Synthesis of Nonracemic Tetrazole GABA Analogs

Nonracemic 3-substituted 4-(1 H -tetrazol-1-yl)butanoic acids, analogs of the neurotropic drugs phenibut, tolibut, and baclofen, were synthesized by a three-component reaction of the R -isomers of the corresponding amino acids, triethyl orthoformate, and sodium azide. The key stage of the synthesis is the asymmetric addition of diethyl malonate to nitroalkenes, catalyzed by a Ni(II) complex of (S,S)- N,N′ -dibenzylcyclohexane-1,2-diamine.