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Asymmetric reactions of nitrile compounds: an approach to the synthesis of bioactive molecules

Final Report Summary - ARNIIF (Asymmetric reactions of nitrile compounds: an approach to the synthesis of bioactive molecules)

Synthetic chemistry plays a key role in the preparation of new molecules that can find use as new drugs, agrochemicals, fine chemicals, polymers, or high value materials. Of particular importance is the ability to form carbon-carbon bonds in a controlled manner, as this allows the construction of the carbon frameworks in the desired molecules. With this bond formation often comes the necessity to control the absolute configuration at the carbon atom, in other words, which mirror image of the product is formed. This is crucial in drugs as different mirror images of small molecules often have different biological properties, since they interact with the large biomolecules of nature (enzymes) that themselves exist as single mirror image forms. An important method to prepare carbon-carbon bonds is to remove a proton from a compound using a base (usually a group I or group II metal species) and to react the new metallated intermediate with an electrophile. A useful compound that is very amenable to this deprotonation is a nitrile and good yields of the substituted compound with a new carbon-carbon bond can be formed. However these products are formed as mixtures of mirror images and it is seen as a huge challenge in the synthetic chemistry community to be able to transfer the optical purity from the nitrile to the product.

This Marie Curie International Incoming Fellowship commenced in October 2014 and ran for two years. The objectives of the Fellow (Dr Arghya Sadhukhan) were to investigate whether it was possible to perform selective reactions with optically active metallated nitriles. Six workpackages were studied, involving WP1 and 2: the preparation of chiral nitriles and their metallation; WP3: the rate at which the metallated mirror images interconvert; WP4: a study of their structures; WP5: their ability to undergo further transformations; WP6: any selectivity in the presence of chiral ligands. All six workpackages were studied and we were delighted to find that highly selective reactions were discovered. Workpackages 1–4 were most successful and allowed the formation of products without significant loss of optical activity and we were able to quantify the rates of interconversion, together with proposing plausible structures.

The Marie Curie Fellowship allowed Dr Sadhukhan to enhance his strengths in research, to experience the European research environment, and to transfer knowledge and skill to other researchers, particularly through the co-supervision of two PhD students. In addition, the Fellow attended personal development and training events. The results of the research have been published in a high impact journal and by presentations at conferences.

In terms of the research, we can conclude that the project has been successful and has led to new knowledge and understanding of metallated nitriles compounds. Before the project commenced it was unclear how general this was likely to be and we were unaware of any structural data. This project has allowed us to explore the scope of this chemistry and to understand the requirement for at least two equivalents of base, since two metal ions are present in the intermediate. The ability to transfer the chirality (single mirror image form) from the starting nitrile to the substituted nitrile product is remarkable and is likely to impact on how synthetic chemists think about these intermediates. This could have implications for use in academic or industrial laboratories in future, as researchers use this chemistry to prepare enantiomerically enriched nitrile products. The potential for application in the pharmaceutical industry sector could make an impact on health and well-being and hence have long term socio-economic impact.

The project has made a huge impact on the research fellow, Dr Sadhukhan. He has benefitted from scientific and technical training in activities directly related to the project and has gained very valuable experience in the EU. He supervised two PhD students and helped to run a research laboratory. These activities have helped him to mature as an individual and as a research leader, by strengthening his ability to direct projects and manage a team. These aspects will impact the future employment that Dr Sadhukhan will undertake.

The main dissemination activities have been the reporting of the results through the presentation of the results at conferences and, in particular, through a very high impact publication in the scientific literature. This publication is in one of the top-ranking journals in chemistry (Chemical Science) with a very high impact factor and is highly regarded internationally. The work is open access and can be found at:
Both Dr Sadhukhan and Prof Coldham disseminated the results of the research at several conferences. Dr Sadhukhan also presented his results at regular research group meetings and to visitors to the Department, thereby improving his communication skills. The results of the metallated nitrile chemistry have so far been presented at three international conferences and one national conference during the period of this grant. A highlight was the international symposium on carbanion chemistry in France, where Dr Sadhukhan was given the opportunity to present his work as a poster and to meet academics and industrial chemists from across the world. At the same meeting, Prof Coldham presented the results as a plenary lecture presentation. It is hoped from all these dissemination activities that particular interest in this science will be stimulated to lead to further work in this area.

The address of the project public website can be found at: