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Abstract
When fluorine is incorporated into organic molecules, the C-F bond participates in a variety of stereoelectronic interactions with adjacent functional groups. These interactions can have a profound influence on the conformation of the molecule. Thus, controlled introduction of fluorine can be exploited as a tool for creating shape-controlled bioactive molecules, with the potential to tailor their activity and selectivity towards biomolecular targets. In this project, novel synthetic methodologies for the preparation of fluorinated amino acids have been developed.
A series of backbone homologated alpha,beta,gamma-trifluoro-delata-amino acids were synthesised via an approach involving three successive deoxyfluorinations. This synthetic strategy allowed for the stereospecific introduction of three fluorine atoms along the carbon chain, generating a number of novel isomers of alpha,beta,gamma-trifluoro-delta-amino acids. Notable features of this synthetic approach include the successful stereochemical control throughout, and an expedient method for converting a nitroaryl moiety into a carboxylic acid group.
Solid-state and solution-state analysis of the target molecules revealed that varying the stereochemistry of the fluorine atoms confers strikingly different conformations. The favoured conformation of the different isomers was rationalised by the known stereoelectronic effects of C-F bond incorporation.
Finally, in an attempt to develop a new synthetic methodology, electrophilic fluorination methods were investigated towards the synthesis of alpha,beta,gamma-trifluoro-delta-amino acids. The electrophilic fluorination of protected piperidine-2,4-diones via asymmetric organocatalysis was not successful, since the desired monofluorinated product was formed in only a low yield alongside undesired difluorinated and aldol products. To overcome these limitations, another new synthetic strategy was proposed based on the concept of fluorocyclisation. A model fluorocyclisation reaction was attempted, but this method met with limited success.
Overall, this project has completed the synthesis and conformational analysis of different stereoisomers of alpha,beta,gamma -trifluoro-delta-amino acids, the first time that these novel molecules have been studied. These fluorinated amino acids have the potential to be used as building blocks for the synthesis of shape-controlled bioactive peptides in the future.