Limits...
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.

Show MeSH

Related in: MedlinePlus

Outline foractivation of aryl nitromethane (nucleophile, Nu) andimine (electrophile, E) by a bifunctional catalyst.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4120989&req=5

fig2: Outline foractivation of aryl nitromethane (nucleophile, Nu) andimine (electrophile, E) by a bifunctional catalyst.

Mentions: As an alternativeto an extensive exploration of the impact of quinoline substituentson enantioselection,19 an effort that affordedlittle improvement in this case, we reasoned that the insensitivityof aryl nitromethane additions to added strong acid (e.g., TfOH) mightoffer the opportunity to explore combinations of amidine and amide functionalities projected from the diamine backbone.The conceptual framework for this modification was also rather differentby comparison to previous bis(amidine) modifications. Beginning fromits free base form, the catalyst would be expected to form a saltwith the aryl nitromethane at the amidine (eq 1, Figure 2), but the greatest level of dual activation is expected to involve electrophile binding to the polar ionic hydrogenbond concomitant with nitronate counterion binding to the (amide)polar covalent hydrogen bond. Figure 2 illustratesthis conceptually, progressing from substrates and catalyst in A to catalyst-bound product in D. The initialactivation event is catalyst deprotonation of the nitroalkane, butin this arrangement (B), the nitronate reactivity maybe attenuated by a strong ion pair and imine activation by an amideN–H may be relatively weak. Exchange of the hydrogen bond acceptors(Figure 2, C), however, leadsto a more reactive nitronate due to charge separation and increasedactivation of the imine. An arrangement such as this might maximizethe benefit of drawing the counterion away from the electrophile bindingsite while providing discrete directional control. Elements of thisapproach overlap with developments in the field of anion binding catalysis,particularly when the catalyst involves two polar covalent hydrogenbond donors.28 Other catalyst systems usenot only a Brønsted basic catalyst but also a Brønsted baseadditive (e.g., Et3N).29


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)

Outline foractivation of aryl nitromethane (nucleophile, Nu) andimine (electrophile, E) by a bifunctional catalyst.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Outline foractivation of aryl nitromethane (nucleophile, Nu) andimine (electrophile, E) by a bifunctional catalyst.
Mentions: As an alternativeto an extensive exploration of the impact of quinoline substituentson enantioselection,19 an effort that affordedlittle improvement in this case, we reasoned that the insensitivityof aryl nitromethane additions to added strong acid (e.g., TfOH) mightoffer the opportunity to explore combinations of amidine and amide functionalities projected from the diamine backbone.The conceptual framework for this modification was also rather differentby comparison to previous bis(amidine) modifications. Beginning fromits free base form, the catalyst would be expected to form a saltwith the aryl nitromethane at the amidine (eq 1, Figure 2), but the greatest level of dual activation is expected to involve electrophile binding to the polar ionic hydrogenbond concomitant with nitronate counterion binding to the (amide)polar covalent hydrogen bond. Figure 2 illustratesthis conceptually, progressing from substrates and catalyst in A to catalyst-bound product in D. The initialactivation event is catalyst deprotonation of the nitroalkane, butin this arrangement (B), the nitronate reactivity maybe attenuated by a strong ion pair and imine activation by an amideN–H may be relatively weak. Exchange of the hydrogen bond acceptors(Figure 2, C), however, leadsto a more reactive nitronate due to charge separation and increasedactivation of the imine. An arrangement such as this might maximizethe benefit of drawing the counterion away from the electrophile bindingsite while providing discrete directional control. Elements of thisapproach overlap with developments in the field of anion binding catalysis,particularly when the catalyst involves two polar covalent hydrogenbond donors.28 Other catalyst systems usenot only a Brønsted basic catalyst but also a Brønsted baseadditive (e.g., Et3N).29

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