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: 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
• Journal: The Journal of organic chemistry (J Org Chem) Vol. 79 Issue 15 Pg. 6913-38 (Aug 01 2014) ISSN: 1520-6904 [Electronic] United States
• PMID: 25017623 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Amidines
• Diamines
• Imidazolines
• Stilbenes

Topics

• Amidines (chemistry)
• Apoptosis
• Catalysis
• Cell Line, Tumor
• Chromatography, High Pressure Liquid
• Diamines (chemistry)
• Fluorescence Polarization
• Humans
• Imidazolines (chemistry)
• Molecular Structure
• Organic Chemistry Phenomena
• Protein Interaction Domains and Motifs
• Stereoisomerism
• Stilbenes (chemistry)