Counter-ion Directed Enantioselective Approaches to Axially Chiral Materials

Axial chirality is a term used to refer to stereoisomerism resulting from the non-planar arrangement of four groups in pairs around a chirality axis. Such compounds are exemplified by hindered biaryls, certain classes of spiro compounds, and allenes. Atropisomerism is a phenomenon whereby restricted rotation about a single bond leads to the formation of stereoisomers, and is a key feature of natural products, drug molecules and catalysts. It's increasing importance in all of these fields means that new methods for the enantioselective synthesis of atropisomeric compounds are extremely important. The aim of this proposal is to develop and exploit new catalytic enantioselective methods for the construction of axially chiral molecules. We propose that chiral ammonium counter-ions can be employed to control the stereochemistry of these reactions through kinetic resolution and dynamic kinetic resolution processes. We also propose a light-mediated racemization process that can be coupled with a counter-ion-mediated kinetic resolution, enabling the dynamic kinetic resolution of biaryls with large barriers to rotation at room temperature. Finally, we aim to use these reactions as exemplars to probe the kinetics and mechanism of enantioselective phase-transfer catalysis.

This research will provide new strategies for the synthesis of a range of axially chiral molecules, and elucidate mechanistic aspects of a key catalysis technique. Ultimately, this will lead to new green synthetic methods and enhance the knowledge base of synthetic chemistry as a whole, and provide access to useful functional molecules. In addition, this research will provide excellent training for the postdoctoral workers on the project, but will also be valuable for researchers in other disciplines such as medicinal chemistry, materials and catalysis. Through high quality publications, international meetings, interactions with the pharma industry, and collaborative research projects we will present our research to a broad audience. The outputs from this work will benefit academic researchers in the field of enantioselective catalysis through the development of new strategies for controlling axial chirality. Our focus on phase-transfer catalysis and mechanism will be of interest to researchers in the broad field of catalysis, but especially those with a focus on physical organic chemistry and the fields of counter-ion mediated processes. In addition, phase-transfer catalysis constitutes a green technology and hence this work will be of interest to those working in fields related to sustainable chemistry. Our work is likely to be of interest to those working in the pharmaceutical and agrochemical science fields, as the methods and insights from mechanism are likely to inform future strategies in the construction of complex materials.

Our work will be promptly published in high quality journals; these are regularly examined by industry, specialist magazines and the popular press; this aids significantly in broadly disseminating academic work. Our research outputs will all be open access, and our data and pre-publication papers will be archived in Oxford's open access archive (https://ora.ox.ac.uk). It is anticipated that both PDRAs will attend one international and one national conference per year. This gives the PDRAs the opportunity to present their research to other academics, students and end users working in relevant areas. The PI regularly attends national and international conferences and speaks at other academic institutions and industrial companies. This enables engagement with potential end-users of our work. We have close collaborative links with major international initiatives including the Target Discovery Institute and the Structural Genomics Consortium; these existing collaborations will enable us to explore any translational aspects of our work that emerge. This is particularly relevant given increasing interest in the application of three-dimensional scaffolds in drug discovery. Our collaboration with Prof Robert Paton's group (University of Oxford) will enable us to calculate transition states for our reactions; these conclusions may be generalized to other classes of reaction. This collaborative work will be of interest to those working in quantum calculation, particuarly with a focus on applications in catalysis.