Novel transformations on azetidines

Thesis

This thesis describes transformations on azetidines, with focus on functionalisation α- to N. Direct asymmetric azetidine functionalisation has been a long-standing challenge, with limited examples in the literature. Recent work within the Hodgson group developed the N-tert-butoxythiocarbonyl (Botc) directing/activating group as an effective and practical means to effect asymmetric α-lithiation—electrophile trapping on azetidines. This thesis describes significant expansion and mechanistic understanding of this methodology.

The feasibility of accessing enantioenriched 2,4-disubstituted azetidines by α’- lithiation—electrophile trapping is explored, with modifications of the N-directing group detailed.

Additionally, examination of an α-boronic ester ‘synthetic handle’ as a means to functionalise azetidines is detailed. This includes developing a means to synthesise an enantioenriched α-boronic ester azetidine via asymmetric α-lithiation—borylation, with subsequent development of an asymmetric 1,2-metallate rearrangement homologation reaction, to give highly enantioenriched azetidines with control of the two contiguous stereocentres. Derivatisation of the homologated azetidines is described, allowing for access to a range of 2-substituted azetidines previously inaccessible via direct α-lithiation—electrophile trapping.

Finally, studies in the origins of the enantiodetermining mechanisms for the asymmetric α-lithiation—electrophile trapping of N-Botc azetidine show an intriguing electrophile dependent mechanism, which can rationalise the origins of the differing sense of asymmetric induction for particular electrophiles

Authors: Delany, PK

• DOI: 10.5287/ora-n1mzdpydr
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: lithiation; azetidine; mechanism; boronic ester; organic chemistry; asymmetric
• Subjects: Boronic esters; Azetidine lithiation; mechanistic studies; Asymmetric synthesis