Design, Synthesis and Characterisation of Fluorescent Purine Nucleosides Containing Rigid ‘Phenyl-ethynyl-phenyl-’ Moieties: Identification of New Pd2(dba-Z)3 Catalysts for Sonogashira Cross-couplings

Abstract
This thesis describes the design, synthesis and characterisation of novel fluorescent purine nucleosides, which directly address the general lack of commercially available analogues for studying DNA and RNA polymerases in a biological context. C8 purine modification is an advantageous position for fluorescent-labelling that can potentially minimise interactions along the Watson-Crick base pairing edge. An organic rigid-rod system, namely a ‘phenyl-ethynyl-phenyl-’ group was linked to the purine, inducing adequate fluorescence properties. A series of C8-modified purine nucleosides, containing highly conjugated linear ethynyl linker motifs, were synthesised, employing Sonogashira cross-coupling chemistry and catalytic Pd/Cu. The development of new Pd catalysts capable of performing these reactions was deemed necessary for these Sonogashira cross-coupling reactions, exploiting the ligand properties of olefins (alkenes).
A series of dibenzylidene acetone (dba-Z) alkene ligands and their novel Pd complexes were synthesised and characterised. Detailed NMR spectroscopic and TEM analyses were required to determine the composition and structure of the dinuclear ‘Pd-dba-Z’ complexes. The Pd2(dba-Z)3 complexes were found to be useful catalysts for use in the cross-coupling reactions of suitably halogenated nucleosides. A library or adenosine and guanosine compounds has been prepared, using the newly developed Pd catalysts.
Molecular self-assembly is principal to many areas of study in biology and supramolecular chemistry. The biophysical behaviour of the synthesised fluorescent nucleoside compounds has been examined and a detailed study by UV-Vis and fluorescence spectroscopy. The solvatochromism properties of the compounds are reported. DMSO showed the largest quantum yields in comparison with other solvents for all the fluorescent nucleosides. While in water, the quantum yields were found to be relatively small, values are workable in a biological context. The modified-guanosine and adenosine analogues exhibit photophysical characteristics which may prove useful in future studies.
The development of a C-H bond functionalisation methodology for the catalytic direct arylation of inosine at the C8 position has been investigated. Such chemistry is advantageous for the introduction of aromatic groups, avoiding pre-functionalisation (halogenation) of the nucleoside substrates, as compared to traditional cross-coupling reactions, e.g. Suzuki-Miyaura. Some limitations with the methodology have been identified.
In a separate strand to the thesis, the design, synthesis and characterisation of platinum complexes containing phosphine-alkene ligands, based on a chalcone-ferrocene framework, is detailed (within Appendix A). Platinum complexes containing either the ‘Lei’ ligand and/or ‘ferrocenyl-derived-Lei’ ligand have been further characterised.