Synthesis of Fluorinated β-Amino Acids

The major goal of this review is to provide an overview of the general synthetic methods available in the literature for preparing fluorinated β-amino acids and their derivatives. These compounds have been employed in combination with non-fluorinated amino acids in the design of peptides and peptidomimetics for investigation of their proteolytic stability and influence of molecular composition on the folding properties and biological activity. Fluorinated­ β-amino acids serve as precursors for the β-lactam antibiotics­ and fluoroalkene dipeptide isosteres or as structural components of analogues of natural products. There are several general methods available for introducing into β-amino acids either one or two fluorine atoms at the α-position, as well as α- or β-fluoroalkyl substituents; these methods include reduction of fluorinated β-imino esters, biomimetic transamination of fluorinated carbonyl compounds, Michael-type addition to trifluorocrotonate and α-tri­fluoromethacrylate derivatives, and Reformatsky and Mannich-type reactions of fluorinated substrates. Fluorinated aziridines and β-lactams have been employed as synthetic intermediates for the preparation of the corresponding β-amino acids by facile ring-opening reactions. Other methods discussed in review are fluorination and trifluoromethylation of β-amino acid derivatives, reactions of organometallic reagents with fluorinated imines and related compounds, and metathesis reactions of fluorinated imino esters and imidoyl halides for the synthesis of cyclic derivatives.