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Synthesis, Structure, and Biological Applications of α ‐Fluorinated β ‐Amino Acids and Derivatives
Author(s) -
March Taryn L.,
Johnston Martin R.,
Duggan Peter J.,
Gardiner James
Publication year - 2012
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.201200307
Subject(s) - chemistry , peptidomimetic , amino acid , nucleophile , amine gas treating , amide , electrophile , reagent , combinatorial chemistry , stereochemistry , fluorine , biological activity , organic chemistry , peptide , catalysis , in vitro , biochemistry
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 ArndtEistert 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.