Synthesis, Structure, and Biological Applications of a-Fluorinated ß-Amino Acids and Derivatives

This review gives a broad overview of the state of play with respect to the synthesis, conformational properties, and biological activity of a-fluorinated beta-amino acids and derivatives. General methods are described for the preparation of monosubstituted a-fluoro-beta-amino acids (Scheme 1). Nucleophilic methods for the introduction of fluorine predominantly involve the reaction of DAST with alcohols derived from a-amino acids, whereas electrophilic sources of fluorine such as NFSI have been used in conjunction with Arndt?Eistert homologation, conjugate addition or organocatalyzed Mannich reactions. a,a-Difluoro-beta-amino acids have also been prepared using DAST; however, this area of synthesis is largely dominated by the use of difluorinated Reformatsky reagents to introduce the difluoro ester functionality (Scheme 9). a-Fluoro-beta-amino acids and derivatives analyzed by X-ray crystal and NMR solution techniques are found to adopt preferred conformations which are thought to result from stereoelectronic effects associated with F located close to amines, amides, and esters (Figs. 26). a-Fluoro amide and beta-fluoro ethylamide/amine effects can influence the secondary structure of a-fluoro-beta-amino acid-containing derivatives including peptides and peptidomimetics (Figs. 79). a-Fluoro-beta-amino acids are also components of a diverse range of bioactive anticancer (e.g., 5-fluorouracil), antifungal, and antiinsomnia agents as well as protease inhibitors where such fluorinated analogs have shown increased potency and spectrum of activity.