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Novel approaches to the synthesis of Wieland-Miescher ketone analogues

Turner, RL; (2014) Novel approaches to the synthesis of Wieland-Miescher ketone analogues. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Important for the regulation of bodily glucose levels and within the fight-or-flight response, the glucocorticoid receptor has become an interesting pharmaceutical target, with the discovery that both natural and synthetic glucocorticoids induce a significant anti-inflammatory effect. Current research focuses on the synthesis and identification of novel selective glucocorticoid receptor modulators, which lack the debilitating side effects associated with these drugs. Building upon the work of previously successful glucocorticoid modulators, pyrazole 2 is the target for this work. The first part of this thesis describes investigations into the synthesis of the Wieland-Miescher ketone (WMK) analogue 1; an important intermediate in the prospective synthesis of pyrazole 2. The traditional route towards WMK analogues via a Robinson annulation proved to be unsuccessful, with a range of catalysts trialed for the key Robinson annulation step and with difficulties arising from the synthesis of the key pyran-3,5-dione precursor. The second route proved to be more successful with the methoxy-protected WMK being afforded, via a 6-step route with a key Birch reduction step. Alpha-Aminosulfonamides are a relatively unknown functionality, which possess the ability to mimic natural amino acids and behave as peptidomimetics. Previous literature has described this advantageous functional group as both synthetically challenging and an unstable moiety. Employing novel radical reaction conditions developed within the Wilden group, a selection of both the unusual alpha-aminosulfonamide and the more readily available beta-aminosulfonamide have been synthesised in significant yields.

Type: Thesis (Doctoral)
Title: Novel approaches to the synthesis of Wieland-Miescher ketone analogues
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/1443288
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