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Title: Strategies for the synthesis of oxetanes as desirable fragments for drug discovery
Author: Morgan, Kate Frances
ISNI:       0000 0004 6495 4778
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Oxetanes are currently receiving attention as important motifs for drug discovery due to their desirable physicochemical properties. Novel small oxetane containing compounds were designed to access new areas of chemical space and to be suitable motifs for incorporation into drug-like compounds or as fragments appropriate for screening in fragment based drug discovery. Methodology to access oxetanes bearing functional groups was investigated, in particular a novel intramolecular C–C bond forming cyclisation was developed due to the sparcity of synthetic methods for oxetane preparation. 2-Aryl sulfonyl oxetanes, designed with desirable fragment-like properties, were synthesised in excellent yields and could be further derivatised in a variety of directions into more lead-like compounds via organometallic intermediates at the intact oxetane and aromatic rings. The oxetane fragments and lead-like derivatives were found to have good half-life values under acidic and basic conditions. In addition, computational analysis determined that there were three possible binding orientations of the fragments. [Molecular diagram appears here. To view, please open pdf attachment] 2-Sulfinyl oxetanes were also synthesised as interesting motifs. The sulfoxide-magnesium exchange was explored as a method to access an oxetanyl organometallic species and incorporate the oxetane motif into a wide variety of compounds. This was challenging, however interesting reactivity was observed. [Molecular diagram appears here. To view, please open pdf attachment] To increase the diversity of oxetane derivatives that could be accessed and the methodology available to incorporate the motif into larger compounds, the synthesis of 2,3-disubstituted oxetanes was explored using an intramolecular epoxide ring opening strategy. More substitution would allow further ways in which to functionalise the oxetane motifs. In addition initial investigation into methodology to incorporate the oxetane motif into a wide array of larger lead-like and drug-like molecules was performed. The 2-oxetanyl sulfinate salt, a potential radical precursor, was not successfully formed. However the 3-oxetanyl radical was obtained by decarboxylation, and successfully reacted with a variety of heterocycles.
Supervisor: Bull, James Sponsor: AstraZeneca (Firm)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral