Discovery and Development of Bifunctional Organic Superbases for Asymmetric Synthesis

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.

This programme is focused on a new cohort-driven approach to the training of next-generation doctoral scientists in the practice of novel and efficient chemical synthesis coupled with an in-depth appreciation of its application to biology and medicine.

This collaborative academic-industrial SBM CDT will have long-term benefit to the chemical industry, including the pharmaceutical, agrochemical and fine chemical sectors. These industries will benefit through: (i) the potential to employ individuals trained with broad and relevant scientific and transferable skills; (ii) new approaches to the investigation of complex biological and medical problems through novel chemistry; and (iii) better and more efficient synthetic methods.

We will link the work of DSTL, and our pharmaceutical and agrochemical partners (GSK, UCB, Vertex, Evotec, Eisai, AstraZeneca, Syngenta, Novartis, Takeda, Sumitomo and Pfizer) through a common theme of synthesis training. The design and synthesis of new compounds is essential for disease treatment and prevention, and for maintaining food security. Synthesis contributes significantly to UK tax revenue and results in sustained employment across a number of sectors. Employers in the finance, law, health, academic, analytical, government, and teaching professions, for example, also recognise the value of the translational skill-sets possessed by synthesis postgraduates, which this programme will provide.

The SBM CDT training programme will adopt an IP-free model to enable completely free exchange of information, know-how and specific expertise between students and supervisors on different projects and across different industrial companies. This will lead to better knowledge creation through unfettered access to information from all academics, partners and students involved in the project. By focussing on basic science, we will engender genuine collaboration leading to enabling technology that will be of use across a wide range of industries.

We will train the next generation of multidisciplinary synthetic chemists with an appreciation of the impact of synthesis in biology and medicine. Their unconstrained view of synthesis will aid in new scientific discoveries leading to new products, which (with appropriate inward investment), can lead to the formation of new companies and new UK employment.

We will, in part through an alliance with the Defence, Science and Technology Laboratory, engage with policy-makers to influence future policy issues involving chemistry such as food security and the rise of antibiotic resistance (both of which are relevant to our programme and are important for society as a whole).

Outreach and public engagement will be a key aspect of our programme; and all students in the proposed SBM CDT will take part in at least one outreach activity. Typical activities include: open days in the Chemistry Department through the 'Outreach Alchemists', engaging with the Oxfordshire Science Festival and participation in the various other activities already in place through the public engagement programme of the Department of Chemistry.

The research output of the students will be disseminated via high impact international publications and lectures; these will be of value to other academics in relevant fields and will be of value in the development of further research funding applications. Outreach activities and research output will also be advertised on a website dedicated to the proposed SBM programme.