LUKE HUNTER
The University of New South Wales, School of Chemistry, Sydney, NSW 2052, Australia

Abstract

This mini-review highlights some recent developments in the study of selectively fluorinated T-amino acids. Specifically, the different stereoisomers of —-difluoro—aminobutyric acid have been synthesised. Conformational analysis reveals that the different stereoisomers exhibit very different conformational behaviour, and this leads to biological applications of these molecules as subtype-selective GABA receptor ligands. Finally, a perspective is given on possible future applications of these molecules as components of shape-controlled bioactive peptides.

INTRODUCTION

Backbone-homologated amino acids (eg. (- and -amino acids) have attracted considerable attention in recent years (1). Peptides containing such non-natural amino acids have been shown to possess several characteristics that are desirable from a drug development perspective, including enhanced stability to metabolism, an ability to adopt well-defined secondary structure, and an ability to engage in productive binding interactions with natural protein targets (2). Also, backbone-homologated amino acids are amenable to functionalisation in ways that are not possible with natural -amino acids, and this opens up possibilities for creating conformationally-restricted amino acid building blocks that can confer additional spatial order when incorporated into therapeutic peptides.
Within this context, fluorine chemistry can play a unique role (3, 4). C−F bonds are known to participate in a variety of stereoelectronic interactions with neighbouring functional groups, and these interactions can favour certain molecular conformations over others. Examples of such stereoelectronic effects include dipole-dipole interactions, charge-dipole interac ...