Investigation of oxetane reactive intermediates for the synthesis of 3,3-disubstituted oxetanes
File(s)
Author(s)
Rojas, Juan
Type
Thesis
Abstract
Four-membered ring heterocycles are attractive motifs for drug discovery due to their low molecular weight, high polarity and marked 3-dimensionality. 3,3-Disubstituted oxetanes have gained further popularity as surrogates for carbonyl groups to improve their physicochemical properties. However, the dearth of synthetic methods to access substituted oxetane motifs has hampered their systematic evaluation as motifs in a pharmaceutical context. This thesis describes the development of methodologies to access new 3,3-disubstituted oxetanes through the generation of oxetane reactive intermediates: carbocations, radicals and carbanions.
Chapter 3 describes the generation of oxetane carbocations from oxetane sulfonyl fluoride precursors through an unprecedented defluorosulfonylation pathway. 3-Aryloxetane carbocations are coupled to nucleophiles to achieve varied substitution in the 3-position. Reaction with amines yields aryl amino-oxetanes as potential isosteres of benzamides and the physicochemical properties of selected amino-oxetane/benzamide pairs are compared. Applicability to drug discovery is shown through late-stage functionalisation and the synthesis of oxetane drug analogues. Defluorosulfonylation proceeds by an SN1 mechanism with rate- determining formation of planar oxetane carbocations, whereby the oxetane structure provides the right balance of carbocation stability to achieve a useful reactivity window.
Oxetane radicals are examined in Chapter 4. Oxetane-3-carboxylic acids are suitable radical precursors via photoredox-catalysed decarboxylation, demonstrated in Giese-type reactions. The influence of ring strain and heterosubstitution on radical reactivity is investigated, showing radical-destabilising and radical-delocalising effects of the oxetane structure as a consequence of ring strain and Bent’s rule, resulting in an exergonic Giese addition. Oxetane benzoates are also shown to be suitable radical precursors in a radical recombination process with cyanopyridines to yield 4-pyridyl diaryl-oxetanes.
Chapter 5 investigates the sulfoxide–metal exchange of oxetane sulfoxides to generate oxetane carbanions. Protonation studies provide evidence for the formation of the unstable anionic intermediates. Reaction of oxetane sulfoxides with 2-pyridylmagnesium chloride favours a ligand-to-ligand coupling pathway to yield 2-pyridyl diaryl-oxetane products.
Chapter 3 describes the generation of oxetane carbocations from oxetane sulfonyl fluoride precursors through an unprecedented defluorosulfonylation pathway. 3-Aryloxetane carbocations are coupled to nucleophiles to achieve varied substitution in the 3-position. Reaction with amines yields aryl amino-oxetanes as potential isosteres of benzamides and the physicochemical properties of selected amino-oxetane/benzamide pairs are compared. Applicability to drug discovery is shown through late-stage functionalisation and the synthesis of oxetane drug analogues. Defluorosulfonylation proceeds by an SN1 mechanism with rate- determining formation of planar oxetane carbocations, whereby the oxetane structure provides the right balance of carbocation stability to achieve a useful reactivity window.
Oxetane radicals are examined in Chapter 4. Oxetane-3-carboxylic acids are suitable radical precursors via photoredox-catalysed decarboxylation, demonstrated in Giese-type reactions. The influence of ring strain and heterosubstitution on radical reactivity is investigated, showing radical-destabilising and radical-delocalising effects of the oxetane structure as a consequence of ring strain and Bent’s rule, resulting in an exergonic Giese addition. Oxetane benzoates are also shown to be suitable radical precursors in a radical recombination process with cyanopyridines to yield 4-pyridyl diaryl-oxetanes.
Chapter 5 investigates the sulfoxide–metal exchange of oxetane sulfoxides to generate oxetane carbanions. Protonation studies provide evidence for the formation of the unstable anionic intermediates. Reaction of oxetane sulfoxides with 2-pyridylmagnesium chloride favours a ligand-to-ligand coupling pathway to yield 2-pyridyl diaryl-oxetane products.
Version
Open Access
Date Issued
2023-04-23
Date Awarded
01/07/2023
Advisor
Bull, James A.
Sponsor
Pfizer (Firm)
Imperial College London
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)