New Catalytic Strategies for Metal-Free C-C Bond Formation

Amines and N-heterocycles are key building blocks for pharmaceutical compounds, arising in 60% of all small-molecule drugs. However, a consortium of major pharmaceutical companies recently identified a lack of practical methods for N-heterocycle synthesis as a serious impediment to drug development (see Nature Chem. 2018, 10, 383). The problem is not that these structures cannot in principle be accessed, but that the existing technology to synthesise them is so laborious and time-consuming that chemists are often forced to overlook regions of chemical space that may well provide the most optimal drug candidates.
The aim of this project is to find new synthetic methods for amine and N-heterocycle synthesis that can be easily applied in industry. My research will address the above challenges for some of the most highly sought-after N-heterocyclic scaffolds, including those containing only a single nitrogen atom and more exotic ring-systems comprising two nitrogen atoms.
Our lab has recently discovered a ground-breaking process to functionalise carbon-hydrogen (C-H) bonds in simple, nitrogen-containing starting materials called primary amines, in which two different catalysts orchestrate a carbon-carbon (C-C) bond formation under visible-light irradiation. I will leverage this novel reactivity to design novel and innovative chemical transformations to assemble important N-heterocycles with unprecedented efficiency, requiring only a single synthetic operation. In contrast, the current state-of-the-art for these targets prescribes extended linear sequences of up to five (or more) chemical steps, so the contributions here are set to be transformative.
We are further setting ourselves the challenge of ensuring that all of our processes are potentially executable on a process scale, which requires kilogram quantities of material. To achieve this goal, I will utilise modern flow chemistry techniques that run chemical reactions in tubing-based reactors, as opposed to conventional glassware. In conjunction with our industrial partner (AstraZeneca), I will also explore the potential for using automated robotic platforms in unity with our chemistry to generate novel libraries of high-value compounds for drug discovery.