SYNTHESES OF GAMMA-FLUORO-ALPHA-AMINO ACIDS

Methods for the synthesis of racemic and optically active title compou nds are presented. Key step of these four-step procedures is the alkyl ation with 1-bromo-2-fluoroalkanes of glycine-ester-derived imines in anhydrous medium using lithium diisopropylamide as a base at low tempe rature or phase transfer catalyzed alkylation with 50% NaOH and trieth ylbenzylammoniumchloride as the phase transfer catalyst, respectively. Subsequent three-step deprotection gave the free acids in 13-33% over all yield. Deracemization of gamma-fluoro-alpha-aminobutyric acid meth yl 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 stereochemica l result was observed giving the (-)-acid with 88% ee. Optically activ e gamma-fluoro-alpha-amino acids were synthesized alternatively by pha se transfer catalysis with N-benzyl-cinchonium chloride or using an au xiliary-directed asymmetric alkylation of the imine derived from (R)-( +)-camphor or (R)-(+)-2-hydroxypinan-3-one. These processes gave diffe rent enantiomers of gamma-fluoro-alpha-aminobutyric acid via a monomer ic lithium enolate in the first or a dimeric lithium enolate in the se cond case, respectively. The enantiomeric excess can be improved by li thium/magnesium exchange.