Studies in the synthesis of prostoglandins

Davis, Peter David (1980) Studies in the synthesis of prostoglandins. University of Southampton, Doctoral Thesis.

Abstract

The many potent biological affects of the prostaglandins make this family of compounds and their structural analogues important synthetic targets. The addition of anions stabilised by dithiocarbamate or dithiocarbonate groups to cyclohex-2-enone was studied with the aim of obtaining a cyclisation reaction and hence a one-step difunctionalisation of cyclic a,8-unsaturated ketones. A bis dithiocarbamate was successfully lithiated and methylated and might be a useful acyl anion equivalent. 2-Alkyl-4-hydroxycyclopent-2-enones are important intermediates in prostaglandin synthesis. A potentially short and flexible route to these compounds via alkylation of sulphur substituted cyclopentenones was examined. In the investigation of a general route to prostaglandins, a Diels-Alder reaction of a 2-alkoxy-l,3-diene was found to be not stereoselective. Dienes of this type were prepared by Wittig reaction of aldehydes with carbonyl stabilised and unstabilised phosphoranes. The generation of dienes containing a protected thiol group was studied with a view to synthesising 6,9-a-thioprostacyclin by a similar route. As part of a second approach to 6,9-a-thioprostacyclin some thermal Lewis acid catalysed and high pressure Diets-Alder reactions of 2,3-dihydrothiophene 1,1-dioxide were attempted with limited success. Methyl 4,5dihydrothiophene-2-carboxylate and some Diets-Alder adducts thereof were prepared. The attempted synthesis of 6,9-a-thioprostacyclin from a Diets-Alder adduct of 2,3-dihydrothiophene 1,1-dioxide by several routes was not successful.

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