Exploring oxetane isosteres for drug discovery through the catalytic generation of Oxetanyl Carbocations
File(s)
Author(s)
Croft, Rosemary
Type
Thesis
Abstract
Oxetanes are valuable motifs for modulating the metabolic susceptibility and physicochemical properties of medicinally promising compounds, as well as replacement motifs for carbonyl, gem-dimethyl and methylene units. For this reason, development of methodology to synthesise novel oxetane derivatives through efficient and robust routes is highly desirable.
In this thesis, the preparation of novel oxetane scaffolds through the in situ generation of oxetanyl carbocations is explored. First, the preparation of 3,3-diaryloxetanes, designed as isosteres for benzophenone and diarylmethane derivatives, through a catalytic Friedel–Crafts reaction is described. Using a lithium catalyst, 3,3-diaryloxetanes and dihydrobenzofuran scaffolds are both selectively prepared in one step by reaction of oxetan-3-ols with phenols. A scope of both scaffolds is exemplified along with further derivatisations of the 3,3 diaryloxetane motif. Studies into the mechanism of the reaction using 1H NMR spectroscopy to observe oxetane ether intermediates are described.
The same lithium catalyst is applied to the thiol alkylation of oxetanols with sulfides towards a wide range of novel 3-sulfanyloxetanes in excellent yields (up to 91%). The sulfide linker presents a versatile site for further derivatisation leading to novel oxetane containing structural classes and building blocks such as sulfoxides, sulfones, sodium sulfinate salts and sulfonyl fluorides. The reactivity of the oxetane-containing sulfinate salts and sulfonyl fluorides is described. In particular, oxetane-containing sulfonyl fluorides show exciting novel reactivity giving 3-aminooxetanes when reacted with a variety of amines instead of the expected sulfonamides. Studies into this unprecedented reactivity are described and compared to other alkyl sulfonyl fluorides.
The final section of this thesis provides full experimental details and data for all compounds synthesised during the course of this research.
In this thesis, the preparation of novel oxetane scaffolds through the in situ generation of oxetanyl carbocations is explored. First, the preparation of 3,3-diaryloxetanes, designed as isosteres for benzophenone and diarylmethane derivatives, through a catalytic Friedel–Crafts reaction is described. Using a lithium catalyst, 3,3-diaryloxetanes and dihydrobenzofuran scaffolds are both selectively prepared in one step by reaction of oxetan-3-ols with phenols. A scope of both scaffolds is exemplified along with further derivatisations of the 3,3 diaryloxetane motif. Studies into the mechanism of the reaction using 1H NMR spectroscopy to observe oxetane ether intermediates are described.
The same lithium catalyst is applied to the thiol alkylation of oxetanols with sulfides towards a wide range of novel 3-sulfanyloxetanes in excellent yields (up to 91%). The sulfide linker presents a versatile site for further derivatisation leading to novel oxetane containing structural classes and building blocks such as sulfoxides, sulfones, sodium sulfinate salts and sulfonyl fluorides. The reactivity of the oxetane-containing sulfinate salts and sulfonyl fluorides is described. In particular, oxetane-containing sulfonyl fluorides show exciting novel reactivity giving 3-aminooxetanes when reacted with a variety of amines instead of the expected sulfonamides. Studies into this unprecedented reactivity are described and compared to other alkyl sulfonyl fluorides.
The final section of this thesis provides full experimental details and data for all compounds synthesised during the course of this research.
Version
Open Access
Date Issued
2018-06
Date Awarded
2018-08
Advisor
Bull, James
Sponsor
Imperial College London
Royal Society (Great Britain)
Engineering and Physical Sciences Research Council
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)