Synthesis, structure, and biological applications of α-fluorinated ß-amino acids and derivatives.

ABSTRACT

This review gives a broad overview of the state of play with respect to the synthesis, conformational properties, and biological activity of α-fluorinated ß-amino acids and derivatives. General methods are described for the preparation of monosubstituted α-fluoro-ß-amino acids (Scheme 1). Nucleophilic methods for the introduction of fluorine predominantly involve the reaction of DAST with alcohols derived from α-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. α,α-Difluoro-ß-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). α-Fluoro-ß-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. 2-6). α-Fluoro amide and ß-fluoro ethylamide/amine effects can influence the secondary structure of α-fluoro-ß-amino acid-containing derivatives including peptides and peptidomimetics (Figs. 7-9). α-Fluoro-ß-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.