Developing a Catalytic Strategy to Address Regiocontrol in Radical Reactions of Aromatic Heterocycles

Lead Research Organisation: University of Cambridge
Department Name: Chemistry

Abstract

Construction of basic heteroarenes with varied substitution patterns is of great importance, but direct transformation of heterocyclic C-H bonds is a major challenge, often due to incompatibility with metal catalysts. Minisci-type additions are radical addition processes in which a basic heterocycle is protonated with a concomitant lowering of its LUMO, before attack by 'nucleophilic' radicals. This is a deceptively simple method with no catalyst required. The problem that has held back its widespread use is a lack of regioselectivity on heterocycles such as pyridines and quinolines due to insufficiently different LUMO coefficients of the C2 and C4 positions. We will develop a catalytic approach to Minisci additions that will allow us to control regioselectivity between C2 and C4. We anticipate that successful realisation of this strategy will allow the wealth of radical chemistry to be applied to valuable basic heterocycles with new-found regiocontrol.

Publications

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Proctor RSJ (2018) Catalytic enantioselective Minisci-type addition to heteroarenes. in Science (New York, N.Y.)

Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509620/1 01/10/2016 30/09/2021
1800778 Studentship EP/N509620/1 01/10/2016 31/03/2020 Rupert St John Proctor
 
Description A Minisci-type reaction (radical addition to an aromatic heterocycle) has been developed that not only directs a reaction towards a particular carbon centre (where otherwise multiple centres reacted) but the transformation installs a chiral carbon centre in the product, providing a new structure with high optical purity (handedness). The reaction has been achieved with radicals (chemical structures that contain an unpaired electron) derived from amino acids. Our reaction employs photoredox catalysis, which utilises compounds that allow better movement of electrons between reacting molecules through the absorption of visible light. High optical purity is achieved by using an enantiopure (of complete optical purity) acid catalyst. This appears to also aid the regioselectivity of the reaction.

Questions about how the reaction works have been raised and collaboration with Prof. Matthew Sigman at University of Utah has recently been completed. We used multivariate linear regression analysis to predictively expand the scope of our reaction to diazines. The predictions of enantioselectivity outcomes for these valuable, pharmaceutically relevant motifs were remarkably accurate in most cases and resulted in a comprehensive exploration of scope, significantly expanding the utility and versatility of our methodology. This successful outcome is a powerful demonstration of the benefits of utilizing MLR analysis as a predictive platform for effective and efficient reaction scope exploration across substrate classes.
Exploitation Route Pharmaceutical industry looking to broaden the library of small, enantioenriched molecules accessible for biomedical testing.
Sectors Agriculture, Food and Drink,Chemicals,Pharmaceuticals and Medical Biotechnology

URL https://pubs.acs.org/doi/10.1021/jacs.9b11658
 
Description Predictive Multivariate Linear Regression Analysis Guides Successful Catalytic Enantioselective Minisci Reactions of Diazines 
Organisation University of Utah
Country United States 
Sector Academic/University 
PI Contribution I, with my supervisor's guidance, performed all practical experimental work in the collaboration.
Collaborator Contribution Jolene P. Reid and Matthew S. Sigman performed the theoretical end of the project, performing calculations and guiding practical laboratory efforts.
Impact We published a paper on using multivariate linear regression analysis for enantioselective Minisci chemistry in the Journal of the American Chemical Society.
Start Year 2018