a-azide but gave 3-benzyloxy-17 a( diethylphosphoramido )estra-1,3,5(1 O)-triene. A key compound, 3-Benzyloxy·6-azidomethyl-17p-acetoxyestra-1,3,5(1 0),6- tetraene was obtained from 3,17P-dihydroxyestra-1,3,5(10)-triene in seven steps. The synthesis involved benzylic oxidation of 3,17p-diacetoxyestra-1,3,5(1 O)-triene with chromium trioxide-3,5-dimethyl pyrazole complex to give the key intermediate, 3-benzyloxy-17 p-hydroxyestra-1,3,5(1 0)-trien-6-one. Sulphur ylid methylene insertion at the p-face of the 6-keto derivative gave 3-benzyloxy-6-spiro -epoxy- 17p-hydroxyestra-1 ,3,5(1 O)-triene. Base promoted isomerisation of the 6-spiro -epoxide gave 3-benzyloxy-6-hydroxymethyl-17p-hydroxyestra-1,3,5(10),6- tetraene. The allylic alcohol was acetylated and the key compound obtained from palladium(O)-catalysed allylic azidation. Other alternative approaches involved regioselective nucleophilic ring opening with azide anion of the 6-spiro -epoxide to give 3-benzyloxy-6-hydroxy-6- azidomethyl-17P-hydroxyestra-1,3,5(10)-triene. Manganese (IV) oxidation of the allylic alcohol gave the allylic aldehyde and its oxime, 3-benzyloxy-6-carbaldoxime- 17p-hydroxyestra-1,3,5(10),6-tetraene was obtained upon treatment with hydroxylamine hydrochloride. 3,17P-Bis(tert-butyldimethylsiloxy)estra-1,3,5(1 O)-triene gave [,,6-3,1713- bis(terl-butyldimethylsilyloxy)estra-1,3,5(1 O)-triene ]-tricarbonylchromium upon treatment with chromium hexacarbonyl. However, subsequent benzylic activation at position 6 and treatment with various electrophiles was unsuccessful.



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© Jonathan Paul Eddolls

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A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.



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