Syntheses of gamma-fluoro-alpha-amino acids

Methods for the synthesis of racemic and optically active title compounds are presented. Key step of these four-step procedures is the alkylation with 1-bromo-2-fluoroalkanes of glycine-ester-derived imines in anhydrous medium using lithium diisopropylamide as a base at low temperature or phase transfer catalyzed alkylation with 50% NaOH and triethylbenzylammoniumchloride as the phase transfer catalyst, respectively. Subsequent three-step deprotection gave the free acids in 13-33% overall yield. Deracemization of gamma-fluoro-alpha-aminobutyric acid methyl and ethyl esters with alpha-chymotrypsin was shown to give the (-)-enantiomers of the esters and (+)-gamma-fluoro-alpha-aminobutyric acid in >98% ee, while from the tert-butylester the opposite stereochemical result was observed giving the (-)-acid with 88% ee. Optically active gamma-fluoro-alpha-amino acids were synthesized alternatively by phase transfer catalysis with N-benzyl-cinchonium chloride or using an auxiliary-directed asymmetric alkylation of the imine derived from (R)-(+)-camphor or (R)-(+)-2-hydroxypinan-3-one. These processes gave different enantiomers of gamma-fluoro-alpha-aminobutyric acid via a monomeric lithium enolate in the first or a dimeric lithium enolate in the second case, respectively. The enantiomeric excess can be improved by lithium/magnesium exchange.