New Frontiers in Transition Metal Free Synthesis

For many years chemists have been using chemical reactions to build complex molecules for an array of diverse applications ranging from drugs and agrochemicals to polymers and new materials as well as many, many others. In particular, reactions that create new carbon-carbon and carbon-heteroatom bonds have been particularly useful and scientists have commonly used catalysts based on transition metals to help them achieve this goal. These catalysts have undoubtedly revolutionised many branches of chemistry by allowing previously inaccessible scaffolds to be prepared.

Despite their general utility, many chemists would prefer not to use these metals if possible. There are a number of reasons for this. Firstly, transition metals are often rare and expensive. This naturally leads to an expensive reaction, especially if undertaken on an industrial scale. Furthermore, many transition metal catalysts also require complex ligands that themselves are expensive and require prior synthesis. Occasionally, the ligand can even be more complex and more difficult to prepare than the target molecule. Chemists are therefore always interested in finding new and efficient ways of preparing complex molecules

A second consideration for scientists employing transition metals is their toxicity. Many of these substances and their compounds are also toxic and extreme effort is required to remove all traces of them from the reaction products. These products are frequently drug molecules and naturally must meet strict safety regulations. Any process that can be developed where such catalysts are eliminated is therefore desirable, however very few have achieved this goal so far.

This proposal seeks to address the above issues and develop new processes that create new carbon-carbon and carbon-heteroatom bonds but without employing transition metals. The work will build on the preliminary work from our own laboratory which suggests that simple bases, some of them known for centuries have a fascinating additional dimension to their personality. We aim to both study and exploit the reactivity of these simple compounds in order to engineer new methods of constructing complex products. In doing so we hope to find out more about these simple compounds and so alert others to the untapped potential that they might offer in developing clean, efficient and economical chemical processes.

The work outlined in the proposal is aimed at developing new chemistry in the absence of transition metals (where these were previously considered essential). Such methodology has long been sought, since although extremely useful, transition metals are often toxic and expensive. Palladium in particular is widely used by the pharmaceutical sector to construct drug molecules on plant scale, however, considerable effort and resource has to be committed to its removal. The methods outlined in this proposal will therefore be of interest to a wide variety of scientists working within the chemical sciences and particularly to those working in the pharmaceutical sector.

Synthetic chemists (both academic and industrial) will find use in the described methodology however the impact will be much wider than in this field alone. Fundamental scientists interested in the behaviour and properties of molecules will be able to use the data that will be collected. The field of research proposed is one of the most competitive and fast moving in organic chemistry at the moment. There is intense global interest in the compounds that the proposal seeks to study. They have fascinated chemists in recent years for their apparent dichotomous behaviour that has, until recently, been overlooked and unexploited. The work in this proposal will provide insight into the mechanism of the processes that have captured the attention of many research workers and will build on early successes in the PIs laboratory. The proposed research will therefore contribute to the knowledge and understanding in the field and establish the PIs laboratory as a world leader in the field.

The development of the methods and compounds described in this proposal have enormous potential to contribute to the success of both fundamental research base and the pharmaceutical industry in the UK. The elimination of transition metals from some of the most popular industrial processes has long been imagined however never realised. The results generated by this programme of research (again, following suitable IP protection) will be particularly targeted towards the pharmaceutical industry by engaging and visiting companies based in the UK and working with them to develop processes that meet their needs. Success of this project will result in these industrial processes being both more economical and more environmentally sustainable and will therefore contribute to the competitiveness of the UK research base and economy as a whole.