Three-step synthesis of (R)- and (S)-thalidomides from ornithine

Three-step synthesis of enantiomerically pure thalidomide is described. D-O rnithine (2) reacted with thionyl chloride in methanol followed by treatmen t with triethylamine to give the (R)-3-amino-piperidin-2-one hydrochloride (3) in good yield. Protection of amino moiety by the use of N-carboethoxyph talimide in DMSO furnished (R)-N-phtaloylpiperidin-2-one (4) as colorless c rystals. Finally, the oxidation using a catalytic amount of RuO2 in the pre sence of excess sodium metaperiodate in a two-phase system gave (R)-thalido mide (1) in good yield without racemization. (S)-Thalidomide (1) was also s ynthesized from L-ornithine (2) in good overall yield. Since all the interm ediates to thalidomide are easily recrystallized, the present method can be performed on a large scale without purification by column chromatography.