• Enantiosective Synthesis Dual-cathalysis Nutlin Ca

Design of small-molecule inhibitors (MDM2 inhibitors) to block the MDM2−p53 protein− protein interaction (PPI) has been pursued as a new anti-cancer therapeutic strategy. The best documented class of compounds, cis-imidazolines (named Nutlins), are selective and potent inhibitors, and selected examples exhibit potency in the nanomolar range. The eutomer (-)-Nutlin-3 induce apoptosis in p53 wild-type cells and show in vivo efficacy in mice xenograft models.
Herein we briefly summarized the main methods for the synthesis of (±)-Nutlin-3 and its derivatives, and we described the enantioselective way for preparing (-)-Nutlin-3.
We also identified an asymmetric, economic and simple route for the desymmetrization of a stilben-meso-diamine as a direct precursor of (-)-Nutlin-3. The desymmetrization is based on a dual-catalytic approach with DMAP and a chiral thiourea that act as a Hydrogen-Bonding Catalyst. Part of the work has been done for the optimization of the reaction conditions in order to improve yield and enantiomeric excess.