title: Preparation of (-)-Nutlin-3 using enantioselective organocatalysis at decagram scale.
abstract: Chiral nonracemic cis-4,5-bis(aryl)imidazolines have emerged as a powerful platform for the development of cancer chemotherapeutics, stimulated by the Hoffmann-La Roche discovery that Nutlin-3 can restore apoptosis in cells with wild-type p53. The lack of efficient methods for the enantioselective synthesis of cis-imidazolines, however, has limited their more general use. Our disclosure of the first enantioselective synthesis of (-)-Nutlin-3 provided a basis to prepare larger amounts of this tool used widely in cancer biology. Key to the decagram-scale synthesis described here was the discovery of a novel bis(amidine) organocatalyst that provides high enantioselectivity at warmer reaction temperature (-20 °C) and low catalyst loadings. Further refinements to the procedure led to the synthesis of (-)-Nutlin-3 in a 17 g batch and elimination of all but three chromatographic purifications.
authors.affiliation: Department of Chemistry & Vanderbilt Institute of Chemical Biology, Vanderbilt University , Nashville, Tennessee 37235-1822, United States.
authors.forename: Tyler A
authors.initials: TA
authors.lastname: Davis
authors.forename: Anna E
authors.initials: AE
authors.lastname: Vilgelm
authors.forename: Ann
authors.initials: A
authors.lastname: Richmond
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Johnston
mesh_terms: D000578:Amidines / Q000737:chemistry*; D000818:Animals; D002384:Catalysis; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D048288:Imidazolines / Q000737:chemistry*; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013696:Temperature; D014407:Tumor Cells, Cultured
chemical_list: D000578:Amidines; D007093:Imidazoles; D048288:Imidazolines; D010879:Piperazines; C482205:nutlin 3