Heterocyclic inflation - efficient routes to medium rings by migratory ring expansion of alkenes

Medium ring (8-12 membered) heterocycles form the core scaffold of a range of naturally occurring biologically active compounds, with the conformational constraints imposed by the cyclic structure attributed to improving the binding of medium ring-containing compounds to their target protein. Thus, these rings are attractive synthetic targets for medicinal chemistry. However, the synthesis of these scaffolds remains very challenging, due to the unfavourable transannular interactions upon ring closure; this is the likely reason for the marked underrepresentation of medium rings in drug discovery. Therefore, new methods are required to provide access to these structures, thereby enabling medicinal chemists to incorporate medium rings into fragment screening libraries and novel drug designs.

A ring expansion strategy is an appealing way to make medium-sized ring compounds, since this can partially reduce the entropic penalty in forming the medium-sized ring, and five- to seven-membered heterocycles are widely available. Previous work in the Clayden group has demonstrated that readily accessible arene-containing amide or urea substrates can undergo an intramolecular aryl migration to generate medium ring compounds. This research project aims to employ this powerful ring expansion strategy to achieve alkenyl migration, rather than aryl migration, which would broaden the scope and enrich the library of potentially bioactive medium ring scaffolds that could be accessed.