Oxidative radical cyclisations for the synthesis of lactones

Thesis

The object of study of this thesis lies on the optimisation of the oxidative radical cyclisation methodology for the preferential formation of gamma-lactones from unsaturated alkyl malonate derivatives.

Chapter 1 introduces the concept of free-radical cyclisation; more extensive explanations are given for the intramolecular oxidative radical cyclisation using manganese(III) and copper(II) salts as oxidants. An overview of the contribution of the Burton group in the field is given, in which both the applicability and the limitations of the transformation are showcased.

Chapter 2 is concerned with the synthesis of the ethisolide family of natural products and one non-natural analogue, in which the oxidative radical cyclisation is key for the construction of the bis-gamme-lactone moiety present in such natural products. The initial limitations of the methodology allowed for the discovery of new conditions for the formation of chloro monocyclic systems and for the development of copper-free oxidative cyclisation conditions for gamma-lactone formation.

Chapter 3 reports the developments on the metal-free oxidative radical cyclisation. Bicyclic gamma-lactones were synthesised from all-carbon alkyl malonate derivatives through anodic oxidation via constant current electrolysis. The development of a novel ionic oxidative cyclisation is also discussed.

Chapter 4 describes our efforts towards the formation of both fused and spiro gamma-lactam-beta-lactone molecules, as potential analogues to proteasome inhibitors, from either gamma-lactam-gamma-lactones or exo-gamma-lactams precursors, previously synthesised through oxidative radical cyclisation.

Full experimental details, NMR spectra for the natural products and for the non-natural analogue, and a comparison between the obtained and the previously reported NMR data are also provided.

Authors: Martinez, S

• DOI: 10.5287/ora-vjykz71vg
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Organic Chemistry; Oxidative Radical Cyclisation
• Subjects: Organic Chemistry