The design of biofunctional cinchona alkaloid derived catalysts : a new departure

Abstract

This thesis reports the synthesis of a novel class of quinine derived catalyst and its application to the field of organocatalysis. Initially, a suite of seven novel C-9 phenol and naphthol substituted quinine derivatives were synthesised. The activity of this suite of catalysts has been explored in a range of reactions. The nature of these catalysts allowed for unprecedented tuneability, indeed it was possible to discriminate between 1,2 and 1,4 addition reactions based on iterative changes to the catalyst structure, which allowed alteration to the distances between hydrogen bond donors and acceptors within the catalyst. It was also possible to identify the conformation of the catalyst as a key component in determining their selectivity. Analysis of the solution phase conformations for several of the catalysts is shown. Efforts towards making C-9 aniline-substituted derivatives have also been attempted; however this was not successful, despite the investigation of a variety of synthetic pathways. The application of the catalysts which proved to be active in 1,2-addition reactions to the dynamic kinetic resolution of azlactones was undertaken. It was possible, based on the choice of C-9 substituent, to select for either product enantiomer without changing the stereochemistry within the catalyst. By optimisation of the azlactone substrate it was possible to increase both the reactivity and selectivity observed. The most suitable of these catalysts was shown to promote the room temperature DKR of azlactones, affording the products derived from hindered α-amino acids in up to 95% ee. Unfortunately for less hindered substrates enantioselectivity observed was uniformly more modest. Further investigation of modifications to the catalyst structure aimed at improving the overall efficiency of this catalytic system has been made, with large improvements in activity and selectivity achieved. The generation of a library of novel catalysts with significantly enhanced activity profiles compared to earlier catalysts of the same class has been described. Key considerations in the synthesis of quinine derivatives modified at several positions have been considered, with the scope of C-9 arylation reactions explored in depth. Furthermore it has been possible, through systematic modification of the catalyst to identify features in the catalyst structure which are key to both the activity and selectivity profile of these systems. The systematic modification of the catalyst structure has been used to optimise catalyst performance in the DKR of azlactones. This has allowed for the DKR of 2,4,6-trichlorobenzene substituted azlactones with enantioselectivity in excess of 90% ee, even using azlactones derived from unhindered amino acids. In the case of hindered azlactones exceptional enantioselectivity could be achieved with ee of up to 97% possible. Interestingly it was also possible to examine the mode of action of the catalyst. It was possible to discount nucleophilic catalysis as a catalyst role despite circumstantial evidence initially favouring it as a possibility. Furthermore, it was possible to observe that the catalysts synthesised were active in more than one conformation, which could favour the promotion of the formation of different product enantiomers. The alteration of the relative populations of these conformations by changes in temperature was shown to be possible and it was even possible, in one case, to demonstrate a temperature dependent change in the sense of enantiocontrol.