Regioselective protection of hydantoins – essential for hydantoin based anti-epileptic drugs

The synthesis and NMR elucidation of six novel mono- and bis-Boc protected hydantoins are reported. The hydantoins 5-methylhydantoin, 5,5-dimethylhydantoin and a pentacycloundecane hydantoin exhibit an increase in substitution and steric hindrance at C-5. Kinetic and reagent controlled monoprotection of the smaller hydantoins achieve regioselective protection at N-1 while the bulky cage hydantoin is protected at N-3′. Hydantoin based anti-epileptic drugs such as 5,5-diphenylhydantoin require regioselective substitution at N-3′ for enhanced pharmaceutical activity. The study enhances our understanding of the activity of the nitrogen atoms on hydantoin rings.