Organocatalytic, diastereo- and enantioselective synthesis of nonsymmetric cis -stilbene diamines: A platform for the preparation of single-enantiomer cis -imidazolines for protein-protein inhibition

Brandon A. Vara, Anand Mayasundari, John C. Tellis, Michael W. Danneman, Vanessa Arredondo, Tyler A. Davis, Jaeki Min, Kristin Finch, R. Kiplin Guy, Jeffrey N. Johnston

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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.

Original languageEnglish
Pages (from-to)6913-6938
Number of pages26
JournalJournal of Organic Chemistry
Volume79
Issue number15
DOIs
StatePublished - Aug 2014

ASJC Scopus subject areas

  • Organic Chemistry

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