The synthesis of medium-sized rings and macrocycles via a cyclisation/ring expansion cascade reaction

The primary aim of this thesis was to expand the scope of the Cyclisation/Ring Expansion (CRE) cascade reaction, originally developed by the Unsworth group. CRE cascade reactions allow the synthesis of medium-sized rings and macrocycles without the need for high dilution conditions. In this thesis, the scope and limitations of this CRE cascade reaction using bis-electrophilic reagents were explored and in unsuccessful cases attempts were made to identify side products. The use of imines as internal nucleophiles was found to be unsuitable with clear side products forming that were quantified and characterised. Utilising multiple internal nucleophiles was also demonstrated, allowing the synthesis of larger ring systems (up to 18-membered). Control reactions were performed for one of these substrates containing two internal nucleophiles, and clearly highlighted the importance of the internal nucleophiles, providing strong evidence for the proposed CRE cascade mechanism. This thesis also presents a new method for the diastereoselective synthesis of atropisomeric anilides based on an intramolecular acyl transfer via a tethered pyridyl moiety. This method was shown to have a broad scope, gave anilides in high dr (up to 99:1) and typically gave products in high yields, which were isolated as single diastereoisomers. Control reactions provided strong evidence for the proposed acyl transfer mechanism and DFT studies provided insights on the transition states for the acyl transfer reaction to justify the observed selectivity. Thermal epimerisation experiments allowed access to both diastereoisomers and demonstrated the stability of the C–N chiral axis (t1/2 = >1000 years at 25 °C).