Discovery and Development of Bifunctional Organic Superbases for Asymmetric Synthesis

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This project falls within the EPSRC Synthetic Organic Chemistry area.Catalysis is one of the most important tools in the modern chemical industry. Without appropriate catalysts and their applications our current quality of living could not be maintained. By the means of catalysis, otherwise challenging and lengthy chemical transformations become accessible at a very high rate and efficiency providing us with precious products that are used in the related chemical industries. One of the greatest advances in the late 20th century was the development of asymmetric catalysis by which we are able to synthesise highly desirable enantioenriched compounds. Organocatalysis has been one of the most important research areas in organic chemistry in the past decades. It utilises substoichiometric small organic compounds for the promotion of chemo - and enantioselective chemical transformations that yield products that are otherwise practically impossible to generate. Our group in the past twenty years has been developing novel chiral organocatalysts, applying them to challenging methodology. In 2013 within our group a new class of bifunctional iminophosphorane (BIMP) catalysts was realised. These catalysts exhibit a very high basicity (superbase), include a chiral backbone and a hydrogen bond donor substituent. These properties enable the catalysts to activate low reactivity compounds with high efficiency. The aim of this project is to further develop iminophosphorane catalysis, accessing out of reach reactants and streamline catalyst syntheses. As previously mentioned, the bifunctional character of BIMP catalysts makes them suitable for the concurrent deprotonation of a pro-nucleophile and the activation of an electrophile. Unfortunately, the very presence of a hydrogen bond donor on the catalyst limits it's basicity. If the acidity of the hydrogen bond donor moiety and the basicity of the iminophosphorane are comparable, the catalyst can deprotonate itself, that can possibly lead to aggregation, and the formation of inactive species. Eliminating this inherent incompatibility of high basicity iminophosphorane catalysts is highly desirable. An appealing replacement for the hydrogen bonding moiety could be a halogen or chalcogen bonding substituent, since these functionalities cannot be deprotonated. Despite the numerous similarities between halogen - and hydrogen bonding, halogen bonding assisted homogeneous catalysis remains largely unexplored, leaving us with the opportunity to study the field of bifunctional halogen bonding catalysis. A further advantage of halogen bonding assisted base catalysis would be that the basicity of the catalyst would not be limited by the Bronsted acidic moiety. Furthermore this could enable us to deprotonate extremely unreactive pro-nucleophiles with a strongly basic catalyst. The production of one of our catalysts requires at least five synthetic steps, rendering catalyst screening and optimisation an arduous process. This is due to the fact that feedstock amino acids utilised in the synthesis of organocatalysts require a considerable amount of chemical manipulation. The use of axially chiral amines for BIMP catalyst synthesis could drastically reduce the synthetic work it takes to access said molecules. We envision that harnessing the axial chiral pool could lead to the more facile synthesis of BIMP catalysts, making them more accessible for the wider chemical community. In summary the project will focus on the development of superbasic catalysts and corresponding methodologies, which will be of interest to the wider organic chemical community and industry.