title: Synthesis, structure, and biological applications of α-fluorinated β-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 β-amino acids and derivatives. General methods are described for the preparation of monosubstituted α-fluoro-β-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-β-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-β-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 β-fluoro ethylamide/amine effects can influence the secondary structure of α-fluoro-β-amino acid-containing derivatives including peptides and peptidomimetics (Figs. 7-9). α-Fluoro-β-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.
authors.affiliation: School of Chemical & Physical Sciences, Flinders University, Adelaide 5042, Australia.
authors.forename: Taryn L
authors.initials: TL
authors.lastname: March
authors.forename: Martin R
authors.initials: MR
authors.lastname: Johnston
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Duggan
authors.forename: James
authors.initials: J
authors.lastname: Gardiner
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D005461:Fluorine / Q000737:chemistry* / Q000494:pharmacology*; D054879:Halogenation; D006801:Humans; D008958:Models, Molecular; D009181:Mycoses / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D005461:Fluorine