Expeditious Synthesis and Biological Characterization of Enantio-Enriched (-)-Nutlin-3

A concise and operationally simple synthesis of enantioenriched Nutlin-3 featuring the desymmetrization of 1,2-bis(4-chlorophenyl)ethane-1,2-diamine as the key step is described. The easy-to-make N-((1R,2R)-2-(3-(3,5-bis(trifluoromethyl) phenyl)thioureido)cyclohexyl)-3,5-bis(trifluoromethyl)benzamide (and N-((1S,2S)-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido) cyclohexyl)-3,5-bis(trifluoromethyl)benzamide)) involved as anion binding in the key desymmetrization step is the completely recoverable chiral auxiliary. An array of biological tests performed with the 84:16 (-)-Nutlin-3 scalemic mixture showed activities comparable to those of the commercial eutomer.