Synthesis of novel thianone analogues of prostaglandins

• Main Author: Miller, Thomas
• Published: University of Surrey 1975
• Subjects: 547
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.465708

An account of work in the synthesis of pharmacalogically interesting, novel prostaglandin analogues containing heterocyclic sulphur is presented. A guide to the prostaglandin literature is included. The route to thianone analogues involved C-alkylation of thian-3,5-dione, and attachment of an unsaturated side-chain by 1,4 addition of a lithium vinylcuprate to a conjugated enone derived from the alkylation product. The alkylation was achieved after a series of model experiments with various alkylating agents and reaction conditions, and the appropriate enone was made via hydride reduction of an enol ether of the alkylated dione, and acid-catalysed rearrangement. This process was confused by side reactions, particularly conjugate reduction of the enol ether. The enone underwent 1,4 additions without complications. It was also proposed to make an enone appropriate for the synthesis of thiolanone analogues of prostaglandins via electrophilic chlorination of the alkylated B-diketone, then ring-contraction by elimination of hydrogen chloride and carbon monoxide. Two potential difficulties due to the presence of sulphur were anticipated: attack by the chlorinating agent at the heteroatom; and hindrance to the conjugate addition stage caused by tautomerism of the enone, whose dienol form would be a thiophene. Model experiments to find suitable reaction conditions with carbocyclic compounds were successful, but electrophilic chlorination hampered their immediate application to the heterocyclic series. Earlier efforts to make thiolanone analogues of prostaglandins were based on a route involving construction of a functionalised thiolanone by Dieckmann cyclisation. Attachment of one side-chain by C-alkylation was to be followed by development of a potential formyl substituent, which would be elaborated to form the unsaturated side-chain via the phosphonate modification of the Witting reaction, a less versatile method than vinylcuprate addition. However, a study of the stages leading to the alkylated thiolanone showed them to be too inefficient for practical purposes, and this route was not pursued further.