Strategies towards the synthesis of prostaglandin analogues

Haupt, Hayley Claire

Strategies towards the synthesis of prostaglandin analogues

Doctoral Thesis

2006

Publisher

University of Cape Town

Department

Department of Chemistry

Faculty

Faculty of Science

Abstract

Different strategies for the synthesis of cyclopentenone prostaglandins and their analogues have been explored. The key transformation critical to the success of each of the described routes involves a Lewis-acid mediated retro Diels-Alder (rDA) reaction as the final step in liberating a 4, 5 disubstituted cyclopent-2-ene-1- one under extremely mild conditions. The first approach involves installation of the a-chain followed by base-mediated methodology to affect regiospecific enolate generation. Effective trapping of the enolate generates the requisite target. Within the context of this strategy both 2- and 3-component coupling protocols have been elaborated. Having demonstrated that the a- and p- sidechains could be installed, the key rDA reaction has been used to generate target analogues. The second approach utilizes a Diels-Alder cycloaddition reaction as the key step. The thermal and Lewis-acid catalysed Diels-Alder reactions between tricyclo[5.2.1.0 2,6]dec-8-en-3-one and 3-hydroxytricyclo[5.2.1.0 2,6]dec-8-ene with butadiene and butadiene sulfone have been investigated. While reaction between the enone and the dienophiles proved to be low yielding, the reaction between the allylic alcohol and butadiene sulfone proceeded readily and in high yield. The derived cycloadduct represents a late-stage intermediate for the synthesis of isoprostanes. Methodologies to perform cis-hydroxylation followed by oxidative cleavage of the cyclohexene moiety have been successfully implemented. Finally, a synthesis was designed for generating oxygen analogues of the prostaglandin targets.

Description

Includes bibliographical references (leaves 173-179).

Keywords

Chemistry

Reference:

Collections

PhD / Doctoral

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