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

Vara BA, Mayasundari A, Tellis JC, Danneman MW, Arredondo V, Davis TA, Min J, Finch K, Guy RK, Johnston JN - J. Org. Chem. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry & Vanderbilt Institute of Chemical Biology, Vanderbilt University , 7330 Stevenson Center, Nashville, Tennessee 37235, United States.

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.

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Parallel pathways to the same enantiomer of cis-imidazolines derived from nonsymmetric cis-stilbene diamines.
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fig1: Parallel pathways to the same enantiomer of cis-imidazolines derived from nonsymmetric cis-stilbene diamines.

Mentions: The use of a diaza-Cope reactionby HLR provided access to a large number of symmetrical cis-stilbene diamines.26 The diaza-Cope reactionis less amenable to the preparation of cis-imidazolinesbearing unique aromatic rings at C4 and C5, and yet access to thesesmall molecules may eventually lead to selective and potent inhibitorsof protein–protein interactions. Application of the aza-Henryapproach to this problem was not without potential complication. Whileconvergence in the imidazoline synthesis would be well-served (topequation in Figure 1), the levels of enantioselectivitycan be attenuated by electronic effects. These challenges are oftenovercome by reagent (catalyst) modification while maintaining a highlevel of catalyst activity. When successful, this typically providesthe most general solution.


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

Vara BA, Mayasundari A, Tellis JC, Danneman MW, Arredondo V, Davis TA, Min J, Finch K, Guy RK, Johnston JN - J. Org. Chem. (2014)

Parallel pathways to the same enantiomer of cis-imidazolines derived from nonsymmetric cis-stilbene diamines.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4120989&req=5

fig1: Parallel pathways to the same enantiomer of cis-imidazolines derived from nonsymmetric cis-stilbene diamines.
Mentions: The use of a diaza-Cope reactionby HLR provided access to a large number of symmetrical cis-stilbene diamines.26 The diaza-Cope reactionis less amenable to the preparation of cis-imidazolinesbearing unique aromatic rings at C4 and C5, and yet access to thesesmall molecules may eventually lead to selective and potent inhibitorsof protein–protein interactions. Application of the aza-Henryapproach to this problem was not without potential complication. Whileconvergence in the imidazoline synthesis would be well-served (topequation in Figure 1), the levels of enantioselectivitycan be attenuated by electronic effects. These challenges are oftenovercome by reagent (catalyst) modification while maintaining a highlevel of catalyst activity. When successful, this typically providesthe most general solution.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry & Vanderbilt Institute of Chemical Biology, Vanderbilt University , 7330 Stevenson Center, Nashville, Tennessee 37235, United States.

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.

Show MeSH
Related in: MedlinePlus