Synthesis and functionalisation of a 3-D spirocyclobutyl piperidine building block for medicinal chemistry

This thesis describes the synthesis and functionalisation of a 3-D building block, cyclobutyl trifluoroborate salt A, for use in a modular synthetic platform that aims to elaborate fragment hits in 3-dimensions. Ni-catalysed photoredox cross-coupling and Suzuki-Miyaura cross-coupling to produce aryl cyclobutanes B were developed. In addition, N-functionalisation of aryl cyclobutanes B afforded five examples of lead-like compounds C.

Chapter 2 describes the development of two different routes to cyclobutyl trifluoroborate salt A, one via a cyclobutene and the other via an enol triflate. The enol triflate route was the preferred route. In this route, the enol triflate underwent Miyaura borylation to introduce a Bpin group. Then, hydrogenation gave the cyclobutyl Bpin compound which was then converted into cyclobutyl trifluoroborate salt A. This gram-scale synthesis was achieved in an overall yield of 68% over four steps.

Chapter 3 describes the cross-coupling of cyclobutyl trifluoroborate salt A with medicinally relevant FragLites to produce aryl cyclobutanes B. Ni-catalysed photoredox cross-coupling and Pd-catalysed Suzuki-Miyaura cross-coupling reactions were successful in cross-coupling six aryl bromides to the building block scaffold.

N-Functionalisation of aryl cyclobutanes B to afford N-functionalised aryl cyclobutanes C for the synthesis of medicinally relevant lead-like compounds is described in Chapter 4. Vector analysis of N-functionalised aryl cyclobutane C (Ar = pyrimidine, R = methanesulfonamide) enabled visualisation of the vectors in chemical space that this lead-like compound accesses.