First stereoselective synthesis and assignment of the absolute configuration of the nebracetam eutomer and derivatives

Abstract

(−)-Nebracetam 1 was stereoselectively prepared for the first time, allowing the determination of its absolute configuration as ( R). The pivotal intermediate in the synthesis, 1-benzyl-4-[( S)-2,2-dimethyl-1,3-dioxolan-4-yl]-pyrrolidin-2-one 6, was previously obtained in 60% yield and 90% ee from an enoate derived from d-mannitol. Two approaches were investigated to synthesize ( R)-(−)-nebracetam 1 and analogues 4 and 5 from 6. Compound 6 was transformed into WEB-1868 2. Mesylation of the hydroxyl group in 2, followed by nucleophilic substitution with azide and reduction led to target 1. Compounds 4 and 5 were synthesized by using morpholine and N-methyl piperazine as nucleophiles. Compounds 4 and 5 were also prepared, in higher yields and similar ee, through the reductive amination of aldehyde 10, obtained in two steps from 6.