The Application of Catalysis based on Hydrogen Bonding and Ion-pairing Interactions to Asymmetric Minisci-type Alkylations of Azines and Iridium-Catalysed C-H Borylation.

Abstract

Recent advances in the incorporation of attractive non-covalent interactions into small molecule catalysts have greatly increased the understanding of how such approaches can be applied to regioselectivity and enantioselectivity challenges in synthetic chemistry. The most widely used interactions, hydrogen bonding and ion-pairing, are employed in this thesis for the accomplishment of two important transformations in an enantioselective manner. The directionality of hydrogen bonding makes it a valuable tool for engendering asymmetry in organic synthesis and the application of this interaction to the Minisci-type addition of prochiral radicals to azines is described in chapter 2. Several strategies for the asymmetric hydroxyalkylation of pyridines and benzopyridines were attempted including generating radicals through the fragmentation of α-hydroxy and β-hydroxy redox-active esters, hydrogen atom transfer using Selectfluor®, and hydrogen atom transfer using organic peroxides. Chapter 4 describes the application of hydrogen bonding and ion-pairing approaches to meta-selective iridium-catalysed C-H borylation. Although there are a several reports of enantioselective ortho-selective borylation of arenes, a reaction that reached more remote positions had not yet been realised. The association of a chiral countercation with an anionic sulfonated ligand gave rise to a complex which could perform the desymmetrisation of benzhydrylamides and phosphinamides with high enantioselectivities. As the sulfonated ligand used in this transformation was originally developed for regioselective borylation of arenes, the application of this chiral countercation approach was demonstrated for benzhydrylamides where there was also a regioselectivity choice. Good regioselectivity was observed with such substrates, albeit with a slight drop in enantioselectivity. Chapter 4.7 then details the attempted extension of this desymmetrisation protocol to kinetic resolutions of unsymmetrical phosphinamides. Unfortunately, poor enantioselectivity was observed with these substrates, despite their structural similarity to the substrates which had previously given excellent enantioselectivity. Chapter 4.8 then details a collaborative project with Dr Kristaps Ermanis on the nature of the transition states for oxidative addition of symmetrical benzhydrylamides and phosphinamides. Density functional theory (DFT) calculations by Dr Ermanis suggested contrasting conformations for the oxidative addition of the two substrate classes and synthetic investigations lent support to the proposed interactions in these transition states.