Syntheses of (S)-5:Substituted 4-Aminopentanoic Acids: A New Class of γ-Aminobutyric Acid Transaminase Inactivators

The syntheses of a new class of γ-aminobutyric acid (γ-Abu) transaminase inactivators, the 5-substituted 4-aminopentanoic acids (1), are described. The synthetic route involves the LiBH4 reduction of (S)-5-carbethoxy- 2-pyrrolidinone, derived from L-glutamic acid, to (S)-5-(hydroxymethyl)-2-pyrrolidinone (3a). The alcohol 3a is converted to the chloride 3c or the bromide 3d with triphenylphosphine and carbon tetrachloride or carbon tetrabromide, respectively. (S)-5-(Fluoromethyl)-2-pyrrolidinone (3b) is prepared from the bromide 3d and silver fluoride. The nitrile 3e is synthesized from the bromide 3d with sodium cyanide impregnated alumina. Each of these lactams 3 is hydrolyzed to the corresponding amino acid (1) salt in 1 N aqueous acid. Racemization at the α-carbon of L-glutamate does not occur during the syntheses.