title: Organocatalytic, diastereo- and enantioselective synthesis of nonsymmetric cis-stilbene diamines: a platform for the preparation of single-enantiomer cis-imidazolines for protein-protein inhibition.
abstract: The finding by scientists at Hoffmann-La Roche that cis-imidazolines could disrupt the protein-protein interaction between p53 and MDM2, thereby inducing apoptosis in cancer cells, raised considerable interest in this scaffold over the past decade. Initial routes to these small molecules (i.e., Nutlin-3) provided only the racemic form, with enantiomers being enriched by chromatographic separation using high-pressure liquid chromatography (HPLC) and a chiral stationary phase. Reported here is the first application of an enantioselective aza-Henry approach to nonsymmetric cis-stilbene diamines and cis-imidazolines. Two novel mono(amidine) organocatalysts (MAM) were discovered to provide high levels of enantioselection (>95% ee) across a broad range of substrate combinations. Furthermore, the versatility of the aza-Henry strategy for preparing nonsymmetric cis-imidazolines is illustrated by a comparison of the roles of aryl nitromethane and aryl aldimine in the key step, which revealed unique substrate electronic effects providing direction for aza-Henry substrate-catalyst matching. This method was used to prepare highly substituted cis-4,5-diaryl imidazolines that project unique aromatic rings, and these were evaluated for MDM2-p53 inhibition in a fluorescence polarization assay. The diversification of access to cis-stilbene diamine-derived imidazolines provided by this platform should streamline their further development as chemical tools for disrupting protein-protein interactions.
authors.affiliation: Department of Chemistry & Vanderbilt Institute of Chemical Biology, Vanderbilt University , 7330 Stevenson Center, Nashville, Tennessee 37235, United States.
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Vara
authors.forename: Anand
authors.initials: A
authors.lastname: Mayasundari
authors.forename: John C
authors.initials: JC
authors.lastname: Tellis
authors.forename: Michael W
authors.initials: MW
authors.lastname: Danneman
authors.forename: Vanessa
authors.initials: V
authors.lastname: Arredondo
authors.forename: Tyler A
authors.initials: TA
authors.lastname: Davis
authors.forename: Jaeki
authors.initials: J
authors.lastname: Min
authors.forename: Kristin
authors.initials: K
authors.lastname: Finch
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Johnston
mesh_terms: D000578:Amidines / Q000737:chemistry*; D017209:Apoptosis; D002384:Catalysis; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003959:Diamines / Q000737:chemistry*; D005454:Fluorescence Polarization; D006801:Humans; D048288:Imidazolines / Q000737:chemistry*; D015394:Molecular Structure; D055601:Organic Chemistry Phenomena; D054730:Protein Interaction Domains and Motifs; D013237:Stereoisomerism; D013267:Stilbenes / Q000737:chemistry*
chemical_list: D000578:Amidines; D003959:Diamines; D048288:Imidazolines; D013267:Stilbenes