The Preparation and Application of Novel Planar Chiral Ferrocenyl Ligands in Asymmetric Catalysis

Asymmetric catalysis, employing both transition-metal complexes of chiral ligands and organocatalysts has become one of the most popular methods for the preparation of enantioenriched and enantiopure compounds. This is important for the synthesis of chiral biologically active compounds or drug targets. The design of efficient and novel chiral ligands and catalysts has become a prominent area of chemistry in itself. In this PhD thesis, the concept of chirality and the importance of chiral synthesis in chemistry is introduced while highlighting the interesting properties of ferrocene and the development of chiral ferrocenyl scaffolds in this expanding area of chiral ligand synthesis. The aim of this project was to exploit the reactivity and selectivity of ferrocenyl mono- and diketone scaffolds optimised previously in the group to develop a range of interesting chiral catalysts and ligands. The first of these novel structures was an extended diol structure which would serve as a second generation to diols produced previously in the group which possessed a quaternary centre at the alpha-ferrocenyl position. Three chiral diols extended by two methylene units, were synthesised in six high yielding steps with minimum purification required. These catalysts were applied in an asymmetric hetero Diels-Alder reaction affording the product in low yield and low enantioselectivity of up to 33% ee. The presence of a tertiary stereocentre at the alpha-ferrocenyl position caused instability issues compared to the previous library. Following on from this, five novel ferrocenyl aniline-containing amino alcohol ligands were developed diastereoselectively in as few as three high yielding steps. These ligands were very successful in asymmetric diethylzinc addition to aldehydes, achieving ees of up to 99% and in asymmetric phenyl transfer reactions with moderate yields and enantioselectivities of up to 88%. With the assistance of X-ray crystallographic studies, transition states for the novel gamma-amino-alcohol system were proposed to explain the stereochemical outcome of the reactions. Finally, a fascinating rearrangement was observed when attempting to synthesise a ferrocenyl phosphoramidite, resulting in the formation of novel chiral phosphonamidate structures. Compounds that possess this moiety have been shown to evoke therapeutic effects such as anti-cancer and anti-viral properties. By utilising both X-ray crystallography and 31P NMR spectroscopy, a mechanistic understanding of phosphonamidate formation was reached, with four diastereomers theoretically possible in their synthesis. By employing a series of secondary amines, six chiral phosphonamidate analogues were synthesised with both a major and minor diastereomers isolated and their structures successfully elucidated