Stereodivergent Synthesis of Enantioenriched 2-Pyrrolidones via Diastereoselective Hydrogenation of ?,?-Unsaturated ?-Lactams

Synthesis of optically enriched racetam analogues was achieved via highly remote diastereocontrolled and enantiocontrolled Pd/C-catalyzed hydrogenation of alpha,beta-unsaturated gamma-lactams. Various mono-and disubstituted 2-pyrrolidones were obtained in excellent yields and stereoselectivities, and a concise and large-scale synthesis of brivaracetam was developed from inexpensive L-2-aminobutyric acid. Surprisingly, stereodivergent hydrogenation was observed by modifying remote functionalized stereocenters and additives, which would provide alternative stereochemical options of chiral racetams synthesis.

Automated summary

Optically enriched racetam analogues were synthesized through highly remote diastereocontrolled and enantiocontrolled Pd/C-catalyzed hydrogenation of alpha,beta-unsaturated gamma-lactams. Various mono- and disubstituted 2-pyrrolidones were obtained with excellent yields and stereoselectivities, and a concise and large-scale synthesis of brivaracetam was developed from inexpensive L-2-aminobutyric acid. Surprisingly, stereodivergent hydrogenation was observed by modifying remote functionalized stereocenters and additives, which would provide alternative stereochemical options for chiral racetams synthesis.