Development of Catalytic Enantioselective Minisci-type Reactions

Abstract

This thesis details the development of a protocol for the catalytic enantioselective Minisci-type addition of prochiral radicals to heteroarenes through the dual techniques of chiral Brønsted acid catalysis and photocatalysis. The first research section details the initial hypothesis, design and implementation of our strategy for the enantioselective -C–H heteroarylation of alcohols by regio- and enantioselective Minisci reaction. The encountered barriers to fully successful realisation of the transformation are discussed. Subsequently, an enantioselective Minisci reaction involving N-acetyl-aminoalkyl radicals, generated by photocatalytic reduction of redox-active esters, is described. The reaction is found to be successful for a range of N-acetyl-aminoalkyl radicals on a range of quinolines and electron-deficient pyridines with high levels of regio- and enantioselectivity. The third research section describes a collaborative effort with Dr Jolene Reid and Prof. Matthew Sigman to establish a quantitative structure-activity relationship (QSAR) between reaction components. The resultant mathematical model allowed the prediction of enantioselectivity for then-undescribed asymmetric Minisci-type reaction of pyrimidines and pyrazines. The final research section addresses the possible degradation pathway observed in our initial hydroxyalkylation strategy by controlling reaction temperature and a crucial switch of photocatalytic system through consideration of the reaction mechanism. Hydrogen atom abstraction is also demonstrated to be effective for radical generation from linear amides, as a synthetically preferable alternative to redox-active esters.