Synthesis of medium rings through ring expansion reactions of metallated ureas containing non-aromatic anion stabilising groups

Abstract

Cyclic structures containing between 8- and 12-members are classified as medium rings. Various bioactive natural products have been isolated containing these cyclic scaffolds, hence they are attractive targets for medicinal chemistry. Despite their promise the number of medium ring motifs in marketed pharmaceuticals is very limited, which is most likely attributed to the difficulties of synthesising them. Many pre-existing routes towards their synthesis use end-to-end cyclisation reactions, which are often limited in scope. Ring expansion reactions are becoming increasingly common as an alternative route towards medium rings as they avoid many of the problems associated with cyclisation reactions.

The Clayden group have reported the used of N to C aryl migrations of N-aryl-N’-benzyl ureas to form enantioenriched α-substituted quaternary amines. More recently they showed that tethering the aryl migrating ring to the nitrogen results in n to n+3 ring expansion reactions under basic conditions forming benzannulated medium rings. The work reported in this thesis aims to utilise this N to C aryl migration chemistry producing alternative benzannulated medium rings from ureas with various anion stabilising groups other than benzyl. Firstly, this concept was successfully applied towards the synthesis of a variety of iminohydantoin bridging medium rings through n to n+2 ring expansion using nitrile stabilised anions (A). These medium rings could then by hydrolysed under acidic conditions forming hydantoin bridging medium rings. This methodology was also applied toward the synthesis of vinylic medium rings from allyl ureas (B). A range of 8-11-membered benzannulated medium rings were isolated. These medium rings were then modified post-ring expansion by exploiting the reactivity of the enamide group through carbolithiation reactions, radical addition and hydrogenation.

Date of Award	21 Jun 2022
Original language	English
Awarding Institution	University of Bristol
Supervisor	Jonathan Clayden (Supervisor) & John Bower (Supervisor)