Enantioselective synthesis of 2-substituted 4-aminobutanoic acid (GABA) analogues via cyanomethylation of chiral enolates

Cyanomethylation by bromoacetonitrile of sodium or lithium enolates derived from (4S,5R)-3-acyl-4-methyl-5-phenyl-1,3-oxazolidin-2-ones usually shows good stereoselectivity; although the reaction of 3-(3-carboxypropanoyl)oxazolidinone 5d is exceptionally unselective, the 3-(pent-4-enoyl)- and 3-(3,4-dimethoxyhydrocinnamoyl)oxazolidinones 5e and 5f are found to be effective synthetic equivalents of 5d. The cyanomethylation products can be converted into 2-substituted derivatives of 4-aminobutanoic acid (gamma-aminobutyric acid, GABA) by the alkaline hydrolysis of the oxazolidinone chiral auxiliary followed by hydrogenation of the cyano group.