Transition-metal catalysed cycloaddition methodology for the convergent asembly of (Hetero) aromatic compounds

The continued development of new medicines by the pharmaceutical industry is a critical endeavour to improve and maintain human health, and the associated benefits to society are obvious. In order to develop new drugs, pharmaceutical chemists must prepare large collections of diverse compounds in order to identify a promising hit , which is then taken on for further development in the production of further collections of compounds. Therefore, as one might imagine, the methods (chemical reactions) which are used to prepare these compounds must be very efficient, reliable, and general in nature.Although a huge number of chemical reactions are known, (a number that continues to grow on a daily basis), only a very small proportion of these reactions are suitable for use in the preparation of these compound libraries. This is because most reactions fail to meet one or more of a list of demanding criteria that are applied in the generation of compound libraries. For example, many reactions only work for a narrow, restricted range of cases, or they require the use of exotic reagents or inconvenient reaction conditions. This limiting factor provides a powerful obstacle to the efficient development of new medicines.The proposed research is aimed at developing a reaction that has been known for a long time, but is rarely used by medicinal chemists in the pharmaceutical industry. This reaction employs a transition-metal catalyst to promote the reaction between several reaction partners to generate cyclic molecules that feature prominently in drugs and drug-like molecules. We will develop new variants of the general methodologies specifically targeted at the requirements of medicinal chemists, as well as modifying existing methodologies that currently do not quite fit these requirements. We anticipate that we can make numerous advances to positively impact the process of drug discovery, developing valuable (and publishable) chemistries along the way.This research will be conducted by a postdoctoral research associate working jointly at the University of Edinburgh and at GlaxoSmithKline, where they will have access to state-of-the-art equipment.

This research resulted in:
1. The development of an effective, convergent, and versatile method to access bicyclic 4-aminopyrimidines (important heterocyclic scaffolds for drug discovery), from the reaction of dinitriles with mononitriles in the presence of catalytic base (potassium t-butoxide).
2. The development of a modular synthesis of multisubstituted benzenes from the Diels-Alder reaction of dienamides with electron-deficient alkynes.