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|Title: ||Synthesis of amino estratrienes as peptidomimetics|
|Authors: ||Eddolls, Jonathan P.|
|Issue Date: ||1995|
|Publisher: ||© Jonathan Paul Eddolls|
|Abstract: ||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
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.|
|Description: ||A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.|
|Appears in Collections:||PhD Theses (Chemistry)|
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