Catalytic, enantioselective synthesis of stilbenecis-diamines: A concise preparation of (−)-Nutlin-3, a potent p53/MDM2 inhibitor

Abstract

The first highly diastereo- and enantioselective additions of aryl nitromethane pronucleophiles to aryl aldimines are described. Identification of an electron rich chiral Bis(AMidine) catalyst for this aza-Henry variant was key to this development, leading ultimately to differentially protected cis-stilbene diamines in two steps. This method then became the lynchpin for an enantioselective synthesis of (−)-Nutlin-3 (Hoffmann-La Roche), a potent cis-imidazoline small molecule inhibitor of p53-MDM2 used extensively as a probe of cell biology and currently in drug development.