A Maitland Japp Inspired Synthesis of 2-Spiropiperidines

With a growing desire to explore three-dimensional chemical space, methods for the
synthesis of spirocyclic compounds, more specifically aza-spirocycles, are becoming of great
interest to medicinal chemists. The synthesis of 3- and 4-spiropiperidines are well
documented, however, there is little precedent for the synthesis of 2-spiropiperidines. The
research detailed in this thesis describes the efforts towards the synthesis of 2-
spiropiperidines via both a stepwise (Scheme i) and a one-pot procedure (Scheme ii), for use
in a fragment drug discovery programme. The scopes of the procedures are demonstrated by
the synthesis of a diverse range of 2-spiropiperidines. The 2-spiropiperidines were utilised as
scaffolds to construct a small library of lead-like compounds that were analysed by LLAMA
and principal moments of inertia analysis. The 2-spiropiperidines were consequently found to
be three-dimensional. Methods for the construction of other structurally interesting
piperidines are also presented, including bridged piperidines, fused piperidines, and 6-
spiropiperidines, though the efforts were unsuccessful.